![](media/image1.jpeg){width="1.9020833333333333in"
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**INFECTIOUS DISEASE INITIATIVE**

*STRATEGIES AND INTERVENTIONS TO*

*UNDERSTAND, CONTAIN, AND RESPOND*

*TO THE DEVELOPMENT AND SPREAD OF*

*for more information please contact:*

**Tony Boni**

**Coordinator, USAID Antimicrobial Resistance Working Group**

**Phone: 202-712-4789**

**Fax: 202-216-3702**

**E-mail: aboni@usaid.gov**

Last updated: June 14, 2002

**TABLE OF CONTENTS**

Page

List of Acronyms 6

Introduction 7

Figure 1: Distribution of Activities by Region, Activity Type, and
Disease 8

Table 1: Partner and Country Distribution 9

***1 ESTABLISHING A GLOBAL STRATEGY AND ACTION PLAN***

1.1 Establishing a Global Strategy and Action Plan 10

1.2 State of the Art Technical Review of Antimicrobial Resistance of
Selected Bacterial

Diarrheal Diseases: Shigellosis, Cholera and Campylobacteriosis 12

1.3 State of the Art Technical Review of Antimicrobial Drug Information
14

4.  Costs and Cost-effectiveness Analysis of Antimicrobial Resistance in
    Developing Countries 15

1.5 Review of Interventions to Improve Antimicrobial Use by Health
Providers 17

6.  Synthesis of Sentinel Policy Documents Concerning Strategies for
    Curbing AMR 19

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7.  Reviews of Antecedents of and Interventions to Decrease
    Inappropriate Antimicrobial Use

> by Health Providers and Community Members 20

8.  Research Priorities for the Prevention and Control of Nosocomial
    Infections in Developing Countries 22

9.  Review of the Effects of Provider Reimbursement Mechanisms and
    Managed Care on the

Use of Antimicrobial Drugs in Eastern Europe/Eurasia and Developing
Countries 22

1.10 Technical Paper on Fixed-Dose-Combination (FDC) Drug Products 24

***2 IMPROVING THE UNDERSTANDING OF ANTIMICROBIAL RESISTANCE***

2.1 Determining the Relative Importance of Various Factors in the
Development of

Antimicrobial Resistance 25

2.2 Mathematical Modeling of Antimicrobial Resistance Emergence and
Spread 27

~~2.3 Non-medical Uses of Antimicrobials and the Impact on Human Health
28~~

2.4 Measuring, Understanding and Changing Irrational Drug Use 29

Page

2.5 Indicators for Measuring Antimicrobial Use in Hospitals 30

6.  ~~Evaluation of the Impact of IMCI Case Management Approach on
    Antimicrobial Use~~

~~Practices and Drug Resistance~~ 31

2.7 Improving the Treatment of Bacterial Meningitis in Developing
Countries 32

8.  Relationship between *in vitro* Antimicrobial Resistance of *S.
    pneumoniae* and *H. influenzae*

Blood Isolates and *in vivo* Response to Penicillin in Severe Pneumonia
33

2.9 Investigation of the Impact of Antimicrobial Agent, Dose, and
Treatment Duration on

Carriage of Resistant Respiratory Tract Pathogens 35

2.10 ~~Impact of Fansidar Use on Cotrimoxazole Resistance~~ 35

2.11 Advocacy and Information to Combat Antimicrobial Resistance 36

2.12 Training on the Rational Use of Drugs for Pharmacy Undergraduates
38

2.13 AMR \'Toolkit\' for Information and Education 39

2.14 Investigation of the Impact of Repeated Mass Azithromycin
Prophylaxis on Antimicrobial

Resistance in Countries Initiating Trachoma Control 40

***3 DEVELOPING METHODS TO DETECT RESISTANCE***

3.1 Comprehensive Laboratory Manual for Isolation, Identification, and
Susceptibility

Testing of Common Outpatient Pathogens 42

3.2 Standardized Sampling Methods for Assessment of *H. influenzae* and
*S. pneumoniae*

Antimicrobial Resistance 44

3.3 Evaluation of Nasopharyngeal Swab Surveillance for Antimicrobial
Resistance among

Respiratory Tract Pathogens 45

~~3.4 *In Vivo* Detection of *N. gonorrheae R*esistance 46~~

5.  Using Clinical Treatment Failures to Monitor Antimicrobial
    Resistance in *S. pneumoniae* and

*H. influenzae* 47

3.6 Magnitude and Trends of Resistance in Priority Infectious Diseases
49

***4 RESPONDING TO DATA ON ANTIMICROBIAL RESISTANCE AND DRUG USE***

4.1 Model Prescribing Information: Drugs Used in Bacterial Infections 50

Page

4.2 Guidelines for National Policy Makers and Health Administrators on
the

Containment of Antimicrobial Resistance 51

4.3 Guidelines for Establishing a National Programme to Promote Rational
Drug Use, and

Rational Use of Antimicrobials in Particular 52

4.  Guidelines for Containing Antimicrobial Resistance at Hospital Level
    (\"Hospital

Package\") 53

***5 PREVENTING AND SLOWING THE SPREAD OF ANTIMICROBIAL RESISTANCE***

5.1 Integrated Country Programs for Containment of Antimicrobial
Resistance 55

5.2 APUA Chapter Development 59

5.3 Antimicrobial Drug Booklet for Pharmacists and Drug Sellers 62

4.  Training Modules for Drug & Therapeutics Committees and Antibiotics
    Sub-Committees 63

5.  Improving the Use of Antimicrobials through Interventions Aimed at
    Health Professionals,

Drug Sellers and Community Health Workers 64

5.6 Promoting Rational Use of Antimicrobials in the Private Sector 67

5.7 Development of an Intervention to Improve Compliance with
Antimicrobial Therapy Using

IMCI Drug Counseling Guidelines 68

5.8 Clinical Efficacy of Short Course Treatment with Ceftriaxone for
Bacterial Meningitis 70

9.  Development of a Clinical Prediction Instrument for
    [Gr]{.underline}oup [A]{.underline} [S]{.underline}treptococcal
    [P]{.underline}haryngitis

(GRASP) 72

5.10 A Multi-Center, Prospective, Observational Study of Clinical
Outcome Following

Amoxycillin Treatment of Non-Severe Acute Respiratory Infection 74

5.11 Efficacy of Short Course Treatment with Oral Amoxicillin for
Non-Severe Pneumonia

and its Relationship with Antimicrobial Resistance 75

5.12 Efficacy of Short Course Treatment with Oral Cotrimoxazole for
Non-Severe Pneumonia

and its Relationship with Antimicrobial Resistance 76

5.13 ~~Increased Specificity of Treatment Guidelines for Non-Severe
Pneumonia~~ 77

5.14 Increased Specificity of Treatment Guidelines for Children with
Wheezing Diagnosed as

WHO-Defined, Non-Severe Pneumonia 79

Page

5.15 Clinical Efficacy of Oral Amoxicillin as Compared to Injectable
Penicillin for the Treatment

of Severe Pneumonia 81

5.16 Management of WHO-Defined, Very-Severe Pneumonia 82

5.17 Epidemiological, Laboratory, and other Technical Assistance 83

5.18 Evaluation of the Impact of Pneumococcal Conjugate Vaccine on
Antimicrobial Resistant

*Streptococcus pneumoniae* 85

19. Studies to Evaluate Behavioral and Policy Interventions to Improve
    the Use of Antimicrobials

at the Household and Community Levels 87

5.20 Home-Based Management of Neonatal Sepsis and Asphyxia by Community
Health Workers 89

21. Impact of IMCI Counseling Guidelines on Compliance with
    Antimicrobial Therapy in the

Home 91

22. Assessing The Effectiveness of Client-Based Job Aids to Support
    Compliance with Antibiotic

Treatment Regimens 93

5.23 Improving Knowledge of Primary Care Physicians and Medical Students
to Enhance Rational

> Prescribing of Antimicrobials through the Use of Established Drug
> Information Centers and
>
> Networks 95

5.24 Improving Patient Counseling and Dispensing Skills of Private Drug
Retailers 98

5.25 Methodology to Assess Malaria Drug Management in Developing
Countries 100

5.26 Methodology to Assess Tuberculosis Drug Management in Developing
Countries 101

5.27 Increased Specificity for Treatment Guidelines for Clinical Overlap
of Non-Severe

Pneumonia and Malaria 103

**LIST OF ACRONYMS**

AIHA American International Health Alliance

APUA Alliance for the Prudent Use of Antibiotics

CDC/NCID Centers for Disease Control and Prevention/National Center for
Infectious Diseases

##### BU/ARCH Boston University/Applied Research on Child Health

ICDDR,B International Centre for Diarrheal Disease Research, Bangladesh:
Centre for Health and Population Research

INCLEN International Clinical Epidemiology Network

INRUD International Network for the Rational Use of Drugs

IUATLD International Union Against Tuberculosis and Lung Disease

JHU/FHACS Johns Hopkins University/Family Health and Child Survival

MSH Management Sciences for Health

PAHO The Pan American Health Organization

QAP II Quality Assurance Project II (USAID)

RPM The Rational Pharmaceutical Management Project (USAID)

USP The United States Pharmacoepial Convention

WHO/CAH World Health Organization/Child and Adolescent Health

WHO/CDS World Health Organization/Communicable Diseases and Surveillance

WHO/HTP/EDM World Health Organization/Health Technology and
Pharmaceuticals/Essential Drugs and Medicines

**INTRODUCTION**

In 1998, USAID launched a new Infectious Disease Initiative to reduce
the threat of infectious diseases of major public health importance[^1].
This 10-year strategy focuses on: antimicrobial resistance (AMR);
tuberculosis; malaria; and surveillance and response. Priorities for
each of the four areas were developed through a consultative process
which involved numerous partners, including the World Health
Organization, the Centers for Disease Control and Prevention, the
National Institutes of Health, universities, and other organizations.

This document summarizes the AMR-related activities that have been
supported by the Office of Health and Nutrition in USAID\'s Global
Bureau since FY1998 with Infectious Disease funding[^2]. (The
distribution of activities is shown in Figure 1 and Table 1.) AMR
activities are listed according to the Agency\'s priority areas: (1*)
Establishing a Global Strategy and Action Plan*; (2) *Improving the
Understanding of AMR*; (3) *Developing Methods to Detect AMR*; (4*)
Responding to Data on AMR and Drug Use*; and (5) *Preventing and Slowing
the Spread of AMR*. Activities were selected by the USAID AMR Working
Group based on their ability to:

-   Contribute to the development of a comprehensive, evidence-based AMR
    strategy and action plan;

-   Address both key USAID program areas (e.g. Child Survival, Maternal
    Health, Reproductive Health) threatened by AMR and priority diseases
    set forth in the USAID Infectious Disease Strategy;

-   Address priority areas identified at technical consultations (e.g.
    WHO\'s meeting on Research Strategies for Determining Antibiotic
    Efficacy in Childhood Pneumonia) and global consensus meetings (e.g.
    International Conference on Improving the Use of Medicines);

-   Fill identified gaps in setting standards, implementing known
    interventions, and developing new ones.

Initially, Infectious Disease activities funded by the Office of Health
and Nutrition in USAID\'s Global Bureau focused on research,
establishing guidelines and standards, and developing/field-testing
tools, interventions, and case-management approaches in order to address
AMR and antimicrobial drug use. One key activity has been WHO's
development of an AMR Global Strategy and Action Plan to identify
research issues and outline effective implementation activities to
assist USAID and other partners in identifying priorities, coordinating
activities, leveraging resources, and increasing awareness of the
importance of limiting the emergence and spread of AMR. In year one
(FY1998) of the USAID Infectious Disease Initiative, AMR research was
mostly focused on resistance to drugs used to treat acute respiratory
infections (ARI) to support the process of revising treatment guidelines
and drug policies as appropriate[^3]. Additional activities addressing
AMR as it relates to diarrheal disease, meningitis, nosocomial
(hospital-acquired) infections, and sexually-transmitted infections
(STIs) have been developed in year 2 and beyond as information from the
technical reviews became available (see AMR Component 1: *Establishing a
Global Strategy and Action Plan*). AME surveillance, drug-resistant
malaria, and drug-resistant TB are described in documents developed by
the USAID Working Groups for surveillance, malaria, and TB,
respectively, as such activities are within the purview of those groups.

At the beginning of the Infectious Disease Initiative, country-specific
implementation of AMR activities was primarily funded by USAID missions.
More recently, however, the Global Bureau\'s Office of Health and
Nutrition has begun to increase investments in the design and
implementation of interventions to address the problem of AMR at the
country level.

Figure 1. Distribution of AMR Activities Supported by the USAID Global
Bureau by Region, Activity Type, and Disease.

![](media/image2.wmf)

**Table 1. Partner and Country Distribution**

<table>
<colgroup>
<col style="width: 10%" />
<col style="width: 10%" />
<col style="width: 7%" />
<col style="width: 7%" />
<col style="width: 10%" />
<col style="width: 8%" />
<col style="width: 18%" />
<col style="width: 7%" />
<col style="width: 7%" />
<col style="width: 13%" />
</colgroup>
<tbody>
<tr class="odd">
<td colspan="2"><strong>Location of Activity</strong></td>
<td><h2 id="apua">APUA</h2></td>
<td><p id="cdc" class="heading">CDC</p></td>
<td><strong>ARCH</strong></td>
<td><strong>JHU</strong></td>
<td><strong>MSH</strong></td>
<td><strong>QAP</strong></td>
<td><strong>USP</strong></td>
<td><strong>WHO</strong></td>
</tr>
<tr class="even">
<td colspan="2"><em><strong>Global</strong></em></td>
<td>1.6</td>
<td>3.1, 3.3</td>
<td></td>
<td>1.2, 1.8</td>
<td>5.4</td>
<td></td>
<td>1.10</td>
<td>1.1,2.2, 2.3,2.11, 2.12, 2.13, 3.6, 4.1,4.2, 4.3, 5.1</td>
</tr>
<tr class="odd">
<td rowspan="13"><em><strong>Africa</strong></em></td>
<td>Region</td>
<td></td>
<td>5.17</td>
<td>1.7</td>
<td></td>
<td>1.5,1.7,1.9, 5.1, 5.4, 5.26</td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td>Ghana</td>
<td></td>
<td></td>
<td>5.5, 5.14, 5.15, 5.19</td>
<td></td>
<td>2.4,2.5, 5.5, 5.19</td>
<td></td>
<td>1.3</td>
<td>5.14, 5.15</td>
</tr>
<tr class="odd">
<td>Kenya</td>
<td></td>
<td>2.10</td>
<td>5.5</td>
<td></td>
<td>2.4, 5.5, 5.26</td>
<td></td>
<td></td>
<td>2.4</td>
</tr>
<tr class="even">
<td>Malawi</td>
<td></td>
<td>2.10</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>2.7, 5.8</td>
</tr>
<tr class="odd">
<td>Mali</td>
<td></td>
<td></td>
<td></td>
<td>5.21</td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td>Mozambique</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>1.3</td>
<td></td>
</tr>
<tr class="odd">
<td>Niger</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>5.22</td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td>Nigeria</td>
<td></td>
<td></td>
<td>5.19</td>
<td></td>
<td>5.19</td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td>South Africa</td>
<td></td>
<td></td>
<td>5.5, 5.10,5.15, 5.19</td>
<td></td>
<td>5.5, 5.19, 5.25</td>
<td></td>
<td></td>
<td>2.4, 2.7, 3.4, 5.8, 5.13, 5.15</td>
</tr>
<tr class="even">
<td><h6 id="tanzania">Tanzania</h6></td>
<td></td>
<td></td>
<td>5.5</td>
<td></td>
<td>5.5</td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td>Uganda</td>
<td></td>
<td></td>
<td>5.5, 5.19</td>
<td>5.7</td>
<td>2.4, 5.5, 5.19</td>
<td></td>
<td></td>
<td>2.4</td>
</tr>
<tr class="even">
<td>Zambia</td>
<td></td>
<td></td>
<td>5.5, 5.15, 5.16</td>
<td></td>
<td>5.5</td>
<td></td>
<td>1.3</td>
<td>2.4, 5.15, 5.16</td>
</tr>
<tr class="odd">
<td>Zimbabwe</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>4.4</td>
</tr>
<tr class="even">
<td rowspan="13"><em><strong>Asia and Near East</strong></em></td>
<td>Region</td>
<td></td>
<td>5.17</td>
<td>1.7</td>
<td></td>
<td>1.5,1.7,1.9, 5.1, 5.4</td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td>Bangladesh</td>
<td></td>
<td></td>
<td>5.16</td>
<td>5.8, 5.20</td>
<td></td>
<td></td>
<td></td>
<td>5.12, 5.16</td>
</tr>
<tr class="even">
<td>Cambodia</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>1.4</td>
</tr>
<tr class="odd">
<td>Egypt</td>
<td></td>
<td></td>
<td>5.14</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>5.14</td>
</tr>
<tr class="even">
<td>India</td>
<td></td>
<td></td>
<td>5.14, 5.15, 5.16, 5.19</td>
<td>5.9</td>
<td>5.19</td>
<td></td>
<td></td>
<td>5.9, 5.14, 5.15, 5.16</td>
</tr>
<tr class="odd">
<td>Indonesia</td>
<td></td>
<td></td>
<td>5.5</td>
<td></td>
<td>5.5</td>
<td></td>
<td></td>
<td>2.4,5.12</td>
</tr>
<tr class="even">
<td>Nepal</td>
<td></td>
<td>2.14</td>
<td>5.5, 5.19</td>
<td>5.20</td>
<td>2.5, 5.4, 5.5, 5.19</td>
<td></td>
<td>1.3, 5.3, 5.24</td>
<td></td>
</tr>
<tr class="odd">
<td>Pakistan</td>
<td></td>
<td></td>
<td>1.4, 5.14, 5.15, 5.16</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>2.7, 3.5, 5.8, 5.11, 5.14, 5.15, 5.16</td>
</tr>
<tr class="even">
<td>Papua New Guinea</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>5.27</td>
</tr>
<tr class="odd">
<td>Philippines</td>
<td></td>
<td></td>
<td>5.5, 5.19</td>
<td>5.9</td>
<td>2.4, 5.4,5.5, 5.19</td>
<td></td>
<td></td>
<td>2.4, 5.6</td>
</tr>
<tr class="even">
<td>Thailand</td>
<td></td>
<td></td>
<td>5.5, 5.14,5.19</td>
<td>5.9</td>
<td>5.5, 5.19</td>
<td></td>
<td></td>
<td>5.14</td>
</tr>
<tr class="odd">
<td>Vietnam</td>
<td></td>
<td></td>
<td>5.5, 5.10, 5.15, 5.19</td>
<td></td>
<td>5.5, 5.19</td>
<td></td>
<td></td>
<td>2.7, 5.8, 5.13, 5.15</td>
</tr>
<tr class="even">
<td>Yemen</td>
<td></td>
<td></td>
<td>5.16</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>5.16</td>
</tr>
<tr class="odd">
<td rowspan="6"><em><strong>Europe and Eurasia</strong></em></td>
<td>Region</td>
<td></td>
<td>5.17</td>
<td></td>
<td></td>
<td>1.7, 1.9, 5.26</td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td>Croatia</td>
<td></td>
<td></td>
<td></td>
<td>5.9</td>
<td></td>
<td></td>
<td></td>
<td>5.9</td>
</tr>
<tr class="odd">
<td>Latvia</td>
<td></td>
<td></td>
<td></td>
<td>5.9</td>
<td></td>
<td></td>
<td></td>
<td>5.9</td>
</tr>
<tr class="even">
<td>Moldova</td>
<td></td>
<td></td>
<td>5.19</td>
<td></td>
<td>5.19</td>
<td></td>
<td>5.23</td>
<td></td>
</tr>
<tr class="odd">
<td>Russia</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>1.3, 5.23</td>
<td></td>
</tr>
<tr class="even">
<td>United Kingdom</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>1.4</td>
</tr>
<tr class="odd">
<td rowspan="11"><em><strong>Latin America and
Caribbean</strong></em></td>
<td>Region</td>
<td></td>
<td>5.17,5.18</td>
<td>1.7</td>
<td></td>
<td>1.5,1.7,1.9, 5.1, 5.4</td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td>Argentina</td>
<td>5.2</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>2.8</td>
</tr>
<tr class="odd">
<td>Brazil</td>
<td></td>
<td></td>
<td></td>
<td>5.9</td>
<td></td>
<td></td>
<td></td>
<td>2.8, 5.9,</td>
</tr>
<tr class="even">
<td>Colombia</td>
<td>5.2</td>
<td></td>
<td>5.14, 5.15</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>2.8, 5.14, 5.15</td>
</tr>
<tr class="odd">
<td>Dom. Rep.</td>
<td>5.2</td>
<td>2.9</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>2.8</td>
</tr>
<tr class="even">
<td>Guatemala</td>
<td></td>
<td></td>
<td></td>
<td>3.2, 5.8</td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td>Haiti</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td>Mexico</td>
<td></td>
<td></td>
<td>5.5,5.15, 5.16</td>
<td></td>
<td>5.5</td>
<td></td>
<td></td>
<td>5.15, 5.16</td>
</tr>
<tr class="odd">
<td>Paraguay</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td>Peru</td>
<td></td>
<td></td>
<td></td>
<td>2.1</td>
<td></td>
<td></td>
<td>1.3</td>
<td>2.8</td>
</tr>
<tr class="odd">
<td>Venezuela</td>
<td>5.2</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
</tbody>
</table>

**Implementing Organization:** WHO/CAH, WHO/CDS, WHO/HTP/EDM

**Status:** On-going (Funded: FY1998; Expected Completion: FY2001)

**Objective(s):**

1\. Define the magnitude of the problem of AMR in different pathogens
and patient populations, and quantify the morbidity, mortality and cost
attributable to AMR;

2\. Define and attempt to quantify the relative importance of the
different causal factors favoring the emergence and spread of AMR;

3\. Develop a global strategy founded on evidence-based interventions.

**Description:**

1\. Define and maintain updated an action plan with milestones and time
lines, indicating roles for partners;

2\. Establish a baseline through data gathering (from existing study
sites, published literature and commissioned reviews (see \"*Expert
Technical Reviews*\" listed below) to document levels of resistance (and
trends where available) in specified patient groups for priority
diseases (pathogens) and data on morbidity, mortality and cost impacts
of resistance;

3\. Develop a framework of causal factors that favor the emergence and
spread of resistance and identify elements that can be targeted for
interventions;

4\. Seek consensus on framework and relative importance of causal
factors;

5\. Document interventions that have been shown to effectively target
specific elements; define the gaps in knowledge of effective
interventions; prepare an inventory of research planned/underway to fill
gaps; seek consensus on interventions and the knowledge gaps;

6.  Encourage the testing of additional interventions;

7.  Assess the cost-effectiveness/cost-benefit of interventions;

8\. Develop a programme of evidence-based interventions to be
implemented at country level; revise and refine as new data become
available;

9\. Assist Member States in the introduction and implementation of the
containment strategy.

**Expected Outcomes, Results and Progress Indicators**

1\. An action plan updated regularly and shared between partners;

2\. Baseline data on magnitude and impacts of AMR in major public health
disease priorities;

3\. Framework of causal factors with individual elements targeted for
interventions; interventions proven and those to be researched;

4\. Partners working together to develop and test additional
interventions;

5\. A global strategy based on the consensus of experts, and
implementable at national level

[Progress indicators]{.underline}: This is a multi-year project. With
the first year funding the following will be used as indicators of
progress: Action plan prepared; Data gathering initiated to establish
baseline on magnitude and impacts of AMR; Framework of causal factors
and interventions drafted; Consensus meeting planned.

**Partners/Collaborating Institutions:** APUA; AIHA; Cambridge
University/UK; Canadian International Agency (CIDA); ICDDR,B; CDC;
Cochrane Group; Conféderation Mondiale de l'Industrie de la Santé
Animale (COMISA); Consumers Union; European Commission; European
Medicines Evaluation Agency (EMEA); International Pharmaceutical
Federation (FIP); Food and Agriculture Organization (FAO); Global Health
Research Forum; Gonococcal Antimicrobial Surveillance Programme (GASP)
Collaborating Centres; BU/ARCH; Hoffmann La Roche Pharmaceuticals;
INCLEN; International Federation of Pharmaceuticals Manufacturers
Associations (IFPMA); INRUD; International Society for Infectious
Diseases (ISID); International Society of Chemotherapy (ISC);
International Union of Pharmacology; JHU/FHACS; RPM/MSH; Menzies
Research Institute/Australia; National Drug Regulatory Authorities;
National Governments; School of Public Health/Boston University; South
African Institute for Medical Research/Johannesburg; South Africa
Universities (various);

US Federal Department of Agriculture (USDA); Wellcome Trust Epidemiology
Research Centre (University of Oxford)/UK; WHO Collaborating Centre for
Surveillance of Antimicrobial Resistance; Brigham and Women's
Hospital/Boston; WHO Divisions (HQ) and Regional and Country Offices;
World Bank.

**Results to Date:** Consensus workshops were held with partner and
regional organizations to develop and review the strategy. The final
version (WHO Global Strategy for Containment of Antimicrobial Resistance
\[WHO/CDS/CSR/DRS/2001.2\]) was released in September 2001 along with an
edition of the Essential Drugs Monitor featuring AMR (see activity
2.11), and a CD-ROM that includes:

-   the complete WHO Global Strategy;

-   some of the technical reviews listed below;

-   a "Fact Sheet on AMR" (see activity 2.13);

-   "Frequently Asked Questions" (see activity 2.13);

-   slide sets on the problem of resistance and strategic interventions;

-   a draft version of "Surveillance Standards for AMR" (prepared by
    WHO); and

-   a draft version of "Manual for the Laboratory Detection of AMR Among
    Bacterial Pathogens of Public Health Concern in the Developing
    World" (prepared by CDC---see activity 3.1).

An executive summary of the strategy is available in English, French,
Spanish, and Russian. A Spanish translation of the complete strategy is
being prepared.

The WHO Global Strategy has been distributed to WHO Regional Offices,
WHO Country Representative Offices, Ministries of Health in all Member
States, donor agencies, and all those who attended consultations or
provided comments during the development of the strategy. The WHO/CSR
Anti-infective Drug Resistance web page has been updated to provide
access to all documents related to the WHO Global Strategy. Hardcopies
of the document can be requested by contacting: cdsdocs@who.int

*Next steps:*

The main objective is to establish partnerships for the implementation
of the WHO Global Strategy for the Containment of Antimicrobial
Resistance. Collection of information on "who is doing what where" in
the field of AMR is being continued and the analysis of this information
will become the basis for discussion at a future meeting to define an
agenda for global advocacy and research.

**Implementing Organization:** JHU/FHACS

**Status:** Completed (Funded: FY1998; Completed: FY1999)

**Rationale:** In developing countries, antibiotics are clinically
useful in a few diarrheal diseases including those due to *Shigella
species*, *Vibrio cholerae*, and *Campylobacter jejuni*. Unfortunately,
antibiotics are used for diarrhea caused by many other agents for which
they are not indicated and an inappropriate antibiotic is frequently
used for these specific diseases. The combination of the indiscriminate
use and inappropriate use of antibiotics has been followed by the
widespread occurrence of antibiotic-resistant strains and these
resistant strains have become dominant in many regions. *Shigellae
spp.*, for example, have become successively resistant to sulfa,
tetracycline, ampicillin, trimethoprim, and nalidixic acid. Most of
these resistance patterns were due to plasmids (except the quinolones);
thus, the Shigella could serve as mediators of resistance to other
bacteria.

Among the *Shigellae spp*. there are four species and multiple
serotypes. Of these different varieties of Shigellae, *Shigella
dysenteriae* type 1 (Shiga bacillus) has caused major epidemic disease
in Central America, Africa and South Asia, and the widespread use of
modern antibiotics, though potentially lifesaving for the individual has
rapidly been followed by the spread of clones which are antibiotic
resistant. The spread of these antibiotic resistant clones has been
devastating with high case fatality rates (\>5% with treatment) and high
overall mortality. Even when the newest-generation effective antibiotics
have been developed, their high costs have prevented their use. If they
had been used on a wide-scale, there is concern that resistance would
eventually develop to these drugs as well.

Although less dramatic than the epidemic Shiga bacillus, the more
endemic *S. flexneri* has actually been a larger public health threat,
because of higher overall incidence rates, more widespread disease on a
global basis, and interaction on nutrition and growth as well as direct
mortality. Antibiotic resistance in this genus has also increased
steadily, and rates of antibiotic resistance for ampicillin and
trimethoprim are now approaching the same high level as for Shiga.

*V. cholerae* has also become resistant to multiple antibiotics and
epidemics due to resistant strains have been widespread in Asia, Africa
and South America. As with Shigella, the resistance if plasmid mediated,
and the emergence of resistance strains seems to follow the
inappropriate use of antibiotics. *C. jejuni* is another bacterial cause
of diarrhea as well as a cause of Guillain-Barre syndrome. Antibiotics
are not generally used to treat this infection in developing countries,
still these strains are becoming resistant to common antibiotics,
perhaps because of the general antibiotic pressure in the region. Of
particular concern are reports of resistance to ciprofloxacin in *C.
jejuni*.

**Objective(s):**

1\) review the literature on the nature and trends of antibiotic
resistance in *Shigella, V. cholerae* and *C. jejuni*.

2\) define the epidemiological and clinical implications of antibiotic
resistance to these organisms.

3\) define the policy implications of antibiotic resistance to these
organisms and suggest policies for limiting their public health impact.

**Description:** A literature review will be conducted by at least two
persons who are expert in the field of. A microbiologist will carry out
the review of bacterial mechanisms of resistance and an epidemiologist/
clinician will carry out the review of antibiotic resistance in the
community and health facilities. Sections of the review will include: a)
a summary of basic principles and mechanisms in antibiotic resistance;
b) examples of the development of epidemics due to resistant strains as
well as examples (if any) of the re-emergence of sensitive strains; c)
the clinical implications of case management of patients with resistant
organisms including the complications to the patients being treated with
inappropriate antibiotics; d) review of programs in which a more
rational approach was attempted for using antibiotics in diarrhea; e)
review of reasons for the continued use of inappropriate antibiotics; f)
cost-effectiveness implications of antibiotic use for diarrhea; g)
policy implications for the management of diarrhea.

**Expected Output, Results, and Progress Indicators**: Shigellosis and
cholera are major public health problems and occur in both epidemic and
endemic patterns. Antibiotics are the major clinical intervention for
the individual patient and can be lifesaving, yet appropriate uses of
antibiotics are becoming increasingly difficult. The review of
antibiotic resistance in shigellosis will assist policy makers in
developing treatment guidelines for management of patients, management
of epidemics, and plans for providing essential drugs to countries.
Further, it will assist other USAID-sponsored projects which may be
monitoring antibiotic resistance and will serve as a useful model
organism for intervention studies. By combining microbiological with the
clinical and epidemiological aspects, an overall understanding of the
nature of the problem will be defined, and will lead to interventions
for control and reversal of the antibiotic resistance for this and
possibly other infections.

**Countries/Regions:** The work will be done in Baltimore at JHU, with
communications with other offices at WHO, PAHO, and international
centers.

**Partners:** Not applicable.

**Results to Date:** Review is being prepared for publication.

**Implementing Partner:** USP

# Status: Completed (Funded FY1998; Completed FY1998)

**Rationale:** Although individual copies of the USP DI or another
source of unbiased drug information may be found in one or two offices
in many countries around the world, the vast majority of drug
information that is commonly used in developing countries is produced by
the pharmaceutical industry. This latter information may be disseminated
directly by the manufacturer through product inserts or indirectly
through advertising placed by the industry in professional journals and
newsletters. Although, by its very nature, a manufacturer's information
is biased toward its own products, the real danger lies in the
inconsistent quality of industry information combined with an almost
unlimited capacity for dissemination. A state of the art review by
country is required to determine the quality of readily available,
commonly-used drug information including accuracy, currency,
completeness and local relevance.

The pharmaceutical industry accounts for the majority of drug
information available in developing countries, however, other sources,
especially WHO and other donor organizations are beginning to provide
drug information relative to their specific programs, e.g. EPI, UNAIDS,
UNFPA, vertical disease programs. In order to fully evaluate the quality
of industry and locally-produced information, information disseminated
by international organizations must be examined at the same time to
identify contradiction and disagreement.

**Objective(s):** To determine what, if any, drug information needs to
be created for specific countries or regions to help eliminate practices
which lead to AMR and to provide guidance to international bodies
attempting to develop drug information for developing countries as part
of broader health programs.

**Description:** USP will conduct a review of the most accessible and
widely-used AM drug information available in selected developing
countries by hiring local consultants to collect the available
professional literature, e.g., journals, newsletters, Standard Treatment
Guidelines, manuals. At the same time, USP will collect drug information
produced by other international organizations for use in support of
health sector programs in developing countries. USP staff will review
and evaluate the quality of the information, including the content of
both the articles and the advertising, against generally accepted
prescribing recommendations, including USP standards in drug information
development. Draft versions of the country analyses, with copies of the
original information reviewed, will be provided to USP's International
Health Advisory Panel for further input and a request for
recommendations. The International Panel will also be called upon to
assist with collection of the material. Results of the review will be
disseminated through WHO, USAID, FIP, INRUD and other international
networks and organizations.

**Expected Outputs, Results and Progress Indicators**: A series of
country-specific analyses of the quality of drug information sources and
recommendations for modifications or additional information sources
required by each country to help reduce AMR.

[Progress indicators]{.underline}: Number of information materials
received from local partners, number of institutional programs reviewed,
number of draft analyses documents prepared, number of drafts circulated
to Panel, number of Panel comments received by USP, number of completed
analyses by end of RPM project, copies of final review disseminated
through various channels.

**Countries/Regions:** The state of the art review will cover 6-8
developing countries including Ghana, Mozambique, Nepal, Peru, Russia,
and Zambia.

**Partners:** Local governmental and non-governmental organizations,
e.g., the Drug Information Network of Nepal, INRUD and PharmedInfo, will
be identified to collect the primary information to be reviewed.
Institutions to be asked for materials for review: WHO/HTP/EDM; WHO/EPI;
UNICEF; USAID supported vertical disease programs; UNFPA; others.

**Results to Date:** Technical review completed for six countries
(Ghana, Mozambique, Nepal, Peru, Russia, and Zambia) and results
presented at the AMR Partners meeting in Washington in March 2001. An
overview of the study has been disseminated to all USAID missions via
the monthly mailing. The missions in the six participating countries
have received their country report and the overview of the whole study.
The drug information centers in Russia, Nepal and Mozambique have also
received their respective country reports and the overview.

Recommendations from the review include:

-   Efforts should be made to make the concept of access to objective
    drug information part of national health policy.

-   Regulatory support to enhance availability of objective, timely
    information on drugs and to improve regulation of drug promotion
    should be a priority.

-   Information dissemination strategies should be established to ensure
    access to appropriate information at all levels (practice and
    geographic).

-   Availability of locally-appropriate information, including
    information on AMR, should be a priority.

-   Development and dissemination of treatment guidelines should be a
    central part of a drug information strategy.

-   Research on how to best effect appropriate prescribing and use
    should be conducted, if necessary, to appropriately define options.

-   Creation of appropriate audience-specific educational materials
    should be encouraged.

-   Model medical curricula and continuing education initiatives,
    focusing on critical prescribing messages and development of
    essential skills, should be implemented.

-   The central role of the health care provider in patient education
    should be stressed.

-   Effective mechanisms for information and experience sharing (e.g.,
    medication errors) should be explored.

-   Initiatives supporting the development of culturally-sensitive drug
    information for consumers should be implemented.

-   Innovative initiatives to enhance consumer understanding of
    appropriate drug use should be considered (e.g., educating
    children).

**Implementing Organizations:** BU/ARCH and Global Forum for Health
Research

**Implementing Organizations:** BU/ARCH and Global Forum for Health
Research

**Status:** On-going (Funded FY1998; Completed FY2002)

**Rationale:** The resistance of disease-causing organisms to standard
first-line treatments results in a wide range of direct costs (due to
prolonged hospital stays, additional treatment with different, often
more expensive, antibiotics, etc.) and indirect costs (such as lost
labor due to excess illness itself or additional care burdens for other
family members). It also extends the period during which individuals are
infectious and creates more opportunities for the spread of infection to
others.

Although the kinds of costs attributable to AMR are easy to identify,
very little is known about their magnitude and impact. A better
understanding of these costs and their allocation among households,
governments, and society at large is needed to assess the economic
burden imposed by resistance and help government policy makers and
international donors make more efficient policy, programmatic, and
resource allocation decisions. Developing countries are deeply affected
by increasing resistance as they have more limited resources to invest
in second-line therapy to treat resistant infections or in funds to
improve public health and thereby reduce exposures. For these countries,
some sense of how the costs of AMR compare to the costs of the diseases
with which it is associated, at a national level, is critical for
efficient allocation of scarce public health resources.

To begin to fill this gap in our knowledge of the economic impact of
AMR, BU/ARCH carried out a detailed assessment of the incremental
treatment costs associated with resistance for one disease in one
country.

**Objective(s):** Lay out a methodology for assessing the direct costs
of resistance, as a percentage of the total direct costs of childhood
pneumonia; apply the methodology to the case of pneumonia caused by *S.
pneumoniae* and *H. influenzae* among under-five year old children in
Pakistan to provide preliminary evidence on how serious the costs of AMR
are likely to be; and identify the most important issues for additional
research.

**Description:** The study will start with a systematic review of
previous research of the problem of AMR and its costs. Childhood
pneumonia in Pakistan was selected for the case study because it is one
of the most widely documented examples of AMR. The study will describe
the burden of childhood pneumonia in Pakistan, current approaches to
treatment of pneumonia, and resistance to the first-line antibiotics
used in treatment. A model for identifying and allocating the costs of
AMR will be developed and applied to the case study. The results of the
case study will be a set of estimates of the incremental costs of
treatment of resistant bacterial pneumonia children in Pakistan and a
set of recommendations for policy responses and future research.

**Countries/Regions:** Cambodia, Pakistan, United Kingdom

**Partners:** Global Forum on Health Research for Development

**Results to Date (BU/ARCH):** The case study found in Pakistan that the
incremental costs of AMR depend almost entirely on the severity of the
original case of pneumonia, whether the case becomes more severe after
first line treatment fails, and whether the case is treated at a public
or private health facility. For a single case of resistant pneumonia,
the incremental cost of resistance (as a share of the full cost of
treating a resistant case) ranged from a low of 1.5 percent, for a
severe case that did not progress and was treated at a public facility,
to a high of 95.3 percent, for any non-severe case that did progress to
severe or very severe and was treated at a private facility. Aggregated
across all cases of resistant bacterial pneumonia among Pakistani
children, the impact of AMR was to raise the cost of treating pneumonia
by an estimated 7-10 percent. This cost was solely for facility-based
treatment; it did not consider any of the indirect costs of AMR, such as
the lost labor productivity of parents who take care of sick children,
or the costs of the increased transmission of disease that resistance
makes possible.

**Results to Date (CAH and GFHR)**: Given the disparate nature of
evidence concerning strategies to combat AMR, CAH is collaborating with
the Global Forum for Health Research (GFHR) and the University of East
Anglia in the UK to:

> i\. review current knowledge concerning the cost and/or effectiveness
> of interventions aimed at reducing the emergence and transmission of
> AMR; and
>
> ii\. explore the feasibility of and issues involved in, the
> development of an economic model to assess the cost-effectiveness of
> interventions to address AMR.

The first phase has been completed at the University of East Anglia, UK
and a report has been published in September 2001 by the Global Forum
for Health Research ("*Interventions against antimicrobial resistance
\-- A review of the literature* *and* *exploration of modelling
cost-effectiveness"*, authors R.D. Smith, J. Coast, M.R. Millar, P.
Wilton, A.M. Karcher, ISBN 2-940286-06-X).

The first part of the report (Interventions against antimicrobial
resistance: a review of the literature) reviews current knowledge
concerning the cost and/or effectiveness of interventions aimed at
reducing the emergence and transmission of AMR. This review revealed the
somewhat narrow focus of the literature on this topic. Much that
currently exists is strongly focused on 'closed' hospital systems and
concentrates on the effects of policies aimed at reducing transmission
rather than reducing the emergence of resistance.

The second part of the report (Interventions against antimicrobial
resistance: modelling cost effectiveness) explores the feasibility of,
and issues involved in, the development of an economic impact model to
assess the cost-effectiveness of interventions to address AMR.
Considering the four criteria that a model should satisfy (feasibility,
sensitivity, relevance, and flexibility), this review identified two
broad options for the development of such a model:

1.  a "macro-model" approach which attempts to integrate factors within
    a broad-based model aiming at assessing strategies on a more
    "global" level; and

2.  a "suite" of micro sub-models, each embedded within a given set of
    primary parameters, such as country, disease, and level of
    intervention (e.g. community or hospital), which determine which of
    the "suite" of sub-models is most appropriate for that context.

The macro-model approach is likely to be more feasible, in terms of data
requirements more closely matching the current level of data
availability and be the more relevant from a governmental perspective.
However, this model would be expected to be less sensitive to small
changes in parameters, although both models are likely to be reasonable
flexible.

The next phase of this project has already been initiated. It comprises:

1.  the development of a tool which would be the theoretical model using
    available data from an experimental site; and

2.  a project to pilot test the model under real conditions in Cambodia.

A final report is expected at the end of 2002 or early 2003.

**Implementing Organizations**: RPM/MSH

**Status:** Completed (Funded: FY1998; Completed: FY1998)

**Rationale:** A significant force driving the spread of AMR is the
inappropriate use of antimicrobials in primary care and hospital
settings. Studies have documented problems such as over-prescribing as
well as inappropriate selection and dosing of antibiotics by health care
providers, unfettered access to antimicrobials by consumers, and a
failure to adhere to clinically desirable treatment regimens.
Consequently, many educational, managerial and regulatory interventions
focusing on health providers have been widely recommended and
implemented. However, not all the proposed interventions have been
rigorously tested to determine their impact on the use of
antimicrobials.

**Objective(s):** To review and update knowledge about the effectiveness
of interventions designed to improve the use of antimicrobials by health
providers.

**Description:** Using explicitly-predefined criteria for appropriate
study design, the review will identify: interventions that have been
rigorously tested; the settings where the interventions have taken
place; the methods used to improve antimicrobial use, and; whether the
intervention succeeded or failed to achieve its objectives. The review
will cover interventions that target antimicrobial use by health
providers working in primary care facilities, hospitals, and retail drug
outlets. Interventions to improve community or patient drug use behavior
are beyond the scope of this review.

The review will analyze relevant studies that (a) have been previously
collected for the 1997 Chiang Mai Conference on Improving Use of
Medicines (ICIUM); (b) were presented at the ICIUM Conference; (c) have
been published or reported since then. The INRUD bibliography database
will be used to identify relevant studies not previously reviewed or
reported since 1996. Through RPM collaborators in the Russian Federation
and the Newly Independent States, a search will be made for studies that
may have been undertaken and reported in Russian and other Eastern
European languages.

**Expected Outputs, Results and Progress Indicators:**

[Output]{.underline}: Review paper on the effectiveness of interventions
to improve use of antimicrobials by health providers.

[Results]{.underline}: 1. Up-to-date critical review of effectiveness of
interventions to improve antimicrobial use by health providers is made
available for dissemination;

2\. Gaps in current knowledge about effectiveness of interventions to
improve antimicrobial use by health providers are identified.

[Progress indicators]{.underline}:

1\. Literature search completed;

2\. Review paper drafted.

**Countries/Regions:** Review will cover studies in Africa, Asia, Latin
America, and Eastern Europe/Eurasia.

**Partners:** INRUD (Ghana); WHO/HTP/EDM; Harvard Drug Policy Group.

**Results to Date:** The review has been completed and presented to
USAID. The review is being added as an attachment to the WHO global
strategy to contain AMR, which will be published in September 2001

**Implementing Organization:** Alliance for the Prudent Use of
Antibiotics

**Status:** On-going (Funded: FY1999; Expected Completion: FY2001)

**Rationale:** Expert study groups such as the American Society for
Microbiology, Infectious Diseases Society of America, Centers for
Disease Control and Prevention, and Institute of Medicine have reported
on the problem of antimicrobial resistance (AMR). Their sentinel reports
identify factors that impact resistance and strategies to control its
emergence and spread (see Appendix A). Viewed together, these documents
represent a consensus of opinion from a variety of relevant disciplines,
suggesting actions needed to curb AMR. Documentation of this consensus,
as well as variance of opinions on alternate strategies, would provide a
useful framework for a global strategy to combat AMR. To capitalize on
the expert opinion represented, these documents should be reviewed to
identify points of agreement and dissent on research needs and
prevention and control strategies. By creating a single review document,
APUA will provide USAID and WHO with a framework for developing a global
strategy to improve the use of antibiotics and contain AMR.

**Objective:** Review the expert policy documents concerning strategies
for curbing AMR*;* synthesize their conclusions and recommendations; and
in conjunction with members of APUA's Scientific Advisory Board, develop
a single review document, which would assist WHO and partners in the
development of the global strategy.

**Description:** APUA staff will: (1) compile the major expert policy
documents produced in both industrialized and developing countries,
including selected countries from the APUA Chapter Network; (2) review
and develop a brief summary of individual documents; (3) create an
outline of major issues and strategies to be addressed (i.e. background
on AMR\--issues and needs; prevention and control of AMR\-- research,
prevention practices, surveillance; strategies and resources to control
AMR\--public health strategies, resources for research and
data-collection; legal, ethical, and regulatory issues related to
controlling AMR; conclusions and recommendations); (4) develop a single
review document identifying areas of agreement and disagreement; (5)
create tables that systematically summarize the information from the
major reports on AMR; (6) develop draft document that suggests
priorities based on compilation of recommendations; (7) coordinate draft
review by selected members of the APUA Scientific Advisory Board; (8)
refine document based on committee's recommendations; (9) submit draft
document to USAID and WHO for comments; (10); revise document; and (11)
submit the final document to USAID and WHO for input into the process of
global strategy formulation.

**Expected Outputs, Results and Progress Indicators:**

[Output:]{.underline} a review paper that synthesizes the conclusions
and recommendations of the existing policy documents on AMR, reflects
the insight of APUA's Scientific Advisory Board as to the global
implications and strategy and suggests priority actions.

[Results:]{.underline} the report will provide an up-to-date overview of
findings and recommendations from sentinel documents produced by
multidisciplinary expert groups. The document will be of use to the
USAID global bureau working group, USAID missions, WHO global strategy
partners and policy makers who fund the ID/AMR project. This document
will contribute to the development of a framework for the global AMR
strategy, and enable decision-makers at all levels to better determine
future research and policy directions, and develop an action plan for
controlling AMR.

[Progress indicators]{.underline}: individual reviews completed, outline
of paper completed, draft paper and tables completed, meeting of
scientific reviewers completed, final paper published and disseminated.

**Countries/Regions:** Not applicable.

**Partners:** None.

**Results to Date:** The review was completed in 2001 and will be
published along with the WHO Global AMR Strategy.

**Implementing Organizations:** BU/ARCH and RPM/MSH

**Status:** Completed (Funded: FY1999; Completed: FY2001)

**Rationale:** The 1997 International Conference on Improving Use of
Medicines (ICIUM) marked a major milestone in international efforts to
promote quality use of medicines by health providers and consumers, and
to develop rational pharmaceutical policies. For the first time, there
exists a consensus about appropriate methodologies for implementing and
assessing interventions in these areas, coherent summaries of previous
experience, as well as an agreed agenda of priority policy
implementation and intervention research topics.

Research focused on interventions targeting the practices of physicians,
paramedics, and other health providers working in primary care,
hospital, or retail pharmacy setting are an important contribution,
especially if it could be achieved and maintained on a widespread level
in the community. However, there are two important issues which make
this, on its own, unlikely to succeed. Firstly, self medication is
popular in all countries. In many developing countries over 80% of all
drugs are purchased by people for themselves or for a family member
without prescription (Malek, A, unpublished). Secondly, whether or not
consumers consult health workers in formal health care channels, it is
ultimately people's own decision-making and understanding that
determines whether a drug will be used or not and whether it will
properly used. These decision are in turn shaped by many factors
including the social, cultural and economic context in which they live
and the commercial pressures to which they are exposed by marketing.
When people take medicines, they do so on the basis of rational
decisions which at times may contradict what ought to be done from a
biomedical perspective. For example the very poor may take medicine
because they have come to believe that this offers a way out of misery,
hunger and pain. The contradiction between different rationalities and
how to bridge them is the challenge for improving drug use in the
community (Hardon, A, 1997).

This proposal calls for a comprehensive review on antecedents of and
interventions to improve inappropriate antimicrobial use by health
providers and community members. It is expected that this review will
answer these questions:

-   *what do we know about the factors that underlie inappropriate use
    of antimicrobials?*

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-   *what do we know about the structure of interventions that have
    attempted to improve inappropriate use?*

-   *have the interventions been well-designed given the causative
    factors?*

**Objectives:**

1\. To identify factors that underlie inappropriate use of
antimicrobials amongst health providers and community members.

2.  To investigate and document the structure of interventions that have
    been attempted to improve inappropriate use of antimicrobials by
    health providers and community members.

3.  To investigate whether the interventions have been designed in
    consideration of causative factors.

4\. To recommend strategies to address key priorities in improving the
inappropriate use of antimicrobials by health providers and community
members.

**Description:** *Source of Materials:* These reviews would access all
the material on both health provider and community-oriented
interventions collected for the ICIUM conference. The INRUD bibliography
would be a primary source for identifying supplementary materials,
although the extensive collection on community use of antimicrobials at
WHO/EDM and the University of Amsterdam would also be included.
Additional search will also be performed within the Med-line, Pop-line
database and also other related centers such as the one at the
University of Groningen. For these reviews to be reasonably complete, a
more active process of information gathering would be needed, since a
large amount of useful material of determinants of use has never been
published. For example, there is a substantial amount of unpublished
materials on community use of antimalarials. This material gathering
could be carried out through existing research networks as was done in
collecting the ICIUM review materials.

*Personnel:* The review would be prepared by Dr. Aryanti Radyowijati and
Dr. Hilbrand Haak, supervised by the staff from the ARCH project and RPM
staff. The supervision covers comments on versions of the manuscript as
it develops, and participation in the revision of the draft documents. A
meeting will be held at the beginning of the review process to develop a
detailed plan for the reviews, and during the revision process.

*Timing:* This review will require six months periods of person-works,
divided into two steps. The first step is to gather the existing
materials for the review, which is 2 person-months of work. And the
second step for reading and writing the review, which is 4 person-months
of work.

#### Expected Outputs, Results and Progress Indicators:  {#expected-outputs-results-and-progress-indicators .unnumbered}

#### [Output]{.underline}, a review of Antecedents of and Interventions to Improve Antimicrobial Use by Health Providers and Community Members. {#output-a-review-of-antecedents-of-and-interventions-to-improve-antimicrobial-use-by-health-providers-and-community-members. .unnumbered}

#### [Results:]{.underline} policy makers in developing countries will have access to a framework and results that will help guide policy decisions in designing strategies to encourage appropriate use of antimicrobial drugs. {#results-policy-makers-in-developing-countries-will-have-access-to-a-framework-and-results-that-will-help-guide-policy-decisions-in-designing-strategies-to-encourage-appropriate-use-of-antimicrobial-drugs. .unnumbered}

#### [Progress Indicators]{.underline}: relevant studies identified; relevant studies reviewed; and report drafted. {#progress-indicators-relevant-studies-identified-relevant-studies-reviewed-and-report-drafted. .unnumbered}

####  {#section .unnumbered}

#### Countries/Regions: The review will cover studies in Africa, Asia, Latin America and Eastern Europe/Eurasia. {#countriesregions-the-review-will-cover-studies-in-africa-asia-latin-america-and-eastern-europeeurasia. .unnumbered}

####  {#section-1 .unnumbered}

#### Partners: WHO/HTP/EDM {#partners-whohtpedm .unnumbered}

**Results to Date:** The review was completed in April 2001 and
presented to the USAID AMR working group. The review was well received
with some suggestions for additional material to be incorporated. The
authors will complete this assignment in 2001.

**Implementing Organization:** JHU/FHACS

**Status:** Completed (Funded: FY1999; Completed: FY2000)

**Description.** The epidemiology, risk factors and etiology of
nosocomial infections in developing countries will be reviewed.
Epidemiologic information important for the control of nosocomial
infections, but for which information is sparse, will be identified and
specific research questions proposed. Strategies for the prevention and
control of nosocomial infections in developing countries will be
reviewed and the data on their effectiveness critically examined.
Prevention and control strategies requiring further research will be
identified. The emergence and spread of antibiotic‑resistant bacteria
within health care settings, and strategies to control antibiotic
resistance, will also be considered. The review will focus on the
epidemiology and control of nosocomial infections in health centers and
district hospitals. The use of antibiotics outside health care
facilities or in animal husbandry will not be considered in this review.

**Countries/Regions:** Not applicable.

**Partners:** None.

**Results to Date:** Review is being prepared for publication.

Implementing Organization: RPM/MSH

**Status:** Completed (Funded: FY1999; Completed: FY2001)

Rationale: National health reforms in Eastern Europe/Eurasia and
developing countries are introducing changes in health services
organization, delivery, and finance. Social health insurance schemes are
being implemented, principles of managed care applied, and
incentive-based mechanisms to reimburse providers introduced. These
changes are expected to influence provider and consumer behaviors in
support of cost-effective health systems. However, some changes may
introduce new conflicts and unanticipated consequences. Changes in the
ways providers are rewarded for providing services would be expected to
alter prescribing practices and influence communication with patients
about the appropriate use of drugs. Patients' decisions to purchase and
consume a full course of antimicrobial drugs would be expected to be
influenced, in part, by the way providers communicate with patients. The
influence of health reforms on the use of antimicrobial drugs is
extremely important because of the adverse clinical, economical and
ecological consequences of inappropriate use and positive effects
associated with appropriate use. It is critical to assess the impact of
health reforms on the use of antimicrobial drugs so that countries can
integrate lessons learned into not only the design of their national
reforms but also in monitoring their impact. Provider or "supply side"
responses will be the focus of this review. This study will build on a
previous review undertaken by RPM that examined, among other things, the
impact of patient charges (demand side interventions) on antimicrobial
drug use.

Objective(s): To assess both positive and negative lessons learned on
the impact of managed care and provider reimbursement mechanisms on the
use of antimicrobial drugs in Eastern Europe/Eurasia and developing
countries by systematic analysis of findings from published and
unpublished studies.

Description: A comprehensive and systematic review of published and
unpublished studies on the impact of managed care and provider
reimbursement mechanisms on the use of antimicrobial drugs in developing
countries will be undertaken. An analytical framework will be developed
to provide a structure for evaluating the impact of the above reforms
(interventions) on the behavior of providers and consumers in use of
antimicrobial drugs. This review will build on the experience of other
efforts to identify studies that assess the impact of interventions on
drug use in general and antimicrobial use in particular. Previous
approaches started from a general drug use perspective. This review
proposes to identify relevant studies searching for studies on the
impact of managed care and provider reimbursement mechanisms.

On-line search engines, and databases such as the INRUD Bibliography and
the Cochrane Library will be used to identify relevant published studies
and overviews. In addition, World Bank task managers and USAID
contractors that work on health reform in Eastern Europe/Eurasia and
developing countries will be contacted to identify unpublished studies.
Studies that will be included in the review will have the following
characteristics:

-   Studies that focus on the use of antimicrobial drugs;

-   Studies that examine the impact of one or more of following
    interventions: managed care, provider payment mechanisms;

-   Studies that include an assessment of the impact of the intervention
    on the use of antimicrobial drugs;

-   Studies of these interventions in developing countries and Eastern
    Europe/Eurasia.

Because it is anticipated that few rigorous studies will be identified,
this review will also search for systematic overviews and relevant
primary reports on the impact of managed care and provider reimbursement
mechanisms on drug utilization in general and antimicrobials in
particular, in North America and Western Europe. This study will then
attempt to identify lessons learned from developed country experiences
that should be considered in he potential implementation of such
approaches in developing countries and Eastern Europe/Eurasia.

**Expected Outputs, Results and Progress Indicators:**

[Outputs]{.underline} include a bibliography of published studies that
meet selection criteria and a report on "The Effects of Provider
Reimbursement Mechanisms and Managed Care on the Use of Antimicrobial
Drugs in Eastern Europe/Eurasia and Developing Countries".

[Results]{.underline}: policy makers in developing countries will have
access to a framework and results that will help guide policy decisions
in designing health reforms that encourage appropriate use of
antimicrobial drugs. [Progress Indicators]{.underline}: compilation of
studies that meet criteria; analytical framework completed; literature
review completed; and assessment of lessons learned completed.

**Countries/Regions:** Studies in Africa, Asia, Latin America and
Eastern Europe/Eurasia.

**Partners:** WHO/EDM.

Results to Date: The research was conducted and a paper written by RPM
staff. Final editing of the paper is currently underway and completion
of project projected for October 2001. The findings from the review were
presented at the Global Health Council annual meeting June 2000.

# Implementing Organization: USP

**Status:** Completed (Funded FY1999; Completed: FY2001)

**Rationale:** Although fixed-dose combination (FDC) drug products are
generally discouraged in rational drug use strategies, there may be a
place in therapy for such combinations when a patient must take multiple
medicines and compliance is essential (e.g., treatment of tuberculosis
or malaria). Combination drug therapy trials will soon be starting in
several African countries to look at the efficacy of artemisinin
derivatives in conjunction with other drugs for the treatment of
malaria. Pending acceptable outcomes of these trials, the question of
need and appropriateness of FDC therapy will have to be addressed. With
many issues impacting the decision to accept FDCs (e.g., need for
compliance, manufacturing standards, optimal dosing regimens, potential
adverse reactions), USP believes it is necessary to identify and analyze
the relevant issues and make this information available to procurement
offices, manufacturers, essential drugs programs, health ministries, and
other concerned parties before decisions on registration and production
are made. Only in this way can a responsible plan of action be developed
to ensure that safe, needed, high-quality products with proven
therapeutic advantages are produced and distributed.

**Objective(s):** 1) To identify and analyze the issues surrounding use
of FDCs. 2) To establish a generic protocol for issues that need to be
addressed in the development of FDC products. 3) To examine the pros and
cons of FDC products proposed for malaria therapy and make
recommendations for what needs to be considered in developing optimal
combinations and ensuring appropriate use.

**Description:** Fixed-dose combination (FDC) drug products are widely
produced and marketed throughout the world. Such products represent a
relatively simple way a drug manufacturer can extend its product lines
(and profits) at a minimal cost. Although most FDCs would be considered
as irrational therapy, there is some support for their use in cases
where multiple-drug regimens can be reasonably standardized and
compliance to therapy is absolutely essential. There is a considerable
body of knowledge relating to FDCs. In addition, because of their
widespread registration and availability, there is considerable
experience with their use in patient care (either by a care-giver or
through self-care).

This activity would focus on collecting available FDC information and
experiences (by literature and policy review and through interviews with
key individuals who are knowledgeable about FDCs), analyzing the issues
presented, identifying the pertinent areas of concern, and subjecting
the draft report to the scrutiny of experts and other interested
parties. As part of the information/experience collection, selected FDCs
on the market will be used as case studies/examples; policies of
regulatory agencies and manufacturers will be explored; and research
relating to the effect of FDCs on patient compliance/adherence will be
reviewed. A group of experts will be asked to serve as a reviewing body,
with opportunity for public review and comment. The process will be open
and transparent. Most of the discussions will make place via mail,
telephone, and e-mail, with one face-to-face meeting of the individuals
serving on the reviewing body scheduled towards the end of the
deliberation period. The final draft document will be published for the
review and comment of all interested parties.

**Expected Outputs, Results, and Progress Indicators:**

[Output:]{.underline} a state of the art examination of the issues
surrounding the need for, risks/benefits of, and production and use of
FDC drug products (with specific information relating to potential FDCs
for use in malaria initiatives).

[Expected results]{.underline}: 1) an increase in informed
decision-making relating to the need for and production and use of FDCs,
in general. 2) Appropriate decisions relating to the development of FDCs
for use in the prevention and treatment of malaria. 3) An increased
understanding of the potential role FDC drug products may or may not
have in rational drug therapy.

[Progress indicators]{.underline}: literature search with evaluation of
papers, key person interviews, draft outline of paper, participation of
wide body of experts, draft paper, USP panel consensus, public review,
final paper.

**Countries/Regions:** Not applicable.

**Partners:** Not applicable.

**Results to Date:** This paper focussed on FDCs using artemisinin and
derivatives for malaria and FDCs for tuberculosis. The paper supports
the use of artemisinin FDCs provided they are controlled for quality.
Artemisinin derivatives are very active; they work quickly and are
eliminated quickly, thus it is less likely that resistance to them will
develop.

The paper supports the use of FDCs for tuberculosis provided uniformity
of individual dosage amounts included in FDCs by different companies and
in different countries is improved and quality is monitored,
particularly the bioavailability of rifampin in combinations.

The paper has been disseminated to USAID Washington.

**Implementing Organization:** JHU/FHACS

**Status:** On-going (Funded: FY1998; Expected Completion: FY2002)

**Rationale**: Resistance to antibiotics of several disease-causing
microorganisms has emerged as a worldwide public health problem in
recent years. Antibiotic resistance has complicated the treatment of
malaria, tuberculosis, cholera and sexually transmitted diseases, and is
the major concern regarding the efficacy of the case management strategy
for controlling childhood pneumonia and bacterial dysentery.

Frequent use of antibiotics has been shown to be the main factor in the
development of AMR. This is true on both the individual and population
levels, so that individuals with prior treatment with an antibiotic and
populations with high rates of antibiotic use have higher levels of
drug-resistant organisms. Overuse by populations has a multiplying
effect because even those individuals without prior antibiotic use are
at increased risk from the resistant organisms in their environment.

Overexposure to antibiotics can occur through their veterinary use in
animal feeds and from their inappropriate use by public health programs
and facilities, private physicians, pharmacists, other health workers
and individuals. What is unknown is the relative influence and
interaction of these exposures in determining a population's carriage
rate of resistant organisms, and therefore the most effective approaches
to limiting AMR in populations. There is a need to develop and test a
method to assess the relative importance and interactions of these
factors.

**Objective(s):** To develop a model in one country that describes the
relative importance and interactions of several sources of antibiotic
exposure to the level of AMR in the population; to test and refine the
model using data from a second country; and to use the refined model to
suggest the most effective approaches to limiting AMR.

**Description**: We propose to develop a model, using data collected in
one developing country, that examines the relative importance of a
population's various exposures to antibiotics, and the interrelationship
between the exposures, to the population's carriage rate of
drug-resistant bacteria; and to then test the predictive strength of the
model in a second country.

In several communities in each country, data relevant to all possible
antibiotic exposures of a large magnitude will be collected through
site-appropriate methods, including surveys, observation, and
examination of records at farms, public health facilities, private
physicians' offices, pharmacies and households. Antibiotic resistance
carriage rates will be determined by sampling and testing nasopharyngeal
and enteric organisms from children at a variety of sites in each
community. Using data from the first country, regression models will be
developed to examine the strength of and interrelationship among various
types of antibiotic exposures, including for example, possible additive
or multiplicative effects among the exposures, in determining a
community's rate of antibiotic resistance. Data from the second country
will be used to test and refine the model.

**Expected Outputs, Results and Progress Indicators**: The expected
output of this activity is a statistical model that will attempt to
elucidate the relative importance and the interrelationship of various
factors in the development of AMR. Development of the model would
benefit USAID, other donors and countries in their quest to limit and
reverse the trend of increasing AMR. Application of the model by
countries should suggest the most effective approaches to this problem
in their particular settings and hence relevant policy directions.
Progress related to application of the model by a country would be
indicated by: (1) the model succeeding in identifying the most effective
approach(es) to the problem of AMR in the country, and (2) assuming the
implementation of appropriate policies suggested by the country
findings, decreasing levels of AMR.

**Countries/Regions:** Peru.

**Partners**: PRISMA. We intend to investigate the possibility of
collaborating with WHO/CDS on this study.

**Results to Date:** Data collection has been completed in all four
study communities in each of three regions (urban slum, coastal, Amazon)
of Peru. The data includes household, pharmacy, health facility, market
and farm surveys on antimicrobial use and distribution; child
nasopharyneal and rectal cultures for *S. pneumoniae* and *E. coli*,
respectively; and cultures of household animal and environmental
specimens for *E. coli*, all of which will be tested for AMR. Data
collection is proceeding in the final study region (Andean). The data
should be ready for analysis in the second quarter of 2002.

**Implementing Organization:** WHO/CDS

**Status:** On-going (Funded: FY1998; Expected Completion: FY2003)

**Rationale:** Mathematical modeling techniques have been used
effectively to map outbreaks and spread of infections and the potential
effects of intervention strategies, such as immunization. Similar
techniques can also be applied to model the emergence and spread of AMR.
In particular, human-to-human spread and animal-to-human transfer of
resistant strains and resistance genes can be studied. The impact of
resistance containment interventions, such as introduction of
antimicrobial usage policies, infection control guidelines and improved
hygienic practices in food animal production can be evaluated.

**Objective(s):** Through sharing the expertise available in
mathematical modeling at the Wellcome Trust Epidemiology Research
Centre, University of Oxford, UK and the access to extensive data sets
through WHO and its Collaborating Centres, the objective is to construct
models of AMR emergence and spread and to test the effect on the model
of the application of specific interventions.

**Description of Activities:** These activities will be undertaken in
partnership with the Wellcome Trust Epidemiology Research Centre,
University of Oxford, UK.

1\. Definition of data sets available to WHO and those required for
particular models of human-to-human spread and animal-to-human transfer
of resistant strains and resistance genes.

2\. Selection of one or two scenarios for which sufficient data exist
for construction of models.

3\. Establishment of mathematical models for one or two scenarios
(depending on data availability and complexity).

4\. Examination of effect of resistance containment interventions on the
model.

5\. Design and execution of a field study to test the interventions
which are predicted from the model to be effective. (Further funding
will be required for this activity.)

**Expected Outcomes, Results and Progress Indicators:** The results of
activities 1-4 will be mathematical models showing the theoretical
effects of specific interventions to contain AMR. The results of
activity 5 will show whether interventions effective in the model
translate in practice. The process can be iterative and further
refinement of the models should be possible on the basis of the results
of field studies.

[Progress indicators 1998]{.underline}: Agreement established with
Wellcome Trust Epidemiology Centre on scenario to be studied; Data needs
defined; Appropriate data sets identified; Modeling commenced.

**Countries/Regions:** To be determined.

**Partners:** Wellcome Trust Epidemiology Research Centre; University of
Oxford, UK; WHO/CDS; WHO Collaborating Centre for Surveillance of
Antimicrobial Resistance; Brigham and Women's Hospital, Boston, USA;
Johns Hopkins University, USA; Menzies Research Institute, Australia.

**Results to Date:** After some delay, discussions are underway with the
authors, groups within WHO, and other interested partners. A second
small workshop has been held under the auspices of the Nuffield Trust
and the leadership of Dr. Richard Smith to explore potential projects.
It is hoped that one such may be linked to an implementation project of
the WHO Global AMR Strategy in a developing country in 2002.

**Implementing Organization:** WHO/CDS

**Status:** Discontinued (Funded: FY1998)

**Rationale:** In addition to the use of antimicrobial in human
medicine, significant amounts are used in other sectors, namely food
animal production, agriculture and aquaculture, thus adding to the
global selective pressure favoring emergence of resistance. However,
there are insufficient data available to be able to make a reasonable
assessment of the risk to human health of the non-medical uses of
antimicrobial. WHO initiated the gathering of information and the
definition of priorities at its meeting in 1997 (The Medical Impact of
the Use of Antimicrobial in Food Animals. Report WHO/CDS/ZOO/ 97.4).
This Proposal outlines the continuation of this activity and will be
supplemented by a review (see the \"*Expert Technical Reviews*\" section
of activity 1.1:\"Establishing a Global Strategy and Action Plan\").

**Objective(s):** Identification of the existing data and the data
needed in order to allow risk analysis for the non-medical uses of
antimicrobial on human health.

**Description**:

1\. Meetings of a collaborative working group between WHO and key
partners to advocate for operational research and data gathering to fill
identified gaps, including strengthening of surveillance of AMR in
bacteria from food of animal origin;

2\. Definition of collaborative activities with industry working group
(established with IFPMA and COMISA);

3\. Preparation and dissemination of reports.

**Expected Outcomes, Results and Progress Indicators:** Detailed report
of evidence for potential human health impact of non-medical uses of
antimicrobial.

[Progress indicators in 1998]{.underline}: Establish Working Group with
FAO and other partners; Complete review of impact on human health of
non-medical uses of antimicrobial (see Component 1); Define agenda for
Working Group.

**Countries/Regions:** Not applicable.

**Partners:** WHO/CDS; WHO Food Safety Unit; FAO; European Commission;
US Department of Agriculture; US FDA; European Medicines Evaluation
Agency; International Federation of Pharmaceutical Manufacturers
Associations (IFPMA); Confederation Mondiale de l\'Industrie de la Santé
animale (COMISA).

**Results to Date:** A consultation was convened to draft WHO Global
Principles for Containment of Antimicrobial Use in Food Animals (January
2000). Subsequently, an electronic discussion group was organized to
obtain comment from all stakeholders on draft global principles (March
2000). Consensus was reached at a WHO Consultation (June 2000) that
included participation by the Food and Agriculture Organization and the
Office International des Epizooties and 14 other international
organizations. The WHO Global Principles are available at::
http://www.who.int/emc/diseases/zoo/who_global_principles/

index.htm. WHO will commission a review of antimicrobial use in
aquaculture in 2001.

This activity has subsequently been discontinued.

**Implementing Organization:** WHO/HTP/EDM

**Status:** On-going (Funded: FY1998; Expected Completion: FY2001)

**Rationale:** Irrational use of antibiotics is considered a major
contributing factor in the development of AMR. One third of
prescriptions in developing countries are for antibiotics. Any
intervention to promote rational use of antibiotics should be preceded
by analysis of *[why]{.underline}* certain behaviors occur. The set of
WHO/INRUD quantitative indicators for rational drug use issued in 1993
is now widely used and has become the global standard to describe
prescribing patterns. A similar set of simple standard methods for
non-quantitative research has been developed to study
*[why]{.underline}* certain drug use patterns exist. Field studies with
non-quantitative standards are needed before they can be issued by WHO.

**Objective(s):** Validated standard methods for non-quantitative
research which document why certain drug use patterns exist. This is a
fundamental prerequisite to developing interventions to change
irrational prescribing behavior. The final standards would be used by
rational drug use researchers, national rational drug use and essential
drug use programmes and training officers.

**Description of Activities:** The draft manual of non-quantitative
indicators will be field tested in four countries. These tests would be
conducted in close collaboration with INRUD/MSH. The final version of
the manual would be disseminated to national essential drug programmes,
researchers and trainers in rational drug use and relevant
non-governmental organizations.

**Expected Outcomes, Results, and Progress Indicators:** A practical
manual on standard methods for non-quantitative research which will
allow the definition and understanding of the reasons for irrational
prescribing in developing countries (prior to designing intervention
strategies).

[Progress indicators, Year 1:]{.underline} Protocol for study agreed;
locations agreed for field tests in 4 countries; study undertaken;
report on results of studies. [Year 2]{.underline}: Additional funding
needed; final version of manual drafted, agreed and issued; manual
disseminated.

**Countries/Regions:** Potential field test sites include Benin,
Indonesia, Kenya, Philippines, South Africa, Uganda, and Zambia.

**Partners:** WHO; MSH; International Network for Rational Use of Drugs
(INRUD); national governments and/or universities in countries of the
field test.

# Results to Date: The draft manual was compiled by WHO and field tested by MSH in Kenya, Uganda, Ghana and the Philippines. Substantive changes were recommended to produce a simpler, more-concise manual that spends less time on method description and addresses how to use and analyze the information. WHO/EDM and MSH are currently discussing next steps.

**Implementing Organization:** RPM/MSH

**Status:** On-going (Funded: FY1998; Expected Completion: FY2001)

**Rationale:** Core indicators and a simple methodology have been
developed to study drug use in outpatient settings. These indicators can
easily be adapted to study antimicrobial drug use. However, the ICIUM
Conference also identified a need to define indicators and design an
appropriate methodology to assess drug use in general, and antimicrobial
specifically, in hospitals.

**Objective(s):** Develop and test a rapid assessment methodology and
indicators to assess antimicrobial use in hospitals

**Description:** Tasks include a focused literature review and survey of
key researchers and INRUD members. RPM intends to produce a draft
instruction manual that would include the rationale, definition, and
calculation for proposed indicators, model data collection forms and
proposed methods, and techniques to collect data needed to derive the
indicators. Key members of the INRUD Network, WHO HTP/EDM, USP advisory
panels (Drug Utilization Review and International Health), and leading
drug use intervention researchers will be invited to review the proposed
methodology and indicators.

RPM will conduct a field test of these indicators, data collection forms
and data collection methods and techniques. It is expected that members
of the INRUD network will collaborate in the field test. Results of the
field test will be reviewed at a post-field test workshop and the
indicators and instruction manual revised accordingly.

Once the manual is revised, its availability will be announced in
electronic and print fora (E-drug, INRUD News, Essential Drug Monitor).
It will be determined later if it may be appropriate to publish the
manual in collaboration with WHO. Field test results may be published in
the INRUD News, Essential Drugs Monitor and a peer-reviewed journal. The
methodology will be incorporated in the INRUD-WHO Promoting Rational
Drug Use and the MSH Managing Drug Supply courses.

**Expected Outputs, Results and Progress Indicators:**

[Outputs]{.underline}: list of key references on Hospital Drug Use
Studies and Indicators; compilation of key readings on Hospital Drug Use
Studies and Indicators; set of core indicators for hospital drug use
(including antimicrobial agents); manual on how to investigate drug use
in hospitals.

[Results]{.underline}: set of hospital drug use indicators and
methodology for data collection available and field tested

[Progress indicators]{.underline}: literature review completed; key
readings compiled; core hospital drug use indicators drafted; manual on
how to collect hospital drug use indicator data drafted; hospital drug
use indicator methodology field tested; manual on hospital drug use
indicator revised.

**Countries/Regions:** Field tests in Ghana and Nepal.

**Partners:** INRUD country core group members are expected to
collaborate in technical review of indicators and methodology;
WHO/HTP/EDM is expected to collaborate in technical review of indicators
and assessment methodology; USP staff and advisory panelists will be
asked to provide technical review of indicators and assessment
methodology; others to be identified through the literature review.

# Results to Date: The final draft was completed under RPM and field tested in Ghana and Nepal. Needed amendments were highlighted. Under RPM Plus these amendments have been made and the document is under final editing as an on-going working draft.

**Implementing Organization:** CDC/NCID

**Status:** Discontinued (Funded: FY1998)

**Rationale:** In many countries widespread overuse of antibiotics
occurs due to treatment of upper respiratory infections and
uncomplicated diarrhea. WHO case management schema --- either vertical
ARI and diarrheal disease control programs or IMCI --- recommend
antibiotic use only for children with diagnosed pneumonia or dysentery.
Adherence to these recommendations may lead to a substantial decrease in
overall antibiotic prescribing. Moreover, when a standardized case
management approach is used, the proportion of children who are treated
with antibiotic courses of appropriate dose and duration is likely to
increase. These changes in antibiotic use practices may have a major
impact on the spread of antibiotic resistance within a community.

**Objective:** Evaluate the impact of case management implementation on
antibiotic prescribing practices, antibiotic use by patients, and
carriage of antibiotic resistant pathogens.

**Description:** Before implementation of case management, baseline data
will be collected including rates of antibiotic prescribing and use
among children; respiratory tract carriage rates for resistant *S.
pneumoniae* and *H. influenzae*; and, if possible, carriage rates for
resistant fecal flora. Local investigators will be trained in study
methods including epidemiological survey techniques and laboratory
methods for isolation, identification, and susceptibility testing of
respiratory tract and enteric pathogens. Susceptibility test results
from these baseline investigations will inform the selection of
appropriate antibiotic therapy for case management guidelines. During
case management training, the risk of antibiotic resistance and the
importance of strict adherence to prescribing guidelines will be
emphasized. After one year of case management implementation (and
potentially at intervals thereafter), rates of antibiotic prescribing,
use, and resistance will be assessed among patients managed by
IMCI-trained providers and compared with rates among patients of
untrained providers.

**Expected Outputs, Results and Progress Indicators:** Success of this
activity will be assessed by: 1) establishing baseline data on
antibiotic prescribing, use, and resistance; 2) training local
investigators in epidemiological and laboratory methods that will lead
to sustainability of capacity; and 3) evaluating the impact of IMCI on
antibiotic prescribing, use, and resistance. Results of this study may
provide an additional impetus for adoption of IMCI as a strategy to
decrease the spread of resistance.

**Countries/Regions:** Areas that are in the process of implementing
IMCI would be appropriate for this activity. This includes sites in
Central Asia (Kazakhstan), Bangladesh (in conjunction with ICDDR,B), and
several sites in Africa or Latin America. We will work with
international partners to identify the best site for this activity.

**Partners**: WHO; BU/ARCH (depending on study site).

**Implementing Organization:** WHO/CAH

**Status:** On-going (Funded: FY1998; Expected Completion: FY2003)

**Rationale:** Antimicrobial resistance of *S. pneumoniae* to penicillin
is increasingly being reported from developed countries but there is
limited data from the developing countries. Third generation
cephalosporins have become the first line antimicrobial for the
treatment of bacterial meningitis in developed countries. Whereas, in
the developing countries penicillin + chloramphenicol are still used for
the treatment of bacterial meningitis because the third generation
cephalosporins are very expensive. Children suffering from penicillin
resistant pneumococcal bacterial meningitis do not respond well even to
chloramphenicol. These children should be treated with injectable third
generation cephalosporins to reduce morbidity and mortality. But,
unfortunately information about the prevalence of penicillin resistant
*S. pneumoniae* and *H. influenzae* from developing countries is
limited. This information will help the countries to decide which
antimicrobial to use for the treatment of bacterial meningitis.

**Objective(s):** To use AMR data to guide treatment of bacterial
meningitis.

**Description:**

1\. Designing and implementing a multi-country study to strengthen
facilities for CSF; culture and basic susceptibility testing to examine
the prevalence of *S. pneumoniae*, *H. influenzae,* and *N.
meningitidis*;

2\. Developing facilities for CSF cultures and basic susceptibility
testing where they are not available;

3\. Developing drug-switch guidelines based on AMR data.

**Outcomes, Results and Progress Indicators:**

1\. To document AMR rates for common bacteria causing meningitis;

2\. To help build capacity in epidemiological research and microbiology;

3\. To assist developing countries in decision making to change, when
appropriate, the first line antimicrobial use guidelines for the
treatment of bacterial meningitis.

[Progress Indicators]{.underline}: Development of a research protocol.
Initiation of data collection for prevalence of AMR. Development of
drug-switch guidelines.

**Country(s)/Region:** The study will be conducted in Malawi, Pakistan,
South Africa, and Vietnam.

**Partners:** The WHO Division of Emerging and other Communicable
Diseases (EMC) has developed CSF culture facilities for *N.
meningitidis* in the meningitis belt countries. There is a need to
include *S. pneumoniae* and *H.influenzae* cultures in CSF testing*,*
and if possible to extend it to other developing countries. INCLEN has
recently conducted invasive bacterial infections surveillance (IBIS)
study in several centres and their experience will be drawn upon for
this activity. JHU/FHACS and INCLEN along with WHO/CAH are currently
testing the clinical efficacy of a short-course treatment for bacterial
meningitis (see activity 5.8).

**Results to Date:** Data collection was initiated in April 2001 and is
expected to last 2 years.

**Implementing Organization:** WHO/CAH

**Status:** On-going (Funded: FY1998; Expected Completion: FY2001)

**Rationale:** WHO ARI case management guidelines recommend penicillin
for children suffering from severe pneumonia. Results from the
surveillance network for invasive *S. pneumoniae* in children less than
five years old implemented by the SIREVA (Region System of Vaccine --
initiative sponsored by PAHO and by the Canadian International
Development Agency) in Argentina, Brazil, Chile, Colombia, Mexico and
Uruguay have shown a 10-26% reduced susceptibility to penicillin of the
isolated strains. There is, however, some controversy whether the
clinical outcome of pneumonia reflects the current levels of *in vitro*
penicillin resistance. Results of studies attempting to establish the
correlation between diminished susceptibility to penicillin of *S.
pneumoniae* and severity of pneumonia have been inconclusive due to
selection bias in recruitment of participants and incomplete recording
of clinical outcomes. With the emergence and spread of the
drug-resistant strains of *S. pneumoniae* clinicians are worried about
the clinical efficacy of penicillin in pneumonia patients.

Although there are suggestions that the emergence of drug-resistant
pneumococci may result in treatment failures, no prospective study has
been conducted to evaluate the impact of drug-resistant *S. pneumoniae*
on the clinical outcome of pneumococcal pneumonia in Latin America. Most
of the reports on drug resistance available in the Region are derived
either from laboratory surveillance systems or from retrospective
analysis of non-representative sampling from hospitalized patients.

**Objective(s):**

1\. To investigate the relationship between *in vitro* penicillin
resistance of *S. pneumoniae* and the clinical outcome of current
recommended therapy for severe pneumonia as defined by the standard ARI
case management.

2\. To generate data to guide ARI therapy policy for the countries of
the PAHO region.

**Description:**

1\. A proposal development workshop to be held to develop a protocol to
study this question.

2\. In a multi-centre (18 hospitals in five countries) observational
study of hospitalized children with severe pneumonia on injectable
penicillin treatment will be observed.

3\. Blood cultures will be obtained in all patients to identify and
document the resistance patterns of *S. pneumoniae*.

**Expected Outcomes, Results** **and Progress Indicators**

1\. To better understand the relationship between in vitro resistance to
penicillin and antimicrobial clinical efficacy in the management of
severe pneumonia.

2\. To support or improve current IMCI guidelines for treatment of
severe pneumonia.

3\. This activity will build capacity in epidemiological and
microbiologic research.

[Progress Indicators]{.underline}: A proposal finalization workshop was
held in Santo Domingo, Dominican Republic and participants from five
Latin American countries participated; Initiation of data collection.

**Country(s)/Regions:**

*Argentina:* Hospital Pedro de Elizalde Buenos Aires, Hospital Durand
Buenos Aires, Hospital Sor Ludovica La Plata, Hospital Notti Mendoza;
*Brazil:* Hospital das Clínicas/UFMG, Belo Horizonte, Instituto Materno
Infantil, Recife, Inst Ped. Pueri. M. Gesteira, Rio de Janeiro, Hospital
Universitário, Salvador, Hospital Aliança, Salvador, Hospital Santa
Casa, São Paulo, Hospital Darci Vargas, São Paulo;

*Columbia:* Hospital La Misericordia Bogotá, Clínica Colsubsidio Bogotá,
Hospital Universitário Cali, Hospital San Vicente de Paúl Medellin;
*Peru*: Instituto de Salud del Niño; *Dominican Republic:* Hospital
Robert R. Cabral Santo Domingo, Hospital de Los Mina Santo Domingo.

**Partners:** Pan American Health Organization (PAHO) and WHO/CAH will
jointly fund and co-ordinate this research activity. PAHO will have the
primary responsibility of co-ordination. However, monitoring activities
will be conducted by WHO. Applied Research for Child Health (ARCH),
Harvard Institute of International Development (HIID), Harvard
University, Cambridge will also co-fund (for a small amount) this large
multi-centre study. Requested budget will be WHO's share towards this
activity. Finally, the technical expertise for quality control will be
provided by the Canadian International Agency (CIDA). The requested
funds would support the clinical, microbiology work, monitoring and data
analysis.

**Results to Date:** Data collection in this large, multi-centre study
has been completed and a data analysis workshop is scheduled to take
place in Sao Paolo from 30-31 August 2001. Results of this important
study was presented at the IUATLD World Conference on Lung Health held
in Paris (France) from 1-4 November 2001 (see abstract below).

> "Studies attempting to establish an association between diminished
> susceptibility to penicillin of *S. pneumoniae* and severity of
> pneumonia are often inconclusive due to selection bias in recruitment
> of participants and incomplete recording of clinical outcomes.
> Although these reports suggest that the emergence of drug-resistant
> pneumococcus will result in treatment failures, no prospective study
> has been conducted to evaluate the impact of drug-resistant *S.
> pneumoniae* on the clinical outcome of pneumococcal pneumonia in Latin
> America. Thus, this multicentre prospective observational study aims
> at investigating the relationship between penicillin resistance of *S.
> pneumoniae* and the clinical outcome of current recommended therapy
> for severe pneumonia as defined by the standard ARI case management.
> The investigation has been carried out in 4 countries (Argentina,
> Brazil, Dominican Republic, and Peru). 1,142 children, aged 3-59
> months, hospitalized with severe pneumonia have already been included
> in this study. The diagnosis of severe pneumonia is based on WHO
> guidelines for the management of ARI in children. One of the three
> schemes has been used for the initial treatment: (1) Ampicillin
> intrvenously (150 mg per kg/24 hours) for children aged 3-24 months
> and Aqueous penicillin G intravenously (200,000 unites per kg/24
> hours) for children \> 24 months; or (2) Ampicillin intrvenously (150
> mg per kg/24 hours) for children aged 3-59 months; or (3) Aqueous
> penicillin G intravenously (200,000 unites per kg/24 hours) for
> children 3-59 months. Six deaths (0.5%) have been occurred, however,
> 1,032 (90%) children have been successfully treated, i.e. the
> antibiotic is not changed and patients are switched to home treatment
> with oral amoxycillin (50 mg per kg/day) to complete a course of 10
> days of therapy. The isolation rate has been 6% with a resistance rate
> of 21.9%. The preliminary results show no association between
> penicillin resistance of *S. pneumoniae* and treatment failure
> (*p*\>0.05)."

Another year will be needed to complete the recruitment of patients to
meet the originally-calculated sample size.

Implementing Organization: CDC/NCID

**Status:** On-going (Funded: FY1998; Expected Completion: FY2002)

Rationale: Antibiotic use has been shown to be a significant risk factor
for carriage of and infection with resistant pathogens. However, the
importance of antibiotic dose, treatment duration, and the impact of
non-compliance with therapy have not been evaluated for common
outpatient pathogens. Assessing the importance of these factors is
crucial in developing interventions to prevent the spread of resistance.

Objective(s): Assess the impact of antibiotic dose, agent and
noncompliance with therapy on nasopharyngeal (NP) carriage of
nonsusceptible respiratory pathogens.

Description: This evaluation was conducted through a prospective
randomized trial in an outpatient clinic in the Dominican Republic.
Children aged 6 - 59 months and requiring antibiotics for respiratory
illness were eligible for inclusion in the study; those enrolled were
randomized to receive routine or high-dose therapy with cotrimoxazole or
amoxicillin. Impact of the different treatment courses on NP carriage of
nonsusceptible pathogens was assessed by culture before and after
therapy. Compliance was evaluated by history and pill count and those
data were incorporated along with drug and dose in a model with
resistant carriage as an outcome.

Countries/Regions: Dominican Republic

Partners: Fundacion Dominicana de Infectologia

Results to Date:

1)  The risk of penicillin nonsusceptible pneumococcal carriage and
    trimethoprim-sulfamethoxazole nonsusceptible pneumococcal carriage
    were each significantly lower in the short-course, high-dose group
    compared to the standard course group at 28-days post-enrollment.

2)  The protective effect of short-course, high-dose therapy was
    stronger in households with at least three children.

3)  Adherence to treatment was higher in the short-course, high-dose
    group.

4)  Dissemination of findings through JAMA publication: \[Schrag SJ,
    Pena C, Fernandez J, Sanchez J, Gomez V, Perez E, Feris JM, and
    Besser RE (2001) Effect of short-course, high-dose amoxicillin
    therapy on resistant pneumococcal carriage: a randomized trial.
    [JAMA]{.underline} *286* (1): 49 -- 56.\]

5)  Provision of evidence base in support of benefits on controlling AMR
    via shorter treatment regimens.

**Implementing Organization:** CDC/NCID

**Status:** Discontinued because suitable site could not be identified
(Funded: FY1998)

**Rationale:** With the spread of chloroquine resistant falciparum
malaria, fansidar (pyrimethamine sulfadiazine) has become first line
therapy for malaria in many parts of the world. Because this agent and
cotrimoxazole both affect folic acid biosynthesis, use of one agent may
increase resistance to the other. In a study conducted in Malawi, use of
fansidar was shown to significantly increase the proportion of children
who carried cotrimoxazole resistant pneumococci at 28 days after
therapy. These data suggest that widespread use of fansidar may increase
transmission of cotrimoxazole resistant respiratory tract pathogens and
increase the overall rate of resistance in the community. If this
occurred, it could have important implications on the use of
cotrimoxazole to treat bacterial infections or may indicate a need to
modify malaria case management recommendations to decrease fansidar use
and reduce selective pressure for resistance.

**Objective**: Assess the impact of fansidar use on NP carriage of
cotrimoxazole resistant respiratory tract pathogens and on rates of
cotrimoxazole resistance in the community.

**Description**: Two approaches could be taken in this investigation;
which is optimal would depend on the specific characteristics of the
study area. The first approach is to identify two malaria endemic areas:
one where chloroquine remains the recommended therapy for malaria and
another where fansidar is being introduced as therapy. In the fansidar
use area, NP carriage of cotrimoxazole resistant respiratory tract
pathogens will be assessed before and after therapy for children who
receive fansidar versus those who receive no antimicrobial. In addition,
longitudinal NP swab surveillance, according to guidelines developed in
the above surveillance proposal, will be conducted in the fansidar and
the control areas to determine whether trends in cotrimoxazole
resistance differ between the two areas, controlling for cotrimoxazole
use in each area. A second approach would be to perform cross sectional
surveys in areas with different rates of malaria (e.g., holoendemic,
seasonal, and no malaria) and compare rates of cotrimoxazole resistance
controlling for differences in cotrimoxazole use.

**Expected Outputs, Results and Progress Indicators:** Results of this
study will confirm an impact of fansidar on cotrimoxazole resistance on
an individual level and determine whether there also is an effect at the
community level. Results of this study will be presented at
international meetings and a manuscript submitted to a peer reviewed
journal. In addition, results may be used by WHO to revise
recommendations for case management and for surveillance of resistance.

**Countries/Regions**: The most likely site for this study is
Sub-Saharan Africa where fansidar is being introduced in many areas due
to the prevalence of chloroquine resistance. CDC has previous experience
and study sites in Malawi and in Kenya that may be appropriate for this
study

**Partners:** We would seek collaboration in the laboratory aspects of
this project from the South African Institute for Medical Research which
provided collaboration for the previous study in Malawi.

**Implementing Organization:** WHO/HTP/EDM

**Status:** Completed (Funded: FY1998; Completed: FY2000)

**Rationale:** Antimicrobial resistance is a growing problem worldwide,
with major implications for the cost and effectiveness of
pharmacotherapy. The Essential Drugs Monitor was established in 1985 and
is published by the WHO/HTP/EDM on a twice yearly basis in English,
French, Spanish and Russian. The latest print run totalled 21,000
English, 6,000 French, 4,300 Spanish and 3,000 Russian copies. A
readership questionnaire survey, has shown that each copy is read by 8
people. The total readership therefore is estimated as being some
quarter of a million made up of policy makers, health practitioners,
academics, development workers in over 160 countries. Distribution has
been mainly to individuals who have personally subscribed through
interest and the current numbers have accumulated on that basis; a
certain proportion go to libraries. It is an influential advocacy and
information medium which reaches an unusually large spectrum (both
geographically and professionally) of people involved in the
pharmaceutical sector. Contributors are drawn from a wide range of
organizations and individuals. The latest edition (No 24) whose theme is
"Networking for Action" has articles from Acción Internacional por la
Salud (AIS Bolivia), African Drug Regulatory Authorities (AFRDRAN),
Appropriate Health Resources and Technology Action Group (AHRTAG),
Action for Rational Drugs in Asia (ARAD), Alliance for the Prudent Use
of Antibiotics (APUA), BUKO Pharma-Kampagne (Germany), the Cochrane
Collaboration, E-Drug, Health Action International (HAI), International
Clinical Epidemiology Network (INCLEN), International Network for the
Development of Pharmacotherapy Teaching (INDEPTH), International Network
for Rational Use of Drugs (INRUD), International Society of Drug
Bulletins (ISDB), The Network, Association for Rational Use of
Medication in Pakistan, Medical Lobby for Appropriate Marketing (MaLAM),
La Revue Prescrire, Scottish Intercollegiate Guidelines Network (SIGN),
as well as from WHO divisions and others. The volume contains 21 book
reviews.

A theme issue of the Essential Drug Monitor would have a pre-selected
important and influential target audience and result in increased global
awareness of the problem of AMR.

**Objective(s):** The Essential Drugs Monitor is orientated towards
developing countries. The objectives are (1) to increase awareness
through focus on key topics in National Drug Policy; (2) to report on
both descriptive and intervention research and country activities; (3)
to present news items in the field of essential drugs; and (4) to
provide a bibliography on aspects of pharmacotherapeutics (note: several
pages are usually devoted to book reviews). A theme issue devoted to
antimicrobial, produced in English, French, Spanish and Russian, will
increase awareness of selected aspects of AMR and pharmaco-therapeutics,
drawing on the opinions and experience of a wide range of organizations
and individuals. It will also present some success stories and serve as
a guide for further reading on the subject.

**Description:** WHO/HTP/EDM will develop and disseminate a theme issue
of The Essential Drugs Monitor devoted to antimicrobial. WHO/HTP/EDM
will select, commission, review, adapt, reject or accept material in the
normal way, with full editorial control. The outcome of the November
1998 WHO meeting on the Global Strategy for the Containment of
Antimicrobial Resistance will be covered. Clear terms of reference
including time frames would be agreed with contributors. The issue will
be translated and published in the usual four languages. Expanded
distribution would be pursued through the WHO/HTP/EDM and WHO/CDS
networks in addition to the WHO Regional Offices. The print run would be
increased according to need.

**Expected Outcomes, Results, and Progress Indicators:** A theme issue
of the Essential Drugs Monitor. Distribution of information to lead to
improved knowledge of the causes and extent of the problem of AMR, how
it is being tackled, and overviews of current research. A theme issue
could be available in the first half of 1999.

[Progress indicators]{.underline}: Designation of commissioning
assistant editor; decisions on time frame; decisions on contents
selection of contributors; commissioning of contributors with well
defined terms of reference; review and editing of drafts; compilation;
proof reading; printing; distribution.

**Countries/Regions:** 160 countries

**Partners:** WHO/HTP/EDM (Essential Drugs Monitor); other organizations
would be selected from a wide range of organizations and individuals and
the choice would be an editorial decision.

**Results to Date:** The special edition (issue No. 28 & 29) of the
Essential Drug Monitor that highlights the threat of AMR was published
and distributed in September 2001 and is available at
http://www.who.int/medicines/library/monitor/EDM2829en.pdf

French and Spanish translations have also been published and
distributed. Translations in Russian and Chinese and presently being
undertaken are will be completed in early 2002.

**Implementing Organization:** WHO/HTP/EDM

**Status:** On-going (Funded: FY1999; Expected Completion: FY2003)

Rationale: Much work has been done to improve undergraduate medical
curricula. There is a great need to do the same for pharmacy
undergraduate curricula in developing countries. A core curriculum for
pharmacy in developing countries is needed, which includes drug
management issues and the role of the pharmacist to prevent AMR,
including promoting rational use of antimicrobials, and infection
control.

Objective(s): To prepare training materials for undergraduate pharmacy
students, with the intention to transfer to them the knowledge, skills
and attitudes necessary to prevent AMR.

###  {#section-2 .unnumbered}

### Description: Regional workshops with heads of pharmacy schools in Asia, Latin America and Francophone Africa; development of a document with core curriculum and practical recommendations how to review/adapt any existing curriculum; field testing of the document; production of a WHO core curriculum with relevant training materials. This is a project which will require 2-3 years to complete. {#description-regional-workshops-with-heads-of-pharmacy-schools-in-asia-latin-america-and-francophone-africa-development-of-a-document-with-core-curriculum-and-practical-recommendations-how-to-reviewadapt-any-existing-curriculum-field-testing-of-the-document-production-of-a-who-core-curriculum-with-relevant-training-materials.-this-is-a-project-which-will-require-2-3-years-to-complete. .unnumbered}

**Expected Output, Results and Progress Indicators:**

[Outputs]{.underline} include a WHO document with a core pharmacy
curriculum, and key training materials for undergraduate pharmacy
training for developing countries in English, French, Spanish and
Russian. [Indicators]{.underline}: 1999, collecting existing training
materials; developing core curriculum and training materials; 2002,
field testing of materials in at least three pharmacy schools in
developing countries; 2003, finalizing, editing, translating, and
printing of materials in English, French, Spanish and Russian.

**Countries/Regions:** Global.

**Partners:** WHO Collaborating Centre on Research and Training in
Pharmacy Practice, Aberdeen, Scotland; International Pharmacy Federation
(FIP); pharmaceutical professional associations in developed and
developing countries.

**Results to Date:** Two of the WHO/Geneva collaborators involved in the
production of the "Guide to Good Pharmaceutical Practice" attended an
April 2001 meeting in Zimbabwe with the Deans of Schools of Pharmacy
from Tanzania, Ethiopia, Uganda, Kenya, Zimbabwe, and South Africa. One
topic discussed was the introduction of rational drug use into
curricula. The draft manual was nearing completion as of November 2001.
Review of the draft document will begin in 2002.

**Implementing Organization:** WHO/CDS

**Status:** On-going (Funded: FY1999; Expected Completion: FY2002)

**Rationale:** Effective containment of AMR will require the
coordination and collaboration of many different stakeholders who have
different levels of knowledge and understanding of AMR. Simple and more
in-depth information, making reference to different stakeholder groups
and packaged in a visually-attractive, user-friendly format can be a
valuable tool for individual and group learning about resistance and
ways in which it can be contained. Such a tool can also be used as a
basis for advocacy.

**Objective(s):** To develop a multi-media tool to provide a basis for
dissemination of information and advocacy about AMR.

**Description:** Communication with international partners to identify
existing materials; preparation of appropriate new materials;
collaboration with external technical expert to develop video and CD-ROM
and to package toolkit.

**Expected Output, Results and Progress Indicators:**

[Outcomes]{.underline} include a tool for information, education and
advocacy to: (a) rapidly inform non-specialists of key information; and
(b) cover each topic more comprehensively for more specialist
educational uses. [Indicators]{.underline} include: feedback from
interested parties; new needs identified and materials prepared; and
toolkit prepared and assembled.

**Countries/Regions:** Not applicable.

**Partners:** None.

**Results to Date:** Materials related to AMR, including the WHO Global
Strategy and review documents (see Activity 1.1) have been assembled to
produce a CD-ROM as the first version of an AMR Tool Kit. Materials are
organized in three main groups:

1.  [Introduction to the resistance problem]{.underline}

-   About the WHO Global Strategy---1 page summary

-   Key statements from the WHO Global Strategy

-   WHO fact sheet on AMR

-   Questions and answers about AMR

-   Slide set on the magnitude and trends of the AMR problem

    1.  [WHO Global Strategy]{.underline}

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-   Executive summary (in English, French, Russian, and Spanish)

-   WHO Global Strategy (full text in English and Russian)

-   WHO Global Principles for the Containment of Antimicrobial
    Resistance in Animals Intended for Food (in English)

-   Background review documents (in English)

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-   Antibiotic Resistance: Synthesis of Recommendations by Expert Policy
    Groups (Alliance for the Prudent Use of Antibiotics)

-   Antimicrobial Resistance in *Neisseria gonorrheae* (John Tapsall)

-   Antimicrobial Resistance in Shigellosis, Cholera, and
    Campylobacteriosis (David A. Sack, Christine Lyke, Carol McLaughlin,
    and Voravit Suwanvanichkij)

-   Drug Resistance in Malaria (Peter B. Bloland)

-   Infection Control Programmes to Contain Antimicrobial Resistance
    (Lindsay E. Nicolle)

-   Interventions and Strategies to Improve the Use of Antimicrobials in
    Developing Countries (Drug Management Program)

-   Resistant Pneumococcal Infections (Stephanie J. Schrag, Bernard
    Beall, and Scott Dowell)

-   (Executive Summary) Interventions against Antimicrobial Resistance:
    A Review of the Literature and Exploration of Modeling and
    Cost-Effectiveness (Global Forum for Health Research: Richard D.
    Smith, Joanna Coast, Paula Wilton, and Anne-Marie Karcher)

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-   WHO documents cited as reference in the WHO Global Strategy

-   Slide presentation of the WHO Global Strategy

    1.  [Tools]{.underline}

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-   Software

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-   WHONET 5.1 (multilingual version) software for the management of
    microbiology laboratory data and analysis of antimicrobial
    susceptibility test results. WHONET 5 user's manual in English and
    Russian.

-   SDRTB3 software designed to assist collection and analysis of data
    on drug resistance in tuberculosis. User's manual in English.

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-   Database---brief summary of the objectives and weblink to
    Antimicrobial Resistance Information Bank (AR InfoBank )

-   Surveillance standards

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-   Assessment of Therapeutic Efficacy of Antimalarial Drugs for
    Uncomplicated Falciparum Malaria in Areas with Intense Transmission
    (in English)

-   Guidelines for Surveillance of Drug Resistance in Tuberculosis (in
    English)

-   Surveillance Standards for Antimicrobial Resistance (draft)

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-   Assessment tools

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-   Antimicrobial Resistance Surveillance: Assessment Tool for National
    Networks (draft)

-   Protocol for the Assessment of National Communicable Disease
    Surveillance and Response Systems: Guidelines for Assessment Teams

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-   Laboratory manual for the detection of AMR among bacterial pathogens
    of public health concern in the developing world (draft)

It is planned to produce an updated version of this CD-ROM that would
include: final versions of the documents presently in draft form; a
windows version of the SDR TB software (presently being tested); and a
revised version of the WHO Report of Infectious Diseases 2000,
Overcoming Antimicrobial Resistance.

Implementing Organization: CDC/NCID

Status: On-going (Funded: FY1999; Expected Completion: FY2002)

**Rationale:** Mass chemoprophylaxis with azithromycin is the
cornerstone of a global initiative to eliminate trachoma, a leading form
of preventable blindness. Recent evidence suggests that blindness caused
by the bacteria *Chlamydia trachomatis* can be prevented by a simple
regimen of azithromycin along with improved hygiene. A number of African
countries with high trachoma burden are planning to implement trachoma
control programs in collaboration with donor agencies (*e.g.* the
International Trachoma Initiative, the Carter Center, the Proctor
Foundation of UCSF, Helen Keller International) and industry partners
(Pfizer, Inc.). Control programs consist of repeated mass
chemoprophylaxis of entire villages \[or sub-populations of villages, as
with the Proctor Foundation's approach of administering prophylaxis to
all children under ten, and also treating the families of infected
children\], along with educational campaigns about hygiene, surgery and
environmental changes.

In communities with limited health care access, repeated mass exposure
to macrolide antibiotics may reduce the incidence of bacterial diseases
in addition to trachoma, such as group A streptococcal pharyngitis, skin
infections and acute rheumatic fever. However, antibiotic prophylaxis
may also have the adverse effect of increasing AMR in both *C.
trachomatis* and other bacterial pathogens. Measuring antibiotic
resistance in *C. trachomatis* is technically challenging; however,
there is suggestive evidence that some strains have reduced sensitivity
to macrolide antibiotics. For the case of other bacterial pathogens, a
study in an Aboriginal Australian population found that azithromycin
treatment to control trachoma resulted in an increased prevalence of
macrolide-resistant *Streptococcus pneumoniae* that persisted for months
following treatment. *S. pneumoniae* is one of the leading bacterial
causes of acute respiratory infections in children in the developing
world. Although macrolide antibiotics are not a standard treatment for
respiratory illness in developing countries, resistance to macrolide
antibiotics in *S. pneumoniae* is often associated with resistance to
other antimicrobial classes commonly used in these settings, such as
sulfa and penicillin. This raises the concern that mass treatment
programs may reduce the burden of trachoma but increase the burden of
AMR in common respiratory tract pathogens.

Objective(s):

1)  Determine the impact of mass azithromycin prophylaxis on the
    prevalence of antimicrobial resistant pneumococcal carriage and
    invasive disease

2)  Institute surveillance for potential benefits of community
    prophylaxis by monitoring the incidence of skin infections and acute
    respiratory infections.

**Description:** Three geographically separate regions were selected for
inclusion in the study on the basis of their exposure to azithromycin
prophylaxis: one had received no past treatment at baseline, one had
received treatment six months prior, and one had received two
treatments, one each six and eighteen months prior to baseline; only the
region with no prior exposure received azithromycin in the course of
this study. Each child 6 months -- 10 years of age had the nasopharynx
swabbed at baseline (day 0) before they received azithromycin to
determine the baseline carriage of antimicrobial resistant *S.
pneumoniae*; the same protocol was followed in regions not receiving the
azithromycin. A follow-up swab survey on study participants was
conducted ten days later and then again at a six months following
baseline. Additionally, interviews were conducted to assess the rates of
acute respiratory infections (ARI) and diarrhea, and photographs taken
for a masked evaluation of the prevalence of impetigo. Oropharyngeal
(OP) swabs were also collected to measure carriage of group A
streptococci (GAS).

A possible add-on study in the follow-up period would involve examining
the susceptibility patterns of *C. trachomatis* by collecting eye swabs.
It is not certain we will be able to include this component of the study
due to logistical concerns, such as necessity for dry ice / liquid
nitrogen, as well as the challenge of performing susceptibility tests in
*C. trachomatis*. To date (2001), we have not been able to perform this
component of the investigation.

**Expected Outputs, Results and Progress Indicators:** Results of this
study will help clarify whether mass antibiotic treatment leads to
increased AMR in the common bacterial respiratory pathogen *S.
pneumoniae*. In addition to this central question, the study will also
determine whether mass antibiotic therapy acts to reduce the incidence
of health problems unrelated to trachoma, such as impetigo, diarrhea and
ARI. This will help countries with endemic trachoma assess the costs and
benefits of initiating trachoma control programs, as well as impact
future decisions regarding the overall risks and benefits of mass
treatment with a broad-spectrum antibiotic. We hope to contribute to a
general framework for evaluating the impact of mass treatment programs
that can be used when future antibiotic prophylaxis interventions are
proposed.

Countries/Regions: Nepal

Partners: Geta Eye Hospital, Nepal; Proctor Foundation (University of
California, San Francisco); Nepalese Society for Comprehensive Eye Care
(NNJS).

Results to Date:

1)  No azithromycin-resistant pneumococci were isolated from any of the
    345 children in the currently-treated (no prior exposure) or
    single-previous-exposure groups at any time point, while
    azithromycin-resistance was found in 4.3% of those with 2 previous
    exposures (p\<0.001, vs. the other 2 groups).

2)  Azithromycin treatment was significantly associated with a decrease
    in the prevalence of impetigo and diarrhea 10 days after treatment,
    though this effect was not sustained at 180 days.

3)  The absence of macrolide-resistant pneumococci after one mass
    treatment with azithromycin in Nepal is encouraging. We found
    short-term benefits in addition to the known effectiveness of
    trachoma control.

4)  The findings of azithromycin-resistance after 2 mass treatments
    suggest the need for resistance monitoring when multiple rounds of
    antimicrobial are given.

5)  A manuscript summarizing findings has been submitted to [The
    Lancet]{.underline} (*draft enclosed*).

6)  Findings were presented at a WHO-sponsored international workshop
    for trachoma program implementers and the International Trachoma
    Initiative. \[Fry AM, Jha HC, Chaudary JPS, Elliott J, Hyde T,
    Pohkorel BK, Dowell, S: "Preliminary findings of a study to
    determine the secondary effects of mass treatment with azithromycin
    for the elimination of blindness due to trachoma." WHO Alliance for
    the Global Elimination of Trachoma. December 5-7, 2000: Geneva,
    Switzerland.\]

7)  Mass azithromycin prophylaxis is proceeding in trachoma-endemic
    regions in Asia and Africa; results from this project have helped
    evaluation plans of the agencies and community health professionals
    involved.

Implementing Organization: CDC/NCID

Status: On-going (Funded: FY1998; Expected Completion: FY2002)

Rationale: Within developing countries, surveillance for AMR will
require that hospital or reference laboratories can appropriately
isolate, identify and test the susceptibility of common community
acquired pathogens. There is currently no single, technically
appropriate source that includes this information.

Objective(s):

1)  Integrate, update and supplement existing pathogen and
    syndrome-specific manuals to include information on isolation,
    identification and susceptibility testing for *Haemophilus
    influenzae*, *Neisseria meningitidis*, *Streptococcus pneumoniae*,
    *Neisseria gonorrhoeae*, *Salmonella* typhi, *Shigella dysenteriae*
    and *Vibrio cholerae*.

2)  Field test, assess the appropriateness of and modify the newly
    developed laboratory manual.

Description: Laboratory manuals dealing with isolation, identification
and/or susceptibility testing of some of the pathogens listed above have
been developed by CDC in conjunction with the World Health Organization
(WHO), but the manuals have published separately and are not all
currently available or up to date. In addition, susceptibility testing
methods are not included in all the manuals and the methods included
until now have not addressed the appropriate use of antimicrobial
gradient strips for rapid and accurate MIC testing. Under this project,
CDC microbiologists have worked to develop new chapters and made
necessary revisions and additions to pre-existing manuals, and this has
all been integrated into a single manual with a common format for each
of the pathogens. After assessing the resources that a laboratory
implementing the standardized procedures enumerated in the manual would
require, it was determined that the appropriate target audience was
reference laboratories.

**Expected Outputs**, **Results and Progress Indicators:** An integrated
laboratory manual appropriate for developing country settings.

Countries/Regions: Global

Partners: WHO, PAHO.

Results to Date:

1)  The newly developed manual was field tested in one developing
    country setting with the laboratory capacity for but without a
    current comprehensive system of isolation, identification and
    susceptibility testing of common pathogens of public health concern.

2)  Following a 'wet workshop' in Zimbabwe, modifications were made to
    the format and content of the draft document. Since that time,
    microbiologists working in Ghana, Bangladesh and South Africa have
    reviewed the document to gauge the readability and practicality of
    the format.

3)  The draft document has undergone final review by technical experts
    in several countries as well as by WHO.

4)  The current document will be included on CD-ROM with other World
    Health Organization AMR surveillance tools in early FY2002; WHO will
    be responsible for its distribution.

5)  The final version of the first edition of the "Manual" will be
    available for translation, production and distribution in FY2002.

6)  The expected output is an integrated laboratory manual appropriate
    for use in regions with limited resources, available in English,
    French, and Spanish.

7)  The "Manual" is to be incorporated as a key training tool for
    developing country laboratory capacity-building in the new WHO
    Laboratory Training Facility in Lyon, France.

**Implementing Organization:** JHU/FHACS

**Status:** On-going (Funded: FY1998; Expected Completion: FY2002)

**Rationale:** Antimicrobial resistance in disease causing bacteria has
increased throughout the world in recent years. Although standard
laboratory methods for performing antimicrobial susceptibility on
bacterial isolates have been developed, no standard sampling methods
have been developed by national or international agencies. Sampling
methods for determining the incidence and prevalence of AMR have varied
considerably in studies published to date, making comparisons between
populations and geographic areas difficult. Antimicrobial susceptibility
testing is technically difficult, expensive, and not generally available
in most developing country settings. It is not necessary or practical to
set up expensive laboratory facilities and test every bacterial isolate
in order to estimate the incidence of resistant bacteria in every
population. A simplified sampling method would allow valuable data to be
collected with the least expenditure of resources.

A similar situation existed with regard to assessment of immunization
coverage rates before the standardized EPI cluster sampling method was
developed and implemented. Public health officials had great difficulty
in assessing and comparing the effectiveness of programs in different
populations. EPI cluster sampling has proven to be an important tool
providing standardized assessment for evaluation of immunization
coverage in developing countries throughout the world. A similar
standardized methodology would be invaluable for comparison of AMR
patterns and trends in different population as the epidemic of AMR
increases and as interventions are developed to try to control this
problem.

**Objective(s):** To develop a standardized sampling method for
assessing AMR in defined populations.

**Description:** We will evaluate several industrial sampling methods as
candidates for a standardized sampling method to determine the
prevalence of antimicrobial resistant *Haemophilus influenzae* and
*Streptococcus pneumoniae* in different populations including
asymptomatic children in the general community, outpatients and
hospitalized patients. We will evaluate nasopharyngeal cultures in all
populations and evaluate isolates from normally sterile sites (blood,
cerebrospinal fluid, pleural and joint fluid from sick outpatients and
hospitalized patients.

Data from laboratory records from studies that have already been
completed will be reviewed to develop models that can be used to compare
different sampling industrial sampling methods.

The simplest approach would be a plan with a fixed *n* determined on the
basis of the magnitude of change that is to be detected and the risk of
failing to detect the change. If the sample is to be taken from several
populations (hospitals), a somewhat more complex design would be needed
as an adaptation of the EPI approach to account for the "design" effect.

Depending upon the specific situation, four industrial sampling designs
might be considered. The first is a double sampling method that starts
with a small n to determine whether conditions are clearly so "good" or
"bad" that a decision can be made on the basis of limited evidence. If
conditions are in the "gray" area, a second sample is taken, and the
decision is based upon the aggregate information.

Sequential sampling represents a further refinement of this technique.
In that case certain formulas are applied to establish bounds of
experience. Every child would be tested and results plotted in
chronological order, until the chart takes you above or below the two
boundary lines. At that point it is possible to stop sampling and make a
definitive judgment. Obviously, this needs to be explained by means of a
diagram. The point, however, is that you continue sampling only until
the precise moment when you have enough information to draw appropriate
conclusions.

Another method calls for the sampling of every *kth* product (child)
until trouble is found. Thereafter, every child would be tested until
the trouble is corrected. I am not sure that your situation is such that
"trouble" arises and is corrected, so that you can return to "normal"
surveillance, but some modification of this approach might be relevant.

Finally, there is the normal-tightened-reduced sampling procedure. This
begins with a designated "normal" sample size and criteria for decision
making. If conditions are found to be "suspect" according to
predetermined rules, a more stringent sample design is introduced. In
contrast, if a predetermined period of time without difficulty elapses,
a reduced, less costly sampling procedure is triggered.

In the second year of the project, sampling methodologies will be field
tested in several developing country settings. Optimal culture methods
will be used including selective media if appropriate in the surveys.

**Expected Outputs, Results, and Progress Indicators:** This project
will develop a standardized sampling methodology that can be utilized
for assessment of AMR in different populations. We will develop a first
draft of a manual that can be field tested in other populations. As with
other field methods, we anticipate the need for careful validation in
multiple settings before the methodology is finalized.

**Countries/Regions:** Data from sentinel surveillance performed in
Guatemala and on site studies will be conducted in year 2.

**Partners:** We will set up collaborate with CDC investigators, the
World Health Organization and other organizations addressing this
problem in countries throughout the world. CDC has developed
standardized methodologies for laboratory testing that will be used in
all studies. We will seek their assistance in applying the sampling
methods to data sets that they have developed and coordinate our
activities with the global efforts.

The study will be conducted at the three major referral hospitals in
Guatemala City, Guatemala: Hospital General San Juan de Dios (HGSJD),
Hospital Roosevelt (HR) and the General Hospital of the Institute of
Guatemalan Social Security (IGSS). These three hospitals provide care to
over 90% of all children with infectious disease problems in the city.

**Results to Date:** The study is underway and data collection has been
completed in Las Pampas and is nearing completion in Iquitos.

Implementing Organization: CDC/NCID

**Status:** Completed (Funded: FY1998; Completed: FY2000)

Rationale: CDC and WHO have developed a manual for surveillance of
respiratory tract pathogens that recommends testing susceptibilities of
*S. pneumoniae* isolates obtained from nasopharyngeal (NP) swabs of
children with pneumonia. Since these recommendations were developed, NP
surveillance studies have been conducted in at least eight countries in
Africa and Asia. Although each study used NP isolates for surveillance,
they differed substantially in who was enrolled (some studies included
children with upper respiratory infections or no illness), and in the
duration of surveillance (ranging from two weeks to a several month
"pneumonia season"). The impact of variations in surveillance methods on
the results obtained by NP surveillance is unclear. Moreover,
reaffirming the usefulness of this approach relative to other
surveillance methods (*e.g.* using isolates from normally sterile sites
like blood or CSF) would help countries and international organizations
develop appropriate surveillance systems.

Objective(s):

1)  Develop agreement among investigators and other experts regarding
    the optimal approaches to surveillance for resistance among
    respiratory tract pathogens using NP isolates and the usefulness of
    NP swab surveillance relative to other methodologies.

2)  Disseminate findings of review with international partners.

Description: Meetings with investigators from sites where surveillance
has been conducted using NP isolates and with other experts were held in
order to summarize results from investigations with data both published
and unpublished. Furthermore, the meetings allowed for assessment of the
impact of different approaches to study enrollment and varying durations
of surveillance on the results of the studies. Finally, the team of
investigators evaluated the impact of variations in surveillance methods
on the results obtained by NP surveillance in order to synthesize
optimal surveillance methodology.

**Expected Output, Results, and Progress Indicators:** Results of the
surveillance data analysis and the deliberations and consensus of the
group will be presented in a report. In addition, the recommendations
for epidemiological methods of surveillance included in the CDC/WHO
manual will be revised to reflect the consensus optimal methodology.

Countries/Regions: Global.

Partners: WHO; Investigators who have conducted NP swab surveillance for
resistant respiratory tract pathogens; experts who would be influential
in gaining global acceptance of such a system.

Results to Date:

1)  Findings were presented at an international meeting and used to
    inform and guide NP-swab specimen sampling approaches for public
    health investigators around the globe.

2)  Results of the surveillance data analysis and the deliberations and
    recommendations of the group have been compiled as a manuscript and
    submitted for publication..

**Implementing Organization:** WHO/CDS

**Status:** Discontinued (Funded: FY1998)

**Rationale:** At present, the detection of AMR requires the collection
of specimens from patients, isolation of the pathogen and determination
of its antimicrobial susceptibility in the laboratory (*in vitro*). Thus
detection of resistance is severely limited by availability of necessary
resources and technical skills. In addition, the relationship between
resistance detected in vitro and clinical outcome has been questioned
for some infections, notably those of the respiratory tract. Therefore
alternative cost-effective methods to detect resistance in the clinic
setting are needed. One approach to this, which has been applied in the
field to detect resistance to antimalarials, is through analysis of
treatment failures in a cohort treated according to prevailing treatment
guidelines.

**Objective(s):** To establish, as a first model, *in vivo* method to
detect AMR in *Neisseria gonorrhoeae*, the causative agent of
gonorrhoea. This infection is chosen as a model because resistance
detected in vitro appears to correlate well with clinical failure.

**Description:** Establishment (in collaboration with the WHO Office of
HIV/AIDS and Sexually Transmitted Diseases, AD) of study design, based
on lot quality assurance, to detect gonorrhoea resistant to
antimicrobial treatment. Critical review of study design with experts in
the WHO Gonococcal Antimicrobial Surveillance Programme (GASP). Field
test in parallel with laboratory tests to detect resistance in vitro.
Laboratory tests will be carried out in one or more of the laboratories
participating in GASP and will provide the opportunity for strengthening
techniques in these laboratories.

**Expected Outcomes, Results and Progress Indicators:** In-vivo method
for detection of resistance in gonorrhoea, evaluated in the field.

[Progress indicators in 1998]{.underline}: Establish, in collaboration
with WHO/AD and GASP coordinators, a study design and costing; Identify
a study site with suitable field and laboratory facilities; Identify a
study team.

**Countries/Region(s):** The field study will be carried out in southern
Africa in partnership with the South African Institute for Medical
Research, Johannesburg, South Africa.

**Partners:** WHO/CDS; Gonococcal Antimicrobial Surveillance Programme
(GASP) Collaborating Centres; South African Institute for Medical
Research, Johannesburg, South Africa.

**Results to Date:** Collaboration with the local partner has so far not
occurred. Activity discontinued.

**Implementing Organization:** WHO/CAH

**Status:** On-going (Funded: FY1998; Expected Completion: FY2002)

**Rationale:** Surveillance of AMR has been of little practical use to
monitor the clinical efficacy of oral cotrimoxazole as the first line of
treatment for children with WHO defined pneumonia. Data show that even
in the presence of high rate of in-vitro AMR to cotrimoxazole, this
antimicrobial is clinically effective. On the other hand, recent reports
of increasing penicillin resistance have raised concerns about its
clinical efficacy. At present there is very little data indicating that
penicillin or cotrimoxazole resistance leads to clinical failure in
pneumonia. At the same time there is limited information available about
the effect of prior use of antimicrobial on clinical outcome and AMR.

**Objective(s):**

1\. To study whether trends in the number of clinical failures in
non-severe and severe pneumonia can be used to monitor the prevalence of
AMR.

2\. To study the effect of prior antimicrobial use on clinical outcome
of WHO defined pneumonia and AMR.

**Description:**

1\. A study, conducted in the community as well as in the hospital, will
determine the relationship between treatment failures assessed
clinically and prevalence of AMR to the first line antimicrobial
determined on nasopharyngeal swab isolates of *S. pneumoniae* and *H.
influenzae*.

2\. A detailed history of prior antimicrobial use will be obtained at
the beginning of therapy with special reference to the antimicrobial
recommended by WHO ARI standard case management guidelines e.g.
cotrimoxazole, amoxicillin, chloramphenicol etc.

**Expected Outcomes, Results and Progress Indicators:**

1\. Development of a tool to monitor trends in AMR by monitoring
clinical efficacy of first line antibiotics recommended for the
management of pneumonia.

2\. Better understanding on the relationship between prior antimicrobial
use, clinical efficacy and AMR.

[Progress indicators]{.underline}: development of the research protocol;
initiation of data collection.

**Country(s)/Regions:** Pakistan (Aga Khan Health Services, Chitral)

**Partners:** Not applicable.

**Results to Date:** The study was initiated in October 2000 in 14
first-level health facilities. Data collection was completed in 2001 and
results were presented at the IUATLD meeting (Paris, November 1-4,
2001)---see abstract below presented by Dr. Q. Noorani (Aga Khan Health
Services, Chitral).

> "A monitoring tool was developed to manage non-severe pneumonia using
> WHO guidelines and to communicate with parents. It included data
> collection at baseline and at follow up visits, instructions for the
> health workers, and advice for parents regarding management of
> children with non-severe pneumonia. Children aged 2-59 months with
> non-severe pneumonia were recruited in the 14 community-based health
> facilities. Each child was followed up two and five days after
> enrollment. Children not brought for follow up were visited at home.
> The primary outcome was treatment failure, which included change of
> antibiotic therapy, loss to follow up, and deaths. Of 949 children
> enrolled, 336 (35.4%) were less than one year old, and 607 (64.0%)
> were male. 125 (13.2%) children failed therapy on cotrimoxazole. 94
> (9.9%) children were followed up at home. No death was recorded. The
> treatment failure was more likely in children who had wheeze at first
> examination (OR 1.8 95% CI 1.23-2.65 p=0.003) or children below 2
> years age (OR 1.20 95% CI 1.01-1.30 p=0.046). The results of this
> study show that the monitoring tool is quite useful for health workers
> to document and monitor clinical outcome of pneumonia patients. It is
> also a useful tool to communicate with parents."

The results from the study will be published soon.

**Implementing Organization:** WHO/CDS

**Status:** On-going (Funded: FY1999; Expected Completion: FY2002)

**Rationale:** The data that exist on the magnitude and trends of AMR
are seriously lacking in quantity, quality and comparability.
Furthermore there are very few studies showing trends in resistance over
time, or linking in-vitro resistance to antimicrobial use or clinical
outcome. For some infectious diseases (such as tuberculosis) progress
has been made in establishing internationally-accepted methods for data
gathering. For other diseases there is still much to do in the area of
standardisation of methods. Furthermore external quality assurance is
essential to the collection of valid data.

The combination of these activities for several different diseases under
one project will facilitate the synergy between projects and the sharing
of learning about different resistance challenges.

**Objective(s):**

1.  To measure the magnitude and monitor trends in resistance in
    tuberculosis (including MDR-TB), malaria, and other priority
    bacterial infections;

2.  To develop national capacities, provide technical assistance for
    resistance monitoring, and maintain international networks of
    reference laboratories for external quality control;

3.  To disseminate information on magnitude and trends of AMR.

**Description:**

1.  Expand and continue to implement projects for monitoring MDR-TB in
    high priority countries;

2.  Prepare and evaluate DRS protocols following standardised
    methodological guidelines. This will include technical advice, site
    visits and quality assessment;

3.  Organise a meeting to review the data collected through monitoring
    of drug-resistant malaria by determining therapeutic efficacy of
    anti-malarial drugs;

4.  Strengthen monitoring of gonococcal resistance and improve the
    epidemiological basis of the data collection;

5.  Provide guidelines and training to enable the building/strengthening
    of networks to monitor other priority bacterial infections;

6.  Maintain and expand as required networks of reference laboratories
    for quality assurance of antimicrobial susceptibility testing (incl.
    MDR-TB and DR-malaria)

**Expected Output, Results and Progress Indicators:**

1.  Accurate and representative resistance data and trends in MDR-TB
    from 15-20 new projects validated by reference laboratories and
    sound epidemiological methods;

2.  Report of meeting and recommendations to countries for monitoring
    drug resistant malaria (pending outcome of clinical trials of
    combination therapy);

3.  Gathering of accurate and representative resistance data on drug
    resistance in malaria initiated and first report complete;

4.  Networks for AMR monitoring in other bacterial infections
    strengthened in 10 countries;

5.  Data sharing on AMR optimized;

6.  Reports from external quality assurance schemes.

**Countries/Regions:** To be determined.

**Partners:** These activities will be carried out in close
collaboration with all other relevant groups in WHO/CDS cluster,
especially Dept. of Control and Prevention, Dept. of Research and
Development (TDR) and Roll Back Malaria, and with the STI/UNAIDS Working
Group, with WHO Regional Offices and with the IUATLD and other external
partners in public health and academic institutions around the world.

**Results to Date:** The information on AMR surveillance networks and
resistance data (published by these networks) collected through the
Antimicrobial Resistance Information Bank
(<http://oms2.b3e.jussieu.fr/arinfobank/>) was analyzed and an
evaluation report will soon be submitted for publication. WHO was able
to identify and collect information on 74 on-going surveillance networks
worldwide with a total of 90 countries participating in at least one
surveillance network. The geographical distribution of these networks
shows important gaps in coverage. (Additional information on networks in
the Western Pacific Region is expected, as a result of an on-going
assessment of this activity by the WHO Office in that Region.) The
amount of resistance data collected is small and its assembly proved
very labor intensive because of the differing formats of the different
data sets submitted.

There are major gaps in both geographic and bacterial species coverage.
Even with the relatively small amount of data collected, the degree of
diversity in the systems is striking. There would seem a clear need for
the development and adoption of an international standard, and
principally national authorities should benefit from standardizing
methods within their country to provide comparable data from different
sources. A weakness common to almost all resistance surveillance
activities reviewed is the lack of a sound epidemiological basis. For
data to be used in decision making at a national policy level they have
to be of epidemiological significance. It is therefore proposed that
resistance surveillance should be conducted according to standards such
as those drafted in "WHO Surveillance Standards for Antimicrobial
Resistance."

WHO is presently studying the possibility of transferring part of the
information collected through ARInfoBank into the Global Atlas of
Infectious Diseases (developed by WHO) and restricting resistance data
collection to epidemiologically-significant information as is being
attempted by the European Antimicrobial Resistance Surveillance System.
WHO has a memorandum of understanding with the European Antimicrobial
Resistance Surveillance System for data sharing and would like to
negotiate other similar data sharing agreements in the future.

**Implementing Organization:** WHO/HTP/EDM

**Status:** On-going (Funded: FY1998; Expected Completion: FY2001)

**Rationale:** It is generally believed that over prescribing or
irrational prescribing of antimicrobials, is a major factor in the
development of resistance to antimicrobials.

**Objective(s):** To produce a manual of treatment guidelines for
prescribers on the rational use of antimicrobials to complement the WHO
Model List of Essential Drugs. These guidelines will contain
independent, scientific, non-biased and practical information. It is the
intention to provide up-to-date source material for adaptation by
national authorities, particularly in developing countries, that wish to
develop national drug formularies, treatment guidelines for
antimicrobials, drug compendia and similar material.

**Description:** The first draft of this manual is almost completed. It
now needs to be reviewed and edited by an infectious disease specialist
before being subjected to a broad consultative procedure including
review by the relevant technical divisions within WHO, national Drug
Regulatory Authorities, scientists, relevant non-governmental
organizations including the International Society of Chemotherapy,
International Union of Pharmacology and the International Federation of
Pharmaceutical Manufacturers Associations. Relevant parts of the manual
on establishing a national programme on promotion of rational drug use
and antimicrobials in particular (see activity 4.3: \"Guidelines for
Establishing a National Programme\....\") will be included and frequent
cross referencing made.

Dissemination of the manual to all national regulatory authorities and
the relevant non-governmental organizations is routine. Additional
dissemination will be undertaken as appropriate by HTP/EDM and CDS.

**Expected Outputs, Results, and Progress Indicators:** The publication
of a manual of WHO Model Prescribing Information \"Drugs used in
Bacterial Infections\". This will be in two phases: (1) Development and
review of draft material; and (2) A consensus consultation on the draft
will be held. In year 1, a consultation would be held to finalize the
draft text on drugs used in bacterial infections. The text will be
edited and published by WHO in 2001.

**Country/Regions:** The six Regional Offices of WHO will be involved in
the consultative procedure.

**Partners/Collaborating Institutions:** All relevant technical
divisions within WHO, National Drug Regulatory Authorities,
non-governmental organizations including the International Society of
Chemotherapy, International Society of Infectious Diseases (ISID),
International Union of Pharmacology and the International Federation of
Pharmaceutical Manufacturers Associations and relevant Professional
Associations will be involved in both the review and the consensus
meeting.

**Results to Date:** "WHO Model Prescribing Information: Drugs Used in
Bacterial Infections" (ISBN 92 4 140107 9) was published in September
2001. It is now being translated into French and Spanish and should be
completed in 2002.

**Implementing Organization:** WHO/HTP/EDM

**Status:** On-going (Funded: FY1998; Expected Completion: FY2001)

**Rationale:** It is recognized that there are practices for containment
of resistance to antimicrobials, supported by scientific evidence, which
in order to be implemented efficiently at national level need to be
transmitted to policy makers and health administrators.

**Objective(s):** To develop a briefing document for policy makers and
health administrators. This will be a policy and advocacy document
detailing the roles of Ministries of Health, training institutions,
health institutions, professional associations, industry and consumer
organizations in the task of containing AMR.

**Description:** A skeleton outline has been prepared. This will be
developed in consultation with all relevant technical divisions within
WHO, national drug regulatory authorities, scientists, relevant
non-governmental organizations, including the International Society of
Chemotherapy, International Union of Pharmacology, the International
Federation of Pharmaceutical Manufacturers Associations and the
Consumers Union, and relevant professional associations.

Dissemination of the manual to all national regulatory authorities and
the relevant non-governmental organizations is routine. Additional
dissemination will be undertaken as appropriate by HTP/EDM and CDS:

**Expected Outputs, Results, and Progress Indicators:** Preparation of a
briefing document (with consultation at the draft stage) containing
consolidated information on resistance mechanisms, health impact, and
practical action for national policy makers and in-country healthcare
education programs. The document will be used in the \"WHO Country
Intervention Packages\" (see activity 5.1: \"Integrated Country
Programmes for Containment of AMR\").

**Country/Regions:** The six Regional Offices of WHO will be involved in
the consultative procedure and a meeting to discuss the draft document.

**Partners/Collaborating Institutions:** Partners include all relevant
technical divisions within WHO; National Drug Regulatory Authorities;
non-governmental organizations including the International Society of
Chemotherapy; International Society of Infectious Diseases (ISID);
International Union of Pharmacology; the International Federation of
Pharmaceutical Manufacturers Associations; and the Consumers Union. The
relevant Professional Associations will be involved in both the review
and the consensus meeting.

**Results to Date:** (see Activity 5.1)

**Implementing Organization:** WHO/HTP/EDM

**Status:** On-going (Funded: FY1998; Expected Completion: FY2001)

**Rationale:** Irrational use of antimicrobials is considered a major
contributing factor in the development of AMR and one third of
prescriptions in developing countries are for antimicrobials. The
evidence on the efficacy of various types of interventions to promote
rational drug use is incomplete and not easily accessible. It is very
necessary for governments to have a briefing document from WHO with
practical advice on how to design and implement a cost-effective
programme to promote rational drug use, particularly the rational use of
antibiotics.

**Objective(s):** To make existing knowledge on efficacious
interventions accessible to decision makers through provision of
guidelines to design and implement cost-effective programmes to promote
rational drugs use, with emphasis on the containment of AMR

**Description:** Commission an analysis of current evidence based
interventions available to promote rational use of drugs (special
emphasis on cost effectiveness and antimicrobials). The draft report of
this analysis will be used as the basis for a review by a global panel
of experts on implementation of such interventions at national level.
The draft document produced will be field-tested before finalization.
Activities will be undertaken with INRUD and the School of Public Health
in Boston, and other experts as needed. Relevant parts of the national
guidelines on containing AMR (see activity 4.1: \"Model Prescribing
Information \-- Drugs Used in Bacterial Infections\") will be included
in this manual and frequent cross referencing made. The final document
would be complementary to that proposed in activity 4.1. The final
version of the manual would be disseminated to ministries of health,
national regulatory authorities, essential drug programmes, researchers
and trainers in rational drug use as well as appropriate relevant
non-governmental organizations by HTP/EDM and CDS.

**Expected Outputs, Results, and Progress Indicators:** A WHO manual on
how to establish and implement a national program to promote rational
drug use, within the scope of a national drug policy, with a special
chapter on promoting the rational use of antibiotics and containing AMR.

[Year 1:]{.underline} Current funding would allow: commissioning of an
analysis of current evidence based interventions available to promote
rational use of drugs (special emphasis on antimicrobials); production
of a draft report on the analysis; review of report by global panel of
experts on implementation of interventions at national level;

[Year 2:]{.underline} Further funding would be required for field
testing of the draft document at country level; finalization of document
to become a WHO manual (see activity 4.2: \"Guidelines for National
Policy Makers and Health Administrators on the Containment of AMR\");
publication dissemination as for the activities 2.4 (\"Measuring,
Understanding and Changing Irrational Drug Use\") and 4.2.

**Country/Regions:** WHO/HTP/EDM in Geneva

**Partners/Collaborating Institutions:** International Network for the
Rational Use of Drugs (INRUD); Prof. Richard Laing of the School of
Public Health of Boston University; WHO/CDS.

**Results to Date:** (see Activities 4.4 and 5.1)

**Implementing Organization:** WHO/HTP/EDM; WHO/CDS

**Status:** On-going (Funded: FY1998; Expected Completion: FY2002/2003)

**Rationale:** There is a great need to promote rational drug use (RDU),
and especially rational antimicrobial use, in hospitals because they
represent a large proportion of the drug use in most countries and
because they set an example through their teaching functions. Likewise,
it is important to emphasise the need for high standards of infection
control to prevent spread of resistant strains in the hospital
environment, from patient to patient, or from patient to health care
worker and vice versa. In developed countries the organizational
structures that promote rational drug use and infection control
procedures are Hospital Drugs and Therapeutics Committees (HDTCs) and
Infection Control Committees (ICCs). These are rarely operational in
developing countries. Thus guidelines that combine the formation and
strengthening of these committee structures and the provision of
guidance for RDU and infection control, with particular reference to
containing AMR, should be beneficial.

**Objective(s):** To develop practical guidelines to assist hospital
staff to effect a reduction in the emergence and spread of AMR at
hospital level.

**Description:**

1\. Review of available guidelines on establishment and function of
HDTCs and ICCs;

2\. Modification of guidelines if required for developing country
conditions;

3\. Development of draft text on RDU (see Review, AMR Component 1) and
infection control to be incorporated into guidelines \[note - these
guidelines are incorporated into a manual on drugs and therapeutics
committees that is written and now being edited (2001). The manual is
being made consistent with an international training course that has
been developed by MSH\];

4\. Pilot in at least two developing countries and evaluate changes in
actual prescribing of antimicrobials;

5\. Review text with global consultation;

6\. Issue document and disseminate through Ministries of Health and
university teaching hospitals, essential drug projects, RUD projects,
and appropriate non-governmental agencies.

**Expected Outputs, Results, and Progress Indicators:** This is a
multi-year project whose final outcome should be: establishment and
greater understanding of the value of HDTCs and ICCs; improved
antimicrobial prescribing in hospitals where HDTCs are operative;
improved infection control where ICCs are operative.

[Progress indicators]{.underline} include: (1998) vailable guidelines on
establishment and function of HDTCs and ICCs reviewed and modified as
necessary; review (see AMR component 1) completed; (2001)draft text
prepared for RDU (based on Review) and infection control sections to be
incorporated into guidelines; completed draft text prepared for pilot
study; (2002) pilot countries identified and field testing initiated.

**Country/Regions:** Zimbabwe.

**Partners/Collaborating Institutions:** WHO Action Programme on
Essential Drugs; AIHA; School of Public Health, Boston University;
International Federation of Infection Control (IFIC); public sector;
church-related and private hospitals in the pilot countries.

**Results to Date:** A WHO consultant facilitated a meeting in Zimbabwe
in early 2000 with Drug and Therapeutic Committee (DTC) members of eight
hospitals and a draft manual on "Establishing an Effective Drug and
Therapeutics Committee: the Zimbabwe Experience" was finalized. Each of
the hospitals also made a final presentation of their drug utilization
review projects, six of which related to antimicrobials. The consultant
concluded that the DTCs can be powerful channels for conducting
interventions to promote more rational use of drugs, including
antimicrobials, but that they only worked if there was sufficient
continuity of staff within a hospital. Thus, it was found that such
committees worked well in the mission hospitals, but not the government
ones, where continuity of staff and motivation were lower.

All eight hospitals conducted a survey of drug-use indicators for
inpatients. In addition, individual hospitals conducted the following
projects related to antimicrobials:

-   Evaluation of a single dose regimen (1 gm amoxycillin) versus a 5-7
    day course of amoxycillin prophylaxis in cesarean section. The
    intervention was well implemented and there was no increase in
    infection rate or length of stay in the hospital, but there was a
    decrease in cost.

-   Evaluation of intramuscular versus intravenous quinine for cerebral
    malaria. The study showed no difference in outcome.

-   Reduction of inappropriate amoxycillin use through and educational
    intervention in a staff meeting. Amoxycillin use was reduced by 20%,
    but there was an increase in the use of cotrimoxazole, doxycycline,
    and erythromycin.

-   Slight reduction in the use of ceftriaxone through a regulatory
    intervention whereby approval of the medical superintendent was
    necessary prior to use. However, there are some evidence that
    chloramphenicol use and mortality increased slightly.

A contract was issue for a two-year project in Ghana (Noguchi Memorial
Institute for Medical Research) to conduct research on interventions to
improve antibiotic prescribing habits of doctors in a teaching hospital.

The second draft for the WHO DTC Manual was completed and sent out for
review. WHO/EDM will collaborate with MSH on the further development and
field testing of this manual in conjunction with the development and
running on an international course on DTCs. WHO/EDM and MSH conducted
international courses on DTCs in Indonesia (June 2001: 42 participants
from 24 countries) and Kenya (October 2001: 37 participants from 18
countries). A third course was conduct in December 2001 (Nepal only).
During these courses, WHO/EDM participated in fully reviewing and
revising the training materials developed by MSH. A longer-term goal
(extending beyond 2001) is to build on contacts made through the 2001
training activities to conduct an extended program for technical support
(of several year duration) to a group of hospitals in several developing
counties.

Additional comments on the draft DTC manual were incorporated in
December 2001. Following the review of this draft, the final version
will be produced by the end of 2002.

Given the high frequency with which hospital-acquired infection are
caused by antimicrobial-resistant pathogens, it was decided that the
"Practical Guide to the Prevention of Hospital-Acquired Infections",
originally produced by WHO in 1979 should be completely revised. This is
being orchestrated by WHO/CDS under the leadership of Dr. G. Ducel and
Professor Lindsay Nicolle and the revised text has been reviewed
internally and externally, Next steps include editing, production, and
distribution which should be completed by 2002.

**Implementing Organization:** WHO/CAH; WHO/CDS; WHO/HTP/EDM

**Status:** On-going (Funded: FY1998; Expected Completion: not yet
determined)

**Rationale:** Although containing the emergence and spread of AMR is
complex, multi-factorial and not completely understood, it is believed
that measures can be initiated in countries in a coordinated and
integrated manner. These include:

• [Surveillance]{.underline}: Quality data from laboratory-based
surveillance of AMR in key bacterial pathogens can be used to improve
patient care and infection control/outbreak containment practices at the
local level and to raise local awareness of resistance problems.
Establishment of national surveillance networks can provide data to
support policy development, develop resistance containment strategies
and make projections of future priority health issues. In addition, for
diseases such as respiratory infections, in which the correlation
between in vitro AMR and clinical outcome is questioned, systems to
monitor treatment efficacy will have to be established.

• [Education and training]{.underline}: Education on the causes of AMR,
interventions that are effective for its containment and particularly on
the rational use of antimicrobial agents raises awareness of resistance
and improves antimicrobial prescribing practices. Pre-service and
continuing in-service training in the clinical diagnosis and the proper
management of infection, using simplified assessment and treatment
algorithms such as the ones developed for the Integrated Management of
Childhood Illness (IMCI), improves the accuracy of diagnosis and the
appropriateness of treatment.

• [Guidelines and Policies]{.underline}: All countries have some
regulatory mechanisms in place. These need to be strengthened to include
specific measures to assure strict regulation of quality and
availability of antimicrobial, and ethical standards of promotion. Many
countries also have in place an essential drug policy to promote the
rational use of drugs. This should be expanded to include a specific
section on the problem of AMR.

**Objective(s):** To establish processes for the introduction a model
package of interventions to contain AMR and to demonstrate the
efficiency and benefit of an integrated approach to resistance
containment at national and local levels.

**Description:** The package will contain a series of activities to be
initiated, together with indicators of efficiency and benefit, in the
selected countries.

1.[Situation analysis]{.underline}: Surveillance studies to determine
the prevalence of priority infectious diseases, prevailing AMR patterns
and knowledge of antimicrobial use. (Disease surveillance will be
coordinated with other Divisions in WHO).

2.[Activities in laboratory-based surveillance]{.underline}:

> 2.1. Provision of laboratory-based training in microbiological
> diagnosis and detection of resistance and analysis of resistance data,
> and laboratory capacity strengthening;
>
> 2.2.Training trainers in order to enable sustainable in-country
> technical training in lab-based resistance detection;
>
> 2.3.Assistance to countries to establish external quality assurance
> schemes for antimicrobial susceptibility tests;
>
> 2.4.Assistance in initiating a national surveillance network.

3.[Activities in education and training]{.underline}:

> 3.1.Development of continuing education programmes for laboratory
> technologists, prescribers and other healthcare professionals;

3.2.Public education programmes;

> 3.3.Development of training modules for health workers in the use of
> assessment and treatment algorithms, such as the ones developed and
> used in the IMCI;
>
> 3.4.Development of a core undergraduate medical and pharmacy
> curriculum for training in the rational use of drugs particularly
> antimicrobials.

4\. [Activities in guidelines and policy formulation]{.underline}:

> 4.1.Organization of workshops to bring together policy-makers,
> physicians, pharmacists, laboratory staff, nurses and community health
> workers to review national AMR data and current antimicrobial use
> practices, to identify constraints in information flow and to develop
> national plans of action for the surveillance and containment of
> resistance;
>
> 4.2.Assistance in development of national antimicrobial use guidelines
> and drug use indicators relevant for antimicrobial use. These
> activities will, as far as possible, be integrated within the scope of
> a national policy to promote rational drug use.

**Expected Outputs, Results, and Process Indicators:** This is a
multi-year project and the outcomes therefore represent ultimate
outcomes.

• Knowledge of the pattern of prevalent infectious diseases, prevailing
resistance patterns and patterns of antimicrobial drug use;

• Improved laboratory surveillance of AMR, including facilities for
monitoring resistance of common bacteria;

• Mechanisms for better information flow between surveillance
information, national treatment guidelines, essential drug lists, supply
and training;

• Pre- and in-service training for health workers;

• A raised public awareness of the problem of AMR;

• A national policy to promote the rational use of antimicrobials,
including specific chapters on rational use antibiotics in humans,
animals and agriculture;

• National treatment guidelines for the public and private sector;

• A national voluntary code for ethical drug promotion.

[Indicators]{.underline}:

• Agreement with pilot countries to initiate project;

• Report of situation analysis available within 3 months of initiation;

• Training activities initiated within 6 months of start;

• Quality assured surveillance data available within 12 months;

• Public information package prepared and initiated within 6 months;

• Continuing education package prepared and initiated within 12 months.

[Outcomes]{.underline}:

• Package of materials prepared and collated;

• Baseline data available on AMR in priority bacterial diseases;

• National policy to promote rational use of antimicrobials in force;

• Voluntary code for ethical drug promotion in force.

**Countries/Regions:** Three pilot developing/transition countries will
be identified by WHO. Criteria for inclusion to be considered will
include: (1) existence of national drug policy; (2) existence of an
essential drug programme with a rational use of drugs component; (3)
existence of suitable microbiology laboratory facilities; (4) existence
or experience of WHO projects including IMCI; (5) political willingness
to be involved in a project.

**Partners/Collaborating Institutions:** WHO divisions CHD, CDS,
HTP/EDM, ASD/STD; WHO/UNAIDS working group; Gonococcal Antimicrobial
Surveillance Program, (GASP); American International Health Alliance;
International Society for Infectious Diseases; International Clinical
Epidemiology Network; Alliance for the Prudent Use of Antibiotics
(APUA); RPM/MSH; U.S. Pharmacopeia; Ministries of Health and
universities in three developing countries.

**Results to Date:**

[Integrated country programs for containment of AMR, including
activities 4.2, 4.3, and 5.6 (WHO/EDM, WHO/CAH,
WHO/CDS/CSR)]{.underline}

Surveillance Standards for Antimicrobial Resistance are in final draft
and have been incorporated in proposals for field testing.

The workshops organized for the finalization of the WHO Global Strategy
for the Containment of Antimicrobial Resistance permitted the
identification and prioritization of intervention to be undertaken at
national and local levels to contain resistance. These are highlighted
schematically in Table 8 of the Strategy.

Given the complexity and cross-cutting nature of the work needed to
contain resistance, the fact that countries differ with regard to the
current status of their national strategies and implementation of
interventions and the costs associated with implementation of an
integrated national program, it was considered to be more feasible to
initiate in developing countries, in partnership wherever possible, as
series of individual projects each related to one or more of the
interventions recommended in the Global Strategy. By implementing some
of the interventions recommended in the Global Strategy at the country
level, critical experience can be gained and used in further developing
national strategies to contain AMR.

WHO/EDM and WHO/CDS/CSR has started the process of developing local
projects to contain AMR, with a view to continuing the learning process
with regard to what interventions work and raising awareness. Nine sites
in India were visited in April 2001, one site in Vietnam in July 2001,
and three sites in South Africa in September 2001. At each visit, WHO
explained the type of projects they were interested in and invited each
site to submit proposals for funding. As of November 2001, proposals had
been received from five sites in India and the proposals had undergone
several revisions. It is hope that proposals will be completed in early
2002. Visits to other sites in Asia and Africa are planned in 2002 to
start up projects. WHO is planning on holding a follow-up workshop at
the end of 2002 for funded projects. It is envisaged that each project
at each site will cost approximately US\$30,000 per year and that each
project will last at least 3 years.

######### Drug use and resistance in the community (WHO/EDM with RPM/MSH, BU/ARCH, and CHANGE)

A workshop on the integration of data on antimicrobial usage and AMR was
held in March 2000.

Discussions were held with RPM/MSH and BU/ARCH to develop a process to
foster operational research related to community-based interventions to
promote the rational use of antimicrobials. A workshop was held in
Bangkok (November 29-December 8, 2000) to further develop the 10 best
(out of 20 submitted) community-based proposals to promote rational use
of antibiotics at the household level. Five of the proposals included
surveillance of AMR as an additional endpoint for monitoring the effect
of the various interventions. (The proposals were adjusted in accordance
with the final draft of the Manual of Surveillance Standards for
Antimicrobial Resistance and it is hoped that the proposals can serve as
preliminary field tests.) Of the ten proposals, four have passed through
the external review stage. WHO/EDM issued a contract to co-fund
(together with RPM/MSH) the formative phase of a project on improving
the treatment of ARI at the community level in Nepal. WHO/EDM has also
agreed to co-fund the formative phase of at least two other projects
nearing technical completion.

[Guidelines for national programs to promote the rational use of
antimicrobials]{.underline}

Activities 4.2 and 4.3 have been included in Activity 5.1. To be
finalized in 2002 are two short briefing documents aimed at policy
makers on the subjects of (1) national strategies to promote the
rational use of drugs (including antibiotics) and (2) containing AMR.
With further experience, such briefing documents may be expanded.

A policy perspective paper on medicines entitled "Core Components of a
National Program to Promote the Rational Use of Drugs" has been drafted,
revised, and sent for external review. Another policy perspective paper
entitled "Core Components of a National Program to Contain Antimicrobial
Resistance" is being drafted.

*Next steps:*

As WHO moves forward in implementing the Global Strategy, activities and
new funds will focus on integrated country programs. The aim is to pilot
projects in selected countries (mainly India and South Africa) to
contain AMR with the following objectives:

-   Developing a new methodology in the integrated surveillance of AMR
    and antimicrobial drug use that can be used in many different
    countries, leading to coordinated linked surveillance of AMR and
    antimicrobial drug use;

-   Development, implementation, and evaluation of interventions to
    contain AMR using these surveillance data;

-   Building capacity in developing a multidisciplinary approach to AMR.

It should be noted that such country projects can only be undertaken on
the basis of a considerable long-term commitment of funds and technical
staff since most interventions take several years to develop and
implement and nationwide replication can only be expected after several
years.

**Implementing Organization:** Alliance for the Prudent Use of
Antibiotics

**Status:** Completed (Funded: FY1998; Completed: September 1999)

**Rationale:** APUA is an independent, grassroots organization whose
mission is to promote public health through education and research
concerning antibiotic resistance and the prudent use of antibiotics
around the world. Founded in 1981, with members in over 100 countries,
APUA provides a network that facilitates international exchange of
information and supports country-based efforts to curb antibiotic
resistance. APUA proposes to keep pace with the escalating emergence of
antibiotic resistance worldwide by expanding its network of foreign
affiliated chapters and by increasing the package of chapter services as
a model for more aggressive local intervention. The goal is to create a
global network of highly specialized experts working in a more
coordinated way to attack the antibiotic resistance problem at country
and global levels.

APUA national chapters facilitate global planning to curb antibiotic
resistance by performing these vital functions: raising awareness about
the problem of resistance within a country and the dangers of incorrect
antibiotic usage and faulty prescription; communicating information on
proper antibiotic usage; conducting related research and educational
projects; allowing for a multidisciplinary approach to interventions;
fostering practically applicable and scientifically sound solutions;
affording a local platform for input and feedback into any global
planning effort ; and providing local leaders with regular international
networking opportunities to enhance their knowledge and effectiveness at
the local level.

The APUA chapter also provides a natural link between data and action
within the country. As research findings are documented in country and
through the international APUA chapter network, they will be conveyed to
clinicians and policy makers. The APUA affiliation empowers chapter
members through support of their own research efforts and an
international affiliation to enable them to act as more effective
advocates for more prudent use of antibiotics in their country.

Last but not least, the APUA chapter can also act as an early warning
and intervention system. By increasing understanding of the resistance
problem within the country, and encouraging implementation of more
prudent antibiotic usage policy and practice, an APUA chapter can be
influential in containing an emergent resistant pathogen before it
spreads to the rest of the world. The APUA network publicizes and
encourages replication of successful local antibiotic resistance
interventions, many of which have been spurred by the APUA chapter and
membership network.

**Objective(s):** APUA chapters will further the global effort to curb
antibiotic resistance by addressing the following critical objectives:

> • To establish and mobilize local networks to raise public and
> professional awareness and advocate for national programs and policies
> to curb antibiotic misuse and resistance;

• To develop in-country leadership and capacity to advocate and
intervene in order to curb antibiotic resistance by linking researchers
to the international scientific community;

-   To act as a grassroots early warning source regarding resistance
    problems;

> • To foster national and regional coordination of antibiotic
> resistance research and surveillance and intervention activities;
>
> • To increase the understanding of key governmental and other decision
> makers about the problem of antibiotic resistance and the need for
> prudent antibiotic use;
>
> • To increase the number and quality of local surveillance and
> research efforts related to antibiotic resistance and use; and
>
> • To improve local scientific and clinical practice through
> publicizing and developing standards and guidelines on prudent
> antibiotic use and antibiotic resistance surveillance.

**Description:**

A. Development of New Chapters

> • Identification of qualified leaders in appropriate professional
> societies and government and non-governmental organizations through
> APUA scientific advisory board and other partners' contacts;
>
> • Preparation of introductory packets;
>
> • Initial telephone contacts and mailings of APUA chapter information
> and background packet to 100-200 potential members;
>
> • Explaining of chapter guidelines and agreement;
>
> • Gaining agreement on contract and chapter representation;
>
> • Organization of initial chapter meeting;
>
> • Identification of chapter technical support needs;
>
> • Establishing initial link with other chapters;
>
> • Mailing of APUA newsletters;
>
> • Assistance with outline of chapter goals and objectives.

B. Support of Established Chapters

> • Identification of local chapter needs and provision of technical
> assistance;
>
> • Assistance with development of local work plans, priority objectives
> and activities reflecting both local needs and those relating to the
> global planning effort;
>
> • Establishment of electronic and other links with other APUA chapters
> and the larger scientific community dealing with antibiotic
> resistance;
>
> • Annual chapter surveys: develop, conduct, compile and disseminate
> results;
>
> • Organization of local workshops regarding antibiotic research and
> education;
>
> • Dissemination of educational and membership materials: newsletter,
> video, relevant publications and materials to key authorities and
> professional groups;
>
> • Compilation and dissemination of standards and guidelines on
> antibiotic resistance surveillance and antibiotic use;
>
> • Providing technical assistance to country to advise on research and
> training needs;
>
> • Development of guidelines for review of chapter small grants
> proposals;
>
> • Providing small grants for local research, surveillance and
> educational programs;
>
> • Translation of APUA educational materials into Spanish and wide
> distribution of them;
>
> • Encouraging and editing original research from chapters for
> inclusion in the APUA newsletter;
>
> • Publishing and disseminating APUA newsletter to chapter members and
> relevant contacts;
>
> • Collecting and disseminating chapter success stories;
>
> • Assistance with development of local guidelines for surveillance and
> antibiotic use;
>
> • Conducting mentoring and international networking and exchange
> programs;
>
> • Development of model training sessions;
>
> • Development of press packages.

**Expected Outputs, Results, and Progress Indicators:** 1) New chapters
developed;

2\) increase in membership for new and existing chapters; 3) key
organizations contacted, aware of and/or involved in chapter activities;
4) number of APUA newsletters distributed; and number of educational
materials translated and disseminated; 5) original research findings
submitted from chapters to APUA; 6) documentation of local resistance
trends; 7) chapter research and educational programs, meetings,
publications; 8) educational materials and research findings distributed
to appropriate professional, policy groups and donors; 9) local and
regional networking training sessions for relevant local practitioners,
researchers and policy makers; 10) regional and international networking
meetings for chapter leaders (teleconferencing, email, chat groups, in
person); 11) other evidence of collaborations, including number of
exchanges among scientists; 12) number of speakers provided from the
international office to local meetings; 13) media coverage of chapter
activities and issues; 14) model chapter programs to track and curb
resistance identified and disseminated; 15) surveys of chapters and
compilation and dissemination of findings.

**Countries/Regions:** Argentina, Colombia, Dominican Republic,
Venezuela, and other countries in Latin America that were developed
before this grant.

**Partners/Collaborating Institutions:** To maximize impact, APUA will
work with other organizations including PAHO, WHO, RPM, and INRUD to
implement a logical division of labor and minimize duplication. APUA
will collaborate with national and global authorities to coordinate
training and dissemination of information to help ensure that chapter
activities impact national drug policies. In order to foster
sustainability and cost sharing, APUA will work with chapters to help
secure funding from appropriate sources to support activities.

**Results to Date:** Establishment of four new chapters and support of
existing chapters on outputs #1, 2, 3, 4, 5, 7, 8, 10, 11, 12 and 13.
Less progress made with the established chapters on outputs #6, 9, 14
and 15 because of limited resources.

**Implementing Organization:** USP

**Status:** Completed (Funded: FY1998; Expected Completion: FY2002)

**Rationale:** Although national drug policies usually prohibit
pharmacists and drug sellers from dispensing antimicrobials without a
prescription, it has been documented that a large percentage of
antibiotics are taken through self-medication, with the antibiotics
often being made available by untrained PHC workers or retail drug
sellers. Through USP's experience in Nepal, it has been observed that
training requirements to become a licensed drug seller are minimal and
no \"refresher\" training is required. Drug information available to the
retailer comes almost exclusively from the pharmaceutical industry.
Current, unbiased information is required for appropriate dispensing and
for advising consumers about side-effects and how to take their
medicines. Studies have shown that 68% of retailers in Nepal have no
qualifications to sell drugs, let alone to prescribe. In one study, a
therapeutically-appropriate full course of antibiotic treatment was
received less than 25% of the time in retail shops.

**Objective(s):** To decrease the amount of inappropriate dispensing of
antimicrobial drugs by private sector retailers and to improve their
consumer counseling practices.

**Description:** Using Nepal ID funding, USP will research the
antimicrobial drug knowledge and consumer counseling practices of drug
sellers in Nepal in cooperation with the NCDA. Emphasis will be placed
on antimicrobials used to treat high priority diseases such as
pneumonia, Shigella and sexually transmitted infections. A template for
a booklet for pharmacists and drug sellers (which can be adapted by
other countries) will be completed using the Nepal research results and
USP's patient information database, appropriately adapted for Nepal. In
addition, information relating to appropriate counseling techniques will
be included based on USP's patient counseling guidelines, again, adapted
for Nepal. Nepal ID funds will allow the booklet to be tested in Nepal.
Core funds will be used to develop the template, disseminate the booklet
outside of Nepal as a model and to assist other countries with
adapting/translating the model for local use through a sub-agreement
mechanism. Core funds will also be used to develop a facilitator's guide
for use by trainers of retailer-groups.

**Expected Outputs, Results, and Progress Indicators:**

[Output:]{.underline} Booklet for pharmacists and drug retailers to use
to improve dispensing and to counsel consumers on the proper use of
antimicrobial drugs.

[Progress Indicators:]{.underline} Research methodology and tools
developed, e.g., number of surveys completed, number of focus groups
held, etc., amount and quality of data collected and analyzed, format
for booklet developed, drugs to be included identified, general AM
information developed, drug-specific information developed, draft
template developed.

**Countries/Regions:** Nepal

**Partners/Collaborating Institutions:** NCDA, USAID-Nepal, MSH, DINoN

**Results to Date:** Research has been completed on the antimicrobial
(AM) drug knowledge and consumer counseling practices of drug sellers in
Nepal. Development of the booklet on AM drugs has been delayed until the
training intervention described under 5.24 could be field tested and
evaluated. The field test and evaluation have now been completed and
results will be used to guide the development of the booklet so the
format will be useful to the drug sellers, but also for nurses and
physicians in rural areas. It will be published in the Nepali language
with Nepal ID funds. The booklet is envisioned as a tool for the
training intervention, but also as a stand-alone product that can be
adapted for other countries with core funds.

**Implementing Organization:** RPM/MSH

**Status:** On-going (Funded: FY1998; Expected Completion: FY2002)

**Rationale:** The First International Conference on Improving Use of
Medicines identified the need to develop guidelines and performance
indicators for Drug and Therapeutics Committees (DTC), a key structural
component of an effective pharmaceutical management system. Although
these committees have been in existence for many decades in both
advanced industrialized and developing countries materials are
unavailable to assist in capacitating committee members to effectively
carry out their roles. Relative to an antimicrobial focus, there is a
need to develop relevant skills to select appropriate (effective, safe
and economic) antimicrobials for national or local formularies and
promote their appropriate use. DTC members do not receive prior training
to develop such skills.

**Objective(s):** Develop and test a set of training modules aimed at
members of DTCs and Antibiotics Sub-committees of local hospital and
national levels

**Description:** The materials will include, minimally, sessions on (1)
the role and functions of a DTC, (2) criteria for antimicrobial drug
selection, (3) economic analyses for antimicrobial drug selection, (4)
the appropriate use of in vitro antimicrobial susceptibility testing,
(5) how to evaluate the clinical literature on drug efficacy and safety,
(6) how to conduct analyses to target drug use interventions, (7) a
framework to improve the use of antimicrobial drugs, (8) effective
strategies to improve antimicrobial drug use, (9) sources of reliable
information on antimicrobial drugs, and (10) effective communication
skills and team work.

Tasks include a review of relevant literature and a selective survey of
these committees to gather information to design the training modules.
RPM intends to prepare (1) a discussion paper on the role of these
committees and the need for skills development in developing countries
and (2) a draft outline of modules, stating the rationale, objectives,
key content, and a preliminary list of suggested readings for each
module, that will be reviewed before actual drafting of modules. Once
the modules are drafted, an alpha course will be organized and conducted
in collaboration with interested partners.

Once the alpha course has conducted, availability of materials will be
announced in electronic and print fora (E-drug, INRUD News, Essential
Drug Monitor). Field test results may be published in the INRUD News,
Essential Drugs Monitor and a peer-reviewed journal. Subsequent course
may be organized through INRUD, WHO, or other interested organizations
for regional or national level training of trainers.

**Expected Outputs, Results and Progress Indicators:**

[Outputs:]{.underline} list of key references on DTCs; compilation of
key readings on DTCs; discussion paper on role of DTCs; a set of
training modules for DTCs; report on field test of training modules.

[Results:]{.underline} set of training modules available and field
tested; core group of trainers trained.

[Progress indicators:]{.underline} literature review completed; key
readings compiled; training modules drafted; training modules (alpha
course) field tested.

**Countries/Regions:** Africa or Asia (to be determined)

**Partners/Collaborating Institutions:** INRUD country core group
members are expected to collaborate in technical review of modules;
WHO/HTP/EDM is expected to collaborate in technical review of modules;
USP staff and advisory panelists will be asked to provide technical
review; potential partners who may provide support for participants to
attend the alpha course may include Danida, NORAD, SIDA, WHO HTP/EDM,
WHO country programs, and World Bank field projects.

**Results to Date:** The DTC training material was completed and alpha
tested in Bangkok in June 2000 under RPM. Under RPM Plus the material
was modified from the Bangkok experience and sent out for external
review to four reviewers. A collaboration was developed between WHO for
RPM Plus to produce the training material and WHO to produce a
complementary manual. The modified material was tried in a country
workshop in the Philippines in April and then in an International
workshop in Indonesia in June 2001. Forty-two participants from 24
countries attended. Each participant agreed on plans for follow on
activities. These will be monitored with necessary technical assistance
by E-mail. A further regional course is planned for Kenya in October
2001. The material is being translated into Spanish for a course in
Latin America in the autumn of 2001.

There are plans to incorporate an infection control module and a module
on drug information and drug information centers to the DTC training
materials. These additional modules are expected to be developed during
the summer of 2001. In addition, there are plans to develop an infection
control quality improvement process for hospitals in developing
countries.

**Implementing Organizations**: BU/ARCH and RPM/MSH

**Status:** On-going (Funded: FY1998; Expected Completion: FY2002)

**Rationale:** Inappropriate antimicrobial use in primary care settings
is widespread. This is felt to be a major force driving the spread of
community-acquired AMR. Numerous studies have documented both
over-prescribing as well as inappropriate selection and dosing of
antibiotics by health care providers, unfettered access to
antimicrobials by consumers, and a failure to adhere to clinically
desirable treatment regimens.

Antibiotic therapy is a mainstay of hospital therapy. Antibiotics
typically are both the most frequently used, and by far the most
expensive, category of drugs in a hospital budget. Although unnecessary
use of antibiotics in hospitals appears to be as widespread as in
primary-care settings, even appropriate use can drive the rapid
development of resistance because of the intensity of pressure in a
self-contained ecosystem. There has been very little documented
experience from developing countries in how best to improve the use of
antibiotics in hospital settings.

In 1997, the First International Conference on Improving Use of
Medicines (ICIUM) was held in Chiang Mai, Thailand. It was co-sponsored
by the CIH/ARCH, INRUD, RPM, USP, and WHO/HTP/EDM. The conference
identified key topics for research on improving prescribing and
dispensing practices, improving community use of medicines, and
developing effective pharmaceutical policies and regulations. In line
with these priority areas, the partner organizations (RPM, INRUD,
CIH/ARCH, and WHO/HTP/EDM) issued a joint call for proposals emphasizing
the most important gaps in experience that were identified at ICIUM.
Areas highlighted in the call for proposals were the need for innovative
interventions to improve malaria case management, and the scarcity of
well-designed interventions in hospital and private sector settings. In
response to the call for submissions, 88 pre-proposals for intervention
research were submitted from Africa, Asia, and Latin America. They were
reviewed and ranked by a panel from amongst the collaborating partners.
The partners assisted the researchers, using a structured process, to
develop completed proposals and to implement and analyze their research.

**Objective(s):**

• Strengthen capacity to develop, conduct, analyze and disseminate
effective interventions to improve the use of antimicrobial drugs

• Support intervention research to improve the use of antimicrobial
drugs

**Description:** The drug use research portfolio includes several
studies proposing innovative approaches to behavior change among health
workers, including small interactive group discussions with drug
sellers, or the use of local hospital specialists as educational leaders
to facilitate change among primary health care physicians.

In addition, a number of studies target the use of antibiotics in
hospitals. Their focus ranges from teaching hospitals to district
hospitals; public to private to mission institutions; neonatal intensive
care units to pediatric outpatient departments; specialists to general
medical officers. A number of studies focus on improving and expanding
the role of Pharmacy and Therapeutics Committees, the mainstay in many
*developed* countries of efforts to improve the quality of prescribing.

The fifteen (15) top-ranked research pre-proposals that address
antimicrobial drug use were submitted by investigators in Asia and
Africa (one in Mexico), reviewed, approved and funded. They include:

• *Ghana*: An Intervention to Improve Antibiotic Prescribing Habits of
Doctors in a Teaching Hospital -- Ofori-Adjei

• *Indonesia*: Reducing the Use of Expensive Antibiotics for Acute
Respiratory Tract Infections (ARI) in Children Utilizing a Small Group
Face-to-Face Intervention - Rustamadji

• *Indonesia*: Small Group Discussion Among Paramedics at the Health
Centre Level to Improve Compliance to Standard Treatment Guidelines for
Acute Respiratory Tract Infections(ARI) - Hidayati

• *Kenya*: Study to Assess the Effect of an Educational Intervention to
Influence Cost-Effective Prescribing in the Use of Antibiotics in the
Treatment of Non-Pneumonia ARI and Malaria in 10 Mission Hospitals in
Kenya -- Gitau

• *Mexico*: Effectiveness of An Educational Strategy, Based on Critical
Analysis of Clinical Practice, to Improve Appropriateness of Treatment
of Common Diseases in Family Medicine Clinics -- Reyes/Morales

• *Nepal*: Test of Strategies for Implementing Standard Treatment
Schedules in Improving Use of Drugs - Kafle.

• *Philippines*: Improving Private Physicians' Prescribing Patterns in
the Diagnosis and Treatment of Uncomplicated Urinary Tract Infection
through Clinical Practice Guidelines - Saniel

• *Philippines*: The Effect of an Educational Activity on the Dispensing
Practices of Drug Store Clerks - Galang

• *Philippines*: The Effect of an educational Intervention on the Drug
Purchasing Practices of Local Officials in the Philippines -- Sia

• *Tanzania*: Improving Appropriate Dispensing Practices of
Antimalarials and Antimicrobial Agents in Treating Malaria and Diarrhea
in Dar-es-Salaam, Tanzania -- Nsimba

• *Thailand*: Improving Economic Rationality of Antibiotic Prescribing
in a Teaching Hospital through an Educational Strategy to Promote
Generic Prescribing -- Anansakunwatt

• *Uganda*: Improving Rational Drug Use by Private Physicians in Uganda:
An Educational Intervention Study -- Ogwal-Okeng

• *Uganda*: Improving the Dispensing of Drugs for Treatment of Acute
Respiratory Tract (ARI) Infections in Children Under Five Years of Age
by Private Pharmacists and Dispensers in Kampala District, Uganda by
Using Small Group Face-to-Face Intervention - Tumwikirize

• *Uganda*: The Impact of Decentralization on Utilization of Health
Services, Use and Availability of Drugs in Apac and Lira District
Hospitals, Uganda - Anokbonggo

• *Vietnam*: Improving Community Drug Use Focusing on Hospital
Out-Patients through Peer Review and Implementation of Guidelines --
Dung

• *Zambia*: The Effect of an Intervention to Promote Correct Use of
Antimalarial Drugs at Household Level in Nakonde District, Northern
Province, Zambia - Kaona

Each partner of the Joint Research Initiative on Improving the Use of
Medicines (JRIIUM) plans to contribute their intellectual labor through
the structured proposal development and data analysis workshops and
on-going field technical support to implement selected studies. The
JRIIUM will also fund participants to attend the workshops and selected
studies.

**Expected Outputs, Results, and Progress Indicators:** The principal
outputs of this component are a set of intervention research studies
aimed at behavior change among health providers, their analysis, and the
dissemination of the results to the global and national programs
responsible for infectious disease case management. Researchers and
policy makers concerned with slowing the spread of AMR will also benefit
from these research results.

By the end of the Policy Paper and Data Analysis Workshop, each team is
expected to produce the following: a draft manuscript, a policy paper
from the study incorporating the analyses completed by the researchers
during the workshop and a short oral presentation of research results to
workshop participants. Manuscripts will be reviewed by ARCH and RPM
technical staff and external reviewers. Technical support will be
provided to facilitate publication in appropriate journals. Every six
months researchers are required to submit scientific updates to the
JRIIUM's scientific secretariat at the ARCH Project to assess progress.
These reports provide details of project status, problems, presentations
made or papers written. The study will be deemed completed only when the
research team has submitted a final scientific report to ARCH and USAID.
Once the study has been funded, ARCH and RPM project staff provide
technical assistance and monitoring of the research which includes site
visits, formation of safety and/or data monitoring committees, financial
management oversight and other related activities.

At the end of this process, capacity to undertake and disseminate
intervention research to improve antimicrobial drug use will also have
been strengthened in developing countries.

**Countries/Region:** Asia, Africa, and Latin America (see Description
for countries)

**Partners/Collaborating Institutions:**

• INRUD/MSH will co-fund workshop activities, provide technical support
to researchers, and fund selected studies; some INRUD country core group
members will participate in research proposal development and data
analysis workshops as technical resource persons and others may
participate as participants/researchers

• WHO/HTP/EDM will co-fund workshop activities, provide technical
support to researchers, and fund selected studies.

**Results to Date:** The first proposal development workshop was hosted
by the WHO Collaborating Centre for Clinical Pharmacology and Drug
Policy Studies in Indonesia, secretariat for the Indonesia INRUD Country
Core Group, in May 1998. The second proposal development workshop was
hosted by the secretariat for the Uganda INRUD Country Core Group, in
September 1998. ARCH and RPM continue to provide technical support to
selected researchers who are carrying out the study protocols developed
at these workshops. RPM has provided financial support for one
intervention study, and ARCH has supported eleven studies. An Asia Data
Analysis and Policy Paper Workshop was recently concluded in Hanoi,
Vietnam from July 7 -- 17, 2001 for the eight teams who participated in
the Proposal Development Workshop that was held in Indonesia in May
1998. An Africa Data Analysis and Policy Paper Workshop will be held in
Kampala, Uganda in late 2001/early 2002 for the seven African research
teams.

**Implementing Organization:** WHO/HTP/EDM

**Status:** On-going (Funded: FY1998; Expected Completion: not yet
determined)

**Rationale:** In most developing countries 50-90% of antimicrobial
drugs are purchased directly in the private sector, often without
prescription. About half of the customers buy less than one day's supply
at a time. Improving the rational use of antimicrobials in the private
sectors needs to be a mixture of regulatory approaches towards drug
promotion, continuous education through professional associations,
consumer education and active dialogue with the pharmaceutical industry.

**Objective(s):** To establish and document functional mechanisms to
improve rational use of drugs in general and antimicrobials in
particular in the private sector to act as a model for other countries.

**Description:**

• Assist 3 developing countries in developing a national strategy and
action plan to promote rational use of antimicrobial drugs in the
private sector to include: (1) strengthening regulatory control over
sales and drug promotion; (2) working with professional associations to
encourage rational use of antimicrobials; (3) working with consumer
groups active in the wider community; and (4) working with industry
associations on development and enforcement of self-regulatory codes.

• Based on the experience in these countries prepare a draft manual with
guidelines on developing and implementing such a plan.

• Production and dissemination of the guideline to all national
regulatory authorities, ministries of health and the relevant
non-governmental organizations. Additional dissemination will be
undertaken as appropriate by WHO (HTP/EDM, and CDS).

**Expected Outputs, Results, and Progress Indicators:** More rational
use of drugs in general, and antibiotics in particular in three
countries; a WHO guideline on how to promote rational use of drugs,
including antimicrobials in the private sector, tested in several
developing countries.

[Progress indicators]{.underline}: Depending on the countries chosen and
their national drug policies and plans, organise a national survey on
the use of antibiotics; develop and update antimicrobial use guidelines;
investigate legal and regulatory situation; integrate training
programmes through professional associations and continuing medical
education, making links with ongoing activities with the public sector
and the national essential drug programme.

**Countries/Regions:** Philippines.

**Partners/Collaborating Organizations:** WHO/CDS; INRUD; IFPMA; FIP;
non-governmental organizations; international networks.

**Results to Date:** (see Activity 5.1)

**Implementing Organization:** JHU/FHACS

**Status:** Completed (Funded: FY1998; Completed: FY2001)

**Rationale:** The integrated management of childhood illness (IMCI)
approach developed by WHO and UNICEF is being adopted by an increasing
number of developing countries as their primary intervention to improve
facility and community-based management of sick children. The
prescription of antimicrobials for sick children with bacterial
infections is a key element of the IMCI approach. The IMCI clinical
algorithm recommends oral antimicrobials and home treatment for sick
children with clinical diagnoses of non-severe pneumonia, malaria,
dysentery, and acute ear infections. The effectiveness of the IMCI drug
counseling guidelines on compliance with antimicrobial therapy in the
home has not been evaluated. This is a key programmatic issue. If
sub-therapeutic treatment doses are being given in the home, then there
is an increased risk of the development of AMR and an increased risk of
mortality for the individual child. This study will determine the impact
of IMCI counseling guidelines on compliance with antimicrobial therapy
in the home, develop programmatic interventions to improve compliance
and test the effectiveness of these interventions.

**Objective(s):**

• To evaluate the impact of the IMCI treatment counseling guidelines on
compliance with antimicrobials for sick children in the home

• To identify barriers to compliance with antimicrobial treatment in the
home following IMCI treatment counseling

• To develop and test the effectiveness of interventions using the IMCI
approach to improve compliance with antimicrobial treatment for sick
children in the home

**Description:**

***Phase 1* (3 months)** Data collected in this phase will be used to
design locally-appropriate instruments for subsequent phases.

[Semi-structured interviews with service providers and
officials.]{.underline} To examine institutional factors that facilitate
or obstruct adherence to treatment recommendations, a series of 15
interviews will be conducted with officials of the IMCI program of the
Ministry of Health, district health officials and health facility
personnel at the hospital, dispensary and health post level. The
interviews will cover obstacles encountered in implementing the IMCI
approach in Uganda, factors limiting adherence to treatment
recommendations, suggestions (methods or specific questions) for data
collection on treatment-seeking, and perceptions of the AMR problem in
Uganda.

[Semi-structured interviews on knowledge and perceptions of
medications]{.underline}. A sample of 30 parents of young children will
be administered a 30 minute semi-structured interview on knowledge and
perceptions of medications. Topics will include free-listing of types of
medications, pile sorting (classification) of locally-available
medications for children, and local names for medications.

[Direct observation of provider-patient interaction]{.underline}*.*
Activity in the waiting room and patient-provider interaction in health
facilities will be directly observed in facilities which have and have
not implemented the IMCI approach. Approximately 2 days of observation
will be conducted in each facility selected.

[Exit interviews]{.underline} Exit interviews will be conducted with
parents of young children upon leaving the health facility. Respondents
will be administered a brief survey about how long they waited, what
happened in the appointment, what treatment they were told to take,
etc., in order to assess the degree to which people understand the
information they are being given.

***Phase 2* (3 months)**

[Evaluation of compliance with treatment recommendations]{.underline} In
the districts chosen for the study, lists of facilities that are
performing \"gold standard\" IMCI \[applying the 3 components of
treatment counseling; explain, demonstrate, verify comprehension\] and
of facilities that have not yet implemented IMCI will be compiled.
Children receiving outpatient care at the two types of facilities will
randomly be selected for follow-up. The IMCI clinical classification of
all children will be determined by trained observers. Children selected
for follow-up will be \<5 years of age and have a clinical diagnosis of
pneumonia, malaria, dysentery or acute ear infection. Children will
receive the nationally recommended first-line antimicrobial agent for
their clinical diagnosis. All children will be followed-up in the home
after 5 days. The two groups will be compared on compliance with
treatment. Serum samples may be collected on a sub-sample of children to
correlate compliance histories with serum levels of antimicrobials.
Qualitative and quantitative data will be collected from compliers and
non-compliers with antimicrobial therapy. Areas of particular interest
will include the formulation of the medicines, the type of illness,
perceived severity of illness, perceived quality of the counseling
received, and the role of other family members on treatment practices.
It is unlikely that the mortality outcome for the two groups will be
able to be compared due to the large sample sizes that would be needed.
Barriers to compliance with a full course of antimicrobials will be
identified.

***Phase 3* (3 months)**

[Intervention development]{.underline}. Data from the second phase will
be analyzed. Data on barriers to antimicrobial compliance will be used
to develop an intervention or interventions that can be implemented at
the time of the facility visit. These interventions will be developed
with local health staff and program managers. An emphasis will be placed
on developing interventions that are feasible using local resources,
acceptable to local staff and communities, and time efficient. Potential
interventions will be pre-tested.

***Phase 4* (3 months)**

A design similar to Phase 2 will be implemented. Facilities already
implementing \"gold standard\" IMCI counseling will be randomized to
continue with existing counseling, or to implement an improved
counseling approach based on the results of the preceding phases. A
costing element will be added to estimate the cost of adding the
intervention (s) to routine outpatient practice. All children will be
followed up in the home at 5 days and compliance with treatment will be
assessed. The same variables will be evaluated. Qualitative and
quantitative methods will again be used to assess compliers and
non-compliers. The effectiveness and cost-effectiveness of the
intervention (s) to improve antimicrobial compliance will be determined.

**Expected outputs, results and progress indicators:**

[Outputs:]{.underline} a cost-effective intervention (s) to improve
compliance with antimicrobial therapy given to sick children at health
facilities using the IMCI approach.

[Results:]{.underline} a reduction in the number of sub-therapeutic
doses of antimicrobials given to sick children and a slowing in the
development of AMR to common childhood pathogens; a reduction in overall
mortality for sick children managed as outpatients with antimicrobials.

[Progress indicators:]{.underline} data from phases 1 and 2 analyzed and
presented: Barriers to compliance with antimicrobial therapy at home
following counseling at outpatient health facilities; intervention to
improve compliance with treatment recommendations developed and
pre-tested; intervention implemented and evaluated.

**Countries/Regions:** Uganda was selected as the site for the following
reasons: 1) High morbidity and mortality amongst children \<5 from lower
respiratory tract infections and malaria; 2) Commitment by the ministry
of health to use IMCI as its primary child health strategy; 3) Active
implementation of IMCI in the country and availability of trained health
workers; 4) Strong JHU links with ministry of health staff and research
institutions in the country; and 5) Availability of highly trained local
research counterparts.

**Partners/Collaborating Institutions:** Ministry of Health in Uganda
and the Ugandan Institute of Public Health (research expertise); the
protocol will be developed in collaboration with WHO/CAH which is
coordinating the global IMCI initiative. CHD has identified compliance
with antimicrobial therapy as a key research area. Coordination with WHO
in Uganda will allow locally trained staff to be identified. CHD will be
involved with the interpretation and dissemination of results;
participation will be critical if wider recommendations for improving
antimicrobial compliance are to be made. Collaboration with INRUD will
be sought for the development of methods to investigate the behavioral
aspects of compliance with antimicrobial therapy.

**Results to Date:** Study completed and results presented at a
community IMCI conference in Baltimore (January 2001).

**Implementing Organizations:** JHU/FHACS and WHO/CAH

**Status:** On-going (Funded: FY1998; Expected Completion: FY2003)

**Rationale:** Early identification and prompt antibiotic therapy have
been crucial in reducing the mortality and morbidity from meningitis
over the last 40 years. Recently the treatment of meningitis has been
complicated by the emergence of high rates of *Streptococcus pneumoniae*
resistant to penicillin, and the increase in *Haemophilus influenzae*
type b (Hib) strains resistant to ampicillin and chloramphenicol. Third
generation antibiotics (ceftriaxone and cefotaxime) have become the
standard drugs for initiating antibiotic treatment of meningitis in most
developed and some developing countries. The optimal duration of therapy
for bacterial meningitis is not clear and recommendations have varied in
different countries. In the United States, the recommended duration of
treatment has been 7-10 days for meningitis due to Hib, 10-14 days for
*S. pneumoniae* meningitis, and 7 days for *Neisseria meningitidis*.
Antibiotic treatment courses as short as 3-to-5 days have been shown to
be highly effective in children and adults with meningitis due to *N.
meningitidis*.

Recommendations for duration of treatment for meningitis caused by Hib
and *S. pneumoniae* were derived from clinical case series of meningitis
conducted primarily in the 1960\'s with antibiotics that are not as
effective as the new cephalosporins. For example, relapses appear to be
more frequent following chloramphenicol therapy, which is bacteriostatic
for many bacteria, and organisms are killed relatively slowly. In
contrast, third generation cephalosporins are rapidly bactericidal
resulting in sterilization of the cerebrospinal fluid within 48 hours in
almost all patients who have meningitis due to susceptible organisms.
Recent studies have demonstrated that 6-to-7 days of ceftriaxone therapy
can cure meningitis due to Hib and *S. pneumoniae* without increased
rates of relapse or neurological sequelae. Maintaining intravenous
infusions over a 10-day period can be difficult and tax the limited
resources available in many developing country hospitals. A 5-day
treatment course would make the use of these more expensive antibiotics
feasible and cost-effective. If a shorter treatment course is proved to
be efficacious, it would have profound implications for the treatment of
bacterial meningitis all over the world. This would have special
implications for IMCI in the developing countries. It is also expected
that short (5 days) course of injectable third generation cephalosporin
(ceftriaxone or cefotaxime) is less likely to cause AMR as compared to
the 10 days course in treatment of bacterial meningitis.

**Objective(s):** To compare the safety and rates of bacteriologic cure,
relapse, deafness and other sequelae in children with acute bacterial
meningitis due to *H. influenzae* type b, *S. pneumoniae* and *N.
meningitidis* who receive 5 vs. 10 days of therapy with ceftriaxone.

**Description:** A multi-centre study will be set up in developing
countries. Bacterial meningitis cases among children will be randomized
to two treatment groups. One group will receive 5 days of injectable
third generation cephalosporin (ceftriaxone or cefotaxime) followed by 5
days placebo in a blinded manner and the other group will be randomized
to injectable third generation cephalosporin (ceftriaxone or cefotaxime)
for 10 days. Cerebrospinal fluid and blood isolates will be obtained
before treatment and after 24-48 hours of treatment to see the
persistence of bacteria in the cerebrospinal fluid or blood. Facilities
for CSF cultures and basic susceptibility testing will be developed
where they are not available.

**Expected Outputs, Results, and Progress Indicators:**

• AMR rates for common bacteria causing bacterial meningitis will be
documented;

• It will provide information that will help the developing countries to
decide whether to change the first line antimicrobial guidelines for the
treatment of bacterial meningitis;

• Short (5 days) course of injectable third generation cephalosporin
(ceftriaxone or cefotaxime) is less likely to cause AMR as compared to
the 10 days course in treatment of bacterial meningitis;

• Short (5 days) course of injectable third generation cephalosporin
(ceftriaxone or cefotaxime) is as efficacious as 10 days course for
bacterial meningitis;

• Capacity building of the research institutions regarding clinical and
microbiological work;

• Negotiations with the pharmaceutical industry to bring down the price
of ceftriaxone.

[Progress Indicators:]{.underline} development of a research protocol;
initiation of data collection.

**Countries/Regions:** Guatemala, Pakistan, South Africa, and Vietnam (a
total of ten tertiary care hospitals). WHO will conduct studies in
Pakistan and South Africa; JHU will conduct studies in Guatemala:
Hospital General San Juan de Dios (HGSJD); Hospital Roosevelt (HR); and
the General Hospital of the Institute of Guatemalan Social Security
(IGSS). (The HGSJD will be the coordinating center.) To get adequate
number of patients which are representative would require at least 4-5
sites. Bangladesh may be added in order to reach the desired sample
size.

**Partners/Collaborating Organizations:** WHO will host a meeting to
standardize methodologies (enrollment, treatment guidelines, outcome
measures and patient assessment). JHU data from Latin America and
WHO-sponsored data from Africa and Asia will complement each other and
will be representative of all developing regions. A prospective
meta-analysis of the data from both studies will be performed after
completion.

WHO has approached Hoffmann La Roche Pharmaceuticals, Switzerland
(manufacturers of ceftriaxone) for donation of ceftriaxone for the above
mentioned studies. Negotiations have started and Roche is considering
the request favourably. The study medicine cost (ceftriaxone) alone for
both JHU and WHO supported studies could be as high as 300-350,000 US\$.
WHO is also in negotiations with Roche Pharmaceuticals, Switzerland for
bringing down the price of ceftriaxone in order to make it more
accessible to the needy patients in the developing countries.

**Results to Date:** The drug supply issues have been resolved and, in
collaboration with Johns Hopkins University, a satisfactory placebo has
been developed. The drugs for the study were donated by Medochemie
(Malta) and were made available to the study sites in March 2001. Data
collection was therefore started at all sites in April 2001 and is
expected to last two years (Pakistan, South Africa, Vietnam). Because of
difficulties recruiting sufficient numbers of cases, the study may
expand to also include Bangladesh. This activity also includes funds for
activity 2.7.

**Implementing Organizations:** JHU/FHACS and WHO/CAH

**Status:** On-going (Funded: FY1998; Expected Completion: FY2003)

**Rationale:** Pharyngitis or sore throat is a common ailment the world
over, and is especially common in children. Pharyngitis due to group A,
beta-hemolytic *Streptococcus* assumes a special significance because of
the risk of subsequent rheumatic fever (RF) and chronic rheumatic heart
disease (RHD) in the infected host. RHD is a major public health problem
in developing countries today, where it is the leading cause of
cardiovascular morbidity and mortality in children and young adults.
Besides the enormous economic burden of medical and surgical costs,
these illnesses cause great suffering and hardship to the victims and
their families, with repeated hospitalisations, disability and premature
death.

In economically developed countries, RF and RHD are largely controlled,
due to antibiotic treatment of streptococcal pharyngitis and
improvements in living standards. However, antibiotic treatment of all
pharyngitis episodes is wasteful\--since it means overtreatment of 70 -
80% of cases\--and there are concerns about health costs, penicillin
allergy, and alteration of normal throat flora. One of the major
problems is that unnecessary antibiotic use for sore throat may result
in emergence of drug-resistant strains of other pathogens especially *S.
pneumoniae* and *H. influenzae* which has already been noted in some
parts of the world.

In developing countries, these same problems exist and are compounded by
other deficiencies. The prevalence of Group A streptococcal pharyngitis
(GRASP) in these countries is largely unknown due to paucity of studies.
Secondly, facilities for performing throat cultures levels and
agglutination tests as well as determining antibody titres are not
generally available. Lastly, because of lack of awareness, many patients
do not seek medical care. Since it is not desirable to treat all
pharyngitis with antibiotics and laboratory facilities are usually not
available, it would be useful to have a clinical prediction rule for
GRASP, especially for use in developing countries.

**Objectives:** To identify the optimal set of clinical findings in
children between 24 months and 12 years of age that are predictive of
GRASP as documented by positive throat culture and/or serology. Data
from the study will be used to create clinical prediction instruments
tailored to health care providers with different levels of training
(physicians, mid-level practitioners and community health workers) in
various clinical settings (outpatient departments, emergency
departments, and rural and urban ambulatory practices). Based on study
data, a cost-effectiveness analysis will be conducted to determine the
appropriate threshold for treatment and throat culture in different
settings.

Secondary objectives include describing: the prevalence of GRASP in
children seeking care for the complaint of sore throat under different
conditions (i.e., season, age) in different geographical areas;
variations in serotypes, M-types and serologic response to Group A
streptococcal infection in different geographical areas and the
relationship of these markers to the clinical virulence of Group A
streptococci causing pharyngitis; the frequency of secondary
complications of GRASP in different countries; the patterns of
developing of AMR in infected and uninfected patients following
treatment with antibiotics; and the prevalence of the carrier state in
non-symptomatic patients.

**Description:** In many developing countries it is not possible to
obtain a throat culture needed for identification of GRASP prior to the
prescription of appropriate antibiotics. This collaborative,
multi-center study seeks to improve the diagnosis and management of
streptococcal sore throat by determining the clinical findings that
reliably predict GRASP using standardized laboratory protocols. The goal
of the study is to help clinicians make more rational use of the
clinical history and examination in determining the need for antibiotic
therapy. A second goal is to reduce the unnecessary use of antibiotics
in patients having a low probability of streptococcal pharyngitis. Local
capacity will be built by standardizing methodology for culture and
serology.

**Expected Outputs, Results, and Progress Indicators:**

[Outputs]{.underline}: (1) uniform prospectively collected data on the
prevalence of streptococcal pharyngitis in a variety of developing
country sites; (2) uniform and prospectively collected information
regarding the correlation of signs and symptoms in young children with
the proven presence of streptococcal pharyngitis; (3) prospective data
on the serology of streptococcal infections in selected sites; (4)
prospective data on the prevalence rates of AMR for *S. pneumoniae* and
*H. influenzae*.

[Results]{.underline}: development of a clinical algorithm presumptive
treatment of streptococcal pharyngitis for use in health clinics of
developed countries.

[Progress indicators]{.underline}: (1) development of a joint research
protocol; (2) the number of sites (countries) in which activities are
initiated; (3) number of studies completed; (4) number of children
evaluated; and (5) scientific presentations and papers.

**Country/Regions:** Brazil, Croatia, India, Latvia, Philippines,
Thailand

**Partners:** INCLEN, University of North Carolina, Universidade Federal
Do Rio De Janeiro, WHO Collaboration Centre for Reference and Research
in Streptococci (Prof. E. Kaplan, University of Minneapolis), and others
not yet identified.

**Results to Date:** Results of the pilot study supported by INCLEN and
WHO to differentiate between sore throat due to viral infections from
those needing antibiotic treatment were analyzed in a workshop held in
Bangkok (Thailand) in October 2000. Following this analysis, a proposal
for a larger study was finalized in the same workshop. This study will
be a multi-centre study conducted in four countries (Brazil, Croatia,
India and Latvia); patient recruitment started in 2001.

This study has two arms, on diagnostic and the other therapeutic. The
diagnostic arm is a prospective, observational multi-site study to
develop clinical guidelines to allow clinicians to provide antimicrobial
therapy for those children with a high probability of streptococcl
pharyngitis and therefore reduce indiscriminate use of antibiotic. The
therapeutic arm is a prospective randomized, open label, active control
equivalence study comparing intramuscular benzathine penicillin G with a
single daily dose of amoxycillin.

**Implementing Organization:** BU/ARCH

**Status:** Completed (Funded: FY1998; Completed: FY2000)

**Rationale:** The widespread and inappropriate use of antibiotics in
the treatment of simple pneumonia, which is often non-bacterial in
origin, is potentially a major contributor to the development of AMR.

**Objective(s):** The main objective of the study is to strengthen the
ARI research portfolio towards reducing the unnecessary use of
antimicrobials for non-severe pneumonia. The goal of the first stage
observational component of the study was to determine clinical failure
rates using a standard case management approach. This observational data
was used to determine the feasibility of conducting a second stage study
to determine the safety and efficacy of a placebo controlled equivalency
trial comparing no antimicrobials with the use of amoxycillin. These
findings on the latter study would support the more restricted use of
antibiotics in non-severe pneumonia and if adopted, would significantly
reduce the pressure for the development of antibiotic resistance as well
as the cost of care.

**Description and Countries/Regions:** This study will determine the
feasibility of conducting a placebo controlled study of oral amoxycillin
in the treatment of non-severe pneumonia. Specific aims sought will be
the proportion of children with antibiotic exposure prior to
presentation to the health facility, proportion with signs of
consolidation on X ray and the failure rate of oral amoxycillin in the
treatment of non-severe pneumonia. The research studies will be
conducted in South Africa and Vietnam.

**Expected Outputs, Results, and Progress Indicators:** The principal
output of this component is the conduct of the specified research
studies, their analysis, and the dissemination of the results to the
global and national programs responsible for ARI case management.
Researchers and policymakers concerned with slowing the spread of AMR
will also benefit from the research results.

**Countries/Regions:** South Africa and Vietnam.

**Partners/Collaborating Institutions:** All the activities will operate
within well-functioning consortia with WHO/CAH (see activity 5.13:
\"Increased Specificity of Treatment Guidelines for Non-Severe
Pneumonia\").

**Results to Date:** The study was completed in 2000. Because of a high
degree of prior antibiotic exposure (up to 44%) and the presence of
signs of consolidation on chest x-ray in more than 20% of cases, it was
deemed that a placebo-controlled study (see 5.13) would not be feasible
in these populations.

**Implementing Organization:** WHO/CAH

**Status:** On-going (Funded: FY1998; Expected Completion: FY2001)

**Rationale:** At present WHO ARI Control Programme recommends oral
antimicrobials for the treatment of non-severe pneumonia for five days.
Cotrimoxazole is recommended two times a day as compared for oral
amoxicillin, which is recommended three times a day. It is also known
that the patients do not comply well with the recommended duration of
therapy for five days and may take the antimicrobials for as little as
2-3 days. Similarly, often they may take oral medicines twice a day
instead of thrice a day. There are two very important public health
issues related to these problems. First, what are the implications of
this \"shorter\" duration of antimicrobial use on development of AMR.
Second, oral amoxicillin is three times more expensive than oral
cotrimoxazole. If it were shown that a shorter duration (3 days) of oral
amoxicillin is as efficacious as 5 days of therapy, it would have
profound implications for the public health policy. It would reduce the
cost of treatment and will also improve the patient compliance to
treatment. There is a need to find out the effect of a shorter course of
therapy on AMR for *Streptococcus pneumoniae* and *Haemophilus
influenzae* and whether it is as efficacious as the normal five days
course of oral amoxicillin for non-severe pneumonia. We expect that
conducting a clinical efficacy trial by comparing the two regimens and
collecting the AMR data can answer this question.

**Objective(s):** To study which duration (3 versus 5 days) is less
likely to lead to the emergence of resistant strains of *S. pneumoniae*
and *H. influenzae* and to test the efficacy of 3 days oral amoxicillin
therapy as compared to five days therapy for non-severe pneumonia.

**Description:** The aim of this research is to optimize antimicrobial
use for childhood diseases to slow the emergence and spread of AMR. In a
multi-centre trial, non-severe pneumonia cases among children 2-59 month
old will be randomized to two treatment groups. One group will be
randomized to oral amoxicillin for 3 days followed by 2 days placebo in
a blinded manner and the other group will be randomized to oral
amoxicillin for 5 days. Nasopharyngeal isolates will be obtained before
and after treatment to see the resistance levels of *S. pneumoniae* and
*H. influenzae* to penicillin, cotrimoxazole, ampicillin etc.

**Expected Outputs, Results, and Progress Indicators:**

[Outputs]{.underline}: a shorter course of oral amoxicillin is less
likely to lead to the emergence of resistant strains of *S. pneumoniae*
and *H. influenzae*; simplified IMCI treatment guidelines.

[Progress Indicators]{.underline}: development of a research protocol;
initiation of data collection.

**Countries/Regions:** Pakistan (total of 6 hospitals in Gilgit,
Islamabad, Lahore, Multan, and Rawalpindi.)

**Partners/Collaborating Institutions:** CDC/Respiratory Diseases Branch
is planning to conduct a study the impact of compliance on development
of AMR. Theirs is an observational study and they do not plan to do any
intervention. We will collaborate with them so that there is no
duplication of the data and both studies complement each other's
results.

**Results to Date:** The study conducted in Islamabad was completed in
2001 and the results were presented at the IUATLD meeting (Paris,
November 1-4)---see abstract below presented by Dr. T. Hazir.

> "The optimum duration of therapy for most infections, especially ARI,
> is not based on strong scientific evidence. Conventionally antibiotics
> are used till patient is afebrile or laboratory parameters are normal.
> Use of antibiotics contributes to the development of AMR. If a shorter
> course is found to be effective for treatment of pneumonia, it would
> reduce the cost of treatment, enhance patient compliance and
> contribute toward containment of AMR. In this study we compared the
> clinical efficacy of 3 days vs 5 days of oral amoxicillin for
> treatment of non-sever pneumonia. In this multicentre double blind
> randomized controlled trial, we recruited 1953 children, aged 2-59
> months, with non-severe pneumonia (WHO criteria) diagnosed in the
> outpatient departments of seven hospitals in five cities of Pakistan.
> Patients were randomly assigned on and 1:1 basis to either 3 days or 5
> days of amoxicillin therapy. Oral amoxicillin was given 15 mg/kg/dose
> thrice a day. The primary outcome was treatment failure, which
> included change of antibiotic therapy or death. 980 children were
> randomized to 3 days and 973 to 5 days duration of amoxicillin
> therapy. Five days after enrolment, the treatment failure in the 3
> days group was 18.1% as compared to 16.5% in the 5 days group. No
> significant differences were found in the two therapeutic groups.
> Chest radiograph was obtained in 1847 children, of which 259 had
> radiological pneumonia. Of the 475 naso-pharangeal aspirates obtained,
> 99 were positive for RSV. The treatment failure rate was more likely
> in infants (OR 1.43, 95% CI 1.12-1.18), who had respiratory rate \> 60
> breaths per minute (OR 1.44, 95% CI 1.007-2.06) or those who had been
> ill longer before presentation (OR 1.59, 95% CI 1.20-2.11). In
> conclusions, three days duration of therapy with oral amoxicillin was
> as effective as 5 days therapy for treatment of non-severe pneumonia
> in children 2-59 months old. However, with a high therapy failure in
> both groups, the treatment guidelines need to be reviewed."

The results of this study have been submitted for publication.

**Implementing Organization:** WHO/CAH

**Status:** On-going (Funded: FY1998; Expected Completion: FY2003)

**Rationale:** At present WHO ARI Control Programme recommends oral
antimicrobials for the treatment of non-severe pneumonia for five days.
Cotrimoxazole is the first line antimicrobial recommended two times a
day. It is also known that the patients do not comply well with the
recommended duration of therapy for five days and may take the
antimicrobials for as little as 2-3 days. There are two very important
public health issues related to these problems. First, what are the
implications of this \"shorter\" duration of antimicrobial use on
development of AMR. Second, if three days treatment is as effective as
five day therapy, it would reduce the cost of treatment and will also
improve the patient compliance to treatment. There is a need to find out
the effect of a shorter course of therapy on AMR for *S. pneumoniae* and
*H. influenzae* and whether it is as efficacious as the normal five days
course of oral cotrimoxazole for non-severe pneumonia. We expect that
conducting a clinical efficacy trial by comparing the two regimens and
collecting the AMR data can answer this question.

**Objective(s):** To study which duration (3 versus 5 days) is least
likely to lead to the emergence of resistant strains of *S. pneumoniae*
and *H. influenzae*; to study whether 3 days oral cotrimoxazole therapy
is as efficacious as five days of therapy for non-severe pneumonia.

**Description:** The aim of this research is to optimize antimicrobial
use for childhood diseases to slowdown the emergence and spread of AMR.
In a multi-centre trial, non-severe pneumonia cases among children 2-59
month old will be randomized to two treatment group. One group will be
randomized to oral cotrimoxazole for 3 days followed by 2 days placebo
in a blinded manner and the other group will be randomized to oral
cotrimoxazole for 5 days. Nasopharyngeal isolates will be obtained
before and after treatment to see the resistance levels of *S.
pneumoniae* and *H. influenzae* to penicillin, cotrimoxazole, ampicillin
etc.

**Expected Outputs, Results, and Progress Indicators:** It is expected
that shorter course of oral cotrimoxazole is less likely to lead to the
emergence of resistant strains of *S. pneumoniae* and *H. influenzae*.
Development of simplified treatment guidelines for non-severe pneumonia,
for inclusion in the IMCI package.

[Progress Indicators]{.underline}: development of a research protocol;
initiation of data collection.

**Countries/Regions:** Bangladesh (Shishu Hospital) and Indonesia
(Bandung)

**Partners/Collaborating Institutions:** None.

**Results to Date:** A protocol to investigate the efficacy of short
course treatment with oral cotrimoxazole for non-severe pneumonia and
its relationship with AMR has been finalized. Two sites, one in
Bangladesh and one in Indonesia, have been identified. The study
objectives are: (i) determine the clinical efficacy of a 3-day course of
oral cotrimoxazole in the treatment of non-severe pneumonia compared to
the standard 5-day course of oral cotrimoxazole; and (ii) monitor the
emergence of resistant strains of *Streptococcus pneumoniae* and
*Haemophilus influenzae* in the two treatment groups. Delays have been
experienced in gaining local ethical clearance. Data collection began in
September 2001.

**Implementing Organization:** WHO/CAH

**Status:** Discontinued (Funded: FY1998)

**Rationale:** In the past decade, resistance to commonly used
antimicrobials among bacteria causing acute respiratory disease (ARI) in
children has increased in prevalence. This has raised concerns about the
current clinical management guidelines for non-severe pneumonia
recommended by the World Health Organization (WHO) for use in the
developing world. Many children with simple pneumonia treated according
to the WHO guidelines are lost to follow-up, and many do not complete
the recommended course of therapy because they may improve quickly. This
may mean that the duration of an appropriate antimicrobial regimen may
be too brief, and that any left over medicine may be used
inappropriately in the future. Both of these behaviours are potential
risk factors for the selection and amplification of drug resistance
genes among respiratory pathogens. When the WHO ARI guidelines were
first developed, it was recognized that many, if not the majority of
children with so-called non-severe pneumonia may have non-bacterial
infections and would not benefit from the use of antimicrobials.
However, to maximize the number of children treated who really need
antimicrobials, all children with fast breathing were recommended for
antimicrobial treatment at the cost of also treating many children who
did not need a drug. At that time, however, AMR was not common among the
major lower respiratory tract bacterial pathogens. Because of increase
in the AMR it has become essential to reduce unnecessary and
inappropriate antimicrobial use, and increase the specificity of the WHO
management guideline. If antimicrobial treatment for non-severe
pneumonia can be shown to be of little benefit in some well defined
cases, there would be a justification to revise the present clinical
management guideline so that patients at low risk of bacterial infection
would not receive an antimicrobial at the initial encounter.

**Objective(s):** To determine whether children 2 to 59 months of age
with WHO defined non-severe pneumonia have an equivalent clinical
failure rate when they are treated with oral amoxicillin compared to no
amoxicillin; to improve the specificity of treatment guidelines for
non-severe pneumonia.

**Description:** In a multi-center trial of non-severe pneumonia among
children 2-59 month old cases will be randomized to two treatment
groups. One group will be randomized to oral amoxicillin for 5 days and
the other group will be randomized to oral placebo for 5 days. Blood
cultures nasopharyngeal swabs for *S. pneumoniae* and *H. influenzae*
and nasopharyngeal aspirates for RSV virus will be obtained in these
children.

NOTE: The sample size needed to answer this question is much bigger
study than what was anticipated before the proposal development
workshop. It means that some sites would have to collect data for up to
18 months in order to get enough patients over two acute respiratory
infection (ARI) seasons. It is expected that approximately one-third of
this amount will be spent on microbiology and the rest on the clinical
aspects of the study.

**Expected Outputs, Results, and Progress Indicators:**

• Development of revised recommendations for the management of WHO
defined non-severe pneumonia, to be included in the IMCI case management
guidelines;

• A research protocol has been developed in a proposal development
workshop (Canberra, Australia) to answer this question;

• Oral amoxicillin is as effective as no oral amoxicillin in WHO defined
non-severe pneumonia;

• Building research capacity regarding clinical, epidemiology and
microbiology of the involved institutions.

[Progress Indicators]{.underline}: development of a research protocol;
initiation of data collection.

**Countries/Regions:** Vietnam (Ho Chi Minh City) and South Africa
(Durban).

**Partners/Collaborating Organizations:** This will be a large
multi-center trial. BU/ARCH and WHO/CAH co-funded the proposal
development workshop in Canberra, Australia and will co-ordinate the
study together (see activity 5.10: \"A Multi-Center, Prospective,
Observational Study of Clinical Outcome Following Amoxycillin Treatment
of Non-Severe Acute Respiratory Infection\"). INCLEN also supported one
researcher and one facilitator to attend the proposal development
workshop.

**Results to Date:** The feasibility of conducting this study was
dependant on the outcome of activity 5.10 (above) which was a
preliminary observational cohort study of the failure rate and frequency
of prior antimicrobial use in a population of children 2-59 months. The
descriptive studies in Vietnam and Durban to investigate the case
management of non-severe pneumonia, with and without wheeze, have been
completed and the results presented at the 2001 IUATLD meeting (Paris,
November 1-4)---see abstract below presented by Dr. D. Thea.

> "IMCI guidelines recommend antibiotic use in children with non-severe
> pneumonia (NSP) but concern with increasing AMR requires a
> re-evaluation of this policy. Much NSP in non-bacterial, and does not
> pose a high risk of ARI mortality. Inappropriately treated children
> may be exposed to the known risks of antibiotic use and the community
> is at risk of the potential selection of drug resistant strains. The
> goal of this study was to determine the failure rate of standard
> therapy for NSP (amoxicillin), its association with RSV and level of
> prior antibiotic use in children 2-59 months old with NSP. This study
> was a prospective single-arm observational study based at two sites:
> Referral Centres in Durban, South Africa and Ho Chi Minh City,
> Vietnam. The study population comprised children 2-59 months of age
> presenting with cough and tachypnea without sign of severe or very
> severe pneumonia. Children with malnutrition, hypoxemia (\<90%), or
> conditions requiring antibiotic treatment, or measles within the last
> month were excluded. CXR and nasal aspirate were obtained at enrolment
> and the subjects were given oral amoxicillin X 5 days. Subjects were
> evaluated at 48 hours, 5 days (primary outcome) and 10 days for signs
> of pneumonia. Failure was defined as persistence (5 and 10 days) or
> deterioration of signs of NSP, or change of antibiotic. RSV antigen
> was determined from nasal washings using a standard clinical kit
> (Abbot). 194 subjects were enrolled in the two study sites; 95 in
> Vietnam and 99 in Durban. Subjects enrolled at the Durban site were
> significantly more likely at presentation to be febrile (96% vs. 72%),
> stunted (-1.0 vs. --0.2 HFA Z-score), have a higher RR (57 vs. 50
> bpm), positive CXR (75% vs. 48%), and significantly less likely to
> have used antibiotics for the current episode (11% vs. 44%).
> Cumulative failure was 2.6%, 5.7%, and 11% at 48 hrs, 5 days and 10-12
> days, respectively. RSV was detected in 23% of children and was
> associated with failure at 48 hours and wheezing at presentation (40%
> vs. 21%, p\<0.05). Prior antibiotic use occurs in a high proportion of
> children presenting to these facilities with NSP. Failure of
> amoxicillin therapy in NSP occurs approximately 6% of cases on day 5
> and was associated with the presence of RSV in nasal aspirates."

**Implementing Organization:** WHO/CAH and BU/ARCH

**Status:** On-going (Funded: FY1998; Expected Completion: FY2003)

**Rationale**: The ARI case management guidelines recommend use of oral
antimicrobials for non-severe pneumonia, which is defined as cough or
difficult breathing plus fast breathing. This is recognized to be a
definition of pneumonia that is relatively imprecise, and results in the
inclusion of substantial numbers of children that have bronchospasm due
to asthma, RSV infection or hyper-reactive airway disease rather than
pneumonia. A more precise definition of non-severe pneumonia would
assist in patient care decisions and in efforts to minimize the
inappropriate use of antibiotics.

If antimicrobial treatment can be shown to be of little benefit to
children presenting with wheezing and inappropriately categorized as
having non-severe pneumonia, there would be a justification to modify
the present ARI case management guidelines so that these children do not
receive an antibiotic.

In order to determine how to increase the specificity of ARI case
management guidelines, WHO convened a meeting of members of the ARCH
Project and six clinical researchers in the field of respiratory
infections and wheezing to seek their opinions about this issue in
December, 2000. This panel recommended that studies be undertaken to
assess the efficacy of a new therapeutic approach for children with
suspected non-severe pneumonia who present with wheezing. While the
experts acknowledged the value of studying this through a randomized
controlled trial (RCT), some recommended collecting more descriptive
data before designing such a clinical trial.

In order to define the research question, the technical consultation
discussed the methodological issues related to this research. Current
published and unpublished data from India, Pakistan, Thailand, and
Vietnam were reviewed with the intent of designing a study to refine the
ARI case management guidelines concerning children presenting with
difficulty breathing and wheezing. However, in discussing the
characteristics of the study question (i.e., study population,
intervention, effect of intervention and outcome) several limitations to
the RCT were identified:

-   A relatively small proportion of children with non-severe pneumonia
    have audible wheezing.

-   Relatively large numbers of children presenting with cough or
    difficult breathing receive antibiotics before presentation to the
    hospital, thus enrolling patients who have not received antibiotics
    will be quite challenging

-   A fairly large number of patients, categorized as non-severe
    pneumonia with wheezing, will be required to address this issue.

-   There are ethical concerns about the possibility of increases in
    mortality in non-severe pneumonia patients randomized to placebo.

-   Data from a non-severe study in Vietnam suggested that the likely
    impact of antibiotic over-prescription in cases categorized as
    non-severe pneumonia plus wheezing may be small, although these data
    did not include data from the RSV bronchiolitis \'season\'.

The panel of experts was also concerned that health workers do not
consistently recognize wheezing. Because wheezing is audible in only
one-third of cases, many children with signs of pneumonia but inaudible
wheezing may be inaccurately categorized as non-severe pneumonia, and
inappropriately given antibiotics rather than a trial of
bronchodilators.

It was concluded that available information was inadequate to design a
RCT that was feasible and not prohibitively expensive. It was decided
instead to conduct a study to model the likely impact of (i) improving
the clinical recognition of wheezing, and (ii) more extensive use of
rapid acting bronchodilators in this population of children. This
information would be helpful in determining the feasibility of a RCT.

**Objective(s):** To determine the feasibility of a conducting a RCT to
assess the need for antimicrobial treatment of children 2-59 months of
age who present with fast breathing and wheeze and to increase the
specificity of treatment guidelines for children with wheezing diagnosed
as WHO defined non-severe pneumonia.

**Description:** In a multi-center trial of children 2-59 month old with
wheeze who are determined to be suffering from non-severe pneumonia will
be observed for 5-7 days after treatment with oral bronchodilators for
recurrence or treatment failure. Nasopharyngeal swabs for *S.
pneumoniae* and *H. influenzae* and nasopharyngeal aspirates for RSV
virus will be obtained in these children.

**Expected Outcomes, Results, and Progress Indicators:**

• Development of revised recommendations for the management of wheezing
children, to be included in the IMCI case management guidelines;

• Determination of the feasibility of mounting a RCT of oral amoxicillin
compared with placebo in children with wheezing assessed as WHO defined
non-severe pneumonia;

• Building research capacity regarding clinical, epidemiology and
microbiology of the involved institutions.

[Progress Indicators]{.underline}: development of a research protocol;
initiation of data collection.

**Countries/Regions:** The study will be conducted in Colombia, Egypt,
Ghana, India, Pakistan, and Thailand.

**Partners/Collaborating Organizations:** This will be a large,
multi-center trial. BU/ARCH and CHD/WHO co-funded the proposal
development and will co-ordinate the study together (see activities 5.10
and 5.13).

**Results to Date:** Work progressed to increase specificity of
treatment guidelines for children with wheezing diagnosed as
WHO-defined, non-severe pneumonia. A model research proposal was
developed, reviewed and finalized during a workshop held in Geneva in
December 2000. A multi-centre study involving six countries (Colombia,
Egypt, Ghana, India, Pakistan and Thailand) will soon be initiated. The
main objectives of the study are to: (i) follow the clinical course of
children 1-59 months presenting in the outpatient department (OPD) with
wheeze along with cough and difficult breathing; (ii) define the
clinical characteristics of children with wheeze; and (iii) determine
how many children treated for wheeze relapse within 7 days.

**Implementing Organization:** BU/ARCH and WHO/CAH

**Status:** On-going (Funded: FY1998; Expected Completion: FY2002)

**Rationale:** At present for WHO defined severe pneumonia treatment
with injectable benzyl penicillin is recommended after the child has
been hospitalized. There are several issues, which are related to this
hospitalization. First is higher cost of therapy, hospitalization and
other indirect costs. Second, risks associated with hospitalization such
as nosocomial infections, risks of injectable therapy leading to
hepatitis B and C, HIV and other viral infections. Finally, in some
circumstances the referral to the hospital may not be possible due to
economic or logistic reasons. In one study from Pakistan oral
amoxicillin was found quite efficacious in children with WHO defined
severe pneumonia. If these results were replicable in other settings, it
would be possible to reduce the number of referrals and admissions for
injectable therapy, which will in turn result in less nosocomial
hospital infections. It is also expected that it is also less likely to
lead to emergence of penicillin-resistant strains of *S. pneumoniae* and
*H. influenzae*. This study has very important implications for the
Integrated Management of Childhood Illnesses (IMCI) strategy. It will
optimize antimicrobial use for childhood diseases to slowdown the
emergence and spread of AMR.

**Objective(s):** To determine whether children 2 to 59 months of age
with WHO defined severe pneumonia have an equivalent clinical failure
rate when they are treated with oral amoxicillin compared to injectable
penicillin.

**Description:** In a multi-centre trial, severe pneumonia cases among
3-59 months old will be randomized to either therapeutic regimen. One
group will be randomized to oral amoxicillin for 7 days and the other
group will be randomized to injectable benzyl penicillin for 7 days.
Nasopharyngeal swabs will be obtained from all patients to assess
penicillin-resistant strains of *Streptococcus pneumoniae* and
*Haemophilus influenzae*. NOTE: The sample size needed to answer this
question is more than 1700 severe pneumonia patients. This is a much
bigger study than what was anticipated before the proposal development
workshop. It means that some sites would have to collect data for up to
18 months in order to get enough patients over two acute respiratory
infection (ARI) seasons. This funding will be used for both clinical and
microbiology work planned for this study.

**Expected Outputs, Results, and Progress Indicators:**

-   Development of revised recommendations for the management of severe
    pneumonia, to be included in the IMCI case management guidelines;

-   A research protocol has been developed in a proposal development
    workshop (Durban, South Africa) to answer this question;

-   Oral amoxicillin is as effective as injectable benzyl penicillin in
    WHO defined severe pneumonia;

-   This study will improve the capacity for epidemiological and
    microbiological research in the institutions involved.

[Progress Indicators]{.underline}: development of a research protocol;
initiation of data collection.

**Countries/Regions:** The study will be conducted in South Africa
(Departments of Paediatrics Child Health at University of Cape Town,
Cape Town and University of Natal, Durban), Ghana (Kitampo Vitamin A
Project (KIVAP), Kintampo), Zambia (Tropical Diseases Research Centre,
Ndola), Colombia (Unidad de Epidemiologia Clinica, Faculdad de Medicina,
Pontifica Universidad Javeriana Carrera, Bogota), Mexico (Division de
Investigacion Medica, Instituto Nacional de Pediatria, Mexico), and a
few countries in Asia (India, Pakistan, and Vietnam).

**Partners/Collaborating Institutions:** BU/ARCH (WHO and ARCH co-funded
the proposal development workshop in Durban, South Africa and will
co-ordinate the study together).

**Results to Date:** The multi-centre clinical trial to compare the
efficacy of injectable penicillin with oral amoxycillin in the treatment
of severe pneumonia in children is progressing in seven of the original
sites (Colombia, Ghana, India, Mexico, Pakistan, South Africa/Durban,
and Vietnam), but not in South Africa/Capetown or Zambia, which has had
decreasing patient enrollment. Interim analyses were performed in April
2000 and April 2001 by the Data Safety and Monitoring Board (DSMB) that
confirmed the originally calculated sample size. So far, enrollment for
this study has reached 75% of the projected sample size. Therefore,
patient recruitment in this study will continue until April 2002.

A data analysis workshop for investigators from all sites involved in
the study is being planned for June/July 2002. A draft article for
publication will be written by the end of 2002.

**Implementing Organization:** BU/ARCH and WHO/CAH

**Status:** On-going (Funded: FY1998; Expected Completion: FY2003)

**Rationale:** WHO ARI case management guidelines categorize pneumonia
in children 2-59 months old into non-severe, severe and very severe
pneumonia. Children suffering from very severe pneumonia are referred
for hospitalization and injectable chloramphenicol therapy. Although,
pneumonia was recognized as the major killer of children under five
years old, not much data was available for ideal treatment of these very
sick children diagnosed as very severe pneumonia. A number of
experienced paediatricians from developed and developing countries were
consulted and taking into account efficacy and cost, they recommended
chloramphenicol as the drug of choice for very severe pneumonia.

This recommendation needs to be re-visited. First, many of these
children assessed as very severe pneumonia may in fact also have
bacterial meningitis or septicaemia. Symptoms and clinical signs overlap
for these three conditions. Data shows that in presence of AMR, a number
of these children with bacterial meningitis may not respond to
injectable chloramphenicol. Second, there is limited data on the
aetiology of very severe pneumonia cases. Data showed *H. influenzae*
and *S. pneumoniae* to be the common bacterial organisms causing
bacterial meningitis, non-severe and severe pneumonia cases. It is
possible that for very severe pneumonia, some other bacteria are
responsible which are less susceptible to chloramphenicol. Finally, many
paediatricians do not believe chloramphenicol is the right treatment and
use a combination of penicillin and gentamicin instead. There is lack of
scientific data to support either choice.

**Objective(s):** Identify bacteria causing very severe pneumonia and
document their AMR pattern; compare the clinical efficacy of injectable
chloramphenicol with injectable penicillin plus gentamicin for very
severe pneumonia cases in children less than five-year-old.

**Description:** In a clinical trial, very severe pneumonia cases among
2-59 months old children will be randomized to two treatment groups. One
group will be randomized to injectable chloramphenicol for 7 days and
the other group will be randomized to a combination therapy of
injectable penicillin and gentamicin for 7 days. Blood cultures will be
obtained to document the aetiology and susceptibility patterns of
etiologic agents. Nasopharyngeal swabs would be obtained to document
carriage and resistance rates in children with very severe pneumonia.

**Expected Outputs, Results, and Progress Indicators:**

• Development of revised recommendations for the management of children
with very severe pneumonia, to be included in the IMCI case management
guidelines;

• Better scientific data to improve treatment guidelines for very severe
pneumonia cases, resulting in more appropriate antimicrobial use in the
referral level facilities.

[Progress Indicators]{.underline}: development of a research protocol;
initiation of data collection.

**Countries/Regions:** Study sites include Bangladesh, India, Mexico,
Pakistan, Yemen, and Zambia.

**Partners/Collaborating Organizations:** BU/ARCH coordinates this
activity with WHO/CAH.

**Results to Date:** The study has been initiated in eight tertiary care
hospitals in six countries (Bangladesh, India, Mexico, Pakistan, Yemen
and Zambia). Enrollment for this study is approximately 35% of the
desired sample size. It is projected to continue for another 12-18
months.

Implementing Organization: CDC/NCID

Status: On-going (Funded: FY1998; Expected Completion: FY2005)

Rationale: Epidemological, laboratory, and other technical expertise are
important for the development and conduct of surveillance, for
investigation of the factors contributing to the spread of resistance,
and for the development and evaluation of intervention programs.
Development of a global strategy for investigation and prevention of AMR
is important so that activities can be focused on the highest priority
areas and can be coordinated to achieve the greatest impact. In
addition, promoting the goal of controlling AMR with USAID personnel and
Ministries of Health may lead to more activities and support for this
activity.

Objective(s):

1)  Provide epidemiological and laboratory assistance to other
    organizations participating in activities to combat the spread of
    AMR.

2)  Assist in the development of a global strategy to address the spread
    of AMR.

Description: CDC epidemiologists have considerable international
experience in development and evaluation of surveillance, investigation
and intervention programs. In addition, there is a long history of
collaboration with WHO and other international organizations on issues
related to child survival and AMR. Given this background and context, we
propose CDC participates in the development of a global strategy to
address the spread of AMR and, at USAID's request, participate in the
technical review of proposals and consultancies with other partners.
Similarly, CDC laboratory personnel and epidemiologists can provide
expert review and training at CDC or in the field.

Expected Outputs, Results, and Progress Indicators:

-   Technical assistance to countries requesting laboratory and
    epidemiological consultations.

-   Training of foreign scientists.

-   Consultations with partners to help develop global strategy.

Countries/Regions: Argentina, Bangladesh, Brazil, Chile, Czech Republic,
Dominican Republic, Ecuador, the Gambia, Ghana, Kenya, Mexico, Peru,
South Africa, Uruguay, Zimbabwe, as well as Global activities via WHO,
USAID, WHO/AFRO and PAHO.

Partners/Collaborating Institutions: WHO; other organizations requesting
assistance

Results to Date:

1)  Development and publication of review requested by USAID; findings
    disseminated in [Clinical Microbiology Reviews]{.underline} \[Schrag
    SJ, Beall B, and SF Dowell (2000) Limiting the spread of resistant
    pneumococci: biological and epidemiologic evidence for the
    effectiveness of alternative interventions. [Clinical Microbiology
    Reviews]{.underline} *13* (4): 588-601.\] *(Reprint enclosed.)*

2)  Support of participation in international pneumococcal resistance
    meeting

3)  Support of international researcher's attendance to present on
    resistance at International Conference on Emerging Infectious
    Diseases (Atlanta, Georgia, USA).

4)  Support of laboratory supplies and educational materials for
    training purposes.

5)  Participation in meetings sharing information with other
    international public health agencies to inform policy and practice.

6)  Technical consultation for study of pneumococcal disease in The
    Gambia, West Africa.

7)  Technical assistance with analysis of epidemiological and
    microbiological data.

8)  Training of microbiologists from Bangladesh, Brazil, Chile, Czech
    Republic, Denmark, Dominican Republic and Mexico at the CDC
    Streptococcal Reference Laboratory (a WHO Collaborating Center for
    Streptococcal Research).

9)  Facilitation of microbiologic testing of pneumococcal cultures from:
    Argentina, Brazil, Canada, Chile, Dominican Republic, Ecuador,
    Mexico, Nepal, Peru and Uruguay.

10) Support of coordinator for capacity-building, epidemiology and
    laboratory training activities.

11) Technical consultations to support development of country-level
    surveillance for AMR.

12) Participation in meetings to develop global strategy to combat AMR
    and to boost laboratory and epidemiological capacity.

Implementing Organization: CDC/NCID

**Status:** On-going (Funded: FY1999; Expected Completion: FY2003)

**Rationale:** *Streptococcus pneumoniae* is the predominant cause of
bacterial pneumonia and a major cause of meningitis, sepsis, and ear
infections. This organism has become increasingly resistant to multiple
classes of oral and parenteral antibiotics, complicating clinical
management decisions and increasing the cost of caring for children in
both developed and resource-poor countries. Protein-polysaccharide
conjugate vaccines directed against 7, 9, or 11 pneumococcal serotypes
are under investigation in several countries. A 7-valent formulation was
shown to be efficacious against bacteremic disease, otitis media, and
radiographically confirmed pneumonia with consolidation among infants
studied in a Northern California managed care population. Preliminary
studies suggest that pneumococcal conjugate vaccines reduce
nasopharyngeal carriage of pneumococci due to serotypes included in the
vaccine, but may increase carriage of other serotypes (non-vaccine
types). To date, the majority of pneumococci associated with penicillin
resistance are caused by serotypes included in the seven-valent
protein-polysaccharide conjugate vaccine formulation. In the United
States, where the vaccine was approved for use in early 2000 but has not
yet been widely administered, data from the Active Bacterial Core
surveillance (ABCs) system estimates the proportion of resistant
invasive pneumococcal disease caused by vaccine-serotypes to be 77%. A
study of a Northern California managed care population showed the
7-valent conjugate vaccine to be efficacious against bacteremic disease,
otitis media and radiographically-confirmed pneumonia with consolidation
among infants. Preliminary studies also suggest that pneumococcal
conjugate vaccines may reduce nasopharyngeal carriage of
vaccine-serotypes and increase carriage of non-vaccine serotypes.
Because the carriage of *S. pneumoniae* in the nasopharynx is associated
with its transmission, and because it is believed that the vaccine will
effectively target those invasive serotypes that carry resistance, we
hypothesize the conjugate vaccine may effectively function as an
anti-resistance tool.

The potential for pneumococcal conjugate vaccines to reduce
nasopharyngeal colonization and therefore transmission of drug resistant
pneumococci is great. While large and small-scale studies of
immunogenicity and effectiveness of pneumococcal conjugate vaccine are
in progress, the focus of most of these is impact of vaccine on clinical
endpoints (bacteremia, otitis media, pneumonia) rather than AMR.
Quantifying the impact of conjugate vaccine on resistant carriage will
provide important data for decision-makers trying to determine potential
benefits of these new prevention tools. We propose a study to be located
in a community with high-prevalence of drug-resistant pneumococci
designed to assess the impact of widespread introduction of pneumococcal
conjugate vaccine on carriage of drug resistant pneumococci. We will
focus susceptibility testing on both beta-lactam agents (*e.g.*,
penicillin, amoxicillin, or cephalosporin) and
trimethoprim-sulfamethoxazole, the first line therapeutic agents for
respiratory infections in most developing countries. High-level
penicillin-resistant organisms are considered to be markers for
pneumonia treatment failures.

Objective(s):

1)  Determine the impact of widespread introduction of pneumococcal
    conjugate vaccine on carriage of penicillin and
    trimethoprim-sulfamethoxazole nonsusceptible pneumococci in
    vaccinated infants and unvaccinated older children.

2)  Determine the impact of widespread introduction of pneumococcal
    vaccine on carriage of susceptible pneumococci in vaccinated
    infants.

**Description:** Rates of pneumococcal disease are higher among the
Alaska Native population than the general population of the United
States, with rates of invasive pneumococcal disease similar to rates
found in the developing world. This project involves sequential carriage
studies in children before and at increasing community levels of uptake
of pneumococcal conjugate vaccine.

Investigators use cluster design for sequential assessments of
pneumococcal carriage and include collection of simple data elements
regarding relevant confounders and/or risk factors for the carriage of
resistant pneumococci. Characterization of the serotype will be
performed to evaluate vaccine impact.

**Expected Outputs, Results, and Progress Indicators:** The
[output]{.underline} of the study will be a report comparing the
proportion of children before and after the introduction of conjugate
vaccine to the population who are colonized with nonsusceptible
pneumococci. These data will fill a gap in understanding of the full
impact of pneumococcal conjugate vaccines which in some areas will help
overcome barriers to vaccine use. [Progress indicators]{.underline} will
include: (1) identification of partner organizations, research
collaborators, and potential field setting for study; (2) development of
protocol in concert with local investigators; (3) obtaining appropriate
OPRR approved project assurance and IRB approvals (by local ethics
committee, CDC IRB, and other partners as appropriate); (4) training of
laboratory and field staff in study methods; (5) conduct vaccination and
initial carriage study; (6) completion of laboratory studies on baseline
carriage study; (7) analyze risk factors for resistant carriage at
baseline; (8) complete follow-up carriage studies (likely to be two
annual carriage studies); (9) analysis of epidemiologic and laboratory
results from follow-up carriage studies; (10); presentation of study
results to local authorities, research community, and partners; and (11)
publication of final report of study results.

Countries/Regions: This study takes place in Anchorage, Alaska, but
falls under the USAID International Antimicrobial Resistance Initiative
as a result of population health disparities between the Alaska Native
population and the rest of the United States. (Alaskan villages are a
suitable setting because of the anticipated widespread introduction of
conjugate vaccines in the United States before other sites in the world,
the availability of baseline data on resistance, the availability of
ongoing laboratory-based surveillance for invasive disease, and the fact
that Alaskan villages reflect developing country settings with very high
rates of respiratory and invasive pneumococcal diseases.)

Partners: Arctic Investigations Program (NCID/CDC); Alaska Native
Medical Corporation.

Results to Date:

1)  Two trips to Alaska by epidemiologists for collection of baseline
    data and collection of early post-vaccine exposure data.

2)  Initial prevalence of cotrimoxazole resistance was very high
    (\>75%); and 36% of isolates were nonsusceptible to penicillin.

3)  At very early stages of vaccine uptake, overall resistance was
    unchanged although the clinic with the highest proportion of
    participants receiving at least one dose of vaccine showed a
    significant increase in overall carriage and a decrease in carriage
    of strains resistant to cotrimoxazole.

4)  Preliminary results have been disseminated locally to clinicians and
    will be presented at the 2001 meeting of the Infectious Diseases
    Society of America.

5)  Follow-up studies in 2002 are essential to evaluate impact of higher
    vaccination coverage on carriage of nonsusceptible and susceptible
    strains and the persistence of trends detected in 2001.

# 

# Implementing Organizations: BU/ARCH and RPM/MSH

# 

**Status:** On-going (Funded: FY1999; Expected Completion: FY2004)

# Rationale: The 1997 International Conference on Improving Use of Medicines (ICIUM) marked a major milestone in international efforts to promote quality use of medicines by health providers and consumers, and to develop rational pharmaceutical policies. For the first time, there exist a consensus about appropriate methodologies for implementing and assessing interventions in these areas, coherent summaries of previous experience, as well as an agreed agenda of priority policy implementation and intervention research topics. Four organizations (WHO/EDM, INRUD, RPM, and ARCH) have collaborated to advance this agenda through a joint intervention research initiative, including a series of research proposal development workshops and a subsequent research program.

The overall goal of the post-ICIUM initiative is to increase the
capacity for drug use intervention research and to stimulate a critical
mass of research projects in the priority areas. The first phase of the
joint initiative has focused on interventions targeting the practices of
physicians, paramedics, and other health providers working in primary
care, hospital, or retail pharmacy settings. A call for proposals on
these topics by the sponsoring organizations resulted in 88 submissions
that were reviewed and prioritized. The top-ranked 22 of the
pre-proposals were invited to advance to the next stage of full proposal
development, either independently or during one of two proposal
development workshops that were held in 1998 in Yogyakarta, Indonesia
and Kampala, Uganda. These projects are either already underway or
nearing completion.

USAID has been an active participant both in ICIUM and in the growing
drug use intervention research initiative through its support to WHO/EDM
and to the ARCH and RPM programs. Many of the priority topics for
implementation and research identified at ICIUM are in areas of
traditional USAID interest, such as improving pharmaceutical management
of common childhood infections or reducing child and maternal mortality
through more effective drug use in hospitals. In 1998, the USAID AMR
Initiative enabled the expansion of the drug use portfolio to its
current level by supporting the development and implementation of
several proposals in the first phase that focused on antimicrobial use
by health providers.

The second phase of the joint initiative will emphasize the two
remaining research priority areas identified at ICIUM. First, proposals
have been sought in the areas of improving patient compliance with
antimicrobial therapy and improving patterns of antibiotic use within
households or in the wider community. Participants at ICIUM recognized
the critical need to inform and empower patients and consumers, who are
the ultimate decision-makers in the use of medicines. Although consumer
organizations and health educators have tried individual education and
media-based approaches to modify patient and community behavior, few
have been adequately evaluated. Effective patient and consumer education
about antibiotic use is a neglected area that requires focused research
to identify promising strategies, and much greater advocacy.

Secondly, there will be a call for proposals for studies evaluating
policies that affect the way antibiotics are used in the community.
Studies that critically examine the impacts of common economic and
pharmaceutical sector policies on use of antimicrobials are
conspicuously lacking, despite the fact that these policies are widely
employed. The topics and methods for these analyses could be diverse.
Studies might examine, for example, the impacts of including or
excluding a particular antimicrobial on a formulary or national
essential drug list; a change in national or district-level policy
regarding the antibiotic of choice for treating pneumonia; the impact of
decentralization and local purchasing on appropriate use on
antimicrobials; or the effects of increased patient cost-sharing for
brand name or reserve antibiotics.

As emphasized at ICIUM, both community-focused and policy-analytic
studies frequently require the use of multiple research methodologies,
quasi-experimental designs, and longitudinal analyses. Practical
examples of such methods and designs in developing countries are quite
limited. This set of studies will add to experience in this area, and
result in tools and approaches that can be employed in future studies.

Objective(s):

-   To identify practical methods and tools for evaluating
    community-oriented interventions or policies that seek to improve
    antimicrobial use;

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-   To facilitate the design, implementation, and evaluation of at least
    four intervention studies that aim to improve household and
    community drug use;

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-   To develop capacity to conduct and evaluate interventions or to
    evaluate policies intended to improve community use of
    antimicrobials

Description: This activity will follow the model for research capacity
building and successful proposal development that has been employed by
ARCH/ADDR for many years, and which formed the basis for the work in the
first phase of the drug use intervention initiative (see section 5.5).

During the first year, a request for proposals was circulated through
the research networks of the partners and other related organizations.
Twenty-two (22) pre-proposals were reviewed independently by each
partner, and priorities for support were made based on the collective
results of these reviews. Ten (10) research teams were invited to attend
a proposal development workshop in Bangkok, Thailand from November 29 --
December 8, 2000 in Bangkok, Thailand at which the research ideas were
clarified and developed into full proposals. These proposals are in the
process of being reviewed by a panel consisting of the workshop
facilitators and external reviewers, revised according to their
comments, and, when acceptable, approved for funding.

It is envisaged that at least four (4) studies will be implemented by
the research teams by early FY 2002. The typical study of this type will
be two years duration. Technical support will be provided as required
during the process of study implementation, with at least one visit per
year b technical experts to each study team.

During the third year, research teams will be invited to participate in
a data analysis workshop. Initial analyses of data will be completed,
and research teams will prepare policy briefs for disseminating results
of their studies at a local and national level. Their final reports will
be revised for publication in national and international scientific
journals in order to maximize the value of the lessons learned.

Expected Outputs, Results and Progress Indicators: It is expected that
this activity will result in the design, funding, and initiation of at
least 4-6 investigator-initiated studies on the priority topics by the
end of FY 2002; completion of the interventions and collection and
cleaning of outcomes data by the end of FY 2003; and completed data
analyses, study reports, and policy dissemination by the end of FY 2004.

Countries/Region: Countries will be determined by the results of a
competitive review of submitted proposals. Currently, Nigeria, Ghana,
Uganda and South Africa from Africa; Philippines, Thailand, Vietnam,
India and Nepal from Asia and Moldova from Eastern Europe are
represented in the proposals under review.

# Partners: WHO/EDM; INRUD; CHANGE Project; RPM/MSH

# 

# Results to Date: These partners agreed on a framework for the Phase II studies --- Appropriate Drug Use for the Treatment of Infectious Diseases at the Household and Community Level. In addition to the community intervention, the framework specified two things: (1) the research is to focus on improving antimicrobial use (antibiotics and/or antimalarials) due to the growing problem of resistance and widespread consumer misuse of this class of drugs; and (2) the interventions to be tested are to encompass all relevant suppliers of medicines at the community level, including mobile drug vendors, drug retail shop owners, community health workers, health center personnel, and private practitioners. 

# 

# The partners sent requests to 20 research teams around the world asking them to submit letters of interest (LOIs) to improve a critical problem in their context and, if possible, to combine an AMR surveillance component. To qualify, the teams had to have close links with community organizations. From the received LOIs, 10 teams were chosen and asked to submit preproposals, which they all did; these 10 groups were then invited to a proposal development workshop in Bangkok from November 29 to December 8, 2000. The 10 research teams came from Ghana, India, Moldova, Nepal, Nigeria, the Philippines, South Africa, Thailand, Uganda, and Vietnam. Seven teams worked on proposals for community interventions that addressed drug use for acute respiratory infections (ARI) in rural and urban slum environments. The other teams developed proposals on drug use for malaria, tuberculosis, and antibiotic use in general. The researchers made significant progress in drafting the proposals, and final versions were expected during the first quarter of this year. No funding for any project was assured at this stage. However, it is expected that the final proposals will be strong enough to attract the required support for implementation.

A similar process for assessing policy interventions will be started
later in 2001.

**Implementing Organization:** JHU/FHACS

**Status:** On-going (Funded: FY1999; Expected Completion: FY2004)

**Rationale:** Neonatal mortality rates remain unacceptably high in
developing countries. Almost half of neonatal deaths in developing
countries are associated with infection, and 60% of deaths occur during
the first week of life. Limited understanding of the causes of neonatal
mortality in developing countries is based on studies of hospitalized
infants that may not reflect causes of neonatal mortality in the
community. In a recent study in Gadchiroli District, Maharashtra, India,
Bang et al. trained village health workers (VHWs) to diagnose and manage
sepsis in newborns and to provide perinatal and neonatal care. The net
percent decline for neonatal mortality was 62% and for infant mortality
46%. The mortality due to sepsis was reduced by 76%. Although promising,
the use of antibiotics in the community to reduce neonatal mortality
must be shown to be effective in other settings, and the impact on the
prevalence of antibiotic-resistant bacteria assessed.

**Objective(s):**

1\. Evaluate the impact on neonatal mortality of management of neonatal
sepsis by VHWs

2\. Evaluate the impact on colonization with antibiotic-resistant
bacteria of home administration of antibiotics by VHWs to neonates with
suspected sepsis

3\. Evaluate the cost-effectiveness of a community-based approach to
neonatal care and the management of neonatal sepsis

**Description:** The project will be conducted in two countries. In each
country, communities will be

randomized to control or intervention arms. Criteria for study sited
selection include high rates of infant mortality and home delivery, poor
access to health care, availability of VHWs and a minimum of 6000 live
berths per year. With a baseline neonatal mortality rate of 50/1000, an
individually-randomized study with 1605 newborns in each group would be
sufficient to detect a reduction of 40% in the intervention arm. As this
is a community-randomized trial, doubling the sample size should be
sufficient to account for between-community variability. We anticipate
enlisting 10-15 communities, and 3210 newborns, for each study arm in
each country.

Baseline data to be collected during the first year will include: 1)
neonatal mortality rates; 2) causes of neonatal deaths based on verbal
autopsy reports; and 3) newborn care practices. VHWs from the
intervention community will be trained in neonatal care, including the
recognition and management of neonatal sepsis. To further improve
neonatal survival, VHWs and Trained Birth Attendants (TBAs) in the
intervention community will be instructed in:1) the recognition and
management of complicated pregnancy; 2) appropriate hygiene during
delivery and the immediate post-partum period; 3) neonatal
resuscitation; and 4) newborn warming.

After completion of the baseline data collection and training, VHWs will
perform regular home visits in the intervention community on days 1, 3,
7, 14, 21 and 28. If the birth weight is less than 2500 grams, home
visits will take place daily until one month of age. VHWs will be
trained to diagnose neonatal sepsis using the following criteria: 1)
temperature greater than 38 C or less than 36 C; 2) poor feeding; 3)
lethargy; 4) erythema and tenderness around the umbilicus; 5) a
combination of diarrhea, vomiting and/or abdominal distention; and 6)
severe pneumonia. Parents of infants diagnosed with sepsis will be
encouraged to take the child to the nearest hospital. If not feasible,
the VHW will initiate antibiotic therapy. The antibiotic regimen will be
parenteral ampicillin and gentamicin, or oral cotrimoxazole and
parenteral gentamicin. The VHW will maintain a record of the daily
clinical status and outcome for each infant diagnosed with sepsis. VHWs
will visit newborn infants in the control community within 24 hours of
birth. If the infant weighs less than 2,500 grams, the mother will be
advised to take the infant to the nearest hospital or health care
facility. The VHW will visit the home and weigh the infant again at one
month of age. A trained health care worker will perform a verbal autopsy
to determine the cause of death for all infants who die.

Colonization with antibiotic-resistant bacteria will be assessed in a
sub-sample of one month old infants during the baseline data collection
period and at the end of the intervention. Nasopharyngeal and
stool/rectal swabs will be obtained from one month old infants and
cultured for penicillin-resistant *Streptococcus pneumoniae* and
ampicillin-resistant *Escherichia coli*. Costs will be recorded during
the training and intervention periods, and categorized as service costs
or research costs. Anticipated costs include training, equipment, wages,
incentives, drugs, supplies and transportation.

**Expected Outputs, Results and Progress Indicators:** Cause-specific
neonatal mortality rates and rates of colonization with
antibiotic-resistant bacteria during the pre-intervention and
intervention periods will be compared for each community, and between
the control and intervention groups. The cost-effectiveness of
community-based neonatal care will be evaluated.

**Countries/Regions:** Bangladesh

**Partners:** ICDDR,B

**Results to Date:** The study has been initiated, but several years may
be needed in order to evaluate the impact on the intervention on
mortality.

**Implementing Organization:** JHU/FHACS

**Status:** On-going (Funded: FY1999; Expected Completion: FY2002)

**Rationale:** The integrated management of childhood illness (IMCI)
approach developed by WHO and UNICEF is being adopted by an increasing
number of developing countries as their primary intervention to improve
facility and community-based management of sick children. The
prescription of antimicrobials for sick children with bacterial
infections is a key element of the IMCI approach. The IMCI clinical
algorithm recommends oral antimicrobials and home treatment for sick
children with clinical diagnoses of non-severe pneumonia, malaria,
dysentery, and acute ear infections. The effectiveness of the IMCI drug
counseling guidelines on compliance with antimicrobial therapy in the
home has not been evaluated. This is a key programmatic issue. If
sub-therapeutic treatment doses are being given in the home, then there
is an increased risk of the development of AMR and an increased risk of
mortality for the individual child. This study will determine the impact
of IMCI counseling guidelines on compliance with antimicrobial therapy
in the home, investigate barriers to compliance. This study will
complement another study now being conducted in Uganda with USAID AMR
funds by Johns Hopkins University and Institute of Public Health,
Kampala, Uganda.

**Objective(s):**

1\. To evaluate the impact of the IMCI treatment counseling guidelines
on the number of sick children seen at Community Health Centers (CSCOM)
that complete a full course of antimicrobial treatment at home.

2.  To identify barriers to completing a full course of antimicrobial
    treatment in the home following IMCI Treatment counseling.

**Description:** [Study Site]{.underline} The study will be conducted in
sikasso Region, Bougouni District, Mali. For the purposes of this study,
Bougouni District can be divided into 3 zones.

Zone 1: This comprises two rural arrondissements and the commune (urban
area) of Bougouni where Save The Children USA has implemented a USAID
BHR/PVC Child Survival grant from September 30, 1995 to September 29,
1999. Activities implemented under the grant included immunization,
improved case management of diarrhea and malaria in health centers and
in the home, nutrition including Vitamin A distribution, family planning
and maternal health. There were no specific intervention activities
related to acute respiratory infections.

Zone 2: This comprises 3 rural arrondissements where the Save The
Children project will be expanding its activities through mission
funding from USAID/ Bamako after the current child survival project in
Zone 1 ends.

Zone 3: This comprises 6 other rural arrondissements that are not
included in either of the Save The Children projects.

Study Design Time 1 Time 2 Time 3

Zone 1 M I M

Zone 2 M I M

Zone 3 M

I=Intervention: Personnel in Health Centers receive a modified IMCI
training course including the complete IMCI training on counseling of
parents on how to administer the drug to the sick child.

M= Measurement: Measurement of reported doses of antimicrobials given in
the home will be conducted. For children receiving antimicrobials for
diarrhea or ARI at health facilities, home visits will be made after 5
days. Completion of the course of antimicrobials will be assessed by
history and by counting antimicrobials remaining after 5 days. Exit
interviews will also be conducted with a sample of parents of young
children upon leaving the health facility. Respondents will be
administered a brief survey about how long they waited, what happened in
the appointment, what treatment they were told to take, etc.

# Comparisons:

1)  Comparison of Zone 2 at Times 1 and 2 and Zones 2 and 3 at Time 2
    will show how much IMCI training of health personnel improves
    compliance in health facilities that had not otherwise been
    upgraded.

2\) Comparison of Zones 1 and 2 at Time 2 will show how much better IMCI
training is than the routine training implemented as part of many PVO
child survival projects that include diarrhea and malaria case
management.

3\) Comparison of Zone 1 at Times 2 and 3 will show how much improvement
results from IMCI training in facilities that have already had some
upgrading.

[Other data collection methods:]{.underline} A sample of 30 parents of
young children will be administered a semi-structured interview on
knowledge and perceptions of medications.

**Countries/Regions:** Save The Children USA is just completing a four
year Child Survival Project (CS XI) (September 30, 1995 to September 29,
1999) in Bougouni District, Sikasso Region, Mali. Save The Children has
developed local capacity to carry out operations research, and is eager
to build on existing activities. While not providing funds, Save The
Children will make some project resources available for the study.

**Partners:** Ministry of Health and Population Services (MSSP), Mali.

**Results to Date:** After obtaining local ethical approval and hiring a
project coordinator, the study started in April 2001.  Data collection
for the first component (evaluation of IMCI training in health
facilities on compliance in the home) was completed in October 2001and
most of the data have been entered. Data analysis will begin soon.  Data
collection for the second component (evaluation of improved counseling
by volunteer managers of drug kits on compliance in the home) had just
started by December 2001 and should be completed by the end of March
2002.  Data collection and write-up should be finished by the end of
June 2002.

Implementing Organization: **Quality Assurance Project II**

Status: **On-going (Funded: FY1999; Expected Completion: FY2001)**

**Rationale:** Even when drugs are correctly prescribed and the
patient/caretaker is counseled, the patient often forgets, prematurely
discontinues, or interrupts the treatment regimen. This problem can be
addressed through a combination of interventions: better communication
and counseling of the patient, involvement of family or community
members in the provision of care, follow up visits of community health
workers, and job aids that directly support compliance by the
patient/caretaker.

One of the support tools that has received attention in improving work
performance is job aids. They have shown to 1) enhance performance by
reducing errors caused by poor recall and faulty decision making, 2)
promote compliance with standards, and 3) reduce costs of training and
retraining. Job aids provide reminders, information as needed and
substitute for experience or training. Several studies have shown the
effectiveness of job aids on worker performance while client-based job
studies are rare. Child nutrition cards maintained by mothers and
instructions for preparation of ORS are exceptions. Hence information
addressing the effectiveness of job aids to support patient or caretaker
compliance with prescribing practices in developing countries is very
limited, and additional research is warranted.

QAP's work on the design of job aids for health providers has been
successful with low level health workers in developing countries. For
example, health workers are able to properly diagnose malaria using a
diagnostic kit and job aid, without additional training. The QAP is
currently improving job aids for IMCI classification, treatment and
counseling. This study proposes to use the same job aids design approach
(named PETAL) for the development of client-based job aids to ensure
proper use of antibiotics. The PETAL method includes obtaining input
from end users and identifying their needs, looking at use under actual
field conditions, detailing problems with job aid use and addressing
them, before the job aid is supplied to end-users.

**Objective(s):** To develop and evaluate the effectiveness of client
and provider job aids to enhance caretaker adherence to antibiotic
regimens (specifically oral cotrimoxazole) for the treatment of
pneumonia in children.

**Description:** The study will be conducted in two phases. Phase 1 will
utilize a qualitative methodology to assess parental knowledge about
common respiratory infections, medications (specifically antibiotic
therapy), traditional remedies, health seeking behavior, cultural
beliefs about wellness and illness, traditional dissemination of
information, and the appropriate way to deliver a message to caretakers
of children. Observation of health center activities will include
patient counseling, counseling materials, and the number and duration of
antibiotic stock outs.

Based on the Phase 1 results, we will develop appropriate messages and
strategies for behavior change for caretakers of children with
pneumonia. A local artist will use images of mothers giving their
children the antibiotic to convey messages on proper administration and
storage, and completion of the entire 5-day course. These images will be
displayed on a medication envelope for the cotrimoxazole and the
antibiotic regimen (dose, frequency, and number of days) will be shown
on the reverse side. The images will also be delivered on a counseling
card and poster for the health worker to use (the poster will also
convey good interpersonal communication by the health worker). The Niger
Ministry of Public Health will incorporate this activity into its
training program for health workers on interpersonal communication and
use of the medication envelopes, counseling card and poster.

# **Phase 2 will be an efficacy trial of the above interventions.** The dependent variable, adherence to the antibiotic regimen, will be measured with a pill count on day 4 or 5 after the clinic consultation. Two measures will be calculated with these data; 1) the proportion of caretakers who adhered to the antibiotic regimen, and 2) a ratio of observed pills to expected pills.

Expected Outputs, Results and Progress Indicators: [Expected
Output:]{.underline} the development and testing of a set of client and
provider job aids to enhance compliance with cotrimoxazole treatment for
childhood pneumonia. [Expected Results:]{.underline} IMCI program in
Niger will have a set of effective job aids to use by providers and
clients. [Progress Indicators]{.underline}: formative research
completed; job aids developed and pre-tested; job aids tested for
effectiveness and report drafted.

Countries/Regions: **Niger (Boboye District)**

Partners: **Ministry of Public Health, Niger**

Results to Date:

***[Phase 1]{.underline}.* The qualitative research found that pneumonia
was considered a serious childhood illness, however there were
constraints to seeking care at health centers. The cost of the visit,
usually borne by the father, and the availability of cheap medicines in
the market, coupled with occasional drug stock-outs at the health
centers, combined to impede care seeking at health centers.**

Although both women and men thought that cotrimoxazole was a very
effective treatment for pneumonia, they often used traditional remedies
before taking the child to the health center. Women said that
cotrimoxozole was convenient and effective, because children liked its
taste and it "helped the small children breathe better." **We found that
only 2 or 3 days of the full 5-day course of cotrimoxazole were
dispensed at the first visit. Parents are advised to return for the rest
of the treatment at a follow-up appointment.**

**Little counseling by health workers was observed during the baseline
study. Parents were given the antibiotic in unmarked paper cones.
Medication was improperly stored in the home and most parents did not
make sure that the infant swallowed the entire dose.**

*[Phase 2.]{.underline}* A sample of 675 caretakers of children with
pneumonia (348 in the experimental group and 327 in the control group)
from 8 health centers (4 experimental and 4 control) were visited at
home 4 to 5 days after the initial consultation. There were no
significant differences between the experimental and control groups for
the child's characteristics (age, birth order, sex) nor the mother's
characteristics (age, educational level, marital status). However,
household characteristics and characteristics of the health center visit
did differ significantly. The size of the household was larger in the
control group (9.3 vs. 7.4 persons) and households in the experimental
group had more radios (68% vs. 44%). The control group lived farther
from the health center than the experimental group (2.9 vs. 2.3 km) and
the caretaker stated that improvements were needed in care at the health
center more often in the experimental group (75% vs. 42%). In addition
to cotrimoxazole, more children were prescribed aspirin in the control
group (49% vs. 36%) however more children were prescribed chloroquine in
the experimental group (93% vs. 63%).

The experimental group had greater adherence to the antibiotic regimen
than the control group, even if a full 5-day course of medication was
dispensed at the initial visit (Table 1).

**Table 1.** Description of differences in experimental and control
group for dependent variables (patient adherence, follow-up appointment,
maternal knowledge, child's health, medication storage and preparation)

+------------------------------------+----------+----------+----------+
|                                    | Control  | Expe     | Level of |
|                                    | Group    | rimental | Sign     |
|                                    |          | Group    | ificance |
+------------------------------------+----------+----------+----------+
| Patient adherence (% who adhered   | 76%      | 90%      | \<.001   |
| to regimen)                        |          |          |          |
+------------------------------------+----------+----------+----------+
| Patient adherence                  | .929     | .980     | \< .001  |
|                                    |          |          |          |
| (ratio of observed to expected     | .920     | .980     | \< .001  |
| pill count)\*                      |          |          |          |
|                                    | .952     | .979     | \< .001  |
| 3 days of medication received      |          |          |          |
| initially                          |          |          |          |
|                                    |          |          |          |
| 5 days of medication received      |          |          |          |
| initially                          |          |          |          |
+------------------------------------+----------+----------+----------+
| Kept follow-up appointment (% yes) | 58%      | 79%      | \< .001  |
+------------------------------------+----------+----------+----------+
| Maternal knowledge (% correct)     | 99%      | 99%      | NS       |
|                                    |          |          |          |
| Number of pills                    | 97%      | 93%      | .01      |
|                                    |          |          |          |
| Number of times per day            | 98%      | 99%      | NS       |
|                                    |          |          |          |
| Number of days                     |          |          |          |
+------------------------------------+----------+----------+----------+
| Child's health (Mother's           | 35%      | 47%      | .002     |
| perception, % yes)                 |          |          |          |
|                                    | 65%      | 53%      | .002     |
| Improved completely                |          |          |          |
|                                    | 46%      | 38%      | .03      |
| Improved a little                  |          |          |          |
|                                    | 25%      | 13%      | \< .001  |
| Still has a cough                  |          |          |          |
|                                    | 42%      | 28%      | \< .001  |
| Still has a fever                  |          |          |          |
|                                    |          |          |          |
| Still has nasal discharge          |          |          |          |
+------------------------------------+----------+----------+----------+
| Medication storage (% correct)     | 87%      | 91%      | .04      |
+------------------------------------+----------+----------+----------+
| Used clean water to mix medication | 73%      | 94%      | \< .001  |
| (% correct)                        |          |          |          |
+------------------------------------+----------+----------+----------+

\* Note: ratio closer to 1 indicates greater adherence

####  {#section-7 .unnumbered}

###### Further analysis using a multifactorial ANOVA design was completed to assess the effect on patient adherence of the interaction between the use of job aids and type of health worker. We found that adherence was significantly less in caretakers attending clinics staffed with lower-level health workers; however, adherence was better in those clinics staffed with lower-level health workers using the job aids (Adj R^2^ = .101, p\<.001.) 

The results indicate that the job aids did have an effect on improving
patient adherence, especially when used by lower-level health workers.
Country IMCI programs could use a set of job aids for clients and
providers, such as those described here, to improve counseling and
caretaker adherence to medication regimens**.** We would also like to
propose that this methodology be used to develop job aids to increase
adherence to treatment regimens for other diseases or in the private
drug sector to improve adherence for caretakers who choose to seek care
outside of the health center.

**Implementing Organization:** USP

**Status:** On-going (Year Funded: FY1999; Expected Completion: FY2002)

**Rationale:** It is generally accepted that the misuse of antimicrobial
drugs, resulting in part from a lack of appropriate drug use
information, contributes to AMR. Based on the state of the art technical
review of antimicrobial drug information in Russia, Nepal, Peru, and
Ghana, USP has found that, in general, physicians lack concise
up-to-date information on the use of antimicrobials, especially
information on basic use, pharmacokinetics, pediatric and geriatric use,
drug interactions, and treatment of side effects. In addition, more
information is needed on appropriate perioperative infection
prophylaxis; recommendations for adjustment of treatment regimens, e.g.,
parenteral to oral therapy, as the patient improves; and practical
comparisons among antimicrobial agents, in particular within families of
drugs. This review also found that there is very little drug information
included in disease-specific standard treatment guidelines and that
these guidelines tend to be poorly disseminated within countries.

Many countries, both developed and developing, have existing mechanisms
for disseminating drug and therapeutics information. In most cases, the
mechanism takes the form of drug information centers and networks. In
fact, in research conducted by USP, it was found that the number of drug
information centers in developing countries was increasing at a
significantly faster rate than was the case for developed countries. The
presence of these information centers and networks offers a unique
opportunity to build grassroots efforts in educating health care
professionals and students about the problem of AMR and in providing
information to improve rational prescribing and use of antimicrobials.

**Objective(s):** To develop and evaluate prototype programs and
materials for primary care physicians and medical students that would
improve access to and understanding of information relating to the
appropriate prescribing of antimicrobial agents.

**Description:** The proposed activity takes advantage of the ongoing
USP activities in the Russian Federation and Moldova that relate to the
provision of unbiased drug information. Specifically, the activities
will build on the Russian translation/adaptation of the USP DI database
and the establishment of the 12-member All-Russia Drug Information
Network (ARDIN) and the Moldovan Association DRUGS. USP will work with
members of ARDIN and the Moldovan Association DRUGS in the development
of strategies for improving access to unbiased information about
antimicrobial agents and in the creation of a training module for
educating practitioners and students about their appropriate use.
Concurrently, USP will work with PHARMEDINFO to publish a subset of the
translated/adapted USP DI antimicrobial information monographs as an
inexpensive reference for clinicians. The information will be condensed
from the full monographs included in the Russian USP DI
translation/adaptation. The format for the monographs will be developed
through consultation with MOH officials and medical specialists, with
input from ARDIN and DRUGS members. Where appropriate, local adaptations
of the information will also be included in those materials developed
for use in a specific geographic area. This process will not only serve
to develop relevant, useful information but it will also raise awareness
of the problem of AMR and build demand for appropriate training and the
handbook. PHARMEDINFO will publish up to 20,000 copies of the handbook
(depending on costs) and make them available for use in the training
initiatives. It is anticipated that PHARMEDINFO will also make copies
available at a subsidized rate for other clinical health care providers
and will make the information available via electronic means, such as
the Internet. The information will also serve as a resource for articles
published in local and regional newsletters and bulletins that are
developed by the drug information centers. Local and regional ARDIN
members will coordinate use and evaluation of the teaching modules in
their respective areas. After appropriate evaluation and revision,
through a "training-the-trainers" approach, ARDIN members and the
Association DRUGS will work to involve other information centers and
institutions in Russia, Moldova, and potentially other Eastern
Europe/Eurasia countries in effectively using the training module in
their respective populations.

**Expected Outputs, Results and Progress Indicators:**

[Outputs]{.underline} include a strategy for improving access to
unbiased information about antimicrobial agents; training module for
teaching practitioners and students about the appropriate use of
antimicrobial agents; prototype of handbook (Russian language) for
clinicians on proper use of antimicrobial drugs; newsletter/bulletin
articles.

[Results]{.underline}: Increased availability of and access to unbiased
information on appropriate use of antimicrobials; increased number of
DIC inquiries and responses relating to antimicrobial agents; increased
number of educational encounters relating to appropriate antimicrobial
drug use; increased recognition of the importance of appropriate use of
antimicrobial agents in an attempt to decrease AMR; increased knowledge
among practitioners on appropriate antimicrobial prescribing.

[Progress indicators]{.underline}: availability of training module;
availability of antimicrobials handbook; number of articles published in
newsletters/bulletins; number of continuing education
programs/participants; number of inquiries to DICs; improved prescribing
of antimicrobials as determined by DUR.

**Countries/Regions:** Russia, Moldova, and other Eastern Europe/Eurasia
countries as determined appropriate and feasible; potential for
replication in other developing countries.

**Partners:** PHARMEDINFO, ARDIN, Association DRUGS.

**Results to Date:** Antimicrobial Textbook and Training Modules were
developed by 39 Russian scientists under coordination of USP and its
primary partner in Russia, PHARMEDINFO. Fifty five thousand copies of
the Textbook and one thousand copies of the Training Modules were
published. They were distributed, free of charge, throughout Russia and
the Newly Independent States by PHARMEDINFO. Full text of the Textbook
is available on WWW at www.antibiotic.ru/ab

-   A total of 34,790 copies of the Antimicrobial Textbook were
    distributed throughout Russian Oblasts, including 7,200 to medical
    and pharmacy schools.

-   NIS countries received 1,850 copies, with at least 100 copies
    distributed to each country.

-   More than 2,000 copies were distributed in response to individual
    requests from health care professionals.

-   Approximately 1100 copies were sent with Farmatsia medical journal.

-   Over 16,000 copies were distributed at professional workshops and
    conferences, including the Man and Drugs Conference, as well as
    among authors.

The Antimicrobial Textbook includes two monographs on TB. The first on
drugs used in treatment of TB. It includes information on ftivazide,
isoniazid, metazide, opiniazide, rifampicin, streptomycin, pyrazinamide,
ethambutol, kanamycin, amikacin, rifabutin, cycloserin Е, capreomycin,
ethionamide, prothionamide, ciprofloxacin, ofloxacin, lomefloxacin,
sodium para-aminosalicylate, and thioacetazone. The second provides
information on the rational treatment of TB. It includes information on
various regimes and schemes of therapy, including Directly Observed
Therapy (DOT); therapy of multi-resistant TB; TB therapy in patients
with HIV/AIDS; and therapies in children; during pregnancy; in patients
with kidney and liver problems; and others.

Seven RPM-sponsored antimicrobial courses took place in various Russian
and NIS regions (Pskov, Vladivostok, Tomsk, Saint Petersburg, Ryazan,
and Novgorod regions of Russia, as well as in Moldova). The courses were
conducted by ARDIN drug information centers together with local medical
and pharmacy faculties. More than 1,000 health care professionals have
participated in the courses. All participants received a copy of the
Antimicrobial Textbook. The book received high praise from students and
from teachers delivering lectures. All lectures were based on book
materials. A number of medical and pharmacy school faculty members said
that they would use the Antimicrobial Textbook in education of students,
and they requested additional copies

Two questionnaires (25-30 questions each) were developed to evaluate a
level of knowledge before and after the training course. The results of
testing showed a dramatic increase in the percentage of correct answers.
For example, among 136 participants in Novgorod before courses, 35% had
a "low level of knowledge" (less than 25% of correct answers) and only
0.8% had "excellent level of knowledge" (more than 80% of correct
answers) about the topics presented. After school, only 0.7% were "low
level," whereas 37% scored as having an "excellent level" of knowledge.
The percent of "good level of knowledge\" (70 -- 80% of correct answers)
increased from 4% to 33%.

After the first successful course, the Health Care administration of
Saint Petersburg Region asked the local DIC staff to conduct additional
courses for health care professionals of the region and agreed to
provide financial support. The second course was conducted in Novgorod
with the financial support of local Evangelical Church.

Saint Petersburg DIC staff has been conducting a study to examine the
effects of these courses. This study, which is ongoing, began in 1999.
During this study, 584 case histories before the initiation of the
courses and 96 case histories after the initiation of the courses in
outpatient health care facilities were analyzed. The findings include
these pertinent facts:

-   Use of gentamicin in patients with pneumonia has decreased from 10.9
    % to 3.1 %.

-   Use of fluoroquinolones in patients with pneumonia has decreased
    from 19.8% to 10.4 %. This is a positive fact for Russia since only
    second generation fluoroquinolones are registered there. The
    second-generation fluoroquinolones have a low effect on
    Gram-positive cocci, including S. pneumoniae, which is a main cause
    of pneumonia. Their application as monotherapy can promote selection
    of the resistant strains and development of resistance to
    fluoroquinolones.

-   The percentage of injections given has decreased from 64.4% to
    58.6%, indicating that the preferred method of medicating, oral
    antibiotic therapy, is increasing in use.

# Implementing Organization: USP

**Status:** On-going (Year Funded: FY1999; Expected Completion: FY2002)

**Rationale:** Most people in Nepal receive antimicrobial drugs directly
from a private drug seller or chemist, usually without a prescription.
Through USP's experience in Nepal, it has been observed that training
requirements to become a licensed drug seller are minimal and no
"refresher" training is required. Studies have shown that 68% of
retailers in Nepal have no qualifications to sell drugs, let alone to
prescribe. In one study, a therapeutically-appropriate full course of
antibiotic treatment was received less than 25% of the time in retail
shops. Using Nepal Infectious Diseases funding, USP has researched the
antimicrobial drug knowledge and consumer counseling practices of
licensed private sector drug sellers in Nepal in cooperation with the
Nepal Chemists and Druggists Association (NCDA). Based on the results of
this research the RPM project is developing a training intervention to
improve patient counseling and dispensing of antimicrobial drugs used to
treat the most common infectious diseases in Nepal. It is anticipated
that the training intervention will become institutionalized as a part
of the new legal requirements for becoming a licensed drug retailer
currently being enacted by the Dept. of Drug Administration, HMG-Nepal
and later rolled out to reach the majority of drug sellers in the
country.

**Objective(s):** To reduce the spread of resistance to antimicrobial
drugs used to treat the most common infectious diseases in Nepal
(tuberculosis, malaria, STI's, pneumonia, diarrheal diseases, and
kala-azar) by improving the skills of the major provider of
antimicrobial drugs: private retailers.

**Description:** *Progress to date* includes research that has been done
with the private sector retailers on the dispensing of and patient
counseling for antimicrobials during FY 99 using funds from the 1998
allocation of ID money. The Manoff Group was contracted to develop a
research plan, manage data collection and analysis and present findings
and recommendations for an appropriate intervention. Manoff has worked
in collaboration with New Era, a local Nepali research group.
Preliminary results of the research show that:

-   drug retailers dispense antibiotics for illnesses that do not
    necessarily call for antibiotic treatment;

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-   Drug retailers learn what antibiotics to dispense by observing what
    doctors prescribe for the same illness;

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-   Drug retailers do minimal, if any, labeling of medicines dispensed

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-   Drug retailers provide very little or no counseling to their clients
    when they dispense medicines to them;

-   Drug retailers often sell less than the required/appropriate amount
    of antibiotics;

-   To some extent, drug retailers see themselves as health care
    providers, not just businessmen;

-   Drug retailers would welcome more training on drug selling;

-   Drug retailers have very few, if any reference materials, and do not
    make effective use of those that they do have.

The findings from the qualitative portion of the research, which
examines *why* the above findings are true, will inform the design and
development of training and reference materials. For example, simple and
easy‑to‑use reference materials on appropriate packaging and labeling
may be indicated. In addition, support for drug retailers' encouraging
clients to follow a full course of antibiotic treatment, instead of
taking the medicine just until they feel better, may be appropriate.

**In process:** A training intervention has been developed and
field-tested in collaboration with RPM/MSH. Core funds are being used to
develop the draft training materials which can be adapted by other
countries.

**Planned for FY 2000:** Core funds will also be used to develop a
facilitator's guide for use by trainers of retailer-groups. Nepal ID
funds will be used to evaluate the field test and revise the
intervention and materials for Nepal. Additional core funds are
requested to disseminate the training materials outside of Nepal as a
model and to assist other countries with adapting/translating the model
for local use through a sub-agreement mechanism. During FY 2000, the
intervention will be evaluated and a rollout implementation phase will
be planned. The group of drug sellers who go through the field-test
training will be compared to a group of untrained drug sellers three
months after the training. At the end of the field test, measures such
as decreased AM drug sales, changes to more appropriate products,
increases in repeat customers, improved patient/consumer counseling,
will be used to evaluate impact. The DDA has already agreed, in
principle, to include the training in the new requirements for drug
retailer licensing being established now in Nepal.

**Expected Outputs, Results and Progress Indicators:**

-   [Outputs:]{.underline} Appropriate training materials developed
    which can be adapted for other countries.

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-   [Results]{.underline}: DDA and NCDA staff trained to deliver the
    intervention and monitor improvement in drug retailer's knowledge
    and skills through post-training tests and surveillance mechanism,
    e.g., mystery clients.

-   [Indicators]{.underline}: decreased sales of drugs which have become
    less effective due to increasing resistance; changes to more
    appropriate products; increases in repeat customers; improved
    patient/consumer counseling, e.g., more time spent with customer,
    accurate instructions provided on taking medicine.

**Countries/Regions:** Nepal

**Partners:** Co-funders, USAID-Nepal and RPM/MSH; collaborating
organizations, DDA, NCDA, DINoN, Manoff Group, and New Era.

**Results to Date:** The field test of the training intervention was
implemented in May 2000, later than planned due to political turmoil
within the Nepal Chemists and Druggists Association (NCDA). In FY 01,
the field test was been evaluated using Nepal ID funding. The evaluation
report is currently in the process of being edited. When finalized, the
report will be shared with the USAID mission and all participating
organizations. Revisions to the intervention will be made in and a
rollout will be planned in FY 02. Training materials will be published
and made available for adaptation with core funds, after revisions are
made.

**Implementing Organization:** RPM/MSH

**Status:** On-going (Funded: FY1999; Expected Completion: FY2002).

**Rationale:** The increasing rate of resistance of Plasmodia to
traditional first-line antimalarial drugs such as chloroquine has
prompted WHO, CDC and other organizations to initiate global efforts to
assess the effectiveness of alternate treatment regimens. However,
developing country malaria decision-makers do not have ready access to
sufficient information on which to base policy and programmatic
decisions that can appropriately incorporate findings from these
efforts. To the extent that current management policies and practices
determine the availability and effective use of currently available
antimalarial drugs, program managers need a mechanism to rapidly gather
key information to assess and monitor the functioning of malaria drug
supply. This information can be used to improve existing programs and
policies and slow the emergence and spread of resistance, or to
determine the need to switch to more effective treatment options.

**Objective(s):** Develop and test a rapid assessment methodology and
indicators to assess and monitor the availability and use of
antimalarial drugs in Developing Countries

**Description:** The rapid assessment methodology and indicators will
build upon three existing RPM tools. The *Manual for Rapid
Pharmaceutical Sector Assessment,* a tool for assessing the overall
performance of a pharmaceutical sector, provided the foundation for the
later development for the *Manual for Drug Management for Childhood
Illness (DMCI).* The latter was designed to assess the specific drug
management concerns of countries considering implementing Integrated
Management of Childhood Illness (IMCI) programs and for those with
existing IMCI programs. The *DMCI* approach for assessing IMCI drug will
be adapted to create a new tool for assessing the availability and the
use of drugs to treat malaria. The third RPM tool that will be adapted
for malaria drug management is the Cost Estimate Strategy (CES) tool.
This tool, originally developed to assist Reproductive Health Programs,
estimates drugs and commodities needs and corresponding costs, according
to both actual and normative use patterns. The tool is particularly
useful when considering expanding programs.

The *Drug Management for Malaria (DMM)* tool will follow the same
developmental approach taken by the *DMCI* manual. The manual will
discuss key drug management issues for the treatment of malaria,
indicators for assessing the status of malaria drug management, their
calculation, interpretation, and suggestions for follow-up actions. The
assessment methodology will include a structured questionnaire
instrument to be applied in both the public and private sectors to
obtain data for conducting a cost comparison analysis, lead time
analysis, availability of key drugs analysis, a review of prescribing,
among others. The *CES* tool will be adapted to include the drugs and
medical supplies required for the treatment of malaria as per existing
national and international treatment guidelines, and will be
incorporated into the assessment methodology. A comprehensive data
collectors guide will be developed to accompany the manual.

The tool will be field tested in an appropriate setting. The purpose of
the field test is to clarify concepts, language and presentation of the
material, as well as finesse data collection issues. The field test will
involve collaboration with local counterparts in the design, planning
and implementation and follow-up review and analysis of preliminary
results.

### Expected Outputs, Results and Progress Indicators: {#expected-outputs-results-and-progress-indicators-1 .unnumbered}

### [Output:]{.underline} a *DMM Manual and Data Collectors Guide.* {#output-a-dmm-manual-and-data-collectors-guide. .unnumbered}

### [Results]{.underline}: field-tested malaria drug management assessment methodology and indicators available; team of malaria program managers trained to use the *DMM* tool; team of trained *DMM* data collectors. {#results-field-tested-malaria-drug-management-assessment-methodology-and-indicators-available-team-of-malaria-program-managers-trained-to-use-the-dmm-tool-team-of-trained-dmm-data-collectors. .unnumbered}

[Progress indicators]{.underline}: *DMM Manual* and *Data Collectors
Guide* drafted; *DMM Manual* and *Data Collectors Guide* field tested.

**Countries/Regions:** South Africa

**Partners:** WHO/EDM; WHO/TDR; CDC; INRUD.

**Results to Date:** The Drug Management for Malaria Manual was
developed by RPM and a completed draft published in July 2000. The
Manual is currently being field tested in South Africa. The data
collection for the field test has been completed and findings and an
evaluation of the methodology are expected in August 2001. RPM will make
revisions as recommended from the field test and publish the manual in
2002.

**Implementing Organization:** RPM/MSH

**Status:** On-going (Funded: FY1999; Expected Completion: FY2002).

**Rationale:** In the last decade, tuberculosis (TB) has re-emerged as a
significant public health concern for many countries through the
developing world and Eastern Europe/Eurasia. WHO's Directly Observed
Treatment Short-course therapy (DOTS) has been an important development
in the management of TB. Despite this and other efforts to improve the
treatment and prevention of TB, several factors may adversely affect
their effective implementation. These factors include the emergence of
multi-drug resistant strains, lack of adequate training and supervision
of both providers and recipients, and unreliable or poorly managed drug
supplies. TB program managers may benefit from a tool that can help them
quickly assess TB drug supply in their programs; identify weaknesses in
the system; and once appropriate interventions are designed and
implemented to improve it, monitor their impact.

**Objective(s):** Develop and test a rapid assessment methodology and
indicators to assess and monitor the availability and use of TB drugs.

**Description:** This tool will build upon three existing RPM tools. The
*Manual for Rapid Pharmaceutical Sector Assessment,* a tool for
assessing the overall performance of a pharmaceutical sector, provided
the foundation for the later development for the *Manual for Drug
Management for Childhood Illness (DMCI).* The latter was designed to
assess the specific drug management concerns of countries considering
implementing Integrated Management of Childhood Illness (IMCI) programs
and for those with existing IMCI programs. The *DMCI* approach for
assessing IMCI drug will be adapted to create a new tool for assessing
the availability and the use of TB drugs. The third RPM tool that will
be adapted for TB drug management is the Cost Estimate Strategy (CES)
tool. This tool, originally developed to assist Reproductive Health
Programs, estimates drugs and commodities needs and corresponding costs,
according to both actual and normative use patterns. The tool is
particularly useful when considering expanding programs.

The *Drug Management for Tuberculosis* *(DMTB)* tool will follow the
same developmental approach taken by the *DMCI* manual. The manual will
discuss key drug management issues for the treatment of TB, indicators
for assessing the status of TB drug management, their calculation,
interpretation, and suggestions for follow-up actions. The assessment
methodology will include a structured questionnaire instrument to be
applied in both the public and private sectors to obtain data for
conducting a cost comparison analysis, lead time analysis, availability
of key drugs analysis, a review of prescribing, among others. The *CES*
tool will be adapted to include the drugs and medical supplies required
for the treatment of TB, as per existing national treatment guidelines
and as per internationally recognized guideline such as the WHO DOTS
program, and will be incorporated into the assessment methodology. A
comprehensive data collectors guide will be developed to accompany the
manual.

The *DMTB* tool will be distributed for external peer review with
structured feedback mechanisms. After revisions have been completed to
the tool as per the feedback, the tool will be field tested in an
appropriate setting. The purpose of the field test is to clarify
concepts, language and presentation of the material, as well as finesse
data collection issues. The field test will involve collaboration with
local counterparts in the design, planning and implementation and
follow-up review and analysis of preliminary results.

**Expected Outputs, Results and Progress Indicators:**

[Output]{.underline}: *DMTB Manual and Data Collectors Guide*

[Results]{.underline}: field-tested TB drug management assessment
methodology and indicators available; team of TB program managers
trained to use the *DMTB* tool; team of trained *DMTB* data collectors.

[Progress indicators]{.underline}: *DMTB Manual* and *Data Collectors
Guide* drafted; *DMTB Manual* and *Data Collectors* Guide field tested.

**Countries/Regions:** Tool development will take place in Washington,
DC. One country in either Africa or the NIS (yet to be determined) will
be selected to field test this tool.

**Partners:** WHO/EDM is expected to collaborate in technical review of
the manual; WHO TB program is expected to provide input (need to
identify the program); CDC may participate in the technical review of
the manual.

**Results to Date:** Under RPM, the draft DMTB manual and data
collectors guide were completed. They are awaiting field testing during
2001. The formation of a shorter assessment guide that includes a
continuous monitoring component is being considered based on recent MSH
assessments for the TB Global Drug Fund.

**Implementing Organization:** WHO/CAH

**Status:** On-going (Funded: FY1999; Expected Completion: FY2003)

**Rationale:** Pneumonia and malaria are common conditions in young
children and are leading causes of death. Both pneumonia and malaria are
part of Integrated Management of Childhood Illness (IMCI) algorithm. In
some countries, an overlap in the clinical presentation of pneumonia and
malaria has been reported. Many children meeting pneumonia case
definition (cough and fast breathing and or chest indrawing) have fever
or history of fever and a significant number of children with fever will
meet pneumonia case definition. At present there is no simple method to
differentiate between pneumonia and malaria if a patient with fever
fulfils the pneumonia case management criteria. Consequently, effective
malaria therapy is often required in febrile children with pneumonia.. A
few countries recommend cotrimoxazole (sulphamethoxazole-trimethoprim)
as the first-line antibiotic in non-severe pneumonia and first-line
antimalarial as sulphadoxine-pyramethamine (Fansidar) due to chloroquine
resistance.

This use of both antibiotic and antimalarial drugs has implications for
costs, development of AMR and toxicity if the two sulpha are used
concurrently. Some diagnostic techniques have been developed to diagnose
malaria quickly e.g., dip sticks etc. There is a need to test such
technology to differentiate between clinical overlap of pneumonia and
malaria. It is proposed that a study be designed to do that. A meeting
on "Malaria diagnostics" will be held in Geneva in August this year.
Results and recommendation from that meeting will be used to design this
study.

**Objective(s):** To increase specificity of treatment guidelines for
clinical overlap of pneumonia and malaria.

**Description:** The study will be designed and implemented in an area
with significant clinical overlap of malaria and pneumonia. Children
between 2 and 59 months old who present with fever and fit the case
definition of pneumonia will be tested for malaria using simple and
quick diagnostic tests. This test will be compared with the presence of
malarial parasites in peripheral blood.

**Expected Outcomes, Results, and Progress Indicators:**
[Outcomes]{.underline} include: evaluation of the use of a simple
malaria diagnostic test and its effect on reduction in the use of
antimalarial drugs; strengthened local capacity in epidemiological
research and microbiology; and strengthened local capacity to
differentiate between pneumonia and malaria using simple technology.
[Progress indicators]{.underline} include: development of a research
protocol; initiation of data collection for the study; and development
of better differential diagnosis criteria between pneumonia and malaria.

**Countries/Regions:** Papua- New Guinea.

**Partners/Collaborating Institutions:** Communicable Disease Research
and Development (CRD), Communicable Diseases (CDS) Cluster, WHO.

**Results to Date:** This activity is being developed for Papua-New
Guinea.

[^1]: For more information, see:
    <http://www.info.usaid.gov/pop_health/webid.htm>

[^2]: Other AMR activities supported by USAID regional bureaus and
    country missions are not included in this document.

[^3]: In developing countries, ARIs are the major killer of children and
    successful case management with effective, affordable antibiotics is
    essential for decreasing mortality from ARIs.