Released for public comment: February X, 2011

A PUBLIC HEALTH ACTION PLAN TO COMBAT ANTIMICROBIAL RESISTANCE

Interagency Task Force on Antimicrobial Resistance

Co-Chairs:

Centers for Disease Control and Prevention

Food and Drug Administration

National Institutes of Health

Participating Agencies:

Agency for Healthcare Research and Quality

Centers for Medicare and Medicaid Services

Department of Agriculture

Department of Defense

Department of Veterans Affairs

Environmental Protection Agency

Health Resources and Services Administration

Health and Human Services/ Office of the Assistant Secretary for Preparedness and ResponseA PUBLIC HEALTH ACTION PLAN TO COMBAT ANTIMICROBIAL RESISTANCE

2010

TABLE OF CONTENTS

Executive Summary .................................

................................................... .................................... 1

Introduction and Overview .........................

................................................... ................................. 3

The Focus Areas ...................................

................................................... ..................................... 10

Focus Area I: Surveillance ........................

................................................... ............................. 10

Focus Area II: Prevention and Control .............

................................................... ..................... 18

Focus Area III: Research ..........................

................................................... ............................. 24 Focus Area IV: Product Development ................

................................................... ................... 27 Acronyms and Abbreviations ........................

................................................... ............................ 30- 1 -



## A Public Health Action Plan to Combat Antimicrobial Resistance

Executive Summary

The Interagency Task Force on Antimicrobial Resista nce (hereafter referred to as the Task Force) was created in 1999 to coordinate the activi ties of federal agencies in addressing

antimicrobial a resistance (AR) in recognition of the increasing i mportance of AR as a public health threat. The Task Force is co-chaired by the Centers for Disease Control and Prevention (CDC), the Food and Drug Administration (FDA), and the National Institutes of Health (NIH) and also includes the Agency for Healthcare Researc h and Quality (AHRQ), the Centers for Medicare and Medicaid Services (CMS), the Departmen t of Agriculture (USDA), the Department of Defense (DoD), the Department of Vete rans Affairs (VA), the Environmental Protection Agency (EPA), the Health Resources and S ervices Administration (HRSA), and the Department of Health and Human Services Office of t he Assistant Secretary for Preparedness and Response (HHS/ASPR).

In 2001, the Task Force developed an initial Action Plan, outlining specific issues, goals, and actions important for addressing the problem of AR. This document, entitled A Public Health Action Plan to Combat Antimicrobial Resistance, Par t I: Domestic Issues , reflected a broadbased consensus of participating federal agencies, which was reached with individual input from state and local health agencies, universities, prof essional societies, pharmaceutical companies, healthcare delivery organizations, agricultural pro ducers, consumer groups, and other members of the public. Continued collaboration with these p artners has been vital to achieving successful implementation of the Action Plan.

The 2010 Action Plan is based in part on individual input obtained at a consultants’ meeting held in Atlanta, Georgia, in December 2007. Present at t he public meeting were consultants with wide-ranging expertise in areas such as human and v eterinary medicine, pharmaceutical and diagnostics manufacturing, animal husbandry, clinic al microbiology, epidemiology, infectious diseases and infection control, and state and local public health officials.

The 2010 Action Plan includes action items organize d into four focus areas: Surveillance, Prevention and Control, Research, and Product Devel opment. Within each of these four areas, specific goals are listed. The focus areas and goal s are as follows:

I. Surveillance

• Goal 1: Improve the detection, monitoring, and char acterization of drug-resistant infections in

humans and animals.

• Goal 2: Better define, characterize, and measure th e impact of antimicrobial drug use in

humans and animals in the United States.

a In this document, the term “antimicrobial” is used inclusively to refer to any agent (including an an tibiotic) used to kill or inhibit the growth of microorganisms (bacte ria, viruses, fungi, or parasites). This term gener ally applies to agents intended for healthcare, veterinary, and agr icultural applications.- 2 -

II. Prevention and Control

• Goal 3: Develop, implement, and evaluate strategies to prevent the emergence, transmission, and persistence of drug-resistant microorganisms.

• Goal 4: Develop, implement, and evaluate strategies to improve appropriate antimicrobial use.

III. Research

• Goal 5: Facilitate basic research on antimicrobial resistance.

• Goal 6: Facilitate the translation of basic researc h findings into practical applications for the prevention, diagnosis and treatment of resistant in fections.

• Goal 7: Facilitate clinical research to improve the treatment and prevention of antimicrobial drug resistant infections.

• Goal 8: Conduct and support epidemiological studies to identify key drivers of the emergence and spread of AR in various populations.

IV. Product Development

• Goal 9: Provide information on the status of antiba cterial drug product development and clarify recommended clinical trial designs for anti bacterial products.

• Goal 10: Consider opportunities for international h armonization and means to update susceptibility testing information for human and an imal use.

• Goal 11: Encourage development of rapid diagnostic tests and vaccines.

The Task Force will continue to facilitate coordina tion among agencies and monitor implementation of the plan. As with the 2001 Action Plan, the Task Force will continue to publish annual reports detailing how the plan is be ing implemented, solicit comments from the public, and if necessary, update the plan.- 3 - 

### Introduction and Overview

Background

In the 1940s, the widespread availability of penici llin and the subsequent discovery of streptomycin led to a dramatic reduction in illness and death from infectious diseases. However, bacteria and other disease-causing organisms — viru ses, fungi, and parasites — have a remarkable ability to mutate and acquire resistance genes from other organisms and thereby develop resistance to antimicrobial drugs. When an antimicrobial drug is used, the selective pressure exerted by the drug favors the growth of o rganisms that are resistant to the drug's action. The extensive use of antimicrobial drugs has result ed in drug resistance that threatens to reverse the medical advances of the last half century.

Drug-resistant pathogens are a growing menace to al l people, regardless of age, gender, or socioeconomic background. They endanger people in a ffluent, industrial societies like the United States, as well as in less-developed nations. Examp les of clinically important microbes that are rapidly developing resistance to available antimicr obials include bacteria that cause pneumonia, ear infections, and meningitis (e.g., Streptococcus pneumoniae ), skin, bone, lung, and bloodstream infections (e.g., Staphylococcus aureus ), urinary tract infections (e.g., Escherichia

coli ), foodborne infections (e.g., Salmonella or E. coli acquired from meat, eggs, nuts, fresh produce etc), and infections transmitted in healthc are settings (e.g., enterococci, Acinetobacter baumanii, Pseudomonas aeruginosa , and Klebsiella spp.).

Antimicrobial resistance (AR) is not a new phenomen on; however, the current magnitude of the problem and the speed with which new resistance phe notypes have emerged elevates the public health significance of this issue. In addition, the scarcity of new antimicrobial agents limits treatment options, particularly for patients with i nfections caused by multidrug-resistant organisms. For example, surveillance data for S. pneumoniae , a common cause of bacterial respiratory tract infections, showed that 24 percen t of isolates were not susceptible to penicillin. In addition, resistance to several other antibacter ial drugs is common; 1.5 percent of isolates were resistant to cefotaxime (a "third generation" cephalosporin antibiotic), and resistance to the newer fluoroquinolone antimicrobials has already be en reported. b Nearly all strains of Staphylococcus aureus in the United States are resistant to penicillin, and many are resistant to newer methicillin-related drugs. Vancomycin for man y years has been the only uniformly effective treatment against these methicillin resis tant strains, but over the last decade there have been reported strains of S. aureus with decreased susceptibility and isolates resista nt to vancomycin. The public health burden of methicillin -resistant Staphylococcus aureus (MRSA) is staggering with over 90,000 invasive MRSA infection s per year estimated in the U.S. population. c

b Active Bacterial Core Surveillance (ABCs) Report E merging Infections Program Network Streptococcus pneumoniae , 2008 available at: http://www.cdc.gov/abcs/reports-findings/survreport s/spneu08.pdf

c Klevens RM, Morrison MA, Nadle J, Petit S, Gershma n K, Ray S, Harrison LH, Lynfield R, Dumyati G, Tow nes JM, Craig AS, Zell ER, Fosheim GE, McDougal LK, Car ey RB, Fridkin SK; Active Bacterial Core surveillan ce (ABCs) MRSA Investigators. Invasive methicillin-res istant Staphylococcus aureus infections in the United States. JAMA. 2007 Oct 17;298(15):1763-71.- 4 -

Many other pathogens – including the bacteria that cause tuberculosis and gonorrhea, human immunodeficiency virus, the fungi that cause yeast infections, and the parasites that cause malaria – are also becoming resistant to standard t herapies. For instance, CDC modified treatment recommendations for gonorrhea in 2007 due to increasing and widespread fluoroquinolone resistance in Neisseria gonorrhoeae

. d Even as we act to address the problem of AR, we lose quick and reliable treatment options fo r infections that have been a manageable problem in the United States since the 1940s. Drug choices for the treatment of common infections are becoming increasingly limited and ex pensive – and, in some cases, nonexistent.

The unpredictable and fluid nature of AR is illustr ated by the prevalence of resistant

Acinetobacter baumannii among military personnel in and returning from con flict areas and the hospital outbreaks of Clostridium difficile and Acinetobacter baumannii

. e

Additionally, antimicrobials have been used extensi vely in livestock and poultry since their discovery for the treatment, control, and/or preven tion of animal diseases, as well as for production purposes (e.g., to enhance growth, impro ve feed efficiency). In contrast to human medicine where treatment is customarily directed at the patient, entire groups of animals may be treated by the use of medicated feed and/or water. As a result of continued exposure to antimicrobials, the prevalence of resistant bacteri a in the fecal flora of food animals may be relatively high. Determining the impact of these re sistant bacteria on the management of human infections is an ongoing challenge as many classes of antimicrobials used in food-producing

animals have analogues to human therapeutics and are theref ore capable of selecting for similar resistance phenotypes.

Risk

Drug-resistant infections may be acquired in health care settings (e.g., staphylococcal infections in intensive care units), in the community (e.g., p neumococci acquired from a classmate), and through the food supply (e.g., salmonella acquired from meat or eggs), both domestically and

d Update to CDC’s Sexually Transmitted Diseases Trea tment Guidelines, 2006: Fluoroquinolones No Longer

Recommended for Treatment of Gonococcal Infections. MMWR 56(14);332-336. April 13, 2007.

e Scott P, Deye G, Srinivasan A, Murray C, Moran K, Hulten E, Fishbain J, Craft D, Riddell S, Lindler L , Mancuso J, Milstrey E, Bautista CT, Patel J, Ewell A, Hamil ton T, Gaddy C, Tenney M, Christopher G, Petersen K , Endy T, Petruccelli B.An outbreak of multidrug-resistant Acinetobacter baumannii-calcoaceticus complex infection in the US military health care system associated with mili tary operations in Iraq. Clin Infect Dis. 2007 Jun 15;44(12):1577-84. Epub 2007 May 8. Jones A, Morgan D, Walsh A, Turton J, Livermore D, Pitt T, Green A, Gill M, Mortiboy D. Importation of multidrug-resistant Acinetobacter spp infections with casualties from Iraq. Lancet I nfect Dis. 2006 Jun;6(6):317-8. Moran KA, McAllister CK, Gray PJ Multidrug-resista nt Acinetobacter extremity infections in soldiers. Davis KA,. Emerg Infect Dis. 2005 Aug;11(8):1218-24. Tan ET, Robertson CA, Brynildsen S, Bresnitz E, Tan C, McDonald C. Clostridium difficile -associated disease in New Jersey hospitals, 2000-2004. Emerg Infect Dis. 2007 Mar;13(3):498-500. Munoz-Price LS, Weinstein RA. Acinetobacter infection. N Engl J Med. 2008 Mar 20;358(12):1271-8 1.- 5 -

overseas. While anyone may acquire a drug-resistant infection, certain people are at increased risk, e.g., patients in hospitals and children in d aycare centers. However, resistant microbes are increasingly appearing in new settings. MRSA, which for 30 years was almost exclusively a problem in hospitals, is now occurring in the commu nity. f

Costs

The costs of treating AR infections place a signifi cant burden on society — a burden that is likely to grow larger as the number of cases of dru g-resistant illness increases. Individuals infected with drug-resistant organisms are more lik ely to remain in the hospital for a longer time, and to have a poor prognosis. g In a 2008 study of antimicrobial resistant infecti ons acquired in the hospital, the medical costs attributable to the infection ranged from $18,588 to $29,069 per patient, hospital stays were extended between 6.4 t o 12.7 days, and the attributable mortality of the infection was 6.5%. Using the most conservative estimates, the total cost of resistant infections in the 188 patients from this study was $13.35 million dollars. These findings suggest that significant health and economic benefits are p ossible through efforts to reduce antimicrobial

resistance and healthcare-associated infections.

Solutions

AR will always be with us. The challenge before us is to transform this increasingly urgent threat into a manageable problem. In the past, the Institu te of Medicine (IOM), the American Society for Microbiology, the World Health Organization (WH O), the Congressional Office of Technology Assessment, the Government Accountabilit y Office, and other panels of distinguished experts have provided recommendations and options for government action to address the dangers posed by AR. In addition, a 200 9 U.S.-EU Summit Declaration included a

statement to establish a transatlantic task force o n AR. h The experts agree that we need to improve surveillance for emerging AR problems, to p rolong the useful life of antimicrobial drugs, to develop new drugs, and to utilize other m easures, e.g., improved vaccines, diagnostics, and infection control measures to prevent and contr ol AR.

Despite the urgency of the problem, the achievement of these goals has not been simple or straightforward, and accomplishments to date have b een insufficient. Monitoring, preventing, and controlling AR requires sustained effort, commi tment, and collaboration among many groups in the public and private sectors, and invol vement of the general public. It also requires support and leadership from the federal government and a willingness to address complex and sometimes controversial scientific, medical, and ec onomic issues.

f Klevens RM, Morrison MA, Nadle J, Petit S, Gershma n K, Ray S, Harrison LH, Lynfield R, Dumyati G, Tow nes JM, Craig AS, Zell ER, Fosheim GE, McDougal LK, Car ey RB, Fridkin SK; Active Bacterial Core surveillan ce (ABCs) MRSA Investigators. Invasive methicillin-res istant Staphylococcus aureus infections in the United States. JAMA. 2007 Oct 17;298(15):1763-71.

g Roberts, RR, Hota B, Ahmad I, Scott RD II, Foster SD, Abbasi F, Schabowski S, Kampe LM, Ciavarella GG

, Supino M, Naples J, Cordell R, Levy SB, Weinstein, RA. Hospital and societal costs of antimicrobial-re sistant infections in a Chicago teaching hospital: implicat ions for antibiotic stewardship. Clin. Infect. Dis. 2009; 49:1175-

84.

h http://www.whitehouse.gov/the-press-office/us-eu-j oint-declaration-and-annexes- 6 -

Focus Areas

The 2010 Action Plan includes action items organize d into four focus areas: Surveillance, Prevention and Control, Research, and Product Devel opment. The Action Plan contains specific action items, projects and implementation steps. In addition to these, a selection of AR activities, in which the Task Force will actively engage within the next two years, are highlighted below. i

I. Surveillance

Unless AR problems are detected as they emerge and actions are taken quickly to contain them, the world may soon be faced with previously treatab le diseases that have again become untreatable, as in the pre-antibiotic era. Identifi cation of antimicrobial use information sources and integration of data with existing monitoring an d surveillance systems will allow experts to quickly interpret trends and identify strategies to prevent or mitigate the development and/or spread of AR.

The 2010 Action Plan incorporates several action it ems aimed at strengthening, expanding and coordinating existing national and international su rveillance systems for antimicrobial-resistant microorganisms. Additional action items in this are a focus on reviewing barriers to timely dissemination and updating of surveillance data and providing recommendations and best antimicrobial use practices.

Over the next few years, CDC will address several a ction items in this focus area by continuing to expand and improve its surveillance systems that collect data on AR. For instance, the National Healthcare Safety Network (NHSN) is a surv eillance system that provides healthcare facilities a way to track, analyze, and interpret d ata on healthcare-associated infections (HAIs), including those caused by antimicrobial-resistant p athogens. NHSN will be expanded to improve its capacity for collection and analysis of data on multidrug-resistant organisms (MDROs) and antimicrobial drug use. In addition to monitoring r esistance in healthcare settings, CDC will maintain surveillance activities for pathogens affe cting the general population through efforts such as the Emerging Infections Program (EIP), a po pulation-based network of CDC and state health departments, the Gonococcal Isolate Surveill ance Project, and the National Tuberculosis Surveillance System. Through the EIP program, CDC c losely monitors invasive bacterial pathogens through Active Bacterial Core surveillanc e and tracks resistance among enteric pathogens through the National Antimicrobial Resist ance Monitoring System. In addition to monitoring resistance among bacterial pathogens, CD C will continue to monitor resistance among non-bacterial pathogens such as influenza, ma laria and human immunodeficiency virus, both domestically and internationally.

II. Prevention and Control

The prevention and control of antimicrobial-resista nt infections requires measures to promote the appropriate use

j of antimicrobial agents and prevent the transmissio n of infections (whether drug-

i These highlighted activities are provided as illus trative examples and do not represent a comprehensi ve list. j In this Action Plan, appropriate antimicrobial drug use is defined as use that maximizes therapeutic i mpact while minimizing toxicity and the development of resistan ce. In practice, this means prescribing antimicrobi al therapy- 7 -

resistant or not). While development of new antimic robial agents and effective stewardship of existing agents are cornerstones of activities to p rotect the health of the nation in the face of expanding AR, successful prevention or elimination of resistance occurs with successful prevention or elimination of resistant microbes. Pu blic health initiatives can be successful. For example, drug-resistant malaria is rampant in parts of the world, but malaria was effectively eliminated from the United States through mosquito control efforts. Antibiotic resistance in Haemophilus influenzae was the critical issue that determined antibiotic choice for virtually all invasive bacterial infections in young children in the United States as recently as 15 years ago, but following the introduction of Haemophilus infuenzae serotype b (HIB) vaccines this problem has nearly been eliminated.

Other action items in this area focus on extending the useful life of antimicrobial drugs by encouraging appropriate use through educational eff orts such as the Get Smart: Know When

Antibiotics Work campaigns, preventing infection transmission throu gh improved infection control methods and use of vaccines, and preventing and controlling emerging AR problems in agriculture, human and veterinary medicine.

AR prevention and control activities that will be k ey over the next few years include several interagency collaborations focused on controlling a nd preventing MRSA infections within healthcare settings. Based upon the successful coll aboration between the VA Pittsburgh Healthcare System and CDC that demonstrated a reduc tion of MRSA infections, the initiative was expanded into an additional 17 sites within the Veterans Health Administration (VHA). The successful prevention of MRSA at the local and regi onal levels led the VA to expand its MRSA Prevention Initiative, which is now a nationwide effort to reduce occurrence of healthcareassociated MRSA infection from developing while pat ients are in hospital. VA is also evaluating

lessons learned from the MRSA Prevention Initiative to explore expanding this beyond just MRSA to other MDROs, including Clostridium difficile

.

Also continuing over the next few years is an inter agency initiative to identify and help suppress the spread of MRSA and other related infections thr ough an ongoing partnership between CDC and AHRQ. The two agencies are working together clo sely to identify gaps in the prevention, diagnosis, and treatment of MRSA and related infect ions across the healthcare system and to fund research, implementation, measurement, and eva luation practices that mitigate healthcare

related infections.

Several Task Force member agencies, including AHRQ, CDC, FDA, NIH, CMS and VA, are working to implement the 2008 HHS Action Plan to Prevent Health Care-Associated Infe ctions (HAI) k , which includes both Clostridium difficile and MRSA. By working to implement the HHS HAI Action Plan these agencies and partners will im pact several areas and action items covered

in this 2010 AR Action Plan.

when and only when beneficial to a patient; targeti ng therapy to the desired pathogens; and using the appropriate agent, dose, and duration.

k The HHS Action Plan to Prevent Healthcare-Associat ed Infections is available on the HHS website at: http://www.hhs.gov/ophs/initiatives/hai/infection.h tml- 8 -

III. Research

Understanding the fundamental processes involved in AR within microbes and the resulting impact on humans, animals, and the environment form s an important basis for influencing and changing these processes and outcomes. Basic and cl inical research provides the fundamental knowledge necessary to develop appropriate response s to the emergence and spread of AR in hospitals, communities, farms, and the food supply. Critical activities in this focus area include support of basic research to uncover new targets an d new antimicrobials, investigations into the development of resistance and host-pathogen interac tions, optimization of treatment for resistant pathogens, and translation of research findings int o clinically useful products, such as novel approaches to detect, prevent, and treat antimicrob ial-resistant infections.

In the next few years, NIH will engage in AR resear ch activities that address several action items in this focus area. NIH is addressing the need for clinical trials aimed at identifying ways to

reduce the use of antimicrobials with recent solici tations. Funded projects resulting from these solicitations include late-phase clinical trials to test the absolute need and optimal duration of treatment with off-patent antimicrobials for the fo llowing diseases 1) community-acquired

methicillin-resistant Staphylococcus aureus (CA-MRSA) skin and soft tissue infections 2) urinary tract infections in children and 3) cathete r-associated bloodstream infections. In 2010, NIH will fund additional targeted clinical trials t o reduce the risk of AR focusing on one or more of the following disease areas: (1) acute otitis me dia; (2) pneumonia; (3) pulmonary tuberculosis; and (4) bacteremia.

Recently renewed NIH activities in support of basic research include the Genomic Sequencing

Centers for Infectious Diseases and the Bioinformat ics Resource Centers for Infectious Diseases. The objective of the sequencing centers is to provi de rapid and cost-efficient production of highquality genome sequences of microorganisms and inve rtebrate vectors of infectious diseases and to make the resulting genomic data rapidly and read ily accessible to the broader scientific community through publicly accessible international databases. In addition, the sequencing centers will provide comparative genomics and genot yping services to examine genetic variation in populations and communities of human pathogens a nd also across the human genome to identify genetic associations with observable pheno types in the pathogen and in the human host.

The scope of the bioinformatics resource centers is to provide facilities, equipment, qualified personnel, and all necessary resources and services to collect, archive, update, integrate, and maintain genomics and other types of research data from human pathogens. In addition they provide the scientific community free access to res ources for the query, analysis and display of such information through user friendly interfaces.

IV. Product Development

There is a critical need for new drugs, vaccines, a nd diagnostic tests to treat, prevent, and diagnose infections, including serious and life-thr eatening infections caused by drug-resistant bacteria. FDA is working on a study to better under stand the trends over time in the development of new antibacterial drugs, the number of drugs app roved, and reasons why development programs may not have achieved approval.- 9 -

The 2010 Action Plan incorporates action items that will facilitate the development of vaccines and diagnostic tests for pathogens for which AR pos es a significant problem for treatment or public health.

FDA is working on a number of guidances on approach es to evaluating new antimicrobial products. Providing guidance can help by identifyin g recommended scientific approaches and also to identify areas where additional development al work would be beneficial for the design and conduct of studies. Over the last few years, FD A has held several public workshops and/or Advisory Committee meetings to discuss clinical tri al designs for evaluating antibacterial drugs. FDA has also published several guidance documents t hat describe recommended approaches regarding clinical trial designs. l

One particular example of the efforts to date is th e work to refine clinical trial designs for studying antibacterial drugs for the treatment of h ospital-acquired bacterial pneumonia (HABP) and ventilator-associated bacterial pneumonia (VABP ). As part of these efforts, in 2009, FDA co-sponsored a public workshop with the Infectious Diseases Society of America, the American College of Chest Physicians, the Society of Critica l Care Medicine, and the American Thoracic Society regarding scientific issues in clinical tri al design for HABP and VABP. This public workshop provided information about, and gained per spective from, health care providers, academics, and industry on various aspects of antim icrobial drug development for HABP and VABP, including diagnosis, treatment, trial endpoin ts, and statistical issues in analysis of results

of trials in HABP and VABP.

In the next few years, FDA will engage in activitie s to address a number of the action items in the Product Development focus area. FDA will be w orking to provide clarity on recommended approaches for evaluating new medical products for bacterial disease through publishing guidance documents. FDA plans to publish guidance d ocuments on recommended clinical trial designs for evaluating antibacterial drugs for cond itions such as acute bacterial skin and skin structure infections and hospital-acquired and vent ilator-associated bacterial pneumonia. In addition, FDA also plans to publish guidance for es tablishing performance for in vitro diagnostics assays for MRSA and vancomycin-resistan t enterococci (VRE). These guidances will describe recommended approaches for developing new antimicrobial products for specific

uses.

The Biomedical Advanced Research Development Author ity (BARDA), in the HHS Office of the Assistant Secretary for Preparedness and Respon se m is designing and implementing programs that create partnerships between government and ind ustry based on support and incentives that induce the commercial enterprises to address public health and biodefense priorities.

l Examples of recent guidance documents: Antibacteria l Drug Products: Use of Noninferiority Studies to Support Approval (draft, October 2007), Acute Bacterial Sin usitis: Developing Antimicrobial Drugs for Treatmen t (draft, October 2007), Acute Bacterial Otitis Media: Develo ping Drugs for Treatment (draft, January 2008), Acu te
Bacterial Exacerbations of Chronic Bronchitis in Pa tients with Chronic Obstructive Pulmonary Disease: Developing Antimicrobial Drugs for Treatment (draft, August 20 08), Community-Acquired Bacterial Pneumonia: Develo ping Drugs for Treatment (draft, March 2009), Non-Inferi ority Clinical Trials (draft, March 2010)

m See http://www.phe.gov/about/barda/Pages/default.aspx for more information on BARDA- 10 -

BARDA is currently supporting the development of in travenous formulation of a next generation aminoglycoside antibiotic for the treatment of plag ue and tularemia, as well as ventilatorassociated pneumonia. BARDA is projecting an expan sion of this program in the near-term by supporting the development of more novel antimicrob ial candidates for the treatment and prevention of diseases caused by bacterial threat a gents as well as diseases caused by clinically prevalent infectious diseases, including those that are AR.



### The Focus Areas

Within each of the goals listed for each focus area are several action items that define topic areas for specific projects or implementation steps (numb ered items). Wherever possible, action items are populated with specific projects or implementat ion steps (lettered items) to provide greater specificity for planned federal activities. The act ion items, projects, and implementation steps do not represent an exhaustive list of activities. n The expected completion dates for specific project s and implementation steps are indicated with a date. For example, (2011) means that the work is expected to be completed by the end of the 2011 cal endar year. Some activities are ongoing and are indicated as such. Since project planning is it self an ongoing activity, these will be updated at least every 2 years.



### Focus Area I: Surveillance

Overarching goals

In order to develop and implement effective control strategies there must be 1) continuous or periodic monitoring of infections caused by AR micr oorganisms and 2) comprehensive knowledge of the use of antimicrobial agents across all sectors.

Goal 1: Improve the detection, monitoring, and char acterization of drug-resistant infections in

humans and animals.

1.1 Develop strategies to more accurately assess the bu rden of antimicrobial drug resistance

in the community through the enhancement of existing systems includ ing the EIP, and the Epidemiology and Laboratory Capacity (ELC) site s.

a) Design, and implement (2010) a multi-site community -onset pneumonia etiology study among persons admitted with pneumonia and evaluate the specific role of antibacterial and antiviral resistance in determining outcomes as sociated with pneumonia (2011).

n Because of the rapidly evolving nature of AR, ther e will likely be new or emerging challenges in anti microbial resistance subsequent to the publication of this Ac tion Plan. The Task Force is committed to identifyi ng and responding to these issues as they arise.- 11 -

b) Facilitate surveillance for resistant enteric bacte ria by construction of a web interface for data entry and reporting results between state and federal participants in the National Antimicrobial Resistance Monitoring System (NARMS) (2012).

c) Implement electronic tools to query resistance prev alence among enteric pathogens collected in NARMS (2015).

d) Report regular summaries of antimicrobial resistanc e trends and mechanisms among foodborne bacterial pathogens on the NARMS website and in the literature (2011 and ongoing).

e) Expand the Gonococcal Isolate Surveillance Project (GISP) to include a State public health laboratory for sentinel site reference susce ptibility testing (2011) and initiate a CDC administered external quality assessment testin g to ensure accurate testing at all 5 sentinel sites (2012).

f) Expand GISP to include surveillance to identify th e emergence of cephalosporinresistant Neisseria gonorrheae by monitoring for gonorrhea cephalosporin treatmen t failures (2011).

Coordinator: CDC; Collaborators: FDA, USDA, VA

1.2 Develop strategies to more accurately assess the bu rden of antimicrobial resistance in healthcare settings through the enhancement of existing systems includ ing NHSN, the
EIP, and ELC sites.

a) Expand NHSN to use electronically captured antimicr obial susceptibility data from participating facilities for reporting of resistanc e rates and trends; (have an expansion plan by 2010, pilot the plan in 2011, provide resul ts of pilot in 2012, develop a webbased query for users in 2014 and provide ongoing p eriodic reports of the collected

resistance data.

b) Report regular summaries to provide national estima tes of the resistance burden using data reported on HAIs to NHSN (2011 and ongoing).

c) Evaluate the utility of electronic rules for identi fying and reporting central line-associated bloodstream infections (2010), surgical site infect ions (2011), catheter-related urinary tract infections (2012), and ventilator-associated pneumonia (2011), including associated pathogens; and compare electronic algorithms with t raditional manual surveillance by infection control professionals (CLABSIs 2011).

g) Develop a system to collect representative sets of bacterial isolates to assess changes in resistance mechanisms or strains nationally and wor k with the Clinical and Laboratory Standards Institute (CLSI) to determine the impact of changes on antimicrobial susceptibility testing and reporting practices in t he United States.- 12 -

h) Collect convenience samples of bacterial and funga l isolates through the EIP to assess changes in antimicrobial-resistant pathogens such a s MRSA (2011), Clostridium difficile (2011), and selected gram-negative bacteria (2012), as well as community-associated pathogens such as S. pneumoniae

, N. meningitidis , and Salmonella spp.; determine the feasibility of routine isolate submission for valid ation of antimicrobial susceptibility data submitted to NHSN (2012).

i) Design (2010), pilot (2010) and implement (2011) a periodic national prevalence survey for healthcare-associated infections, including tho se caused by antimicrobial-resistant pathogens.

Coordinator: CDC; Collaborator: VA

1.3 Assess the presence of antimicrobial-resistant micr oorganisms, such as MRSA, Clostridium difficile , and vancomycin-resistant enterococci (VRE), among food animals, retail meats, and household environment in the Unit ed States. Assessment should include comparison of isolates from humans, environment, re tail meats, and food animals.

a) Design and implement a 1 year prevalence study of M RSA, VRE, and Clostridium difficile from retail meat (2011).

b) Evaluate the quantity of Clostridium difficile recovered from retail meats in FoodNet sites (2010).

c) Conduct a pilot study to evaluate Clostridium difficile environmental contamination in households of infected and non-infected patients (2 010).

d) Characterize and compare recovered food bacterial i solates with those associated with environmental assessments and human illness (2012).

Coordinator: CDC; Collaborators: FDA, USDA

1.4 Identify patient populations colonized or infec ted with antimicrobial-resistant pathogens which may be important both for transmission of pat hogens themselves and the transfer of resistance genes (e.g. vancomycin-resistant Staphylococcus aureus ). Use this information to develop prevention strategies.

a) Identify populations at risk for Clostridium difficile and MRSA infections based on data from population-based surveillance systems (2010).

b) Conduct studies of colonization with antimicrobial- resistant S. pneumonia to determine the effects of antimicrobial use and pneumococcal v accination on colonization (2012).

Coordinator: CDC; Collaborator: NIH, VA- 13 -

1.5 Strengthen and expand multi-state, national and international surveillance systems for antimicrobial-resistant microorganisms and ensure a dequate sentinel surveillance for the emergence and spread of critical resistance phenoty pes (e.g., penicillin-resistance in Group A Streptococcus , extensively drug-resistant tuberculosis (XDR TB), oseltamivirresistant influenza viruses), and strive for more t imely dissemination of surveillance data.

a) I ncrease the number and capacity of public health la boratories that routinely monitor for

influenza antiviral resistance by developing new assays for rapid testing for antivir al resistance (2011) and developing web-based reportin g systems (2012).

b) Increase the capacity of state public health labora tories to identify antimicrobial-resistant organisms among cases of culture-negative clinical syndromes (e.g., meninigitis, empyema) using real-time polymerase chain reaction (PCR) for species-specific genes and markers of antimicrobial resistance (2013).

c) Routinely evaluate isolates captured through ABCs w ith unusual resistance profiles (e.g., penicillin-resistant Group A or Group B Streptococcus , or vancomycin resistance among any of the Streptococcus pathogens) to identify resistance and characterize the molecular mechanisms (2010 and annually).

d) Assess the impact of including fluoroquinolone susc eptibility data to the national TB reporting system for enhanced detection of XDR TB ( 2010)

e) Complete a pilot exercise to expand routine nationw ide surveillance for MDR TB and determine whether this additional surveillance prov ides useful information that warrants broader implementation (2010).

f) Organize, plan and conduct a NARMS public scientifi c meeting to highlight results and related AR research and solicit input from stakehol ders and international partners on future enhancements and improvements (2010).

Coordinator: CDC; Collaborators: DoD, FDA, USDA, VA

1.6 Work with public health associations, including Ass ociation of Public Health Laboratories (APHL) and Council of State and Territ orial Epidemiologists (CSTE), to

define minimal surveillance activities for AR for l ocal, state, and regional health departments. Enhance the accurate detection and ide ntification of AR by clinical and public health laboratories.

a) Develop consensus definitions for outbreaks of anti microbial-resistant pathogens that are reportable to health departments to optimize the de tection, investigation and resolution of outbreaks (2011).

b) Disseminate expert recommendations for effective st ate-based surveillance for multidrugresistant organisms related to healthcare-associate d infections (2010).- 14 -

c) Implement standard protocols for antimicrobial susc eptibility testing through CDC’s ELC Program (2010 and ongoing).

d) Develop and implement an antimicrobial susceptibili ty testing training program for public health laboratories (2012).

e) Establish a web-based training program, updated ann ually, on laboratory detection of AR (pilot in 2013 and implement in 2014).

Coordinator: CDC

1.7 Promote participation of microbiologists and local, state, and national public health workers in the design of systems to collect and dis seminate AR data to appropriate endusers. Identify methods to assist laboratories in s ummarizing and disseminating AR data to appropriate end-users and provide methods for in dividual laboratories to compare their data with data in surrounding regions.

a) Establish state-based surveillance networks utilizi ng NHSN to aggregate local-level data on healthcare-associated infections, multidrug-resi stant organisms, and/or Clostridium difficile infections for targeted prevention interventions ( 2010-2011).

b) Coordinate the collection of AR data for select vet erinary bacterial pathogens by partnering with State veterinary diagnostic laborat ories (2011).

Coordinator: CDC; Collaborators: FDA, USDA, VA

1.8 Collaborate with surveillance systems in other part s of the world to build global surveillance of AR microorganisms.

a) Establish liaisons with reference laboratories in c ountries without well-developed surveillance systems, both to improve the accuracy of global surveillance for resistance and to improve local use of the data (2010 and ongo ing).

b) Support and assist WHO on matters related to integr ated surveillance of AR and containment of food-related AR through participatio n in the newly establish WHO Advisory Group on Integrated Surveillance of Antimi crobial Resistance (WHOAGISAR) (2010 and ongoing).

• NARMS scientists from FDA, CDC and USDA will provid e expert advice to the WHO-AGISAR steering committee through participation and information sharing (2010-2012).

• Support laboratory capacity building activities in WHO member countries for AR monitoring by developing AR modules for Global Food borne Infections Network training courses (2011-2012).- 15 -

c) Develop collaborations with International Emerging Infections Program (IEIP) sites to improve surveillance systems for AR, facilitate pre vention programs, and ensure appropriate responses to outbreaks of resistant org anisms (2010 and ongoing).

d) Collaborate with IEIP sites to expand surveillance systems to measure the burden of AR and the impact of infection control interventions i n healthcare settings (2011).

Coordinator: CDC; Collaborators: DoD, FDA, USDA

1.9 Develop national and international surveillance sys tems to monitor understudied areas, such as resistance in protozoan parasites (e.g. Plasmodium spp.) helminthes or understudied sexually transmitted diseases (e.g., T. pallidum, T. vaginalis , HSV), neglected tropical diseases, and resistance to disi nfectants, sanitizers, and insecticides.

a) Identify resistance mechanisms in Trichomonas and use this information to develop laboratory tests for detection of resistance (2012)

.

b) Identify and characterize markers of artemisinin-ba sed combination therapies (ACT) resistance in malaria for the purpose of developing new laboratory tests for surveillance (2012).

c) Work with international partners to conduct in viv o/ in vitro studies to monitor the efficacy of anti-parasitic drugs (2013).

d) Collect a repository of specimens with characterize d antimalarial drug sensitivity patterns for the development of laboratory test development and quality control (2012). Laboratory tests will be used to expand surveillanc e.

e) Work with international partners to improve laborat ory capacity in endemic countries for the detection and surveillance of malaria drug- res istant parasites (2012).

f) Evaluate current strategies for deploying insectici des for public health that reduce or minimize resistance and as necessary develop new st rategies. (2012).

Coordinator: CDC; Collaborator: DoD

1.10 Assess the risk of AR emergence and spread in food borne pathogens due to environmental contamination by antimicrobial drug r esidues and pesticides in collaboration with the existing Pharmaceuticals in the Environment Subcommittee of the Office of Science and Technology Policy.

Coordinator: FDA; Collaborator: EPA- 16 -

Goal 2: Better define, characterize, and measure th e impact of antimicrobial use in humans and

animals in the United States.

2.1 Identify sources of antimicrobial use information i n the United States for humans, animals, agriculture, aquaculture, and other sector s to establish baseline data on antimicrobial use. Develop a standard for collectin g and reporting schemes for antimicrobial use data (comparable to “defined dail y doses” in humans) that allow aggregation, reporting, and comparisons of trends a cross sectors.

a) Gain access to and summarize de-identified data on antimicrobial use from market research companies, health maintenance organization s, federal healthcare systems, and other medical care systems in the United States to aid in quantifying antimicrobial use in humans and understanding geographical heterogeneity in antimicrobial use (2011).

b) Perform a national antibiotic use point-prevalence survey - pilot survey to be completed by 2010 and full survey by 2012.

c) Revise the Antibiotic Use and Resistance module of NHSN to accept electronic data on antibiotic use from healthcare facilities by 2011 a nd begin receiving data by 2012.

d) Collect and publish animal antimicrobial drug distr ibution data through implementation of Section 105 of the Animal Drug User Fee Amendmen ts of 2008 (2010).

e) Collect data through the National Animal Health Mon itoring System to produce 3 reports on antimicrobial use practices on livestock and pou ltry operations in the United States. These reports (shown below) will be produced by Jul y 2011:

• Food Safety Pathogens Isolated from U.S. Dairy Oper ations, 1996-2007

• Antimicrobial Use and Resistance on Beef Cow-calf O perations in the U.S. 2007-08

• Antimicrobial Use and Resistance Across Livestock a nd Poultry Operations - A compilation of data from the National Animal Health Monitoring System studies

Coordinator: FDA, CDC; Collaborators: USDA, VA

2.2 Develop mathematical models to guide studies of use and resistance in both humans and animals by collating existing data on correlations between antimicrobial use and

antimicrobial resistance from studies in healthcare and veterinary institutions (e.g., cephalosporin use and prevalence of vancomycin-resi stant enterococci) and community settings (e.g., fluoroquinolone use for respiratory tract infections and macrolide resistance in pneumococci).

a) Compare retail pharmacy sales of outpatient oral an timicrobials to geographic differences in bacterial resistance (2011).

Coordinator: CDC; Collaborators: NIH, USDA, VA- 17 -

2.3 Implement systems to detect the development and spr ead of resistance in microorganisms during implementation of new programs that signific antly impact antimicrobial drug use (e.g., pay-for-performance mandates on antibiotic t iming for community-acquired pneumonia, guidelines for intrapartum prophylaxis t o prevent neonatal group B streptococcocal disease, mass population-based trea tment campaigns for trachoma or helminthic infections, or large studies of treating partners or contacts).

a) Monitor the use of intrapartum antimicrobial prophy laxis for the prevention of neonatal group B streptococcal infections and the potential impact of prophylaxis on resistant cases of neonatal sepsis (2013).

Coordinator: CDC- 18 -



### Focus Area II: Prevention and Control

Overarching goals

Federal agencies are strong advocates of prevention and control measures that will both decrease the development of new resistant microorganisms and stop the transmission of existing resistant microorganisms in healthcare institutions, communit ies, and agriculture.

Goal 3. Develop, implement, and evaluate strategies to prevent the emergence, transmission, and persistence of drug-resistant microorganisms.

3.1 Implement and evaluate the impact of community-base d interventions, such as vaccination campaigns and the promotion of appropri ate antibiotic use to reduce the spread of AR microorganisms, rates of disease, and antimicrobial use, and to improve patient outcomes.

a) Estimate the effectiveness of pneumococcal and infl uenza vaccines on drug-resistant infections caused by those pathogens (2012).

b) Evaluate factors that influence the prescribing pra ctices of primary care physicians, including academic detailing and benchmark analysis (2011).

Coordinator: CDC; Collaborators, DoD, VA

3.2 Promote use of appropriate interventions, inclu ding checklists, to reduce the risk of

infection associated with catheters and other devic es and procedures in healthcare settings.

a) Facilitate multicenter prevention collaborative foc used on device and procedure-related infections in at least 20 states by 2012.

b) Design and implement systems to measure healthcare processes that are linked to

outcome data in order to measure the adherence of h ealthcare personnel to prevention

measures.

c) Correlation between adherence to best catheter inse rtion practices and CLABSI rates (2011).

d) Revise and publish HICPAC guidance for prevention o f catheter-associated bloodstream infections (2010).

e) Revise and publish HICPAC guidance for prevention o f surgical site infections (2011).

Coordinator: CDC; Collaborators: AHRQ, VA- 19 -

3.3 Identify and promote successful AR prevention and c ontrol programs in healthcare settings that utilize existing recommendations for preventing transmission of AR organisms.

a) Establish state-based MDRO and Clostridium difficile prevention collaborative in at least 10 states by 2011 and evaluate impact by 2013.

b) Evaluate impact of the CMS-Quality Improvement Orga nization MRSA prevention initiative by 2012.

c) Evaluate impact of the Department of Veterans Affai rs National MRSA prevention initiative (2012). Explore the expansion of prevent ion initiatives to include other MDRO including Clostridium difficile and multidrug-resistant gram-negative pathogens (2 010).

d) Facilitate initiation of at least one regional, mul ti-center prevention collaborative in which acute and long-term care facilities address p revention of multi-drug resistant infections in a coordinated manner (2011).

Coordinator: CDC; Collaborators: AHRQ, VA, CMS

3.4 Evaluate the effectiveness of infection-control pra ctices, products, and devices in healthcare facilities, including long-term healthca re and outpatient settings.

a) Expand CDC’s Prevention Epicenter Program to includ e academic centers, integrated health systems, and healthcare departments to suppo rt early translation of technical advances and epidemiologic knowledge into evidence- based recommendations (2011).

b) Initiate studies that will assess the dynamics of c ontamination of the healthcare environment and the ability of cleaning and disinfe ction methods to reduce environmental contamination (2011).

c) Evaluate the impact of state-based CDC-funded HAI p revention collaborative by 2013.

d) Quantify the national impact of HAI prevention effo rts by publishing annual national summary statistics (standardized infection ratio) o f HAI data reported to CDC’s NHSN (2010 and ongoing).

Coordinator: CDC; Collaborators: AHRQ, DoD, VA

3.5 Identify factors that reduce transmission of drug-r esistant pathogens, including infection control, in veterinary, agriculture and aquaculture settings, and formulate guidelines on “best practices.”- 20 -

a) Identify critical control points on-farm for dairy production that will decrease antimicrobial resistant salmonellae (2011). Evaluat e interventions in dairy production that will decrease antimicrobial resistant salmonellae ( 2012).

b) Make available grant funds of up to $4 million thro ugh USDA’s National Integrated Food Safety Initiative to support systematic studie s that identify intervention strategies for effective mitigation of AR throughout the food chain. Grant awards will be announced in June 2010. These 4-year grants will be gin in 2010 and must be completed

no later than 2015.

c) Identify factors important for assuring that antimi crobial drugs are used judiciously in veterinary, agriculture and aquaculture environment s (2010).

Coordinators: FDA, USDA

3.6 Promote research and development of processing tech nologies to minimize microbial

contamination of food.

a) Develop alternatives to current antimicrobial treat ments and sanitizers for processing poultry carcasses (e.g. natural Generally Recognize d as Safe [GRAS] products) (2011). Evaluate alternative sanitizers for poultry process ing and their reduction of food pathogens (2012).

b) Develop alternatives to current processing treatmen ts for the reduction of Escherichia

coli in beef (2011). Evaluate effectiveness of processi ng treatments (2012).

c) Identify processing interventions to decrease antim icrobial-resistant microorganisms in eggs (2011). Evaluate alternative interventions in egg processing for reduction of antimicrobial-resistant microorganism (2012).

Coordinator: USDA

3.7 Expand public health education campaigns targeting food producers, food handlers, and the general public about food safety practices that reduce microbial contamination of

food.

a) Co-host the 2010 Food Safety Education Conference: USDA and NSF International will co-host a 3-day conference sponsored by HHS, FDA, C DC, and WHO. The conference is designed for attendees to share the most current re search, learn best practices, and explore cutting-edge strategies for reducing foodbo rne illness.

b) Launch new USDA Food Safety Mobile Program in sprin g 2010 as part of the Food Safety and Inspection Service’s ongoing consumer ed ucation campaign to reach consumers where they live. The USDA Food Safety Mob ile will travel throughout the United States visiting local community events to ed ucate consumers about food safety. The revamped program will offer consumers in-depth, interactive, hands-on demonstrations on the science of food safety based on the four Be Food Safe Campaign messages: Clean, Separate, Cook and Chill. The Mobi le’s interactive learning stations are designed to improve consumer’s food safety awarenes s, knowledge, and behavior.- 21 -

c) Host USDA Nutrition Month to include Food Safety Da y on March 10, 2010 to increase consumer awareness about food safety.

Coordinator: USDA

3.8 Promote infection control education at all stages o f training and practice for healthcare workers in human and veterinary medicine.

a) Complete basic infection control curriculum for pos ting on the CDC website by 2011.

b) Develop a plan for infection control education of v eterinary medicine workers by 2011.

Coordinator: CDC; Collaborator: USDA, VA

3.9 Develop interagency programs in collaboration with regulators, payers, professional societies and other stakeholders to promote effecti ve hand hygiene strategies in communities and healthcare settings and to foster t he use of biomedical devices and behaviors that prevent the transmission of infectio us organisms in community settings.

a) Develop a plan to collaborate with WHO on their han d hygiene promotion campaign (2010).

b) In collaboration with academic partners, complete r esearch studies that evaluate the impact of novel technologies for measuring hand hyg iene adherence in the healthcare setting (2011).

Coordinator: CDC; Collaborator: AHRQ, VA

Goal 4: Develop, implement, and evaluate strategies to improve appropriate antimicrobial use.

4.1 Identify factors and strategies that promote approp riate antimicrobial use (i.e., best practices) or discourage inappropriate use in all t ypes of healthcare settings, including inpatient and outpatient facilities, clinics and of fices. Facilitate the implementation of these strategies.

a) Develop algorithms and reporting tools to facilitat e local monitoring of antimicrobial use (design 2010, pilot 2011, and implement 2012) and r esistance rates (develop 2010 and pilot 2011).

b) Develop a “change package” for improving antimicrob ial use in in-patient healthcare settings by 2010.

c) Collaborate with a network of hospitals to identify patient-level indications for and factors associated with antibiotic use to help guid e efforts on improving use by 2011.- 22 -

d) Examine knowledge, attitudes, and behaviors of healthcare providers regarding adverse events and antimicrobial use (focus testing to be c ompleted in 2010).

e) Examine the impact of improved antimicrobial use on adverse events associated with antimicrobials, especially Clostridium difficile infections by 2011.

f) Evaluate the benefits and potential unintended cons equences of clinical guidelines and policies that bear on antimicrobial use and affect patient care, reimbursement, or other areas of medical practice (e.g., increased use of a ntimicrobial agents in emergency rooms for unconfirmed community-acquired pneumonia) (2012 ).

Coordinator: CDC; Collaborators: AHRQ, FDA, VA

4.2 Promote, implement, and evaluate guidelines for app ropriate antimicrobial use in agricultural and veterinary settings. Specifically

,

a) Seek appropriate expert input to update specific as pects of guidance 152 (particularly the antimicrobial drug ranking in Appendix A of guidanc e) and publish revised draft guidance for public comment (2011).

b) Publish and seek public comment on draft guidance o utlining FDA’s current thinking on the judicious use of medically important antimicrob ial drugs in food-producing animals (2010).

c) Publish a revised order to prohibit certain extrala bel uses of cephalosporin antimicrobial drugs in food producing animals due to AR concerns (2011).

d) Survey orchards periodically for emerging resistanc e among agricultural bacterial plant pathogens (e.g., Erwinia amylovera

, Pseudomonas syringae , and Xanthomonas campestris ) to tetracycline, streptomycin, gentamicin, or oth er antimicrobial agents that may be used, such as kasugamycin. Monitoring is con ducted to comply with pesticide use

authorization.

Coordinators: CDC, FDA; Collaborators: EPA, USDA

4.3 Promote the development of improved field-based met hods to measure the quality of antimalarial drugs, given that poor quality drugs c ontribute to antimicrobial drug

resistance.

Coordinator: CDC

4.4 Develop, implement, and evaluate treatment algorith ms for management of common clinical syndromes frequently treated with antibiot ics (e.g., ventilator-associated and community-acquired pneumonia, acute bronchitis and sinusitis, and asymptomatic bacteriuria and sexually transmitted diseases.- 23 -

a) Update the Principles of Judicious Use of Antimicrobial Agents for Pediatric Upper Respiratory Infections and develop and disseminate academic detaining she et with diagnosis and treatment algorithms (2012).

b) Update the Guidelines for Appropriate Antibiotic Use for Treat ment of Acute Respiratory Tract Infections in Adults and develop and disseminate academic detailing she et with diagnosis and treatment algorithms (2014).

Coordinator: CDC; Collaborator: NIH, VA- 24 -



### Focus Area III: Research

Overarching goals

Encourage, conduct and support basic and translatio nal research to enhance our understanding of factors leading to the development of AR microorgan isms, their transmission in various settings, and optimal modes of prevention, diagnosis and ther apy.

Goal 5: Facilitate basic research on AR.

5.1 Conduct and support genetic, biochemical and struct ural studies of AR factors to enable the identification of novel drug, diagnostic and va ccine targets.

Coordinator: NIH

5.2 Investigate naturally occurring mechanisms of resis tance, gene transfer, and hostpathogen interactions.

Coordinators: CDC, NIH; Collaborators: FDA, USDA

5.3 Investigate the role of biofilms in the development of resistant microorganisms and transfer of resistance genes among diverse genera o f microorganisms.

Coordinators: CDC, NIH; Collaborators: FDA, USDA

5.4 Develop and make available genomics, metagenomic, b ioinformatics, proteomics, structural biology, molecular imaging, and other em erging research technologies. Ensure that genomic, proteomic, and other related data set s are made publicly available rapidly through searchable public online databases and prov ide data analysis tools to assist researchers in using these resources.

Coordinator: NIH; Collaborators: CDC, DoD, FDA, USD A

5.5 Bring new researchers into the field by utilizing a ppropriate strategies such as training and research opportunities.

Coordinators: CDC, NIH; Collaborator: FDA, VA

Goal 6: Facilitate the translation of basic researc h findings into practical applications for the prevention, diagnosis and treatment of resistant in fections.- 25 -

6.1 Facilitate preclinical studies, including toxicolog y, pharmacokinetics, pharmacodynamics, and in vitro and in vivo activity of antimicrobial agents to inform the treatment of resistant pathogens.

Coordinator: NIH; Collaborators: CDC, FDA, VA

6.2 Encourage, support and conduct basic and clinical r esearch on the development and use of vaccines and novel or alternative approaches for prevention and treatment of infections in human and veterinary medicine.

Coordinators: NIH, USDA; Collaborators: CDC, DoD, F DA, VA

6.3 Encourage, support and conduct research on the deve lopment of novel diagnostic technologies to rapidly distinguish among pathogens and their resistant subtypes at the point of care.

Coordinator: NIH; Collaborator: VA

6.4 Support development of novel broad spectru m antimicrobials with dual indications for community-acquired infections and biodefense threat agents.

Coordinator:HHS/ASPR; Collaborator: NIH, CDC

Goal 7: Facilitate clinical research to improve the treatment and prevention of AR infections.

7.1 Conduct and support clinical research to evaluate t he safety and efficacy of novel drugs and vaccines for pathogens where resistance threate ns effective treatment.

Coordinator: NIH; Collaborator: VA

7.2 Design and implement studies focused on optimizing the dose and duration of antibacterial agents prescribed for treatment of co mmunity-acquired pneumonia, urinary tract infections, skin and soft-tissue infections, and other infectious illnesses.

Coordinator: NIH; Collaborator: VA- 26 -

Goal 8: Conduct and support epidemiological studies to identify key drivers of the emergence and spread of AR in various populations.

8.1 Investigate the interplay among AR, colonization, a nd disease in acute, long-term care, and outpatient facilities.

Coordinator: CDC; Collaborator: NIH, VA

8.2 Support research on how prevalence data on antimicr obial resistance can be used to help guide treatment choices. For example, define geogra phic heterogeneity of resistance rates and determine impact of treatment decisions.

a) Define appropriate methods for collection and distr ibution of information on prevalence of resistance to community physicians and veterinar ians.

Coordinator: CDC; Collaborators: FDA, USDA, VA

8.3 Evaluate the utility of monitoring sentinel human p opulations (e.g., farm, abattoir, fruit and vegetable, and food processing plant workers) a nd persons in the general community

for infection or colonization with resistant enteri c bacteria to identify reservoirs of resistant organisms.

a) Investigate risk factors for AR development in Salmonella and Campylobacter in food animals (2014).

Coordinator: CDC; Collaborator: FDA, USDA

8.4 Develop options to capture and record AR research for all federal agencies.

Coordinators: CDC, NIH; Collaborators: AHRQ, EPA, F DA, USDA- 27 -



### Focus Area IV: Product Development

Overarching goals

Encourage the development of new antimicrobial prod ucts to improve our capacity to diagnose, prevent and treat infections, including infections caused by resistant microorganisms.

Goal 9: Provide information on the status of antiba cterial drug product development and clarify recommended clinical trial designs for antibacteria l products.

9.1 Examine trends over time for new drug applicati ons for systemic antibacterial drugs.

a) Perform pilot phase of study to evaluate trends ove r time for new drug applications for systemic antibacterial drugs (2010). Complete asses sment of trends over time for new drug applications for systemic antibacterial drugs (2011) and publish findings (2012).

Coordinator: FDA

9.2 Publish guidance documents for the following c onditions describing recommended approaches on clinical trial designs for evaluating antibacterial drugs.

a) Publish draft guidance on recommended approaches to clinical trial designs for evaluating antibacterial drugs for acute bacterial skin and skin structure infections (2010). Publish final guidance (2012).

b) Publish draft guidance on recommended approaches to clinical trial designs for evaluating antibacterial drugs for hospital acquire d and ventilator associated bacterial pneumonia (2010). Publish final guidance (2012).

c) Publish updated guidance on recommended approaches to clinical trial designs for evaluating antibacterial drugs for community-acquir ed bacterial pneumonia. Publish updated draft guidance (2010) and final guidance (2 012).

Coordinator: FDA

9.3 Publish guidance documents for the following t ypes of devices to provide recommendations regarding product development.

a) Publish final guidance document on premarket notifi cation [510(k)] submissions for medical devices that include antimicrobial agents ( 2012).

b) Publish draft guidance for establishing performance for in vitro diagnostics assays for MRSA and VRE (2011). Publish final guidance (2012).

c) Publish draft guidance document for establishing pe rformance for in vitro diagnostic assays for Clostridium difficile. Publish final gu idance (2011).

Coordinator: FDA- 28 -

9.4 Provide regulatory advice on recommended regul atory pathways for evaluating products that target unmet medical or veterinary needs inclu ding approaches to evaluating nontraditional products, e.g., cytokine, probiotics, a nd antimicrobial peptides (ongoing).

Coordinator: FDA; Collaborator: USDA

9.5 Evaluate use of the Orphan Drug Act, or simila r incentives, to encourage development and marketing of new antimicrobial agents for human medicine.

a) Part 15 public hearing held April 28, 2008, on issu es in AR and the Orphan Drug Act.

Coordinator: FDA

9.6 Sponsor a study to evaluate incentives to prom ote the development of antibacterial drugs and rapid diagnostic tests (including antimicrobial susceptibility tests), including the impact of such strategies upon appropriate use of s uch products.

Coordinator: HHS/ASPE

Goal 10: Consider opportunities for international h armonization and means to update susceptibility testing information for human and an imal use.

10.1 Pursue interagency collaborations to discuss international harmonization of standards and regulatory requirements for antimicrobial products (e.g., International Conference on Harmonization, International Cooperation on Harmoni zation of Technical Requirements for Registration of Veterinary Medical Products) (o ngoing).

Coordinator: FDA

10.2 Collaborate with relevant international organ izations and use international expert consultations (e.g., the WHO, the World Organizatio n on Animal Health, CLSI standards Institute, the European Committee on Antimicrobial Susceptibility Testing) to enhance product development (ongoing).

Coordinator: FDA; Collaborator: NIH

10.3 Develop a strategy for periodic updating of s usceptibility testing information for antimicrobial agents approved for use in humans and animals in the United States (ongoing).

a) Participate in multi-laboratory method trial studie s to develop standardized in vitro antimicrobial susceptibility testing methods for ve terinary pathogens where such tests are lacking (2010-2011)

Coordinators: CDC, FDA; Collaborator: USDA

Goal 11: Encourage development of rapid diagnostic tests and vaccines.- 29 -

11.1 Encourage development, testing, and evaluati on of new rapid diagnostic methods for human and veterinary use to help guide antimicrobia l therapy. Specifically, promote the development of tests for infections cause by fastid ious (e.g. TB) or difficult to culture organisms (e.g. Treponema pallidum , the agent of syphilis) and rapid point-of-care diagnostics to identify patients with viral respira tory infections who do not need antimicrobial agents.

a) Encourage improved diagnostic tests for resistant T B by conducting a FDA/CDC/NIH co-sponsored meeting to identify gaps in TB diagnos tics and to explore models and strategies that may expedite the development of new diagnostics (2010). Work to develop, evaluate, and implement molecular tests fo r the detection of MDR-TB directly from pulmonary specimens (2012).

b) Encourage development of rapid point-of-care tests to confirm diagnoses of possible bacterial respiratory infections including otitis m edia, sinusitis, and pneumonia and rapid point-of-care tests to identify pathogens associate d with these infections (ongoing).

c) Collaborate with partners to develop and evaluate r apid methods for identification and

characterization of Clostridium difficile , MRSA, and other multidrug-resistant organisms for human, animal, and plant sources to support nat ional surveillance efforts.

Coordinators: CDC, FDA; Collaborators: NIH, USDA HH S/ASPR, VA

11.2 Encourage development, testing, and evaluati on of new vaccines for human pathogens for which AR poses a significant problem for treatm ent or public health. Specifically,

a) Working with stakeholders, examine strategies to ma ximize the quality and the quantity of candidate vaccines for prevention of antimicrobi al-resistant infections of public health significance (ongoing).

b) Conduct research to facilitate development of vacci nes for resistant pathogens such as Staphylococcus aureus, Mycobacterium tuberculosis, Clostridium difficile, enteric pathogens and Neisseria gonorrhoeae (ongoing).

c) Conduct research to facilitate development of vacci nes for viral respiratory infections that may contribute to increased antibiotic use due to s ubsequent or co-bacterial infections or inappropriate antibiotic use (ongoing).

Coordinator: FDA; Collaborators: CDC, NIH, VA

11.3 Support advanced development of vaccines for resistant pathogens such as Staphylococcus aureus

Coordinator: HHS/ASPR- 30 - 

### Acronyms and Abbreviations

AHRQ Agency for Healthcare Research and Quality

APHL Association of Public Health Laboratories

AR Antimicrobial resistance

ASPE Office of the Assistant Secretary for Planning and Evaluation

ASPR Office of the Assistant Secretary for Prepar edness and Response (HHS)

BARDA Biomedical Advanced Research Development Aut hority

CDC Centers for Disease Control and Prevention

CLSI Clinical and Laboratory Standards Institute

CMS Centers for Medicare and Medicaid Services

CSTE Council of State and Territorial Epidemiolo gists

DoD Department of Defense

EPA Environmental Protection Agency

FDA Food and Drug Administration

HAI Healthcare-associated infection

HAP Hospital-acquired pneumonia

HHS Department of Health and Human Services

HRSA Health Resources and Services Administration

IPEC Inpatient Evaluation Center

MDRO Multidrug-resistant organism

MRSA Methicillin-resistant Staphylococcus aureus

NHSN National Healthcare Safety Network

NIH National Institutes of Health

USDA United States Department of Agriculture

VA Department of Veterans Affairs

VAP Ventilator-associated pneumonia

VHA Veterans Health Administration

XDR TB Extensively drug-resistant tuberculosis