SUPPLEMENT ARTICLE

The Global Impact of Drug Resistance

David H. Howard,1 R. Douglas Scott II,2 Randall Packard,3 and DeAnn Jones4
1
Rollins School of Public Health, Emory University, and 2Division of Healthcare Quality Promotion, Centers for Disease Control and Prevention,
Atlanta, Georgia; 3Department of the History of Science, Medicine, and Technology and Department of History, Johns Hopkins University,
Baltimore; and 4Department of Drug Information, University Hospital, University of Alabama at Birmingham

Measuring the impact of drug resistance is an important step in understanding the scope of the problem and
formulating policies to limit the emergence and spread of resistant organisms. Studies have focused on
measuring the increased costs, morbidity, and mortality in patients with infections due to resistant versus
susceptible organisms. These have generally found that resistance worsens outcomes. By focusing only on
infected patients, however, they may understate the impact of resistance. It is important to recognize that
resistance also affects the treatment of individuals with nonresistant organisms. In areas with high rates of
resistance, physicians and governments have changed empiric therapy for malaria, tuberculosis, acute respi-
ratory infections, and other diseases, increasing overall treatment costs. In some instances, these costs may
exceed those attributable to treatment failure.

Estimates of the impact of antimicrobial resistance can
help policy makers formulate policies that encourage
appropriate use of antimicrobial drugs and prevent the
emergence and spread of resistant organisms. In this
article, we describe a framework for measuring the im-
pact of resistance, and we review previous research on
this topic. The term “impact” here refers to the in-
creased treatment costs, prevention costs, and morbid-
ity and mortality that result from resistance.
Many microorganisms have displayed antimicrobial
resistance, but we focus mainly on the pathogens re-
sponsible for malaria, tuberculosis (TB), diarrheal dis-
eases, and lower respiratory tract infections. According
to the World Health Organization (WHO), these are 4
of the top 5 infectious diseases in terms of years of life
lost (the fifth being AIDS) [1]. To date, most studies
on the impact of antimicrobial resistance have focused
narrowly on resistance to antibacterials and, more spe-
cifically, resistance among enterococcal and Staphylo-
Financial support: AstraZeneca.
Reprints or correspondence: Dr. David H. Howard, Rollins School of Public
Health, Emory University, 1518 Clifton Rd. NE, Room 610, Atlanta, GA 30322
(dhhowar@emory.edu).
Clinical Infectious Diseases 2003; 36(Suppl 1):S4–10
 2003 by the Infectious Diseases Society of America. All rights reserved.
1058-4838/2003/3602S1-0003$15.00
coccus aureus strains causing infections in hospitalized
patients [2]. Emergence of resistance in these organisms
is a worrisome trend in developed countries, but de-
veloping nations face a much greater threat from the
growth of resistance in pathogens causing community-
acquired diseases such as malaria.
FRAMEWORK FOR MEASURING THE
BURDEN OF RESISTANCE
For most diseases, the burden of the illness consists
entirely of treatment costs, morbidity and mortality
among the ill, and the costs of public prevention efforts.
Infectious diseases are different. Because they often are
communicable, fear of contagion may induce even un-
infected individuals (and their physicians) to alter their
behavior [3]. The financial and psychological costs as-
sociated with these behavioral changes add to the bur-
den of infectious diseases. Philipson and Posner [4]
argue that in the case of AIDS, for example, some in-
dividuals living in areas with a high prevalence of in-
fection will avoid risky sexual activities. They contend
that the forgone welfare from these activities is a com-
ponent of the burden of disease. These costs are ex-
cluded from standard measures of the cost of AIDS.
Most studies of the impact of antimicrobial resistance
measure costs, morbidity, and mortality in patients

S4 • CID 2003:36 (Suppl 1) • Howard et al.

 Table 1. Categorizing the impact of drug resistance.
Category Initial susceptibility testing
Case 1: Empiric therapy ineffective
against resistant organisms
Patients with IDSO
Patients with IDRO Incremental cost of second-line therapy
Case 2: Empiric therapy effective
against resistant organisms
Patients with IDSO Not applicable
Patients with IDRO Not applicable
NOTE. IDRO, infections due to resistant organisms; IDSO, infections due to susceptible organisms.
identified as having an infection due to a resistant organism.
For the reasons stated above, however, simply adding up the
incremental costs of persons with infections due to resistant
organisms understates the burden of resistance. Just as the
number of individuals infected with HIV in a given area may
affect individuals’ sexual behavior [3], local susceptibility pat-
terns may influence even physicians’ empirical treatment of
patients with infections due to susceptible organisms [5–7].
Before the identification of the infecting agent and its resistance
pattern, patients often are given empiric therapy. In areas where
resistant organisms are prevalent, physicians use alternative
drugs rather than the medication that, in the absence of resis-
tance, would be preferred on the basis of cost, dosing schedule,
or side effect profile [5–7]. This substitution occurs for most
newly diagnosed patients, not just those with infections due to
resistant organisms. The excess drug costs, inconvenience, and
side effects experienced by patients in areas where physicians
have switched empiric therapies is a seldom-measured com-
ponent of the burden of resistance. Other components of the
burden of resistance include the cost of expanded prevention
and drug-administration efforts (e.g., directly observed therapy
[DOT] for TB) that result from concerns about resistance, and
the cost of the increase in disease incidence that results from
the transmission of infection from individuals whose infections
due to resistant organisms are not treated in a timely manner.
In some instances, use of antimicrobials will reduce disease
prevalence [8]. Because effective treatment for susceptible path-
ogens reduces their transmission, drug-resistant strains will be
responsible for a larger proportion of total cases [9]. Ultimately,
the impact of treatment on transmission will be negated, and
prevalence may return to pretreatment levels [10].
For reasons outlined above, studies that examine only the
costs of treatment failure in patients with infections due to
resistant organisms may understate the impact of resistance.
The degree to which the cost of treatment differs from the
actual burden will depend on how heavily physicians weigh
individual versus community characteristics when choosing in-
No initial susceptibility testing
No costs No costs
Incremental cost of second-line therapy
Increased hospital length of stay
Incremental morbidity and mortality
Incremental cost of empiric therapy
Incremental cost of empiric therapy
itial therapy. Practices such as susceptibility testing, which pro-
vides more information about patients’ infections, will diminish
the impact of community characteristics on physicians’ choice
of therapy. In the absence of susceptibility testing, however,
physicians have few clues to help them predict whether or not
a patient is infected with a resistant pathogen, and therapy will
be selected on the basis of the prevailing levels of resistance in
the community. In such instances, the costs of substitution of
empiric therapies may account for a large portion of the total
burden of resistance [5].
Another factor to consider in measuring resistance-induced
drug substitution is the income and wealth of patients and
countries. Physicians in developed countries may be quicker to
switch empiric therapies in response to increasing resistance
levels, whereas patients in developing countries may have to
make do with older drugs and the high rate of treatment failure
with which they are associated. Consequently, for the same
underlying rate of resistance, the burden will be larger in de-
veloping countries.
Table 1 characterizes the costs of resistance according to
whether or not susceptibility testing is performed at diagnosis
and whether or not empiric therapy is effective against resistant
organisms (where resistance is defined relative to older drugs).
When empiric therapy is ineffective against resistant organisms
and physicians do not perform susceptibility testing, only pa-
tients with infections due to resistant organisms will incur costs
due to resistance. The magnitude of these costs will depend on
the length of time that patients with infections due to suscep-
tible organisms receive ineffective therapy. If physicians per-
form susceptibility testing immediately, then the cost of resis-
tance will consist only of the incremental cost of second-line
therapy and the costs of susceptibility testing. If the prevalence
of resistance is high, then physicians will begin using second-
line drugs as empiric therapy [5, 7]. As stated above, the in-
cremental cost of these drugs comprises the burden of resistance
because patients with infections due to resistant organisms are
treated with effective therapy initially. Obviously, there are
Global Impact of Drug Resistance • CID 2003:36 (Suppl 1) • S5
many episodes that do not fit neatly into this framework. It is
important to realize, however, that local practice patterns have
an impact on the types of costs associated with resistance.
RESISTANCE AND EMPIRIC THERAPY CHOICE
Few data exist on the impact of resistance on physicians’ choice
of empiric therapy. One study (1980–1998) that used data on
physicians’ drug choices for patients with otitis media at-
tempted to link changing patterns of antibiotic use to increasing
levels of resistance among Streptococcus pneumoniae [5]. The
study found that in the late 1990s, rising levels of resistance
increased antibiotic expenditures for otitis media by 20%. Treat-
ment patterns for other infectious diseases have not been sub-
ject to formal analysis, although clinical guidelines and trends
in use of various agents suggest a link between resistance and
use of newer, more expensive agents. In this section, we review
treatment guidelines, WHO reports, and other published lit-
erature on treatment patterns. In the next section of this article,
we will examine efforts to measure the costs of therapeutic
responses to resistance.
Chloroquine was the main antimalarial agent used for first-
line treatment of malaria for decades. During the past 10 years,
Plasmodium falciparum and Plasmodium vivax have grown in-
creasingly resistant to chloroquine in many areas of the world
[11]. Health care providers in Malawi and Kenya have discon-
tinued the use of chloroquine as first-line therapy and have
begun using sulfadoxine-pyrimethamine in its place. Resistance
to sulfadoxine-pyrimethamine has been documented in East
Africa, and it may not be long before it too has to be replaced
[11]. In parts of Southeast Asia, only multidrug therapies are
effective against Plasmodium strains that have developed resis-
tance to all 4 leading antimalarial drugs [12].
The WHO recommends a change in first-line treatment when
25% of patients treated experience recrudescence of infection
[6]. This is an arbitrary figure; an optimal switching policy
would balance the cost of the second-line drugs against the
benefit of prompt treatment [7]. Nevertheless, at some point,
whether it is above or below the 25% threshold, physicians
must switch first-line therapies. Phillips and Phillips-Howard
[7] calculated that the use of quinine versus chloroquine as
first-line therapy in 150 million patients with malaria would
increase spending by as much as $100 million (1990 US dollars),
a relatively large amount for the countries in which malaria is
endemic. Besides costing more, drugs such as quinine that re-
place chloroquine often are associated with higher rates of side
effects, the financial and psychological costs of which should
be attributed to resistance.
Multidrug-resistant TB (MDR-TB), which is caused by
strains resistant to ⭓2 antituberculous drugs, has been increas-
ing in a number of regions around the world. The WHO has
S6 • CID 2003:36 (Suppl 1) • Howard et al.
promoted DOT, which helps to ensure that all patients receive
a full course of the standardized drug therapy for the treatment
of TB. Depending on Mycobacterium tuberculosis resistance pat-
terns, patients are given a 3- to 4-drug regimen for a total of
6 months. In the United States, hospitals and physicians use
M. tuberculosis drug-susceptibility testing to individualize treat-
ment. As a result of a lack of financial resources, susceptibility
testing is not the standard of care in most developing countries
that have a high prevalence of MDR-TB. In these countries,
treatment is selected on the basis of regional susceptibility pat-
terns. Local prevalence rates of resistance to isoniazid 14%
require treatment with 4 first-line drugs, including isoniazid,
rifampin, pyrazinamide, and either ethambutol or streptomycin
[13]. Although the additional drugs increase the probability of
successful treatment, they also increase the chance of unwanted
side effects and augment the financial burden of the disease.
DOTS-Plus regimens, used in areas with high rates of resistance,
may include fluoroquinolones or additional drugs as empiric
therapy, further increasing treatment costs.
Diarrheal diseases are one of the leading causes of morbidity
and mortality worldwide, with the greatest burden of severe
illness involving infants and young children in developing
countries. Irrespective of future improvements in economic
development and progress in health care delivery, diarrheal
diseases are predicted to remain a leading health problem dur-
ing the next 30 years [14]. Adding to this dilemma is the large
increase in antimicrobial resistance that has emerged among
many of the major bacterial pathogens, including Shigella dy-
senteriae, Campylobacter, and Salmonella [15–18]. In sub-Sa-
haran Africa, S. dysenteriae has become resistant to multiple
drugs, with strains that are resistant to all common antimicro-
bial agents except fluoroquinolones [19]. The WHO recom-
mends that physicians use drugs that are active against at least
80% of the local Shigella isolates [20]. Drug price data in the
developing world are difficult to obtain, but in the United
States, the price of some of the newer fluoroquinolones may
exceed that of trimethoprim-sulfamethoxazole by 400% [1].
Given these price differentials, it is unlikely that developing
countries will strictly adhere to the WHO’s 80% switching cri-
teria. Nevertheless, even a small amount of switching can in-
crease costs substantially.
Acute respiratory infections comprise the fourth leading
cause of mortality worldwide, killing 13 million people each
year [1]. The majority of deaths result from lower respiratory
tract infections that occur in developing countries with high
poverty rates and inadequate medical care. The primary bac-
terial agents that cause lower respiratory infections include S.
pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis.
The rise in antimicrobial resistance among these pathogens has
been documented in many regions and now poses a major
challenge worldwide [21].
 Clinical guidelines for respiratory diseases commonly advise
physicians to tailor empiric therapy to local susceptibility pat-
terns. The Infectious Diseases Society of America (IDSA) guide-
lines for community-acquired pneumonia in adults, for ex-
ample, advise physicians to consider “regional antibiotic
susceptibility patterns for S. pneumoniae” when selecting an-
tibiotics for outpatients [22]. Unlike similar guidelines for ma-
laria, TB, or diarrheal diseases [6, 13, 19], the IDSA guidelines
do not state a specific level of resistance after which standard
empiric therapy should be removed. The guidelines recommend
that physicians use penicillin or amoxicillin to treat penicillin-
susceptible S. pneumoniae and cefotaxime, ceftriaxone, a fluor-
oquinolone, or vancomycin to treat penicillin-resistant S. pneu-
moniae. The cost of an amoxicillin treatment is about $6 (1999
US dollars), and the cost for levofloxacin, one of the recom-
mended fluoroquinolones, is $69 [20]. Suppose that, initially,
all newly diagnosed pneumonia patients in a given region re-
ceive amoxicillin. If resistance caused the market share of lev-
ofloxacin to increase from 0% to 10%, then total empiric-
therapy spending in this population would increase by 1100%.
Thus, small changes in prescribing habits brought about by
antimicrobial resistance can have a large impact on drug costs.
We used drug use data from the National Ambulatory Med-
ical Care Survey [23] for the years 1980–1996 and drug price
data from the 1996 Medical Expenditure Panel Survey [24] to
calculate the average cost of a new prescription for patients
diagnosed with otitis media (figure 1). Many factors contrib-
Figure 1. Average prescription prices, 1980–1996
uted this increase, but it is interesting to note that it occurred
concurrently with a large increase in the level of penicillin-
resistant S. pneumoniae.
RESISTANCE AND TREATMENT FAILURE
As mentioned above, previous research on the impact of re-
sistance has focused on measuring costs, morbidity, and mor-
tality in patients with infections due to resistant organisms. The
incremental effects of resistance will be inversely related to the
effectiveness of empiric therapy. When physicians use ineffec-
tive drugs as empiric therapy, resistance will manifest itself
clinically as treatment failure, and costs, morbidity, and mor-
tality will be greater for patients with infections due to resistant
organisms than for patients with infections due to susceptible
organisms.
There is a growing body of literature on the cost and health
impacts of resistance and treatment failure in hospital settings.
In 1992, the US Office of Technology Assessment (OTA) de-
veloped a summary estimate of the hospital cost of antibiotic
resistance resulting from 6 different organisms (methicillin-
resistant S. aureus [MRSA], vancomycin-resistant enterococci
[VRE], imipenem-resistant Pseudomonas aeruginosa, methicil-
lin-resistant coagulase-negative staphylococci, ampicillin-resis-
tant Escherichia coli, and resistant Enterobacter) causing infec-
tions at 5 different sites [25]. The types of health care–acquired
infections (HAI) included surgical site infections, pneumonias,
Global Impact of Drug Resistance • CID 2003:36 (Suppl 1) • S7
bacteremias, urinary tract infections, and a fifth category con-
taining other miscellaneous infections. The OTA estimated that
the cost of extra hospitalizations resulting from infections with
the resistant organisms listed above was ∼$1.3 billion (1992 US
dollars).
Recent studies examining the attributable morbidity, mor-
tality, and costs associated with sensitive and resistant S. aureus
and enterococci in hospitals (for a review of studies before 1987,
see Holmberg et al. [2]) now offer contradictory conclusions
about the impact of these organisms. A key factor underlying
these differing results is patient severity of illness and how it
is used to evaluate HAI on patient outcomes. Matched cohort
studies that do not adequately adjust for patient severity pro-
duced overestimates of the attributable mortality due to HAI
[2].
An example of a study that did not control for severity of
underlying disease of studies comes from Rubin et al. [26]. This
study examined the economic and health impacts of both com-
munity-acquired and health care–acquired MRSA infections
(pneumonia, bacteremia, and endocarditis for mortality and
costs; and surgical site infection, osteomyelitis, and septic ar-
thritis for costs only) within all New York metropolitan hos-
pitals in 1995. They used an administrative database on hospital
discharges to estimate the attributable mortality rate for MRSA
(based on unmatched group comparisons between infected and
uninfected patients) to be 21% (vs. 8% for methicillin-suscep-
tible S. aureus [MSSA]). The attributable per-patient hospital
costs associated with treatment of all MRSA infections was
$2500 higher than cost for patient treatment for all MSSA
infections (a total attributable costs of $34,000 for MRSA and
$31,500 for MSSA). The extra attributable cost of treating just
nosocomial MRSA compared with MSSA was $3700 (total at-
tributable costs of $31,400 for nosocomial MRSA and $31,500
for nosocomial MSSA).
Other comparative studies that did not explicitly control for
severity of illness also observed attributable cost impacts of
MRSA and VRE. Abramson and Sexton [27] used what they
called a prospective pairwise-matched nested case-control study
design in an intensive care unit (ICU) population; they esti-
mated the attributable total patient costs due to MRSA primary
nosocomial bloodstream infections to be ∼$27,000 (although
there was no observed mortality effect). Other studies have
found a patient mortality rate attributable to nosocomial VRE
bacteremia of 31% (as opposed to non-VRE patient controls,
37%) and an attributable per-patient cost of $98,367 over non-
VRE patient controls [28, 29].
Other studies have used severity of illness at admission to a
specific ward or ICU as a matching criterion. Chaix and co-
workers [30] conducted a retrospective case-control study that
matched patient severity of illness at admission to ICU. Their
results showed a significant difference in mortality between ICU
S8 • CID 2003:36 (Suppl 1) • Howard et al.
patients with health care–acquired MRSA infections (bactere-
mia, lower respiratory tract, urinary tract, or catheter-related
infections) when compared with ICU patients without MRSA
infections (67% vs. 30%). The attributable cost per MRSA in-
fection was estimated at $9300.
Montecalvo et al. [31] used severity of illness at admission
to an oncology ward as part of their matching criteria in con-
ducting a historical analysis to measure the cost savings asso-
ciated with an intervention to reduce VRE infections in an
adult oncology ward. The estimated excess hospitalization cost
due to VRE was $15,385. The annual net hospital cost savings
due to the enhanced infection control program was $189,318
(due to 8 fewer VRE infections, fewer VRE colonizations, and
reductions in antimicrobial use).
Studies that use severity of illness measured either just before
or at the onset of infection report differing results, possibility
as a result of varying matching algorithms. After matching
patients for severity of illness at the onset of bacteremia, Stosor
et al. [32] found a significant difference in the mortality rate
for bacteremic patients with VRE versus bacteremic patients
with vancomycin-susceptible enterococci (VSE) (76% vs. 41%)
and significantly greater average per-patient total hospital costs
of $27,000 for VRE patients over VSE patients ($83,897 for
VRE and $56,707 for VSE). However, other studies have found
that after controlling either for severity of illness at onset of
bacteremia or for changes in patient severity of illness up to
the onset of infection, acquiring MRSA and VRE do not sig-
nificantly increase the risk of mortality [33–35].
The varying treatment and prescribing practices across hos-
pitals also can influence study results. Infection control prac-
tices can vary depending on the type of hospital (privately
owned hospitals, teaching/academic hospitals, or public hos-
pitals) and the case mix of the hospital population [36].
Given these problems, inferences about the economic burden
of resistance in HAIs on the basis of single-center studies are
limited. Most studies do not attempt to measure the cost of
resistance from a societal perspective (including all the eco-
nomic impacts on patients, physicians, health care providers,
third-party buyers, drug manufacturers, and overall societal
welfare) [37]. Phelps [38] attempted to measure the external
social cost of resistance, including the costs of prescribing more-
expensive drugs (both inside and outside hospitals), the costs
of additional hospital days, and the costs of premature death
for the United States. The estimated costs (1989 US dollars)
ranged from $100 million to $30 billion annually (depending
on varying the rate of resistance, the rate of inappropriate use,
and the incidence of premature death). The wide range of these
estimates reflected the uncertainties associated with both the
epidemiologic and economic information needed to measure
the economic burden of resistance. Many of these uncertainties
remain today.
 Recent studies document the burden malaria and other dis-
eases place on the developing world [39]. However, in contrast
to the number of studies on the costs associated with VRE and
MRSA, little research has been performed on the impact of
resistance on treatment failure and its associated costs in ma-
laria, TB, or similar diseases.
The DOT treatment failure rate for patients with MDR-TB
can be as high as 95% [40]. Treatment failure in TB is associated
with use of hospital services and more expensive drugs and
increased mortality. In South Africa, treatment costs are $12,000
per patient with MDR-TB versus $500 per patient with sus-
ceptible TB [41]. The spread of M. tuberculosis resistance in
Russia has corresponded to an increase from 9% to 30% in
mortality rates among those treated [40]. Patients with strains
resistant to ⭓2 drugs can be especially difficult to treat. Farmer
et al. [40] report that in Peru, it costs more than $8000 to treat
a patient with a 5-drug–resistant strain compared with $277 to
treat a patient with a 2-drug–resistant strain. Extrapolating
these figures to the Russian Federation, Farmer et al. calculate
that the spread of 5-drug–resistant strains could increase treat-
ment costs by $100 million. One study estimated that care for
patients with strains resistant to first-line therapy in the United
States can be as high as $180,000 [42]. The resurgence of TB
in New York City has been associated with increases in public
expenditures of hundreds of millions of dollars over a 15-year
period [43], although it is difficult to determine the costs at-
tributable to resistance versus the costs attributable to increased
incidence generally.
A few studies have attempted to link mortality and chlo-
roquine resistance in patients with malaria. However, these have
small sample sizes and lack internal validity when outcomes
for individuals with infections due to resistant versus nonre-
sistant organisms are compared. In the absence of comprehen-
sive studies, information about the impact of resistance can be
discerned from trends in mortality rates. In Senegal, for ex-
ample, one study shows sharp increases in childhood mortality
from malaria during a period corresponding to increases in the
rate of chloroquine-resistant strains [44]. A disadvantage of
these types of studies is that it is impossible to control for
secular trends in factors other than resistance that affect out-
comes. In the Senegal study, one must accept the authors’ as-
surances that the increase in mortality due to malaria was not
the result of a decrease in the prevalence of other childhood
diseases.
CONCLUSION
The preceding discussion has attempted to provide a framework
for assessing the impact of antimicrobial resistance in terms of
increased treatment costs, prevention costs, and morbidity and
mortality that result from resistance. Efforts to describe the
global impact of antimicrobial resistance are hampered by the
lack of data on the impact of resistance outside of hospital
settings. Estimates of the cost of treating a patient with MDR-
TB in Russia or Peru, for example, are not subject to the kind
of scrutiny and review devoted to estimates of the cost of med-
ical procedures in the United States. Even efforts to measure
the economic costs of resistance to MRSA or VRE in US hos-
pitals have suffered from methodological problems and often
are of questionable validity. Finally, there has been little, if any,
effort to assess the larger societal and macroeconomic costs of
resistance, especially in the developing world, related to lost
wages, the costs of caring for orphaned children, and the impact
of increased infant and child mortality on fertility patterns and
demographic growth, or the costs for surveillance and other
systemwide interventions of the type recommended by the
WHO [45]. In short, although there is little doubt that anti-
microbial resistance is increasing the global burden of disease,
we are a long way from being able to quantify this burden.
Acknowledgment
We thank Ralph Cordell of the Centers for Disease Control
and Prevention for valuable advice and comments.
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