Antimicrobial Resistance: Data to Assess Public Health Threat From
Resistant Bacteria Are Limited (Letter Report, 04/28/99,
GAO/HEHS/NSIAD/RCED-99-132).

Pursuant to a congressional request, GAO provided information on the
potential threat to the public's health from antimicrobial resistant
bacteria, focusing on: (1) what is known about the public health
burden--in terms of illnesses, deaths and treatment costs--due to
antimicrobial resistance; (2) potential future burden, given what is
known about the development of resistance in microbes and usage of
antimicrobials; and (3) federal efforts to gather and provide
information about resistance.

GAO noted that: (1) although many studies have documented cases of
infections that are difficult to treat because they are caused by
resistant bacteria, the full extent of the problem remains unknown; (2)
GAO 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; (3) the
public health burden attributable to resistant tuberculosis and
gonorrhea is relatively well characterized because nationwide
surveillance systems monitor these diseases; (4) 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; (5) 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; (6)
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; (7) 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; (8) 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; (9) the Centers for Disease Control and Prevention (CDC)
is the primary source of information about the number of infections
caused by resistant bacteria; (10) CDC also collects information on
resistance found in bacterial samples and the use of antibacterial drugs
in human medicine; (11) CDC, the Department of Agriculture, and the Food
and Drug Administration are collaborating on efforts to monitor
resistant bacteria that can contaminate the food supply; (12) the
Department of Defense conducts surveillance for antibacterial resistance
at 13 military sites in the United States and at its 6 overseas
laboratories; and (13) the World Health Organization serves as a
clearinghouse for data on resistance in bacteria isolated from people
and animals from many different countries.

--------------------------- Indexing Terms -----------------------------

 REPORTNUM:  HEHS/NSIAD/RCED-99-132
     TITLE:  Antimicrobial Resistance: Data to Assess Public Health
	     Threat From Resistant Bacteria Are Limited
      DATE:  04/28/99
   SUBJECT:  Public health research
	     Disease detection or diagnosis
	     Infectious diseases
	     Health research programs
	     Health hazards
	     Data collection
	     Medical information systems
	     Drugs
	     Interagency relations
	     International organizations
IDENTIFIER:  CDC Hospital Infections Program
	     CDC National Nosocomial Infections Surveillance System
	     CDC Gonococcal Isolate Surveillance Project
	     Vancomycin Intermediate Resistant Staphylococcus Aureus
	     Bacterium
	     National Animal Health Monitoring System
	     National Antimicrobial Resistance Monitoring System

******************************************************************
** This file contains an ASCII representation of the text of a  **
** GAO report.  This text was extracted from a PDF file.        **
** Delineations within the text indicating chapter titles,      **
** headings, and bullets have not been preserved, and in some   **
** cases heading text has been incorrectly merged into          **
** body text in the adjacent column.  Graphic images have       **
** not been reproduced, but figure captions are included.       **
** Tables are included, but column deliniations have not been   **
** preserved.                                                   **
**                                                              **
** Please see the PDF (Portable Document Format) file, when     **
** available, for a complete electronic file of the printed     **
** document's contents.                                         **
**                                                              **
** A printed copy of this report may be obtained from the GAO   **
** Document Distribution Center.  For further details, please   **
** send an e-mail message to:                                   **
**                                                              **
**                                            **
**                                                              **
** with the message 'info' in the body.                         **
******************************************************************
ANTIMICROBIAL RESISTANCE: Data to Assess Public Health Threat From
Resistant Bacteria Are Limited GAO/HEHS/NSIAD/RCED-99-132 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

GAO United States 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

GAO/ HEHS/ NSIAD/ RCED- 99- 132 Antimicrobial Resistance Page 1

B-281564

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.)

Results in Brief Although many studies have documented cases of
infections that are 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

GAO/ HEHS/ NSIAD/ RCED- 99- 132 Antimicrobial Resistance Page 2

B-281564

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.

Background Bacteria exist almost everywhere in water, soil,
plants, animals, and 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).
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).

GAO/ HEHS/ NSIAD/ RCED- 99- 132 Antimicrobial Resistance Page 3

B-281564

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.

GAO/ HEHS/ NSIAD/ RCED- 99- 132 Antimicrobial Resistance Page 4

B-281564

Data Insufficient to Determine Full Extent of Public Health Burden
Associated With Antibacterial Resistance

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

Estimates From Hospital Data

The primary source of information on cases of disease caused by
resistant 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 Infection With Drug- Resistant Bacteria Among
Diagnoses, 1994 Through 1997

1994 1995 1996 1997 a

Number of discharges 11,000 18,000 22,000 43,000 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).

GAO/ HEHS/ NSIAD/ RCED- 99- 132 Antimicrobial Resistance Page 5

B-281564

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
by Selected Resistant Bacteria in the United States in 1995

Resistant Bacteria Cases

Methicillin- resistant S. aureus 70,000 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 Disease

Another source of information on cases of disease caused by
resistant 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

GAO/ HEHS/ NSIAD/ RCED- 99- 132 Antimicrobial Resistance Page 6

B-281564

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 Resistant Bacteria, by Year of Case Report

0 500

1000 1500

2000 2500

0 20

40 60

80 100 Number

1993 1995 1997 1996 1994 14.0 2,475

12.9 2,181

12.6 1,763

13.4 2,049

13.5 2,373

Percentage 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).

GAO/ HEHS/ NSIAD/ RCED- 99- 132 Antimicrobial Resistance Page 7

B-281564

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 Resistant Bacteria in GISP Cities, by Year of Case Report

0 400

800 1200

1600 2000

0 20

40 60

80 100 Number

1991 Number of Resistant Gonorrhea Cases

1993 1997 1994 1995 1996 1992 32.4

1,699 30.4 1,602

1,526 1,542 33.4 1,513

30.5 31.6 29.0 1,347

33.6 1,814

Percentage 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).

GAO/ HEHS/ NSIAD/ RCED- 99- 132 Antimicrobial Resistance Page 8

B-281564

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 Costs

The number of deaths caused by resistant bacteria cannot be
determined 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. aureus in Metropolitan New York City Hospitals in 1995, by
Resistance Category

Deaths Direct medical costs

Resistance Number of cases Percent of

cases Number Total Per patient

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.

GAO/ HEHS/ NSIAD/ RCED- 99- 132 Antimicrobial Resistance Page 9

B-281564

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 Type

Patient type Cost per patient

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.

Increasing Resistance and Widespread Antibacterial Use Could
Increase Public Health Burden

Existing data on resistant bacteria, which can cause infections,
and antibacterial use, which can promote the development of
resistance, provide clues for understanding how the future U. S.
public health burden could develop. Because resistant bacteria
from anywhere in the world could result in an infection in the
United States, the development of resistance globally must also be
considered. 14 The data available suggest 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.

GAO/ HEHS/ NSIAD/ RCED- 99- 132 Antimicrobial Resistance Page 10

B-281564

Available Data Indicate That Antibacterial Resistance Is
Increasing

Without routine testing and systematic data collection globally,
the prevalence of resistant bacteria worldwide cannot be
determined. Data 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.

GAO/ HEHS/ NSIAD/ RCED- 99- 132 Antimicrobial Resistance Page 11

B-281564

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.

GAO/ HEHS/ NSIAD/ RCED- 99- 132 Antimicrobial Resistance Page 12

B-281564

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.

GAO/ HEHS/ NSIAD/ RCED- 99- 132 Antimicrobial Resistance Page 13

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 Widely, but Data Quantifying Use and
Residues Are Limited

Antibacterials are used around the world for a number of purposes
in various settings, and their use can vary from country to
country. Antibacterial drugs are used in both people and animals.
Antiseptics and disinfectants are used in hospitals, homes,
schools, restaurants, farms, 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.

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

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.

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

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.

GAO/ HEHS/ NSIAD/ RCED- 99- 132 Antimicrobial Resistance Page 16

B-281564

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.

GAO/ HEHS/ NSIAD/ RCED- 99- 132 Antimicrobial Resistance Page 17

B-281564

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).

GAO/ HEHS/ NSIAD/ RCED- 99- 132 Antimicrobial Resistance Page 18

B-281564

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 and International Agencies Are Collecting Some
Information About Antibacterial Resistance

A number of federal agencies and international organizations that
receive U. S. funds collect information about the number of
resistant infections, the prevalence of resistant bacteria, the
cost of treating resistant disease, and the use of antibacterials;
some ongoing efforts involve collaboration among several agencies.
In addition, nearly two dozen agencies are coordinated under the
Committee on International Science, Engineering, and Technology of
the White House National Science and Technology Council to address
the threat of emerging infectious diseases, which includes drug-
resistant infections. Efforts to improve existing data sources 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.

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

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 infections among
hospitalized patients.  Collects from the states reports of every
case of TB diagnosed in the United States.  Conducts nationwide
surveillance for gonorrhea, and monitors antibacterial 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.  Made drug- resistant S. pneumoniae nationally
reportable in 1995.

 Established an international surveillance program involving more
than 30 countries in 1997; the program distributes information
about emerging resistance.

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 network and database on
antibiotic resistance in bacteria that normally live in close
contact with people and animals but generally do not cause disease
in their primary hosts.

Intends to award a contract to establish a network for linking
multidisciplinary investigators focusing on S. aureus and
antibacterial resistance and establish a repository for samples of
resistant S. aureus.

(continued)

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

B-281564

Ongoing efforts Newly initiated efforts Other efforts and
potential data sources Food and Drug Administration

Samples domestically produced and imported food, and analyzes them
for pesticide residues, including antibacterials, to enforce
tolerances set by EPA.

Proposed a framework for ensuring human safety from new and
existing animal drugs, which includes collecting more detailed
drug sales information than currently collected. Requested
marketing data to be reported on a state or regional basis to
facilitate monitoring for resistance for some recently approved
fluoroquinolone antibacterial products used in cattle and poultry.

 Data that sponsors are required to submit in annual reports on
approved human and animal drugs could be used to estimate
antibacterial production.  Data purchased from IMS, a private
company, could be used to assess the distribution of antibacterial
drugs.

Department of Agriculture

 Samples meat and poultry products and analyzes them for residues,
including antibacterials, to enforce tolerances set by EPA.
Through the National Animal Health Monitoring System, periodically
assesses the patterns of antibacterial drug use by veterinarians
and in animal production.

Developing a program to test for the presence of microorganisms in
produce and will make these samples available for research.

Centers for Disease Control and Prevention, Food and Drug
Administration, and U. S. Department of Agriculture

CDC collaborates with FDA and USDA under the National
Antimicrobial Resistance Monitoring System Enteric Bacteria
program to monitor resistance in Salmonella, Campylobacter, and E.
coli isolated from

people and Salmonella isolated from animals. In fiscal year 1998,
the National

Antimicrobial Resistance Monitoring System Enteric Bacteria
program was expanded to include monitoring for Campylobacter and
E. coli in 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)

GAO/ HEHS/ NSIAD/ RCED- 99- 132 Antimicrobial Resistance Page 21

B-281564

Ongoing efforts Newly initiated efforts Other efforts and
potential data sources Department of Defense

In some developing countries, tropical medical research units
collaborate with their host nations to develop networks for
surveillance of emerging infections; they also study resistance in
bacteria that cause disease acquired in the community.

 Studies on antibacterial resistance in S. pneumoniae and
Streptococcus pyogenes are under way at 13 military sites in the
United States.  Collaborating with MRL Pharmaceutical Services, a
private company, to develop a system for collecting laboratory
data on resistance from military hospitals in the United States.

Data on beneficiaries could be used to learn more about resistant
infections, antibacterial drug use, and treatment costs.

Department of Veterans Affairs

Conducts an annual census in VA facilities nationwide to collect
data on infections, including those caused by drug- resistant TB
and resistant Enterococcus and pneumococcus.

Developed a national surveillance system to track 14 diseases and
disease- causing microbes, including several resistant bacteria,
in all 171 VA health care facilities.

Data on beneficiaries could be used to learn more about resistant
infections, antibacterial drug use, and treatment costs.

U. S. Agency for International Development

Funds studies in India to determine drug resistance levels of
bacteria that cause pneumonia.

 Funds numerous surveillance activities and studies around the
world.  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.

GAO/ HEHS/ NSIAD/ RCED- 99- 132 Antimicrobial Resistance Page 22

B-281564

Conclusions Although many studies have documented cases of
infections that are 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.

Agency Comments We provided a draft of this report to CDC, EPA,
FDA, the Health Care 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.

GAO/ HEHS/ NSIAD/ RCED- 99- 132 Antimicrobial Resistance Page 23

B-281564

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

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

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

Contents Letter 1 Appendix I Scope and Methodology

28 Appendix II Resistant Bacteria

29 Appendix III Antibacterial Uses

35 Appendix IV Cost of Treating Resistant Infections

39 Appendix V Major Contributors to This Report

41 Tables Table 1: Estimated Number of Yearly Short- Stay Hospital

Discharges Listing Infection With Drug- Resistant Bacteria Among
Diagnoses, 1994 Through 1997

5 Table 2: Estimated Number of Hospital- Acquired Infections

Caused by Selected Resistant Bacteria in the United States in 1995

6 Table 3: Cases, Deaths, and Treatment Costs of Patients Infected

With S. aureus in Metropolitan New York City Hospitals in 1995, by
Resistance Category

9 Table 4: Expenditures in 1991 for Outpatient TB Therapy, by

Patient Type 10

Table 5: Number and Rate of U. S. Antibacterial Drug Prescriptions
Written by Office- Based Physicians, 1980, 1981, 1985, and 1989
Through 1997

16

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

Contents

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

20 Figures Figure 1: Number and Percentage of Tuberculosis
Patients

Infected With Resistant Bacteria, by Year of Case Report 7

Figure 2: Number and Percentage of Gonorrhea Patients Infected
With Resistant Bacteria in GISP Cities, by Year of Case Report

8 Figure 3: Penicillin Resistance in S. pneumoniae, 1979 Through

1997 12

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

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

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.

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

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

GAO/ HEHS/ NSIAD/ RCED- 99- 132 Antimicrobial Resistance Page 29

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 Antibacterial Resistance Differ

Laboratories may use different types of antibacterial
susceptibility tests, which can produce varying results.
Discrepancies in test results can have 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 Found Around the World in People and
Animals

In addition to determining the clinical effect of antibacterials
against bacteria, antibacterial susceptibility tests are used to
detect the emergence 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

GAO/ HEHS/ NSIAD/ RCED- 99- 132 Antimicrobial Resistance Page 30

Appendix II Resistant Bacteria

nonexistent among nonhospitalized people. 35 Similarly,
investigators from the SENTRY 36 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.

GAO/ HEHS/ NSIAD/ RCED- 99- 132 Antimicrobial Resistance Page 31

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 Transfer to Different Kinds of Bacteria

In addition to testing for resistance in bacterial samples from
people and animals, some laboratories around the world are
examining bacteria for 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.

GAO/ HEHS/ NSIAD/ RCED- 99- 132 Antimicrobial Resistance Page 32

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.

GAO/ HEHS/ NSIAD/ RCED- 99- 132 Antimicrobial Resistance Page 33

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.

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

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 Antibacterials

In the United States, all drugs introduced into interstate
commerce, 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

GAO/ HEHS/ NSIAD/ RCED- 99- 132 Antimicrobial Resistance Page 35

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.

GAO/ HEHS/ NSIAD/ RCED- 99- 132 Antimicrobial Resistance Page 36

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.

GAO/ HEHS/ NSIAD/ RCED- 99- 132 Antimicrobial Resistance Page 37

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.

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

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 bacteria 54 the number of which were first
extrapolated from a group of sentinel hospitals to all U. S.
hospitals 55 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.

GAO/ HEHS/ NSIAD/ RCED- 99- 132 Antimicrobial Resistance Page 39

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.

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

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

Ordering Information The first copy of each GAO report and
testimony is free. Additional copies are $2 each. Orders should be
sent to the following address, accompanied by a check or money
order made out to the Superintendent of Documents, when necessary.
VISA and MasterCard credit cards are accepted, also. Orders for
100 or more copies to be mailed to a single address are discounted
25 percent.

Orders by mail: U. S. General Accounting Office P. O. Box 37050
Washington, DC 20013

or visit: Room 1100 700 4th St. NW (corner of 4th and G Sts. NW)
U. S. General Accounting Office Washington, DC

Orders may also be placed by calling (202) 512- 6000 or by using
fax number (202) 512- 6061, or TDD (202) 512- 2537.

Each day, GAO issues a list of newly available reports and
testimony. To receive facsimile copies of the daily list or any
list from the past 30 days, please call (202) 512- 6000 using a
touchtone phone. A recorded menu will provide information on how
to obtain these lists.

For information on how to access GAO reports on the INTERNET, send
an e- mail message with "info" in the body to:

info@ www. gao. gov or visit GAO's World Wide Web Home Page at:
http:// www. gao. gov

PRINTED ON RECYCLED PAPER

United States General Accounting Office Washington, D. C. 20548-
0001

Official Business Penalty for Private Use $300

Address Correction Requested Bulk Rate

Postage & Fees Paid GAO Permit No. G100

*** End of document. ***