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Antimicrobial Resistance Interagency Task Force
2007 Annual Report (Released June 2008)

Executive Summary

Surveillance

Surveillance for resistant microorganisms and antimicrobial agent use remains a priority at Centers for Disease Control and Prevention (CDC), Food and Drug Administration (FDA), Department of Agriculture (USDA), and other federal agencies.  Data on patterns and rates of antimicrobial resistance are collected for a variety of microorganisms including over 15 species of bacteria, Mycobacterium tuberculosis, yeasts and moulds, viruses, and selected parasites through a series of ongoing surveillance systems.

Methicillin Resistant Staphylococcus aureus

According to CDC’s Active Bacterial Core Surveillance (ABCs) system, there are approximately 94,000 new cases of invasive methicillin-resistant Staphylococcus aureus (MRSA) infection reported annually in the United States, resulting in over 19,000 deaths. In contrast, data from the National Healthcare Safety Network (NHSN) indicate that the incidence of central line-associated bloodstream infections per 1,000 central line days in 2006 decreased by 49.6% compared to 2005 data, while the incidence of central line-associated methicillin-susceptible S. aureus (MSSA) infections decreased even more substantially, by 70.1% (see figure). Data on invasive MRSA infections from the ABCs system for 2005-2006 also show a decrease in hospital-onset and healthcare-associated MRSA infections, confirming this downward trend.  Although community onset infections of MRSA did not decrease significantly, there was a downward trend.

Streptococcus pneumoniae

ABCs data through 2006 show that invasive pneumococcal disease (IPD) caused by antimicrobial-resistant S. pneumoniae isolates covered by the conjugate vaccine (designated PCV7) remain low; however, infections caused by multidrug resistant serotype 19A strains are increasing (see figure). Development of a 13-valent pneumococcal conjugate vaccine is in progress.  Data from ABCs will help document the vaccine’s impact on invasive infections caused by drug-resistant pneumococci. 

IPD rates among children under 5

Tuberculosis

A pilot exercise was initiated in 2007 to provide additional surveillance data for tuberculosis (TB) cases reported as multi-drug resistant (MDR) or extensively drug resistant (XDR) from four geographic areas, which provide about 55% of the reported MDR-TB cases in the United States.  The results of this pilot will provide important information on the burden and impact of MDR-TB and inform CDC on how a nationwide supplemental registry for MDR/XDR TB would assist public health efforts. 

As shown in the accompanying global map, drug-resistant tuberculosis continued to spread internationally and is now approaching critical proportions.  A focus on providing care in low resource, high burden areas is critical for preventing the transmission of drug-resistant TB in health care settings, especially among HIV-infected persons.  In November 2006, a Federal TB Task Force convened to discuss the possible U.S. Government response to the global threat of XDR-TB.  In 2007, an action plan was developed, which is currently undergoing review.

Percent MDR TB, New Cases, 1994 - 2007

Sexually Transmitted Diseases

The Gonococcal Isolate Surveillance Project (GISP) provides national antimicrobial susceptibility data to guide recommendations for treating gonorrhea in the United States. Data from GISP showed increases in fluoroquinolone resistance (shown below) in all regions of the country prompting CDC to revise its sexually transmitted disease (STD) Treatment Guidelines in 2007.  CDC no longer recommends fluoroquinolones for the treatment of gonorrhea.  As a result, CDC recommends only one class of antibiotics, the cephalosporins, for the treatment of gonococcal infections.  Continued monitoring for the emergence of cephalosporin resistance will remain a critical CDC activity. 

CDC is working with the World Health Organization to expand its sentinel surveillance system for monitoring antimicrobial resistance of Neisseria gonorrhoeae in the Western Pacific Region. 

CDC launched a sentinel surveillance project to monitor azithromycin-resistant syphilis in the United States.  Residual clinical specimens and demographic data are submitted to CDC from STD clinics in 11 cities for screening.

Influenza

In 2007, surveillance for resistance to both classes of licensed anti-influenza drugs, M2 blockers (the adamantanes, amantadine and rimantadine) and neuraminidase inhibitors (NI’s) (i.e., oseltamivir and zanamivir) in seasonal influenza viruses was expanded. Over 3,500 influenza A and B viruses isolated in 46 states and 73 foreign countries (Africa, North America, South America, Asia, Europe, and Oceania) were tested for antiviral resistance. Resistance to M2 blockers among influenza A(H3N2) viruses continued to be very high worldwide especially in South Asia (essentially 100% in China) (see figure).  A rise of M2-blocker resistance was also detected among A(H1N1) viruses circulated in the United States  Resistance to the licensed NI’s was low (<1%) among influenza A and B viruses circulating during several previous seasons. Therefore, the use of NIs rather than M2 blockers has been recommended by CDC and public health agencies in other countries through the 2008 influenza season.

In the early 2007-2008 influenza season, a small (5.5%), but noticeable, increase in resistance to oseltamivir was detected among influenza A(H1N1) viruses circulating in the United States. Around the same time, a very high frequency of oseltamivir resistance was reported for A(H1N1) viruses circulating in Norway (up to 66%) and some other countries in Europe. All oseltamivir-resistant A(H1N1) viruses shared the same mutation (H274Y) in the neuraminidase gene. They all were susceptible to M2 blockers and to another licensed NI, zanamavir.  The alarming increase of resistance to oseltamivir among influenza A(H1N1) viruses prompted the Influenza Division of CDC to enhance surveillance efforts within the United States and to develop new methods for drug resistance detection.

Global spread of A(H3N2)

Testing of available, highly pathogenic avian A(H5N1) viruses for their susceptibility to M2 blockers and NIs was expanded.

Antimicrobial Agent Use

The National Hospital Ambulatory Medical Care Survey (NHAMCS) is an annual national survey that collects data on the utilization of ambulatory medical care services provided by hospital emergency and outpatient departments in the United States. Findings are based on a sample of visits to emergency departments and outpatient clinics.  NHAMCS monitors trends in prescription of antimicrobial drugs in hospital emergency and outpatient departments. Antimicrobial prescribing in ambulatory care settings decreased from 154 antimicrobials per 1,000 visits in 1993-94 to 123 antimicrobials per 1,000 visits in 2005-06 (down by 20%) (see figure).  This decline was observed in all age groups, except for persons 15-24 years of age.  Among children and adolescents less than 15 years of age, decreasing trends in antimicrobial prescribing rates were found in the physician office and emergency department (ED) settings, but not in the hospital outpatient department (OPD).  For persons 15 years of age and over, antimicrobial prescribing rates increased by 29% in the OPD and 15% in the ED; no change was observed in physician offices. 

Ambulatory Care AR Prescribing rates

Prevention and control

The Agency for Healthcare Research and Quality’s (AHRQ) Centers for Education and Research on Therapeutics (CERTs) program is a national initiative to increase awareness of the benefits and risks of new, existing, or combined uses of therapeutics through education and research.   2007 data show that a CERTs intervention in 16 communities in Massachusetts was responsible for a 4.2% decrease in antibiotic prescribing there among children aged 24 to <48 months and a 6.7% decrease among those aged 48 to <72 months. The intervention effect was greatest among Medicaid-insured children and for broad-spectrum antimicrobial agents. The sustained, multifaceted, community-level intervention was only moderately successful at decreasing antibiotic use across all indications beyond the underlying downward trend.

CDC’s “Get Smart: Know When Antibiotics Work” program is a long-standing, multifaceted educational and social marketing program. Building upon suggestions from a recent external review of the program, Get Smart’s goals were revised in 2007 with new funding focused on updating and enhancing Get Smart’s package of interventions to reduce antimicrobial use. 

The Department of Veterans Affairs (VA) activities during the past year included a ground-breaking MRSA Prevention Initiative.  Because of concerns for increasing occurrence of MRSA infections, in January 2007, the Under Secretary for Health of the Veterans Health Administration announced Directive 2007-002, which directed all acute care facilities nationwide within the Veterans Health Administration to initiate a program for the prevention of MRSA.  The graph below demonstrates the increasing burden of MRSA among VA patients.

MRSA trends

The new program would use a bundle of evidence-based practices including rigorous hand hygiene, stringent use of contact precautions, active surveillance screening, and implementing cultural change to achieve optimal practices in the prevention of spread of MRSA.  Over 90% of facilities now have a dedicated MRSA Prevention Coordinator to assist with the implementation of the program.  Even though this initiative is directed at MRSA, data from the Pittsburgh VA Medical Center (which initiated the demonstration project in collaboration with CDC) indicate that implementation has a positive effect on decreasing other antibiotic-resistant infections as well.  It is the anticipated that the lessons learned from this project will result in decreased transmission of MRSA and other antibiotic-resistant organisms in VA healthcare facilities. 

VA’s ongoing efforts to reduce healthcare-associated infections, through its Inpatient Evaluation Center (IPEC) programs has resulted in a decrease in ventilator-associated infections (VAPs) and central venous catheter-related bloodstream infections (CR-BSIs) in VA ICUs nationwide.

The Department of Veterans Affairs is continuing its performance-based management for achieving quality healthcare outcomes, including monitors for both influenza and pneumococcal immunizations.  Pneumococcal vaccination has been a long-standing performance monitor, and data from the VA system demonstrate that by achieving significant vaccination coverage within its population, there has been a concomitant reduction in pneumococcal pneumonia (see figure).

pneumococcal pneumonia and vacccination

Research

Recent years have seen a dramatic reduction in the availability of new antimicrobial agents, particularly antibacterial agents.  As microorganisms develop resistance to the existing arsenal of antimicrobial drugs, there are fewer effective drugs available for treatment.  The National Institutes of Health (NIH) is supporting innovative research that will keep the antimicrobial pipeline primed with new potential therapeutics while simultaneously supporting efforts to reduce the pressure on the existing drug arsenal. 

The quest for genuinely novel antimicrobial therapeutics relies on the exploration and development of new strategies, much of which emerges from the efforts of academic investigators and small biotechnology companies.  NIH seeks to facilitate these efforts by using the existing biothreat and emerging infectious disease infrastructure and resources that will enable the efficient progression of a basic research concept to product development.  These resources include in vitro screening of lead compounds against a battery of biothreat agents and antimicrobial resistant strains of emerging pathogens.  In addition, animal models are available to evaluate toxicity and efficacy of potential therapies and vaccines, including new antimicrobials or immunotherapies.

A second approach to the problem of a dwindling antimicrobial pipeline is to reduce the need for new antimicrobial agents.  This can be accomplished principally by reducing the rate of emergence and spread of antimicrobial resistant strains and maximizing the effective lifetime of the drugs currently available.  There are NIH-supported efforts on both fronts.

Antimicrobial use modifications that reduce or eliminate selective pressures on microbes can impact patterns of resistance.  Proper dosing of an antimicrobial drug during patient treatment is one approach that could potentially delay the emergence of antimicrobial resistance.  Proper dosing requires an understanding of how and at what rate a drug moves into and out of the body (pharmacokinetics) as well as the in vivo concentrations that produce the desired microbiological outcomes (pharmacodynamics).  In 2007, NIH solicited research applications aimed at determining the proper dosing of currently prescribed antimicrobial agents used in the treatment of clinically relevant infectious disease for which drug resistance poses a significant problem.  Applications will be funded in FY2008. 

Although antibiotics are still commonly prescribed to children with acute otitis media (AOM), the necessity of treating these infections remains controversial.  The results of an NIH sponsored placebo-controlled clinical trial evaluating the effectiveness of antimicrobial agents for treating AOM is in progress.  The time to resolution of symptoms in young children diagnosed with AOM receiving antimicrobial therapy will be determined and compared with that in children receiving placebo. These data will guide the decision making for physicians treating young children with AOM, thus reducing the overuse of antimicrobials that can increase the risk of resistance.

Skin and soft-tissue infections caused by community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) are an emerging public health issue; however, there is insufficient knowledge to guide effective treatments. NIH is supporting two studies to determine the effectiveness of a variety of treatments for skin and soft-tissue infection. One study will examine the duration of antimicrobial therapy using only oral, generic antibiotics; the other will determine the absolute need for antimicrobials and whether abscess drainage alone is a sufficient alternative. If successful alternative treatments for CA-MRSA are identified, then final option drugs, such as vancomycin and linezolid, can be reserved for the treatment of highly resistant hospital-acquired MRSA infections.

In 2007, CDC no longer recommended fluoroquinolones as primary therapy for gonorrhea due to rising fluoroquinolone resistance (see figure).  There is growing concern about the emergence of cephalosporin resistance and the limited options for the treatment of gonorrhea, particularly, in patients with serious adverse reactions to penicillins or cephalosporins.  CDC and NIH are collaborating in sponsoring a randomized clinical trial evaluating the efficacy of two combination therapies as salvage regimens for uncomplicated urogenital gonorrhea.  The efficacy of each regimen will be assessed and the information will help guide development of additional approaches for treating gonococcal infection.

GISP isolates by year

With the goal of combating and reducing the emergence of antimicrobial resistance, NIH, CDC, and FDA support innovative research that will lead to the development of new treatments for infectious diseases.  Continued support of clinical trials and studies that seek to improve the use of the existing antimicrobial arsenal through optimal dose determination and the substitution of alternative treatments will continue.

Improving the detection of bacterial contamination of food continues to remain a top public health priority.  Since 2007, FDA has developed and evaluated several microarray-based assays for the reliable detection, discrimination, and multilocus typing of all Listeria species, four Campylobacter species (C. jejuni, C. coli, C. lari, and C. upsaliensis), Bacillus anthracis, enterotoxins of Staphylococcus spp., toxin genes of Clostridium perfringens, and genes involved in bacterial drug resistance (Staphylococcus spp, and Streptococcus spp.).  The results of this study show the feasibility of rapid organism detection and characterization.

USDA has developed a technique for identifying and tracking the different genes responsible for antimicrobial resistance and virulence in bacteria. This technique can identify resistance and virulence genes in key bacterial species of public health and veterinary importance. This will help to establish the source, spread and epidemiology of those genes, a fundamental component of research. Analysis of bacteria collected by this project has identified common genes in different species of bacteria co-cultured from the same animal.

Product development

As antimicrobial agents lose their effectiveness, new products must be developed to prevent, rapidly diagnose, and treat infections. To address these and other Action Plan issues, three strategies have been embraced by members of the Interagency Taskforce. First, to ensure researchers and drug developers are informed of current and projected gaps in the arsenal of antimicrobial drugs, vaccines, and diagnostics, and of potential markets for these products;  second, to stimulate development of priority antimicrobial agents for which market incentives are inadequate, while fostering their appropriate use; and third, to optimize the development and use of veterinary drugs and related agricultural products that reduce the transfer of antimicrobial resistance to pathogens that can infect humans.  Numerous success stories have arisen from this three-tiered strategy.  Some highlights from the past year follow.
FDA continues regulatory activities in the development and production of influenza related products.  Influenza immunization is currently recommended for children 6-59 months of age.  At the February 2008 ACIP meeting, there was discussion to include children through 18 years of age.  Five seasonal influenza vaccines are licensed and distributed in the United States.  These vaccines include Medimmune (FluMist®), Sanofi (Fluzone®), Chiron (Fluvirin®), ID Biomedical (FlulavalÒ) and GSK (Fluarix®).

Regulatory pandemic/seasonal influenza activities in 2007:

Since 2007, USDA scientists have developed nucleic acid technology (NAT)-based, polymerase chain reaction-based, DNA microarray tests to detect of all four species of human malaria parasites: Plasmodium falciparum, P.vivax, P. malariae and P.ovale.  In addition, results obtained by DNA microarrays demonstrated that these tests could be used for the reliable species discrimination of the human Plasmodium.  The value of these NAT-based tests as a tool for screening donor blood for malaria infection is being evaluated.  USDA scientists are also working to develop an enzyme linked immunosorbent assay as a blood-screening test to detect antibodies specific for all four species of Plasmodium that cause human infection.  Screening for malarial antibodies could be used as a criterion to guide donor deferral policy for malaria risk.

Laboratory studies at CDC have focused on development of more sensitive and rapid diagnostics for drug-resistant tuberculosis, human immunodeficiency virus, and other sexually transmitted infectious agents.  This includes development of ultra-sensitive real-time PCR assays for HIV drug resistance.  These assays (see figure) expand detection of mutant viruses (red bars) that comprise less than 20% of the virus population and are missed in about half the cases of transmitted HIV drug resistance by conventional sequencing methods (grey bars).  Collaborations with CDC partners will allow for the assessment of the clinical utility of these more sensitive tests and the clinical impact of minority drug resistant viruses on the responses to antiretroviral treatmen.

FDA has clarified regulatory requirements to both industry and the scientific community in several fora.  To further discussion on obstacles and issues that might exist in technology transfer, FDA Center for Devices and Radiological Health assisted device manufacturers in the most efficient way to get an alternative method for detecting vancomycin resistance in S. aureus to market by offering protocol advice and providing an expedited review option.

It is essential that clinical trials evaluating a new drug be performed in a manner that allows for assessment of the benefits and the risks of the drug in the condition under study.  A better assessment of the benefits that a drug may provide and balancing these benefits with risks should provide better quality information on antibacterial drugs to foster appropriate use and ideally reduce inappropriate use that is also contributing to the development of resistance.  To that end, FDA has been revising its guidance to industry on the development of drugs for the treatment of bacterial infections.  In October of 2007, FDA published a draft guidance document on appropriate trial design for antimicrobial drugs.  FDA has also recently published draft guidance documents on developing drugs for acute bacterial sinusitis (October 2007) and acute bacterial otitis media (January 2008). 

In January of this year, FDA co-sponsored a workshop with the Infectious Diseases Society of America on the topic of clinical trial designs for community acquired pneumonia (CAP).  The workshop provided a platform for the discussion of issues in trial designs for CAP.  The Agency also convened an advisory committee meeting in April 2008 to get additional advice and the Agency is now actively engaged in writing a draft guidance document that will provide the Agency’s thinking on informative trial designs in CAP.

CDC has been conducting field studies at several international laboratories to evaluate the feasibility and cost effectiveness of liquid TB medium culture and drug susceptibility testing systems.  Similarly, the sensitivity and specificity of a novel PCR-based technology are being evaluated against the geographically diverse archive of TB isolates and will soon be evaluated in field studies.  Research on drug susceptibility testing is also part of a comprehensive, systems approach to accelerating the diagnosis and treatment of MDR-TB in an ambulatory care environment.  Importantly, a novel, low-cost, rapid test method (a direct, nitrate reductase colorimetric method) is being used to screen acid-fast bacillus smear-positive specimens for MDR-TB.  Recent results demonstrated a decrease in laboratory turn around time from 3 months to 1 month.  CDC has been collaborating with international partners in the development and commercialization of a diagnostic test kit based on this same nitrate reductase colorimetric method as well as a PCR-based BioChip technology for rapid detection of MDR-TB.

Action Plan To Combat Antimicrobial Resistance Update

Recently, the Task Force held a consultants meeting to obtain input and recommendations for revising and updating “A Public Health Action Plan to Combat Antimicrobial Resistance.” In addition to over fifty consultants from the United States, nine international consultants from Canada, Denmark, France, Germany, The Netherlands, and United Kingdom participated in the meeting.  The consultants included experts from human and veterinary medicine, the pharmaceutical and diagnostics industries, animal husbandry industry, clinical microbiology, epidemiology, infectious disease and infection control specialists, and state and local public health departments.  Representatives of most of the federal agencies also participated. The open meeting was also attended by members of the public including representatives of a variety of professional societies, advocacy groups, and concerned citizens. The discussions focused on four topic areas:  surveillance; prevention and control; research; and product development.  The consultants focused on issues that they felt were critical to address over the next 3-5 years.  Based on comments from the consultants and the federal agencies,  the revised Action Plan has been reformatted around five focus areas: 1.)  reducing inappropriate antimicrobial use, 2.)  reducing the spread of antimicrobial resistant microorganisms in institutions, communities, and agriculture, 3.)  enhancing laboratory capacity to detect resistant microorganisms, 4.) encouraging the development of new anti-infective products, vaccines, and adjunct therapies, and 5.) supporting basic research on antimicrobial resistance.  The Task Force plans on submitting the revised Action Plan for public comment this Fall.