oversight

Antimicrobial Resistance: Data to Assess Public Health Threat From Resistant Bacteria Are Limited

Published by the Government Accountability Office on 1999-04-28.

Below is a raw (and likely hideous) rendition of the original report. (PDF)

                         United States General Accounting Office

GAO                      Report to Congressional Requesters




April 1999
                         ANTIMICROBIAL
                         RESISTANCE
                         Data to Assess Public
                         Health Threat From
                         Resistant Bacteria Are
                         Limited




GAO/HEHS/NSIAD/RCED-99-132
      United States
GAO   General Accounting Office
      Washington, D.C. 20548

      Health, Education, and
      Human Services Division

      B-281564

      April 28, 1999

      The Honorable Edward M. Kennedy
      Ranking Minority Member
      Committee on Health, Education,
        Labor, and Pensions
      United States Senate

      The Honorable Tom Harkin
      Ranking Minority Member
      Committee on Agriculture,
        Nutrition, and Forestry
      United States Senate

      The Staphylococcus aureus bacterium (S. aureus)—one of the most
      common causes of infections worldwide—has long been considered
      treatable with antimicrobial drugs. Recently, however, a number of S.
      aureus infections were found that resisted most available
      antimicrobials—including vancomycin, the last line of treatment for these
      and some other infections. For example, several years ago in Japan, a
      4-month-old infant who had developed an S. aureus infection following
      surgery died after a month of treatments with various antimicrobials,
      including vancomycin. About a year later, three elderly patients in the
      United States with multiple chronic conditions were infected with this
      type of S. aureus—now known as vancomycin intermediate-resistant
      Staphylococcus aureus (VISA). They were treated with numerous
      antimicrobials for an extended period of time and eventually died, but it is
      unclear what role VISA played in their deaths. More recently, a middle-aged
      cancer patient in Hong Kong was admitted to a hospital with a fever and
      died despite 2 weeks of treatment for VISA.

      Cases like these have heightened concern about antimicrobial resistance.
      To better understand the potential threat to the public’s health, you asked
      us to (1) summarize what is known about the current public health
      burden—in terms of illnesses, deaths, and treatment costs—due to
      antimicrobial resistance; (2) assess the potential future burden, given what
      is known about the development of resistance in microbes and usage of
      antimicrobials; and (3) describe federal efforts to gather and provide
      information about resistance. Although resistance has been observed in
      many kinds of microbes—including bacteria, viruses, parasites, and
      fungi—the scope of this report, the first in a series you have requested, is
      limited to bacteria. To conduct our work, we reviewed scientific and




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                   medical literature and spoke with experts in government agencies as well
                   as in academia and private industry. We conducted our work between
                   June 1998 and April 1999 in accordance with generally accepted
                   government auditing standards. (For more information about our scope
                   and methodology, see app. I.)


                   Although many studies have documented cases of infections that are
Results in Brief   difficult to treat because they are caused by resistant bacteria, the full
                   extent of the problem remains unknown. More specifically, we found
                   many sources of information about the public health burden in the United
                   States attributable to resistant bacteria, but each source has limitations
                   and provides data on only part of the burden. For example, the public
                   health burden attributable to resistant tuberculosis (TB) and gonorrhea is
                   relatively well characterized because nationwide surveillance systems
                   monitor these diseases. However, little is known about the extent of most
                   other diseases that can be caused by resistant bacteria, such as otitis
                   media (middle ear infection), gastric ulcers, and cystitis (inflammation of
                   the bladder) because they are not similarly monitored.

                   The development and spread of resistant bacteria worldwide and the
                   widespread use of various antibacterials create the potential for the U.S.
                   public health burden to increase. Data indicate that resistant bacteria are
                   emerging around the world, that more kinds of bacteria are becoming
                   resistant, and that bacteria are becoming resistant to multiple drugs. While
                   little information is publicly available about the actual quantities of
                   antibacterials produced, used, and present in the environment, it is known
                   that antibacterials are used extensively around the world in human and
                   veterinary medicine, in agricultural production, and in industrial and
                   household products and that they have been found in food, soil, and water.

                   A number of federal agencies and international organizations that receive
                   U.S. funds collect information about different aspects of antibacterial
                   resistance, and some ongoing efforts involve collaboration among
                   agencies. For example, the Centers for Disease Control and Prevention
                   (CDC) is the primary source of information about the number of infections
                   caused by resistant bacteria. CDC also collects information on resistance
                   found in bacterial samples and the use of antibacterial drugs in human
                   medicine. The U.S. Department of Agriculture (USDA) collects information
                   about resistant bacteria in animals and antibacterial drug residues in food.
                   The Food and Drug Administration (FDA) also has a program to monitor
                   antibacterial residues in food. CDC, USDA, and FDA are collaborating on



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             efforts to monitor resistant bacteria that can contaminate the food supply.
             The Department of Defense conducts surveillance for antibacterial
             resistance at 13 military sites in the United States and at its 6 tropical
             overseas laboratories. Internationally, the World Health Organization
             serves as a clearinghouse for data on resistance in bacteria isolated from
             people and animals from many different countries. Over the next several
             years, ongoing efforts to improve existing data sources and to create new
             ones may allow better characterization of the public health burden.
             Moreover, several agencies have data or access to data that, although not
             originally intended for these purposes, could be used to learn more about
             the number of resistant infections, treatment costs, and antibacterial
             usage.


             Bacteria exist almost everywhere—in water, soil, plants, animals, and
Background   humans. Bacteria can transfer from person to person, among animals and
             people, from animals to animals, and through water and the food chain.
             Most bacteria do little or no harm, and some are even useful to humans.
             However, others are capable of causing disease. Moreover, the same
             bacteria can have different effects on different parts of the host body. For
             example, S. aureus on the skin can be harmless, but when they enter the
             bloodstream through a wound they can cause disease.

             An antibacterial is anything that can kill or inhibit the growth of bacteria,
             such as high heat or radiation or a chemical. Antibacterial chemicals can
             be grouped into three broad categories: antibacterial drugs, antiseptics,
             and disinfectants. Antibacterial drugs are used in relatively low
             concentrations in or upon the bodies of organisms to prevent or treat
             specific bacterial diseases without harming the organism. They are also
             used in agriculture to enhance the growth of food animals.1 Unlike
             antibacterial drugs, antiseptics and disinfectants are usually nonspecific
             with respect to their targets—they kill or inhibit a variety of microbes.
             Antiseptics are used topically in or on living tissue, and disinfectants are
             used on objects or in water. (For more information on resistant bacteria,
             see app. II; for more on antibacterial use, see app. III.)

             Antibacterial resistance describes a feature of some bacteria that enables
             them to avoid the effects of antibacterial agents. Bacteria may possess
             characteristics that allow them to survive a sudden change in climate, the
             effects of ultraviolet light from the sun, or the presence of an antibacterial

             1
              For more information on the use of antibacterial drugs in animal feed, see Food Safety: The
             Agricultural Use of Antibiotics and Its Implications for Human Health (GAO/RCED-99-74, Apr. 28,
             1999).



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chemical in their environment. Some bacteria are naturally resistant. Other
bacteria acquire resistance to antibacterials to which they once were
susceptible.

The development of resistance to an antibacterial is complex. Susceptible
bacteria can become resistant by acquiring resistance genes from other
bacteria or through mutations in their own genetic material (DNA). Once
acquired, the resistance characteristic is passed on to future generations
and sometimes to other bacterial species.

Antibacterials have been shown to promote antibacterial resistance in at
least three ways: through (1) encouraging the exchange of resistant genes
between bacteria, (2) favoring the survival of the resistant bacteria in a
mixed population of resistant and susceptible bacteria, and (3) making
people and animals more vulnerable to resistant infection.2 Although the
contribution of antibacterials in promoting resistance has most often been
documented for antibacterial drugs, there are also reports of disinfectant
use contributing to resistance and concerns about the potential for
antiseptics to promote resistance. For example, in the case of
disinfectants, researchers have found that chlorinated river water contains
more bacteria that are resistant to streptomycin than does nonchlorinated
river water.3 Also, it has been shown that some kinds of Escherichia coli
(E. coli) resist triclosan—an antiseptic used in a variety of products,
including soaps and toothpaste.4 This raises the possibility that antiseptic
use could contribute to the emergence of resistant bacteria.

While antibacterials are a major factor in the development of resistance,
many other factors are also involved—including the nature of the specific
bacteria and antibacterial involved, the way the antibacterial is used,
characteristics of the host, and environmental factors. Therefore, the use
of antibacterials does not always lead to resistance.




2
 See, for example, (1) F. Doucet-Populaire and others, “Inducible Transfer of Conjugative Transposon
Tn1545 from Enterococcus faecalis to Listeria moncytogenes in the Digestive Tracts of Gnotobiotic
Mice,” Antimicrobial Agents and Chemotherapy, Vol. 35 (1991), pp. 185-87; (2) V. L. Yu and others,
“Patient Factors Contributing to the Emergence of Gentamicin-Resistant Serratia marcescens,” The
American Journal of Medicine, Vol. 66 (1979), pp. 468-72; and (3) R. P. Mouton and others,
“Correlations Between Consumption of Antibiotics and Methicillin Resistance in Coagulase Negative
Staphylococci,” Journal of Antimicrobial Chemotherapy, Vol. 26 (1990), pp. 573-83.
3
J. L. Armstrong and others, “Selection of Antibiotic-Resistant Standard Plate Count Bacteria During
Water Treatment,” Applied and Environmental Microbiology, Vol. 44 (1982), pp. 308-16.
4
 L. M. McMurry and others, “Triclosan Targets Lipid Synthesis,” Nature, Vol. 394 (1998), pp. 531-32.



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                                         Although we found many sources of information about the public health
Data Insufficient to                     burden in the United States attributable to resistant bacteria, each source
Determine Full Extent                    provides data on only part of the burden. Specifically, we found
of Public Health                         information about resistant diseases that result in hospitalization or are
                                         acquired in the hospital and information about two specific diseases—TB
Burden Associated                        and gonorrhea. Moreover, no systematic information is available about
With Antibacterial                       deaths from diseases caused by resistant bacteria or about the costs of
                                         treating resistant disease. Consequently, the overall extent of disease,
Resistance                               death, and treatment costs resulting from resistant bacteria is unknown.


Estimates From Hospital                  The primary source of information on cases of disease caused by resistant
Data                                     bacteria is the National Hospital Discharge Survey (NHDS)—conducted
                                         annually by CDC’s National Center for Health Statistics (NCHS).5 It estimates
                                         drug-resistant infections among hospitalized patients, including both
                                         patients with a resistant infection that caused them to be hospitalized and
                                         patients who acquired a resistant infection while in the hospital for
                                         another reason. According to this survey, in 1997, hospitals discharged
                                         43,000 patients who had been diagnosed with and treated for infections
                                         from drug-resistant bacteria. (See table 1.)

Table 1: Estimated Number of Yearly
Short-Stay Hospital Discharges Listing                                                1994             1995             1996              1997a
Infection With Drug-Resistant Bacteria   Number of discharges                       11,000           18,000           22,000              43,000
Among Diagnoses, 1994 Through 1997       a
                                             Data for 1997 are unpublished.

                                         Source: CDC, NCHS, National Hospital Discharge Survey.



                                         These numbers, however, should be interpreted cautiously. The survey’s
                                         diagnostic codes for designating infections with drug-resistant bacteria
                                         are, in most cases, not required for reimbursement, and they went into
                                         effect only in October 1993—though the survey has been conducted since
                                         1965. Therefore, estimating the number of cases of infections with
                                         drug-resistant bacteria based on these codes likely results in an
                                         underestimate. In addition, increases in the number of discharged patients
                                         who had been treated for infections from drug-resistant bacteria may
                                         reflect an increase in the use of the new codes and not an actual increase
                                         in the incidence of resistant infections.




                                         5
                                          E. J. Graves and L. J. Kozak, “Detailed Diagnoses and Procedures, National Hospital Discharge
                                         Survey, 1996,” Vital and Health Statistics, Series 13, No. 138 (NCHS, 1998).



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                                        Data on five predominant bacterial infections acquired in hospitals from
                                        CDC’s Hospital Infections Program further suggest that the estimates
                                        derived from NHDS may be too low. Since the discharge survey is not
                                        limited to specific infections and includes diseases acquired outside the
                                        hospital, it would be expected that estimates derived from the survey
                                        would be greater. However, estimates from the Hospital Infections
                                        Program indicate that the number of resistant infections acquired in
                                        hospitals is many times greater. (See table 2.)

Table 2: Estimated Number of
Hospital-Acquired Infections Caused     Resistant Bacteria                                                                       Cases
by Selected Resistant Bacteria in the   Methicillin-resistant S. aureus                                                          70,000
United States in 1995
                                        Methicillin-resistant coagulase-negative Staphylococcus                                 121,000
                                        Vancomycin-resistant Enterococcus                                                        14,000
                                        Ceftazidime-resistant Pseudomonas aeruginosa                                             10,000
                                        Ampicillin-resistant E. coli                                                             64,000
                                        Total                                                                                   279,000
                                        Source: CDC, Hospital Infections Program, unpublished extrapolation from the National
                                        Nosocomial Infections Surveillance system.



                                        These estimates should also be interpreted cautiously. CDC estimated the
                                        number of cases for each type of resistant bacteria by extrapolating from
                                        data on the 276 hospitals participating in CDC’s National Nosocomial
                                        Infections Surveillance (NNIS) system to all hospitals in the United States.
                                        NNIS hospitals, however, are not representative of all hospitals; they are
                                        disproportionately large, urban, and affiliated with medical schools, and
                                        therefore likely to have more severely ill patients. Moreover, unlike NHDS,
                                        which surveys discharge codes that denote actual infections, the NNIS
                                        hospitals test bacterial samples in laboratories and thus may be detecting
                                        resistant bacteria that did not necessarily result in a patient treated for
                                        infection. Consequently, these CDC extrapolations probably overestimate
                                        the number of cases of these types of resistant bacterial disease.


Data From Surveillance of               Another source of information on cases of disease caused by resistant
Disease                                 bacteria is data developed through surveillance of infectious diseases.
                                        However, nationwide data on such diseases are currently limited to TB and
                                        gonorrhea.

Tuberculosis                            CDC’s Division of Tuberculosis Elimination collects reports of all verified
                                        TB cases from states. TB is an infectious disease, most commonly of the




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                                      lungs, caused by Mycobacterium tuberculosis. In response to increased
                                      incidence of TB in the late 1980s and early 1990s, CDC, in conjunction with
                                      state and local health departments, expanded national surveillance to
                                      include tests for resistance for all confirmed cases reported in 1993 and
                                      later. In 1997, the most recent year for which data have been published,
                                      tests were performed on 88.5 percent of confirmed TB cases reported in
                                      the United States.6 Of these, 12.6 percent were resistant to at least one
                                      antituberculosis drug. Although the number of cases of TB has declined,
                                      the proportion of cases that are resistant has remained relatively stable
                                      (see fig. 1).


Figure 1: Number and Percentage of
Tuberculosis Patients Infected With   Number                                                                                Percentage
Resistant Bacteria, by Year of Case   2500                       2,373                                                             100
                                          2,475
Report                                                                                  2,181
                                                                                                              2,049
                                      2000                                                                                            80


                                                                                                                              1,763
                                      1500                                                                                            60



                                      1000                                                                                            40



                                          500                                                                                         20

                                                14.0             13.5                   12.9                   13.4            12.6

                                            0                                                                                         0

                                            1993                 1994                   1995                   1996            1997

                                                       Number of Resistant TB Cases
                                                       Percentage of TB Cases That Are Resistant



                                      Source: CDC, Division of Tuberculosis Elimination.


Gonorrhea                             Through its Division of Sexually Transmitted Disease Prevention, CDC also
                                      conducts nationwide surveillance of gonorrhea, which is caused by the
                                      bacterium Neisseria gonorrhoea. CDC supplements nationwide
                                      surveillance of gonorrhea infections with a Gonococcal Isolate
                                      Surveillance Project (GISP), a network consisting of clinics in 27 cities. In
                                      1997, 33.4 percent of the gonococcal samples collected by GISP were


                                      6
                                       CDC, “Reported Tuberculosis in the United States, 1997” (Atlanta, Ga.: July 1998).



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                                        resistant to penicillin, or tetracycline, or both.7 Figure 2 shows that the
                                        proportion of gonorrhea resistant to these drugs has remained relatively
                                        stable since 1991.


Figure 2: Number and Percentage of
Gonorrhea Patients Infected With        Number                                                                                     Percentage
Resistant Bacteria in GISP Cities, by   2000                                                                                              100
Year of Case Report                                        1,814
                                              1,699
                                                                          1,602
                                        1600                                              1,526          1,542                               80

                                                                                                                        1,347         1,513

                                        1200                                                                                                 60



                                            800                                                                                              40
                                                  32.4      33.6                                         31.6                         33.4
                                                                           30.4           30.5                           29.0


                                            400                                                                                              20



                                              0                                                                                              0

                                              1991          1992           1993           1994           1995           1996          1997

                                                         Number of Resistant Gonorrhea Cases
                                                         Percentage of Gonorrhea Cases That Are Resistant



                                        Source: CDC, Division of Sexually Transmitted Disease Prevention.


Other Diseases                          Nationwide data on other diseases that can be caused by resistant bacteria
                                        are not yet available, but efforts are under way to monitor invasive
                                        diseases caused by Streptococcus pneumoniae (S. pneumoniae), including
                                        meningitis and bacteremia.8 This bacterium was once routinely treatable
                                        with penicillin; however, since the mid-1980s, penicillin resistance has
                                        emerged, and some infections are susceptible only to vancomycin. In 1995,
                                        resistant S. pneumoniae was designated as a nationally reportable disease,
                                        and by 1998, 37 states were conducting public health surveillance on this
                                        bacterium.9


                                        7
                                         CDC, “Sexually Transmitted Disease Surveillance, 1997” (Atlanta, Ga.: Sept. 1998).
                                        8
                                         Meningitis is inflammation of the membranes surrounding the brain or spinal cord; bacteremia is an
                                        infection of the blood.
                                        9
                                         Emerging Infectious Diseases: Consensus on Needed Laboratory Capacity Could Strengthen
                                        Surveillance (GAO/HEHS-99-26, Feb. 5, 1999).



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                                        We found no efforts yet under way to collect systematic information on
                                        bacterial resistance in other diseases that have exhibited resistance to the
                                        antibacterial drugs usually used to treat them. Many common diseases
                                        caused by bacteria that have exhibited resistance—such as otitis media,
                                        gastric ulcers, cystitis, and strep throat—are typically acquired outside the
                                        hospital. In addition, they typically do not result in hospitalization, are
                                        often treated without laboratory identification of the underlying cause,
                                        and are not notifiable. Thus, they are not reflected in existing data sources.


Deaths and Treatment                    The number of deaths caused by resistant bacteria cannot be determined
Costs                                   because the standard source of data on deaths—vital statistics compiled
                                        from death certificates—does not distinguish resistant infections from
                                        susceptible ones. A number of studies provide some information about
                                        deaths, but they are generally small studies of outbreaks in a single
                                        hospital or community. These studies suggest that infections from
                                        resistant bacteria are more likely to be fatal than those from nonresistant
                                        bacteria.10 One recent study on deaths in a larger population over a
                                        relatively longer period of time—all hospitalized patients in 13 New York
                                        City metropolitan area counties in 1995—found that patients with
                                        infections from methicillin-resistant Staphylococcus aureus (MRSA) were
                                        more than 2.5 times more likely to die than patients with infections from
                                        methicillin-sensitive Staphylococcus aureus (MSSA).11 (See table 3.)

Table 3: Cases, Deaths, and Treatment
Costs of Patients Infected With S.                                                  Deaths
aureus in Metropolitan New York City                        Number of        Percent of                      Direct medical costs
Hospitals in 1995, by Resistance        Resistance             cases             cases       Number                  Total    Per patient
Category
                                        MRSA                      2,780                21%        590        $94,500,000          $34,000
                                        MSSA                     10,770                 8         810        339,400,000           31,500
                                        Source: Rubin and others, “The Economic Impact of Staphylococcus aureus Infection in New
                                        York City Hospitals,” p. 14.



                                        Because the number of cases of resistant disease is not known and the
                                        average treatment cost of cases is not available, we are unable to estimate
                                        the overall cost of treating drug-resistant bacterial disease. Although
                                        information about the cost of treating infections caused by resistant
                                        bacteria is limited, it suggests that resistant infections are generally more

                                        10
                                          S. D. Holmberg and others, “Health and Economic Impacts of Antimicrobial Resistance,” Reviews of
                                        Infectious Diseases, Vol. 9, No. 6 (1987), pp. 1065-78.
                                        11
                                         R. J. Rubin and others, “The Economic Impact of Staphylococcus aureus Infection in New York City
                                        Hospitals,” Emerging Infectious Diseases, Vol. 5, No. 1 (1999), pp. 9-17.



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                                    costly to treat than those caused by susceptible bacteria.12 For example, in
                                    the study of the impact of S. aureus infections in metropolitan New York
                                    City hospitals, direct medical costs—consisting of hospital charges,
                                    professional fees during hospitalization, and medical services after
                                    discharge—were 8 percent higher for a patient with MRSA than for a patient
                                    with MSSA. The higher cost of treating MRSA infections reflects the higher
                                    cost of vancomycin use, longer hospital stay, and patient isolation
                                    procedures. Similarly, a study of the cost of treating TB, based on a survey
                                    of five programs—in Alabama; Illinois; New Jersey; Texas; and Los
                                    Angeles, California—showed that outpatient therapy costs for
                                    multidrug-resistant TB were more than 3 times as great as for susceptible
                                    TB.13 (See table 4.) Appendix IV describes other studies of the cost of
                                    treating resistant disease.

Table 4: Expenditures in 1991 for
Outpatient TB Therapy, by Patient   Patient type                                                                         Cost per patient
Type                                Susceptible TB                                                                                   $2,300
                                    Single-drug-resistant TB                                                                          5,000
                                    Multidrug-resistant TB                                                                            8,000
                                    Source: Brown and others, “Health-Care Expenditures for Tuberculosis in the United States,” p.
                                    1598.




                                    Existing data on resistant bacteria, which can cause infections, and
Increasing Resistance               antibacterial use, which can promote the development of resistance,
and Widespread                      provide clues for understanding how the future U.S. public health burden
Antibacterial Use                   could develop. Because resistant bacteria from anywhere in the world
                                    could result in an infection in the United States, the development of
Could Increase Public               resistance globally must also be considered.14 The data available suggest
Health Burden                       that antibacterial resistance is increasing worldwide and that antibacterial
                                    agents are used extensively. Consequently, the U.S. public health burden
                                    could increase.




                                    12
                                     Holmberg and others, “Health and Economic Impacts of Antimicrobial Resistance,” and L. A. Lee
                                    and others, “Increase in Antimicrobial-Resistant Salmonella Infections in the United States,
                                    1989-1990,” Journal of Infectious Diseases, Vol. 170, No. 1 (1994), pp. 128-34.
                                    13
                                     R. E. Brown and others, “Health-Care Expenditures for Tuberculosis in the United States,” Archives
                                    of Internal Medicine, Vol. 155, No. 15 (1995), pp. 1595-1600.
                                    14
                                     The transport of resistant bacteria by people, animals, and products creates the opportunity for such
                                    bacteria to enter the United States and contribute to an increase in the public health burden. Each
                                    year, tens of millions of travelers enter and depart from the United States, and in 1997, over 9 billion
                                    kilograms of fruits and vegetables in this country were imported.


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Available Data Indicate        Without routine testing and systematic data collection globally, the
That Antibacterial             prevalence of resistant bacteria worldwide cannot be determined. Data
Resistance Is Increasing       from laboratories that monitor for resistant bacteria, however, show that
                               resistance in human and animal bacteria is increasing in four ways.

                           •   Bacteria known to be susceptible are becoming resistant. Some bacteria
                               that were once susceptible to certain antibacterials are now resistant to
                               them. For example, Yersinia pestis, which causes plague, was universally
                               susceptible to streptomycin, chloramphenicol, and tetracycline. Extensive
                               testing of samples of specific kinds of Yersinia pestis collected between
                               1926 and 1995 in Madagascar had not detected any multidrug resistance. In
                               1995, however, a multidrug-resistant sample was isolated from a 16-year
                               old boy in Madagascar.15

                           •   The proportion of resistant bacteria is increasing in some populations of
                               bacteria. Although existing surveillance systems predominantly monitor
                               the development of resistance in bacteria from sick people in specific
                               countries, and while different geographical areas may exhibit different
                               antibacterial resistance patterns, data overall indicate that a greater
                               proportion of samples being tested are positive for resistance.16 For
                               example, according to data from CDC, S. pneumoniae is becoming
                               increasingly resistant in the United States—that is, an increasing
                               percentage of S. pneumoniae samples that are tested in CDC laboratories
                               are resistant to penicillin. (See fig. 3.)




                               15
                                M. Galimand and others, “Multidrug Resistance in Yersinia pestis Mediated by a Transferable
                               Plasmid,” New England Journal of Medicine, Vol. 337 (1997), pp. 677-80.
                               16
                                 Of the studies we identified that examined the resistance patterns of particular populations of
                               bacteria, most found the percentage of resistant bacteria increased over time. However, in some cases,
                               the percentage of bacteria resistant to a specific antibacterial has been relatively stable or declined.



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Figure 3: Penicillin Resistance in S. Pneumoniae, 1979 Through 1997




                                          Source: CDC, Sentinel Surveillance Network (1979 through 1994) and Active Bacterial Core
                                          Surveillance system (1995 through 1997).




                                          Studies also show that resistance is increasing in other countries. For
                                          example, a DOD-funded study on diarrhea-causing bacteria isolated from
                                          indigenous persons in Thailand over 15 years shows that ciprofloxacin
                                          resistance among Campylobacter samples increased from 0 percent before
                                          1991 to 84 percent in 1995.17 In Iceland, the frequency of
                                          penicillin-resistant samples of S. pneumoniae rose from 2.3 percent in
                                          1989 to 17 percent in 1992, after detecting penicillin-resistant S.



                                          17
                                           C. W. Hoge and others, “Trends in Antibiotic Resistance Among Diarrheal Pathogens Isolated in
                                          Thailand Over 15 Years,” Clinical Infectious Diseases, Vol. 26 (1998), pp. 341-45.



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    pneumoniae for the first time in 1988.18 In the Netherlands,
    metronidazole-resistant Helicobacter pylori in several Dutch hospitals
    increased from 7 percent in 1993 to 32 percent in 1996.19

    In addition to increases in resistance in bacteria that affect people,
    resistance among bacteria in animals has also been increasing. In Finland,
    two surveys—carried out in 1988 and 1995—studied the prevalence of
    inflamed udders in cows and the antibacterial susceptibility of the bacteria
    that caused them. The investigators found that the proportion of certain
    types of S. aureus resistant to at least one antibacterial drug increased
    from 37 percent in 1988 to almost 64 percent in 1995.20 In the Netherlands,
    a study of Campylobacter isolated from poultry products between 1982
    and 1989 showed that resistance to quinolones increased from 0 percent to
    14 percent.21

•   Bacteria are becoming resistant to additional antibacterials. Some bacteria
    that were considered resistant to a particular antibacterial drug have
    developed resistance to additional antibacterials. For example, in 1989, a
    multiresistant clone of MRSA was detected in Spain and a multiresistant
    clone of penicillin-resistant S. pneumoniae was detected in Iceland.22
    Similarly, a few cases of MRSA have exhibited an intermediate level of
    resistance to vancomycin, in addition to their resistance to many other
    antibacterials.

•   Resistant bacteria are spreading. Over the past decade, a number of
    resistant bacteria are also believed to have spread around the world.
    Bacteria can be traced by their DNA patterns. Evidence that the DNA
    patterns of resistant bacteria from geographically diverse places are the
    same or very similar combined with evidence that resistance in these
    bacteria have been prevalent in one place and not in the other allows
    researchers to conclude that a bacterial clone has spread. With

    18
     S. Soares and others, “Evidence for the Introduction of a Multiresistant Clone of Serotype 6B
    Streptococcus pneumoniae from Spain to Iceland in the Late 1980s,” Journal of Infectious Diseases,
    Vol. 168 (1993), pp. 158-63.
    19
     E. J. van der Wouden and others, “Rapid Increase in the Prevalence of Metronidazole-Resistant
    Helicobacter pylori in the Netherlands,” Emerging Infectious Diseases, Vol. 3 (1997), pp. 385-89.
    20
     V. Myllys and others, “Bovine Mastitis in Finland in 1988 and 1995—Change in Prevalence and
    Antimicrobial Resistance,” Acta Vet Scand, Vol. 39 (1998), pp. 119-26.
    21
     H. P. Endtz and others, “Quinolone Resistance in Campylobacter Isolated From Man and Poultry
    Following the Introduction of Fluoroquinolones in Veterinary Medicine,” Journal of Antimicrobial
    Chemotherapy, Vol. 27 (1991), pp. 199-208.
    22
     A clone is genetically and biochemically identical or nearly identical to the parent bacterium.
    Bacteria are considered clones if there are enough similarities that the probability that the bacteria are
    different approaches 0.


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                          B-281564




                          international travel and trade and the continuous exchange of bacteria
                          among people, animals, and agricultural hosts and environments, resistant
                          bacteria can spread from one country to another. For example, in 1989, a
                          multidrug-resistant MRSA, known as the Iberian clone, was identified during
                          an outbreak in Spain. This clone has spread to hospitals in Portugal, Italy,
                          Scotland, Germany, and Belgium.23 In 1998, resistant Shigella on parsley
                          entered the United States from Mexico, causing two outbreaks of
                          shigellosis in Minnesota.24


Antibacterials Are Used   Antibacterials are used around the world for a number of purposes in
Widely, but Data          various settings, and their use can vary from country to country.
Quantifying Use and       Antibacterial drugs are used in both people and animals. Antiseptics and
                          disinfectants are used in hospitals, homes, schools, restaurants, farms,
Residues Are Limited      food processing plants, water treatment facilities, and other places. While
                          measures of total antibacterial use in most countries are not available,
                          some data have been published on the total amount of antibacterials
                          produced or sold in the United States. Figure 4 shows the total weight of
                          antibacterial drugs (chemicals, not finished products) produced in the
                          United States from 1950 to 1994.




                          23
                           R. Mato and others, “Spread of the Multiresistant Iberian Clone of Methicillin-Resistant
                          Staphylococcus aureus (MRSA) to Italy and Scotland,” Microbial Drug Resistance, Vol. 4 (1998), pp.
                          107-12.
                          24
                            Minnesota Department of Health, unpublished data.


                          Page 14                              GAO/HEHS/NSIAD/RCED-99-132 Antimicrobial Resistance
                                           B-281564




Figure 4: Antibacterial Drug Production, by Year




                                           a
                                            According to the U.S. International Trade Commission, data on antibiotics were not published in
                                           1992 to avoid disclosure of individual company operations.


                                           Source: Reports of the U.S. International Trade Commission.




                                           Page 15                              GAO/HEHS/NSIAD/RCED-99-132 Antimicrobial Resistance
                                             B-281564




                                             According to the Environmental Protection Agency (EPA), a total of
                                             3.3 billion pounds of active ingredients were produced for disinfectants in
                                             1995.25 We found no estimates of production, sales, or usage of antiseptics.
                                             Overall accumulations of antibacterial residue in soil, water, and food are
                                             unknown. However, studies have shown that while some antibacterial
                                             drugs are rapidly degraded in soil, others remain in their active form
                                             indefinitely and that 70 to 80 percent of the drugs administered on fish
                                             farms end up in the environment.26

                                         •   Antibacterial drugs are used to prevent and treat disease in humans. NCHS
                                             estimates that from 1980 until 1997, the U.S. antibacterial drug
                                             prescription rate remained approximately constant at about 150
                                             prescriptions per 1,000 physician office visits (see table 5). Since 1992,
                                             NCHS has collected data on drugs prescribed in hospital emergency and
                                             outpatient departments. These data indicate that in 1996, the last year for
                                             which all data are available, antibacterial drugs were prescribed 19 million
                                             times a year in emergency departments and 8 million times a year in
                                             outpatient departments, for a total of 133 million prescriptions for
                                             physician office, hospital emergency, and outpatient settings combined.27


Table 5: Number (in Millions) and Rate (per 1,000 Visits) of U.S. Antibacterial Drug Prescriptions Written by Office-Based
Physicians, 1980, 1981, 1985, and 1989 Through 1997
                               1980    1981     1985     1989     1990     1991    1992     1993    1994     1995     1996                   1997
Millions of prescriptions        86      87         88       109       111        103       127        109           97   111      106        108
Rate per 1,000 visits           149     149        139       157       158        154       167        152       142      160      145        137
                                             Note: Prescriptions for topical antibacterial drugs are not included.

                                             Source: NCHS, public use data tape documentation and National Ambulatory Medical Care
                                             Survey for years shown.



                                             In general, use of antibacterial drugs differs among the countries that have
                                             been studied.28 (Most countries studied are developed countries, but India,
                                             South Africa, several Latin American nations, and other less developed

                                             25
                                              National Service Center for Environmental Publications, “Streamlining Registration of Antimicrobial
                                             Pesticides, EPA Progress Report, 1997” (EPA739R97001).
                                             26
                                              B. Halling-Sorensen and others, “Occurrence, Fate and Effects of Pharmaceutical Substances in the
                                             Environment: A Review,” Chemosphere, Vol. 36 (1998), pp. 357-93.
                                             27
                                              Personal communication with L. F. McCaig, NCHS, based in part on L. F. McCaig and J. M. Hughes,
                                             “Antimicrobial Drug Prescribing in Ambulatory Care Settings in the United States, 1995-96,”
                                             presentation at the 1998 convention of the American Public Health Association.
                                             28
                                              N. F. Col and R. W. O’Connor, “Estimating Worldwide Current Antibiotic Usage: Report of Task
                                             Force 1,” Reviews of Infectious Diseases, Vol. 9, Supplement 3 (1987), pp. S232-S243.



                                              Page 16                              GAO/HEHS/NSIAD/RCED-99-132 Antimicrobial Resistance
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    countries have also been studied.) For example, Japan and Spain have
    higher rates of cephalosporin sales than do the other countries studied.
    The Danish Antimicrobial Resistance Monitoring and Research
    Programme has reported that antibiotic consumption in Denmark’s
    primary care sector declined from 12.8 defined daily doses per 1,000
    population in 1994 to 11.3 in 1997.29 Available reports indicate that the
    amount of antibacterial drug use per person in some other developed
    countries, such as Canada, is greater than in the United States.30 In less
    developed countries—including Kenya, Bangladesh, and Nigeria—use of
    some antibacterial drugs tends to be relatively great for the segment of the
    population who can afford them.31

•   Antibacterial drugs are used to prevent and treat disease in food animals,
    pets, and plants. Antibacterial drugs, often the same ones used to prevent
    and treat disease in humans, are also used in veterinary medicine, fish
    farming, beekeeping, and agriculture. Veterinarians prescribe antibacterial
    drugs to treat disease in food animals, such as cattle and swine, and in
    companion animals, such as dogs and cats. A variety of antibacterial drugs
    are available without prescription in feed stores and pet stores.32 Fish
    farmers who raise fish, such as salmon, catfish, and trout, put antibacterial
    drugs in water to treat bacterial infection; and beekeepers use
    antibacterial drugs to prevent and treat bacterial infection in honeybees.
    Antibacterial drugs are also sprayed on some fruits and vegetables, such as
    pears and potatoes, as well as on other crops, such as rice and orchids.
    Chemical industry sources estimated that in 1985, the total weight of
    antibacterial drugs used to treat and prevent disease in cattle, swine, and
    poultry in the United States was 13.8 million pounds, but they have not
    published more recent estimates.

•   Antibacterial drugs are used to enhance the growth of food animals and
    other commercially important animals. Antibacterial drugs are also often
    administered in the United States as feed additives to enhance growth and
    increase feed efficiency. As feed additives, they are primarily used for food
    animals, such as livestock and poultry, but they are also given to other
    commercially important animals, such as mink. Many antibacterial drugs
    used to promote growth can be purchased without a prescription.


    29
      Eurosurveillance Weekly, Feb. 4, 1999.
    30
     Health Protection Branch—Laboratory Centre for Disease Control, “Controlling Antimicrobial
    Resistance: An Integrated Plan for Canadians,” Canada Communicable Disease Report, Vol. 23S7.
    31
      For example, I. N. Okeke and others, “Socioeconomic and Behavioral Factors Leading to Acquired
    Bacterial Resistance to Antibiotics in Developing Countries,” Emerging Infectious Diseases, Vol. 5
    (1999), pp. 18-27.
    32
      S. B. Levy, The Antibiotic Paradox (New York: 1992), p. 175.
    Page 17                               GAO/HEHS/NSIAD/RCED-99-132 Antimicrobial Resistance
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    Chemical industry sources estimated that in 1985, 4.5 million pounds of
    antibacterial drugs were used for growth enhancement in cattle, swine,
    and poultry.

    Some other developed countries, such as Canada, also use antibacterial
    drugs for growth enhancement. However, because of concerns about
    antibacterial resistance, several countries have banned certain uses of
    some drugs or particular drugs altogether. For example, Sweden banned
    all antibacterials for use in animal feed without prescription, and the
    European Union banned several specific antibacterial feed additives. FDA
    has efforts under way to determine if similar actions are warranted in this
    country.33

•   Antibacterials are applied to various surfaces and environments to inhibit
    bacterial growth. Antibacterials are also used to disinfect various surfaces
    and environments in institutional settings, such as hospitals and
    laboratories; in industrial settings, such as food processing and
    manufacturing plants; and in environmental health settings, such as water
    treatment facilities. They are also used as antiseptics to disinfect skin and
    wounds. The presence of antibacterials in hundreds of consumer products,
    including soaps, cat litter, cutting boards, and even ballpoint pens,
    contributes to the public’s exposure to them. According to industry
    sources, almost 700 new antibacterial products were introduced between
    1992 and the middle of 1998. Many of these, such as cribs and toys, are for
    use by children. The American Academy of Pediatrics’ Committee on
    Infectious Diseases is conducting a study of the use and safety of
    antibacterials in these products and other consumer products, such as
    hand soaps, that children may come into contact with.

•   Antibacterial residues in some foods are monitored, but little is known
    about other residues. USDA inspects meat and poultry for antibacterial
    residues and reports on all samples with detectable levels. However, the
    levels of antibacterials in food that might promote resistance are not
    known and, therefore, cannot be factored into the current limits. USDA also
    regularly tests samples of fruits and vegetables for contamination by
    certain pesticides, such as insecticides, but not for antibacterials. EPA
    assesses risks of toxicity, but not antibacterial resistance, from residues
    on fruits and vegetables using data collected by USDA.




    33
     See FDA, “A Proposed Framework for Evaluating and Assuring the Human Safety of Microbial
    Effects of Antimicrobial New Animal Drugs Intended for Use in Food-Producing Animals” (1999).



    Page 18                             GAO/HEHS/NSIAD/RCED-99-132 Antimicrobial Resistance
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                      Residues can also end up in water and soil. Studies in Europe have shown
                      that antibacterials can be found in bodies of water that supply drinking
                      water.34 However, we know neither the extent to which antibacterials in
                      the environment promote the development of resistance nor how much
                      antibacterial residue ends up in the environment or in food (with the
                      exception of meat) or drinking water.



                      A number of federal agencies and international organizations that receive
A Number of Federal   U.S. funds collect information about the number of resistant infections,
and International     the prevalence of resistant bacteria, the cost of treating resistant disease,
Agencies Are          and the use of antibacterials; some ongoing efforts involve collaboration
                      among several agencies. In addition, nearly two dozen agencies are
Collecting Some       coordinated under the Committee on International Science, Engineering,
Information About     and Technology of the White House National Science and Technology
                      Council to address the threat of emerging infectious diseases, which
Antibacterial         includes drug-resistant infections. Efforts to improve existing data sources
Resistance            and to create new ones are under way at several agencies, and we expect
                      that over the next few years new information will allow better
                      characterization of the public health burden. Several agencies also have
                      data or access to data that, although not originally intended for these
                      purposes, could be used to learn more about the numbers of resistant
                      infections, treatment costs, and usage of antibacterials. Table 6
                      summarizes the ongoing and newly initiated efforts of agencies to collect
                      information as well as potential data sources.




                      34
                       J. Raloff, “Drugged Waters: Does It Matter That Pharmaceuticals Are Turning Up in Water
                      Supplies?” Science News, Vol. 153 (Mar. 21, 1998), pp. 187-89.



                      Page 19                              GAO/HEHS/NSIAD/RCED-99-132 Antimicrobial Resistance
                                                 B-281564




Table 6: Information on the Number of Resistant Infections, Resistant Bacteria, Treatment Costs, and Antibacterial Use
Collected by Federal Agencies and Federally Funded Organizations
Ongoing efforts                             Newly initiated efforts                   Other efforts and potential data sources
Centers for Disease Control and Prevention
— Through NHDS, estimates drug-resistant          — Made drug-resistant S. pneumoniae
infections among hospitalized patients.           nationally reportable in 1995.
— Collects from the states reports of every       — Established an international surveillance
case of TB diagnosed in the United States.        program involving more than 30 countries
— Conducts nationwide surveillance for            in 1997; the program distributes
gonorrhea, and monitors antibacterial             information about emerging resistance.
resistance in Neisseria gonorrhoea.
— Through NNIS, reports antibacterial
resistance rates for bacteria associated with
hospital-acquired infections.
— Collects data on resistant bacteria,
resistant infections, and antibacterial use in
hospitals.
— Collects data on use of antibacterial drugs
for nonhospitalized patients.
— Monitors drug resistance in S. pneumoniae
from patients with meningitis or infection of
the bloodstream.
Centers for Disease Control and Prevention and U.S. Geological Survey (USGS)
                                                  CDC is conducting a study on the
                                                  presence of pharmaceuticals, including
                                                  antibacterial agents, in confined animal
                                                  feed operations in Ohio and Iowa and on
                                                  resistance patterns in the microbial
                                                  communities of these operations. USGS
                                                  will be testing the surface water around
                                                  these facilities for residues.
Health Care Financing Administration
                                                                                                 Data on beneficiaries could be used to
                                                                                                 learn more about resistant infections,
                                                                                                 antibacterial drug use, and treatment costs.
National Institutes of Health
                                                  Funds a project to establish the first         Intends to award a contract to establish a
                                                  network and database on antibiotic             network for linking multidisciplinary
                                                  resistance in bacteria that normally live in   investigators focusing on S. aureus and
                                                  close contact with people and animals but      antibacterial resistance and establish a
                                                  generally do not cause disease in their        repository for samples of resistant S.
                                                  primary hosts.                                 aureus.
                                                                                                                                 (continued)




                                                 Page 20                           GAO/HEHS/NSIAD/RCED-99-132 Antimicrobial Resistance
                                                   B-281564




Ongoing efforts                                     Newly initiated efforts                         Other efforts and potential data sources
Food and Drug Administration
Samples domestically produced and                   Proposed a framework for ensuring human         — Data that sponsors are required to
imported food, and analyzes them for                safety from new and existing animal drugs,      submit in annual reports on approved
pesticide residues, including antibacterials, to    which includes collecting more detailed         human and animal drugs could be used to
enforce tolerances set by EPA.                      drug sales information than currently           estimate antibacterial production.
                                                    collected. Requested marketing data to be       — Data purchased from IMS, a private
                                                    reported on a state or regional basis to        company, could be used to assess the
                                                    facilitate monitoring for resistance for some   distribution of antibacterial drugs.
                                                    recently approved fluoroquinolone
                                                    antibacterial products used in cattle and
                                                    poultry.
Department of Agriculture
— Samples meat and poultry products and                                                             Developing a program to test for the
analyzes them for residues, including                                                               presence of microorganisms in produce
antibacterials, to enforce tolerances set by                                                        and will make these samples available for
EPA.                                                                                                research.
— Through the National Animal Health
Monitoring System, periodically assesses the
patterns of antibacterial drug use by
veterinarians and in animal production.
Centers for Disease Control and Prevention, Food and Drug Administration, and U.S. Department of Agriculture
CDC collaborates with FDA and USDA under            In fiscal year 1998, the National
the National Antimicrobial Resistance               Antimicrobial Resistance Monitoring
Monitoring System—Enteric Bacteria program          System—Enteric Bacteria program was
to monitor resistance in Salmonella,                expanded to include monitoring for
Campylobacter, and E. coli isolated from            Campylobacter and E. coli in animals.
people and Salmonella isolated from animals.
Environmental Protection Agency
                                                                                                    Data that manufacturers are required to file
                                                                                                    annually on products registered with the
                                                                                                    EPA could be used to estimate
                                                                                                    antibacterial production.
Environmental Protection Agency and U.S. Geological Survey
                                                    EPA is conducting a study on the
                                                    presence of pharmaceuticals, including
                                                    antibacterial agents, in a farm environment
                                                    and on resistance patterns in the microbial
                                                    communities of the farm. USGS will be
                                                    testing the surface and ground water
                                                    around the farm for residues.
                                                                                                                                    (continued)




                                                   Page 21                           GAO/HEHS/NSIAD/RCED-99-132 Antimicrobial Resistance
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Ongoing efforts                                   Newly initiated efforts                       Other efforts and potential data sources
Department of Defense
In some developing countries, tropical            — Studies on antibacterial resistance in S. Data on beneficiaries could be used to
medical research units collaborate with their     pneumoniae and Streptococcus pyogenes learn more about resistant infections,
host nations to develop networks for              are under way at 13 military sites in the   antibacterial drug use, and treatment costs.
surveillance of emerging infections; they also    United States.
study resistance in bacteria that cause           — Collaborating with MRL Pharmaceutical
disease acquired in the community.                Services, a private company, to develop a
                                                  system for collecting laboratory data on
                                                  resistance from military hospitals in the
                                                  United States.
Department of Veterans Affairs
Conducts an annual census in VA facilities        Developed a national surveillance system Data on beneficiaries could be used to
nationwide to collect data on infections,         to track 14 diseases and disease-causing learn more about resistant infections,
including those caused by drug-resistant TB       microbes, including several resistant           antibacterial drug use, and treatment costs.
and resistant Enterococcus and                    bacteria, in all 171 VA health care facilities.
pneumococcus.
U.S. Agency for International Development
Funds studies in India to determine drug          — Funds numerous surveillance activities
resistance levels of bacteria that cause          and studies around the world.
pneumonia.                                        — Studies antimicrobial drug use in
                                                  Mozambique, Russia, Peru, Nepal, and
                                                  Ghana.
World Health Organization
— Helps countries establish national
surveillance networks to detect resistant
bacteria in humans and animals, and
provides computer software (WHONET) for
collecting and analyzing antimicrobial
resistance data.
— Coordinates the sharing of data collected
from different countries to provide a global
database.




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                      Although many studies have documented cases of infections that are
Conclusions           difficult to treat because they are caused by resistant bacteria, the full
                      extent of the problem remains unknown. The development and spread of
                      resistant bacteria worldwide and the widespread use of various
                      antibacterials create the potential for the U.S. public health burden to
                      increase. A number of federal and federally funded agencies are collecting
                      information about different aspects of antibacterial resistance, and some
                      ongoing efforts involve collaboration among agencies. However, there is
                      little information about the extent of the following:

                  •   common diseases that can be caused by resistant bacteria, are acquired in
                      the community, and do not typically result in hospitalization, such as otitis
                      media;
                  •   the development of resistant properties in bacteria that do not normally
                      cause disease but that can pass these properties on to bacteria that do;
                  •   antibacterial use, particularly in animals, and antibacterial residues in
                      places other than food; and
                  •   the development of resistant disease and resistant bacteria and the use of
                      antibacterials globally.

                      Without improvements in existing data sources and more information in
                      these areas, it is not possible to accurately assess the threat to the U.S.
                      public health posed by resistant bacteria. As you have requested, we will
                      be conducting further studies to (1) explore options for improving existing
                      data sources and developing new ones; (2) identify the factors that
                      contribute to the development and spread of antimicrobial resistance; and
                      (3) consider alternatives for addressing the problem.


                      We provided a draft of this report to CDC, EPA, FDA, the Health Care
Agency Comments       Financing Administration (HCFA), the National Institutes of Health (NIH),
                      USDA, and to experts at other agencies. In general, the agencies agreed with
                      our findings. The Department of Health and Human Services (HHS)
                      concurred with the information and conclusions presented in the report
                      but “is concerned that the draft report . . . is not as unequivocal as it could
                      be in stating the gravity of the problem.” While we recognize that resistant
                      bacteria threaten public health, we concluded that currently available data
                      on the public health and economic consequences of antibacterial
                      resistance are too limited for us to characterize the full extent of the
                      problem. The agencies also provided technical or clarifying comments,
                      which we incorporated as appropriate.




                      Page 23                      GAO/HEHS/NSIAD/RCED-99-132 Antimicrobial Resistance
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As agreed with your office, unless you publicly announce its contents
earlier, we plan no further distribution of this report until 30 days from the
date of this letter. At that time, we will send copies to the Honorable
Donna E. Shalala, Secretary of HHS; the Honorable Jeffrey Koplan, Director
of CDC; the Honorable Jane Henney, Commissioner of FDA; the Honorable
Nancy-Ann Min DeParle, Administrator of HCFA; the Honorable Harold
Varmus, Director of NIH; the Honorable Carole Browner, Administrator of
EPA; the Honorable Dan Glickman, Secretary of USDA; and other interested
parties. We will make copies available to others upon request.

If you or your staff have any questions, please contact me at (202) 512-7114
or Cynthia Bascetta, Associate Director, at (202) 512-7101. Other major
contributors to this report are listed in appendix V.

Sincerely yours,




William J. Scanlon
Director, Health Financing
  and Public Health Issues




Page 24                      GAO/HEHS/NSIAD/RCED-99-132 Antimicrobial Resistance
Page 25   GAO/HEHS/NSIAD/RCED-99-132 Antimicrobial Resistance
Contents



Letter                                                                                             1


Appendix I                                                                                        28
Scope and
Methodology
Appendix II                                                                                       29
Resistant Bacteria
Appendix III                                                                                      35
Antibacterial Uses
Appendix IV                                                                                       39
Cost of Treating
Resistant Infections
Appendix V                                                                                        41
Major Contributors to
This Report
Tables                  Table 1: Estimated Number of Yearly Short-Stay Hospital                    5
                          Discharges Listing Infection With Drug-Resistant Bacteria Among
                          Diagnoses, 1994 Through 1997
                        Table 2: Estimated Number of Hospital-Acquired Infections                  6
                          Caused by Selected Resistant Bacteria in the United States in
                          1995
                        Table 3: Cases, Deaths, and Treatment Costs of Patients Infected           9
                          With S. aureus in Metropolitan New York City Hospitals in 1995,
                          by Resistance Category
                        Table 4: Expenditures in 1991 for Outpatient TB Therapy, by               10
                          Patient Type
                        Table 5: Number and Rate of U.S. Antibacterial Drug                       16
                          Prescriptions Written by Office-Based Physicians, 1980, 1981,
                          1985, and 1989 Through 1997




                        Page 26                   GAO/HEHS/NSIAD/RCED-99-132 Antimicrobial Resistance
          Contents




          Table 6: Information on the Number of Resistant Infections,                20
            Resistant Bacteria, Treatment Costs, and Antibacterial Use
            Collected by Federal Agencies and Federally Funded
            Organizations


Figures   Figure 1: Number and Percentage of Tuberculosis Patients                    7
            Infected With Resistant Bacteria, by Year of Case Report
          Figure 2: Number and Percentage of Gonorrhea Patients Infected              8
            With Resistant Bacteria in GISP Cities, by Year of Case Report
          Figure 3: Penicillin Resistance in S. pneumoniae, 1979 Through             12
            1997
          Figure 4: Antibacterial Drug Production, by Year                           15




          Abbreviations

          CDC        Centers for Disease Control and Prevention
          DNA        deoxyribonucleic acid
          DOD        Department of Defense
          EPA        Environmental Protection Agency
          FDA        Food and Drug Administration
          GISP       Gonococcal Isolate Surveillance Project
          HCFA       Health Care Financing Administration
          HHS        Department of Health and Human Services
          ICARE      Intensive Care Antimicrobial Resistance Epidemiology
          MRSA       methicillin-resistant Staphylococcus aureus
          MSSA       methicillin-sensitive Staphylococcus aureus
          NCHS       National Center for Health Statistics
          NHDS       National Hospital Discharge Survey
          NIH        National Institutes of Health
          NNIS       National Nosocomial Infections Surveillance
          OTA        Office of Technology Assessment
          TB         tuberculosis
          USDA       U.S. Department of Agriculture
          USGS       U.S. Geological Survey
          VISA       vancomycin intermediate-resistant Staphylococcus aureus
          VRE        vancomycin-resistant Enterococcus


          Page 27                    GAO/HEHS/NSIAD/RCED-99-132 Antimicrobial Resistance
Appendix I

Scope and Methodology


             Although resistance has been observed in many kinds of microbes—
             including bacteria, viruses, parasites, and fungi—the scope of our work
             was limited to bacteria. The scope of our work was also limited to
             resistance to chemical antibacterials, although bacteria can be resistant to
             other phenomena, such as radiation or extremes of temperature. We
             focused on estimating the numbers of cases of illness and death caused by
             resistant bacteria and on estimating the costs of treating resistant
             infections; we did not, however, attempt to capture all aspects of the
             public health burden. Our focus is on what is known about the burden in
             the United States resulting from resistance, but we considered global
             developments in assessing the potential future burden. The federal efforts
             we examined include international activities assisted by federal funds. We
             did not attempt to examine all federal efforts related to antimicrobial
             resistance, but focused on efforts to collect and provide information on
             cases of resistant infections, resistance in bacteria, use of antibacterials,
             and the cost of treating resistant diseases.

             To conduct our work, we reviewed scientific and medical literature;
             identified sources of data; and consulted experts in government, including
             those at the Centers for Disease Control and Prevention (CDC), the
             National Institutes of Health, the Food and Drug Administration (FDA), the
             Health Care Financing Administration, the Agency for Health Care Policy
             and Research, the Environmental Protection Agency (EPA), the U.S.
             Department of Agriculture (USDA), the Department of Veterans Affairs, the
             Department of Defense (DOD), the U.S. Agency for International
             Development, and the World Health Organization. We also consulted
             experts in academia and private industry. We did not conduct our own
             statistical analyses to estimate the public health burden or independently
             verify the databases or analyses of others. We conducted our work
             between June 1998 and April 1999 in accordance with generally accepted
             government auditing standards.




             Page 28                     GAO/HEHS/NSIAD/RCED-99-132 Antimicrobial Resistance
Appendix II

Resistant Bacteria


               Bacteria are single-celled microbes that exist almost everywhere—in
               water, soil, plants, animals, and humans. They can transfer between hosts
               and be carried across borders through travel and trade. They typically live
               as members of communities of different organisms, such as fungi and
               algae. Bacteria and other microbes that normally occupy a particular niche
               are referred to collectively as the microflora of that niche. These
               organisms compete with each other for nutrients, oxygen, and space.
               Those that do not compete successfully are likely to be eliminated from
               the habitat. A foreign microbe usually has difficulty establishing itself in a
               stable community for this reason. Preventing foreign microbes from
               colonizing a site of the body is one of the most important benefits
               provided by normal microflora to their hosts. If an environmental
               disturbance, such as the introduction of an antibacterial drug, changes the
               balance of the community by killing the microflora susceptible to the
               effects of the drug, resistant foreign bacteria would have the opportunity
               to grow in the community and possibly cause disease.

               Most bacteria are harmless, and some are even useful to their hosts. For
               example, some bacteria normally found in the digestive tracts of animals
               and people help their hosts to digest nutrients that are important sources
               of energy, proteins, and vitamins. While most bacteria are benign, others
               are capable of causing disease. For example, E. coli O157:H7—which can
               be found in the feces of healthy cattle and can transfer to people through
               contaminated undercooked ground meat or unpasteurized milk products
               and juices—produces a toxin that causes severe stomach and bowel
               disorders and can result in failure of the blood-clotting system, acute
               kidney failure, and even death. The same bacteria that can cause disease in
               an individual may also be part of that individual’s normal microflora.
               Enterococcus faecalis is part of the microflora of the human intestine and,
               until recently, were generally considered harmless. These bacteria are
               harmless while they remain in the intestine, but when they enter the
               bloodstream through a wound or as a complication of invasive medical
               procedures, they can cause a blood infection.

               Like other living things, as bacteria grow and multiply, they also evolve
               and adapt to changes in their surroundings, which includes the
               introduction of antibacterial drugs into their environment. Some bacteria
               may have mutations in their DNA that allow them to avoid the effects of the
               antibacterial and outgrow the other bacteria in the population. They may
               also acquire plasmids—small, circular, self-replicating DNA molecules in
               addition to their own chromosomes—carrying genes that confer resistance
               to specific antibacterials. Like the bacteria that move freely between hosts



               Page 29                      GAO/HEHS/NSIAD/RCED-99-132 Antimicrobial Resistance
                            Appendix II
                            Resistant Bacteria




                            and environments, these plasmids can be transferred from one bacterium
                            to another within a species and sometimes between certain species of
                            bacteria.


Methods of Assessing        Laboratories may use different types of antibacterial susceptibility tests,
Antibacterial Resistance    which can produce varying results. Discrepancies in test results can have
Differ                      therapeutic consequences if testing indicates that a particular type of
                            bacteria will be susceptible to a specific antibacterial while, in practice,
                            the drug fails to eliminate the infection. In general, however, the drug of
                            choice usually can treat the susceptible strains successfully. Even in some
                            instances where a susceptible organism is not killed, it is not necessarily a
                            failure of the test to predict clinical susceptibility. Many other factors,
                            including the site of the infection and the duration of treatment, can make
                            a susceptible bacteria appear clinically resistant.

                            In addition to the use of different tests to determine resistance, countries
                            currently follow a number of laboratory standards for interpreting the test
                            results. One study found that Scandinavia, Germany, the Netherlands, the
                            United Kingdom, and France all follow different standards. Spain and
                            some other southern European countries are mainly under the influence of
                            the standards followed in the United States. Therefore, the
                            breakpoints—where lines are drawn to distinguish between susceptible
                            and intermediate resistance or intermediate resistance and high
                            resistance—can differ among various countries around the world,
                            although data sets should be comparable at laboratory facilities that use
                            the same method and standards over time.


Resistant Bacteria Are      In addition to determining the clinical effect of antibacterials against
Found Around the World in   bacteria, antibacterial susceptibility tests are used to detect the emergence
People and Animals          and spread of resistance. While there is a lack of routine testing and
                            systematic data collection on antibacterial resistance globally, existing
                            data on resistant bacteria in particular hosts and from specific geographic
                            locations show that a variety of resistant bacteria can be found in people
                            and animals in many different areas around the world. The level of
                            resistance, however, can vary among settings and geographic areas. For
                            example, while vancomycin-resistant Enterococcus (VRE) occurs in both
                            hospitalized and nonhospitalized individuals in Europe, a study of healthy
                            individuals; hospitalized patients; and farm animals in Houston, Texas,
                            indicates that in the greater Houston metropolitan area, VRE is rare or




                            Page 30                     GAO/HEHS/NSIAD/RCED-99-132 Antimicrobial Resistance
Appendix II
Resistant Bacteria




nonexistent among nonhospitalized people.35 Similarly, investigators from
the SENTRY36 Antimicrobial Surveillance Program found that the
proportion of VRE isolated from the bloodstream of patients in the United
States during a 6-month period was about 18 percent, while none of the
Enterococcus samples from Canada were vancomycin resistant.37

Much of the testing and surveillance are also conducted predominantly on
patient samples, so the data do not reflect the levels of resistance for
bacteria in all other environments. These efforts, however, provide some
information about where resistant bacteria can be found. For example, in
Portugal, the prevalence of methicillin-resistant S. aureus has remained
high at 50 to 65 percent in Portuguese hospitals between 1992 and 1995.38
In the United States, the National Antimicrobial Resistance Monitoring
System—Enteric Bacteria,39 which tests Salmonella samples isolated from
people, found that 21.7 percent of the Salmonella samples were resistant
to streptomycin, while all were susceptible to ciprofloxacin. A DOD medical
research unit in Peru tested disease-causing bacteria that affect the
intestine and found that 38 percent of the Campylobacter samples were
resistant to ciprofloxacin; 52 percent of the Shigella samples, 99 percent of
the Salmonella samples, and 85 percent of the E. coli samples were
resistant to azithromycin; and all Vibrio cholerae samples were sensitive
to quinolones.40 CDC investigators tested Shigella from patients in
outpatient clinics in Burundi and found that 100 percent were multidrug
resistant.41

Testing of bacteria that colonize animals has also shown varying levels of
resistance among different species of animals. For example, the April 1998

35
 T. M. Coque and others, “Vancomycin-Resistant Enterococci From Nosocomial, Community, and
Animal Sources in the United States,” Antimicrobial Agents and Chemotherapy, Vol. 40 (1996), pp.
2605-9.
36
 SENTRY is a global surveillance program designed to detect trends in antimicrobial resistance. It is
sponsored by Bristol-Myers Squibb Co., and over 72 laboratories from four continents currently
participate.
37
 M. A. Pfaller and others, “Bacterial Pathogens Isolated From Patients With Bloodstream Infection:
Frequencies of Occurrence and Antimicrobial Susceptibility Patterns From the SENTRY Antimicrobial
Surveillance Program (United States and Canada, 1997),” Antimicrobial Agents and Chemotherapy,
Vol. 42 (1998), pp. 1762-70.
38
  I. S. Sanches and others, “Multidrug-Resistant Iberian Epidemic Clone of Methicillin-Resistant
Staphylococcus aureus Endemic in a Hospital in Northern Portugal,” Microbial Drug Resistance, Vol.
1 (1995), pp. 299-306.
39
 The program was established by USDA, FDA, and CDC, with participation from local and state health
departments.
40
  DOD, unpublished data.
41
 Personal communication with Robert V. Tauxe, Chief, Foodborne and Diarrheal Diseases Branch,
Division of Bacterial and Mycotic Diseases, National Center for Infectious Diseases, CDC.
Page 31                               GAO/HEHS/NSIAD/RCED-99-132 Antimicrobial Resistance
                              Appendix II
                              Resistant Bacteria




                              Report of the National Antimicrobial Resistance Monitoring
                              System—Enteric Bacteria shows that for samples of Salmonella from sick
                              animals, 75 percent of swine samples, 69 percent of turkey samples,
                              37 percent of cattle samples, 23 percent of horse samples, and 13 percent
                              of chicken samples tested positive for resistance to tetracycline. The same
                              samples were all susceptible to ciprofloxacin. Percentages were lower
                              when samples from healthy animals are included. In the Netherlands, a
                              study of bacterial samples taken from 23 dogs and 24 cats at an urban
                              general veterinary practice showed that 48 percent of the dogs and
                              16 percent of the cats were colonized with VRE. This incidence of VRE in
                              pets exceeded that among the people living in the same geographic area,
                              which was 2 to 3 percent.42 In an effort to establish a baseline of resistance
                              to therapeutic antibacterial agents among bacteria from food animals in
                              Denmark, the Danish Integrated Antimicrobial Resistance Monitoring
                              Programme tested indicator bacteria (such as E. coli and Enterococcus
                              faecalis), zoonotic bacteria (such as Campylobacter jejuni), and animal
                              pathogens (such as Actinobacillus pleuropneumoniae).43 The results from
                              their study showed that resistance to all of the antibacterial agents can be
                              found, although there were significant differences in the occurrence of
                              resistance among different bacterial species.44


Resistance Genes Can          In addition to testing for resistance in bacterial samples from people and
Transfer to Different Kinds   animals, some laboratories around the world are examining bacteria for
of Bacteria                   the presence and transfer of specific resistance genes. Genetic exchanges
                              do not occur indiscriminately within bacterial populations. Barriers to
                              gene transfers—such as destruction of genes considered foreign by the
                              host bacterium—can reduce the likelihood of successful transfer events.
                              Nevertheless, data on the transfer of resistance genes between different
                              kinds of bacteria can provide some information about where these genes
                              may have been acquired and how they spread to different environments
                              and geographic locations. A number of studies examining the DNA
                              sequences of resistance genes show similarities among these genes in
                              evolutionarily diverse bacteria, suggesting that some transfers have been
                              occurring naturally between certain kinds of bacteria. For example,
                              plasmids carrying resistance genes that were found in bacteria isolated


                              42
                                 A. van Belkum and others, “Vancomycin-Resistant Enterococci in Cats and Dogs,” Lancet, Vol. 348
                              (1996), pp. 1038-39.
                              43
                               Indicator bacteria are bacteria that easily acquire resistance and are found in different animal
                              species; zoonotic bacteria are bacteria that can be transmitted between animals and humans.
                              44
                               F. M. Aarestrup and others, “Resistance to Antimicrobial Agents Used for Animal Therapy in
                              Pathogenic, Zoonotic, and Indicator Bacteria Isolated From Different Food Animals in Denmark: A
                              Baseline Study for the Danish Integrated Antimicrobial Resistance Monitoring Programme
                              (DANMAP),” APMIS, Vol. 106 (1998), pp. 745-70.
                              Page 32                                GAO/HEHS/NSIAD/RCED-99-132 Antimicrobial Resistance
Appendix II
Resistant Bacteria




from patients suffering from multiresistant Shigella infections on a Hopi
Indian reservation in New Mexico appeared to come from multiresistant E.
coli.45

Most studies on the exchange of resistance genes among different
bacterial species have been conducted under laboratory-defined
conditions. While some of these studies suggest that resistance genes can
be transferred between certain species and even across bacterial genera,46
evidence of gene transfer in the laboratory demonstrates only that the
transfer is possible, not whether that transfer will occur in nature. Many
studies are also focused on bacteria isolated from patients. Even where
there is surveillance for resistance, the surveillance systems tend to be
limited to the monitoring of specific bacterial diseases, such as TB and
gonorrhea, or disease-causing bacteria, such as S. pneumoniae. Therefore,
less information is available on the prevalence of resistant genes in
bacteria isolated from healthy people and that do not generally harm their
primary host. Nevertheless, there is some evidence that resistance genes in
these bacteria may play a role in the spread of antibacterial resistance.

For example, an interspecies gene transfer appears to have occurred in the
United States in 1979, when a multiresistant plasmid was identified in
Kentucky in hospital patients and personnel infected with S. aureus. A
year earlier, a like plasmid was isolated from Staphylococcus epidermidis
on hospital patients, which suggests that the same plasmid was transferred
from these bacteria to S. aureus.47 Bacteria from different body sites of
one host may also exchange genes. For example, studies on
tetracycline-resistant Bacteroides and Prevotella suggest that genetic
exchange may occur between bacteria from the gastrointestinal tract and
bacteria found in the mouth.48 In a study of gene transfers in simulated
natural microenvironments, transfers were observed between bacteria

45
 R. V. Tauxe and others, “Interspecies Gene Transfer In Vivo Producing an Outbreak of Multiply
Resistant Shigellosis,” Journal of Infectious Diseases, Vol. 160 (1989), pp. 1067-70.
46
 Like other organisms, each bacterium is a member of an order, a family, a genus, and a species. A
species can be further subdivided into strains of bacteria. Staphylococcus and Escherichia are genera,
while aureus is a species of Staphylococcus and coli is a species of Escherichia.
47
 Staphylococcus epidermidis and S. aureus are bacteria that normally live on the skin and mucous
membranes of humans. M. L. Cohen and others, “Common R-plasmids in Staphylococcus aureus and
Staphylococcus epidermidis During a Nosocomial Staphylococcus aureus Outbreak,” Antimicrobial
Agents and Chemotherapy, Vol. 21 (1982), pp. 210-15.
48
 N. B. Shoemaker and others, “Evidence for Natural Transfer of a Tetracycline Resistance Gene
Between Bacteria From the Human Colon and Bacteria From the Bovine Rumen,” Applied and
Environmental Microbiology, Vol. 58 (1992), pp. 1313-20; and D. G. Guiney and K. Bouie, “Detection of
Conjugal Transfer Systems in Oral, Black-Pigmented Bacteroides spp.,” Journal of Bacteriology, Vol.
172 (1990), pp. 495-97.



Page 33                               GAO/HEHS/NSIAD/RCED-99-132 Antimicrobial Resistance
Appendix II
Resistant Bacteria




from different hosts—cow E. coli to fish Aeromonas salmonicida in
marine water, cow E. coli to human E. coli on a hand towel treated with
cow’s milk, and pig E. coli to human E. coli on a cutting board.49 Resistant
bacteria, therefore, are not only a potential cause of disease but also may
be a source of resistance genes that can be transferred to benign and
disease-causing bacteria of diverse origins.




49
 H. Kruse and H. Sorum, “Transfer of Multiple Drug Resistance Plasmids between Bacteria of Diverse
Origins in Natural Microenvironments,” Applied and Environmental Microbiology, Vol. 60 (1994), pp.
4015-21.



Page 34                             GAO/HEHS/NSIAD/RCED-99-132 Antimicrobial Resistance
Appendix III

Antibacterial Uses


                    Antibacterials are recognized as major contributors in the development of
                    antibacterial resistance. There are many kinds of antibacterials, varying in
                    how they are used and in the agencies that have jurisdiction over them.
                    Both the amount and usefulness of information on the quantities of
                    antibacterials used are limited.


How They Are Used   Pharmacologists and physicians recognize several classes of antibacterial
                    drugs that can differ in their mechanisms of action, killing, or inhibiting
                    the growth of bacteria in varied ways. Therefore, for a given kind of
                    bacterial infection in a human, a particular antibacterial drug will usually
                    be the drug of choice—or first-line treatment—with one or more
                    second-line treatments usually available if the drug of choice cannot be
                    used or fails to stop the infection. The therapeutic uses of antibacterial
                    drugs are well known, but their preventive role may be less appreciated.
                    About half of all antibacterial drugs used on surgical patients in large
                    hospitals are used to prevent possible infections. The percentage of the
                    antibacterial drugs prescribed outside the hospital for preventive as
                    opposed to therapeutic purposes is unknown. Antibacterial drugs are also
                    used to prevent and treat disease in plants and animals and to promote
                    growth in food animals.

                    Antiseptics and disinfectants are also used for a variety of purposes. For
                    example, phenolic compounds, such as triclosan, are used in hand soaps
                    and toothpastes; nitrogen heterocycles are used as preservatives in
                    cosmetics and other products; sulfur compounds are used as food
                    preservatives; and gaseous sterilants are often used in hospitals on
                    equipment that cannot be sterilized at high temperatures. Other commonly
                    used antiseptics and disinfectants include chlorine; ethyl alcohol;
                    formaldehyde; hydrogen peroxide; and metal compounds, such as
                    mercurochrome.


Jurisdiction Over   In the United States, all drugs introduced into interstate commerce,
Antibacterials      including antibacterials used in human and animal medicine, are subject to
                    FDA approval. All pesticides, including antibacterial drugs used on plants,
                    must be registered with EPA. Most antibacterial drugs for human use
                    require a prescription, but a few that are topically applied are available
                    without a prescription. In some other countries, however, antibacterial
                    drugs for humans that act systemically may be available without a
                    prescription. Some antibacterial drugs for animal use require a




                    Page 35                     GAO/HEHS/NSIAD/RCED-99-132 Antimicrobial Resistance
                  Appendix III
                  Antibacterial Uses




                  prescription, but some are available without a prescription in pet stores
                  and feed stores. FDA determines whether a prescription is required.

                  FDA also has jurisdiction over other antibacterials that come in direct
                  contact with people, such as antiseptic hand soaps. EPA has jurisdiction
                  over those that do not, such as detergents, antibacterials used to
                  impregnate cutting boards, and gases used to sterilize equipment. Some
                  products do not neatly fall under a single agency. FDA and EPA are
                  attempting to clarify some of the “gray area” between their respective
                  jurisdictions, with special attention to those products that may come in
                  contact with food.

                  FDA requires manufacturers to maintain distribution records, including
                  quantity, for drug products administered to humans and animals. These
                  data are required to be reported annually to FDA, but FDA does not compile
                  them to yield estimates of aggregate antibacterial drug usage. FDA’s Center
                  for Drug Evaluation and Research, which handles human drugs, expects
                  that when it moves to a planned new computer system and requires
                  certain changes to the way marketing information is submitted,
                  preparation of such estimates will be easier. FDA’s Center for Veterinary
                  Medicine, which handles animal drugs, has initiated some special
                  postapproval programs to monitor the use of fluoroquinolone
                  antibacterials in poultry and cattle. The center is also changing the way
                  marketing information is submitted and enhancing its database to
                  facilitate development of information on antibacterial usage generally. EPA
                  requires producers of pesticides, some of which are antibacterials, to
                  report annually on the amounts of pesticide produced, distributed, and
                  sold during the past year. It has provided usage estimates for some kinds
                  of antibacterial pesticides.50


Quantities Used   We found some data on usage, but different sources of data capture use in
                  different ways, such as weight produced, weight sold, amount sold in
                  dollars, number of prescriptions, and number of doses. The U.S.
                  International Trade Commission published annually the weights of all
                  antibiotics (chemicals, not finished products) produced in the country
                  from 1950 to 1994. These figures do not necessarily indicate the amount of
                  antibiotics used domestically, as some produced here may have been
                  exported, and some produced elsewhere may have been imported.
                  Although there is some indication of an increase in production over the
                  years, the figures sometimes fluctuate for unknown reasons. For example,

                  50
                    “Streamlining Registration of Antimicrobial Pesticides: 1997 EPA Progress Report.”



                  Page 36                               GAO/HEHS/NSIAD/RCED-99-132 Antimicrobial Resistance
Appendix III
Antibacterial Uses




from 1993 to 1994, the weight almost tripled, from nearly 29 million
pounds to 83 million pounds. Such fluctuations suggest that these figures
be interpreted with caution. Moreover, these figures reveal nothing about
how much of each antibacterial drug is used in each setting at a given
point in time and geographic location.

Settings in human medicine using antibacterial drugs are ambulatory
settings (physicians’ offices, emergency rooms, and outpatient clinics) and
inpatient settings (hospital wards and rooms). The National Center for
Health Statistics (NCHS) estimates the use of commonly prescribed drugs in
ambulatory settings for the country as a whole and for large geographic
regions. Since 1980, NCHS has periodically collected data on drugs
prescribed in physicians’ offices as part of its series of National
Ambulatory Medical Care Surveys. Since 1992, NCHS has also collected data
on drugs prescribed in hospital emergency and outpatient departments as
part of the National Hospital Ambulatory Medical Care Survey.

While NCHS does not survey hospitals to obtain national estimates of
antibacterial drug use in inpatients, such estimates can be derived by
combining NCHS’ estimates of the average inpatient population and data
from CDC’s Intensive Care Antimicrobial Resistance Epidemiology (ICARE)
project, which obtains usage rates aggregated over most antibacterial
drugs from its 41 participating hospitals. When rates from the ICARE survey
are projected to the entire population of U.S. hospitals, it is estimated that
about 82 million daily doses of antibacterial drugs were administered in
hospitals in 1995. This figure is an underestimate to the extent that the
survey does not include all antibacterial drugs, and it is an overestimate to
the extent that the hospitals in ICARE’s sample probably tend to use more
antibiotics than does the average hospital.

Records from pharmaceutical companies and large health care insurers or
health plans may also contain information on drug use in ambulatory care
but are not generally available to the public. FDA has, for the purpose of
studying adverse drug reactions, obtained usage data from IMS Health, a
company that collects them and sells them to firms in the pharmaceutical
industry and to other customers. FDA, in collaboration with GAO, analyzed
these data to estimate ambulatory use. The resulting estimates tend to be
higher than those derived from the NCHS data and, unlike the NCHS data,
decline over the years from 1993 to 1997. The reasons for these
discrepancies include methodological differences in data collection and
analysis.




Page 37                      GAO/HEHS/NSIAD/RCED-99-132 Antimicrobial Resistance
Appendix III
Antibacterial Uses




Other potential sources for human usage data include agencies that
provide health care, such as DOD, the Department of Veterans Affairs, the
Health Care Financing Administration, and various private managed care
and health insurance plans. These sources may not collect such data from
all whom they serve or be able to provide nationally representative usage
estimates, but the available data could be used to assess use in defined
segments of the population.

Companies that manufacture drugs for animals and plants do not usually
publish production data, but the Animal Health Institute, an industry
association, has released data on sales in dollars of antibacterials used in
animals. In 1991, the last year for which the data were released, the
amounts were $382 million for feed additives and $369 million for
pharmaceuticals. Other data from the same source indicate that in the
early 1980s, the total annual sales by weight for use in livestock and
poultry varied between 10 million and 12 million pounds.




Page 38                      GAO/HEHS/NSIAD/RCED-99-132 Antimicrobial Resistance
Appendix IV

Cost of Treating Resistant Infections


               Most cost-of-treatment studies are limited to infections acquired in
               hospitals—often in only one specific site of infection—and to a small
               number of cases in a single hospital. In addition, these studies generally
               use only hospital costs. The few exceptions that we identified are
               summarized below.

               A 1987 study reviewed 185 reports of investigations of bacterial infections
               in sporadic cases and outbreaks in hospital and community settings during
               the 1970s.51 According to the authors of the study, deaths, the likelihood of
               hospitalizations, and length of hospital stays were “usually at least twice
               as great” for patients infected with drug-resistant bacteria as for those
               infected with drug-susceptible bacteria. The study is limited by the small
               number of cases in any single outbreak report and by the small number of
               comparisons with case data on both antimicrobial susceptibility or
               resistance and length of hospital stay.

               A 1989 study developed an economic model to determine the potential
               magnitude of the problem posed by drug-resistant bacteria and the data
               needed to provide a more definitive statement about its extent.52 The
               author concluded that the annual cost resulting from the reduced
               effectiveness of antimicrobial drugs “appears to be at least $100 million
               and may exceed $30 billion.” The 300-fold range comes from the author’s
               use in the economic model of differing estimates of (1) the occurrence of
               resistant disease and its case fatality rates, (2) antibiotic use, and (3) the
               value of human life.

               A 1995 report by the now defunct Office of Technology Assessment (OTA)53
               applied the 1987 twofold length of hospital stays to the charges for extra
               days of hospitalization in three hospitals in 1975 resulting from five kinds
               of hospital-acquired infections caused by six bacteria54—the number of
               which were first extrapolated from a group of sentinel hospitals to all U.S.
               hospitals55—and then reduced to the fraction that were drug-resistant in



               51
                 Holmberg and others,“Health and Economic Impacts of Antimicrobial Resistance.”
               52
                 C. E. Phelps, “Bug/Drug Resistance,” Medical Care, Vol. 27, No. 2 (1989), pp. 194-203.
               53
                 OTA, Impacts of Antibiotic-Resistant Bacteria (OTA-H-629, Sept. 1995).
               54
                 R. W. Haley and others, “Extra Charges and Prolongation of Stay Attributable to Nosocomial
               Infections: A Prospective Interhospital Comparison,” American Journal of Medicine, Vol. 70, No. 1
               (1981), pp. 51-58.
               55
                R. W. Haley and others, “The Nationwide Nosocomial Infection Rate: A New Need for Vital
               Statistics,” American Journal of Epidemiology, Vol. 121, No. 2 (1985), pp. 159-67.



               Page 39                                GAO/HEHS/NSIAD/RCED-99-132 Antimicrobial Resistance
Appendix IV
Cost of Treating Resistant Infections




hospitals in CDC’s National Nosocomial Infections Surveillance system.56
Using an estimate of $661 million for the extra charges for hospitalization
in 1992 for these proportions of the five kinds of hospital-acquired
bacterial infections, OTA doubled the costs and concluded that the extra
hospital costs associated with five drug-resistant, hospital-acquired
bacterial infections is $1.3 billion per year.




56
  W. J. Martone and others, “Incidence and Nature of Endemic and Epidemic Nosocomial Infections,”
in Hospital Infections, 3rd ed., J. V. Bennett and P. S. Brachman, eds. (Boston, Mass.: Little, Brown, and
Co., 1992), pp. 577-96.



Page 40                                GAO/HEHS/NSIAD/RCED-99-132 Antimicrobial Resistance
Appendix V

Major Contributors to This Report


               The major contributors to this report are Angela Choy, Donald Keller,
               Michele Orza, and Richard C. Weston.

               Others who contributed include Claude Adrien, George Bogart, Natalie
               Herzog, Lynne Holloway, Erin Lansburgh, Stuart Ryba, and Karen Sloan.




(108388)       Page 41                    GAO/HEHS/NSIAD/RCED-99-132 Antimicrobial Resistance
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