# Presentation: 547864

## BACTERIAL   PNEUMONIA

-  Developing Antimicrobial
-    Drugs For Treatment
- Alma C. Davidson, M.D.
-  Division of Anti-Infective Drug Products
-  ODE IV
- July  30, 1998

- July 1998

**Notes:**
Greetings!  
Introduction............

This afternoon, in the next 20 minutes or so, I’m going to talk briefly about  some of the highlights of the document on Developing Antimicrobial Drugs for Treatment of Bacterial Pneumonia.

## 
Separation of CAP from NP
More stringent criteria for NP
Need  for NP patients to have both fever and leukocytosis plus at least one of the other signs and symptoms 

- Separation of CAP from NP
- More stringent criteria for NP
- Need  for NP patients to have both fever and leukocytosis plus at least one of the other signs and symptoms

- ISSUES in ACM - March 1997

- July 1998

**Notes:**
At the outset, let me say some background about this document for the sake of the new members in the committee and for those who were present in 1997 to refresh our memories. In the Advisory Committee Meeting of March 1997 some of the issues that were stressed were as follows: 
First, the separation of Community-acquired pneumonia and Nosocomial Pneumonia  into two  documents
Secondly, that the criteria for Nosocomial Pneumonia be more stringent; and in NP patients to have both fever and leukocytosis plus at least one of the other signs and symptoms

## ISSUES in ACM -  cont’d 

- Diagnostic criteria for ventilator-associated pneumonia (VAP)
- Subsetting patients with VAP
- How to handle patients who have evidence
-     of multiple pathogens in sputum
- Gram stain should correlate with culture results.

- July 1998

**Notes:**
The other issues that were addressed and unresolved were as follows:
1. How to set the diagnostic criteria for
    ventilator-associated pneumonia 
2. Subsetting patients with ventilator-
   associated pneumonia 
3. How to handle patients who have evidence   
    of multiple pathogens in the sputum
4. That Gram stain of sputum should correlate  
    with culture results. ( This issue including 
    some issues that are of interest to the   
    industry and investigators will be addressed
    by Dr. Sousan Altaie  our microbiologist.

## Questions and Comments fromIndustry - cont’d

- Are blood cultures necessary for outpatients with pneumonia?
- No

- July 1998

**Notes:**
The next question was that of clarification of the
Division’s view of the role of blood cultures and
susceptibility testing for outpatients with pneumonia.  
- The answer is that, we do not require blood cultures for outpatients with pneumonia. But we do require blood cultures in all hospitalized and
pediatric patients. Rather, It is a clinical judgement call by the physician when ordering such laboratory tests.

## Questions and Comments fromIndustry - cont’d 

- Eliminate blood cultures as inclusion criteria since these are pending for two days after enrollment.
- Recommend  eliminating fever as inclusion criteria since fever is absent from one-third of pneumonia cases, especially in the elderly
- Recommend eliminating WBC count since labs often pending for several hours at time of prestudy visit or are being sent to central lab

- July 1998

**Notes:**
The next comments referred to the inclusion criteria:
- eliminating blood cultures as inclusion criteria
  since these are pending for two days after
  enrollment
-recommend eliminating fever since fever is 
 absent from one-third of pneumonia case, 
 especially in the elderly, and
- recommend eliminating WBC count since labs
  are often pending for several hours at time of
  prestudy visit or are being sent to a central lab
*The Division reply to these comments is that all
these inclusion criteria contribute to the overall diagnostic criteria of bacterial pneumonia, hence the
above should be present, in particular, the Nosocomial
Pneumonia indication.

## Questions and Comments fromIndustry - cont’d 

- For atypical pathogens, are sputum screen and   culture required for inclusion ?
- We prefer culture where applicable;
- sputum screen not needed.

- July 1998

**Notes:**
Lastly, for this question of atypical pathogens, are sputum screen and culture required for inclusion ? 
Our answer to this is that we still prefer culture  to this type of pathogens. However, sputum
screen is not necessary. The issue of alternate
diagnostic test, such as serology, may be used to establish infection with one of these pathogens and should be discussed with the reviewing division prior initiation of the study.

##  Changes in New Document

- Separation of CAP and NP
- Disease definition and additional text in
-     inclusion and exclusion criteria of CAP
- Clarification of evaluation visits
- Dichotomous clinical outcome responses
- Nosocomial pneumonia - inclusion and
-    exclusion criteria

- July 1998

**Notes:**
The next slide shows the changes in the new
document:
- Separation of Community-acquired pneumonia and Nosocomial pneumonia
- Disease Definition and some additional text in the inclusion and exclusion criiteria of CAP
- Clarification of evaluation visits
- Dichotomous clinical outcome responses of
  clinical cure and clinical failure
- Nosocomial pneumonia  including inclusion and exclusion criteria

-

## NOSOCOMIAL  PNEUMONIA

- July 1998

**Notes:**
In the next few minutes, I will present the highlights of the Nosocomial Pneumonia document. For details, please refer to the actual document. Just, in case you want to know the Gram stains shown here: Any takers?
They are Strep pneumoniae from the top
and the two at the bottom are: 
Hemophilus influenzae and Pseudomonas aeruginosa 

## Disease Definition

- new cough
- auscultatory findings
- new infiltrate or progressive infiltrate(s) on
-    chest radiograph, accompanied by:
- fever or hypothermia, leukocytosis, sputum
-     production
- Etiology: polymicrobial

- July 1998

**Notes:**
Let me start with the disease definition of Acute Nosocomial  bacterial pneumonia which is broadly defined as a pneumonia characterized by a new cough with auscultatory findings of
pneumonia in conjunction with a new inflitrate or progressive infiltrate or infiltrates on chest
radiograph accompanied by: fever or hypothermia, leukocytosis and sputum production which could be purulent , caused by polymicrobial organisms

## Disease Definition - cont’d

- Acquired by a patient in the following      settings:
- in a hospital or long-term-care facility after   being admitted for >48 hours  or
- <7 days after a patient is discharged from hospital  ( patient’s initial hospitalization should be 3 days duration )

- July 1998

**Notes:**
Continuing with the definition :
Acquired by a patient in the following settings:
1. In a hospital or long-term-care facility after
    being admitted for >48 hours or

2. <7 days after a patient is discharged from the
    hospital with the caveat that the patient’s 
    initial hospirtalization should be 3 days   
    duration.

## Risk  Factors

- Risk  Factors

- Host factors ( e.g. extremes of age, severe                                        underlying disease )
- Colonization by gram-negative microorganisms
- Aspiration or reflux
- Prolonged mechanical ventilation
- Factors that impede adequate pulmonary toilet

- July 1998

**Notes:**
The risk factors associated with the development of
NP are the following:
1. Host factors such as in patients with extremes of age and patients with severe underlying disease 
including immunosuppression 
2. Factors that enhance colonization of the oropharynx, trachea, and upper gastrointestinal tract
by gram-negative microorganisms ( administration of
antimicrobials, ICU admission, and others
3. Factors that favor aspiration or reflux such as
endotracheal intubation and insertion of nasogastric tube
4.Prolonged use of mechanical ventilation with potential exposure to contaminated equipment as well as contaminated or colonized hands of health care staff
5. Factors that impede adequate pulmonary toilet.

## Problems in Diagnosis of NP

- Clinical criteria lack specificity
- No “gold standards” for diagnostic procedures (e.g. invasive procedures)
- High potential for more than one ongoing infectious process
- Use of antimicrobials in ICU empirically or use for infections of other sites or organs.

- July 1998

**Notes:**
Before, I go any further, let me say some of the
problems and difficulties associated with the
diagnosis of Nosocomial Pneumonia,to mention a few:
- For one, the clinical criteria lack specificity
- There is no “gold standards” for diagnostic
 procedures for example, invasive procedures
- There is high potential for more than one on-
going infectious process in the ICU, thereby
relying on a positive culture from a sterile site
(e.g., blood) as a basis for definition of the cause of pneumonia more difficult.
- The common use of antimicrobials in the ICU 
empirically or use for infections of other sites or organs.

## Nosocomial  Bacterial Pneumonia - Etiology

-  Gram-negative enteric bacilli (predominant)
-  Gram-positive cocci, including: *Staphylococcus aureus  *( e.g.,* MRSA  *), *Streptococcus pneumoniae*
-  Anaerobes
-  Others

- July 1998

**Notes:**
The next slide presents the implicated pathogens in nosocomial bacterial pneumonia.
-Gram-negative enteric bacilli which are the
predominant microorganisms.
- Gram-positive cocci, including Staphylococcus
aureus, especially methicillin- resistant strains
and other Gram-positive cocci such as
Streptococcus pneumoniae have emerged as
important isolates recently.
-Anaerobes account for few cases, and
lastly, other microorganisms including, Legionella pneumophila and other species as well as Haemophilus influenzae .

## Inclusion Criteria (Clinical)

- The following clinical findings should be
-  present:
- Fever or hypothermia
- Leukocytosis or leukopenia

- July 1998

**Notes:**
The diagnosis of nosocomial bacterial pneumonia should be based on the clinical, radiographic, and microbiologic criteria, which
will be presented in a short while.
First, let me talk about the proposed Clinical Inclusion criteria.
Fever or hypothermia, leukocytosis or leukopenia should be present. Please refer to
the document for definitions.

## Inclusion Criteria (Clinical)

* **And* * at least two of the following :*
- new cough
- new onset of purulent sputum or significant changes in character of sputum
- auscultatory findings
- dyspnea
- tachypnea

- July 1998

**Notes:**
Continuing on the clinical inclusion criteria....
At least two of the following signs and symptoms:- new cough
                 - new onset of purulent sputum or
                  tracheal secretions or significant
                  changes in character of sputum
                 -dyspnea, tachypnea if any or all of
                  these are progressive in nature

## Inclusion Criteria  (Clinical )

- Inclusion Criteria* * (Clinical )

- Hypoxemia by pulse oximetry or by arterial blood gas
- Respiratory failure requiring mechanical    ventilation
- Intubated patients requiring increased oxygenation

- July 1998

**Notes:**
Continuing on .....
-Evidence of hypoxemia obtained by pulse oximetry or by arterial blood gas determination
- Respiratory failure requiring mechanical
ventilation, and in
- Intubated patients requiring increased oxygenation

## Inclusion Criteria (Radiographic)

- New or evolving infiltrate (s) on chest radiograph which is not related to another disease process.
-  Caveat:  State of hydration

- July 1998

**Notes:**
The chest radiograph taken within 48 hours prior initiation of therapy, should show a new or
evolving infiltrate or infiltrates which is not related to another disease process such as,
congestive heart failure, atelectasis or ARDS.
- There’ a caveat to this: The state of hydration of the patient at the time hydration of the initial radiograph should be taken into consideration. Repeat films after hydration or diuresis are acceptable provided they are taken within the above time frame.

## Inclusion Criteria (Microbiologic)

- Inclusion Criteria (Microbiologic)

- Gram stain and culture of respiratory tract specimen
- Antimicrobial susceptibility testing should
-     be performed on pathogenic isolates
- Alternate diagnostic tests ( *Legionella *)

- July 1998

**Notes:**
The microbiologic criteria:
- Gram stain and culture of sputum or respiratory tract specimens obtained by methods mentioned in the document:. Microscopic examination of the Gram stained specimens should show presence of microorganisms and <10 squamous epithelial cells and >25 polymorphonuclear cells per low power field for suitability of culture.
-Antimicrobial susceptibility testing should be
performed on pathogenic isolates.
- Alternate diagnostic tests may be used to establish infection, for example, pneumonia due to Legionella pneumophila  and other species; isolation by culture is preferred, however, use of such alternative tests should be discussed with the Division prior to initiation of the study.

## Inclusion Criteria (Microbiologic)

- Inclusion Criteria (Microbiologic)

- Blood cultures, two sets ( aerobic and anaerobic from two different sites ) - up to 48 hours prior to initiation of therapy

- July 1998

**Notes:**
Two sets of blood cultures,aerobic and anaerobic from two different sites should be
obtained prior to initiation of the study drug in all patients. Blood cultures taken up to 48 hours prior initiation of therapy are acceptable.

Antimcrobial susceptibilty testing should be performed on pathogens associated with respiratory tract infections.

## Inclusion Criteria (Microbiologic)

- Blood culture isolates should be utilized to
-     corroborate with the sputum culture results in cases where multiple pathogens are isolated.

- July 1998

**Notes:**
In cases, where multiple pathogens are isolated
in the sputum, the blood culture isolates should be utilized to corroborate with the sputum culture results.

## Caveat:

- No consensus on criteria for interpretation of culture results of specimens obtained from mechanically ventilated patients

- July 1998

**Notes:**
 Because in evaluation of Nosocomial pneumonia, there does not seem to be a consensus in the literature on the criteria for
interpretation of culture results of the specimens obtained from mechanically ventilated patients, the proposed assessment plan for the culture data should be written down
and presented to the reviewing division a priori.

## PEDIATRIC PATIENTS

- Same clinical and radiographic criteria
-    ( definitions of fever and WBC different from adults )
- Blood cultures could be substituted when sputum is lacking

- July 1998

**Notes:**
In  pediatric populations, the clinical and radiographic inclusion criteria are the same as in adults. However, the definitions of fever and leukocytosis are different from
those in the adults. The definitions are found in the new document for your reference.
Since there is difficulty in obtaining sputum
in pediatric patients, then blood cultures
could be substituted.

## Exclusion  Criteria 

- Exclusion  Criteria

- Patients excluded in CAP and in general
-     considerations ( COPD not excluded )
- Patients with sustained shock
- APACHE II score <8 or >25
- Known or suspected concomitant bacterial
-     infection requiring additional systemic
-     treatment

- July 1998

**Notes:**
These are the proposed exclusion criteria:
-Patients excluded in the indication of Community-acquired pneumonia and patients
excluded in general considerations. However,
COPD patients are not excluded.
-Patients with sustained shock. The definition is
in the document.
-APACHE II score of less than 8 and greater than 25.
-Patients with known or suspected concomitant
bacterial infection requiring additional systemic treatment

## Exclusion Criteria- cont’d

- Chronic immunosuppressive therapy
- Neutropenia
- Epilepsy or seizure
- Recent alcohol or drug abuse or dependence

- July 1998

**Notes:**
To continue,
- Chronic immunosuppressive therapy
-Neutropenia ( absolute neutrophil count of
<1000/mm )
- Patients with epilepsy or seizure
- Patients with recent evidence of alcohol or drug abuse or dependence.

## Drug and Drug Dosing Regimens

- The proposed duration of study drug and  comparator may vary depending on
-     specific antimicrobial agent and
-     respiratory pathogen isolated.

- July 1998

**Notes:**
On drug and drug dosing regimens, the
proposed duration of the study drug and 
comparator may vary depending on the
specific antimicrobial agent and respiratory pathogen isolated.

## EVALUATION  VISITS 

- EVALUATION  VISITS

-  Pre-therapy
-  On- therapy
-  End-of-therapy  ( Optional )
-  Early Post-therapy ( Optional )
-  Test-of- Cure

- July 1998

**Notes:**
The evaluation visits include:
- Pre-therapy
-On therapy
-The end -of- therapy and early post-therapy visits are optional.
- Test of Cure Visit

## Pre-Therapy  Visit 

- Documentation of history ( including risk
-    factors ), P.E. , chest x-ray, lab tests ( Gram stain, culture and susceptibility testing, blood cultures ), and baseline O saturation by pulse oximetry or arterial blood gas;
-    Apache II Score ( if available ) in  ICU patients

- July 1998

**Notes:**
During the pretherapy visit, the history of the patient including any risk factors, physical examination, chest x-ray, laboratory tests such
as Gram stain, culture and susceptibility testing
of sputum or other respiratory tract secretions,
blood cultures, oxygen saturation by pulse
oximetry or by arterial blood gas analysis should be documented in the case report form.
The APACHE II score ,if available should also
be included in ICU patients to assess the severity of the illness.

## On-Therapy Visit

- On-Therapy Visit

- Daily clinical assessments should be      recorded in the case report form
- Laboratory assessments to be made during the course of the study should be tailored to the antimicrobial agent.

- July 1998

**Notes:**
On-therapy visit: The daily clinical assessments
should be recorded in the case report form and
the laboratory assessments to be made during
this visit should be tailored to the antimicrobial agent under study.

## On-Therapy Visit - cont’d

- On-Therapy Visit - cont’d

- General principles during this visit:
- Culture of respiratory tract secretions obtained by semi-invasive technique(s) and susceptibility testing, should be obtained at 72 hours after initiation of therapy in patients who are clinically failing.

- July 1998

**Notes:**
Continuing on ......
The general principles to be considered during this visit are:
1. Culture of respiratory tract secretions obtained by semi-invasive technique(s) and
susceptibility testing, should be obtained at 72 hours after initiation of the study drug in patients who are clinically failing.

## On Therapy Visit - cont’d

- Blood cultures and susceptibility testing should be repeated at 72 hours if (+) at entry or if patient is clinically failing.

- July 1998

**Notes:**
 2. Blood cultures and susceptibility testing should be repeated at 72 hours if positive at
entry visit or if patient is clinically failing.

##  Test-of-Cure Visit

-  Test-of-Cure Visit

- 7 - 14 days  after completion of therapy
- Repeat culture and susceptibility testing should be done in patients with continuing significant respiratory secretions.

- July 1998

**Notes:**
The test-of-cure visit should be at least 7 to 14
days after completion of therapy.
Repeat culture and susceptibility testing should be done in patients with continuing significant respiratory secretions to assess microbiologic
response and to monitor the emergence of
resistance.

## OUTCOME

- Clinical Outcome - primary efficacy  variable
- Clinical responses
- 	1. Clinical cure
-     2. Clinical failure

- July 1998

**Notes:**
The clinical outcome is the primary efficacy
variable for the indication of bacterial pneumonia.
Dichotomous clinical responses include clinical
cure and clinical failure. Please refer to the
document for the respective definitions. 
All failures should be carried forward at the
test-of-cure visits.

## Microbiologic Outcome

- Eradication ( Documented  eradication )
- Presumed eradication
- Persistence ( Documented  persistence )
- Presumed persistence

- July 1998

**Notes:**
The microbiologic outcome include the
following responses: eradication or documented
eradication, presumed eradication, persistence
or documented persistence and presumed
persistence.
Please refer to the document for respective definitions.

## Slide 34

- July 1998

**Notes:**
QUESTIONS TO THE ADVISORY
COMMITTEE MEMBERS

## QUESTIONS  to  ACM :

*QUESTIONS  to  ACM :*

- 1. How should we set the diagnostic
-     criteria for ventilator-associated
-     pneumonia ?
- 2.  Should we screen BALs in a similar
-      manner as sputum (in terms of
-      cytological screening) to determine
-      adequacy of specimen ?

- July 1998

**Notes:**
The number one question is a revisit, How do
we set the diagnostic criteria for ventilator-associated pneumonia? 
#2. Should we screen the bronchoalveolar lavage specimens in a similar manner as
sputum to determine adequacy of the specimen? 

## ACKNOWLEDGMENT

- Thanks to the following colleagues :
- Renata  Albrecht, M.D.
- Mercedes  Albuerne, M.D.
- John  Alexander, M.D.
- Sousan  Altaie, Ph.D.
- Lillian Gavrilovich, M.D.
- Holli Hamilton, M.D., MPH
- Mamodikoe  Makhene, M.D., MPH
- Alexander  Rakowsky, M.D.

- July 1998

**Notes:**
I would like to express thanks to my following
colleagues in helping out with the review of this
guidance document.