Antibiotic Resistance
Data Gaps Will Remain Despite HHS Taking Steps to Improve Monitoring Gao ID: GAO-11-406 June 1, 2011Infections 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.
RecommendationsOur recommendations from this work are listed below with a Contact for more information. Status will change from "In process" to "Open," "Closed - implemented," or "Closed - not implemented" based on our follow up work.
Director: Marcia G. Crosse Team: Government Accountability Office: Health Care Phone: (202) 512-3407GAO-11-406, Antibiotic Resistance: Data Gaps Will Remain Despite HHS Taking Steps to Improve Monitoring
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United States Government Accountability Office:
GAO:
Report to the Committee on Agriculture, House of Representatives:
June 2011:
Antibiotic Resistance:
Data Gaps Will Remain Despite HHS Taking Steps to Improve Monitoring:
GAO-11-406:
GAO Highlights:
Highlights of GAO-11-406, a report to the Committee on Agriculture,
House of Representatives.
Why GAO Did This Study:
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.
What GAO Found:
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 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.
What GAO Recommends:
To better control the spread of resistance, GAO recommends that HHS‘s
Centers for Disease Control and Prevention (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.
View [hyperlink, http://www.gao.gov/products/GAO-11-406] or key
components. For more information, contact Marcia Crosse at (202) 512-
7114 or crossem@gao.gov.
[End of section]
Contents:
Letter:
Background:
Federal Agencies Do Not Routinely Quantify Amount of Antibiotics
Produced for Human Use, but Sales Data Show Over 7 Million Pounds of
Antibiotics Were Sold in 2009:
Data Gaps Remain Despite CDC's Efforts to Expand Its Limited
Monitoring of Antibiotic Use; CDC, NIH, and FDA Have Implemented
Efforts to Promote Appropriate Use:
CDC's Monitoring of Antibiotic-Resistant Infections Has Limitations in
Assessing the Overall Problem of Antibiotic Resistance:
Federal Agencies Do Not Monitor Antibiotic Disposal, but Have Examined
the Presence of Antibiotics in the Environment, and Studies Find that
Such Antibiotics Can Increase the Population of Resistant Bacteria:
Conclusions:
Recommendations:
Agency Comments:
Appendix I: Methodology for Reviewing Scientific Evidence on
Antibiotic Resistance in the Environment:
Appendix II: Bacteria and the Development of Antibiotic Resistance:
Appendix III: Centers for Disease Control and Prevention's
Surveillance Systems for Monitoring Antibiotic Resistance:
Appendix IV: Topical Antiseptics and Antibiotic Resistance:
Appendix V: Comments from the Department of Health and Human Services:
Appendix VI: GAO Contact and Staff Acknowledgments:
Tables:
Table 1: CDC's Six Surveillance Systems that Provide Information to
Monitor Antibiotic Resistance, by System Purpose and Infection
Transmission Setting:
Table 2: Amount of Antibiotics Sold in 2009 and Additional
Information, by Antibiotic Class:
Table 3: Amount of Antibiotics Sold in 2009, by Route of
Administration:
Table 4: Amount of Antibiotics Sold in 2009, by Type of Purchaser:
Table 5: Five National Studies that Measured the Presence of
Antibiotics in the Environment, Conducted by EPA and USGS:
Table 6: CDC's Surveillance Systems for Monitoring Antibiotic
Resistance, by Bacteria, Geographic Coverage, and Examples of Data Use:
Table 7: Five National Studies that Measured the Presence of
Antiseptic Active Ingredients in the Environment, Conducted by EPA and
USGS:
Abbreviations:
ABCs: Active Bacterial Core Surveillance:
ANDA: Abbreviated New Drug Application:
CCL: Contaminant Candidate List:
CDC: Centers for Disease Control and Prevention:
CMS: Centers for Medicare & Medicaid Services:
DOI: Department of the Interior:
EIP: Emerging Infections Programs:
EPA: Environmental Protection Agency:
FDA: Food and Drug Administration:
GISP: Gonococcal Isolate Surveillance Project:
HAI: healthcare-associated infection:
HHS: Department of Health and Human Services:
MDRO: multidrug-resistant organism:
MIC: minimum inhibitory concentration:
MRSA: Methicillin-resistant Staphylococcus aureus:
NAMCS: National Ambulatory Medical Care Survey:
NARMS: EB: National Antimicrobial Resistance Monitoring System:
Enteric Bacteria:
NCQA: National Committee for Quality Assurance:
NDA: New Drug Application:
NHAMCS: National Hospital Ambulatory Medical Care Survey:
NHSN: National Healthcare Safety Network:
NIH: National Institutes of Health:
NNDSS: National Notifiable Diseases Surveillance System:
NTSS: National Tuberculosis Surveillance System:
PhRMA: Pharmaceutical Research and Manufacturers of America:
RCRA: Resource Conservation and Recovery Act:
SDWA: Safe Drinking Water Act:
TB: tuberculosis:
UCMR: Unregulated Contaminant Monitoring Rule:
USGS: United States Geological Survey:
USITC: United States International Trade Commission:
[End of section]
United States Government Accountability Office:
Washington, DC 20548:
June 1, 2011:
The Honorable Frank D. Lucas:
Chairman:
The Honorable Collin Peterson:
Ranking Member:
Committee on Agriculture:
House of Representatives:
Over 60 years ago penicillin was the first antibiotic introduced to
treat bacterial infections, leading to a dramatic drop in deaths from
bacterial infections that were previously untreatable, as well as
significant gains in life expectancy. The eventual emergence and
spread of bacterial infections that are resistant to antibiotics,
however, has jeopardized these gains because infections that were once
easy to cure with antibiotics are becoming difficult, if not
impossible, to treat. Some bacterial infections, such as certain types
of pneumonia and gonorrhea that are acquired in the community, have
developed resistance to almost all currently available antibiotics.
Furthermore, the bacterial infections that contribute most to human
disease are also those in which antibiotic resistance is most common,
such as respiratory tract infections and infections acquired in
hospitals. Although not all infections acquired in hospitals are
resistant to antibiotics, individuals with resistant infections are
more likely to have a poor prognosis and to remain in the hospital for
a longer time, resulting in greater medical costs.[Footnote 1]
While the development of antibiotic resistance is not new, as
resistance is a natural biological phenomenon and can occur when any
antibiotic is present, it is accelerated by a variety of factors
including the inappropriate use of antibiotics in the absence of a
bacterial infection and the prolonged use of antibiotics to treat
patients who are critically ill. Antibiotic-resistant bacteria that
are present in the human body can be spread to others. In addition,
antibiotic-resistant bacteria that occur in the environment, either
from natural causes or their discharge into soil or bodies of water,
may spread their resistance to other bacteria.
Scientists, public health officials, and clinicians agree that
antibiotic resistance has become a national and global health
challenge. While there are various causes of antibiotic resistance--
including the use of antibiotics in humans and animals--the actual
scope of the overall problem is not clear and there is uncertainty
about the relative contributions of each cause.[Footnote 2]
Recommendations for government action to address antibiotic resistance
have been made by various organizations and scientific experts,
including a task force made up of federal agencies, and there is
agreement that, among other things, improved surveillance of
antibiotic use and antibiotic-resistant infections is needed to
adequately understand antibiotic resistance and implement effective
strategies to help control this complex problem.[Footnote 3] Further,
a congressional committee[Footnote 4] and others have made
recommendations to increase the geographic coverage of existing
federal agency surveillance to address concerns such as gaps in the
ability to track and monitor certain antibiotic-resistant infections,
such as methicillin-resistant Staphylococcus aureus (MRSA).
Questions have been raised as to whether federal agencies, including
the Department of Health and Human Services (HHS), have adequately
assessed the relationship among the volume of antibiotics produced for
human use, the human use of antibiotics, the presence of antibiotics
in the environment, and the problem of antibiotic resistance. The
House Committee on Agriculture asked us to evaluate how federal
agencies track the occurrence of antibiotic resistance and the use and
disposal of antibiotics into the environment. In this report, we (1)
describe efforts by federal agencies to quantify the amount of
antibiotics produced for human use, (2) describe and evaluate HHS
efforts to monitor antibiotic use and promote the appropriate use of
antibiotics by humans, (3) examine HHS efforts to monitor cases of
antibiotic-resistant infections in humans in the United States, and
(4) describe federal efforts to monitor the disposal of antibiotics
intended for human use, federal efforts to monitor the presence of
antibiotics in the environment, and the scientific evidence regarding
the role of antibiotics in the development of antibiotic-resistant
bacteria in the environment.
To describe efforts to quantify the amount of antibiotics produced for
human use by federal agencies, we interviewed HHS officials to
determine whether HHS collects information about, and quantifies, the
amount of antibiotics that are produced for human use. We also
reviewed documents from HHS and the U.S. International Trade
Commission (USITC)--a federal agency that collects and analyzes trade
data to inform U.S. trade policy--to learn about federal efforts to
quantify antibiotic production in the United States. We purchased 2009
national sales data for antibiotics from IMS Health to estimate the
volume of antibiotics produced in the United States for human use.
[Footnote 5] IMS Health provided us the total volume of antibiotics,
in kilograms, that were sold, based on all antibiotic drugs that were
included in the Red Book Advanced database, as of April 2010.[Footnote
6] We converted the total volume from kilograms to pounds. To further
describe the antibiotics that were sold in 2009, we classified the
total volume of antibiotics by antibiotic class, the route of
administration (e.g., oral), and the types of pharmacies that
purchased antibiotics (e.g., chain store pharmacy). To assess the
reliability of IMS Health data, we reviewed existing information about
the data and interviewed officials knowledgeable about the data to
assess their completeness.[Footnote 7] We determined that the data
were sufficiently reliable for their use in this report.
To describe HHS efforts to monitor the use of antibiotics in humans,
we reviewed HHS documents and interviewed HHS officials. We reviewed
HHS documents describing the various surveys that HHS uses to
routinely collect data about antibiotic use, including information
about the survey samples, the types of data that are gathered, and how
antibiotic use is measured. We also reviewed agency documents that
summarize trends in antibiotic use, based on the surveys. We
interviewed HHS officials with responsibility for the surveys about
the strengths and limitations of each survey and how the agency uses
the collected data to monitor antibiotic use. To evaluate HHS's
efforts to monitor antibiotic use, we compared HHS's data collection
and monitoring activities with broad guidelines for monitoring
antibiotic use, which we identified by reviewing relevant HHS
documents and expert organization (e.g., World Health Organization)
guidelines. To describe HHS efforts to promote the appropriate use of
antibiotics, we reviewed documents from HHS about programs and
activities focused specifically on decreasing inappropriate antibiotic
use. We also interviewed officials from HHS about the objectives and
implementation of these programs and activities. To evaluate HHS's
efforts to promote the appropriate use of antibiotics, we reviewed
relevant HHS documents and research articles in peer-reviewed journals
about the effectiveness of intervention programs to reduce
inappropriate antibiotic use and we interviewed HHS officials about
the strengths and limitations of its program to promote appropriate
antibiotic use and how the agency has evaluated its program.
To examine HHS efforts to monitor cases of antibiotic-resistant
infections in humans, we reviewed agency documents from HHS and
interviewed HHS officials and representatives from an HHS advisory
committee on healthcare infection control. We reviewed HHS documents
describing each of the agency's surveillance systems that are used to
monitor antibiotic resistance. The documents described the purpose and
objectives of each system, and what surveillance data are collected
and how the data are collected; the documents also provided annual
summary information about monitored infections. We interviewed HHS
officials with responsibility for each of the surveillance systems
about the strengths and limitations of each system and how the data
gathered by each system are used by the agency. We also interviewed
four members of a federal advisory committee that provides guidance to
HHS regarding infection control, surveillance, and prevention, as well
as officials from three organizations that serve as liaisons to the
committee, to obtain their opinions of the strengths and limitations
of HHS's surveillance systems.[Footnote 8]
To describe federal efforts to monitor the disposal of antibiotics
intended for human use, we interviewed officials from the
Environmental Protection Agency (EPA), HHS, and the Department of the
Interior's (DOI) United States Geological Survey (USGS) to determine
if these agencies collect data about the disposal of antibiotics and,
if applicable, how they use such data for monitoring. We also reviewed
relevant federal laws under which EPA may have responsibility to
regulate disposal of certain antibiotics and to monitor certain
antibiotics in drinking water, as well as a Food and Drug
Administration (FDA) consumer guidance document describing recommended
disposal practices for unused drugs. We interviewed officials from the
Pharmaceutical Research and Manufacturers of America (PhRMA) to learn
about the drug disposal practices that are commonly used by
pharmaceutical manufacturers.[Footnote 9] To describe federal efforts
to monitor the presence of antibiotics found in the environment, we
reviewed documents describing relevant studies conducted by EPA and
USGS, including methods for selecting study sample sites and the study
findings. We focused on the extent to which antibiotics were present
in environmental settings, including soil, sediment, and bodies of
water, and in certain pathways to the environment, such as waste water
in treatment plants. We interviewed EPA and USGS officials to obtain
background information and context about the studies as well as EPA's
use of the study findings. We also interviewed EPA and USGS officials
about their plans for further related studies.
To describe the scientific evidence regarding the role of antibiotics
in the development of antibiotic-resistant bacteria in the
environment, we conducted a literature review and interviewed agency
officials. Our literature review included 105 articles that met
defined search criteria on antibiotic resistance in the environment,
published on or between January 1, 2007, and July 8, 2010. The
articles included those published in peer-reviewed journals. In our
review, we analyzed the scientific findings reported about antibiotic
concentrations that induce environmental bacteria to become resistant
and the ability of environmental bacteria to spread resistance through
the transfer of resistance genes. We also interviewed EPA and USGS
agency officials to obtain context for the scientific evidence
presented in the articles. For a detailed description of our
literature review, see appendix I.
We conducted our performance audit from March 2010 to June 2011 in
accordance with generally accepted government auditing standards.
Those standards require that we plan and perform the audit to obtain
sufficient, appropriate evidence to provide a reasonable basis for our
findings and conclusions based on our audit objectives. We believe
that the evidence obtained provides a reasonable basis for our
findings and conclusions based on our audit objectives.
Background:
Antibiotics and the Development and Spread of Antibiotic-resistant
Bacteria:
Antibiotics are drugs that are used to treat bacterial infections.
[Footnote 10] 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 appendix 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.[Footnote 11]
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.
Antibiotic Disposal and Pathways for Antibiotics to Enter the
Environment:
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.[Footnote 12]
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.[Footnote 13]
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.
[Footnote 14] In addition, some areas may use onsite septic systems to
treat wastewater and in these systems wastewater is discharged below
the ground's surface.[Footnote 15] 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.[Footnote 16],[Footnote 17]
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.[Footnote
18] 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.[Footnote 19]
Federal Agency Responsibilities:
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.[Footnote 20] 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)[Footnote 21] and released A
Public Health Action Plan to Combat Antimicrobial Resistance (Action
Plan) in 2001.[Footnote 22] 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.[Footnote 23]
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).[Footnote 24] 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's Monitoring of Antibiotic Resistance in Healthcare and Community
Settings:
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.[Footnote 25] 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.[Footnote 26] 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 appendix III for additional information
about each of the six systems.)
Table 1: CDC's Six Surveillance Systems that Provide Information to
Monitor Antibiotic Resistance, by System Purpose and Infection
Transmission Setting:
Surveillance system: National Healthcare Safety Network (NHSN);
Purpose of surveillance system and role in monitoring antibiotic
resistance: To provide a database for healthcare facilities to report
their healthcare-associated infection (HAI) and antibiotic resistance
surveillance data to allow them to estimate the occurrence of such
events, monitor trends, and identify patient safety problems.[A] CDC
compiles data on antibiotic resistance across participating facilities;
Infection transmission setting: Spread in healthcare settings, such as
from healthcare personnel to patient or from patient to patient.
Surveillance system: Active Bacterial Core Surveillance (ABCs) [of the
Emerging Infections Programs (EIP) Network][B];
Purpose of surveillance system and role in monitoring antibiotic
resistance: To monitor trends in disease and deaths caused by invasive
bacterial infections of public health importance, such as meningitis
caused by Neisseria meningitidis. ABCs is also used to monitor trends
in antibiotic resistance, track new resistance mechanisms, and
evaluate the effect of public health interventions;
Infection transmission setting: Spread in the community, from person
to person (e.g., by exchange of respiratory secretions), or in
healthcare settings, such as from healthcare personnel to patient or
from patient to patient.
Surveillance system: National Antimicrobial Resistance Monitoring
System: Enteric Bacteria (NARMS: EB);
Purpose of surveillance system and role in monitoring antibiotic
resistance: To monitor trends in antibiotic resistance among enteric
bacteria from humans and to conduct research to better understand the
emergence, persistence, and spread of antibiotic resistance.[C] NARMS:
EB is also used to provide data to assist FDA in making decisions
related to the approval of safe and effective antibiotic drugs for
animals and to promote interventions to reduce resistance;
Infection transmission setting: Spread in the community and in other
settings, such as through eating food contaminated with fecal matter
or eating undercooked poultry.
Surveillance system: Gonococcal Isolate Surveillance Project (GISP);
Purpose of surveillance system and role in monitoring antibiotic
resistance: To monitor trends in antibiotic resistance in Neisseria
gonorrhoeae--the bacterium that causes gonorrhea--in order to
establish a basis for selecting treatment guidelines for gonorrhea;
Infection transmission setting: Spread in the community, from person
to person, through sexual contact.
Surveillance system: National Tuberculosis Surveillance System (NTSS);
Purpose of surveillance system and role in monitoring antibiotic
resistance: To monitor national trends in tuberculosis (TB), including
groups at risk for TB, and to evaluate outcomes of TB cases. CDC also
uses NTSS to monitor antibiotic resistance in Mycobacterium
tuberculosis--the bacterium that causes tuberculosis;
Infection transmission setting: Spread in the community, from person
to person, by breathing infected air during close contact.
Surveillance system: National Notifiable Diseases Surveillance System
(NNDSS);
Purpose of surveillance system and role in monitoring antibiotic
resistance: To monitor certain infectious diseases, such as human
immunodeficiency virus infection and measles. CDC also uses NNDSS to
monitor antibiotic resistance in the bacteria Streptococcus
pneumoniae, with a focus on assessing the impact of immunization
against invasive Streptococcus pneumoniae infection. Streptococcus
pneumoniae causes infections such as pneumonia and meningitis;
Infection transmission setting: Spread in the community, from person
to person, such as by exchange of respiratory secretions.
Source: GAO analysis of CDC information and scientific literature.
[A] NHSN also allows facilities to report on 'laboratory-identified'
event surveillance data for certain HAIs that are resistant to
multiple drugs--such as multidrug-resistant Klebsiella infections--as
well as Clostridium difficile infections; such data are more easily
obtained because they come primarily from laboratory test results
without clinical evaluation of patients. Clostridium difficile
infections may develop due to the prolonged use of antibiotics during
healthcare treatment.
[B] As part of EIP's Healthcare Associated Infections Surveillance,
CDC has monitored Clostridium difficile infections in healthcare and
community settings since 2009.
[C] FDA coordinates the NARMS program and works with CDC to manage
NARMS: EB, the human component of the program. FDA and the United
States Department of Agriculture test for antibiotic-resistant enteric
bacteria in retail meats and food animals, respectively. Enteric
bacteria are found in the intestinal tracts of humans and animals.
[End of table]
Federal Agencies Do Not Routinely Quantify Amount of Antibiotics
Produced for Human Use, but Sales Data Show Over 7 Million Pounds of
Antibiotics Were Sold in 2009:
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 Do Not Routinely Quantify the Amount of Antibiotics
Produced for Human Use:
Federal agencies, including FDA and USITC, do not routinely quantify
antibiotic production for human use.[Footnote 27] 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.
[Footnote 28] 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.[Footnote
29] 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.[Footnote 30] USITC
no longer collects and quantifies antibiotic production, but did so
until 1994.[Footnote 31]
Over 7 Million Pounds of Antibiotics Were Sold in 2009 for Human Use
and Most Antibiotics Sold Share Common Characteristics:
Most of the 7.4 Million Pounds of Antibiotics Sold Fell into Five
Antibiotic Classes:
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.[Footnote 32] 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.
Table 2: Amount of Antibiotics Sold in 2009 and Additional
Information, by Antibiotic Class:
Antibiotic class: Penicillins;
Amount sold (in pounds): 3,336,890;
Amount sold (in kilograms): 1,516,768;
Percentage of total antibiotics sold: 45.2;
Examples of drugs within antibiotic class: Penicillin, Amoxicillin,
Oxacillin, Piperacillin;
Examples of bacterial infections treated by some drugs within
antibiotic class: Group A Streptococcal infections, some pneumonia
infections caused by Streptococcus pneumoniae, bacterial ear
infections, some urinary tract infections caused by Escherichia coli,
and some Staphylococcus aureus infections.
Antibiotic class: Cephems;
Amount sold (in pounds): 1,094,681;
Amount sold (in kilograms): 497,582;
Percentage of total antibiotics sold: 14.8;
Examples of drugs within antibiotic class: Cephalexin, Cefuroxime,
Cefotetan, Cefixime, Ceftriaxone;
Examples of bacterial infections treated by some drugs within
antibiotic class: Skin infections, respiratory tract infections, intra-
abdominal infections, gonorrhea, and bacterial meningitis.
Antibiotic class: Folate Pathway Inhibitors;
Amount sold (in pounds): 1,064,456;
Amount sold (in kilograms): 483,843;
Percentage of total antibiotics sold: 14.4;
Examples of drugs within antibiotic class: Sulfonamides, Trimethoprim-
Sulfamethoxazole;
Examples of bacterial infections treated by some drugs within
antibiotic class: Urinary tract infections and other types of
infections.
Antibiotic class: Quinolones;
Amount sold (in pounds): 664,894;
Amount sold (in kilograms): 302,225;
Percentage of total antibiotics sold: 9.0;
Examples of drugs within antibiotic class: Ciprofloxacin, Levofloxacin;
Examples of bacterial infections treated by some drugs within
antibiotic class: Urinary tract infections, respiratory tract
infections, and other infections.
Antibiotic class: Macrolides;
Amount sold (in pounds): 382,139;
Amount sold (in kilograms): 173,700;
Percentage of total antibiotics sold: 5.2;
Examples of drugs within antibiotic class: Erythromycin, Azithromycin;
Examples of bacterial infections treated by some drugs within
antibiotic class: Some respiratory tract infections.
Antibiotic class: Other;
Amount sold (in pounds): 844,467;
Amount sold (in kilograms): 383,849;
Percentage of total antibiotics sold: 11.4;
Examples of drugs within antibiotic class: Tetracyclines,
Oxazolidinones, Aminoglycosides, and other classes;
Examples of bacterial infections treated by some drugs within
antibiotic class: Skin infections and other infections.
Antibiotic class: Total;
Amount sold (in pounds): 7,387,527;
Amount sold (in kilograms): 3,357,967;
Percentage of total antibiotics sold: 100.0;
Examples of drugs within antibiotic class: [Empty];
Examples of bacterial infections treated by some drugs within
antibiotic class: [Empty].
Source: GAO analysis of IMS Health data and summary of CDC and NIH
information.
Notes: Classes are identified according to the Clinical and Laboratory
Standards Institute classification system. According to this
classification system, certain antibiotic classes can be further
classified into subclasses. For example, the cephem class includes the
subclass of cephalosporins. The total amount of antibiotics sold does
not take into account the dose, which varies by individual antibiotic,
or the total number of individuals who were prescribed or treated with
antibiotics.
[End of table]
The Majority of Antibiotics Sold for Human Use in 2009 Were for Oral
Administration and for Use in Outpatient Settings:
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.[Footnote 33] Oral forms of antibiotics
and injectable forms, such as intravenous injections, together
accounted for 99 percent of the total pounds sold.
Table 3: Amount of Antibiotics Sold in 2009, by Route of
Administration:
Route of administration: Oral;
Amount sold (in pounds): 6,454,670;
Amount sold (in kilograms): 2,933,941;
Percentage of total antibiotics sold: 87.4%.
Route of administration: Injection;
Amount sold (in pounds): 854,281;
Amount sold (in kilograms): 388,310;
Percentage of total antibiotics sold: 11.6%.
Route of administration: Other[A];
Amount sold (in pounds): 78,576;
Amount sold (in kilograms): 35,717;
Percentage of total antibiotics sold: 1.1%.
Route of administration: Total;
Amount sold (in pounds): 7,387,527;
Amount sold (in kilograms): 3,357,967;
Percentage of total antibiotics sold: 100.0%.
Source: GAO analysis of IMS Health data.
Note: Individual entries may not sum to totals because of rounding.
[A] Examples of other routes include administration by ear drops or
inhalation.
[End of table]
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.
Table 4: Amount of Antibiotics Sold in 2009, by Type of Purchaser:
Type of purchaser: Chain store pharmacies[A];
Amount sold (in pounds): 3,906,132;
Amount sold (in kilograms): 1,775,515;
Percentage of total antibiotics sold: 52.9%.
Type of purchaser: Independent pharmacies[B];
Amount sold (in pounds): 923,770;
Amount sold (in kilograms): 419,896;
Percentage of total antibiotics sold: 12.5%.
Type of purchaser: Nonfederal hospitals;
Amount sold (in pounds): 852,247;
Amount sold (in kilograms): 387,385;
Percentage of total antibiotics sold: 11.5%.
Type of purchaser: Food store pharmacies[C];
Amount sold (in pounds): 745,526;
Amount sold (in kilograms): 338,876;
Percentage of total antibiotics sold: 10.1%.
Type of purchaser: Clinics;
Amount sold (in pounds): 232,672;
Amount sold (in kilograms): 105,760;
Percentage of total antibiotics sold: 3.1%.
Type of purchaser: Long-term care facilities;
Amount sold (in pounds): 228,662;
Amount sold (in kilograms): 103,937;
Percentage of total antibiotics sold: 3.1%.
Type of purchaser: Federal facilities[D];
Amount sold (in pounds): 219,533;
Amount sold (in kilograms): 99,788;
Percentage of total antibiotics sold: 3.0%.
Type of purchaser: Other[E];
Amount sold (in pounds): 278,984;
Amount sold (in kilograms): 126,811;
Percentage of total antibiotics sold: 3.8%.
Type of purchaser: Total;
Amount sold (in pounds): 7,387,527;
Amount sold (in kilograms): 3,357,967;
Percentage of total antibiotics sold: 100.0%.
Source: GAO analysis of IMS Health data.
[A] Chain store pharmacies include businesses that consist of four or
more stores with the same name that are owned and operated by the same
organization.
[B] Independent pharmacies are privately owned pharmacies that operate
fewer than four stores.
[C] Food store pharmacies include pharmacies that are located in
grocery stores.
[D] Federal facilities include, for example, Department of Veterans
Affairs hospitals and public health outpatient facilities.
[E] Other includes mail order pharmacies and pharmacies located in
such entities as health maintenance organizations and prisons.
[End of table]
Data Gaps Remain Despite CDC's Efforts to Expand Its Limited
Monitoring of Antibiotic Use; CDC, NIH, and FDA Have Implemented
Efforts to Promote Appropriate Use:
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 Annually Collects Certain National Data on Antibiotic
Prescriptions to Monitor Antibiotic Use, but Data Do Not Allow for
Important Analyses:
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).[Footnote 34] NAMCS
is based on a sample of visits to office-based physicians and
community health centers.[Footnote 35] NHAMCS is based on a sample of
visits to emergency and outpatient departments and hospital-based
ambulatory surgery locations.[Footnote 36],[Footnote 37] 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.[Footnote
38] 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 in
Outpatient and Inpatient Settings, but Gaps in Information Will Remain:
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.[Footnote 39] 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.
[Footnote 40] 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.[Footnote 41] 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.[Footnote 42] Furthermore,
CDC officials do not know if the survey will be repeated.[Footnote 43]
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.[Footnote 44] 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. Footnote 45] 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.
[Footnote 46] 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.
[Footnote 47]
CDC's Get Smart Program Promotes Appropriate Antibiotic Use to
Providers and Patients:
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.
[Footnote 48] CDC launched its Get Smart program in 1995 with the
overall goal of reducing the increasing rate of antibiotic resistance.
[Footnote 49] 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. Footnote
50] 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.
[Footnote 51] 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, but
It Is Unclear to What Extent Its Program to Promote Appropriate
Antibiotic Use Contributed to Recent Trends:
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.[Footnote 52] 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.[Footnote 53] 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.[Footnote 54]
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.[Footnote 55] 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.[Footnote 56] 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.[Footnote 57] 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 Activities Have Complemented CDC's Efforts to Promote
Appropriate Antibiotic Use:
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.[Footnote 58]
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.[Footnote 59] 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.[Footnote 60] 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.[Footnote
61] 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.[Footnote 62]
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.[Footnote 63] 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.[Footnote 64] 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.[Footnote 65]
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.[Footnote 66],[Footnote 67] 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 [the
antibiotic] 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:
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.
Data Gaps in CDC's Monitoring of Antibiotic-Resistant Infections in
Healthcare Settings Limit Its Ability to Produce Accurate National
Estimates:
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,[Footnote 68] 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[Footnote 69] 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.[Footnote 70] 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.[Footnote 71] 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[Footnote
72] from their intensive care units.[Footnote 73] 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.[Footnote 74] Participating facilities
may submit data about different types of HAIs, and this includes
information about whether the HAIs are resistant to antibiotics.
[Footnote 75] 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.[Footnote
76] 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.[Footnote 77] 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 for Some Infections:
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.[Footnote 78] 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.[Footnote 79] 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[Footnote 80]
infection-causing bacteria--group A and B Streptococcus, Neisseria
meningitidis, Streptococcus pneumoniae, and MRSA.[Footnote 81],
[Footnote 82] 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.[Footnote 83] 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.[Footnote 84]
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.[Footnote 85] 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.[Footnote 86],[Footnote 87]
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.[Footnote 88] 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.[Footnote 89]
CDC Is Taking Steps to Improve Its Monitoring of Antibiotic-Resistant
Infections in Healthcare Facilities, but These Steps Will Not Improve
CDC's Ability to Assess the Overall Problem of Antibiotic Resistance:
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.
[Footnote 90] 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.[Footnote 91] 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.[Footnote 92] 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.[Footnote
93] 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.[Footnote
94] 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.[Footnote 95] 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.
[Footnote 96] 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 Monitor Antibiotic Disposal, but Have Examined
the Presence of Antibiotics in the Environment, and Studies Find that
Such Antibiotics Can Increase the Population of Resistant Bacteria:
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.
Federal Agencies Do Not Monitor the Disposal of Most Antibiotics
Intended for Human Use, but Have Measured the Presence of Antibiotics
in the Environment:
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.[Footnote 97]
According to EPA, antibiotics enter the environment through various
pathways into water, soil, and sediment, such as wastewater discharged
from treatment plants.[Footnote 98] 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.[Footnote 99] Under this system, EPA receives information
from hazardous waste generators through the Biennial Reporting System.
[Footnote 100] 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.[Footnote 101]
Erythromycin is the only antibiotic on the third CCL list (CCL 3)--the
current CCL that was published in October 2009.[Footnote 102]
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.[Footnote 103] 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.[Footnote 104]
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.
[Footnote 105],[Footnote 106] (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.[Footnote 107] 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.
Table 5: Five National Studies that Measured the Presence of
Antibiotics in the Environment, Conducted by EPA and USGS:
Name of study (agency that conducted the study): Pharmaceuticals,
Hormones, and Other Organic Wastewater Contaminants in U.S. Streams,
1999-2000: A National Reconnaissance (USGS);
Year(s) study was conducted: 1999-2000;
Description of study sites: 139 streams across 30 states;
Examples of antibiotics detected[A]: Ciprofloxacin, Erythromycin,
Tetracycline.
Name of study (agency that conducted the study): A National
Reconnaissance of Pharmaceuticals and Other Organic Wastewater
Contaminants in the United States - I) Groundwater (USGS);
Year(s) study was conducted: 2000;
Description of study sites: 47 groundwater sites across 18 states;
Examples of antibiotics detected[A]: Lincomycin, Sulfamethazine,
Sulfamethoxazole.
Name of study (agency that conducted the study): A National
Reconnaissance for Pharmaceuticals and Other Organic Wastewater
Contaminants in the United States - II) Untreated Drinking Water
Sources (USGS);
Year(s) study was conducted: 2001;
Description of study sites: 25 ground-and 49 surface-water sources of
drinking water in 25 states and Puerto Rico;
Examples of antibiotics detected[A]: Azithromycin, Ciprofloxacin,
Erythromycin.
Name of study (agency that conducted the study): Targeted National
Sewage Sludge Survey (EPA);
Year(s) study was conducted: 2006-2007;
Description of study sites: 74 publicly owned plants that treat
wastewater in 35 states;
Examples of antibiotics detected[A]: Azithromycin, Ciprofloxacin,
Erythromycin.
Name of study (agency that conducted the study): Transport of
Chemicals from Wastewater Effluents (EPA and USGS);
Year(s) study was conducted: 2002;
Description of study sites: 10 wastewater treatment plants in 10
states;
Examples of antibiotics detected[A]: Erythromycin, Sulfamethoxazole,
Trimethoprim.
Source: GAO analysis and summary of EPA and USGS information.
[A] Detected antibiotics include those used for treatment by both
animals and humans.
[End of table]
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.[Footnote 108]
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.[Footnote 109] 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.[Footnote 110] 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.[Footnote 111]
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.[Footnote 112] 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.[Footnote 113] 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.
Studies Find Antibiotics Present in the Environment at Certain
Concentration Levels Can Increase the Population of Resistant Bacteria
Due to Selective Pressure:
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.[Footnote 114]
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.[Footnote 115] 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.[Footnote 116] 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.[Footnote 117] 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.[Footnote 118],[Footnote
119] 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.[Footnote 120]
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.[Footnote 121]
Conclusions:
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.
Recommendations:
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.
Agency Comments:
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
[hyperlink, 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.
Signed by:
Marcia Crosse:
Director, Health Care:
[End of section]
Appendix I: Methodology for Reviewing Scientific Evidence on
Antibiotic Resistance in the Environment:
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."[Footnote 122] 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.[Footnote 123]
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.
[End of section]
Appendix II: Bacteria and the Development of Antibiotic Resistance:
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.[Footnote 124] In addition, the same bacteria that may
cause disease in one individual may not cause disease in another.
[Footnote 125] 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.[Footnote 126]
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.[Footnote 127] 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.[Footnote 128] 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.[Footnote 129] 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.[Footnote 130] 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.[Footnote 131] 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.[Footnote 132]
[End of section]
Appendix III: Centers for Disease Control and Prevention's
Surveillance Systems for Monitoring Antibiotic Resistance:
Table 6: CDC's Surveillance Systems for Monitoring Antibiotic
Resistance, by Bacteria, Geographic Coverage, and Examples of Data Use:
Surveillance system: Active Bacterial Core Surveillance (ABCs) [of the
Emerging Infections Programs (EIP) Network[A]];
Bacteria monitored for antibiotic resistance: group A and group B
Streptococcus; Neisseria meningitidis; Streptococcus pneumoniae;
methicillin-resistant Staphylococcus aureus (MRSA)[B];
Geographic coverage of surveillance: 10 surveillance areas in
California, Colorado, Connecticut, Georgia, Maryland, Minnesota, New
Mexico, New York, Oregon, and Tennessee for group A and B
Streptococcus; Neisseria meningitidis; and Streptococcus pneumoniae;
9 surveillance areas in California, Colorado, Connecticut, Georgia,
Maryland, Minnesota, New York, Oregon, and Tennessee for MRSA;
Examples of how surveillance data were used: 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.
Surveillance system: Gonococcal Isolate Surveillance Project (GISP);
Bacteria monitored for antibiotic resistance: Neisseria gonorrhoeae;
Geographic coverage of surveillance: 29 sexually transmitted disease
clinics located in the West, Midwest, Northeast, and South;
Examples of how surveillance data were used: 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.
Surveillance system: National Antimicrobial Resistance Monitoring
System: Enteric Bacteria (NARMS: EB);
Bacteria monitored for antibiotic resistance: Shigella, Escherichia
coli O157, Campylobacter, typhoidal Salmonella, and non-typhoidal
Salmonella[C];
Geographic coverage of surveillance: 50 states for Shigella, typhoidal
Salmonella, non-typhoidal Salmonella, and Escherichia coli O157;
10 states for Campylobacter--California, Colorado, Connecticut,
Georgia, Maryland, Minnesota, New Mexico, New York, Oregon, and
Tennessee;
Examples of how surveillance data were used: 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.
Surveillance system: National Healthcare Safety Network (NHSN);
Bacteria monitored for antibiotic resistance: Includes, among others,
Enterococcus faecalis; Enterococcus faecium; Staphylococcus aureus;
Acinetobacter; Escherichia coli; Enterobacter; Klebsiella oxytoca;
Klebsiella pneumoniae; Pseudomonas aeruginosa; and Clostridium
difficile;
Geographic coverage of surveillance: Participating healthcare
facilities across the United States;
Examples of how surveillance data were used: 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.
Surveillance system: National Notifiable Diseases Surveillance System
(NNDSS);
Bacteria monitored for antibiotic resistance: Streptococcus pneumoniae;
Geographic coverage of surveillance: Health departments in the 50
states, 5 territories, New York City, and the District of Columbia
voluntarily report cases to CDC;
Examples of how surveillance data were used: 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.
Surveillance system: National Tuberculosis Surveillance System (NTSS);
Bacteria monitored for antibiotic resistance: Mycobacterium
tuberculosis;
Geographic coverage of surveillance: CDC receives information on each
newly reported case of tuberculosis (TB) in the United States;
Examples of how surveillance data were used: 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.
Source: GAO analysis and summary of CDC information.
[A] 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.
[B] Haemophilus influenzae are monitored for antibiotic resistance
periodically.
[C] According to CDC officials, NARMS: EB collects data on Enterococci
from 2 states and has a pilot study to monitor Escherichia coli in 1
state.
[End of table]
[End of section]
Appendix IV: Topical Antiseptics and Antibiotic Resistance:
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.[Footnote
133] Because antiseptics are intended for use in or on humans or
animals,[Footnote 134] 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.[Footnote 135]
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.[Footnote 136]
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.[Footnote 137] 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.[Footnote 138] 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.[Footnote
139] 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.[Footnote 140] (See table 6.) Each of
the studies measured for the presence of triclosan, and the study
involving sewage sludge also tested for triclocarban.[Footnote 141]
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.[Footnote 142] Triclocarban was
found to be present in all sewage sludge samples taken from wastewater
treatment plants located across the United States.:
Table 7: Five National Studies that Measured the Presence of
Antiseptic Active Ingredients in the Environment, Conducted by EPA and
USGS:
Name of study (agency that conducted the study): Pharmaceuticals,
Hormones, and Other Organic Wastewater Contaminants in U.S. Streams,
1999-2000: A National Reconnaissance (USGS);
Year(s) study was conducted: 1999-2000;
Description of study sites: 139 streams across 30 states;
Examples of antiseptic active ingredients tested: Triclosan.
Name of study (agency that conducted the study): A National
Reconnaissance of Pharmaceuticals and Other Organic Wastewater
Contaminants in the United States - I) Groundwater (USGS);
Year(s) study was conducted: 2000;
Description of study sites: 47 groundwater sites across 18 states;
Examples of antiseptic active ingredients tested: Triclosan.
Name of study (agency that conducted the study): A National
Reconnaissance for Pharmaceuticals and Other Organic Wastewater
Contaminants in the United States - II) Untreated Drinking Water
Sources (USGS);
Year(s) study was conducted: 2001;
Description of study sites: 25 ground-and 49 surface-water sources of
drinking water in 25 states and Puerto Rico;
Examples of antiseptic active ingredients tested: Triclosan.
Name of study (agency that conducted the study): Targeted National
Sewage Sludge Survey (EPA);
Year(s) study was conducted: 2006-2007;
Description of study sites: 74 publicly owned plants that treat
wastewater in 35 states;
Examples of antiseptic active ingredients tested: Triclosan and
Triclocarban.
Name of study (agency that conducted the study): Transport of
Chemicals from Wastewater Effluents (EPA and USGS);
Year(s) study was conducted: 2002;
Description of study sites: 10 wastewater treatment plants in 10
states;
Examples of antiseptic active ingredients tested: Triclosan.
Source: GAO analysis and summary of EPA and USGS information.
[End of table]
[End of section]
Appendix V: Comments from the Department of Health and Human Services:
Department Of Health And Human Services:
Office Of The Secretary:
Assistant Secretary for Legislation:
Washington, DC 20201:
May 13 2011:
Marcia Crosse:
Director, Health Care:
U.S. Government Accountability Office:
441 G Street N.W.
Washington, DC 20548:
Dear Ms. Crosse:
Attached are comments on the U.S. Government Accountability Office's
(GAO) draft report entitled, "Antibiotic Resistance: Data Gaps Will
Remain Despite HHS Taking Steps to Improve Monitoring" (GA0-11-406).
The Department appreciates the opportunity to review this report
before its publication.
Sincerely,
Signed by:
Jim R. Esquea:
Assistant Secretary for Legislation:
Attachment:
[End of letter]
General Comments Of The Department Of Health And Human Services (HHS)
On The Government Accountability Office's (GAO) Draft Report Entitled,
"Antibiotic Resistance: Data Gaps Will Remain Despite HHS Taking Steps
To Improve Monitoring" (GAO 11-406)
The Department appreciates the opportunity to review and comment on
this draft report.
The Centers for Disease Control and Prevention (CDC) agrees with the
GAO that monitoring and surveillance of antimicrobial use and the
occurrence of resistant infections are critically important in
preventing the development and spread of antibiotic resistance.
As GAO notes, CDC has previously recognized gaps in the monitoring and
surveillance of antimicrobial use and resistance and is taking
specific steps to address these gaps. As noted in the report, these
steps include:
* The planned prevalence survey of U.S. acute care hospitals;
* Addition of the antimicrobial use and resistance module to NHSN;
* Increase in sample size of the National Ambulatory Medical Care
Survey;
* Acquisition of antimicrobial use data from private vendors;
* Sharing of data among Federal agencies, including FDA, NIH and CMS,
which is expanding its own data collections in collaboration with
CDC's NHSN;
* Continued growth of the NHSN and the enhancement of components which
collect data from outpatient facilities.
Additional CDC activities, not specifically mentioned in the GAO
report, are described in the draft document A Public Health Action
Plan to Combat Antimicrobial Resistance produced by
the Interagency Task Force on Antimicrobial Resistance [hyperlink,
(http://www.cdc.gov/drugresistance/pdf/2010/Interagency-Action-Plan-
PreClearance-03-2011.pdf]. This document identifies over 50 specific
actions being undertaken by Task Force members to improve monitoring
and surveillance of antimicrobial use and resistant infections; for
the majority of these actions, CDC is the lead agency. Among these
actions are:
* Enhancements to the National Antimicrobial Monitoring System;
* Enhancements to the Gonococcal Isolate Surveillance Project;
* Enhancements to antimicrobial resistance monitoring conducted
through the Emerging Infections Program;
* Enhancements to the Active Bacterial Core Surveillance system;
* Enhancements to the national tuberculosis reporting system;
* Collaborations with non-Federal public health agencies (state and
local health departments, the Conference of State and Territorial
Epidemiologists, the Association of Public Health Laboratories), non-
governmental organizations (e.g., the Clinical and Laboratory
Standards Institute), and international organizations (e.g., World
Health Organization) to improve monitoring and surveillance of
antimicrobial resistance.
Updates on CDC's progress toward successful accomplishment of these
action steps will be further documented in the 2010 annual progress
report on the Action Plan, scheduled for release this summer.
CDC believes that the successful, timely accomplishment of the
numerous action steps currently in process and planned by CDC and in
collaboration with Federal and non-Federal partners will result in the
Federal agencies having sufficiently comprehensive information for a
full and complete assessment of the public health impact of antibiotic
resistance and will provide Federal agencies with appropriate
information to identify necessary actions to reduce the occurrence of
antibiotic-resistant infections.
Finally, CDC has initiated the process of developing a strategic plan
for preventing the emergence and spread of antimicrobial resistant
infections, of which a primary component is the monitoring and
surveillance of antimicrobial use and resistance.
[End of section]
Appendix VI: GAO Contact and Staff Acknowledgments:
GAO Contact:
Marcia Crosse, (202) 512-7114 or crossem@gao.gov:
Acknowledgments:
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.
[End of section]
Footnotes:
[1] For example, the medical costs attributable to the treatment of an
antibiotic-resistant infection ranged from about $19,000 to $29,000
per patient in a study of one hospital. In addition, the excess
duration of a hospital stay was about 6 to 13 days and the death rate
was twofold higher among those patients who were treated for such
infections. See R.R. Roberts et al., "Hospital and Societal Costs of
Antimicrobial-Resistant Infections in a Chicago Teaching Hospital:
Implications for Antibiotic Stewardship, Clinical Infectious Diseases,
vol. 49 (2009), pp. 1175-1184.
[2] GAO has ongoing work examining antibiotic use in food animals.
[3] For example, a recent report from the American Academy of
Microbiology outlined several recommendations to help control the
development and spread of antibiotic resistance, including improved
surveillance to better assess the actual scope of the problem. See
American Academy of Microbiology, Antibiotic Resistance: An Ecological
Perspective on an Old Problem (Washington, D.C.: 2009).
[4] See House of Representatives, Departments of Labor, Health, and
Human Services, and Education, and Related Agencies Appropriations
Bill, 2010: Report of the Committee on Appropriations together with
Minority Views, Report 111-220 (Washington, D.C.: July 22, 2009).
[5] The company IMS Health, on a monthly basis, collects data on drugs-
-including antibiotics--purchased by retail pharmacies from about 100
drug manufacturers and about 500 distribution centers. These
manufacturers and distribution centers provide data to IMS Health on
the number of units sold.
[6] The Red Book Advanced database includes a comprehensive list of
drug products approved for use by the Food and Drug Administration.
[7] IMS Health conducts detailed data reliability assessments, which
include comparing monthly data from drug manufacturers and
distribution centers to data from the prior month and the prior year
in order to ensure consistency.
[8] The Healthcare Infection Control Practices Advisory Committee is
comprised of public infection control experts, as well as nonvoting
federal agency representatives and nonvoting liaison representatives
of several national organizations. The committee is charged with
providing advice and guidance to the Secretary of HHS and the Centers
for Disease Control and Prevention, among others, regarding the
practice of healthcare infection control, strategies for surveillance,
and prevention and control of healthcare-associated infections in U.S.
healthcare facilities. The officials we interviewed from the three
liaison organizations represented the Association of Professionals of
Infection Control and Epidemiology, Inc., the Infectious Diseases
Society of America, and the Society for Healthcare Epidemiology of
America.
[9] PhRMA officials provided us information on how pharmaceutical
manufacturers dispose of unused drugs, such as those that are expired
or were recalled, and active ingredients that do not get used in the
manufacturing process.
[10] Antibiotics are a type of antimicrobial. Antimicrobials are drugs
or other chemicals that kill or slow the growth of organisms such as
bacteria, viruses, and fungi.
[11] Diagnostic tests are used to determine the types of bacteria that
cause infection and this information can be used by healthcare
providers to choose an appropriate antibiotic. Different antibiotics
target different types of bacteria.
[12] In addition, some communities conduct pharmaceutical take-back
programs that allow the public to bring unused or expired drugs to a
central location for disposal.
[13] The guidance, available on the FDA Web site, states that
consumers should follow these guidelines unless the drug's label
directs consumers to flush the unused drug down the toilet. FDA
recommends flushing for a small number of drugs to prevent life-
threatening risks from accidental use. See [hyperlink,
http://www.fda.gov/forconsumers/consumerupdates/ucm101653.htm],
downloaded on March 31, 2011.
[14] Wastewater that leaves a treatment plant is known as effluent.
Solid, semisolid, or liquid organic materials that leave a wastewater
treatment plant are known as sewage sludge or biosolids. Sewage sludge
is often applied to land as fertilizer, subject to EPA regulations.
[15] Inadequately treated sewage from such septic systems can be a
cause of groundwater contamination.
[16] In general, a contaminant is any substance or matter in the
environment such as those that have an adverse effect on air, water,
soil, or human health.
[17] For a discussion of wastewater treatment plants and their ability
to remove low concentrations of antibiotics, see J.R. Lefkowitz and M.
Duran, "Changes in Antibiotic Resistance Patterns of Escherichia coli
during Domestic Wastewater Treatment," Water Environment Research,
vol. 81 (2009), pp. 878-885.
[18] Antibiotics can also enter sewage systems as a result of bathing
and washing. Bathing and washing may release antibiotic ingredients
remaining on the skin from the use of topical applications or from
excretion to the skin through sweating.
[19] Antibiotics may also enter the environment as a result of their
use in aquaculture and orchards (e.g., antibiotics may be sprayed on
apple or pear trees to prevent certain infections).
[20] CDC officials told us that the act has been interpreted broadly
to include CDC's surveillance of antibiotic-resistant infections and
the use of antibiotics. See Public Health Service Act, as amended, §
301(a), codified at 42 U.S.C. § 241(a) (2011).
[21] The Public Health Improvement Act required that the Secretary of
HHS establish the Task Force to provide advice and recommendations
related to antibiotic resistance. Under the act, the secretary--in
consultation with the Task Force and state and local public health
officials--is required to develop, improve, coordinate, or enhance
participation in a surveillance plan to detect and monitor emerging
antibiotic resistance. The act also states that the secretary, in
consultation with the Task Force and others, shall develop and
implement educational programs for the general public to increase
awareness of the appropriate use of antibiotics and to instruct
healthcare professionals in the prudent use of antibiotics. See 42
U.S.C. § 247d-5 (2011).
[22] The Task Force includes eight other federal agency members. These
members are the Agency for Healthcare Research and Quality, Centers
for Medicare & Medicaid Services, Health Resources and Services
Administration, HHS Office of the Assistant Secretary for Preparedness
and Response, Department of Agriculture, Department of Defense,
Department of Veterans Affairs, and EPA.
[23] The revised draft Action Plan includes the same focus areas--
surveillance, prevention and control, research, and product
development--as the 2001 Action Plan, along with specific projects or
implementation steps for many of the action items. The revised draft
Action Plan includes expected completion dates for projects or
implementation steps, unlike the 2001 Action Plan.
[24] Hazardous waste has properties, such as being toxic, that make it
dangerous or potentially harmful to human health or the environment.
[25] Surveillance systems include the timely dissemination of data to
persons who can undertake effective prevention and control activities,
such as public health personnel and clinicians.
[26] MRSA infections can also spread in the community, for example, by
having close skin-to-skin contact or by exposure to contaminated items
and surfaces. ABCs monitors MRSA that is spread in the community as
well as in healthcare settings.
[27] In contrast, FDA recently issued a report summarizing data on
antibiotics sold or distributed for use in food-producing animals, as
required by the Animal Drug User Fee Amendments of 2008. This report
indicated that 28.7 million pounds of antibiotics were sold or
distributed for use in food-producing animals in the United States in
2009. This number includes the antibiotic class ionophores, which are
not used in human medicine. Excluding ionophores, the total amount of
pounds of antibiotics that were sold or distributed for use in food-
producing animals in the United States in 2009 was 20.5 million
pounds. According to FDA, these data are limited because they combine
therapeutic and subtherapeutic uses of antibiotics and all species of
animals. Further, these data do not take into account the dose size,
which varies by individual antibiotic and species of animal, or the
total number of animals that received antibiotics. Due to such
limitations in the data, FDA officials noted that comparisons of
antibiotic use between food-producing animals and humans are
problematic. See FDA, 2009 Summary Report on Antimicrobials Sold or
Distributed for Use in Food-Producing Animals (Rockville, Md: 2010).
Available at [hypelink,
http://www.fda.gov/downloads/ForIndustry/UserFees/AnimalDrugUserFeeActAD
UFA/UCM231851.pdf].
[28] NDAs and ANDAs are submitted to FDA by drug sponsors to obtain
approval for their drug to be marketed in the United States.
[29] 21 C.F.R. §§ 314.81(b)(2)(ii)(a), 314.98(c) (2011). Generally,
only aggregated drug distribution data can be made publicly available.
21 C.F.R. § 314.430(g)(2) (2011).
[30] In April 2011, in response to a request from a Member of
Congress, FDA used drug sales data to provide information about the
amount of antibiotics that were sold in the United States in 2009 for
human use, which it provided in correspondence to the Member.
[31] The USITC data on antibiotic production reflected the amount of
antibiotics that were produced--for human and animal use--in the
United States and for sale within or outside of the United States.
USITC began reporting on the production of antibiotics, and other
organic chemicals at the request of the House Committee on Ways and
Means. In 1995, the committee requested that USITC stop its data
collection on production because it determined that this effort was no
longer cost effective or essential for ensuring the competitiveness of
the U.S. industry.
[32] A limitation of comparing total weights across antibiotic classes
is that dosages for antibiotics can vary by antibiotic class.
According to FDA officials, comparing weights within antibiotic class
may also be difficult, but the degree to which antibiotic dosages may
vary within the same class is less than that across classes.
[33] A drug is delivered to the body through oral administration when
taken by mouth (e.g., a pill) and by injectable administration when
delivered to the body through a needle.
[34] NAMCS and NHAMCS are national probability sample surveys that are
designed to provide information about medical care services in the
United States.
[35] The NAMCS sample does not include visits to office-based
physicians who are employed by the federal government.
[36] The NHAMCS sample includes nonfederal short-stay hospitals (i.e.,
average stay of fewer than 30 days) whose specialty is general (i.e.,
medical or surgical) or children's general. The NHAMCS sample also
includes ambulatory surgery centers that are freestanding. Ambulatory
surgery centers are medical facilities where surgical and other
procedures not requiring an overnight hospital stay are performed.
[37] According to CDC officials, CDC is planning to merge NHAMCS with
its current survey on inpatient care (i.e., the National Hospital
Discharge Survey), into one survey called the National Hospital Care
Survey, in 2011. In the integrated survey, data collection for
antibiotic prescriptions will continue for outpatient visits.
[38] The surveys do not collect information on whether the
prescriptions were filled or whether the prescribed treatment course
was completed by the patient. According to CDC officials, this is
because individual patients in the surveys are never identified or
contacted.
[39] Acute care hospitals provide inpatient medical care and other
related services for surgery, acute medical conditions, or injuries,
usually for a short-term illness or condition.
[40] Some antibiotics are used to prevent infections, such as prior to
having certain kinds of surgery that carry a high risk of infection.
[41] CDC officials also stated that information about inpatient
antibiotic use could inform recommendations about antibiotic treatment
by professional groups, such as the Infectious Diseases Society of
America.
[42] The survey is based on a sample of acute care hospitals located
within the 10 EIP surveillance areas (also known as 'catchment'
areas). According to a CDC official, the survey will be representative
of hospitals within the EIP surveillance areas.
[43] CDC officials stated that a decision to repeat the survey will
depend on available resources, and would be better made after the
original survey has been completed. CDC expects to begin data
collection in 2011 and complete its analysis in 2012.
[44] In NHSN, similar types of surveillance information are grouped
into modules. For example, there is a module that captures surgical
site infections.
[45] To illustrate, facilities reported on about 75 commonly used
antibiotics as well as combinations of these antibiotics.
[46] CDC officials also told us that with the redesigned module,
facilities will be able to immediately use their data to evaluate
antibiotic use rates for antimicrobial stewardship activities.
Antimicrobial stewardship includes interventions and programs designed
to improve antibiotic use.
[47] CDC officials stated that there are no plans to provide state-
level estimates with NHAMCS.
[48] Otherwise healthy adults under 50 years old are an additional
target audience.
[49] According to CDC officials, the program was originally named the
National Campaign for Appropriate Antibiotic Use in the Community and
was renamed Get Smart in 2003.
[50] In addition to health insurance companies, other Get Smart
partners include businesses, pharmaceutical companies, foundations,
and professional associations. As an example of how CDC collaborates
with its partners, a health insurance company mailed Get Smart
promotional materials to 320,000 of its customers with children ages 3
to 10 years old. CDC also provided technical support to this company
to develop educational kits that were sent to about 30,000 pediatric,
family practice, and internal medicine offices.
[51] In 2005, CDC launched two additional components of the national
media campaign. These include materials for healthy adults, Spanish
speakers, and American Indians. In 2008, the campaign coordinated its
first national observance, Get Smart About Antibiotics Week, and
through a variety of activities and resources, the messages of the Get
Smart program were delivered to the public.
[52] Both measures are used by HHS, as part of Healthy People 2010, to
assess national progress related to disease prevention.
[53] NCQA is a private organization whose mission is to improve
healthcare quality. As part of its mission, NCQA develops quality
standards and performance measures for a broad range of healthcare
entities. The NCQA measures are used by more than 90 percent of U.S.
health plans to measure performance. CDC officials helped NCQA write
the measures on antibiotic prescribing.
[54] NCQA also measures the percentage of healthy adults (18 to 64
years of age) who did not receive an antibiotic prescription with a
diagnosis of acute bronchitis, characterized by a cough that can last
for up to 3 weeks. Performance on this measure declined between 2005
and 2008 because the percentage decreased.
[55] The American Academy of Pediatrics has recommended influenza
vaccination for healthy children 6 through 24 months of age since
2004. Currently, the American Academy of Pediatrics recommends the
influenza vaccination for healthy children 6 months of age and older.
[56] See J.A. Finkelstein et al., "Impact of a 16-Community Trial to
Promote Judicious Antibiotic Use in Massachusetts," Pediatrics, vol.
121 (2008), pp. e15-e23.
[57] Antibiotic prescribing rates decreased in all three age groups of
children included in the study, regardless of whether educational and
promotional materials were distributed. For example, rates decreased
by 14.5 percent among children 2 years old to less than 4 years old in
communities with educational and promotional materials, and by 10.3
percent in communities without such materials. The greater declines in
antibiotic prescribing rates in communities with educational and
promotional materials were statistically significant in two of the
three age groups.
[58] When a medication is first sold, the drug manufacturer has
exclusive rights, or a patent, to produce that drug for a certain
number of years. After the patent has expired, the drug becomes an off-
patent medication and can be reproduced by other drug manufacturers.
[59] As of March 2011, this study is ongoing, according to an NIH
official.
[60] As of March 2011, both studies are ongoing and continue to enroll
participants, according to an NIH official.
[61] See C.C. Boehme et al., "Rapid Molecular Detection of
Tuberculosis and Rifampin Resistance," New England Journal of
Medicine, vol. 363, no. 1 (2010), pp. 1005-1015.
[62] The test is also being recommended for the early diagnosis of
multidrug-resistant TB and TB in individuals infected with human
immunodeficiency virus.
[63] As part of this effort, NIH has funded basic research, proof-of-
concept studies, and preclinical research, according to an NIH
official.
[64] This candidate is currently in the first phase of clinical
testing, which is supported by a company. A multivalent staphylococcal
vaccine would provide broader protection against a variety of
Staphylococcus aureus strains.
[65] An NIH official further explained that the influenza virus causes
lung damage that often predisposes individuals to bacterial pneumonia.
Thus, fewer cases of influenza would lead to fewer secondary bacterial
infections requiring antibiotic treatment.
[66] See 21 § CFR 201.24 (2011), 68 Fed. Reg. 6081 (Feb. 6, 2003). The
amended drug labeling requirement applies only to antibiotics that are
administered orally or intravenously. Antibiotics that are
administered via a different route, such as those that are applied
topically, are excluded from the labeling requirement.
[67] For FDA information related to antibiotic use, see [hyperlink,
http://www.fda.gov/NewsEvents/PublicHealthFocus/ucm235649.htm]
(downloaded on March 17, 2011).
[68] With laboratory-identified event surveillance data from NHSN, CDC
also monitors certain HAIs caused by multidrug-resistant organisms
(MDRO) as well as Clostridium difficile infections.
[69] Enrollment in NHSN is open to all types of healthcare facilities
in the United States, including acute care hospitals, psychiatric
hospitals, rehabilitation hospitals, outpatient dialysis centers,
ambulatory surgery centers, and long-term-care facilities.
[70] CMS is the agency that, among other activities, administers
Medicare, a health insurance program that helps pay for inpatient care
in hospitals.
[71] CDC officials said that as of January 2011, approximately 4,000
hospitals and other healthcare facilities participated in NHSN. In
comparison, we reported in 2008 that approximately 1,000 hospitals
were participating in NHSN, as of December 2007. See GAO, Health-Care-
Associated Infections in Hospitals: Leadership Needed from HHS to
Prioritize Prevention Practices and Improve Data on These Infections,
[hyperlink, http://www.gao.gov/products/GAO-08-283] (Washington, D.C.:
Mar. 31, 2008). NHSN opened enrollment to all types of healthcare
facilities in 2008. According to the American Hospital Association's
2009 annual survey of hospitals, there are approximately 5,800
hospitals in the United States.
[72] The procedures include, for example, coronary artery bypass graft
and other cardiac surgery, and hip or knee arthroplasty.
[73] Acute care hospitals electing to participate in the Hospital
Inpatient Quality Reporting Program are obligated to report certain
quality data measures to CMS; those that do not participate are
penalized by a reduction in the increase they would otherwise receive
to their annual payments for providing inpatient services to Medicare
beneficiaries. Under the Hospital Inpatient Quality Reporting Program,
NHSN was designated by CMS to serve as the reporting mechanism for
certain HAIs.
[74] In 2008, we similarly stated that NHSN was limited in terms of
its inability to produce reliable national estimates on the frequency
of all HAIs--not just antibiotic-resistant HAIs. This is because NHSN
data do not reflect the full scope of HAIs and the sample is not
representative of facilities nationwide. See GAO-08-283.
[75] Facilities may report on different types of HAIs for which NHSN
has developed detailed definitions and protocols. As part of the
protocols, facilities submit microbiological data for each HAI
identified, provided by the facility's designated clinical
microbiology laboratory. These data include information about the type
of bacteria causing the infection and test results regarding
antibiotic resistance. NHSN also has a protocol for reporting MDROs
and Clostridium difficile infections as laboratory-identified events
and, according to CDC officials, the test results regarding antibiotic
resistance are used to determine whether such cases should be reported.
[76] Central line-associated bloodstream infections, catheter-
associated urinary tract infections, and ventilator-associated
pneumonia are device-associated infections that can be reported
through NHSN. Surgical site infections and postprocedure pneumonia are
procedure-associated infections that can also be reported. MDRO and
Clostridium difficile infections can be reported into NHSN as HAIs or
as laboratory-identified events.
[77] Laboratory-identified event surveillance data from NHSN also
allow CDC to determine, among reported cases, the number of MDRO and
Clostridium difficile infections.
[78] NARMS: EB also collects cases from the District of Columbia, and
NTSS reporting includes the District of Columbia, Puerto Rico, and
other U.S. jurisdictions in the Pacific and Caribbean.
[79] NARMS: EB collects every case, every other case, or every fifth
case of Campylobacter from each of the 10 state health departments,
depending on the number of cases each health department receives.
[80] CDC also monitors Haemophilus influenzae with ABCs, but CDC
officials stated that they do not routinely collect antibiotic
susceptibility testing data for cases of Haemophilus influenzae
infection, in part, because of constraints on time and resources at
CDC's laboratories, but that the agency does conduct some testing for
clusters of cases.
[81] CDC uses ABCs to monitor community-and healthcare-associated
cases of MRSA. CDC also monitors healthcare-associated MRSA through
NHSN.
[82] In addition to ABCs, CDC monitors cases of Streptococcus
pneumoniae through NNDSS. CDC officials told us that NNDSS is used to
monitor cases in areas not covered by ABCs' surveillance. NNDSS relies
on the voluntary submission of case reports and it is considered a
passive surveillance system. In comparison, ABCs is considered an
active surveillance system because it relies on the active
identification and collection of cases on a regular basis.
[83] The 10 states are California, Colorado, Connecticut, Georgia,
Maryland, Minnesota, New Mexico, New York, Oregon, and Tennessee.
CDC's surveillance of Streptococcus pneumoniae, Neisseria
meningitidis, and group A and B Streptococcus is based on geographic
areas located in these 10 states and surveillance of MRSA is based on
geographic areas located in 9 of the 10 states.
[84] Bacterial isolates are sent to CDC and other laboratories for
testing. CDC officials told us that antibiotic susceptibility testing
is conducted on all cases of Neisseria meningitidis, Streptococcus
pneumoniae, group A Streptococcus, and MRSA, as well as a subset of
group B Streptococcus cases that are submitted to ABCs from 8 of the
10 sites.
[85] To illustrate the population sizes covered by ABCs surveillance,
the population for Neisseria meningitidis surveillance is about 41
million and the population for MRSA surveillance is about 19 million,
as of January 2010.
[86] CDC uses ABCs data to calculate national estimates of certain
diseases, based on race and age information from ABCs surveillance
areas and the 2009 U.S. population.
[87] CDC officials stated that the selection of catchment areas in
urban areas allows the agency to capture a significant percentage of
the population in the state.
[88] GISP surveillance collects information about gonorrhea cases from
more locations in the West because CDC officials said they expect
antibiotic resistance in gonorrhea to emerge first in the western
United States and then to spread eastward.
[89] A CDC official told us that he does not believe there are
significant differences between men and women in the frequency of
antibiotic resistance among cases of gonorrhea.
[90] The survey will also be used to inform decision making regarding,
for example, appropriate targets and strategies for preventing HAIs
and the emergence of antibiotic-resistant infections.
[91] The survey will collect information about different species of
Acinetobacter and Klebsiella.
[92] Gram-negative infections include those caused by Klebsiella,
Acinetobacter, Pseudomonas aeruginosa, and Escherichia coli, and are
increasingly resistant to most available antibiotics.
[93] CDC also monitors Clostridium difficile infections through NHSN.
[94] CDC officials also stated that these data will complement the
data on Clostridium difficile infections that are collected through
NHSN.
[95] CDC officials noted that since more than 90 percent of acute care
hospitals (excluding critical access hospitals) participate in CMS's
Hospital Inpatient Quality Reporting Program, NHSN data will be more
representative by 2012.
[96] See 75 Fed. Reg. 50042 (Aug. 16, 2010). Collection and reporting
of data on bloodstream infections associated with central lines is
required for the fiscal year 2013 payment determination and collection
and reporting of surgical site infections is required for the fiscal
year 2014 payment determination.
[97] GAO has ongoing work on pharmaceuticals in drinking water.
[98] Treatment plants include, for example, municipal treatment plants
that treat domestic sewage as well as healthcare and pharmaceutical
manufacturing facility treatment plants.
[99] RCRA's implementing regulations define hazardous waste as
including those wastes specifically listed by EPA as well as those
wastes exhibiting any of several characteristics.
[100] A hazardous waste generator is any person whose processes and
actions produce hazardous waste.
[101] For many contaminants, EPA lacks sufficient information to allow
EPA to make a regulatory determination. See GAO, Safe Drinking Water
Act: EPA Should Improve Implementation of Requirements on Whether to
Regulate Additional Contaminants, GAO-11-254 (Washington, D.C.: May
27, 2011).
[102] 74 Fed. Reg. 51,850, 51,852 (Oct. 8, 2009).
[103] The other two criteria are: "the contaminant is known to occur,
or there is a substantial likelihood that the contaminant will occur,
in public water systems with a frequency and at levels of public
health concern" and "in the sole judgment of the Administrator,
regulation of such a contaminant presents a meaningful opportunity for
health risk reduction for persons served by public water systems." 42
U.S.C. §§ 300g-1(b)(1)(A),(b)(1)(B)(ii) (2011).
[104] EPA expects to publish the next CCL by 2014.
[105] In addition, USGS has completed a national study of streambed
sediment in about 50 streams that are located in 17 states but the
results have not been made available. USGS officials told us that the
agency expects to issue a report in 2012. However, some of the data
have been published and show, for example, that trimethoprim, an
antibiotic, occurred in higher concentrations in streambed sediment,
compared to the overlying stream water. See E.T. Furlong et al.,
"Distributions of Organic Wastewater Contaminants between Water and
Sediment in Surface-Water Samples in the United States," Proceedings
of the 3rd International Conference on Pharmaceuticals and Endocrine
Disrupting Chemicals in Water (2003), pp. 60-62.
[106] The five national studies also measured the presence of the
antiseptic active ingredient triclosan in the environment. (For more
information on triclosan, see app. IV).
[107] In comparison, EPA's targeted national sewage sludge study
sample was designed to be representative of U.S. publicly owned
treatment plants that treat more than one million gallons of
wastewater per day.
[108] Few antibiotics were detected in groundwater. For example,
neither ciprofloxacin nor erythromycin was detected in groundwater.
According to USGS officials, while antibiotics were generally less
likely to be detected in groundwater compared to surface water
systems, the USGS groundwater study's findings document that at least
some antibiotics are able to enter groundwater.
[109] Among the national studies of streams, groundwater, and
untreated drinking water, the maximum antibiotic concentration level
detected was 1.9 micrograms per liter of water--for sulfamethoxazole
detected in streams. A concentration level of 1 microgram per liter of
water is also referred to as 1 part per billion and a detection level
of 1 milligram per liter of water is also referred to as 1 part per
million.
[110] Ciprofloxacin was not detected in the wastewater effluent study.
Other antibiotics were detected in the treated effluent samples,
including sulfamethoxazole and trimethoprim; the maximum concentration
level for sulfamethoxazole was .589 micrograms per liter of water and
the maximum concentration level for trimethoprim was .353 micrograms
per liter of water.
[111] In addition to the wastewater effluent study, USGS has conducted
other, generally smaller-scale studies that examined levels of
antibiotics in various sources of human and animal waste. For example,
in one study USGS found chlortetracycline concentrations ranging from
68 to 1000 micrograms per liter of swine waste lagoon samples. See
Campagnolo et al., "Antimicrobial residues in animal waste and water
resources proximal to large-scale swine and poultry feeding
operations," The Science of the Total Environment, vol. 299 (2002),
pp. 89-95.
[112] EPA officials stated that they selected wastewater treatment
plants that primarily receive wastewater from municipal sources and
that discharge effluent to surface water.
[113] EPA officials stated that while this study will provide the
agency with information that will be useful in terms of the occurrence
frequency and concentration of erythromycin, additional method
development work will be required to produce a method that can be used
for regulatory purposes.
[114] Horizontal gene transfer--the process in which bacteria exchange
genes that are coded for resistance--can also lead to an increase in
the population of antibiotic-resistant bacteria in the environment
because bacteria that were previously nonresistant become resistant.
Studies have shown that concentrated animal feeding operations and
wastewater treatment plants have high densities of antibiotics, as
well as antibiotic-resistant bacteria, and that both characteristics
facilitate gene transfer. For example, one study found that when swine
waste was applied to fertilize soil, resistant bacteria found in the
waste transferred their resistance genes to other bacteria in the
soil. See H. Heuer et al., "Spreading antibiotic resistance through
spread manure: characteristics of a novel plasmid type with low %G+C
content," Environmental Microbiology (2009), vol. 11, pp. 937-949.
[115] See S. Castiglioni, et al., "Novel homologs of the multiple
resistance regulator marA in antibiotic-contaminated environments,"
Water Research, vol. 42 (2008), pp. 4271-4280.
[116] See C.W. Knapp et al., "Indirect Evidence of Transposon-Mediated
Selection of Antibiotic Resistance Genes in Aquatic Systems at Low-
Level Oxytetracycline Exposures," Environmental Science & Technology,
vol. 42 (2008), pp. 5348-5353.
[117] See J. Munoz-Aguayo et al., "Evaluating the Effects of
Chlortetracycline on the Proliferation of Antibiotic-Resistant
Bacteria in a Simulated River Water Ecosystem," Applied and
Environmental Microbiology, vol. 73 (2007), pp. 5421-5425.
[118] The antibiotic concentration level that is known to increase the
population of resistant bacteria because of selective pressure is
referred to as a minimum inhibitory concentration (MIC) level. MIC
levels are determined for specific types of bacteria and antibiotics
and a MIC level reflects the lowest concentration of an antibiotic
that prevents visible growth of a bacterium in two types of laboratory
tests. MIC levels are used to predict the success or failure of an
antibiotic treatment in a clinical setting, and thus, guide healthcare
providers' choice of antibiotics to treat bacterial infections.
According to a USGS official, the low concentration levels of
antibiotics in the environment that have been detected in national
studies are generally characterized as such because they are below MIC
levels.
[119] USGS officials further stated that there is evidence that
antibiotic concentration levels lower than MIC levels can affect,
among other things, bacterial growth in the environment. See J.C.
Underwood et al., "Effects of the Antimicrobial Sulfamethoxazole on
Groundwater Bacterial Enrichment," Environmental Science and
Technology, vol. 45 (2011), pp. 3096-3101.
[120] For example, see J. Fick et al., "Pharmaceuticals and Personal
Care Products in the Environment: Contamination of Surface, Ground,
and Drinking Water from Pharmaceutical Production," Environmental
Toxicology and Chemistry, vol. 28 (2009), pp. 2522-2527. This study
showed high concentrations of certain antibiotics in rivers and lakes
near a wastewater treatment plant in India that receives wastewater
from approximately 90 drug manufacturers. USGS officials told us that
they are currently designing a national study of pharmaceutical
manufacturing facilities that will examine antibiotic concentration
levels in areas proximal to such facilities.
[121] For example, one study, not conducted by USGS, has documented
that triclocarban, an antiseptic active ingredient, persists and
bioaccumulates in soils amended with treated sewage sludge. See C.P.
Higgins et al., "Persistence of Triclocarban and Triclosan in Soils
after Land Application of Biosolids and Bioaccumulation in Eisenia
Foetida," Environmental Toxicology and Chemistry, vol. 30 (2010), pp.
556-563.
[122] A complete list of search terms was variations on the phrases
"antibiotic resistance" or "antimicrobial resistance" found in
combination with any of the following terms: "environment," "ground
water," "surface water," "drinking water," "waste water," "effluent,"
"hospital effluent," "municipal sewage," "animal feeding operation,"
"ecotoxicity," "pharmaceutical plant," "sediment," and "soil."
[123] For the purposes of our literature review, we defined the
environment as water, soil, and sediment, as well as certain
wastewater treatment-related settings and certain agricultural-related
settings that serve as pathways into water, soil, and sediment.
[124] Escherichia coli O157 can also spread through human feces. In
addition to consuming contaminated meat, exposure to Escherichia coli
O157 can occur by consuming other contaminated foods (e.g., milk and
lettuce) or by having direct contact with infected carriers.
[125] Bacteria that cause disease are referred to as pathogenic
bacteria. In order to cause disease, pathogens must be able to enter
the body, which can occur, for example, through the mouth, eyes, or
wounds that tear the skin.
[126] Some bacteria have developed resistance to antibiotics
naturally, long before the development of commercial antibiotics.
[127] Any use of antibiotics--appropriate and inappropriate--creates
selective pressure among bacteria.
[128] A species is a group of organisms--including bacteria--with
common traits, such as similar genetic characteristics.
[129] As an example, Escherichia coli O157 is a strain of the
Escherichia coli species.
[130] The resistance gene was found in cases of Escherichia coli,
Klebsiella pneumoniae, and Enterobacter cloacae infections. The
presence of this particular gene resulted in resistance to certain
antibiotics including the carbapenems subclass; for certain bacterial
infections, carbapenems are considered antibiotics of last resort.
[131] The Clinical and Laboratory Standards Institute, a nonfederal
entity, establishes ranges for the interpretation of test results for
antibiotic resistance.
[132] Test values may also fall into ranges for the 'susceptible' and
'intermediate' categories.
[133] Other active ingredients include iodine and chloroxylenol.
[134] In contrast, disinfectants are used on inanimate surfaces or
objects to destroy or inactivate infectious microorganisms.
Consequently, disinfectants, even if they contain the same active
ingredient as an antiseptic, are regulated as chemicals by the
Environmental Protection Agency.
[135] Federal Food, Drug, and Cosmetic Act of 1938, codified as
amended at 21 U.S.C. § 301 & scattered sections (2011). To be
considered a drug, a product must be intended for use in the
diagnosis, cure, mitigation, treatment, or prevention of disease in
humans or animals, or it must be intended to affect the structure or
any function of the body of humans or other animals. Most antiseptic
products are currently being marketed under the Tentative Final
Monograph for over-the-counter Healthcare Antiseptic Drug Products,
published in 1994. See 59 Fed. Reg. 31,402 (June 17, 1994).
[136] Since bacteria use similar mechanisms to resist the effects of
antiseptics and antibiotics, scientists believe that it may be
possible that exposure and development of resistance to antiseptics
could also result in resistance to antibiotics.
[137] M. Braoudaki and A.C. Hilton, "Adaptive Resistance to Biocides
in Salmonella enterica and Escherichia coli O157 and Cross-Resistance
to Antimicrobial Agents," Journal of Clinical Microbiology, Vol. 42
(2004), pp. 73-78.
[138] E.C. Cole, et al., "Investigation of antibiotic and
antibacterial agent cross-resistance in target bacteria from homes of
antibacterial product users and nonusers," Journal of Applied
Microbiology, Vol. 95 (2003), pp. 664-676.
[139] Officials from FDA and the Centers for Disease Control and
Prevention told us that they do not collect information about the
amounts of antiseptics produced or used in the United States.
According to FDA officials, however, FDA collects annual drug
distribution data for chlorhexidine gluconate products, which are used
as topical antiseptics, but are not covered under FDA's monograph for
antiseptic drug products.
[140] In addition, USGS has completed a national study of streambed
sediment in about 50 streams that are located in 17 states but the
results have not been made available. USGS officials told us that the
agency expects to issue a report in 2012. According to USGS officials,
the national study of streambed sediment also tested for the presence
of triclosan.
[141] As part of an ongoing study, EPA and USGS are measuring for the
presence of triclosan and triclocarban in treated drinking water.
According to EPA officials, findings are expected to be made available
sometime in 2012.
[142] According to USGS officials, the laboratory method used for
measuring triclosan in the agency's stream study was different than
the method used in subsequent USGS studies. USGS officials further
stated that this change in methodology resulted in higher triclosan
detection frequencies in the stream study, compared to subsequent USGS
studies.
[143] Triclosan has been detected in other USGS studies involving
human waste sources. For example, see C.A. Kinney et al., "Survey of
Organic Wastewater Contaminants in Biosolids Destined for Land
Application," Environmental Science and Technology, vol. 40 (2006),
pp. 7207-7215.
[End of section]
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