**2011 PROGRESS TOWARDS IMPLEMENTATION OF:** 

**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 In**  **stitutes 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 Resourc es and Services Administration**  **Health and Human Services/Office of the Assistant Secretary for Health Health and Human Services/**  **Office of the Assistant Secretary for Preparedness and Response**

### Preface

This 2011 revision of the A Public Heal th Action Plan to Combat Antimicrobial Resistance, provides a listing of projects that the Federal Agencies which are part of the Interagency Task Force on Antimicrobial Resistance are pursuing or planning to pursue in an effort to respond to the complex and pressing topic of antimicrobial resistance. The past decade has seen extraordinary

change in the microbiology and epidemiology

of antimicrobial resistant microbes and subsequent changes in treatment and patient outcomes. The Interagency Task Force on Antimicrobial Resistance is making further strides to ensure the currency and relevance of the Action Plan as the Task Force continues to look towards the future by taking the following steps :  Actions, the numbered items which follow each goal, will be re viewed biannually by the Task Force . New actions will be added as needed and existing actions may be modified or deleted in response to progress or changes that occur in the future with regard to antimicrobial resistance . This will allow the Action Plan to be updated over time and to help all Task Force agencies to continue to collaborate most effectivel y in achieving Action Plan goals.  T he listing of projects meant to help combat the issue of antimicrobial resistance (the lettered items which follow be low each action) will be revised annually . New projects may be added , and existing projects may be modified in response to intervening events. Completed projects will be moved to an Action Plan annex and their outcomes will be cross - referenced to the ye arl y progress report for the year during which the project was completed .  A few projects were completed during the review and comment period for this latest version of the Action Plan . Rather than deleting these activities, readers are referred to the rec entl y published document 2009 - 2010 Progress Towards Implementation of: A Public Health Action Plan To Combat Antimicrobial Resistance (available at: http://www.cdc.gov/drugresistance/annualReports.html#ar09 ) for updates about these projects . The Task Force will report on the outcomes of activities planned for completion in 2011 in the 2011 Annual Update which will be available during the first half of 2012. The Task Force and all participating Federal agencies are continuing to stress the importance of good communication with the many stakeholders who share the Task Force’s goals of preventing and controlling antimicrobial resistant infections. The Task Force remains committed to continuing communication with the public and health professionals , since antimicrobial resistance so profoundl y affects public health and clinical medicine. Given th e public health consequences of AR and its ever changing nature, the Task Force will continue to address the issue of antimicrobial resistance in this and future versions of the Action Plan.

### A Public Health Action Plan t **o Combat Antimicrobial Resistanc e**  **Table of Contents** Executive Summary ................................ ................................ ................................ ........................ 1 Introduction and Overview ................................ ................................ ................................ ............. 3 The Fo cus Areas ................................ ................................ ................................ ........................... 11 Focus Area I: Surveillance ................................ ................................ ................................ ........ 11 Focus Area II: Prevention and Control ................................ ................................ ..................... 29 Focus Area III: Research ................................ ................................ ................................ .......... 44 Focus Area IV: Product Development ................................ ................................ ...................... 59 Acron ym s and Abbreviations ................................ ................................ ................................ ....... 66- 1 - 

### 2011 Progress Towards Implementation of: **A Public Health Action Plan to Combat Antimicrobial Resistance**

**Executive Summary** The Interagency

Task Force on Antimicrobial Resistance (hereafter referred to as the Task Force) was created in 1999 to coordinate the activities of federal agencies in addressing antimicrobial a resistance (AR) in recognition of the increasing importance of AR as a public health threat. The Task Force is co - chaired b y the Centers for Disease Control and Prevention (CDC), the Fo od and Drug Administration (FDA), and the National Institutes of Health (NIH) and also includes the Agency for Healthcare Research and Quality (AHRQ), the Centers for Medicare and Medicaid Services (CMS), the Department of Agriculture (USDA), the Department of Defense (DoD), the Department of Veterans Affairs (VA), the Environmental Protection Agency

(EPA), the Health Resources and Serv ices Administration (HRSA), the Department of Health and Human Services Office of the Assistant Secretary for Preparedness and Response (HHS/ASPR) , and the Department of Health and Human Services Office of the Assistant Secretary

for Health (HHS/OASH) . In 2001, the Task Force developed an initial Action Plan, outlining specific issues, goals, and actions important for address ing the problem of AR. This document, entitled A Public Health Action Plan to Combat Antimicrobial Resistance, Part I : Domestic Issues , reflected a broad based consensus of participating federal agencies, which was reached with individual input from state and local health agencies, universities, professional societies, pharmaceutical companies, healthcare delivery

organizations, agricultural producers, consumer groups, and other members of the public. Continued collaboration with these partners has been vit al to achieving successful implementation of the Action Plan. Th e 2011 revision of the Action P lan wa s based in part on individual input obtained at a consultants’ meeting held in Atlanta, Georgia, in December 2007. Present at the public meeting were cons u ltants with wide - ranging expertise in areas such as human and veterinary medicine, pharmaceutical and diagnostics manufacturing, animal husbandry, clinical microbiology , epidemiology , infectious disease s and infection control, and state and local public h ealth officials . The Action Plan includes action items organized into four focus areas: Surveillance, Prevention and Control, Research, and Product Development. Within each of these four areas, specific goals are listed. The focus areas and goals are as follows: I. Surveillance  Goal 1: Improve the detection, monitoring, and characterization of drug - resistant infections in humans and animals.

a In this document, the term “antimicrobial” is used i nclusively to refer to any agent (including an antibiotic) used to kill or inhibit the growth of microorganisms (bacteria, viruses, fungi, or parasites). This term generally applies to agents intended for healthcare, veterinary, and agricultural applicatio ns.- 2 -

 Goal 2: Better define, characterize, and measure the impact of antimicrobial drug use in humans and animals in th e United States. 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 app ropriate antimicrobial use. III. Research  Goal 5: Facilitate basic research on antimicrobial resistance.  Goal 6: Facilitate the translation of basic research findings into practical applications for the prevention, diagnosis and treatment of resistant inf ections.  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 popul ations. IV . Product Development  Goal 9: Provide information on the status of antibacterial drug product development and clari f y recommended clinical trial designs for antibacterial products .  Goal 10: Consider opportunities for international harmonization and means to update susceptibility

testing information for human and animal use.  Goal 11: Encourage development of rapid diagnostic test s and vaccines. The Task Force will continue to facilitate coordination 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 being implemented, solicit comments from the public , and if necessary , update the plan.- 3 - 

### Introduction and Overview Background In the 1940s, the widespread availability of penicillin 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

— viruses, fungi, and parasite s — 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 b y the drug favors the growth of organisms that are resistant to the drug's action. The extensive use of antimicrobial drugs has resulted in drug resistance that threatens to reverse the m edical advances of the last half century . Drug - resistant pathogens are a growing menace to all people, regardl ess of age, gender, or socioeconomic background. They endanger people in affluent, industrial societies like the United States, as well as in less - developed nations. Examples of clinicall y important microbes that are rapidly developing resistance to availa ble antimicrobials 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 infe ctions (e.g., Escherichia coli ), foodbo rne infections (e.g., Salmonella or E. coli acquired from meat, eggs, nuts, fresh produce etc ), and infections transmitted in healthcare settings (e.g., enterococci, Acinetobacter baumanii, Pseudomonas aeruginosa , and Klebsiella spp. ). Antimicrobial resi stance (AR) is not a new phenomenon; however, the current magnitude of the problem and the speed with which new resistance phenoty pes have emerged elevates the public health significance of this issue. In addition, the scarcit y of new antimicrobial agents limits treatment options, particularly for patients with infect ions caused by multidrug - resistant organisms. For example, surveillance data for S. pneumoniae , a common cause of bacterial respiratory

tract infections, showed that 24 percent of isolates were no t susceptib le to penicillin. In addition, res istance to several other antibacterial drugs is common ; 1.5 percent of isolates we re resistant to cefotaxime (a "third gener ation" cephalosporin antibiotic), and resistance to the newer fluoroquinolone antimi crobia ls has already been reported. b Nearl y all strains of Staphylococcus aureus in the United States are resistant to penicillin, and many are resistant to new er methicillin - related drugs . V ancom ycin for many years has been the only

uniforml y effective tr eatment against these methicillin resistant strains, but over the last decade there have been reported strains of S. aureus with decreased susceptibility and isolates resistant to vancom ycin . The public health burden of methicillin - resistant Staphylococcus aureus (MRSA) is staggering with over 90,000 invasive MRSA infections per year estimated in the U.S. population. c

b Active Bacterial Core Surveillance (ABCs) Report Emerging Infections Program Network Streptococcus pneumoniae , 2008 available at: http://www.cdc.gov/abcs/reports - findings/s urvreports/spneu08.pdf c Klevens RM, Morrison MA, Nadle J, Petit S, Gershman K, Ray S, Harrison LH, Lynfield R, Dumyati G, Townes JM, Craig AS, Zell ER, Fosheim GE, McDougal LK, Carey RB, Fridkin SK; Active Bacterial Core surveillance (ABCs) MRSA Investi gators. Invasive methicillin - resistant Staphylococcus aureus infections in the United States. JAMA. 2007 Oct 17;298(15):1763 - 71.- 4 -

Many other pathogens

– including the bacte ria that cause tuberculosis and gonorrhea , human immunodeficiency

virus , the fungi that cause yeas t infections , and the parasites that cause malaria

– are also becoming resistant to standard therapies. For instance, CDC modified its 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 for infections that have been a manageable problem in the United States since the 1940s. Drug choices for the treatment of common infections are becomin g incr easingl y limited and expensive

– and, in some cases, nonexistent. The unpredictable and fluid nature of AR is illustrated b y the prevalence of resistant Acinetobacter baumannii among military personnel in and returning from conflict areas and the h ospital outbreaks of Clostridium difficile and Acinetobacter baumannii . e Additionally , antimicrobials have been used extensively in livestock and poultry

since their discovery for the treatment, control, and/or prevention of animal diseases, as well as f or production purposes (e.g., to enhance growth, improve feed efficiency). In contrast to human medicine where treatment is customarily directed at the patient, entire groups of animals may be treated b y the use of medicated feed and/or water. As a result of continued exposure to antimicrobials, the prevalence of resistant bacteria in the fecal flora of food animals may be relativel y high. Determining the impact of these resistant bacteria on the management of human infections is an ongoing challenge as man y classes of antimicrobials used in food - producing animals have analogues to human therapeutics and are therefore capable of selecting for similar resistance phenoty

pes. Risk Drug - resistant infections may be acquired in healthcare settings (e.g., staphyl ococcal infections in intensive care units), in the community (e.g., pneumococci 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 Treatment 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, Hamilton 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 military 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 Infect Dis. 2006 Jun;6(6):317 - 8. Moran KA, McAllister CK, Gray PJ Multidrug - resistant 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 diseas e 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 - 81.- 5 -

overseas. While anyone may acquire a drug - resistant infection, certain people are at increased risk, e.g., patients in hospitals and children in daycare centers. However, resistant microbes are increasingl y appearing in new settings. MRSA , which for 30 years was almost exclusively a problem in hospitals, is now oc curring in the community . f Costs The costs of treating AR infections place a significant burden on society — a burden that is likely to grow larger as the number of cases of drug - resistant illness increase s . Individuals infected with drug - resist ant organisms are more li kely to remain in the hospital for a longer time, and to have a poor prognosis . g Ina 2008 study of antimicrobial resistant infections acquired in the hospital, the medical costs attributable to the infection ranged from $18,588 to $29,069 per patient, hospital stay s were extended between 6.4 to 12.7 day s, 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 possible through efforts to reduce antimicrobial resistance and healthcare - associated infections. Solutions AR will alway s be with us. The challenge before us i s to transform this increasingl y urgent threat into a manageable problem. In the past , the Institute of Medicine , the American Societ y for M icrobiology , the World Health Organization (WHO) , the Congressional Offi ce of Technology Assessment, the G overnment Accountability Office , the Infectious Disease Society of America, and other panels of distinguished experts have provided recommendations and options for government action to address the dangers posed b y AR. Inaddition, a 2009 U.S. - EU Summit Declaration i ncluded a statement to establish a transatlantic task force on AR. h The experts agree that we need to improve surveillance for emerging AR problems, to prolong the useful life of antimicrobial drugs, to develop new drugs, and to utilize other measures, e.g ., improved vaccines, diagnostics, and infection control measures to prevent and control AR. Despite the urgency

of the problem, the achievement of these goals has not been simple or straightforward, and accomplishments to date have been insufficient. Mo nitoring, preventing, and controlling AR requires sustained effort, commitment, and collaboration among many groups in the public and private sectors, and involvement 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 economic issues.

f Klevens RM, Morrison MA, Nadle J, Petit S, Gershman K, Ray S, Harrison L H, Lynfield R, Dumyati G, Townes JM, Craig AS, Zell ER, Fosheim GE, McDougal LK, Carey RB, Fridkin SK; Active Bacterial Core surveillance (ABCs) MRSA Investigators. Invasive methicillin - resistant 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 - resistant infections in a Chicago teaching hospital: implications for antibiotic stewardship. Clin. Infect. Dis. 2009; 49:1175 - 84. h http://www. whitehouse.gov/the - press - office/us - eu - joint - declaration - and - annexes- 6 -

Focus Areas The Action Plan includes action items organized into four focus areas: Surveillance, Prevention and Control, Research, and Product De velopment. 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. Surveillan ce Unless AR problems are detected as they emerge and actions are taken quickly to contain them, the world may

soon be faced with previousl y treatable diseases that have again become untreatable, as in the pre - antibiotic era. Identification of antimicrobi al use information sources and integration of data with existing monitoring and surveillance s ys tems will allow experts to quickly interpret trends and identify strategies to prevent or mitigate the development and/or spread of AR . The Action Plan incorpo rates several action items aimed at strengthening, expanding and coordinating existing national and international surveil lance s ys tems for antimicrobial - resistant microorganisms. Additional action items in this area focus on reviewing barriers to timely di ssemination and updating of surveillance data and providing recommendations and best antimicrobial use practices . Over the next few ye ars, CDC wi ll address several action items in this focus area b y continuing to expand and improve its surveillance s ys te ms that collect data on AR. For instance, the National Healthcare Safety Network (NHSN) is a surveillance s ys tem that provides healthcare facilities a way

to track, anal yz e, and interpret data on healthcare - associated infections ( HAIs ), including those cau sed by antimicrobial - resistant pathogens. NHSN will be expanded to improve its capacit y for collection and anal ys is of data on multidrug - resistant organisms (MDROs) and antimicrobial drug use. In addition to monitoring resistance in healthcare settings, CD C will maintain surveillance activities for pathogens affecting the general population through efforts such as the Emerging Infections Program (EIP), a population - based network of CDC and state health departments, the Gonococcal Isolate Surveillance Projec t , and the National Tuberculosis Surveillance Sy stem. Through the EIP program, CDC closely monitors invasive bacterial pathogens through Active Bacterial Core surveillance and tracks resistance among enteric pathogens through the National Antimicrobial Res istance Monitoring S ys tem. In addition to monitoring resistance among bacterial pathogens, CDC will continue to monitor resistance among non - bacterial pathogens such as influenza, malaria and human immunodeficiency virus , both domestically

and internationa lly . II. Prevention and Control The prevention and control of antimicrobial - resistant infections requires measures to promote the appropriate use

j of antimicrobial agents and prevent the transmission of infections (whether drug - i These highlighted activities are provided as illustrative examp les and do not represent a comprehensive list. j In this Action Plan , appropriate antimicrobial drug use is defined as use that maximizes therapeutic impact while minimizing toxicity and the development of resistance. In practice, this means prescribing antimicrobial therapy- 7 -

resistant or not). While d evelopment of new antimicrobial agents and effective stewardship of existing agents are cornerstones of activities to protect the health of the nation in the face of expanding AR , successful prevention or elimination of resistance occurs with successful pr evention or elimination of resistant microb es. Public health initiatives can be successful. F or example , drug - resistant malaria is rampant in parts of the world, but malaria was effectivel y eliminated from the United States through mosquito control efforts . Antibiotic resistance in Haemophilus influenzae was the critical issue that determined antibiotic choice for virtuall y all invasive bacterial infections in young children in the United States as recently as 15 ye ars ago, but following the introduction of Haemophilus infuenzae serot yp e b ( HI B ) vaccines this problem has nearl y been eliminated. O ther action items in this area focus on extending the useful life of antimicrobial drugs b y encouraging appropriate use through educational efforts such as the **Get Sm**  **art: Know When Antibiotics Work**  campaigns , preventing infection transmission through improved infection control methods and use of vaccines, and prevent ing and controlling emerging AR problems in agriculture, human and veterinary medicine. AR preventio n and control activities that will be key over the next few years include several interagency

collaborations focused on controlling and preventing MRSA infections within healthcare settings. Based upon the successful collaboration between the VA Pittsburgh Healthcare S ys tem and CDC that demonstrated a reduction 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 regional levels led the VA to expand its MRSA Prevention Initiative, which is now a nationwide effort to reduce occurrence of healthcare associated MRSA infection from developing while patients are in hospital. VA is also evaluating lessons learned from the MRSA Prevention Initi ative to explore expanding this beyond just MRSA to other MDROs, including Clostridium difficile . Also continuing over the next few years is an interagency initiative to identify

and help suppress the spread of MRSA and other related infections through an ongoing partnership between CDC and AHRQ. The two agencies are working together closel y to identify gaps in the prevention, diagnosis, and treatment of MRSA and related infections across the healthcare s ys tem and to fund research, implementation, measurement, and evaluation 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 Infections (HA I) k , which includes both Clostridium difficile and MRSA. By working to implement the HHS HAI Action Plan these agencies and partners will impact several areas and action items covered in this 2010 AR Action Plan. when and only when beneficial to a patient; targeting therapy to the desired pathogens; and using the appropriate agent , dose, and duration. k The HHS Action Plan t o Prevent Healthcare - Associated Infections is available on the HHS webs ite at: http://www.hhs.gov/ophs/initiatives/hai/infection.html- 8 -

III. Research Understanding the fundament al processes involved in AR within microbes and the resulting impact on humans, animals, and the environment forms an important basis for influencing and changing these processes and outcomes. Basic and clinical research provides the fundamental knowledge necessary

to develop appropriate responses 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 and new antimicrobials, inve stigat ions into the development of resistance and host - pathogen interactions, optimiz ation of treatment for resistant pathogens, and translati on of research findings into clinically useful products, such as novel approaches to detect, prevent, and treat antimicrobial - resistant infections. Over the next few ye ars, NIH will engage in AR research activities that address several action items in this focus area. For example, NIH currently supports and continues to solicit clinical trials aimed at identifying ways to reduce the use of licensed antibacterials in both community and healthcare settings These trials focus on areas of greatest antimicrobial drug exposure, including pulmonary

tuberculosis, pneumonia, otitis media, sinusitis, skin and soft tissue infec tion, bacteremia, intraperitoneal infection, and surgical prophylaxis. Eligible strategies include, but are not limited to: shorter courses of antimicrobial treatment ; us ing antimicrobials only where indicated; different dosages/frequencies to achieve desi rable in vivo efficacy ; validation of the key

components of multi - drug therap y; prudent antimicrobial use; optimal use of off - patent antimicrobials to prevent the emergence of resistance; and new indications for licensed products. Recently renewed NI H act ivities in support of basic research include the Genomic Sequencing Centers for Infectious Diseases and the Bioinformatics Resource Centers for Infectious Diseases. The objective of the sequencing centers is to provide rapid and cost - efficient production o f high quality genome sequences of microorganisms and invertebrate vectors of infectious diseases and to make the resulting genomic data rapidl y and readily accessible to the broader scientific community

through publicly

accessible international databases. In addition, the sequencing centers wi ll provide comparative genomics and genoty ping services to examine genetic variation in populations and communities of human pathogens and also across the human genome to identify genetic associations with observable phenoty pes 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 geno mics and other ty pes of research data from human pathogens . Inaddition they provide the scientific community free access to resources for the query , analy sis and display of such information through user friendl y interfaces. IV . Product Development There is a critical need for new drugs, vaccines, and diagnostic tests to treat, prevent, and diagnose infections, including serious and life - threat ening infections caused by drug - resistant bacteria. FDA is working on a study to better understand the trends ove r time in the development- 9 -

of new antibacterial drugs, the number of drugs approved, and reasons wh y development programs may

not have achieved approval. The Action Plan incorporates action items that will facilitate the development of vaccines and diagnost ic tests for pathogens for which AR poses a significant problem for treatment or public health. FDA is working on a number of guidances on approaches to evaluating new antimicrobial products. Providing guidance can help b y identifying recommended scienti fic approaches and also to identify

areas where additional developmental work would be beneficial for the design and conduct of studies. Over the last few years, FDA has held several public workshops and/or Advisory Committee meetings to discuss clinical trial designs for evaluating antibacterial drugs. FDA has also published several guidance documents that describe recommended approaches regarding clinical trial designs. l One particular example of the efforts to date is the work to refine clinical trial d esigns for studying antibacterial drugs for the treatment of hospital - acquired bacterial pneumonia (HA B P) and ventilat or - associated bacterial pneumonia (VABP). As part of these efforts, in 2009, FDA co - sponsor ed a public workshop with the Infectious Diseas es Societ y of America, the American College of Chest Ph ys icians, the Society of Critical Care Medicine, and the American Thoracic Society regarding scientific issues in clinical trial design for HA B P and VABP. This public workshop provide d information about, and gain ed perspective from, health care providers, academi cs , and industry

on various aspects of antimicrobial drug development for HA B P and VA B P, including diagnosis, treatment, trial endpoints, and statistical issues in analy sis of res ults of trials in HABP and VABP. In the next few years, FDA will engage in activities to address a number of the action items in the Product Development focus area. FDA will be working to provide clarity on recommended approaches for evaluating new medical products f or bacterial disease through publishing guidance documents. FDA plans to publish guidance documents on recommended clinical trial designs for evaluating antibacterial drugs for conditions such as acute bacterial skin and skin structure infections and hospi tal - acquired and ventilator - associated bacterial pneumonia. In addition, FDA also plans to publish guidance for establishing performance for in vitro diagnostics assay s for MRSA and vancom ycin - resistant enterococci (VRE). These guidances will describe rec ommended approaches for developing new antimicrobial products for specific uses. The Biomedical Advanced Research Development Authority (BARDA), in the HHS Office of the Assistant Secretary

for Preparedness and Response m is designing and implementing programs l Examples of recent guidance documents: Antibacterial Drug Products: Use of Noninferiority Studies to Support Approval (dra ft, October 2007), Acute Bacterial Sinusitis: Developing Antimicrobial Drugs for Treatment (draft, October 2007), Acute Bacterial Otitis Media: Developing Drugs for Treatment (draft, January 2008), Acute Bacterial Exacerbations of Chronic Bronchitis in Pat ients with Chron ic Obstructive Pulmonary Disease: Developing Antimicrobial Drugs for Treatment (draft, August 2008), Community - Acquired Bacterial Pneumonia: Developing Drugs for Treatment (draft, March 2009), Non - Inferiority Clinical Trials (draft, March 2010)

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

that create partnerships between government and industry based on support and incentives that induce the commercial enterprises to address public health and biodefense priorities. BARDA is currentl y supporting the development of intravenous formulati on of a next generation aminogl ycoside antibiotic for the treatment of plague and tularemia, as well as ventilatorassociated pneumonia. BARDA is projecting an expansion of this program in the near- term by supporting the development of more novel antimicrobial candidates for the treatment and prevention of diseases caused by bacterial threat agents as well as diseases caused by clinically prevalent infectious diseases, including those that are AR.- 11 - 

### The Focus Areas With in each of the goals listed for each focus area are several action items that define topic areas for specific projects or implementation steps (numbered items). Wherever possible, action items are populated with specific projects or implementation steps (l ettered items) to provide greater specificit y for planned federal activities. The action items, projects, and implementation steps do not represent an exhaustive list of activities. n The expected completion dates for specific projects and implementation st eps are indicated with a date. For example, (2011) means that the work is expected to be completed by the end of the 2011 calendar ye ar. Some activities are ongoing and are indicated as such. Since project planning is itself 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 b y AR microorganisms and 2) comprehe nsive knowledge of the use of antimicrobial agents across all sectors. Goal 1: Improve the detection, monitoring, and characterization of drug - resistant infections in humans and animals. 1.1 Develop strategies to more accuratel y assess the burden of antimicrobial drug resistance in the community through the enhancement of existing sy stems including the EIP, and the Epidemiology

and Laboratory

Capacit y (ELC) sites . a) Implement a multi - site community- onset pneumonia etiology study among persons admitted with pn eumonia and evaluate the specific role of antibacterial and antiviral resistance in determining outcomes associated with pneumonia (2011) (see 2009

– 2010 Annual Progress Report) . **Progress:** The study

has been implemented with continued patient enrollment through May 2012. A published final report is expected by the end of 2013. b) Facilitate surveillance for resistant enteric bacteria by construction of a web interface for data entry and reporting results between state and federal participants in the Nationa l Antimicrobial Resistance Monitoring Sy stem (NARMS) (2012).

n Because of the rapidly evolving nature of AR, there will likely be new or emerging challenges in antimicrobial res istance subsequent to the publication of this Action Plan. The Task Force is committed to identifying and responding to these issues as they arise.- 12 -

**Progress:** NARMS representatives participated in regular interagency calls and ad hoc calls with Booz Allen Hamilton contractors and FDA business process improvement experts to help refine goals and requirements for the integrated database. CDC , ARS, and FDA continued to contribute summary data for interagency

executive summary reports which will continue until true integration of specimen - level data can be achieved. ARS and FDA have been usi ng Cry stal Dashboard to post interactive graphs of NARMS data on the web since 2004. ARS provided the templates to CDC and FDA to incorporate data for interactive graphs exhibiting data simultaneously from all three arms of NARMS. Interactive graphs were first added as a supplement to the online publication of the 2005 NARMS Executive Report. ARS also linked the NARMS data with USDA VetNet data for concurrent analy sis of susceptibility and PFGE of isolates. Data is routinely submitted to USDA FSI S for u se in their regulatory program. In 2011, CDC obtained securit y approvals for Crystal Dashboard software that will allow them to post interactive graphs of NARMS data on the NARMS webpage. OCI SO approval was obtained in 2011, and the software was purchas ed. CDC also made major headway on construction of the CDC NARMS database and web tool that will allow CDC to acquire specimen - level data from state participants and ultimately communicate specimen level and summary susceptibility

data back to the particip ants in way s that will allow them to query , report, and share the information they need when they

need it. c) Implement electronic tools to query resistance prevalence among enteric pathogens collected in NARMS (2015). **Progress:** NARMS representatives partic ipated in regular interagency calls and ad hoc calls with Booz Allen Hamilton contractors and FDA business pro cess improvement experts to refine requirements for the integrated database. CDC continued to contribute summary data for interagency

executive summary

reports which will continue until true integration of specimen - level data can be achieved. In2011, CDC obtained securit y approvals for Cry stal Dashboard software that will allow us to post interactive graphs of NARMS data on the NARMS webpage. CDC also made major headway on construction of the CDC NARMS database and web tool that will allow CDC to acquire specimen level data from state participants and ultimately communicate specimen level and summary susceptibility

data back to the participants in way s that will allow them to query , report, and share the information they need when they

need it. d) Report regular summaries of antimicrobial resistance trends and mechanisms among foodborne bacterial pathogens on the NARMS website and in the literature ( 2011 and ongoing). **Progress:** In 2011, NARMS partners published 2009 data in the NARMS Executive Report (FDA), the human isolate annual report (CDC), the food animal annual report (USDA) and the retail meat report (FDA). on the respective NARMS website s . In2011,- 13 -

NARMS scientists published 22 peer - reviewed scientific manuscripts describing clinically - and epidemiologically - relevant trends and mechanisms of resistance among Salmonella , Shigella , Campylobacter , E. coli nd other pathogens. In addition to contributions to peer - reviewed scientific journals, CDC - NARMS scientists continued to work with CL SIto share data relevant to breakpoint decisions, and conducted and presented value - added studies with isolates from the NARMS collection relevant to breakpoint setting for fluoroquinolones and macrolides. These studies included results from drugs and/or methods not routinely tested b y NARMS. In the case of azithromycin, results of preliminary

testing and changes in clinical use of this drug led to the decision to add azithromycin to the routine NARMS test panel for Enterobacteriaceae. CDC also anal yz ed susceptibility

data for outbreak isolates tested from 2004 - 2008 and enhanced testing of isolates from enteric disease outbreaks. ARS and FDA routinel y uploaded provided AR and PFGE information to CDC’s PulseNet database for outbreak investigations and supported FSIS during the outbreak and recall investigations by providing AR and PFGE data. ARS - NARMS also began on farm pilot studies of resistance in swine, bee f, dairy , broiler and turkey production to evaluate the prospects for a new preharvest component for NARMS. ARS - NARMS provided 160 NARMS isolates to FDA for use in the FDA SAFE project to develop new diagnostic tests. e) Expand the Gonococcal Isolate Sur veillance Project (GISP) to include a State public health laboratory

for sentinel site reference susceptibility testing (2011) and initiate a CDC administered external quality assessment testing to ensure accurate testing at all 5 sentinel sites (2012). **P rogress:**  The laboratory successful ly passed the external quality - assessment testing and began testing GISP isolates during 2011. f) Expand GI SP to include surveillance to identify the emergence of cephalosporin resistant Neisseria gonorrheae by monitoring f

or gonorrhea cephalosporin treatment failures (2011). **Progress:** The activity

has started and is ongoing. Coordinator: CDC; Collaborators: FDA, USDA, VA 1.2 Develop strategies to more accuratel y assess the burden of antimic robial resistance in healthcare settings through the enhancement of existing sy stems including NHSN, the EIP, and EL C sites . a) Expand NHSN to use electronicall y captured antimicrobial susceptibility data from participating facilities for reporting of resistance rates and trends; pilot expans ion plan in 2011 - 2012 , provide results of pilot in 2012, develop a web - based query for users in 2014- 14 -

and provide ongoing periodic reports o f the collected resistance data (see 2009

– 2010 Annual Progress Report) . **Progress:** The Antimicrobial Resistance Opt ion of the NHSN Antimicrobial Use and Resistance (AUR) Module is being revised to allow submission of electronically captured data only ; the protocol is undergoing revisions in an attempt to make the d ata model similar to EARS - Net; informatics standardizat ion of data submission via clinical document architecture (CDA) is planned for 2013. Begin piloting of facility submission of aggregate antimicrobial resistance data via CDA in 2012, begin receiving data b y 2014, provide ongoing periodic reports of the col lected resistance data by 2014. b) Report regular summaries to provide national estimates of the resistance burden using data reported on HAI s to NHSN (2011 and ongoing). **Progress:** The first published report of NHSN AR data covered 2006 and fir st half 2007 HAI data. The next r eport will cover 2009 and 2010 compared to 2007 and 2008 HAI data. All data anal ys es and creation of data tables are complete. Writing is in progress. The second report is expected to be published b y summer 2012. c) Evaluate the utility of electronic rules for identifying and reporting central line - associated bloodstream infections, surgical site infections (2011), catheter - related urinary tract infections (2012), and ventilator - associated pneumonia (201 2 ), including associated pathogens ; and compare electronic algorithms with traditional manual surveillance by infection control professionals (CLABSIs 2011) (see 2009

– 2010 Annual Progress Report) . **Progress:** Algorithm - detected central line - associated bloodstream infection reporting measures complete (15 facilities): final results in draft form to be published; details of approach being discussed with two hospital groups for trial implementation (in proprietary

s ys tem) summer 2012. Any reporting to the National Healthcare Safety Network p ostponed until successful exp erience with external partner. VAP measure for adults complete, changed to VAE (Ventilator associated event and infectious ventilator associated complication - iVAC) and plan to implement in 2013. Study to correlate iVAC and VA P prevention bundles in progress through CDC Epicenter program. SSI algorithmic detection work on hold currently . d) Develop a s ys tem to collect representative sets of bacterial isolates to assess changes in resistance mechanisms or strains nationally and wo rk with the Clinical and Laboratory Standards Institute (CL SI) to determine the impact of changes on antimicrobial susceptibility

testing and reporting practices in the United States. **Progress:** MRSA, C. difficile and carbapenem resistant Enterobacetriace ae are received regularl y as part of several population - based surveillance s ys tems. Other organisms with unusual resistance profiles are received for reference confirmation of unusual antimicrobial susceptibility profiles. Proposals for routine isolate col lection in conjunction with EIP surveillance activities have not advanced due to lack of funding.- 15 -

e) Collect convenience samples of bacterial and fungal isolates through the EIP to assess changes in antimicrobial - resistant pathogens such as MRSA (2011), Clo stridium 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 validation of antimicrobial susceptibility data submitted to NHSN (2012). **Progress:** Population - based surveillance for invasive MRSA infections and Clostridium difficile infections (CDI) are ongoing in multiple EIP sites since 2005 and 2009, respectivel y. As part of this surve illance, MRSA (starting 2005, but reduced isolate submission in 2012 from 9 sites to 5 sites (1000/year to 600 per ye ar) and C.difficile isolates (starting 2011) are collected and submitted to CDC for molecular characterization and antimicrobial susceptibi lity testing. Annual reports from the invasive MRSA surveillance program are posted online. CDI surveillance data are expected to be presented and published in 2012. Surveillance for infections due to selected multidrug resistant Gram - negative bacteria is underway in 3 EIP sites, with an additional 2 sites to begin surveillance in 2012. Convenience samples of MRSA and C. difficile have been collected since 2005 and 2009, respectivel y. Isolates of carbapenem resistant E. coli and Klebsiella species are now being submitted (September 2011) as part of the Multi - drug resistant Gram negative Surveillance Initiative (MuGSI) project. Operational consideration for routine isolates submission from NHSN hospital through EIP sites were made in 2011 funding cycle, but considered to be cost prohibitive at this point. f) Implement (2011) a periodic national prevalence survey for healthcare - associated infections, including those caused b y antimicrobial - resistant pathogens (see 2009

– 2010 Annual Progress Report) . **Progress:** The full - scale, healthcare - associated infections and antimicrobial use point prevalence survey

was conducted between May and September 2011 in 183 hospitals in 10 states. More than 11,000 patients were survey ed. Data cleaning is underway , and results are expected to be presented b y fall 2012. Coordinator: CDC; Collaborator: VA 1.3 Assess the presence of antimicrobial - resistant microorganisms, such as MRSA, Clostridium difficile , and vancom ycin - resistant enterococci (VRE), among food animals, retail meats, an d household environment in the United States. Assessment should include comparison of isolates from humans , environment, retail meats, and food animals. a) Design and implement a 1 year prevalence study of MRSA, VRE, and Clostridium difficile from retail meat (2011). **Progress:** Culture anal ys is failed to recover an y isolates of VRE or C. difficile . For MRSA, 3,480 meat samples of chicken breast, ground beef, ground turkey and pork chops were tested, from which 80 MRSA were recovered for an overall prevalence of- 16 -

2.3%. Most (43%) were SCCmec Ty pe IV, and spa ty

pe t008 (30%), and 70% were PVL+. PFGE showed 16% were USA 100, 30% USA 300, and 31% USA 500. Work is ongoing to complete susceptibility testing and genetic anal ys is. b) Evaluate the quant ity

of Clostridium difficile recovered from retai l meats in FoodNet sites (see 2009

– 2010 Annual Progress Report) . **Progress:** During 2010 - 2011, more than 1600 ground beef, ground turkey , pork chop, and chicken breast samples were collected at 9 sites participating in th e NARMS retail meat program and tested for Clostridium difficile . No C. difficile was isolated. A manuscript has been drafted and is currently under review. c) Conduct a pilot study to evaluate Clostridium difficile environmental contamination in households of infected and non - infected patients (see 2009

– 2010 Annual Progress Report) . **Progress:** See 2009 - 2010 Annual Progress Report. d) Characterize and compare recovered food bacterial isolates with those associated with environmental assessments and human ill ness (2012). **Progress:** USDA collaborative study with Texas A&M complete. Three publications involving C. difficile . Clostridium difficile in Poultry and Poultry Meat. 2011. Harvey, R, Norman, K, Andrews, K, Hume, M, Scanlan, C, Callaway , T, Anderson, R, and Nisbet, D. Foodborne Pathogens and Disease. 8(12), 1321 - 1323.. Clostridium difficile in retail meat and processing plants in Texas. 2011. Harvey , R, Norman, K, Andrews, K, Norb y, B, Hume, M, Scanlan C, Hardin, M, and Scott M. J of Veterinary

Diagnos ti c Investigation. 23(4) 807 - 11. Prevalence and genotypic characteristics of Clostridium difficile in a closed and integrated human and swine population. 2011. Norman, K, Scott, M, Harvey , R, Norby , B, Hume, M, and Andrews, K. Applied and Environmental M icrobiology . Aug. 5755 - 5760. Emerging pathogens related to resistance and the NARMS project will be initiated according to FDA needs. Coordinator: CDC; Collaborators: FDA, USDA 1.4 Id entify

patient populations colonized or infected with antimicrobial - r esistant pathogens which may

be important both for transmission of pathogens themselves and the transfer of resistance genes (e.g. vancom ycin - resistant Staphylococcus aureus ). Use this information to develop prevention strategies. a) Id entify

populations at risk for Clostridium difficile and MRSA infections based on data from population - based surveillance s ys tems (see 2009

– 2010 Annual Progress Report) . **Progress:** In 2010, the CDC’s Emerging Infections Program began population - based surveillance for Clostri dium difficile infection (CDI) in select counties across 8 states. The first year of surveillance data is anal yz ed to be presented in summer/fall 2012: focus- 17 -

is determin i ng method s for adjustment of laboratory testing variations and population differences for national estimates. National Estimates should be available in mid - 2013. Population - based surveillance for MRSA began in 2005 in 9 US metropolitan areas, and data from this surveillance has continued to be analy zed annuall y; 2010 estimates demonstrate 8 2,000 invasive infections, compared to 111,000 estimated in 2005. Special studies in 2012 being conducted to identify incidence by

specific patient population to aid in vaccine study design. b) Conduct studies of colonization with antimicrobial - resistant S . pneumoniae to determine the effects of antimicrobial use and pneumococcal vaccination on colonization (2012). **Progress:** NP swabs were collected from children aged 6 - 59 months in an emergency department from July

2010 - July

2011. After broth enrichment, s amples were cultured for SP; isolates were serot yp ed and antimicrobial susceptibility performed. Clinical and immunization records were reviewed. Findings during time periods 1 (July - Dec 2010) and 2 (Jan - July

2011) were compared. A total of 673 children we re enrolled; 196 (29%) were colonized with SP. Mean age of carriers was 27 months. SP carriage was higher among black children, children with asthma, and daycare attendees (p< 0.05). Commonly carried serot ypes included 19A (20.4%), 15B/C (15.3%), 35B (11.2 %), 6C (9.2%), and 11A (8.2%); 23.5% were PCV13 seroty pes. Infants aged 6 - 23 months receiving ≥2 doses of PCV13 increased from 25.2% to 45.4% from period 1 to 2 (p< 0.001). Overall SP carriage rates were unchanged from period 1 to 2, but seroty pe 19A decli ned from 26.6% to 9.7% (P=0.0047) and PCV13 seroty pes declined from 29.8% to 12.5% (P=0.0058). Nonsusceptibility

(I+R) to ceftriaxone and penicillin declined from 23.4% to 7% (P=0.0034), and 25% to 12.5% (P=0.0363), respectively . Coordinator: CDC; Collabo rator: NIH, VA 1.5 Strengthen and expand multi - state, national and international surveillance s ystems for antimicrobial - resistant microorganisms and ensure adequate sentinel surveillance for the emergence and spread of critical resistance phenoty pes (e.g. , penicillin - resistance in Group A Streptococcus , multidrug resistant and extensively drug - resistant tuberculosis (XDR TB), oseltamivir - resistant influenza viruses), and strive for more timely dissemination of surveillance data. a) Increas e the number and ca pacity of public health laboratories (PHL) that routinely monitor for influenza antiviral resistance by d evelop ing new assay s for rapid testing for antiviral resistance (2011) and de velop ing web - based reporting s ys tems (2012). **Progress:** 20 PHL have been trained to do p yr osequencing. Three PHL have been trained to do neuraminidase inhibition assay s and two more will be trained later this year. Web - based reporting s ys tem is currentl y being piloted in several states **.** b) In crease the capacity

of state public health laboratories to identify antimicrobial - resistant organisms among cases of culture - negative clinical sy ndromes (e.g., meninigitis,- 18 -

empyema) using real - time poly merase chain reaction (PCR) for species - specific genes and markers of antimicrobial resist ance (2013). **Progress:** A PCR assay

was completed and published that identifies pneumococcus as well as whether the organism is susceptible or not to beta - lactam and macrolide/lincosamide agents. c) Routinely

evaluate isolates captured through ABCs with unus ual resistance profiles (e.g., penicillin - resistant Group A or Group B Streptococcus , or vancom ycin resistance among any of the Streptococcus pathogens) to identify resistance and characterize the molecular mechanisms (annuall y) (see 2009

– 2010 Annual Pro gress Report) . **Progress:** Trends in the incidence of infections caused by antimicrobial resistant Streptococcus pneumoniae showed that the introduction of the 7 - valent pneumococcal conjugate vaccine in 2000 continued to have substantial benefits in terms o f preventing resistant infections through 2010 when PCV13 was introduced. Increases of resistant infections due to specific clones of the PCV13 seroty pe 19A continued to markedl y increase through 2010. Seroty ping and susceptibility

testing of the majority of year 2010

- 2011 pneumococcal isolates has been completed. To continue tracking of resistant pneumococcal clones, comparative genotypic analysis of all pediatric ABCs isolates from pre PCV13 introduction (2008 - 2009) has been completed and characterizati on of post PCV13 introduction (2011 - 2012) isolates is underway . Invasive GAS isolates are collected in all ABCs sites and GBS isolates in 7 of 10 ABCs site, with 2 of these considering expansion of age groups or catchment areas. All isolates are tested by broth microdilution against a standard panel including beta - lactam antibiotics and vancom ycin, and unusual resistance patterns are flagged for further evaluation. Fortunately , no unusual GAS isolates have been found, although the proportion of macrolide - re sistant isolates that also have constitutive lincosamide - resistance has increased; we remain vigilant for the rarely occurring GBS with increasing MICs to beta lactams. No vancomycin - resistant streptococcal isolates have been identified. Infrastructure for isolate collection is in place and improved logistics planning are ongoing to sustain ongoing evaluation in 2012 and future ye ars. d) Assess the impact of including data on susceptibility to multiple fluoroquinolones and injectable agents (aminogl ycosides and capreom ycin) to the national TB reporting s ys tem for enhanced detection of XDR TB (see 2009

– 2010 Annual Progress Report) . **Progress:** See 2009 - 2010 Annual Progress Report. e) Complete a pilot exercise to expand routine nationwide surveillance for MDR TB to include additional drugs and determine whether this additional surveillance provides useful information that warrants broader implementation (see 2009

– 2010 Annual Progress Report) . **Progress:** See 2009 - 2010 Annual Progress Report.- 19 -

f) Organize, plan , and conduct a NARMS public scientific meeting to highlight results and related AR research and solicit input from stakeholders and international partners on future enhancements and improvements (see 2009

– 2010 Annual Progress Report) . **Progress:** NARMS held a public meeting in St. Louis, MO in July , 2011 with stakeholders from public health (including several participants from CDC), industry , and consumer advocacy

groups. The meeting included domestic and international partners, and discussions focused on samp ling strategies for food animals. As a result, FDA modified funding to USDA to accommodate more on - farm sampling projects, and the isolates from sample sources other than swine are being submitted directly to FDA for susceptibility

testing. Coordinator: CDC; Collaborators: DoD, FDA, USDA, VA 1.6 Work with public health associations, including Association of Public Health Laboratories (APHL) and Council of State and Territorial Epidemiologists (CSTE), to define minimal surveillance activities for AR for local , state, and regional health departments. Enhance the accurate detection and identification of AR b y cl inical and public health laboratories. a) Develop consensus definitions for outbreaks of antimicrobial - resistant pathogens that are reportable to health departments to optimize the detection, investigation and resolution of outbreaks (2011). **Progress:** To date, at least 8 state health departments have administered a survey to acute care facilities within their jurisdiction to estimate regional CRE prevalen ce and to assess for facility

implementation of recommended surveillance prevention measures. At least 6 states had provided feedback of the survey results to acute care facilities via electronic newsletters and/or regional presentations. A summary of the CRE survey

results (aggregate data) was presented at the 2011 Annual CSTE meeting. Following the survey activity , as part of formative research to better understand the health department experience with the CRE survey and their perceived roles and responsi bilities in responding to an emerging pathogen, key informant interviews were conducted with select states. Manuscript in preparation. A toolkit entitled "Guidance for Control of Carbapenem - Resistant Enterobacteriaceae" designed to assist healthcare facil ities and health departments in responding to outbreaks of CRE has been completed and cleared, and is currentl y being formatted for publishing on CDC website. b) Disseminate expert recommendations for effective state - based surveillance for multidrug resistant organisms related to healthcare - associated infections (see 2009

– 2010 Annual Progress Report) . **Progress:** Expert recommendations for surveillance have been shared/published. c) Implement standard protocols for antimicrobial susceptibility testing through CDC’s ELC Program (ongoing) (see 2009

– 2010 Annual Progress Report) .- 20 -

**Progress:** As of December 31, 2011, 332 isolates have been collected; of these susceptibility

phenot ype anal ys is suggests that 35, 16, and 5 isolates expressed AmpC β lactamases, ESBLs and carbapenemases, respectively . Importantly , an outbreak of Enterobacter aerogenes was identified at the Nebraska Medical Center that produced KPC - 4, which hydrolyzes all B - lactam antibiotics. Subsequent infection control and molecular analy sis confirm ed the tranfer of a 66kb plasmid, pNE1280 from E. aerogenes to Serratia marcescens within a hospital unit. pNE1280 is very similar to a previousl y characterized plasmid, pCTXM360, conferring resestance to cefotaxime, but not carbapenems due to the absence of blaKPC - 4. This plasmid has been sequenced and a TN4001 - like transposon that encodes blaKPC - 4 has been identified. A manuscript is being prepared for submission to the Journal of Emerging Infectious Diseases. These results have been presented in post er format at the Missouri Valley Branch ASM meeting in L incoln, NE, the 2011 APHLNational Meeting in Omaha, NE, and the 2011 ASM General Meeting in New Orleans. The surveillance data show that carbapenem resistance has only

been detected in Omaha and in a tertiary care center. The identification of these plasmids resulted from characterizing isolates identified during the surveillance. ESBL and AmpC beta - lactamases have been detected in other geographic locations, but prevalence is very low (<5%). The collection of isolates will continue through the 2012 funding period and beyond until 800 isolates have been collected. d) Develop and implement an antimicrobial susceptibility testing training program for public health laboratories (2012). **Progress:** Se e 2009 - 2010 Annual Progress Report. e) Establish a web - based training program, updated annually , on laboratory detection of AR (pilot in 2013 and implement in 2014). **Progress:** In 2011, a cross - cutting and connective effort between DHQP, DL SS, and DLPP was i nitiated with the planning of the update of the Multi - Level Antimicrobial Susceptibility

Testing Resources (MASTER) training activity . A kickoff meeting was held in summer 2011 and the instructional design team was identified in fall 2011. Internal and e xternal subject matter experts were identified in 1st quarter of 2012. The AST project is on track to be completed b y J anuary 2014. Coordinator: CDC 1.7 Promote participation of microbiologists and local, state, and national public health workers in the d esign of sy stems to collect and disseminate AR data to appropriate end users. Identify

methods to assist laboratories in summarizing and disseminating AR data to appropriate end - users and provide methods for individual laboratories to compare their data wi th data in surrounding regions. a) Establish state - based surveillance networks utilizing NHSN to aggregate local - level data on healthcare - associated infections, multidrug - resistant organisms, and/or Clostridium- 21 -

difficile infections for targeted prevention interventions (2011) (see 2009

– 2010 Annual Progress Report) . **Progress:** Fort y - nine states and 2 territories received funding in 2009 - 2010 through the American Recovery

and Reinvestment Act (ARRA). Funding used to create state - based HAI programs, bring rele vant stakeholders together. At least 10 state - based mandates use NHSN for tracking CDI or MDROs, and several ARRA funded state - healthcare facility collaboratives are underway using NHSN. The surveillance data are guiding the targeting of prevention efforts . Published a CDC Vital Signs summarizing the reporting experience and sharing prevention success from three states’ efforts. Plan to expand use of module nationally as hospitals comply

with pay for reporting requirement of CMS Hospital Quality Reporting P rogram . b) Coordinate the collection of AR data for select veterinary bacterial pathogens by partnering with State veterinary diagnostic laboratories (2011). **Progress:** None . Coordinator: CDC; Collaborators: FDA, USDA, VA 1.8 Collaborate with surveillance s ys t ems in other parts of the world to build global surveillance of AR microorganisms. a) Establish liaisons with reference laboratories in countries without well - developed surveillance s ys tems, both to improve the accuracy of global surveillance for resistance and to improve local use of the data (ongoing) (see 2009

– 2010 Annual Progress Report) . **Progress:** In 2011, NARMS scientists hosted visits from and provided consultation to more than 20 scientists from China, Japan, Haiti, Korea, and Thailand to help the m understand our surveillance programs and to help them design their own such programs. Many of these consultation opportunities were facilitated by the Global Foodborne In fections Network ( GFN ) and international EIP programs as well as support by the min istries of health in the countries. DFWED scientists continued to participate in formal GFN training courses that include an antimicrobial susceptibility testing component. Continued collaboration with the Republic of Georgia National Centers for Disease Control and Public Health (NCDC) on a laboratory - based Salmonella surveillance project, which includes antimicrobial susceptibility testing of Salmonella isolates identified in sentinel sites. b) S upport and assist WHO on matters related to integrated surve illance of AR and containment of food - related AR through participation in the newly establish WHO Advisory Group on Integrated Surveillance of Antimicrobial Resistance (WHO AGI SAR) ( ongoing ). (see 2009

– 2010 Annual Progress Report)- 22 -

 NARMS scientists from F DA, CDC and USDA will provide expert advice to the WHO - AGISAR steering committee through participation and information sharing (2012) (see 2009

– 2010 Annual Progress Report) .  Support laboratory

capacity building activities in WHO member countries for AR m onitoring by

developing AR modules for Global Foodborne Infections Network training courses (2011 - 2012 ) . **Progress:** Representatives from NARMS participated in the 3rd meetings of the WHO Advisory Group on Integrated Surveillance of Antimicrobial Resistance (AGI SAR). For more information on WHO - AGISAR activities see ( http://www.who.int/foodborne_disease/resistance/agisar/en/index.html ). From 2009 to present, NARMS partnered with WHO Global Foodborne Infections Network (GFN) to provide partial support to training activities included on antimicrobial resistance in 14 Asian and L atin American countries. Sixteen projects on antimicrobial resistant, which includes onsite problem solving through NARMS participation, have been initiated. The US NARMS assisted in establishing, and continues to collaborate, with the Canadian CIPARS [Canadian integrated program on antimicrobial resistance surveillance] program to ensure harmonized surveillance in North America (FDA - CVM); CDC , FDA and ARS NARMS scientist s serve as member s of the WHO - Advisory Group on Integrated Surveillance of Antimicrobial Resistance and participated in the WHO - AGISAR meeting in Oslo, Norway

in June of 2011. c) Develop c ollaborations with International Emerging Infections Program (IEIP) sites to improve surveillance s ys tems for AR, facilitate prevention programs, and ensure appropriate responses to outbreaks of resistant organisms (ongoing) (see 2009

– 2010 Annual Progres s Report) . **Progress:** Antibiotic use studies in Guatemala and Egy pt have been completed. The Egy pt IEIP is currentl y developing a communication campaign to reduce antibiotic use with support from CDC's Get Smart program. d) Collaborate with IEIP sites to expand surveillance sy stems to measure the burden of AR and the impact of infection control interventions in healthcare settings (2011). **Progress:** Antimicrobial susceptibility testing for pneumococcal isolates collected during a carriage study in children and HIV - infected adults in Kenya has been completed. Laboratory

data is currently

being merged with the associated epidemiologic information prior to completion of analy sis. Repeat testing of carriage isolates collected after pneumococcal vaccine introduct ion is being considered. Coordinator: CDC; Collaborators: DoD, FDA, USDA 1.9 Develop national and international surveillance s ystems to monitor understudied areas, such as resistance in protozoan parasites (e.g. Plasmodium spp.) helminthes or- 23 -

understudied se xually

transmitted diseases (e.g., T. pallidum, T. vaginalis , Herpes simplex), neglected tropical diseases, and resistance to disinfectants, sanitizers, and insecticides. a) Id entify

resistance mechanisms in Trichomonas and use this information to develop la boratory tests for detection of resistance ( 2012) . **Progress:** Genot yping of a collection of T. vaginalis isolates using microsatellites has revealed existence of two major phylot ypes with resistant isolates aggregating within one of the ph yl ot ypes. This su ggests a single or limited number of genetic differences are associated with resistance and that a molecular tool could be developed to detect resistance more rapidl y than what is possible with standard methods [Conrad, M., A. Gorman, J. A. Schillinger, P. L. Fiori, R. Arroyo, N. Malla, M. L. Dubey , J. Gonzalez, S. Blank, W. E. Secor, and J. M. Carlton. 2012. Population genetics of the sexually transmitted pathogen Trichomonas vaginalis and evidence for sexual recombination. PL oS Negl. Trop. Dis. (In Press) ]. The STD Surveillence Network (SSuN) assessment of prevalence of resistance in T. vaginalis isolates in 6 cities (100 isolates per city) is comple [Kirkcaldy, R.D., P. Augostini, L . E. Asbel LE, K. T. Bernstein, R. P. Kerani, C. J. Mettenbrink, P. Pathel a, J. R. Schwebke, W. E. Secor, K. A. Workowski, D. Davis, J. Braxton, and H. S. Weinstock. 2012. Trichomonas vaginalis antimicrobial resistance in 6 US cities, STD Surveillance Network, 2009 - 2010. Emerg. Infect. Dis. (In Press)]. There is a range of 1.3 t o 7.5% resistance prevlaence among the clinics in the cities tested, with an overall resistance prevalence of 4.3%. b) Id entify

and characterize markers of artemisinin - based combination therapies (ACT) resistance in malaria for the purpose of developing new laboratory tests for surveillance (2012) . **Progress:** We have genoty ped single nucleotide poly morphisms (SNPs) in codons 86, 144, 184, 1034, 1042 and 1246 of the Pfmdr - 1 gene in about 300 specimen from Ken ya and Tanzania and 200 from Ghana (Alam MT. et al . 2011 J. Infect Dis. Jan 15:203(2):220 - 227). Copy number estimate of Pfmdr1 indicated no duplication of this gene in both Ken ya and Tanzania samples. Recently , newer candidate molecular markers associated with potential resistances to artemisinin and othe r partner drugs such as lumefantrine and halofantrine have been describes (Van Ty ne et al. 2011. PLoS Genet. Apr;7(4) and Tim Anderson (personal communication)). Efforts are underway to validate if these new markers can be used for monitoring resistance to ACT. c) W ork with international partners to conduct in vivo/ in vitro studies to monitor the efficacy of anti - parasitic drugs (2013) . **Progress:** In western Kenya, 669 children were screened and 274 were enrolled in a 42 - day in vivo efficacy

trial of dihydroartemisinin - piperaquine and artemether - lumefantrine in the treatment of children aged 6

– 59 months with uncomplicated P. falciparum malaria. The data collection was completed in September 2011 and data anal ys is and manuscript preparation are in progress. The preliminary results after PCR correction indicate that both drugs are still highly efficacious (>90%) in this region. There is significantly more- 24 -

recurrent parasitemia due to reinfection in the first 28 day s after treatment in those children given artemether - lumefantrine. This is likely because the longer half

- life of piperaquine provides a prophylactic effect. Results are consistent with other recent trials with these ACTs in sub - Saharan Africa. There is no evidence of delayed parasite clearance. In Tanzania, an in vivo study was conducted to assess the efficacy of Coartem (Artemether - Lumefantrine, or AL) (the current first line therap y) compared to Dihydroartemisinin - Piperaquine (DP) for the treatment of uncomplicated malaria infection in children aged 6 - 59 months. Clinical, parasitologic, and hematologic parameters were monitored over a 42 - day follow - up period. A total of 323 children were enrolled, 161 into the DP arm and 162 into the AL arm. Data anal ys is is currentl y underway . In Ken ya, 1 29 patients were screened and 83 enrolled for in vitro drug sensitivity testing. Six drugs were tested in these in vitro assay s (chloroquine (CQ), mefloquine (MQ), amadoquine (AQ), dih ydroartemisinin (DHA), artesunate (ARS) and lumefantrine (LU). Seventy two samples provided quality drug sensitivity

data. No significant changes in the drug response (changes in I C50) have been observed in this study period. All of the samples were sequenced to determine the Pfmdr1 SNP prevalence at codons 86, 144, 184, 103 4, 1042 and 1246. Analy sis will be performed to determine if the in vitro drug sensitivity

pattern has any

correlation with the molecular marker profile of Pfmdr - 1 and other molecular markers. Efforts are also underway to collect in vitro drug sensitivity data from Tanzania and Ghana. d) Collect a repository

of specimens with characterized antimalarial drug sensitivity p atterns for the development of laboratory test development and quality control (2012) . Laboratory

tests will be used to expand surveillance . **Progress:** We have collected and saved 83 samples from the in vitro drug sensitivity study in Ken ya . In addition, about 300 specimens from the in vivo study in Tanzania have been collected. e) Work with international partners to improve laboratory ca pacit y in endemic countries for the detection and surveillance of malaria drug - resistant parasites (2012) . **Progress:** Onsite refresher training was provided in Kenya and Tanzania for the in vitro drug sensitivity

assay s. Provided technical support to Tan zania to improve the molecular surveillance capability

there. In addition, two scientists from Ghana visited CDC for a short training to improve drug sensitivity testing in Ghana. f) E valuate current strategies for deploying insecticides for public health th at reduce or minimize resistance and as necessary develop new strategies. (2012). **Progress:** WHO has now incorporated the CDC bottle bioassay protocol developed and introduced b y our group into the WHO inse cticide resistance surveillance guidelines. This ye ar, we have introduced a variant of this assay into Africa, Asia and the Americas that now allows resistance intensity to be measured in small mosquito samples along with- 25 -

the resistance frequency

determinations that, up to now, were the onl y means of det ecting and assessing the importance of specific instances of resistance. This new technique will make it much easier to assess the significance of resistance problems that are becoming a crisis in our large multi - national malaria control programs. Coordin ator: CDC; Collaborator: DoD 1.10 Assess the risk of AR emergence and spread in food borne pathogens due to environmental contamination by antimicrobial drug residues and pesticides in collaboration with the existing Pharmaceuticals in the Environment Subcommittee of the Office of Science and Technology Policy . **Progress:** None . Coordinator: FDA; Collaborator: EP A Goal 2: Better define, characterize, and measure the impact of antimicrobial use in humans and animals in the United States. 2.1 Id entify

sources of ant imicrobial use information in the United States for humans, animals, agriculture, aquaculture, and other sectors to establish baseline data on antimicrobial use. Develop a standard for collecting and reporting schemes for antimicrobial use data that allow aggregation, reporting, and comparisons of trends across sectors. a) Gain access to and summarize de - identified data on antimicrobial use from market research companies, health maintenance organizations, federal healthcare systems, and other medical care s y stems in the United States to aid in quantifying antimicrobial use in humans and understanding geographical heterogeneity in antimicrobial use (2011). **Progress:** Antibioic prescribing data 2005 - 2010 have been received. The data are being anal yz ed, and a manuscript that will characterize outpatient antibiotic use in the U.S. is nearl y complete. An additional data request will be made in 2012 to obtain provider data to analyze the provider factors contributing to high antibiotic prescribing (2 .1 b). b) Perform a national antibiotic use point - prevalence survey - pilot survey to be completed by 2010 and full survey

by 2012 ( see 2009

– 2010 Annual Progress Report) . **Progress:** The full - scale, healthcare - associated infections and antimicrobial use point prevalence sur

vey was conducted between May and September 2011 in 183 hospitals in 10 states. More than 11,000 patients were survey ed. Data cleaning is underway , and results are expected to be presented b y fall 2012. c) Revise the Antibiotic Use and Resistance module of NHSN to accept electronic data on antibiotic use from healthcare facilities by 2011 and begin receiving data by 2012.- 26 -

**Progress:** The Antimicrobial Use Option of the NHSN Antimicrobial Use and Resistance (AUR) Module was revised to allow only submission of e lectronicall y captured data; informatics standardization of data submission via clinical document architecture (CDA) is complete (2011), now piloting facility submission of aggregate antimicrobial use data via CDA (2012), begin receiving data during 2012, and provide ongoing periodic reports of the collected use data by 2013. d) Collect and publish annual reports on animal antimicrobial drug distribution data through implementation of Section 105 of the Animal Drug User Fee Amendments of 2008 (2010 and ongoin g) ( see 2009

– 2010 Annual Progress Report) . **Progress:** The Animal Drug User Fee Amendments of 2008 (ADUFA), Section 105, requires antimicrobial drug sponsors to report the amount of antimicrobial active ingredient in their drug products that have been sol d or distributed for use in food producing animals for each calendar ye ar. ADUFA also requires FDA to summarize the sales and distribution information received from drug sponsors each year and to provide the summaries to the public. FDA published the 2010 summary report of sales and distribution data of antimicrobial drugs approved for food - producing animals on October 28, 2011. On July

27, 2012, FDA published an Advance Notice of Proposed Rulemaking (ANPRM) to solicit comments from the public on possible enhancements to the existing requirements related to the collection of antimicrobial drug sales/distribution data as well as input on alternative methods for monitoring antimicrobial use in food - producing animals. Such information is important for supporti ng FDA’s strategy for promoting the judicious use of medically important antibiotics in food - producing animals. The comment period for this ANPRM is open until September 25, 2012. e) Collect data through the National Animal Health Monitoring Sy stem to produ ce 3 reports on antimicrobial use practices on livestock and poultry operations in the United States. These reports (shown below) will be produced b y July 2011 (see 2009

– 2010 Annual Progress Report):

 Food Safet y Pathogens Is olated from U.S. Dairy Operat ions, 1996 - 2007  Antimicrobial Use and Resistance on Beef Cow - calf Operations in the U.S. 2007 - 08  Antimicrobial Use and Resistance Across Livestock and Poultry Operations - A compilation of data from the National Animal Health Monitoring Sy stem studies **Pr ogress:**  Informational reports on antimicrobial use and resistance in livestock operations are available from the USDA National Animal Health Monitoring S ys tem (NAHMS) at the websi te http://nahms.aphis.usda.gov . Recent examples include Dairy 2007: Salmonella , Listeria , and Campylobacter on U.S. Dairy Operations, 1996 - 2007 (pdf 1.3mb 3/11) (http://www.aphis.usda.gov/animal_health/nahms/dairy /downloads/dairy07/Dairy07_ir_F ood_safet y.pdf). The report Antimicrobial Use and Resistance on Beef Cow - calf Operations in the U.S. 2007 - 08 is currentl y in the clearance process. The report compiling all NAHMS collected data on antimicrobial use and resistance wa s posted to the website in 2012- 27 -

( http://www.aphis.usda.gov/animal_ health/nahms/beefcowcalf/downloads/beef0708/Beef 0708_ir_Antimicrobial.pdf). 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 correlati ons between antimicrobial use and antimicrobial resistance from studies in veterinary and human healthcare settings (e.g., cephalosporin use and prevalence of vancom ycin - resistant enterococci in intensive care units) and community

settings (e.g., fluoroqui nolone use for respiratory tract infections and macrolide resistance in pneumococci). a) Compare retail pharmacy sales of outpatient oral antimicrobials to geographic differences in bacterial resistance (2011). **Progress:** Get Smart Update: A manuscript evaluating the realtionship between antimicrobial prescribing and S. pneumoniae antibioic resistance in ABCs sites was published in the October 1, 2011 edition of Clinical Infectious Diseases, titled "Outpatient Antibiotic Prescribing and Nonsusceptible Streptococcus pneumoniae in the United States, 1996 - 2003." Coordinator: CDC

; Collaborators: NIH, USDA , VA 2.3 Implement s ys tems to detect the development and spread of resistance in microorganisms during implementation of new programs that significantly impact anti microbial drug use (e .g., pay - for - performance mandates on antibiotic timing for community - acquired pneumonia , gu idelines for intrapartum prophylaxis to prevent neonatal group B streptococcocal disease, mass population - based treatment campaigns for trachoma or helminthic infections, or large studies of treating partners or contacts). a) Monitor the use of intrapartum antimicrobial prophylaxis for the prevention of neonatal group B streptococcal infections and the potential impact of prophylaxis on resistant c ases of neonatal sepsis (2013). **Progress:** Intrapartum antimicrobial use in ABCs was last monitored in 2003 and 2004; an evaluation in 2013 or 2014 is being considered to assess the impact of revised newborn group B streptococcal disease prevention guidel ines issued in 2010. Additionally , through HAI activities, point prevalence survey s are being conducted that will capture antibiotic use in labor wards. Active Bacterial Core surveillance continues to conduct surveillance for invasive neonatal sepsis in th e first 3 day s of life in 4 sites and invasive neonatal group B streptococcal disease infections in all 10 ABCs sites. Data from 2007 - 2009 were analyzed to inform the 2010 GBS prevention guidelines. To date, neonatal sepsis trends remain stable overall. As sessments of the US burden of earl y - onset invasive neonatal sepsis, including resistant sepsis, and clinical sepsis based on hospital discharge data were completed and published (2011, 2012).- 28 -

Coordinator: CDC- 29 -



### Focus Area II: Prevention and Control **Overar ching 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, communi ties, 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- based interventions, such as vaccinatio n campaigns and the promotion of appropriate 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 influenza vaccines on drug - res istant infections caused b y those pathogens (2012). **Progress:** As of February 2012, 424 cases and 1,602 controls have been enrolled. Preliminary

evidence from routine surveillance suggests that the most antibiotic - resistant seroty pes are declining. Enrollm ent in the case - control study is expected to continue at least through 2012 and likely well into 2013. b) Evaluate factors that influence the prescribing practices of primary care phy sicians, including academic detailing and benchmark analy sis (2011). **Prog ress:**  HCA has completed this intervention. Coordinator: CDC

; Collaborators, DoD, VA 3.2 Promote use of appropriate interventions, including checklists, to reduce the risk of infection associated with catheters and other devices and procedures in healthcare settings. a) Facilitate multicenter prevention collaborative focused on device and procedure - related infections in at least 20 states by 2012. **Progress:** CDC is currently assessing the impact of the prevention collaboratives that concluded under ARRA fundi ng. With Prevention and Public Health Funds (PPHF) from the Affordable Care Act, CDC was able to fund new prevention collaborative efforts in 15 states. A significant focus of these new prevention efforts is on preventing the transmission of C. difficile and multi - drug resistant organisms in facilities across the continuum of care.- 30 -

b) Design and implement systems to measure healthcare processes that are linked to outcome data in order to measure the adherence of healthcare personnel to prevention measures. **Progress:** CDC continues to partner with academic colleagues using innovative and inexpensive wireless technologies to monitor healthcare worker movement and approximate hand hygiene adherence. In 2011 this partnership resulted in the publication of two manuscripts in an effort to further the science and implementation of hand hygiene adherence measurement. One manuscript used data from wireless sensors as a backdrop for simulated human observers of hand h ygiene practices; b y altering the simulated human ob server schedule, authors were able to determine which observer schedules would all viewing of the maximum number of hand hygiene events and the most diversity in healthcare workers observed. Additionall y, a qualitative anal ys is of healthcare worker percept ions of automated hand hygiene technologies found that transparency about the use of the data and accuracy of the technology

was key to healthcare worker acceptance and buy - in. DHQP continues to collaborate with colleagues to assess the implications of hea lthcare worker movement on other infection control practices in non - acute settings (e.g., dial ys is). c) Correlation between adherence to best catheter insertion practices and CLABSI rates (2011). **Progress:** Rates of adherence to central line insertion practi ces (CLIP) have increased from 92% in 2009 (n=72,606 insertions) to 95% in 2010 (n=108,118 insertions) to 96% in 2011 (n=122,630 insertions) (p<0.0001). Rates of adherence in the Emergency Department, where emergent insertions are most often placed have in creased significantl y from 83% in 2009 to 93% in 2011 (p<0.0001). Adherence to recommended CL IP has improved and is high. In aggregate, these anal ys es suggest that appropriate CL IP is becoming standard of practice and new prevention efforts should address practices like central line maintenance to progress towards elimination of CLABSI. d) Revise and publish HI CPAC guidance for prevention of catheter - as sociated bloodstream infections (see 2009

– 2010 Annual Progress Report) . **Progress:** Published online 2011 http://www.cdc.gov/hicpac/BSI/BSI - guidelines 2011.html. e) Revise and publish HI CPAC guidance for prevention of surgical site infections (2011). **Progress:** In January

2011 participating professional societies and subject matter experts began to submit topics and questions for inclusion in the update. Final selected Core and Arthroplast y section topics and related key questions were presented publically at the June and November 2011 HI CPAC meeting. At the February 2012 HICPAC meeting results presented public ally included: completed literature search, title and abstract screens, full text reviews, and the final selection of citations for data extraction into evidence tables **.**- 31 -

Coordinator: CDC

; Collaborators: AHRQ, VA 3.3 Id entify

and promote successful AR prevention and control 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 b y 2013. **Progress:** 17 CDI collaboratives have been funded and initiated with ARRA funding . b) Evaluate impact of the CMS - Quality Improvement Organization MRSA prevention initiative by

2012. **Progress:** The 9th SOW with data collection and required facil ity reporting for the CMS QI O MRSA prevention initiative ended in July 2011. CDC’s original plan to use the data from this initiative to determine the level of correlation between MRSA HAI rates and MRSA L aboratory - Id entified (Lab ID) Event rates is no lon ger viable, because facilities were not required in the 9th SOW to report both MRSA HAI s and MRSA L ab ID Events concurrently

from the same location within the same month. c) Evaluate impact of the Department of Veterans Affairs National MRSA prevention initi ative (2012). Explore the expansion of prevention initiatives to include other MDRO including Clostridium difficile and multidrug - resistant gram - negative pathogens (see 2009

– 2010 Annual Progress Report) . **Progress:** A manuscript describing the impact of the VA MRSA prevention initiative was published in 2011 in the New England Journal of Medicine (N Engl J Med 2011:1419 - 1430) CDC staff continue to serve as technical advisors to the VA MDRO working group as they

implement CDImeasurement and prevention strategies on a national scale. The work group has developed a campaign focusing on CDI measurement, reporting, and prevention strategy and tools including a reporting s ys tem based on CDC definitions, recommendations for all VA hospitals to migrate to nucleic acid amplification tests (NAATs) or two - step glutamate dehydrogenase and NAAT paradigms, and a soon - to - be published set of key prevention steps for implementation in their acute care hospitals. It is anticipated that the VA CDI prevention initiative will h ave a national impact on VA CDIrates similar to that seen with MRSA prevention. d) Facilitate initiation of at least one regional, multi - center prevention collaborative in which acute and long - term care facilities address prevention of multi - drug resistant infections in a coordinated manner (2011).- 32 -

**Progress:** The Vermont Department of Health (VT DOH) has developed a collaborative that includes all the acute care facilities and most of the long - term care facilities in Vermont. Facilities are organized into groups that include acute and long - term care facilities that share patients. Each group has developed and implemented interventions that target MDROs and healthcare - associated infections. As part of this project, they have collaborated with the World Health Organization (WHO) Collaborating Center for Surveillance of Antimicrobial Resistance to facilitate the direct electronic transfer of laboratory

data to the MDRO module of the National Healthcare Safety Network. Approximately

14 acute care facilities and 25 long term care facilities are currentl y collecting data for submission to NHSN. In addition to the limited data provided back to NHSN the sy stem, this project currentl y collects all laboratory pathogens and has the potential to be a rich source of survei llance information. Coordinator: CDC

; Collaborators: AHRQ, VA, CMS 3.4 Evaluate the effectiveness of infection - control practices, products, and devices in healthcare facilities, including long - term healthcare and outpatient settings. **Progress:** The IOM has r ecommended research to “compare the effectiveness of various screening, proph yl axis, and treatment interventions in eradicating MRSA in communities, institutions, and hospitals.” Particularl y with respect to efforts to decolonize hosts, results differ acco rding to geographical location, location of the patients within the hospital, and institutional and practice norms. Using funds from the American Recovery and Reinvestment Act (ARRA), NIH issued a funding opportunity announcement (RFA - OD 10 - 008) solicitin g applications to conduct preliminary comparative effectiveness research (CER) projects on Eradication Methods for Methicillin Resistant Staphylococcus aureus (MRSA). One grant was funded; research under this project is ongoing. a) Expand CDC’s Prevention Ep icenter Program to include academic centers, integrated health sy stems, and healthcare departments to support earl y translation of technical advances and epidemiologic knowledge into evidence - based recommendations (2011). **Progress:** Successfull y created th e SHEPherD research contract mechanism in fall 2011. The purpose of this indefinite delivery , indefinite quantity contract mechanism is to provide the Centers for Disease Control and Prevention (CDC) and the Division of Healthcare Quality

Promotion (DHQP) an “as needed” mechanism to obtain required research services through issuance of individual task orders. The mechanism was designed specifically

to attract participants particularly well suited to do patient safet y and healthcare epidemiology research, w ith an emphasis on prevention of healthcare associated infections. This is a five year task order mechanism became active 9/30/2011, and includes 13 vendors with access to over 2,500 US hospitals, information on > 30 million covered lives, the VA healthcar e s ys tem, and a number of leading academic HAI investigators. Through the EIP cooperative agreement mechanism, a pilot research project on use of chlorhexidine bathing to reduce MDRO prevalence in long term care facilities has been initiated in colla

boration with the Tennessee Dept of Health. A protocol has been developed and approved by I RBs, and the intervention has begun in a single L TC facility .- 33 -

Through a research contract with Resources for the Future, data collection has been completed for a multi - center study of the epidemiology

of antimicrobial use. b) Initiate studies that will assess the dy namics of contamination of the healthcare environment and the ability of cleaning and disinfection methods to reduce environmental contamination (2011). **P rogress:**  Environmental sampling was initiated in 8 healthcare facilities and has been completed in 3 of these facilities; to date we've collected 320 of 900 samples. We will continue to collect environmental samples through September 30, 2012. Following co mpletion of collection, data will be anal yz ed and presented at scientific meetings and in written scientific communications. c) Evaluate the impact of state - based CDC - funded HAI prevention collaborative by 2013. **Progress:** The Office of Prevention Research and Evaluation has been updating CDC and state - level stakeholders about progress towards ARRA - HAI goals. Currently the evaluation team in OPRE is completing the final analysis of the impact of ARRA funding, including an assessment of quarterly standardized infection ratios (SIRs) in states implementing infection - specific prevention collaboratives. The office is also engaged in a return - on - investment anal ys is using activity - based costing to assess the costs and returns on HAI prevention collaborative implementation from the facility and state/federal perspectives. d) Quantify

the national impact of HAI prevention efforts by publishing annual national summary statistics (standardized infection ratio) of HAI data r eported to CDC’s NHSN (ongoing) (see 2009

– 2010 Annual Progress Report) . **Progress:** National summary statistics reflecting the HAI experience in the U.S. were published in June 2010 for central line - associated bloodstream infections (CLABSI), CLABSI and surgical site infections published in March 2011 (o n line onl y). Annual report added CAUTI cleared for publication April 2012. Annual publication of these summary statistics (i.e., standardized infection ratios) is underway for a spring publication. Coordinator: CDC

; Collaborators: AHRQ, DoD, VA 3.5 Id entify factors that reduce transmission of drug - resistant pathogens, including infection control, in veterinary , agriculture and aquaculture settings (ongoing). a) Id entify

critical control points on - farm for dairy production that will decrease antimicrobial resistant Salmonella e (2011). Evaluate interventions in dairy production that will decrease antimicrobial resistant Salmonella e (2012).- 34 -

**Progress:** ARS researchers in collaboration with the Regional Dairy Quality Management Alliance have been sampling participatin g dairy farms and the surrounding environments for the presence of Salmonella , E. coli , and Listeria . Milk filters have been collected from numerous farms in the area around a farm with a known persistent Salmonella outbreak and anal yz ed for the presence of Salmonella . Preliminary results support the hy

pothesis that milk filters are an effective way to screen for the presence of Salmonella (including resistant Salmonella ) on dairy farms. Evaluate way s to better characterize/control Salmonella , in particul ar multi - drug - resistant Salmonella , for use on commercial dairy

farms to enhance food safet y. a) Develop Salmonella seroty pe - specific real - time PCR method; b) Determine if Salmonella seroty pe changes due to changing environment or acquisition of antimicrob ial resistance; c) Determine if feeding sodium chlorate, with/without nitroethane, is effective in reducing populations of Salmonella as well as E. coli O157:H7 & generic E. coli in milk- replacer fed calves and cull dairy cattle. USDA will hold a workshop in spring 2012 for stakeholders to input on animal health activites the USDA should address for management practices to reduce antimicrobial use, alternatives to antimicrobial use, and antibiotic use monitoring. ARS held an interagency

session on alternati ves to antibiotics in food safet y which will reported at the USDA workshop in the spring. b) Make available grant funds of up to $4 million through USDA’s National Integrated Food Safet y Initiative to support sy stematic studies that identify intervention s trategies for effective mitigation of AR throughout the food chain. These 4 - year grants began in 2010 and will be completed no later than 2015 (see 2009

– 2010 Annual Progress Report) . **Progress:** Work is continuing on the Washington State and Kansas State NI FSI grants. The gr ants will be completed in 2014 Check NIFA website for CRIS project and updates. In 2011, a new grant was awarded. At the Ohio State Universit y, researchers hope to reduce the transmission of antibiotic resistant organisms by wildlife within the food supply using a research, control, and outreach strategy . The researchers believe that wildlife are important reservoirs and vectors for the transmission of antibiotic resistant organisms to food - producing animals. Their research will dete rmine the extent, diversity , and carriage of antimicrobial resistant elements at the wildlife - livestock interface and evaluate the impact of wildlife control on antibiotic resistance in livestock. A comprehensive plan for knowledge s ynthesis and transfer will include the development of risk and economic assessment models, a scoping review of the literature, development of target - audience specific educational materials, and the development of a collection of tools and resources that can be used to enhance the value of the data collected. This 4 - ye ar grant will conclude in 2015. c) Id entify

factors important for assuring that antimicrobial drugs are used judiciously in veterinary , agriculture and aquaculture environments (see 2009

– 2010 Annual Progress Report) .- 35 -

**Progress:** In June 2010, FDA released Draft Guidance 209, Judicious Use of Medicall y Important Antimicrobial Drugs in Food - Producing Animals, which informs the public of FDA’s current thinking on the use of medically - important antimicrobial drugs in foo d producing animals and outlines several broad principles for assuring judicious use. On April 11, 2012, FDA announced the publication of three documents intended to support its strategy

for implementing the principles outlined in Guidance 209 for assurin g the judicious use of medically important antimicrobial drugs in food - producing animals. The three documents include 1) a final guidance for industry (#209), The Judicious Use of Medically Important Antimicrobial Drugs in Food -Producing Animals , that rec ommends phasing out the agricultural production use of medically important drugs and phasing in veterinary

oversight of therapeutic uses of these drugs; 2) a draft guidance (#213), which will assist drug companies in voluntarily removing production uses of antibiotics from their FDA - approved product labels; adding, where appropriate, scientifically- supported disease prevention, control, and treatment uses; and changing the marketing status to include veterinary

oversight; and 3) a draft proposed Veterinary Feed Directive regulation, that outlines way s that veterinarians can authorize the use of certain animal drugs in feed, which is important to make the needed veterinary oversight feasible and efficient. The public comment period for the two draft documents closed on July 12, 2012. FDA is currentl y anal yz ing the submitted comments. Coordinators: FDA, USDA 3.6 Promote research and development of processing technologies to minimize microbial contamination of food. a) Develop alternatives to current antimicrobial treatments and sanitizers for processing poultry carcasses (e.g. natural Generall y Recognized as Safe [GRAS] products) (2011). Evaluate alternative sanitizers for poultry processing and their reduction of food pathogens (2012). **Progress:** Research was compl eted on formulations for novel sanitizers that can be used to reduce microbial contamination of processed poultry . Solutions of alkaline salts of fatty acids that possess antimicrobial activity were examined for use in formulations of an effective poultry processing sanitizer. Experiments were conducted to determine the effect of pH on the antibacterial activity of mixtures prepared by

dissolving caproic, caprylic, capric, lauric, or my ristic acids in solutions of potassium hydroxide (KOH). The high pH o f these solutions was produced b y KOH, and citric acid was used to reduce the pH of the solutions. Results of experiments indicated that there was little difference in the antibacterial activity of fatty acid mixtures between pH 9.5 to 12.5; however, anti bacterial activity

of the solutions increased at pH 13.5 or higher. Findings from these experiments demonstrated that the final pH of sanitizers made from fatty acids may influence the ability

of the sanitizer to reduce microbial contamination of processe d poultry . (new) - Formulations for novel sanitizers will be developed, and improved- 36 -

techniques utilizing sanitizers already approved for commercial use in processing will be designed. Surfactant based sanitizers used alone or in combination with non - chlori ne based sanitizers will be examined as alternatives to chlorine and chlorine dioxide for decreasing microbial contamination of poultry . Additionally , poultry processing conditions associated with broiler carcasses heavily contaminated b y Salmonella will b e evaluated and characterized. Cross contamination during processing will be examined by studying the role of these heavily contaminated carcasses in the spread of Salmonella during processing. Furthermore, factors that influence survival and attachment of pathogenic, spoilage, and indicator microorganisms on poultry skin will be examined. Microorganisms on poultry skin will be examined utilizing Benchtop scanning electron microscop y (SEM) with SEM software and with standard microbiological methods. b) De velop alternatives to current processing treatments for the reduction of Escherichia coli in beef (2011). Evaluate effectiveness of processing treatments (2012). **Progress:** ARS scientists in Clay Center, NE, investigated whether antimicrobial compounds currently

used by the meat industry

to control E. coli O157:H7 are effective against these non - O157 Shiga toxin - producing groups (O26, O103, O111, and O145). They determined that six antimicrobial compounds were equall y effective against E. coli O157:H7 and non - O157 on fresh beef. These results will assist the meat industry in developing effective antimicrobial intervention programs against these newly recognized and regulated pathogens. They also determined the efficacy against Salmonella . Also, ARS evaluated the effectiveness and parameters of UV and UV - ozone as a non - thermal intervention of red meat. Research is being conducted to identify how foodborne pathogens acquire, maintain and transmit genes for antimicrobial resistance and virulence within cattl e from production to processing. To understand a potential avenue b y which Salmonella (MDR Salmonella ) evades beef carcass decontamination steps, ARS has completed a variety of studies on bovine lymph nodes. Pathogens such as Salmonella have the ability t o survive within bovine ly mph nodes. When Salmonella are present in ly mph nodes, they

are protected from chemical and thermal antimicrobial interventions used in packing plants. We collaborated with industry groups and university

scientists in isolating Salmonella from peripheral l ymph nodes of health y cattle presented for harvest. A necessary component of this study was validation of the microbiological anal ys is methods used to detect Salmonella harbored within ly mph nodes. The results of these validat ion studies verified that the pathogens recovered originate from within ly mph node tissues and are not the result of cross contamination of pathogens present on the surrounding adipose tissue. More research will be conducted. ARS scientists in Clay

Center, NE, investigated whether antimicrobial compounds currentl y used b y the meat industry to control E. coli O157:H7 are effective against these non - O157 Shiga toxin - producing groups (O26, O103, O111, and O145). They determined that six antimicrobial compound s were equally effective against E. coli O157:H7 and non - O157 on fresh beef. These results will assist the meat industry in developing effective antimicrobial intervention programs against these newly recognized- 37 -

and regulated pathogens. They also determin ed the efficacy against Salmonella . Also, ARS evaluated the effectiveness and parameters of UV and UV - ozone as a non - thermal intervention of red meat. Research is being conducted to identify how foodborne pathogens acquire, maintain and transmit genes for antimicrobial resistance and virulence within cattle from production to processing. To understand a potential avenue b y which Salmonella (MDR Salmonella ) evades beef carcass decontamination steps, ARS has completed a variety of studies on bovine lymph nod es. Pathogens such as Salmonella have the ability to survive within bovine ly mph nodes. When Salmonella are present in ly mph nodes, they

are protected from chemical and thermal antimicrobial interventions used in packing plants. We collaborated with ind ustry groups and university

scientists in isolating Salmonella from peripheral l ymph nodes of health y cattle presented for harvest. A necessary component of this study was validation of the microbiological anal ys is methods used to detect Salmonella harbor ed within ly mph nodes. The results of these validation studies verified that the pathogens recovered originate from within ly mph node tissues and are not the result of cross contamination of pathogens present on the surrounding adipose tissue. More research will be conducted. c) Id entify

processing interventions to decrease antimicrobial - resistant microorganisms in eggs (2011). Evaluate alternative interventions in egg processing for reduction of antimicrobial - resistant microorganism (2012). **Progress:** This project will promote egg safet y b y improving processing and intervention strategies in three critical areas. The bactericidal effects of critical processing parameters (wash water, sanitizers, and sanitizer application methods) will be determined. Commerci al egg wash detergents do an excellent job of cleaning eggs but are less lethal to bacteria when wash water pH is <10. Currently, the sanitizing chlorine solution sprayed onto eggs after washing does not reduce bacterial numbers. Research is needed to do cument the importance of pH and to identify an effective post - wash egg sanitizer. Second, improved sanitation procedures within processing facilities will be developed through research on the areas and equipment most contaminated in egg processing. A rece nt new law requires egg producers to test for Salmonella e nteritidis (SE) in houses and flocks. Rapid, objective tests specific for SE will enable the egg industry in complying with this rule. Analyzing DNA from Salmonella collected at farms, processing fa cilities, and eggs allow for tracking of important contamination sources. Also, improved testing methods are required for a scientifically- based assessment of how different housing t ypes affect egg microbiology. On a single visit to an egg processing fac ility , environmental, water, and egg samples were collected. Environmental sampling including, rollers, tray s, transport equipment {spindles, belts}, brushes, tanks drains, and egg waste buckets. Temperature and pH readings were recorded for wash water. Eggs from each of the housing s ystems were collected and sampled before and after washing. None of the environmental swab samples were positive for Salmonella or Campylobacter . Pooled egg slurry prepared from unwashed eggs laid by traditionall y caged he ns, was positive for Salmonella .- 38 -

Campylobacter was recovered from pooled slurry prepared from washed eggs laid by hens housed in the enriched cages. 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 Safet y Education Conference: USDA and NSF International will co - host a 3 - day

conference sponsored by HHS, FDA, CDC, and WHO. The conference is designed for attendees to share the most current research, learn best practices, and explore cutting - edge strategies for reducing foodborne illness (see 2009

– 2010 Annual Progress Report) . **Progress:** See 2009 - 2010 Annual Progress Report. b) Launch new US DA Food Safety Mobile Program in spring 2010 as part of the Food Safety and Inspection Service’s ongoing consumer education campaign to reach consumers where they

live. The USDA Food Safety Mobile will travel throughout the United States visiting local community events to educate consumers about food safet y. The revamped program will offer consumers in - depth, interactive, hands - on demonstrations on the science of food safet y based on the four Be Food Safe Campaign messages: Clean, Separate, Cook and Chill. The Mobile’s interactive learning stations are designed to improve consumer’s food safety awareness, knowledge, and behavior (see 2009

– 2010 Annual Progress Report) . **Progress:** The USDA Food Safety Discovery

Z one was launched on May 6, 2010 . For several months during 2010 and 2011, the newl y - revamped Food Safet y Discovery Zone travelled throughout the United States visiting local community events to educate consumers about food safety . Since its launch, the Food Safet y Discovery Zone has reached 982, 94 1 consumers with its food safet y m essages, collected over 17,891 pledges from consumers promising to change behaviors in handling and preparing foods, visited 17 states and Washington, DC and participated in 77 events. The Food Safe Families messages of Cl ean, Separate, Cook, and Chill are being heard, and consumers at every event appreciate the Food Safety Discovery

Z one’s ability

to communicate valuable information in a new and engaging way to both children and adults. As designed, the USDA Food Safety

Di scovery

Z one is increasing consumer food safet y awareness and knowledge and positively impacting consumer safe food - handling behaviors. In FY 2012, the USDA Food Safet y Discovery Zone will be once again visit local venues within the DC Metropolitan area and will also travel to North Carolina, Georgia, Mississippi, L ouisiana, and Texas.- 39 -

c) Host USDA Nutrition Month to inclu de Food Safety Day on March 10, 2010 to increase consumer awareness about food safet y (see 2009

– 2010 Annual Progress Report) . **Progress:** Staffed exhibits on food safet y educatio n at USDA and HHS complexes in W ashington , DC for National Nutrition Month, March 2011. Conduct food safety education events for National Nutrition Month March 2012. Coordinator: USDA 3.8 Promote infection control educ ation at all stages of training and practice for healthcare workers in human and veterinary medicine. a) Complete basic infection control curriculum for posting on the CDC website by 2011. **Progress:** See 2009 - 2010 Annual Progress Report. b) Develop a plan for infection control education of veterinary medicine workers by

2011. **Progress:** See 2009 - 2010 Annual Progress Report. Coordinator: CDC; Collaborator: USDA , VA 3.9 Develop interagency programs in collaboration with regulators, payers, professional societies and other stakeholders to promote effective hand hygi ene strategies in communities and healthcare settings and to foster the use of biomedical devices and behaviors that prevent the transmission of infectious organisms in community settings. a) Develop a p lan to collaborate with WHO on their hand hygiene promotion campaign (see 2009

– 2010 Annual Progress Report) . **Progress:** DHQP continues to communicate with WHO on a regular basis regarding national hand h ygi ene efforts. As of February 2012, over 2500 US f

acilities signed up for WHO’s world - wide hand hygiene campaign. CDC is working together with WHO and partners from Columbia University to anal yz e data from US facilities who completed WHOs hand hygiene framework, which includes an extensive facility survey . b) In collaboration with academic partners, complete research studies that evaluate the impact of novel technologies for measuring hand hygiene adherence in the healthcare setting (2011). **Progress:** CDC continues to partner with academic colleagues using i nnovative and inexpensive wireless technologies to monitor healthcare worker movement and approximate hand hygiene adherence. In 2011 this partnership resulted in the publication- 40 -

of two manuscripts in an effort to further the science and implementation of hand hygiene adherence measurement. One manuscript used data from wireless sensors as a backdrop for simulated human observers of hand h ygiene practices; b y altering the simulated human observer schedule, authors were able to determine which observer sched ules would all viewing of the maximum number of hand hygiene events and the most diversity in healthcare workers observed. Additionall y, a qualitative anal ys is of healthcare worker perceptions of automated hand hygiene technologies found that transparency about the use of the data and accuracy of the technology

was key to healthcare worker acceptance and buy - in. DHQP continues to collaborate with colleagues to assess the implications of healthcare worker movement on other infection control practices in non - acute settings (e.g., dial ys is). Coordinator: CDC

; Collaborator: AHRQ, VA Goal 4 : Develop, implement, and evaluate strategies to improve appropriate antimicrobial use. 4.1 Id entify

factors and strategies that promote appropriate antimicrobial use (i.e., be st practices) or discourage inappropriate use in all types of healthcare settings, including inpatient and outpatient facilities, clinics and offices. Facilitate the implementation of these strategies. a) Develop algorithms and reporting tools to facilitate local monitoring of antimicrobial use (pilot 2011 and implement 2012) an d resistance rates (pilot 2011) (see 2009

– 2010 Annual Progress Report) . **Progress:** The AUR module of NHSN is operating to accept electronic data from pharmacy s ys tems which will dram atically reduce the data collection burden for antibiotic use. Four health departments received funds through ELC to develop a network of 5 - 15 hospitals each and implement reporting through AUR. As of March 2012, 1 facility has successfully

piloted submiss ion. Expectation is 30 facilties by end of 2012 complete validation and implement sustainable reporting, 100 facilities by end of 2013. b) Develop a “change package” for improving antimicrobial use in in - patient healthcare settings (see 2009

– 2010 Annual Pr ogress Report) . **Progress:** Pilot testing of the change package and driver diagram at 8 facilities began in October of 2011. c) Collaborate with a network of hospitals to identify patient - level indications for and factors associated with antibiotic use to h elp guide efforts on improving use by 2011. **Progress:** Data collection on a project to perform in - depth anal ys is of course of antibiotic therap y on patients from a variet y of hospitals around the country was recently

completed by the Center for Disease Dy n amics and Economic Policy . Detailed information on more than 1,000 courses of therap y was obtained and is being anal yz ed to look for factors that influence decisions on antibiotic use.- 41 -

d) Examine knowledge, attitudes, and behaviors of healthcare provider s regarding adverse events and antimicrobial use (see 2009

– 2010 Annual Progress Report) . **Progress:** A second round of formative research with parents and adult patients was completed in 2011. The results from the two rounds of formative research resulted in the developm ent of educational materials to improve provider/patient communication around antibiotic - associated adverse drug events. A manuscript is in progress to describe the outcomes from this study. e) Examine the impact of improved antimicrobial use on adverse events associated with antimicrobials, especiall y Clostridium difficile infections by 2011. **Progress:** The AHRQ funded “ERASE C diff” project continues. Baseline assessments at the various hospitals have been completed and this information is now being used to inform the implementation of interventions to improve antibiotic use. f) Evaluate the benefits and potential unintended consequences 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 antimicrobial agents in emergency rooms for unconfirmed community - acquired pneumonia) (2012). **Progress:** The CDC Epidemiology of Pneumonia in the Community study will complete enrollment in 201 2. The data collected will be used to examine and evaluate antimicrobial use for community- acquired pneumonia in the context of the IDSA clinical practice guidelines which were released in 2007. Preliminary data are currently

being anal yz ed. Coordinator: CDC

; Collaborators: AHRQ, FDA, VA 4.2 Promote, implement, and evaluate guidelines for appropriate antimicrobial use in agricultural and veterinary settings. Specifically , a) Seek appropriate expert input to update specific aspects of guidance 152 (particularl y the antimicrobial drug ranking in Appendix A of guidance) and publish revised draft guidance for public comment (2011 - 2012 ). **Progress:** FDA has received comments indicating that some aspects of guidance 152 (particularl y the antimicrobial drug ranking in Appendix A) are in need of updating. CVM is working in collaboration with CDER to develop a process for obtaining the appropriate input (both form scientific experts and the public) on updating Appendix A, as necessary . b) Publish and seek public comment on draft guidance outlining FDA’s current thinking on the judicious use of medically important antimicrobial drugs in food - producing animals (see 2009

– 2010 Annual Progress Report).- 42 -

**Progress:** In June 2010, FDA released Draft Guidance 209, Judicious Use of Medicall y Important Antimicrobial Drugs in Food - Producing Animals, which informs the public of FDA’s current thinking on the use of medically - important antimicrobial drugs in food producing animals and outlines several broad principles for assuring judicio us use. On April 11, 2012, FDA announced the publication of three documents intended to support its strategy

for implementing the principles outlined in Guidance 209 for assuring the judicious use of medically important antimicrobial drugs in food - produci ng animals. The three documents include 1) a final guidance for industry (#209), The Judicious Use of Medically Important Antimicrobial Drugs in Food -Producing Animals , that recommends phasing out the agricultural production use of medically important dru gs and phasing in veterinary

oversight of therapeutic uses of these drugs; 2) a draft guidance (#213), which will assist drug companies in voluntarily removing production uses of antibiotics from their FDA - approved product labels; adding, where appropriate , scientifically - supported disease prevention, control, and treatment uses; and changing the marketing status to include veterinary

oversight; and 3) a draft proposed Veterinary Feed Directive regulation, that outlines way s that veterinarians can authorize the use of certain animal drugs in feed, which is important to make the needed veterinary oversight feasible and efficient. The public comment period for the two draft documents closed on July 12, 2012. FDA is currentl y anal yz ing the submitted comments. c) Publish a revised order to prohibit certain extralabel uses of cephalosporin antimicrobial drugs in food producing animals due to AR concerns (2011). **Progress:** FDA issued an order in July 2008 to prohibit the extralabel use of the cephalosporin class of antimicrobial drugs in food - producing animals due to antimicrobial resistance concerns. The order was withdrawn in November 2008 to allow the agency

to full y consider comments submitted regarding the July order. In response to the public comments, FDA has developed a revised order that prohibits certain extralabel uses of cephalosporin drugs in cattle, swine, chickens, and turkey s. The revised order was published on January 6, 2012 and went into effect on April 5, 2012. d) Survey

orchards periodically

for em erging resistance among agricultural bacterial plant pathogens (e.g., Erwinia amylovera , Pseudomonas syringae , and Xanthomonas campestris ) to tetracycline, streptomycin, gentamicin, or other antimicrobial agents that may be used, such as kasugam ycin. Monit oring is conducted to compl y with pesticide use authorization. **Progress:** In 2011, extensive resistance monitoring was conducted b y researchers at Michigan State University for the presence of antibiotic resistance in nontarget bacteria that had previous e xposure or no prior exposure to kasugam ycin. The objective of the monitoring effort was to isolate commensal bacteria from apple trees and soil under apple trees treated with kasugamycin and assess resistance to five antibiotics that are critical: ampicill in, cefotaxime, gentamicin, tetracycline, and streptomycin. The data from the 2011 monitoring effort did not reveal an y exceptional findings with the overall- 43 -

conclusion that the current level of use has not impacted the antibiotic resistance profile in app le orchard bacteria. Coordinators: FDA; Collaborators: CDC, USDA 4.3 Promote the development of improved field - based methods to measure the quality of antimalarial drugs , given that poor quality drugs contribute to antimicrobial drug resistance . **Progress:** A colorimetric test for amodiaquine/artesunate has been developed and is currentl y being evaluated on actual samples. A manuscript is being prepared. Coordinator: CDC 4.4 Develop, implement, and evaluate treatment algorithms for management of common clinical sy

ndromes frequently

treated with antibiotics (e.g., ventilator - associated and community - acquired pneumonia, acute bronchitis and sinusitis, and asy mptomatic bacteriuria and sexually

transmitted diseases. a) Update the Principles of Judicious Use of Antimic robial Agents for Pediatric Upper Respiratory Infections and develop and disseminate academic detaining sheet with diagnosis and treatment algorithms (2012). **Progress:** Get Smart update: The University of Utah and CDC are working with experts in the field of pediatrics, infectious diseases, family practice and emergency medicine to update the Principles. The updated Principles have been drafted and will be submitted for publication to the journal Pediatrics late 2012/early 2013. NIAI D is supporting clinical trials to evaluate treatment algorithms, including Targeted Clinical Trials to Reduce the Risk of Antimicrobial Resistance. These are described in section 7.2. b) Update the Guidelines for Appropriate Antibiotic Use for Treatment of Acute Respiratory Tract Infections in Adults and develop and disseminate academic detailing sheet with diagnosis and treatment algorithms (2014). **Progress:** This process has not been initiated but is still planned for 2014 timeline. Coordinator: CDC

; Collaborator: NIH, VA- 44 -



### Focu **s Area III: Research Overarching goals**  Encourage, conduct and support basic and translational research to enhance our understanding of factors leading to the development of AR microorganisms, their transmission in various settings, and optimal modes of p revention, diagnosis and therap y. Goal 5: Facilitate basic research on AR. 5.1 Conduct and support genetic, biochemical and structural s tudies of AR factors to enabl e the identification of novel drug , diagnostic and vaccine targets. **Progress:** NI H funds a wide variet y of grants on the basic mechanisms of antimicrobial resistance through its investigator - initiated R01, R03, and R21 grant programs. Representative examples of ongoing basic research are given below. For a full list of antimicrobial resistance projects, see the NIH RePORTER (Research Portfolio Online Reporting Tool) website. o Daptomycin resistance in Enterococus has been reported, but remains rare in clinical populations. In 2011, two groups of NIAID - supported researchers provided insight int o the mechanism of E. faecalis resistance to daptomycin. The first group found that at least seven proteins in E. faecalis can undergo point mutations that confer resistance to daptomycin. This mechanism is distinct from the transmission of mobile elements described in S. aureus . [Palmer KL et al. Genetic basis for daptom ycin resistance in enterococci. Antimicrob Agents Chemother. 2011 Jul;55(7):3345 - 56]. A second group of investigators described two mutations associated with daptomycin resistance that arose during the course of treatment of a patient with fatal VRE bacteremia [Arias, CA et al. Genetic basis for in vivo daptomycin resistance in enterococci. N Engl J Med. 2011 Sep 8;365(10):892 - 900] o Rapid whole genome sequencing technologies are increasi ngly being used to understand how resistance mutations evolve over time. In 2011, two groups of NIH supported investigators published studies mapping how resistance develops. The first group used a novel in vitro culture s ys tem to generate mutations in r esponse to constant selective pressure of different antibiotics. While some antibiotics generated diverse mutations, others produced a reproducible sequence of mutations leading to resistance. [Toprak E et al. Evolutionary paths to antibiotic resistance under dyn amically sustained drug selection. Nat Genet. 2011 Dec 18;44(1):101 - 5. doi:10.1038/ng.1034]. The second group sequenced drug - resistant strains of M. tuberculosis (Mtb), both lab - generated and isolated from patients, and identified mutations associated with rapid growth. Such mutations likely

represent compensatory

mutations necessary

for drug - resistant strains to overcome the fitness costs of resistance. [Comas I et al. Whole - genome sequencing of rifampicin - resistant Mycobacterium tuberculosiss s trains identifies compensatory mutations in RNA poly

merase genes. Nat Genet. 2011 Dec 18;44(1):106 - 10. doi:10.1038/ng.1038]- 45 -

• NIAID supports several Centers of Excellence for infectious disease research that are conducting studies on antimicrobial resistan ce. o Work conducted at NIAID’s Great Lakes Regional Center of Excellence for Biodefense and Emerging Infectious Diseases began to unravel the molecular basis of cephalosporin resistance in E. faecalis. E. faecalis is naturally resistant to cephalosporins and prior treatment with cephalosporins is an important risk factor for hospital - acquired E. faecalis infections. [Kristich CJ et al. Reciprocal regulation of cephalosporin resistance in Enterococcus faecalis. mBio. 2011 Nov 1;2(6):199 - 211] o The NIAID C enters for Excellence for Influenza Research and Surveillance funds two projects focused on the understanding the fitness cost of and possible prevention strategies for the emergence of oseltamivir - resistant influenza strains. • Ongoing NIAID intramural research aims to identify candidate genes that contribute to drug resistance and study their function, develop gene databases, and screen for new antimicrobial drugs. o High - throughput chemical and gene analy sis methods were used to identify promising n ew leads for antimalarial drugs that could be used in combination to suppress the development of drug resistance [Yuan J et al. Chemical genomic profiling for antimalarial therapies, response signatures, and molecular targets. Science. 2011 Aug 5;333:724 - 9 ] o Researchers provided microbiological evidence for the contribution of the M. tuberculosis gene, gidB, in streptomycin resistance and examined the clinical implications of mutations in this gene [Wong SY et al. Mutations in gidB confer low level strept omycin resistance in Mycobacterium tuberculosiss . Antimicrob Agents Chemother. 2011; 55(6): 2515

–2522] • NIAID made ten awards to establish “International Centers of Excellence for Malaria Research” (RFA - AI - 09 - 017). The seven - ye ar awards will establish International Centers of Excellence for Malaria Research (ICEMRs) in all malaria endemic regions of the globe, including parts of Africa, Asia, the Pacific Islands and Latin America, in an effort to accelerate the control of malaria and help eliminate it wo rldwide. The Centers will also conduct multi - disciplinary research on malaria in all endemic regions of the globe, including research on rates and mechanisms of resistance to antimalarials. Coordinator: NIH 5.2 Investigate naturally occurring mechanisms of r esistance, gene transfer, and host pathogen interactions. **Progress:** NIAI D funds numerous studies on horizontal gene transfer and host - pathogen interactions through its investigator - initiated grants program. For a full list of antimicrobial resistance pro jects, see the NIH RePORTER website. o Examples of funded projects include:- 46 -  Plasmids as vectors of antibiotic resistance: The evolution of plasmid host - range  Host - associated regulation of Pseudomonas aeruginosa colonization and virulence  Mechanism of ho st cell apoptosis inhibition by Mycobacterium tuberculosi s  Studies of fundamental molecular mechanisms of host - patho gen interactions and resistance gene transfer are ongoing in the NIAID intramural research program. NIAID researchers and colleagues provid ed a possible explanation for the worldwide success of a penicillin - resistant S. aureus strain of the 1950s and 1960s (phage t yp e 80/81) and the restriction of related modern MRSA strains (CC30) to hospitals. In addition to penicillin resistance, two gene s contained in nearl y all S. aureus strains, agr and hla, were essential for world dominance of phage - ty pe 80/81 S. aureus . In contrast, key single nucleotide poly morphisms (SNPs) in these genes in contemporary CC30 clones reduce their virulence and restrict them largely to immunocompromised persons or those with other risk factors, such as hospitalized patients. [DeLeo FR et al. Molecular differentiation of historic phage - ty

pe 80/81 and contemporary epidemic Staphylococcus aureus . Proc Natl Acad Sci U S A . 2011 Nov 1;108(44):18091 - 6 **]** 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 of microorganisms. **Progress:** Biofilms p lay

a key role in antimicrobial resistance in a number of different disease states and organ systems. For this reason, many different NIH institutes and centers fund grants on the basic biology of biofilms, as well as the development of novel prevention and treatment strategies to combat biofilms. For a complete list of biofilm related grants, visit the NIH RePORTER website. Representative projects include: o Metabolic heterogeneity and antibiotic susceptibility in biofilms (NIAID) o Prevention of biofil m related infections using a novel, broad spectrum antimicrobial (NIAMS) o Biofilm infections in postsurgical, trauma, and critically- ill patients (NIGMS) • Research on the ph ys iology of staph yl ococcal biofilms and biofilm - associated infection is ongoing i n the NIAID intramural program. NIAID researchers are currently focusing on the mechanisms of biofilm maturation and detachment, which may cause the dissemination of a biofilm - associated infection and lead to severe sepsis and second site infection. Using a mouse model of subcutaneous catheter - related infection, the researchers identified S. epidermidis peptides that promote biofilm maturation and dissemination of biofilm - associated infection. Antibodies to these peptides prevented bacteria from spreading t o all organs except the l ymph nodes, where numbers were significantl y reduced. [Wang R et al. Staphylococcus epidermidis surfactant peptides promote biofilm maturation and dissemination of biofilm - associated infection in mice. J Clin Invest. 2011 Jan 4;12 1(1):238 - 48]. In another study , NIAID researchers and- 47 -

colleagues describe how S. aureus biofilms develop their characteristic structure, providing a deeper understanding of biofilm development processes and an important basis for strategies to interfere w ith biofilm formation [Periasamy S et al. How Staphylococcus aureus biofilms develop their characteristic structure. Proc Natl Acad Sci U S A. 2012 Jan 24;109(4):1281 - 6] Coordinators: CDC

, NIH; Collaborator

s : FDA, USDA 5.4 Develop and make available genomics , metagenomic, bioinformatics, proteomics, structural biology , molecular imaging, and other emerging research technologies. Ensure that genomic, proteomic, and other related data sets are made publicl y available rapidl y through searchable public online dat abases and provide data analy sis tools to assist researchers in using these resources. **Progress:** NIAI D has made a significant investment in genomic - related activities that provide genomic sequencing, structural genomics, sy stems biology , bioinformatics and proteomic resources and reagents to the scientific community . For example, NIAID has sequenced more than 2900 bacterial strains including more than 250 S. aureus strains, all of which have been deposited in GenBank. In addition, 20 Actinomycetes were sequenced and mined for antibiotic gene cluster for potential new antibiotics. Protein expression clones and DNA microarray s are available for a large number of bacteria and 3D structures of man y bacterial proteins have been completed or are in process of being done. NIAID supports Bioinformatics Resource Centers that collect, integrate, and provide open access to research data of microbial organisms in a user friendly format for the scientific community , including bioinformatics anal ys is capabilit y and t ools. • NIAID continues its support of EuPathDB, a bioinformatics resource center for eukaryotic pathogens. Additional contract resources support VectorBase, a bioinformatics resource center for invertebrate vectors of infectious disease. • BEI Resources acquires, authenticates, and produces reagents that scientists need to carry out basic research and develop improved diagnostic tests, vaccines, and therapies. By centralizing these functions within BEI Resources, access to and use of these materials in the scientific community is monitored and quality

control of the reagents is assured. In addition to supplying the infectious disease communit y with materials, BEI Resources also encourages and supports the deposit of materials from researchers and institut ions. Numerous bacterial strains, antigens, and nucleic acid related to resistant pathogens of concern are available through BEI. In 2011, resources from the Malaria Research and Reference Reagent Resource Center (MR4) were moved to BEI . • In 2011, NIAID supported a genome sequencing study of an unusual seroty

pe Shiga toxin - producing Escherichia coli (O104:H4) strain responsible for a large diarrheal outbreak that began in German y in May 2011. The genome of the German outbreak strain can be distinguished from other O104:H4 strains because it contains a prophage encoding Shiga toxin 2 and a distinct set of additional virulence and antibiotic - resistance factors. The authors’ findings suggest that horizontal genetic exchange allowed for the emergence- 48 -

of the h ighl y virulent Shiga - toxin - producing enteroaggregative E. coli O104:H4 strain that caused this outbreak. [Rasko DA et al. Origins of the E. coli strain causing an outbreak of hemoly

tic - uremic sy

ndrome in Germany . N. Engl. J. Med. 2011 Aug 25;365(8):709 - 1 7] • In 2011, NIAID supported a genome sequencing study of clinical isolates of Vibrio cholerae responsible for a cholera epidemic in Haiti

– the first such Haitian outbreak in a century . The results showed that the Haitian clinical isolates shared features with South Asian strains, namel y h ypervirulence, drug resistance, and an enhanced capacity for environmental persistence that is new to cholera in the Western hemisphere. [Chin CS et al. The origin of the Haitian cholera outbreak strain. N. Engl. J. M ed. 2011 Jan 6;364(1):33 - 42. Epub 2010 Dec 9] • Researchers in NIAID’s intramural program have obtained thousands of single nucleotide poly

morphisms (SNPs) from 185 malaria parasites, tested the parasite responses to seven antimalarial drugs, used genoty pe /phenoty

pe data in genome wide association anal ys is, and identified candidate genes associated with parasite responses to mefloquine, dihydroartemisinin, and other drugs. Their 8000 - SNP ty ping array

has been made available to the malaria research community **.** Coordinator: NIH

; Collaborators: CDC, DoD, FDA, USDA 5.5 Bring new researchers into the field by utilizing appropriate strategies such as training and research opportunities. **Progress:** NIAI D supports young scientists and clinical investigators through pre - and post - doctoral National Research Service Awards (NRSA) and various types of career development awards, including: Mentored Research Scientist Award (K01), Independent Scientist Award (K02), Mentored Clinical Scientist Development Award (K08), Mentored P atient Oriented Research Career Development Award (K23), Mid - career Investigator Award in Patient Oriented Research (K24), Mentored Quantitative Research Development Award (K25), and NIH Pathway to Independence Award (K99). o Representative career developm ent projects include:  Characterization of the secretion pathway s for surface proteins in S. aureus (NRSA)  Structural topology

of a small multidrug resistant efflux pump (K22)  MRSA in Children: Epidemiology , pathogenesis, and prevention (K23) • NIH funds scientific conferences through its R13 grant program. In 2011, NIAID provided support for several antimicrobial resistance - related conferences via this mechanism. These conferences offered a limited number of travel awards to enable students to attend an d present their work. o 2011 Antimicrobial Peptides Gordon Research Conference o 2011 Staphyloccocal Diseases Gordon Research Conference- 49 -

• In 2009, the NIAID intramural program began a collaboration with the Henan Provincial Health Bureau to begin studies on highly drug - resistant TB in Zheng Zhou, the capital city

of Henan province in central China. NIAID has provided training in the conduct of clinical trials to scientists and phy sicians from Zheng Zhou and has worked with the province to prepare for the studies. Patient enrollment in the first clinical trial undertaken under this agreement began in March 2010. (ClinicalTrials.gov Identifier: NCT01071603) • In Southeast Asia and Africa, where artemisinin combination therapies are first - line treatments aga inst malaria, NIAID investigators are working with local scientists to define the response to artemisinin. This project will build local research capacity and inform future approaches to artemisinin resistance and malaria treatment in these areas. Coordi nators: CDC, NIH ; Collaborator: FDA Goal 6 : Facilitate the translation of basic research findings into practical applications for the prevention, diagnosis and treatment of resistant infections. 6.1 Facilitate preclinical studies, including toxicology , pharmac okinetics, pharmacodyn amics, and in vitro and in vivo activity of antimicrobial agents to inform the treatment of resistant pathogens. **Progress:** NIAI D funds numerous investigator - initiated R01 and s mall business grants focused on the development of therap eutics for resistant pathogens of concern. Examples of projects focused on the preclinical therapeutics development for resistant infections include: o Antibacterial agents that restrict the emergence of resistance o Novel antibacterials targeting Gram - n egative nonfermenters o A sy nergy - based therapy

against C. difficile • NIAID stimulates preclinical development of therapeutics for infectious diseases via a number of mechanisms. o The Molecular Li braries Roadmap offers public sector biomedical researcher s access to the large - scale screening capacity necessary

to identify

small molecules that can be optimized as chemical probes to study the functions of genes, cells, and biochemical pathway s. These projects may also facilitate the development of new drugs by providing earl y stage chemical compounds that will enable researchers in the public and private sectors to validate new drug targets, which could then move into the drug - development pipeline. Through this program, several novel small molecule inhibitors of bacterial pathway s, including quorum sensing, DNA replication and beta lactamases, have been discovered. o NIAID supports preclinical development of new antibacterial agents through directed contracts to companies involved in novel drug design and s ynthesis. These contracts are- 50 -

solicited by

an annual Broad Agency Announcement, “Development of Therapeutics for BioDefense.” (BAA - NI AI D - DM ID - NI HAI2010097)  Trius Therapeutics has developed a number of lead compounds that have dual - targeting capabilities aga inst Gram - negative bacteria. By targeting the ATP binding subunits of DNA gy rase and Topoisomerase IV, these agents provide broad spectrum activity with an expected low rate of emergence of bacterial resistance. These novel compounds have completed early

s creening for in vitro activity and have shown efficacy in animal infection models. In 2011, one candidate was selected to move into IND - enabling studies necessary to advance to clinical trials in humans.  Achaogen, Inc., is developing novel broad - spectrum aminogl ycosides. Thus far, a number of lead compounds have been identified and screened for preclinical toxicity and efficacy . In 2011, a lead compound was selected to advance into IND - enabling preclinical development. The lead candidate is active against Gram - negative pathogens that are resistant to existing aminogl ycosides as well as pathogens carrying the NDM - 1 enzy me, which confers resistance to virtuall y all licensed antibiotics.  CUBRC Inc., in collaboration with Tetraphase, In c., was awarded a contra ct in 2011 to advance development of TP - 271, a novel tetracycline - based derivative, to treat Gram negative and Gram - positive bacterial pathogens. TP - 271 exhibits high potency against many bacteria that are resistant to other tetracyclines, and therefore r epresents a substantial improvement over existing drugs. IND - enabling preclinical, drug process development and manufacturing, and human Phase I trials will be undertaken.  Enanta Pharmaceuticals was awarded a contract in 2011 to advance EDP - 788, a novel m acrolide molecule for the treatment of Gram - negative and Gram - positive pathogens, including bacteria that are resistant to other macrolides. I ND enabling preclinical safet y studies, animal efficacy

testing in selected pathogens, and Phase I clinical trials will be conducted under this contract. o NIAID’s Partnerships Program supports collaborative efforts and multidisciplinary approaches to advance candidate products or platform technologies through the product development pathway , and has supported numer ous grants addressing resistance since its inception in 2000.  In FY 2010, NIAID funded 19 awards under the “Partnerships for the Development of Therapeutics and Diagnostics for Drug - Resistant Bacteria and Eukaryotic Parasites” research initiative (RFA - AI - 09 - 026), focused on advancing the development of diagnostics and therapeutics for drug - resistant pathogens. Work under these awards continued in 2011.  In FY 2010, NIAID issued the “Partnerships for the Development of New Therapeutic Classes for Select Vir al and Bacterial Pathogens” (RFA - AI - 10 - 010) research initiative. This initiative targets novel therapeutics for three pathogens for which resistances is of concern: Neisseria gonorrhoeae , hepatitis B virus, and Clostridium difficile . Seven awards were m ade in FY 2011: 3 for Clostridium difficile , 1 for Neisseria gonorrhoeae , and 3 for hepatitis B virus.  In FY 2011, NIAID issued the “Targeting Resistance in Select Gram - Negative Pathogens”(RFA - AI - 11 - 009) phased innovation award research initiative. This i nitiative- 51 -

targets early

translational research towards the development of novel therapeutic approaches to treat resistant Gram - negative bacteria. NIAID anticipates making 12 awards in 2012, half of which will advance to the second phase of funding in two ye ars based on the attainment of milestones, programmatic priorities and available funds. o In FY 2007, NIH issued the “Pharmacological Approaches to Combating Antimicrobial Resistance” (RFA - AI - 07 - 025) research initiative, to solicit applications aimed at determining the proper dosing of currentl y prescribed antimicrobial agents used in the treatment of clinicall y relevant infectious disease for which drug resistance poses a significant problem. Funded projects (ongoing) focus on drugs commonly used to treat tuberculosis, influenza, and malaria, as well as hospital - acquired infections caused b y Gram - negative bacteria. Twenty - five publications cite funding under this initiative. • NIAID provides a broad array of pre - clinical and clinical research resource s and services to researchers in academia and industry designed to facilitate the movement of products from bench to bedside. By providing these critical services to the research community , NIAID can help to bridge gaps in the product development pipeline and lower the financial risks incurred b y industry to develop novel antimicrobials. o Two NIAID preclinical services contracts were awarded in FY 2011 that will provide resources to support the broad preclinical development of small molecule and biophar maceutical therapeutics. Services available to researchers include: product sy nthesis, manufacturing and formulation development, pharmacody namic and pharmacokinetic studies, a full range of toxicity testing, and development strategic planning. Multiple new and improved drugs and formulations are being supported under these service contracts to fulfill the regulatory requirements for entering human clinical trials. Examples include studies to support development of an efflux pump inhibitor, a novel broad - spectrum antibacterial for topical use and a novel monobactam with activity against resistant Gram - negative bacteria. o NIAID’s In vitro Assessments of Antimicrobial Activity contracts provide in vitro testing services, including Minimal Inhibitory Concentration (MIC) determination, for candidate therapeutics against a wide array of infectious organisms, including MRSA, VRE, Mycobacterium tuberculosiss , and resistant strains of Klebsiella and Acinetobacter species. This program is a free service to the research and antimicrobial discovery and development communities, whereb y investigators can submit compounds/therapies for screening. o NIAID’s Animal Models of Infectious Diseases contracts provide in vivo animal model efficacy testing services for promis ing therapeutic candidates submitted b y researchers. Animal models are available for a wide range of pathogens, including S. aureus , E. coli , and N. gonorrhoeae . Coordinator: NIH

; Collaborators: CDC, FDA 6.2 Encourage, support and conduct basic and clinical research on the development and use of vaccines and novel or alternative approaches for prevention and treatment of infections in human and veterinary

medicine.- 52 -

**Progress:** NIAI D supports numerous investigator - initiated studies on vaccines for the prevent ion of resistant pathogens of concern. Examples of ongoing studies include: o Staphylococcus aureus vaccine development o Development and manufacture of adjuvants for vaccines targeting MDR tuberculosis o Mucosal vaccines against gonorrhea • The Partnersh ips for Development of Vaccines for Selected Pathogens initiative (RFA AI - 09 - 016) focused on advancing development of vaccines against select pathogens that have a significant impact on public health, including respiratory s yn cy tial virus (RSV), Staphyloco ccus aureus , Pseudomonas aeruginosa , and Clostridium difficile . The six funded awards are ongoing. • For over ten ye ars, the NIAID - supported Tuberculosis Research Materials and Vaccine Testing Contract has provided the research community with materials and reagents to facilitate basic, translational and applied research focused at the control and eradication of Mycobacterium tuberculosiss . The contract also includes the development of animal models and testing of candidate vaccines against tuberculosis. • NIH also supports the development of novel products for infection control, including antimicrobial materials for healthcare facility surfaces and indwelling devices. Examples of current grants include: o Micro - patterned surfaces for reducing the risk of catheter - associated UTI o Biomaterials that prevent biofilm colonization and device - based infections o Design and analy sis of random copol ym ers with antimicrobial activity Coordinators: NIH, USDA; Collaborators: CDC, DoD, FDA 6.3 Encourage, support and con d uct research on the development of novel diagnostic technologies to rapidl y distinguish among pathogens and their resistant subty pes at the point of care. **Progress:** NIAI D, in collaboration with NICHD, CDC, FDA, and the Office of the Global AIDS Coordinat or (PEPFAR) organized a workshop on TB and HIV diagnostics in adult and pediatric populations in June 2011. The purpose of this workshop was for the U.S. government to engage with public and private partners to identify research gaps in the TB diagnostics research field and develop strategies to accelerate and capitalize on current research efforts. Topics included clinical research and development activities in TB diagnostics for adults and particularly pediatrics and strategies for implementing molecular point - of

- care diagnostics for HIV and TB. • Under the auspices of the Transatlantic Taskforce on Antimicrobial Resistance (TATFAR), NIAID staff along with their counterparts in the European Commission’s Directorate General for Research and Innovation orga nized a workshop on the Challenges and Solutions for the Development of New Diagnostic Tests to Combat- 53 -

Antimicrobial Resistance. The workshop took place in September 2011 and brought together academicians, diagnostic developers and regulators from both si des of the Atlantic. The workshop aimed to identify existing barriers and possible solutions in the following areas: o Factors limiting the development and use of contemporary diagnostic tools o I dentification of key

partners that need to join the effort to advance diagnostics into clinical practice o The role of improved diagnostic tests in enhancing clinical development of novel antimicrobials Presentations are posted at the TATFAR website. • NIAID funds numerous investigator - initiated grants focused on the development of diagnostics for resistant pathogens of concern. o Examples of ongoing projects include:  A rapid point - of

- care diagnostic for Neisseria gonorrhoeae STDs  Point of care flu drug resistance test  Rapid molecular testing for neonatal anti biotic - resistant pathogens o Work conducted under an NIAID investigator - initiated grant contributed to the development of the Xpert MTB/RIF TB test, which provides specific, sensitive and rapid detection of Tb and MDR - TB. The time to result of 2 hours for this test is a significant improvement over existing TB diagnostics, which takes 3 - 12 weeks. The World Health Organization endorsed this test in December, 2010. NIAID is supporting studies to understand how best to use this new test in different population s. • Targeted Diagnostics Initiatives o The “Partnerships to Improve Diagnosis and Treatment of Selected Drug - Resistant Healthcare - Associated Infections (U01)” (RFA - AI - 06 - 036) research initiative supports the development of therapeutics or rapid diagnostic s for specific bacterial strains and drug resistant phenot ypes for the following healthcare - associated pathogens: Clostridium difficile , Pseudomonas , Acinetobacter , Enterobacter , Klebsiella , Serratia , Proteus , and Stenotrophomonas maltophilia . Twenty publ ications cite funding from the four funded projects. o The “Partnerships for Point of Care (POC) Diagnostic Technologies for Nontraditional Health Care Settings” (RFA - AI - 08 - 003) research initiative focused on advancing the development of POC diagnostics for pathogens causing sexually transmitted infections (STI s), urinary

tract infections (UTI s), and respiratory infections, many

of which demonstrate a high degree of resistance. Research under the five awarded grants is ongoing. o The “Partnerships fo r Development of Therapeutics and Diagnostics for Drug - Resistant Bacteria and Eukaryotic Parasites” research initiative (RFA - AI - 09 - 026) is described under section 6.1. • The Tuberculosis Clinical Diagnostics Research Consortium (CDRC) was awarded in 2009 and is currently

evaluating four earl y stage diagnostic tests for clinical feasibility and is contributing to cost - effectiveness modeling studies for the Xpert MTB/RIF TB test. Coordinator: NIH- 54 -

6.4 Support development of novel broad spectrum antimicrob ials with dual indications for community - acquired infections and biodefense threat agents. **Progress:** BARDA awarded an additional contract for the development of novel antibiotics. The contract supports the development of a completel y novel class of anti biot i cs and could represent the first novel class of antibiotics to treat hospital acquired gram negative infections in 40 years. The contract supports drug manufacturing, Phase II HAP/VAP studies, Phase III cIAI, as well as animal efficacy studies agains t the biothreat pathogens anthrax, plague , and tularemia. BARDA cont inues management of the develop ment of a next generation aminoglycoside. In 2011, improvements in process chemistry have allowed for more efficient manufacturing processes to be imple me nted. Clinical pharmacology

studies have also been initiated and are completing their in - life phase. 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 c linical research to evaluate the safety and efficacy of novel drugs and vaccines for pathogens where resistance threatens effective treatment. **Progress:** Several NIAID - funded HIV/AIDS clinical research sites in sub - Sahara Africa are partnering wi th Aeras and Crucell to evaluate the safety and efficacy of Aeras 402/Crucell Ad35 TB vaccine in HIV - uninfected infants. • NIAID supports clinical trials infrastructure focused on evaluating new vaccines and therapeutics through the Vaccine and Treatment Evaluation Units (VTEUs) and the Phase I Clinical Trial Units for Therapeutics. Investigators may access these services at no cost. Examples of activities in these clinical trials units include: o Completed:  Two Phase I clinical trials of the antimycobac terial agent, SQ109, have been completed in Phase Iclinical trial units [NCT00866190, NCT01358162]. SQ109 has a molecularl y distinct mechanism of action, and has FDA fast track designation due to activity against an ethambutol - resistant TB strain and pro mise in fulfilling an unmet need for the treatment of MDR - TB.  A recently

completed VTEU supported trial, revealed that strains of community acquired MRSA colonizing healthy children differed significantly from strains associated with staphylococcal infect ions. [Thomsen Iet al. Molecular distinctions exist between community - associated methicillin - resistant Staphylococcus aureus colonization and disease - associated isolates in children. Pediatr Infect Dis J. 2011 May ;30(5):418 - 21] o Ongoing:- 55 -  A Phase I clini cal trial to determine the safety and immune response generated by an experimental endotoxin vaccine for Gram - negative bloodstream infections [NCT01164514]  A Phase I clinical trial to test a novel means of endotracheal tube decontamination to reduce biof

ilm formation, healthcare - associated infections and emergence of resistance  A Phase I study to determine the safet y of nasal decolonization of S. aureus using novel, topical agent  Nasal decolonization of methicillin - resistant S. aureus (MRSA) using top ical antibiotic in neonatal intensive care units  A Phase II study to determine the safet y and effectiveness of novel monoclonal antibody to treat Staphylococcus aureus infection  Two Phase I clinical trials to determine safety, pharmacokinetics, and opt imal dose of a novel narrow spectrum agent with activity against Clostridium difficile  A Phase I trial of the TB vaccine candidate Aeras 422  A trial to assess different vaccination schedules of 13 - valent conjugate S. pneumoniae (Spn) vaccine (Prevnar - 13 ®) in adults 65 years and older • Several studies of drug - resistant TB and clinical trials of novel TB treatments are planned or underway

through the collaborative efforts of NIAID intramural investigators, the Korean Ministry

of Health and Welfare’s Natio nal Masan Tuberculosis Hospital, Yonsei Universit y’s College of Medicine of the Republic of Korea, and private sector partners. Characterization of MDR and XDR TB isolates and their contribution to human disease is being studied under clinical protocol NCT 00341601, which has enrolled more than 750 volunteers. Clinical studies of metronidazole and linezolid to treat DR TB are underway , and a protocol is in development to study meropenem and clavulanic acid for XDR TB treatment. Coordinator: NIH 7.2 Design and implement studies focused on optimizing the dose and duration of antibacterial agents prescribed for treatment of community- acquired pneumonia, urinary tract infections, skin and soft - tissue infections, and other infectious illnesses. **Progress:** NIAI D is su

pporting clinical trials to inform the rational use of existing antimicrobial drugs to help limit the development of antimicrobial resistance. Since 2007, NIAID has made 8 awards for targeted clinical trials designed to help answer key questions about pro per antimicrobial dose, treatment duration and whether antimicrobial treatment is necessary

in all cases. All of these trials are ongoing or in development. More information about each trial can be found at the following links: skin and soft tissue infec tions caused b y CA - MRSA (2007); catheter - related bacteremia and urinary tract infections (2009); Gram - negative bacteremia, acute otitis media and community- acquired pneumonia (2010).- 56 -

• NIAID is supporting a clinical study to optimize the use of colistin, an antibiotic approved in the late 1950s that is increasingly being used today

to treat MDR Gram negative infections. Based on data from 105 critically - ill patients, the preliminary results provide the first science - based colistin dosing recommendations f or patients with varying degrees of kidney

function. [Garonzik SM et al. Population pharmacokinetics of colistin methanesulfonate and formed colistin in critically- ill patients from a multi - center study provide dosing suggestions for various categories of patients. Antimicrob Agents Chemother. 2011 Jul; 55(7):3284 - 94] • Combination therapies are another approach to preventing the emergence of resistance. NIAI D is studying new way s to treat cephalosporin - resistant N. gonorrhea infections by using exist ing antibiotic therapies in combination (i.e., gentamicin and azithromycin vs. gemifloxacin and azithromycin [NCT00926796]). NIAID - supported clinical trials evaluating the effectiveness of different drug combinations in treating influenza, HIV and malaria are also ongoing. • In collaboration with the Global Alliance for TB Drug Development, the NIAID - funded AI DS Clinical Trials Group (ACTG) is participating in a study comparing two Moxifloxacin containing treatment shortening regimens with the standard reg imen in pulmonary

TB (study

A5304/REMOX). In addition, ACTG is evaluating short course Rifapentine and INH to prevent tuberculosis in people with latent TB (TBTC S26, A5279 [NCT01404312]) and the role of empiric TB treatment to reduce earl y morbidity and mortality of TB in HIV infected individuals living in areas with high rates of TB infection (A5274 [NCT01380080]). Coordinator: NIH Goal 8: Conduct and support epidemiological studies to identify key drivers of the emergence and spread of AR in various pop ulations. 8.1 Investigate the interplay among AR, colonization, and disease in acute, long - term care, and outpatient facilities. **Progress:** The Network on Antimicrobial Resistance in Staphylococcus aureus (NARSA), developed and supported by NIAI D, is a multid isciplinary international network of basic scientists, clinical microbiologists, and clinical investigators that focus on S. aureus and other staphylococcal species that exhibit antimicrobial resistance. The Network coordinates with established surveillan ce networks for nosocomial infections, including CDC’s National Healthcare Safety Network (NHSN), for the purpose of collecting information and obtaining samples of isolates from relevant cases identified through these surveillance sy stems. NARSA provides a central repository of staphylococcal isolates to researchers. • NIAID funds numerous grants examining the molecular epidemiology of resistant pathogens. Examples include: o Neighborhood level determinants of pneumococcal disease transmission- 57 -

o Epidemiol ogy

of Acinetobacter baumannii : An emerging nosocomial pathogen o Extra - nasal colonization and epidemiology of community- associated MRSA Coordinator: CDC

; Collaborator: NIH, VA 8.2 Support research on how prevalence data on antimicrobial resistance can be use d to help guide treatment choices. For example, define geographic heterogeneity of resistance rates and determine impact of treatment decisions. a) Define appropriate methods for collection and distribution of information on prevalence of resistance to community phy sicians and veterinarians. **Progress:** In 2008, NIH implemented a new computerized reporting process called Research, Condition, and Disease Categorization (RCDC), which all NIH institutes must now use to categorize and report funding in 215 resear ch, condition, and disease categories, including antimicrobial resistance. The NIH RePORTER (Research Portfolio Online Reporting Tool) is a web query tool within the RCDC sy stem that allows the public to drill deeper into each RCDC category . In addition t o NIH, RePORTER also includes information from AHRQ, CDC, HRSA, SAMHSA, FDA and the VA. This web - based tool provides links to abstracts and other project - level data such as histories and start/end dates. Italso features links to publications and patents associated with the research. Funding levels and project lists for antimicrobial resistance can be found on the NI H RePORT categorical spending website. Coordinator: CDC

; Collaborators: FDA, USDA, VA 8.3 Evaluate the utility of monitoring sentinel human popu lations (e.g., farm, abattoir, fruit and vegetable, and food processing plant workers) and persons in the general community for infection or colonization with resistant enteric bacteria to identify reservoirs of resistant organisms. a) Investigate risk facto rs for AR development in Salmonella and Campylobacter in food animals (2014). **Progress:** See 3.5a for dairy cattle research. ARS scientists are evaluating the effects of antimicrobials on swine intestinal microbiomes, and on the expression and transmission of virulence, fitness, and antimicrobial resistance genes in culture and the host. Develop a functional metagenomic approach to identify gene products that inhibit foodborne pathogen growth, interfere with virulence gene expressions, or reduce antimicrobi al resistance. Specificall y, they are assessing the role of commensal intestinal bacteria in evolution, persistence, or transmission of resistance genes. Publication, PNAS, 2012. Determine particular ecological niches/reservoirs for pathogenic/antimicrobi al - resistant bacteria, identifying nutritional/biological/environmental factors affecting ability to- 58 -

colonize/survive/persist within gut of food - producing animals & their production environment ( e.g. distillers grains, organic acids, other diets, competitive exclusion). Develop understanding of microbial adaption to intrinsic/extrinsic stressors on acquisition/exchange/expression of incompatibility plasmids & antimicrobial resistance elements in foodborne pathogens in production/processing environments **.** Coordinator: CDC

; Collaborator: FDA, USDA 8.4 Develop options to capture and record AR research for all federal agencies. **Progress:** The Action Plan to Combat Antimicrobial Resistance and the annual progress reports are being converted, starting in 2013, to web documents available on the Internet. This transition should greatly facilitate the Task Force’s ability to link information on research activities from various agencies and increase its accessibility . Coordinators: CDC

, NIH ; Collaborators: AHRQ, EPA, FDA , USDA- 59 -



### Focus Area IV: Product Development **Overarching goals** Encourage the development of new antimicrobial products to improve our capacity to diagnose, prevent and treat infections, including infections caused b y resistant microorganisms. Goal 9: Provide information on the status of antibacterial drug product development and clarify recommended clinical trial designs for antibacterial products. 9.1 Examine trends over time for new drug applications for sy stemic antibacterial drugs. a) Perform pilot p hase of study to evaluate trends over time for new drug applications for sy stem ic antibacterial drugs; c omplete assessment of trends over time for new drug applications for s ys temic antibacterial drugs (2011) and publish findings (2012) (see 2009

– 2010 Annual Progress Report) . **Progress:** M anuscript in final stages of preparation. Plan is to submit the manuscript to a peer - reviewed journal in 2012 for consideration for publication. Coordinator: FDA 9.2 Publish guidance documents for the following conditio ns describing recommended approaches on clinical trial designs for evaluating antibacterial drugs. a) Publish guidance on recommended approaches to clinical trial designs for evaluating antibacterial drugs for acute bacterial ski n and skin structure infe ctions (2012) (see 2009

– 2010 Annual Progress Report) . **Progress:** Reviewing comments submitted to the docket in response to draft guidance, including comments from FNIH Biomarkers Consortium. Plan to issue final guidance in 2013 . b) Publish guidance on rec ommended approaches to clinical trial designs for evaluating antibacterial drugs for hospital acquired and ventilator associated bacterial pneumonia (2012 ) (see 2009

– 2010 Annual Progress Report) . **Progress:** Reviewing comments submitted to the docket in r esponse to draft guidance, November 4, 2011 Advisory Committee meeting to discuss endpoints and trial designs for HABP/VABP to make trials more feasible. As part of these efforts there are discussions of the potential role of nonmortality cl inical efficac y endpoints for hospital acquired and ventilator associated bacterial pneumonia. The results of these scientific discussions may

impact upon recommended clinical trial designs for studying antibacterial drugs for HABP/VABP.- 60 -

c) Publish updated guidance on rec ommended approaches to clinical trial designs for evaluating antibacterial drugs for community - acquired bacterial pneumonia. Publ ish updated draft guidance (2011 ) and final guidance (2012) (see 2009

– 2010 Annual Progress Report) . **Progress:** Reviewing comme nts submitted to docket in response to draft guidance, including comments from FNIH Biomarkers Consortium. November 3, 2011 Advisory Committee meeting to discuss new efficacy outcome measure of s ymptom improvement and trial designs for CABP to make trials more feasible. Plan to issue updated draft guidance 2012. Coordinator: FDA 9.3 Publish guidance documents for the following typ es of devices to provide recommendations regarding product development. a) Publish final guidance document on premarket notificat ion [510(k)] submissions for medical devices that include antimicrobial agents (2012 ). **Progress:** None . b) Publish draft guidance for establishing performance for in vitro diagnostics assay s for MRSA and VRE (2011). Publish final guidance (2012) . **Progress:** Two guidance documents for MRSA (nucleic acid based, and culture based) were finalized June 2012; publication is pending. c) Publish draft guidance document for establishing performance for in vitro diagnostic assay s for Clostridium difficile . Publish final guidance (2011) . **Progress:** Draft Guidance published. Currentl y reviewing comments submitted to the docket in response to the draft guidance; final document pending. Draft Guidance for Industry and Food and Drug Administration Staff

– Establishing the Per formance Characteristics of In vitro Diagnostic Devices for the Detection of Clostridium difficile. ( http://www.fda.gov/MedicalDevices/DeviceRegulat ionandGuidance/GuidaneDocument s /ucm234868.htm ) Publication of the Class II special control guidance document, Toxin Gene Amplification Assay s for the Detection of Clostridium difficile is pending (2012).- 61 -

Publication of the Class II special control guidanc e document, Multiplex Nucleic Acid Assay for Identification Of Microorganisms and Resistance Markers from Positive Blood Cultures in pending (2012). Coordinator: FDA 9.4 Provide regulatory advice on recommended regulatory pathway s for evaluating products that target unmet medical or veterinary needs including approaches to evaluating non traditional products, e.g., cy tokine, probiotics, and antimicrobial peptides (ongoing). **Progress:** FDA established a CDER Antibacterial Drug Development Task Force with a goal to address issues in antibacterial drug development for human use. In addition, the Engelberg Center for Health Care Reform at Brookings established the Brookings Council on Antibacterial Drug Development that will identify issues and new approaches to promote antibacterial drug development. Work in providing regulatory advice for product development is ongoing. Coordinator: FDA; Collaborator: USDA 9.5 Evaluate use of the Orphan Drug Act, or similar incentives, to encourage development and market ing of new antimicrobial agents for human medicine. a) Part 15 public hearing held April 28, 2008, on issues in AR and the Orphan Drug Act. **Progress:** See 2009 - 2010 Annual Progress Report. Coordinator: FDA 9.6 Sponsor a study

to evaluate incentives to prom ote the development of antibacterial drugs for human use and rapid diagnostic tests (including antimicrobial susceptibility tests), including the impact of such strategies upon appropriate use of such products. Prepare a report for publication describing the study results (2012) . **Progress:** The study

is ongoing. Coordinator: HHS/ASPE ; Collaborator: FDA Goal 10: Consider opportunities for international harmonization and means to update susceptibility

testing information for human and animal use.- 62 -

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 Harmonization of Technical Requirement s for Registration of Veterinary Medical Products) (ongoing). **Progress:** Ongoing participation in TATFAR including periodic teleconferences. Exchange of guidance documents on clinical trial designs for studying new antibacterial drugs. European Medicine s Agency and FDA representatives are engaging in relevant public meetings and workshops to inform and share in discussions on recommended clinical trial designs for studying antibacterial drugs. Coordinator: FDA 10.2 Collaborate with relevant internatio nal organizations and use international expert consultations (e.g., the WHO, the World Organization on Animal Health, CLSI standards Institute, the European Committee on Antimicrobial Susceptibility Testing) to enhance product development (ongoing). **Progr ess:**  FDA staff attend the twice - ye aerly meeting of CL SIAntimicrobial Susceptibility

Testing Subcommittee. Coordinator: FDA ; Collaborator: NIH 10.3 Develop a strategy for periodic updating of susceptibility testing information for antimicrobial agents a

pproved for use in humans and animals in the United States (ongoing). a) Participate in multi - laboratory method trial studies t o develop standardized in vitro antimicrobial susceptibility testing methods for veterinary pathogens where such tests are lacking (2011) (see 2009

– 2010 Annual Progress Report) . **Progress:** FDA website established that provides the date of FDA's most recent review of a sponsor's in vitro susceptibility interpretative criteria contained in product labeling: http://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CD ER/ucm275763.htm Coordinators: CDC, FDA ; Collaborator: USDA Goal 11: Encourage development of rapid diagnostic tests and vaccines.- 63 -

11.1 Encourage development, testing, and evaluation of new rapid diagnostic methods for human and veterinary

use to help guide antimicrobial therapy . Specifically, promote the development of tests for infections cause b y fastidious (e.g. TB ) or difficult to culture organisms (e.g. Treponema pallidum , the agent of sy philis) and rapid point - of - care diagnostics to identify

patients with viral respiratory infections who do not need antimicrobial agents. **Progress:** In September 2011, NIAID collaborated with the European Commission’s Directorate General for Research and Innovation to organize the TATFAR workshop on the Challenges and Solutions for the Development of New Diagnostic Tests to Combat Antimicrobial Resistance. This is described in section 6.3 . The Office of In vitro Diagnostic Device Evaluation and Safety (O IVD) continues to work with industry

in developing clinical and pre - clinical studies to demonstrate performance of in vitro diagnostic devices for detection of microorganisms and related resistance biomarkers. FDA published the Draft Guidance for Industry and FDA St aff Medical Devices: The Pre - Submission Program and Meetings with FDA Staff . ( http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/Guidan ceDocument s/ucm310375.htm ) FDA allowed marketing of the first nucleic acid test that can identify 12 different bacterial t ypes known to cause bloodstream infections as well as three resistance genes. This was done through the DeNovo process. FDA published the Draft Guidance for Industry and Food and Drug Administration Staff

- Class II Special Controls Guidance Document: Nucleic Acid - Based In vitro Diagnostic Devices for the Detection of Mycobacterium tuberculosiss Complex in Respiratory Specimens ( http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocument s/ucm296205.htm ). Additionally , the Final Guidance for Industry and FDA S taff - Establishing the Performance Characteristics of In vitro Diagnostic Devices for the Detection or Detection and Differentiation of Influenza Viruses was published in 2011 ( http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocument s/ucm079171.htm ). FDA h eld the p ublic m eeting in 2011 - Advancing Regulatory Science for Highl y Multiplexed Microbiology /MCM Devices . A white pap er was published and comments were received and implemented ( http://www.fda.gov/MedicalDevices/NewsEvents/WorkshopsConferences/ucm267410.h tm ). Publication of the draft guidance document , Highl y Multiplexed Microbiological /Medical Countermeasure Devices is pending (2012) .- 64 -

a) Encourage improved diagnostic tests for resistant TB b y conducting a FDA/CDC/NIH co - sponsored meeting to identify gaps in TB diagnostics and to explore models and strategies that may

expedite the development of new diagnostics (2010). Work to develop, evaluate, and implement molecular tests for the detection of MDR - TB directly from pulmonary

specimens (2012). **Progress:** In the NIAID intramural p rogram, several collaborations involving new diagnostic tools are underway , including work on the next generation GenXpert test for RI F; an XDR test for detection of fluoroquinolone and Kanam ycin resistance in Mtb; biomarkers of treatment success; and to a ssess the presence of fragments of Mtb in easily accessible human samples, such as urine and exhaled breath condensate, for development of point of care tests. Encourage development of rapid point - of - care tests to confirm diagnoses of possible bacterial re spiratory infections including otitis media, sinusitis, and pneumonia and rapid point - of - care tests to identify

pathogens associated with these infections (ongoing). In June 2011, FDA held an inter - agency meeting to discuss molecular diagnostics for the de tection of Mycobacterium tuberculosiss complex and the detection of genetic mutations which confer antibiotic resistance in M. tuberculosis complex. b) Encourage development of rapid point - of - care tests to confirm diagnoses of possible bacterial respiratory infections including otitis media, sinusitis, and pneumonia and to identify pathogens associated with these infections (ongoing). **Progress:** None . c) Collaborate with partners to develop and evaluate rapid methods for identification and characterization of Clostridium difficile , MRSA, and other multidrug - resistant organisms from human , animal , and plant sources to support national surveillance efforts (see 2009

– 2010 Annual Progress Report) . **Progress:** See 2009 - 2010 Annual Progress Report. Coordinators: CDC, FDA ; Collaborators: NIH, USDA , HHS/ASPR, VA 11.2 Encourage development, testing, and evaluation of new vaccines for human pathogens for which AR poses a significant problem for treatment or public health. a) Working with stakeholders, examine strateg ies to maximize the quality and the quantity of candidate vaccines for prevention of antimicrobial - resistant infections of public health significance (ongoing).- 65 -

**Progress:** NIAI D has a long - standing intramural research program focused on development and cli nical testing of protot ype malaria vaccines in collaboration with many partners from malaria - endemic countries and the public and private sectors. Specific vaccines under development and a product development timeline (updated May 2010) can be found here. b) Conduct research to facilitate development of vaccines for resistant pathogens such as Staphylococcus aureus, Mycobacterium tuberculosiss , Clostridium difficile, enteric pathogens and Neisseria gonorrhoeae (ongoing). **Progress:** See action item 6.2. c) Con duct research to facilitate development of vaccines for viral respiratory infections that may contribute to increased antibiotic use due to subsequent or co - bacterial infections or inappropriate antibiotic use (ongoing). **Progress:** Vaccines for viral resp iratory infections are a major focus of the NIAID intramural research program. Lead candidates for RSV and human parainfluenza virus 3 (HPIV3) vaccines are in Phase I and II clinical trials supported in part b y collaboration with industry . Coordinator: F

DA ; Collaborators: CDC, NIH, VA 11.3 Support advanced development of vaccines for resistant pathogens such as Staphylococcus aureus . **Progress:** None . Coordinator: HHS/ASPR- 66 - 

### Acronyms and Abbreviations AHRQ Agency for Healthcare Research and Qual ity APHL Association of Public Health L aboratories AR Antimicrobial re s istance OASH Office of the Assistant Secretary for Health ASPE Of fice 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 Authority CDC Centers for Disease Control and Prevention CL SI Clinical and Laboratory Standards Institute CMS Centers for Medicare and Medicaid Services CSTE Council of St ate and Territorial Epidemiologists 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 NI H 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