Antibiotics are drugs that are used to treat bacterial infections. Antibiotics work by killing or slowing the growth of bacteria and they are not effective against nonbacterial infections, such as those caused by viruses. Antibiotic resistance is the result of bacteria changing in ways that reduce or eliminate the effectiveness of antibiotics to cure infection. Antibiotic use forces bacteria to either adapt or die in a process known as “selective pressure.” Selective pressure means that when an antibiotic is used, some bacteria will be killed by the antibiotic while other bacteria will survive. Bacteria are able to survive, in part, because they have certain genetic material that allows them to avoid the effects of the antibiotic. The surviving bacteria will multiply and pass on to future generations their genetic material that is coded for resistance to antibiotics. Any use of antibiotics—appropriate and inappropriate—creates selective pressure among bacteria. (For more information on resistant bacteria, see app. II). The inappropriate use of antibiotics, or the additional use of antibiotics that could have been avoided, can occur when healthcare providers prescribe antibiotics when they are not beneficial, such as to treat a viral infection, or when antibiotic treatments are not targeted to the specific bacteria causing the infection. Inappropriate antibiotic use also occurs when healthcare providers do not prescribe the correct antibiotic dose and duration of treatment. Further, inappropriate use includes when patients do not complete a full course of prescribed antibiotics. Individual consumers, health care facilities, pharmacies, and pharmaceutical manufacturers dispose of unused antibiotics using various methods. For the purposes of this report, the disposal of antibiotics refers to the discard of unused antibiotics by consumers, companies, and others. Common disposal methods for individual consumers include throwing unused antibiotics in the trash, flushing them down the toilet, and pouring them down the drain. According to EPA officials, healthcare facilities and pharmacies often return unused or expired drugs to contracted companies, known as reverse distributors, for manufacturer credit. The reverse distributor is then instructed by the manufacturer to return the unused drug to the manufacturer, or in most cases, the reverse distributor is instructed to dispose of the drugs. The unused drugs are then most likely incinerated as solid waste, subject to state and local environmental regulations. The federal guidelines on how consumers should properly dispose of their unused drugs, including antibiotics, recommend that consumers dispose of their unused drugs either by returning them through a drug take-back program, where available, or by mixing them with coffee grounds or kitty litter and throwing them in the household trash. Unused antibiotics intended for human use may enter the environment through various pathways such as sewage systems and landfills, depending upon the method of disposal and other factors. Unused antibiotics enter sewage systems after they are flushed down the toilet or poured down the drain. Unused antibiotics that enter the sewage system then flow to wastewater treatment plants where, if not removed during the treatment process, they are released into the environment, such as in rivers and streams, as wastewater effluent. In addition, some areas may use onsite septic systems to treat wastewater and in these systems wastewater is discharged below the ground’s surface. Unused antibiotics that are disposed of in the trash could enter the environment if landfills were to leak. Although modern landfills are designed with liners and systems to limit this process by rerouting leachate, that is, liquid generated in landfills, to wastewater treatment plants, the antibiotics that are contained in the leachate may ultimately enter the environment. This can occur if antibiotics are not removed during the wastewater treatment process. In general, wastewater treatment plants are not designed to remove low concentrations of drug contaminants, such as antibiotics. In addition, antibiotics that have been used by humans to treat infections can also enter the environment. Most used antibiotics enter the sewage systems after they are ingested and excreted by individuals because antibiotics are not fully absorbed by the human body. Like unused antibiotics that enter the sewage systems, used antibiotics flow from sewage systems to wastewater treatment plants and may be released into the environment as wastewater effluent or biosolids. Agricultural manure is another potential source of antibiotics entering the environment; some antibiotics used for agriculture are similar to those used by humans. Within HHS, the Centers for Disease Control and Prevention (CDC), FDA, and the National Institutes of Health (NIH) have responsibilities for protecting Americans from health risk, including risk associated with antibiotic-resistant infections. These agencies have a variety of responsibilities related to the surveillance, prevention, and research of infectious disease. CDC has a primary responsibility to protect the public health through the prevention of disease and health promotion. One of CDC’s primary roles is to monitor health, and part of this role involves monitoring antibiotic-resistant infections and the use of antibiotics. CDC’s statutory authority to conduct such surveillance derives from the Public Health Service Act. Tracking the emergence of antibiotic resistance, and limiting its spread, is also part of CDC’s mission. Consistent with this mission, CDC implements prevention strategies, such as educational programs, that are designed to limit the development and spread of antibiotic resistance and the agency monitors antibiotic prescriptions in humans to help reduce the spread of antibiotic resistance. Part of FDA’s responsibility for protecting the public health involves assuring the safety and efficacy of human drugs. FDA reviews and approves labels for antibiotics and provides educational information to consumers and healthcare providers about the appropriate use of antibiotics, and the risk of the development of antibiotic resistance associated with their inappropriate use. FDA also licenses vaccines for use in humans to prevent bacterial infections—including certain antibiotic- resistant infections—as well as viral infections and has the authority for the review of diagnostics, including tests to detect bacterial infections. As the nation’s medical research agency, NIH is responsible for conducting and funding medical research to improve human health and save lives. According to its research agenda on antibiotic resistance, NIH supports and conducts research on many aspects of antibiotic resistance, including studies of how bacteria develop resistance, the development of diagnostic tests for bacterial infections that are or are likely to become resistant to antibiotics, as well as clinical trials such as those to study the effective duration for antibiotic treatments. CDC, FDA, and NIH are also co-chairs of the Interagency Task Force on Antimicrobial Resistance (Task Force) and released A Public Health Action Plan to Combat Antimicrobial Resistance (Action Plan) in 2001. The Action Plan identified actions needed to address the emerging threat of antibiotic resistance and highlighted the need to improve federal agencies’ ongoing monitoring of antibiotic use and of antibiotic-resistant infections. Specifically, the Action Plan stated that establishing a national surveillance plan for antibiotic-resistant infections should be a high priority, and that improved monitoring of such infections was needed to identify emerging trends and assess changing patterns of antibiotic resistance as well as to target and evaluate prevention and control efforts. The Action Plan also specifically stated that surveillance of antibiotic use in humans should be a high priority and was needed to better understand the relationship between antibiotic use and antibiotic resistance. For example, identifying a specific pattern of antibiotic use associated with increased antibiotic resistance could support a response from policymakers, such as to affect change in antibiotic use practices. Further, improved antibiotic use monitoring would help identify prevention activities and anticipate gaps in the availability of existing antibiotics effective in treating bacterial infections. A revised draft Action Plan was published for public comment on March 16, 2011. EPA’s mission includes protecting Americans from significant environmental health risks. As part of its role, EPA sets national standards for the disposal of solid and hazardous waste and the quality of drinking water. EPA generally regulates the disposal of waste, including some unused or expired drugs, under the Resource Conservation and Recovery Act (RCRA). EPA also promulgates national requirements for drinking water quality of public water systems under the Safe Drinking Water Act (SDWA). EPA conducts research on topics related to human health and the environment, including research aimed at understanding drug disposal practices and the potential human and ecological health risks of drugs, such as antibiotics, found in the environment. Within DOI, USGS is responsible for providing scientific information to better understand the health of the environment, including our water resources. USGS conducts large-scale studies to gather information that can provide a basis for evaluating the effectiveness of specific policies; these studies can also be used to support decision making at the local and national levels—for example, decisions related to protecting water quality. In 1998, USGS initiated the Emerging Contaminants Project to improve the scientific understanding of the release of emerging contaminants to the environment, including where these contaminants originate and whether they have adverse effects on the environment. As part of the project, USGS has conducted national studies to measure the presence of unregulated contaminants, including antibiotics, in the environment, and conducts targeted local studies to assess the impact of specific pathways by which antibiotics can enter the environment. CDC has six surveillance systems that provide information to monitor antibiotic resistance that occurs in healthcare and community settings. According to CDC, public health surveillance is the ongoing and systematic collection, analysis, and interpretation of data for use in the planning, implementation, and evaluation of public health practice. The surveillance systems collect information about antibiotic resistance among certain bacteria that cause infections in humans, and the infections are transmitted either in healthcare settings or in the community. For example, CDC’s National Healthcare Safety Network (NHSN) monitors infections that occur in healthcare settings, including those that are resistant to antibiotics, such as MRSA, while CDC’s Active Bacterial Core Surveillance (ABCs) system monitors bacterial infections such as meningitis and pneumonia that are spread in the community or in healthcare settings. Table 1 provides information about the purpose of each CDC surveillance system that monitors antibiotic resistance and summarizes the settings in which the monitored infections are spread. (See app. III for additional information about each of the six systems.) Federal agencies do not routinely quantify the amount of antibiotics that are produced in the United States for human use, but sales data, which can be used to estimate the quantity of antibiotic production, show that over 7 million pounds of antibiotics were sold in 2009 for human use in the United States. These data indicate that most of the antibiotics sold have common characteristics, such as belonging to five antibiotic classes. Federal agencies, including FDA and USITC, do not routinely quantify antibiotic production for human use. FDA does collect annual information on the quantity of drugs that manufacturers distribute from new drug application (NDA) and abbreviated new drug application (ANDA) holders, but the data are not readily accessible. For each approved drug, NDA and ANDA holders are required to report annually to FDA the total number of dosage units of each strength or potency of the drug that was distributed (e.g., 100,000 5 milligram tablets) for domestic and foreign use. This information must be submitted to FDA each year— within 60 days of the anniversary date of approval of the drug application—for as long as the NDA or ANDA is active. The data that NDA and ANDA holders submit to FDA on the quantity of distributed drugs are not readily accessible because, according to an FDA official, they are submitted as part of an annual report in the form of a table and the agency does not enter the data electronically. In addition, because the anniversary dates of approval vary by NDA and ANDA, the reporting periods are not comparable. For drugs with an active ingredient for which there are multiple NDA and ANDA applications, FDA officials stated that one would also need to aggregate the data across multiple applications in order to determine the total quantity of the particular active ingredient. An FDA official told us that the agency rarely uses these data for analyses of drug utilization, drug safety, and drug shortages because other sources of data provide FDA information that is more detailed and timely about the quantities of certain drugs that are available in the market. For example, FDA uses drug sales data, which are available on a monthly basis, to evaluate and address drug safety and drug shortage problems. USITC no longer collects and quantifies antibiotic production, but did so until 1994. In 2009, approximately 7.4 million pounds of antibiotics were sold for human use—which can be used as an estimate of the quantity of antibiotics produced for human use in the United States—and most sold share common characteristics, such as antibiotic classes. Most of the 7.4 million pounds, or about 89 percent, of antibiotics that were sold in 2009 fell into five antibiotic classes: penicillins, cephems, folate pathway inhibitors, quinolones, and macrolides (see table 2). The class of penicillins was the largest group of antibiotics sold in 2009. About 3.3 million pounds of penicillins were sold, which represents 45.2 percent of all antibiotics sold in 2009. Penicillins, such as amoxicillin, are used to treat bacterial infections that include pneumonia and urinary tract infections. Most of the antibiotics that were sold for human use in 2009 were for oral administration and for use in outpatient settings. As shown in table 3, about 6.5 million pounds, or 87.4 percent, of all antibiotics sold for human use in 2009 were intended for oral administration, for example, in the form of pills. Oral forms of antibiotics and injectable forms, such as intravenous injections, together accounted for 99 percent of the total pounds sold. About 5.8 million pounds, or 78.6 percent, of all antibiotics sold for human use in 2009 were purchased by chain store pharmacies, independent pharmacies, food store pharmacies, and clinics (see table 4). This suggests that most of the antibiotics that were purchased in 2009 were intended for use in outpatient settings. Although CDC annually collects certain national data on antibiotic prescriptions to monitor the use of antibiotics, these data have limitations and do not allow for important analyses. CDC is taking steps to improve its monitoring of antibiotic use by collecting and purchasing additional data, but gaps in information will remain. CDC’s Get Smart program promotes the appropriate use of antibiotics and the agency has observed recent national declines in inappropriate antibiotic prescribing; however, it is unclear to what extent its program contributed to the recent declines. NIH and FDA activities have complemented CDC’s efforts to promote the appropriate use of antibiotics. CDC conducts two national health care surveys that gather data, annually, on antibiotic prescribing in outpatient settings—the National Ambulatory Medical Care Survey (NAMCS) and the National Hospital Ambulatory Medical Care Survey (NHAMCS). NAMCS is based on a sample of visits to office-based physicians and community health centers. NHAMCS is based on a sample of visits to emergency and outpatient departments and hospital-based ambulatory surgery locations. Both surveys obtain data from healthcare provider records on patient symptoms, provider diagnoses, and the names of specific drugs, including antibiotics, that were prescribed during the patient visits. CDC officials stated that, among their purposes, CDC uses NAMCS and NHAMCS to monitor antibiotic use in outpatient settings for patient conditions that do not usually require antibiotics for treatment, such as antibiotic prescribing rates for upper respiratory infections, such as the common cold. NAMCS and NHAMCS are limited because they do not capture information about the use of antibiotics in inpatient settings. In inpatient settings, such as hospitals, antibiotics are often used, multiple antibiotics may be used in the same patient, and use may be prolonged. Monitoring overall antibiotic use (i.e., in inpatient and outpatient settings) over time is important for understanding patterns in antibiotic resistance. Information about overall antibiotic use in humans is also needed to routinely assess the contribution that human antibiotic use makes to the overall problem of antibiotic resistance in humans, relative to other contributing factors. For example, monitoring what portion of antibiotic use is attributed to humans versus animals is important to understanding antibiotic resistance. CDC officials told us that more complete information about antibiotic use by humans and animals is needed to help interpret trends from surveillance data and to inform on possible strategies to control the spread of antibiotic resistance, such as through changing antibiotic use practices. NAMCS and NHAMCS data are further limited because they do not allow the agency to assess geographic patterns in antibiotic prescribing practices in outpatient settings. CDC officials told us that the survey samples were designed to obtain national, not state-level estimates. As a result, CDC cannot currently assess the potential effects of geographic variation at the state level in antibiotic prescribing rates on patterns of antibiotic resistance or identify states or other geographic areas in the United States, for instance, which have higher than average antibiotic prescribing for conditions that do not usually require antibiotics for treatment. Information about geographic variation in antibiotic prescribing would allow CDC to anticipate future patterns in antibiotic resistance, given that the use of antibiotics has a direct effect on antibiotic resistance. Such information, according to CDC officials, would also allow CDC to target prevention efforts, such as those aimed at reducing inappropriate antibiotic use. CDC is taking steps to improve its monitoring of antibiotic use, but gaps in information about the use of antibiotics will remain. To address the agency’s lack of data on inpatient antibiotic use, CDC is planning to gather information on antibiotic use with a prevalence survey of U.S. acute care hospitals in 2011. The survey will be conducted during a single time period on a single day and will collect some patient information about the reasons for the antibiotic use, which include treating an active infection or using antibiotics to prevent infection associated with a medical or surgical procedure. According to CDC officials, these data will fill in the gap in its data by providing information about the prevalence of inpatient antibiotic use. CDC officials further stated that having data on the baseline amount of inpatient antibiotic use, and the reasons for that use, will allow the agency to target and evaluate its own prevention efforts. However, the survey findings will not be representative of hospitals nationwide, because the survey sample is limited to selected hospitals located within five entire states and urban areas in five other states. Furthermore, CDC officials do not know if the survey will be repeated. Without periodic data collection and monitoring, CDC cannot assess trends in inpatient antibiotic use or evaluate the effects that changes in antibiotic use may have on antibiotic resistance. Additionally, in 2011, CDC officials told us that the agency plans to reinstate a module of NHSN that will allow participating facilities to report their inpatient antibiotic use, which will provide CDC with some inpatient antibiotic use data, but these data will not be nationally representative. In 2009, CDC temporarily discontinued this module because, according to CDC officials, it was not sustainable due to the high burden on facilities to report such data. CDC has redesigned the module to reduce the reporting burden on facilities; for example, CDC officials told us that, instead of relying on manual entry, facilities will be able to electronically capture and automatically send their data to NHSN. While the module will allow facilities in NHSN to monitor their own antibiotic use, the data will not provide the agency with information about the prevalence of inpatient antibiotic use because NHSN is not based on a nationally representative sample of facilities. To improve CDC’s monitoring of antibiotic use in outpatient settings, CDC officials told us that they are finalizing a contract with a private data vendor to obtain 5 years of national data on antibiotic prescribing in outpatient settings by antibiotic drug, county, and type of provider. According to CDC officials, these data will help the agency understand relationships between antibiotic use and antibiotic resistance in certain geographic areas. CDC officials further stated that these data would help guide the agency’s prevention efforts. With preliminary data on outpatient prescriptions for the antibiotic subclass of fluoroquinolones, CDC has shown wide variation in prescribing across states. Further, CDC plans to increase the size of the NAMCS sample at least fourfold in 2012, which would allow CDC to produce antibiotic prescribing rates for some states that year. CDC’s Get Smart: Know When Antibiotics Work (Get Smart) program promotes appropriate antibiotic use, which is aimed specifically at healthcare providers, patients, and parents of young children. CDC launched its Get Smart program in 1995 with the overall goal of reducing the increasing rate of antibiotic resistance. The program is primarily focused on upper respiratory infections because, according to CDC, such infections account for over half of all antibiotics prescribed by office- based physicians. The Get Smart program works with partners, such as certain health insurance companies, to develop and distribute educational materials. With the goal of educating healthcare providers and the public, the Get Smart educational materials are aimed directly at these populations. For example, the Get Smart program supported the development of an online training program for healthcare providers to improve their knowledge and diagnosing of middle ear disease. The Get Smart program developed and launched a national media campaign in 2003, in partnership with FDA, to provide a coordinated message on appropriate antibiotic use to the public and this message has been disseminated through print, television, radio, and other media. For example, CDC developed a podcast for parents of young children, available on CDC’s Web site, to communicate its message. In the podcast, a pharmacist counsels a frustrated mother about appropriate antibiotic use and symptomatic relief options for her son’s cold. Some materials are aimed at healthcare providers with the goal of educating their patients; for example, the Get Smart program developed a prescription pad for symptoms of viral infections. Healthcare providers can use the communication tool to acknowledge patient discomfort and recommend strategies to their patients for the relief of symptoms associated with viral illnesses—without prescribing an antibiotic unnecessarily. The prescription sheet includes the Get Smart logo and provides information for patients about the appropriate use of antibiotics to treat bacterial infections. CDC has continued to update and expand its materials for the Get Smart program. For example, CDC officials stated that the agency has expanded its educational materials by partnering with Wake Forest University to develop a curriculum for medical students related to appropriate antibiotic prescribing, and the impact of antibiotic use and its inappropriate use on antibiotic resistance, and the agency has developed a continuing education course for pharmacists. CDC officials told us that pharmacists serve as one of the most important health care professionals in promoting appropriate antibiotic use, for example by educating patients about the importance of taking antibiotics exactly as directed. In November 2010, CDC launched another Get Smart program, called Get Smart for Healthcare. This program focuses on improving antibiotic use in inpatient healthcare settings—including hospitals and nursing homes—through antimicrobial stewardship. CDC has observed declines in inappropriate antibiotic prescribing in outpatient settings since its Get Smart program began in 1995, but it is unclear to what extent this program contributed to these trends. For example, using NAMCS and NHAMCS data, CDC found about a 26 percent decline in the number of courses of antibiotics prescribed per 100 children younger than 5 years old for ear infections between 1996-1997 and 2006. Further, CDC reported about a 53 percent decrease in the antibiotic prescription rate for the common cold among all persons between 1996- 1997 and 2006. A similar trend in antibiotic prescribing among children has also been observed with data from the National Committee for Quality Assurance (NCQA). NCQA monitors trends in antibiotic prescribing for the purpose of comparing the performance of healthcare plans. NCQA monitors the percentage of children 3 months to 18 years of age who were diagnosed with an upper respiratory infection and did not receive an antibiotic prescription within 3 days of the office visit, and this measure has shown improvement (i.e., percentage increases in appropriate treatment) between 2003 and 2008. The measures that CDC uses to evaluate the effectiveness of the Get Smart program do not necessarily reflect the effect of the program because they do not capture information about individuals who were exposed to the Get Smart program, compared to those who were not. As a result, it is unclear if the declines in the inappropriate antibiotic prescribing were due to exposure to Get Smart messages and educational materials or from other factors, such as efforts to measure healthcare performance with antibiotic prescribing indicators (e.g., NCQA measures) or the recommended use of influenza vaccines among young children, since 2004. CDC officials told us that they believe the NCQA measures have helped to improve appropriate antibiotic prescribing by improving knowledge of treatment guidelines by physicians and practitioners. In addition, reducing the number of cases of influenza among children is likely to have contributed to declines in inappropriate antibiotic prescriptions because antibiotics are often prescribed in patients with influenza symptoms. The measures that CDC uses to evaluate the effectiveness of the Get Smart program also do not allow CDC to determine, for example, whether declines in inappropriate antibiotic prescribing are attributable to a decrease in demand for antibiotics by patients, or to improved adherence to appropriate prescribing guidelines by healthcare providers. The measures are further limited because they do not allow CDC to determine whether the observed declines are consistent across the United States or are due to decreases in certain geographic areas. CDC officials told us that they rely on other indicators to demonstrate the effectiveness of the Get Smart Program, such as interest in CDC’s Get Smart Web site and media materials. According to these officials, studies examining the impact of educational materials, including Get Smart materials, further demonstrate the effectiveness of the Get Smart program. For example, CDC officials cited a study in Massachusetts where educational materials, including Get Smart materials, were distributed to physicians and their patients in several communities. Findings indicate that in communities where educational and promotional materials about appropriate antibiotic use—including Get Smart materials—were distributed, antibiotic prescribing rates for children declined. Declines were also observed in communities where these educational and promotional materials were not distributed. These findings indicate that factors other than educational and promotional materials focused on the appropriate use of antibiotics may also have led to declines in inappropriate antibiotic prescribing. Without information about which are the most effective ways to reduce inappropriate antibiotic prescribing in outpatient and inpatient settings, CDC cannot target its resources on these preventive approaches. NIH and FDA have complemented CDC’s efforts to promote the appropriate use of antibiotics in humans through various activities. NIH supports research specifically aimed at decreasing the inappropriate use of antibiotics as part of its research agenda to target antibiotic resistance. NIH-funded studies focus on establishing appropriate antibiotic treatment courses, using off-patent antibiotics to treat infections, and developing rapid diagnostic tests to help healthcare providers choose an appropriate antibiotic for treatment. For example, in 2009, NIH began funding a clinical trial to determine whether the standard 2-week antibiotic treatment course for children with urinary tract infections can remain effective if shortened, thereby decreasing the likelihood of antibiotic resistance and preserving the effectiveness of existing antibiotics. In 2007, NIH awarded two 5-year contracts to study whether off-patent antibiotics such as clindamycin and a combination of the drugs trimethoprim and sulfamethoxazole can be used to treat certain skin infections instead of the more recently developed antibiotics, such as Linezolid and Vancomycin, in order to preserve the newer drugs’ effectiveness. Further, since 2002, NIH has supported the development of a new test to rapidly diagnose TB. It currently takes up to 3 months to accurately diagnose TB and to determine its resistance to antibiotics, according to NIH officials. Findings from a recent clinical trial study reported that, within 2 hours, the new test can diagnose a TB infection and determine if it is resistant to the antibiotic rifampin, which is commonly used to treat TB. NIH officials stated that the test is being recommended by the World Health Organization for the early diagnosis of TB and NIH is currently supporting research to improve the test and expand its capabilities. Research on the development of vaccines for bacterial and viral infections is also part of NIH’s research agenda to decrease the inappropriate use of antibiotics, according to an NIH official. An NIH official stated that the agency has funded the discovery and development of several staphylococcal vaccine candidates, for example, through investigator- initiated grants. In addition, an NIH official told us that NIH conducted preclinical animal studies that provided data for the development of a multivalent staphylococcal vaccine candidate, which allowed the candidate to advance to clinical testing. NIH also supports the development of vaccines for viral infections. According to an NIH official, decreasing the occurrence of influenza infections with influenza vaccines may decrease the inappropriate use of antibiotics. Many healthcare providers inappropriately treat viral respiratory infections with antibiotics, so preventing influenza reduces the opportunities for unnecessary antibiotic treatment. FDA activities also complement CDC’s efforts to promote the appropriate use of antibiotics in humans. According to an FDA official, the agency collaborated with CDC on certain Get Smart activities, such as developing an appropriate antibiotic use message for the national media campaign, and amended its drug labeling regulations in 2003 to require that all oral or intravenous antibiotics for human use include additional information on their appropriate use. FDA’s labeling requirement is intended to encourage physicians to prescribe antibiotics only when clinically necessary and to encourage them to counsel their patients about the proper use of such drugs and the importance of taking them exactly as directed. For example, the amended regulation requires that antibiotic labeling include the statement that “prescribing in the absence of a proven or strongly suspected bacterial infection is unlikely to benefit the patient and increases the risk of the development of drug- resistant bacteria.” CDC’s monitoring of antibiotic-resistant infections has limitations in assessing the overall problem of antibiotic resistance. The agency’s monitoring of antibiotic-resistant infections in healthcare facilities has data gaps that limit CDC’s ability to produce accurate national estimates of such infections. For some of these infections monitored by CDC in community settings, in comparison, CDC can provide accurate national estimates. CDC is taking steps to improve its monitoring of antibiotic- resistant infections in healthcare settings, but these efforts will not improve CDC’s ability to assess the overall problem of antibiotic resistance. A sample of healthcare facilities that is not representative—and incomplete information about the entire scope of healthcare-associated infections (HAIs) that are resistant to antibiotics—present data gaps that limit CDC’s ability to produce accurate national estimates of antibiotic resistant HAIs in healthcare settings. Some infections are acquired as a result of medical treatment in a healthcare setting, such as a hospital or outpatient unit, while others are transmitted in the community, such as respiratory infections that are spread in schools and the workplace. According to CDC officials, healthcare settings contribute to the development of antibiotic resistance because of their high volume of susceptible patients, large number of disease-causing bacteria, and high antibiotic usage. CDC uses NHSN to monitor HAIs, including antibiotic- resistant HAIs, at a national level, but the facilities that participate are not a nationally representative sample. Facility enrollment and participation in NHSN is either voluntary, required because of a state mandate, or obligated as a condition of participation in HHS’ Centers for Medicare & Medicaid Services (CMS) Hospital Inpatient Quality Reporting program. According to CDC officials, as of January 2011, 23 states and territories required, or had plans to require, healthcare facilities to use NHSN for their reporting mandate. As of January 1, 2011, all acute care hospitals participating in the CMS Hospital Inpatient Quality Reporting Program are obligated to report into NHSN central-line associated bloodstream infections for certain procedures from their intensive care units. Although the number of participating facilities has increased substantially, because healthcare facilities enroll voluntarily or by mandate, this group of facilities is not representative of facilities nationwide, as a random sample would be. Participating healthcare facilities in states with mandated participation are more likely to be overrepresented in the sample, while facilities in states without mandates are more likely to be underrepresented. The data that participating healthcare facilities supply to NHSN do not reflect the full scope of HAIs that occur within these facilities, further limiting CDC’s ability to provide accurate national estimates about antibiotic-resistant HAIs. Participating facilities may submit data about different types of HAIs, and this includes information about whether the HAIs are resistant to antibiotics. For example, some facilities report data to NHSN on central-line associated bloodstream infections but not other infection types, such as catheter-associated urinary tract infections. Further, participating healthcare facilities may report HAI data to NHSN for certain units within facilities. For example, participating facilities may report data to NHSN on infections that occur in intensive care units but not those that occur in specialty care areas. CDC depends on the microbiology data provided by participating facilities to determine, among reported cases, the number and percentage of certain types of HAIs with resistance to certain antibiotics. Without an accurate national estimate of antibiotic-resistant HAIs, CDC cannot assess the magnitude and types of such infections that occur in all patient populations (i.e., facilitywide) within healthcare settings. CDC’s monitoring of antibiotic-resistant infections in community settings can provide accurate national estimates of antibiotic-resistant infections that are caused by 5 of the 12 bacteria that the agency monitors. These 5 are captured by two surveillance systems, the National Antimicrobial Resistance Monitoring System for Enteric Bacteria (NARMS: EB) and the National Tuberculosis Surveillance System (NTSS), which collect nationally representative data about certain antibiotic-resistant infections; these infections can occur in community settings. Both systems employ sampling strategies that can provide accurate national estimates by collecting representative case information from all 50 states. For NARMS: EB, health departments in all 50 states submit a representative sample of four of the five bacteria it monitors—non- typhoidal Salmonella, typhoidal Salmonella, Shigella, and Escherichia coli O157 cases to NARMS: EB for antibiotic susceptibility testing. To ensure adequate sample size and a random sample for testing, the health departments systematically select and submit to NARMS: EB every 20th non-typhoidal Salmonella, Shigella, and Escherichia coli O157 case as well as every typhoidal Salmonella case received at their laboratories. NARMS: EB cannot produce an accurate national estimate for one of the five bacteria it monitors—Campylobacter—because according to CDC officials, the system collects a sample of the bacteria in 10 states. CDC uses NTSS to collect information about each newly reported case of tuberculosis infection in the United States, including information on drug susceptibility results for the majority of cases that test positive for tuberculosis. CDC’s monitoring of other bacteria that cause antibiotic-resistant infections in community settings cannot provide estimates that are nationally representative because they are derived from samples that do not accurately represent the entire United States. Through ABCs, CDC conducts antibiotic resistance surveillance of five infection-causing bacteria—group A and B Streptococcus, Neisseria meningitidis, Streptococcus pneumoniae, and MRSA. According to CDC officials, these bacteria cause bloodstream infections, sepsis, meningitis, and pneumonia. ABCs is a collaboration between CDC, state health departments, and universities in 10 states. CDC officials told us that for each identified case of infection within their surveillance populations, the ABCs sites conduct a chart review to collect a variety of information, such as underlying disease and risk factors, vaccination history, and demographic information. This information is entered into a case report form and submitted to CDC along with bacterial isolates for additional testing, including tests for antibiotic resistance. ABCs’ monitoring of cases of resistant infections is limited to surveillance areas in 10 states, and the surveillance areas vary somewhat depending on the infection-causing bacterium that is monitored. For example, Neisseria meningitidis is monitored in 6 entire states and in primarily urban areas in 4 other states while MRSA is monitored in 1 entire state and primarily urban areas in 8 other states. According to CDC’s Web site, the population included in the ABCs surveillance areas is roughly representative of the U.S. population on the basis of certain demographic characteristics (e.g., race and age) and urban residence. However, ABCs cannot provide estimates that are nationally representative for rural residence, and some experts have raised concerns because of the underrepresentation of rural areas. Further, since surveillance is critical to providing early warning of emerging resistance problems, limited geographic coverage among monitored infection-causing bacteria impedes CDC’s ability to detect emerging problems. The Gonococcal Isolate Surveillance Project (GISP), which CDC uses to monitor antibiotic resistance in Neisseria gonorrhoeae, the bacterium that causes gonorrhea, cannot provide accurate national estimates of cases of antibiotic-resistant gonorrhea because it collects information only on selected patient populations. Each month, GISP collects case samples from the first 25 men diagnosed with urethral gonorrhea in each participating sexually transmitted disease clinic. The clinics are located in 24 states and they send these samples to designated laboratories for antibiotic susceptibility testing. However, according to CDC officials, most cases of gonorrhea in the United States are not treated in sexually transmitted disease clinics, and are more likely treated in a variety of healthcare settings, such as primary care physicians’ offices. Further, since GISP collects information on cases of gonorrhea from male patients only, the data cannot represent the total U.S. population in order to provide an accurate national estimate of resistant gonorrhea cases. CDC is taking steps to improve its monitoring of antibiotic-resistant infections in healthcare facilities, but CDC’s ability to assess the overall problem of antibiotic resistance will not be improved. With a prevalence survey, CDC is planning to collect additional data in 2011 about HAIs, which may provide more comprehensive information about certain types of HAIs that are resistant to antibiotics. According to CDC officials, the survey of U.S. acute care hospitals—which will also provide data on antibiotic use, as described previously—will allow the agency to more accurately assess the burden of HAIs and antibiotic resistance among those HAIs in healthcare settings. Unlike NHSN, the survey is designed to allow CDC to assess the magnitude and types of HAIs occurring in all patient populations within the sample of acute care hospitals. The survey will collect information about types of infection (e.g., urinary tract infection, bloodstream infection), bacteria causing HAIs, and test results regarding antibiotic resistance. The survey will not collect resistance information for all bacteria that cause HAIs. However, according to CDC officials, the survey will collect resistance information for some of the most common bacteria that cause HAIs, including Acinetobacter, Enterococcus faecalis, Enterococcus faecium, Escherichia coli, Klebsiella, Pseudomonas aeruginosa, and Staphylococcus aureus. While the survey may provide more comprehensive information about certain types of HAIs that are resistant to antibiotics because it is designed to cover all patient populations in the sampled hospitals, the survey will not be able to provide information about the prevalence of all antibiotic-resistant HAIs that occur in U.S. acute care hospitals. A further limitation is that the sample is not representative of U.S. acute care hospitals. As described earlier, this is because the survey is based on a sample of acute care hospitals located within the EIP surveillance areas, according to CDC officials. CDC also plans to enhance its monitoring of HAIs by expanding the geographic coverage of its surveillance of Clostridium difficile infections and CDC officials told us that the agency is piloting additional surveillance for gram-negative infections through the EIP network. According to CDC, the agency began monitoring Clostridium difficile infections through EIP in 2009 in 7 surveillance areas, to obtain more comprehensive and representative information about this infection, including for antibiotic resistance. CDC officials stated that the agency plans to expand its Clostridium difficile monitoring to 10 surveillance areas by summer 2011. In 2 of the 10 surveillance areas (i.e., Oregon and Minnesota), surveillance will occur in rural areas only. CDC officials stated that the data will allow the agency, among other things, to detect Clostridium difficile infections that occur prior to admission to a healthcare facility and to identify new populations at risk. CDC officials also told us that the agency is piloting surveillance for gram-negative infections that are resistant to multiple antibiotics, through the EIP network, as an exploratory effort and feasibility study on how to improve the agency’s monitoring of these infections in healthcare settings. In addition, CDC anticipates that the number of acute care hospitals participating in NHSN will expand in 2011 stemming from the CMS Hospital Inpatient Quality Reporting Program obligation to do so. The expanded participation will, CDC officials believe, result in more representative data about certain HAIs and antibiotic-resistant infections. CMS has expanded its quality data measures to include two HAI measures that will be reported through NHSN. As stated previously, as of January 1, 2011, hospitals are obligated to report on central-line bloodstream infections associated with certain procedures from their intensive care units and on January 1, 2012, hospitals will be obligated to report on surgical site infections. Hospitals will also need to report on antibiotic resistance associated with these two types of infections, given NHSN’s reporting requirements for participation. As part of CDC’s protocols, facilities submit microbiological data for each HAI identified, which includes the type of bacteria causing the infection and test results regarding antibiotic resistance. Federal agencies do not collect data regarding the disposal of most antibiotics intended for human use, but EPA and USGS have measured the presence of certain antibiotics in the environment due, in part, to their disposal. Studies conducted by scientists have found that antibiotics that are present in the environment at certain concentration levels can increase the population of resistant bacteria due to selective pressure. EPA does not monitor the disposal of most antibiotics intended for human use, but EPA and USGS have measured the presence of antibiotics in the environment, including water, soil, and sediment. According to EPA, antibiotics enter the environment through various pathways into water, soil, and sediment, such as wastewater discharged from treatment plants. The disposal of hazardous waste, such as chemicals that are harmful to human health when ingested, is regulated by EPA. Under RCRA, EPA has established a system by which hazardous waste is regulated from the time it is produced until it is disposed. Under this system, EPA receives information from hazardous waste generators through the Biennial Reporting System. EPA officials told us that antibiotics in general do not fall under RCRA’s definition of hazardous waste; as a result, EPA does not generally receive information about the disposal of antibiotics. EPA officials further stated that the agency would receive limited information about antibiotics if they fell under RCRA’s definition of hazardous waste. However, in part because it is the responsibility of the person disposing of a waste to determine whether or not it is hazardous, agency officials could not identify any specific antibiotics that fall under EPA’s regulatory definition of hazardous waste and therefore concluded that it would be a rare occurrence for the agency to receive information on the disposal of antibiotics. Under SDWA, EPA is authorized to regulate contaminants in public drinking water systems. EPA generally requires public water systems to monitor certain contaminants for which there are national primary drinking water regulations—standards limiting the concentration of a contaminant or requiring certain treatment. EPA has not promulgated any drinking water regulation for an antibiotic. EPA is required to identify and publish a list every 5 years of unregulated contaminants that may require regulation, known as the Contaminant Candidate List (CCL). EPA generally uses this list to select contaminants for its periodic regulatory determinations, by which the agency decides whether to regulate a contaminant, but contaminants may remain on the CCL for many years before EPA makes such a decision. Erythromycin is the only antibiotic on the third CCL list (CCL 3)—the current CCL that was published in October 2009. According to EPA officials, the agency is in the process of evaluating CCL 3 contaminants, including erythromycin, and plans to determine whether or not regulation is required for at least five contaminants from the CCL 3 by 2013. EPA’s determination to promulgate a national primary drinking water regulation for a contaminant is made based on three criteria established under SDWA, including that the contaminant may have an adverse effect on human health. To provide information such as that needed to determine whether to regulate the contaminant, EPA has the authority to require a subset of public water systems to monitor a limited number of unregulated contaminants, which the agency has implemented through the Unregulated Contaminant Monitoring Rule (UCMR). On March 3, 2011, EPA proposed the list of contaminants (primarily from the CCL 3) to be monitored under the third UCMR (UCMR 3). Erythromycin was not included on the proposed UCMR 3 list of contaminants, because according to EPA officials, further development of an analytical method that can be used for national monitoring of erythromycin is needed. EPA officials stated that the agency is in the initial stages of development of an analytical method for a number of pharmaceuticals, including erythromycin, and will evaluate the readiness of this analytical method for future UCMR efforts. EPA officials further stated that the agency will continue to evaluate unregulated contaminants, such as erythromycin, for future CCLs and will utilize any new data that become available. EPA and USGS have conducted several studies to measure the presence of antibiotics in the environment, which results partly from their disposal. According to EPA and USGS officials, there is no specific statutory mandate requiring the agencies to collect information about the presence of antibiotics in the environment. However, from 1999 through 2007, the agencies conducted five national studies measuring the presence and concentration of certain antibiotics in streams, groundwater, untreated drinking water, sewage sludge, and wastewater effluent as part of their efforts to study emerging contaminants. (See table 5.) These studies were generally designed to determine whether certain contaminants, including antibiotics, were entering the environment and as a result, some study sites were selected based on being susceptible to contamination. For example, the study examining the presence of antibiotics, and other contaminants, in streams in 30 states was designed to determine whether these contaminants were entering the environment. Therefore, USGS purposely selected study sites susceptible to contamination by humans, industry, and agricultural wastewater. In all five studies antibiotics were found to be present. For example, erythromycin was detected in multiple samples tested in four studies and ciprofloxacin was detected in three studies. According to EPA and USGS officials, the antibiotic concentrations detected in streams, groundwater, and untreated drinking water are low relative to the maximum recommended therapeutic doses approved by FDA for most antibiotics. In contrast, antibiotics were found in relatively higher concentrations in sewage sludge. For example, the maximum concentration level of ciprofloxacin that was detected in streams or untreated drinking water sources was .03 micrograms per liter of water. In comparison, ciprofloxacin was detected in sewage sludge sampled from large publicly owned treatment plants at concentrations ranging from 74.5 to 47,000 micrograms per kilogram of sewage sludge. The maximum recommended therapeutic dose for ciprofloxacin is about 13,000 micrograms per kilogram of weight. According to USGS officials, waste from humans and domestic animals that receive antibiotics (i.e., therapeutic or subtherapeutic doses) are likely to contain antibiotics as a substantial portion of such antibiotic treatments are not fully absorbed through the body. EPA and USGS also have two ongoing studies that measure the presence of antibiotics in wastewater and drinking water. First, EPA is assessing the concentration of pharmaceuticals and other contaminants in municipal wastewater because past studies have suggested that municipal wastewater is a likely source of human pharmaceuticals entering the environment. According to EPA officials, EPA is collecting samples from 50 of the largest municipal wastewater plants in the United States and testing their treated effluents for contaminants, including 12 antibiotics. The study’s findings are expected to be made available sometime in 2012 and may help EPA develop new standards for municipal wastewater treatment, according to EPA officials. Second, EPA and USGS are collaborating on a study to measure the presence of several antibiotics (e.g., erythromycin) and other contaminants in raw and finished drinking water to better determine human exposures to these contaminants through drinking water. During 2011, researchers will take samples from between 20 and 25 drinking water treatment plants across the United States and according to EPA officials, the information will be used to inform EPA decision making about the focus of future monitoring efforts. EPA and USGS officials anticipate the study’s findings to be made available sometime in 2012. Scientific evidence gathered in our literature review shows that, at certain concentration levels, antibiotics present in the environment—in water and soil—can increase the population of resistant bacteria, due to selective pressure. Of the 15 studies we identified that examined this association, 5 examined water-related environments and 10 examined soil-related environments. Among these 15 studies, 11 provided evidence to support the association. Support for this association means that antibiotics present in these environments increased the population of resistant bacteria through selective pressure because bacteria containing resistance genes survived and multiplied. Results for the five studies examining water-related environments generally support an association between the presence of antibiotics and an increase in the population of resistant bacteria caused by selective pressure, although only one tested concentration levels of antibiotics as low as those that have been detected in national studies of U.S. streams, groundwater, and source drinking water. The results of this study were inconclusive as to whether low antibiotic concentration levels, such as levels measured at or below 1.7 micrograms per liter of water, led to an increase in the population of resistant bacteria. Among the four other studies that supported an association between the presence of antibiotics and an increase in the population of resistant bacteria, the lowest concentration level associated with an increase was 20 micrograms of oxytetracycline per liter of water—over 50 times higher than maximum antibiotic concentration levels detected in stream water across the United States. Another of these four studies found that chlortetracycline was associated with an increase in the population of resistant bacteria, but only at concentration levels over 1000 times higher than those that have been detected in streams across the United States. According to USGS officials, scientists generally agree that the population of resistant bacteria would increase in water if the concentration levels of antibiotics that are present were to reach the minimum level that is known to induce antibiotic resistance in a clinical setting. USGS officials further stated that higher concentrations of antibiotics have been found, for example, in waters near to pharmaceutical manufacturing facilities in countries outside of the United States. Results for the 10 studies examining antibiotic resistance in soil-related environments, such as soil and sediment, were more mixed, and we cannot draw comparisons between concentration levels tested in these studies and those that have been found in such environments across the United States. Seven of the 10 studies found evidence to support an association between the presence of antibiotics and an increase in the population of resistant bacteria due to selective pressure, and the association existed at all concentration levels studied. No association existed among the antibiotic concentration levels in the other 3 studies. Because national data about the presence and concentration levels of antibiotics in soil and sediment are not available, we cannot draw comparisons between concentration levels tested in these studies and those commonly found in such environments across the United States. As with water-related environments, USGS officials stated that scientists generally agree that the population of resistant bacteria would increase in soil if the concentration levels of antibiotics that are present were to reach the minimum level that is known to induce antibiotic resistance in clinical settings. USGS officials further stated that antibiotic concentration levels in soils where human and animal waste have been applied as fertilizer are likely to be directly related to the antibiotic concentration levels in these sources. Antibiotics have been widely prescribed to treat bacterial infections in humans and their use contributes to the development of antibiotic resistance, which is an increasing public health problem in the United States and worldwide. Monitoring the use of antibiotics in humans and preventing their inappropriate use, such as prescribing an antibiotic to treat a viral infection, is critically important because the use of antibiotics for any reason contributes to the development and spread of antibiotic resistance. Establishing patterns of antibiotic use is necessary for understanding current—and predicting future—patterns of antibiotic resistance. Monitoring overall antibiotic use in humans, including in inpatient and outpatient healthcare settings, is also needed to evaluate the contribution of such use—relative to other causes, such as animal use—to the overall problem of antibiotic resistance. Such information could help policymakers set priorities for actions to control the spread of antibiotic resistance. CDC is collecting data on antibiotic use and the occurrence of resistance, but the agency’s data sources have limited ability to provide accurate national estimates and do not allow it to assess associations between use and resistance. CDC does not monitor the use of antibiotics in inpatient settings—where antibiotic use is often intensive and prolonged and thus, the risk of antibiotic resistance is greater—although the agency believes such information would help it target and evaluate its own prevention efforts to reduce the occurrence of resistance. Although the agency collects annual data in the United States about the use of antibiotics in outpatient settings, the data do not allow CDC to assess geographic patterns of use in those settings. Similarly, CDC’s monitoring of antibiotic- resistant infections does not allow the agency to assess the overall problem of antibiotic resistance because of gaps in the data it collects. Without more comprehensive information about the occurrence of cases of antibiotic-resistant infections and the use of antibiotics, the agency’s ability to understand the overall scope of the public health problem, detect emerging trends, and plan and implement prevention activities is impeded. Further, the lack of comprehensive information about antibiotic-resistant infections and antibiotic use, and the most effective ways to reduce inappropriate prescribing, impedes CDC’s ability to strategically target its resources directed at reducing the occurrence of antibiotic-resistant infections. CDC is attempting to address the gaps in its data on antibiotic use in humans and on antibiotic-resistant infections by obtaining additional data, but it is not clear whether the steps it is taking will result in more comprehensive information from which the agency could assess the public health impact of antibiotic resistance. Further, it is not clear whether these steps will provide CDC with the information it needs to identify what actions are needed to reduce the occurrence of antibiotic-resistant infections. To better prevent and control the spread of antibiotic resistance, we recommend that the Director of CDC take the following two actions: Develop and implement a strategy to improve CDC’s monitoring of antibiotic use in humans, for example, by identifying available sources of antibiotic use information; and develop and implement a strategy to improve CDC’s monitoring of antibiotic-resistant infections in inpatient healthcare facilities to more accurately estimate the national occurrence of such infections. We provided a draft of this report for review to HHS, EPA, and DOI. HHS provided written comments, which are reproduced in appendix V. HHS, EPA, and DOI provided technical comments, which we incorporated as appropriate. In its written comments, HHS generally agreed with the actions we recommend it take to improve its monitoring of antibiotic use and resistance. HHS says that steps are being taken to address existing gaps in CDC’s monitoring of antibiotic use and the occurrence of antibiotic- resistant infections, and HHS noted that such monitoring is critically important in preventing the development and spread of antibiotic resistance. HHS highlighted examples of the steps CDC is taking, or plans to undertake, to address gaps in CDC’s monitoring of antibiotic use and antibiotic-resistant infections, such as a planned survey of acute care hospitals in the United States. HHS noted that other planned activities to improve the monitoring of antibiotic use and antibiotic-resistant infections are described in the revised draft Action Plan, developed by the Interagency Task Force on Antimicrobial Resistance. HHS stated that CDC believes that the successful, timely accomplishment of its planned and ongoing activities to improve monitoring will result in information that is sufficiently comprehensive for a full and complete assessment of the public health impact of antibiotic resistance, and that this assessment will provide federal agencies with appropriate information to identify necessary actions to reduce the occurrence of antibiotic-resistant infections. HHS stated that it would provide updates on its progress toward the accomplishment of its steps to improve monitoring in the 2010 annual progress report on the Action Plan, scheduled for public release this summer. HHS also commented that it has initiated the process of developing a strategic plan for preventing the emergence and spread of antibiotic-resistant infections, and a primary component of this strategic plan is the monitoring of antibiotic use and resistance. We support this effort and encourage HHS, as it develops its strategic plan, to continue to examine approaches for improving its monitoring of antibiotic use and antibiotic-resistant infections that will help provide the agency with information that is needed to more accurately estimate the national occurrence of antibiotic-resistant infections. As agreed with your offices, unless you publicly announce the contents of this report earlier, we plan no further distribution until 30 days from the report date. At that time, we will send copies to the Secretaries of the Department of Health and Human Services and the Department of the Interior, the Administrator of the Environmental Protection Agency, and other interested parties. In addition, the report will be available at no charge on the GAO Web site at http://www.gao.gov. If you or your staff have any questions about this report, please contact me at (202) 512-7114 or crossem@gao.gov. Contact points for our Offices of Congressional Relations and Public Affairs may be found on the last page of this report. GAO staff who made major contributions to this report are listed in appendix VI. To describe the scientific evidence on the development of antibiotic- resistant bacteria in the environment, we conducted a literature review. We identified literature made available since 2007 that reported scientific findings on antibiotic concentrations that induce bacteria located in the environment to become resistant as well as the ability of bacteria to spread resistance. We conducted a key word search of 39 databases, such as Elsevier Biobase and MEDLINE that included peer-reviewed journals and other periodicals to capture articles published on or between January 1, 2007, and July 8, 2010. We searched these databases for articles with key words in their title or abstract related to both antibiotic resistance and the environment, such as combinations and variations of the words “resistance,” “antibiotic,” and “environment,” and descriptive words for different environmental settings, such as “water,” “sediment,” “soil,” and “sewage.” From these sources, we identified 241 articles, publications, and reports (which we call articles) published from January 1, 2007, through July 8, 2010. Of these 241 articles, we then excluded articles that (1) were not published in English, (2) were available only in an abstract form or in books or book chapters, (3) were not peer- reviewed, (4) contained only a review of past literature, or (5) were unrelated to antibiotic resistance found in the environment such as articles that focused on the effects of antibiotic resistance found mainly in clinical settings. In total, we included 105 articles in our literature review. We supplemented the scientific findings analyzed in our literature review with contextual and background information gathered from articles that were identified as a result of our interviews with officials from the Environmental Protection Agency and the United States Geological Survey. Bacteria are single-celled organisms that live in water, soil, and in the bodies of humans, animals, and plants. Bacteria compete with each other for resources, such as nutrients, oxygen, and space, and those that do not compete successfully will not survive. Most bacteria that are present in humans, such as those found on the skin and in the intestines, are harmless because of the protective effects of the human immune system, and a few bacteria are beneficial. However, some bacteria are capable of causing disease. For example, Escherichia coli O157—which can be found in the feces of animals, such as cattle, and can transfer to people through contaminated undercooked meat—produce a toxin that causes severe stomach and bowel disorders, and death in some cases. In addition, the same bacteria that may cause disease in one individual may not cause disease in another. For example, Streptococcus pneumoniae is a bacterium that is often found in the noses and throats of healthy persons without causing disease, but it can also cause mild illness, such as sinus infections, as well as life-threatening infections such as meningitis. Furthermore, when the immune system is weakened, infection may be caused by certain bacteria that would not generally result in an infection in a healthy human. Like other living things, as bacteria grow and multiply, they also evolve and adapt to changes in their surroundings. Bacteria adapt to their surroundings through selective pressure, which is created by, among other things, the presence of antibiotics. Selective pressure means that when an antibiotic is introduced into a bacterial environment, some bacteria will be killed by the antibiotic while other bacteria will survive. Bacteria are able to survive because they have certain genetic material that is coded for resistance—allowing them to avoid the effects of the antibiotic. The surviving bacteria that are resistant to antibiotics will multiply and quickly become the dominant bacterial type. Bacteria that are susceptible to the effects of antibiotics may become resistant to such antibiotics after acquiring resistant genetic material from bacteria that are resistant through horizontal gene transfer. Horizontal gene transfer is the movement of genetic material between bacteria, and can occur within a species of bacteria and can sometimes occur between certain species of bacteria. Close proximity between bacteria, which allows certain genetic material to be shared, can facilitate gene transfer. The movement of antibiotic-resistant bacteria around the world is accelerated because of international travel and global trade. Individuals can contract bacterial strains—that is, distinct types of bacteria—that are resistant to antibiotics abroad during travel, whether as active infections or as unaffected carriers, and then spread such strains to others at home. The bacterial strains in different parts of the world may also contain different resistance genes than bacterial strains found domestically. For example, in 2010, the Centers for Disease Control and Prevention reported that three bacterial strains included a resistance gene identified for the first time in the United States. The emergence of the resistance gene was traced to patients who had received recent medical care in India. Further, international trade of food and livestock may accelerate the movement of antibiotic-resistant bacteria because food and livestock also carry resistant bacterial strains that can be contracted by humans through consumption. To determine whether bacteria are resistant, tests are performed that measure the susceptibility of pathogenic bacteria to particular antibiotics. The test results can predict the success or failure of an antibiotic treatment, and thus, guide healthcare providers’ choice of antibiotics to treat bacterial infections. The test results include a numeric value, which is then interpreted according to established ranges. For example, a value may be categorized as ‘resistant,’ meaning that the pathogenic bacterium is not inhibited by the concentration of the antibiotic that usually results in growth inhibition. Examples of how surveillance data were used group A and group B Streptococcus; Neisseria meningitidis; Streptococcus pneumoniae; methicillin- resistant Staphylococcus aureus (MRSA) ABCs data were used to show that rates of invasive pneumococcal infections, including antibiotic-resistant infections among children and adults, have declined since a pneumococcal conjugate vaccine was introduced for children in 2000. ABCs data have also shown a decline in the incidence of pneumococcal meningitis resistant to antibiotics. ABCs data on MRSA, collected between 2005 and 2008, were used to identify the genetic makeup of MRSA strains showing unusual patterns of resistance. This information provided the Centers for Disease Control and Prevention (CDC) with evidence that mechanisms of resistance in MRSA were being transferred from healthcare-associated to community-associated strains. Based on GISP data, CDC announced in 2007 that fluoroquinolones were no longer recommended to treat gonorrhea because of antibiotic resistance and that the recommended treatment for gonorrhea was limited to only cephalosporin antibiotics. Neisseria gonorrhoeae isolates collected through GISP have been used to support research on the mechanisms used to resist the effects of antibiotics, according to a CDC official. NARMS: EB data were used in 2005 to support the Food and Drug Administration’s (FDA) withdrawal of approval for the use of enrofloxacin in chickens and turkeys. Enrofloxacin, a fluoroquinolone, marketed under the trade name Baytril, had been approved for use in poultry production. In September 2005, FDA withdrew its approval because of concerns about the spread of fluoroquinolone-resistant Campylobacter from poultry to humans. NARMS: EB data from 1996-2006 were used to identify mechanisms of resistance to cephalosporins among specific types of Salmonella. Participating facilities have used NHSN data to assess their own healthcare-associated infection (HAI) rates, by comparing their rates with national rates. CDC also compiled 2006-2007 data on antibiotic resistance across participating facilities and reported, for example, that as many as 16 percent of all HAIs observed in NHSN were associated with nine multidrug-resistant bacteria, such as MRSA. CDC has determined that NNDSS data are likely to be used to assess the impact of a vaccine that was approved in 2010 to prevent additional strains of Streptococcus pneumoniae. CDC receives information on each newly reported case of tuberculosis (TB) in the United States. In 2010, after expanding the NTSS data collection with the TB Genotyping Information Management System, CDC officials used genotypes identified with the system to assist an investigation of a TB outbreak among healthcare workers. As a result of the investigation, the probable source for the TB outbreak was identified. Since 2009, CDC has monitored Clostridium difficile infections in healthcare and community settings through EIP (as part of its Healthcare Associated Infections Surveillance). CDC officials stated that these data complement the Clostridium difficile data that are captured through the National Healthcare Safety Network and will, among other things, inform vaccine development. Topical antiseptics are products that are used to reduce the risk of infection by killing or inhibiting the growth of microorganisms, such as bacteria, on the skin. Topical antiseptic products are diverse, and include those targeted for healthcare settings, such as surgical hand scrubs and patient preoperative skin preparations; products targeted to consumers for general body cleansing include antibacterial soaps; and products specifically intended for use by food handlers. Topical antiseptics contain a variety of active ingredients; for example, triclosan and triclocarban are commonly used in antibacterial liquid and bar soaps, while alcohol is used in leave-on handwashes. Because antiseptics are intended for use in or on humans or animals, they are considered drugs and are approved and regulated as nonprescription drugs by the Food and Drug Administration (FDA) under the Federal Food, Drug, and Cosmetic Act. There are concerns by public officials, and others, about the possibility that the use of, or exposure to, topical antiseptics causes antibiotic resistance in bacteria. This process is called cross-resistance. FDA has conducted a review of the scientific literature regarding the relationship between exposure to active ingredients in topical antiseptics—including triclosan or triclocarban—and cross-resistance. According to the available scientific evidence that FDA has reviewed, bacteria are able to develop resistance to both antiseptics and antibiotics in the laboratory setting, but the relationship outside of the laboratory setting is not clear. For example, a laboratory study has shown that when certain strains of the bacteria Escherichia coli (E. coli) are exposed to triclosan, the E. coli not only acquire a high level of resistance to triclosan, but also demonstrate cross-resistance to various antibiotics, such as erythromycin and tetracycline. However, a study that examined household use of certain antiseptic products did not show an association between their use and the development of antibiotic resistance. According to FDA, the possibility that bacteria can develop cross- resistance to antibiotics from exposure to antiseptics warrants further evaluation. FDA will seek additional data regarding the safety of topical antiseptic products, for example, on the effects of antiseptics on cross- resistance, when it issues a proposed rule to amend the current monograph for antiseptic drug products. FDA officials told us that they expect the proposed rule to be published for public comment sometime in 2011. The Environmental Protection Agency (EPA) and the United States Geological Survey (USGS) conducted five national studies between 1999 and 2007 that measured for the presence of the antiseptic active ingredients triclosan and triclocarban in the environment. These studies tested for the presence and concentration of the antiseptic active ingredients along with other contaminants including antibiotics, in streams, groundwater, untreated drinking water, sewage sludge, and wastewater effluent. (See table 6.) Each of the studies measured for the presence of triclosan, and the study involving sewage sludge also tested for triclocarban. Triclosan was found to be present in 94 percent of sewage sludge samples, 100 percent of wastewater effluent samples, and 57.6 percent of stream samples tested from sites across the United States. It was also detected in 14.9 percent of groundwater samples and 8.1 percent of untreated drinking water samples. Triclocarban was found to be present in all sewage sludge samples taken from wastewater treatment plants located across the United States. In addition to the contact named above, Robert Copeland, Assistant Director; Elizabeth Beardsley; Pamela Dooley; Cathy Hamann; Toni Harrison; Elise Pressma; and Hemi Tewarson made key contributions to this report.

Summary: Infections that were once treatable have become more difficult to treat because of antibiotic resistance. Resistance occurs naturally but is accelerated by inappropriate antibiotic use in people, among other things. Questions have been raised about whether agencies such as the Department of Health and Human Services (HHS) have adequately assessed the effects of antibiotic use and disposal on resistance in humans. GAO was asked to (1) describe federal efforts to quantify the amount of antibiotics produced, (2) evaluate HHS's monitoring of antibiotic use and efforts to promote appropriate use, (3) examine HHS's monitoring of antibiotic-resistant infections, and (4) describe federal efforts to monitor antibiotic disposal and antibiotics in the environment, and describe research on antibiotics in the development of resistance in the environment. GAO reviewed documents and interviewed officials, conducted a literature review, and analyzed antibiotic sales data. Federal agencies do not routinely quantify the amount of antibiotics that are produced in the United States for human use. However, sales data can be used as an estimate of production, and these show that over 7 million pounds of antibiotics were sold for human use in 2009. Most of the antibiotics that were sold have common characteristics, such as belonging to the same five antibiotic classes. The class of penicillins was the largest group of antibiotics sold for human use in 2009, representing about 45 percent of antibiotics sold. HHS performs limited monitoring of antibiotic use in humans and has implemented efforts to promote their appropriate use, but gaps in data on use will remain despite efforts to improve monitoring. Although HHS's Centers for Disease Control and Prevention (CDC) monitors use in outpatient healthcare settings, there are gaps in data on inpatient antibiotic use and geographic patterns of use. CDC is taking steps to improve its monitoring, but gaps such as information about overall antibiotic use will remain. Because use contributes to resistance, more complete information could help policymakers determine what portion of antibiotic resistance is attributed to human antibiotic use, and set priorities for action to control the spread of resistance. CDC's Get Smart program promotes appropriate antibiotic use; CDC has observed declines in inappropriate prescribing, but it is unclear to what extent the declines were due to the program or to other factors. CDC's program has been complemented by efforts by the National Institutes of Health and the Food and Drug Administration, such as supporting studies to develop tests to quickly diagnose bacterial infections. Gaps in CDC's monitoring of antibiotic-resistant infections limit the agency's ability to assess the overall problem of antibiotic resistance. There are data gaps in monitoring of such infections that occur in healthcare facilities; CDC does not collect data on all types of resistant infections to make facilitywide estimates and the agency's information is not nationally representative. CDC can provide accurate national estimates for certain resistant infections that develop in the community, including tuberculosis. Although CDC is taking steps to improve its monitoring, these efforts will not allow CDC to accurately assess the overall problem of antibiotic resistance because they do not fill gaps in information. Without more comprehensive data, CDC's ability to assess the overall scope of the public health problem and plan and implement preventive activities will be impeded. Federal agencies do not monitor the disposal of most antibiotics intended for human use, but they have detected them, as well as antibiotics for animal use, in the environment, which results partly from their disposal. EPA and DOI's United States Geological Survey have examined the presence of certain antibiotics in environmental settings such as streams. Studies conducted by scientists have found that antibiotics present in the environment at certain concentrations can increase the population of resistant bacteria. To better control the spread of resistance, GAO recommends that CDC develop and implement strategies to improve its monitoring of (1) antibiotic use and (2) antibiotic-resistant infections. HHS generally agreed with our recommendations. HHS, the Environmental Protection Agency (EPA) and the Department of the Interior (DOI) provided technical comments, which we incorporated as appropriate.