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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 coccus aureus strains causing infections in hospitalized
help policy makers formulate policies that encourage patients [2]. Emergence of resistance in these organisms
appropriate use of antimicrobial drugs and prevent the is a worrisome trend in developed countries, but de-
emergence and spread of resistant organisms. In this veloping nations face a much greater threat from the
article, we describe a framework for measuring the im- growth of resistance in pathogens causing community-
pact of resistance, and we review previous research on acquired diseases such as malaria.
this topic. The term “impact” here refers to the in-
creased treatment costs, prevention costs, and morbid-
FRAMEWORK FOR MEASURING THE
ity and mortality that result from resistance.
BURDEN OF RESISTANCE
Many microorganisms have displayed antimicrobial
resistance, but we focus mainly on the pathogens re- For most diseases, the burden of the illness consists
sponsible for malaria, tuberculosis (TB), diarrheal dis- entirely of treatment costs, morbidity and mortality
eases, and lower respiratory tract infections. According among the ill, and the costs of public prevention efforts.
to the World Health Organization (WHO), these are 4 Infectious diseases are different. Because they often are
of the top 5 infectious diseases in terms of years of life communicable, fear of contagion may induce even un-
lost (the fifth being AIDS) [1]. To date, most studies infected individuals (and their physicians) to alter their
on the impact of antimicrobial resistance have focused behavior [3]. The financial and psychological costs as-
narrowly on resistance to antibacterials and, more spe- sociated with these behavioral changes add to the bur-
cifically, resistance among enterococcal and Staphylo- 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-
Financial support: AstraZeneca. fection will avoid risky sexual activities. They contend
Reprints or correspondence: Dr. David H. Howard, Rollins School of Public
that the forgone welfare from these activities is a com-
Health, Emory University, 1518 Clifton Rd. NE, Room 610, Atlanta, GA 30322 ponent of the burden of disease. These costs are ex-
(dhhowar@emory.edu).
cluded from standard measures of the cost of AIDS.
Clinical Infectious Diseases 2003; 36(Suppl 1):S4–10
 2003 by the Infectious Diseases Society of America. All rights reserved.
Most studies of the impact of antimicrobial resistance
1058-4838/2003/3602S1-0003$15.00 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 No initial susceptibility testing


Case 1: Empiric therapy ineffective
against resistant organisms
Patients with IDSO No costs No costs
Patients with IDRO Incremental cost of second-line therapy Incremental cost of second-line therapy
Increased hospital length of stay
Incremental morbidity and mortality
Case 2: Empiric therapy effective
against resistant organisms
Patients with IDSO Not applicable Incremental cost of empiric therapy
Patients with IDRO Not applicable Incremental cost of empiric therapy

NOTE. IDRO, infections due to resistant organisms; IDSO, infections due to susceptible organisms.

identified as having an infection due to a resistant organism. itial therapy. Practices such as susceptibility testing, which pro-
For the reasons stated above, however, simply adding up the vides more information about patients’ infections, will diminish
incremental costs of persons with infections due to resistant the impact of community characteristics on physicians’ choice
organisms understates the burden of resistance. Just as the of therapy. In the absence of susceptibility testing, however,
number of individuals infected with HIV in a given area may physicians have few clues to help them predict whether or not
affect individuals’ sexual behavior [3], local susceptibility pat- a patient is infected with a resistant pathogen, and therapy will
terns may influence even physicians’ empirical treatment of be selected on the basis of the prevailing levels of resistance in
patients with infections due to susceptible organisms [5–7]. the community. In such instances, the costs of substitution of
Before the identification of the infecting agent and its resistance empiric therapies may account for a large portion of the total
pattern, patients often are given empiric therapy. In areas where burden of resistance [5].
resistant organisms are prevalent, physicians use alternative Another factor to consider in measuring resistance-induced
drugs rather than the medication that, in the absence of resis- drug substitution is the income and wealth of patients and
tance, would be preferred on the basis of cost, dosing schedule, countries. Physicians in developed countries may be quicker to
or side effect profile [5–7]. This substitution occurs for most switch empiric therapies in response to increasing resistance
newly diagnosed patients, not just those with infections due to levels, whereas patients in developing countries may have to
resistant organisms. The excess drug costs, inconvenience, and make do with older drugs and the high rate of treatment failure
side effects experienced by patients in areas where physicians with which they are associated. Consequently, for the same
have switched empiric therapies is a seldom-measured com- underlying rate of resistance, the burden will be larger in de-
ponent of the burden of resistance. Other components of the veloping countries.
burden of resistance include the cost of expanded prevention Table 1 characterizes the costs of resistance according to
and drug-administration efforts (e.g., directly observed therapy whether or not susceptibility testing is performed at diagnosis
[DOT] for TB) that result from concerns about resistance, and and whether or not empiric therapy is effective against resistant
the cost of the increase in disease incidence that results from organisms (where resistance is defined relative to older drugs).
the transmission of infection from individuals whose infections When empiric therapy is ineffective against resistant organisms
due to resistant organisms are not treated in a timely manner. and physicians do not perform susceptibility testing, only pa-
In some instances, use of antimicrobials will reduce disease tients with infections due to resistant organisms will incur costs
prevalence [8]. Because effective treatment for susceptible path- due to resistance. The magnitude of these costs will depend on
ogens reduces their transmission, drug-resistant strains will be the length of time that patients with infections due to suscep-
responsible for a larger proportion of total cases [9]. Ultimately, tible organisms receive ineffective therapy. If physicians per-
the impact of treatment on transmission will be negated, and form susceptibility testing immediately, then the cost of resis-
prevalence may return to pretreatment levels [10]. tance will consist only of the incremental cost of second-line
For reasons outlined above, studies that examine only the therapy and the costs of susceptibility testing. If the prevalence
costs of treatment failure in patients with infections due to of resistance is high, then physicians will begin using second-
resistant organisms may understate the impact of resistance. line drugs as empiric therapy [5, 7]. As stated above, the in-
The degree to which the cost of treatment differs from the cremental cost of these drugs comprises the burden of resistance
actual burden will depend on how heavily physicians weigh because patients with infections due to resistant organisms are
individual versus community characteristics when choosing in- 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 promoted DOT, which helps to ensure that all patients receive
important to realize, however, that local practice patterns have a full course of the standardized drug therapy for the treatment
an impact on the types of costs associated with resistance. 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
RESISTANCE AND EMPIRIC THERAPY CHOICE M. tuberculosis drug-susceptibility testing to individualize treat-
ment. As a result of a lack of financial resources, susceptibility
Few data exist on the impact of resistance on physicians’ choice testing is not the standard of care in most developing countries
of empiric therapy. One study (1980–1998) that used data on
that have a high prevalence of MDR-TB. In these countries,
physicians’ drug choices for patients with otitis media at-
treatment is selected on the basis of regional susceptibility pat-
tempted to link changing patterns of antibiotic use to increasing
terns. Local prevalence rates of resistance to isoniazid 14%
levels of resistance among Streptococcus pneumoniae [5]. The
require treatment with 4 first-line drugs, including isoniazid,
study found that in the late 1990s, rising levels of resistance
rifampin, pyrazinamide, and either ethambutol or streptomycin
increased antibiotic expenditures for otitis media by 20%. Treat-
[13]. Although the additional drugs increase the probability of
ment patterns for other infectious diseases have not been sub-
successful treatment, they also increase the chance of unwanted
ject to formal analysis, although clinical guidelines and trends
side effects and augment the financial burden of the disease.
in use of various agents suggest a link between resistance and
DOTS-Plus regimens, used in areas with high rates of resistance,
use of newer, more expensive agents. In this section, we review
may include fluoroquinolones or additional drugs as empiric
treatment guidelines, WHO reports, and other published lit-
therapy, further increasing treatment costs.
erature on treatment patterns. In the next section of this article,
Diarrheal diseases are one of the leading causes of morbidity
we will examine efforts to measure the costs of therapeutic
and mortality worldwide, with the greatest burden of severe
responses to resistance.
illness involving infants and young children in developing
Chloroquine was the main antimalarial agent used for first-
countries. Irrespective of future improvements in economic
line treatment of malaria for decades. During the past 10 years,
development and progress in health care delivery, diarrheal
Plasmodium falciparum and Plasmodium vivax have grown in-
diseases are predicted to remain a leading health problem dur-
creasingly resistant to chloroquine in many areas of the world
ing the next 30 years [14]. Adding to this dilemma is the large
[11]. Health care providers in Malawi and Kenya have discon-
increase in antimicrobial resistance that has emerged among
tinued the use of chloroquine as first-line therapy and have
begun using sulfadoxine-pyrimethamine in its place. Resistance many of the major bacterial pathogens, including Shigella dy-
to sulfadoxine-pyrimethamine has been documented in East senteriae, Campylobacter, and Salmonella [15–18]. In sub-Sa-
Africa, and it may not be long before it too has to be replaced haran Africa, S. dysenteriae has become resistant to multiple
[11]. In parts of Southeast Asia, only multidrug therapies are drugs, with strains that are resistant to all common antimicro-
effective against Plasmodium strains that have developed resis- bial agents except fluoroquinolones [19]. The WHO recom-
tance to all 4 leading antimalarial drugs [12]. mends that physicians use drugs that are active against at least
The WHO recommends a change in first-line treatment when 80% of the local Shigella isolates [20]. Drug price data in the
25% of patients treated experience recrudescence of infection developing world are difficult to obtain, but in the United
[6]. This is an arbitrary figure; an optimal switching policy States, the price of some of the newer fluoroquinolones may
would balance the cost of the second-line drugs against the exceed that of trimethoprim-sulfamethoxazole by 400% [1].
benefit of prompt treatment [7]. Nevertheless, at some point, Given these price differentials, it is unlikely that developing
whether it is above or below the 25% threshold, physicians countries will strictly adhere to the WHO’s 80% switching cri-
must switch first-line therapies. Phillips and Phillips-Howard teria. Nevertheless, even a small amount of switching can in-
[7] calculated that the use of quinine versus chloroquine as crease costs substantially.
first-line therapy in 150 million patients with malaria would Acute respiratory infections comprise the fourth leading
increase spending by as much as $100 million (1990 US dollars), cause of mortality worldwide, killing 13 million people each
a relatively large amount for the countries in which malaria is year [1]. The majority of deaths result from lower respiratory
endemic. Besides costing more, drugs such as quinine that re- tract infections that occur in developing countries with high
place chloroquine often are associated with higher rates of side poverty rates and inadequate medical care. The primary bac-
effects, the financial and psychological costs of which should terial agents that cause lower respiratory infections include S.
be attributed to resistance. pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis.
Multidrug-resistant TB (MDR-TB), which is caused by The rise in antimicrobial resistance among these pathogens has
strains resistant to ⭓2 antituberculous drugs, has been increas- been documented in many regions and now poses a major
ing in a number of regions around the world. The WHO has challenge worldwide [21].

S6 • CID 2003:36 (Suppl 1) • Howard et al.


Clinical guidelines for respiratory diseases commonly advise uted this increase, but it is interesting to note that it occurred
physicians to tailor empiric therapy to local susceptibility pat- concurrently with a large increase in the level of penicillin-
terns. The Infectious Diseases Society of America (IDSA) guide- resistant S. pneumoniae.
lines for community-acquired pneumonia in adults, for ex-
ample, advise physicians to consider “regional antibiotic
RESISTANCE AND TREATMENT FAILURE
susceptibility patterns for S. pneumoniae” when selecting an-
tibiotics for outpatients [22]. Unlike similar guidelines for ma- As mentioned above, previous research on the impact of re-
laria, TB, or diarrheal diseases [6, 13, 19], the IDSA guidelines sistance has focused on measuring costs, morbidity, and mor-
do not state a specific level of resistance after which standard tality in patients with infections due to resistant organisms. The
empiric therapy should be removed. The guidelines recommend incremental effects of resistance will be inversely related to the
that physicians use penicillin or amoxicillin to treat penicillin- effectiveness of empiric therapy. When physicians use ineffec-
susceptible S. pneumoniae and cefotaxime, ceftriaxone, a fluor- tive drugs as empiric therapy, resistance will manifest itself
oquinolone, or vancomycin to treat penicillin-resistant S. pneu- clinically as treatment failure, and costs, morbidity, and mor-
moniae. The cost of an amoxicillin treatment is about $6 (1999 tality will be greater for patients with infections due to resistant
US dollars), and the cost for levofloxacin, one of the recom- organisms than for patients with infections due to susceptible
mended fluoroquinolones, is $69 [20]. Suppose that, initially, organisms.
all newly diagnosed pneumonia patients in a given region re- There is a growing body of literature on the cost and health
ceive amoxicillin. If resistance caused the market share of lev- impacts of resistance and treatment failure in hospital settings.
ofloxacin to increase from 0% to 10%, then total empiric- In 1992, the US Office of Technology Assessment (OTA) de-
therapy spending in this population would increase by 1100%. veloped a summary estimate of the hospital cost of antibiotic
Thus, small changes in prescribing habits brought about by resistance resulting from 6 different organisms (methicillin-
antimicrobial resistance can have a large impact on drug costs. resistant S. aureus [MRSA], vancomycin-resistant enterococci
We used drug use data from the National Ambulatory Med- [VRE], imipenem-resistant Pseudomonas aeruginosa, methicil-
ical Care Survey [23] for the years 1980–1996 and drug price lin-resistant coagulase-negative staphylococci, ampicillin-resis-
data from the 1996 Medical Expenditure Panel Survey [24] to tant Escherichia coli, and resistant Enterobacter) causing infec-
calculate the average cost of a new prescription for patients tions at 5 different sites [25]. The types of health care–acquired
diagnosed with otitis media (figure 1). Many factors contrib- infections (HAI) included surgical site infections, pneumonias,

Figure 1. Average prescription prices, 1980–1996

Global Impact of Drug Resistance • CID 2003:36 (Suppl 1) • S7


bacteremias, urinary tract infections, and a fifth category con- patients with health care–acquired MRSA infections (bactere-
taining other miscellaneous infections. The OTA estimated that mia, lower respiratory tract, urinary tract, or catheter-related
the cost of extra hospitalizations resulting from infections with infections) when compared with ICU patients without MRSA
the resistant organisms listed above was ∼$1.3 billion (1992 US infections (67% vs. 30%). The attributable cost per MRSA in-
dollars). fection was estimated at $9300.
Recent studies examining the attributable morbidity, mor- Montecalvo et al. [31] used severity of illness at admission
tality, and costs associated with sensitive and resistant S. aureus to an oncology ward as part of their matching criteria in con-
and enterococci in hospitals (for a review of studies before 1987, ducting a historical analysis to measure the cost savings asso-
see Holmberg et al. [2]) now offer contradictory conclusions ciated with an intervention to reduce VRE infections in an
about the impact of these organisms. A key factor underlying adult oncology ward. The estimated excess hospitalization cost
these differing results is patient severity of illness and how it due to VRE was $15,385. The annual net hospital cost savings
is used to evaluate HAI on patient outcomes. Matched cohort due to the enhanced infection control program was $189,318
studies that do not adequately adjust for patient severity pro- (due to 8 fewer VRE infections, fewer VRE colonizations, and
duced overestimates of the attributable mortality due to HAI reductions in antimicrobial use).
[2]. Studies that use severity of illness measured either just before
An example of a study that did not control for severity of or at the onset of infection report differing results, possibility
underlying disease of studies comes from Rubin et al. [26]. This as a result of varying matching algorithms. After matching
study examined the economic and health impacts of both com- patients for severity of illness at the onset of bacteremia, Stosor
munity-acquired and health care–acquired MRSA infections et al. [32] found a significant difference in the mortality rate
(pneumonia, bacteremia, and endocarditis for mortality and for bacteremic patients with VRE versus bacteremic patients
costs; and surgical site infection, osteomyelitis, and septic ar- with vancomycin-susceptible enterococci (VSE) (76% vs. 41%)
thritis for costs only) within all New York metropolitan hos- and significantly greater average per-patient total hospital costs
pitals in 1995. They used an administrative database on hospital of $27,000 for VRE patients over VSE patients ($83,897 for
discharges to estimate the attributable mortality rate for MRSA VRE and $56,707 for VSE). However, other studies have found
(based on unmatched group comparisons between infected and that after controlling either for severity of illness at onset of
uninfected patients) to be 21% (vs. 8% for methicillin-suscep- bacteremia or for changes in patient severity of illness up to
tible S. aureus [MSSA]). The attributable per-patient hospital the onset of infection, acquiring MRSA and VRE do not sig-
costs associated with treatment of all MRSA infections was nificantly increase the risk of mortality [33–35].
$2500 higher than cost for patient treatment for all MSSA The varying treatment and prescribing practices across hos-
infections (a total attributable costs of $34,000 for MRSA and pitals also can influence study results. Infection control prac-
$31,500 for MSSA). The extra attributable cost of treating just tices can vary depending on the type of hospital (privately
nosocomial MRSA compared with MSSA was $3700 (total at- owned hospitals, teaching/academic hospitals, or public hos-
tributable costs of $31,400 for nosocomial MRSA and $31,500 pitals) and the case mix of the hospital population [36].
for nosocomial MSSA). Given these problems, inferences about the economic burden
Other comparative studies that did not explicitly control for of resistance in HAIs on the basis of single-center studies are
severity of illness also observed attributable cost impacts of limited. Most studies do not attempt to measure the cost of
MRSA and VRE. Abramson and Sexton [27] used what they resistance from a societal perspective (including all the eco-
called a prospective pairwise-matched nested case-control study nomic impacts on patients, physicians, health care providers,
design in an intensive care unit (ICU) population; they esti- third-party buyers, drug manufacturers, and overall societal
mated the attributable total patient costs due to MRSA primary welfare) [37]. Phelps [38] attempted to measure the external
nosocomial bloodstream infections to be ∼$27,000 (although social cost of resistance, including the costs of prescribing more-
there was no observed mortality effect). Other studies have expensive drugs (both inside and outside hospitals), the costs
found a patient mortality rate attributable to nosocomial VRE of additional hospital days, and the costs of premature death
bacteremia of 31% (as opposed to non-VRE patient controls, for the United States. The estimated costs (1989 US dollars)
37%) and an attributable per-patient cost of $98,367 over non- ranged from $100 million to $30 billion annually (depending
VRE patient controls [28, 29]. on varying the rate of resistance, the rate of inappropriate use,
Other studies have used severity of illness at admission to a and the incidence of premature death). The wide range of these
specific ward or ICU as a matching criterion. Chaix and co- estimates reflected the uncertainties associated with both the
workers [30] conducted a retrospective case-control study that epidemiologic and economic information needed to measure
matched patient severity of illness at admission to ICU. Their the economic burden of resistance. Many of these uncertainties
results showed a significant difference in mortality between ICU remain today.

S8 • CID 2003:36 (Suppl 1) • Howard et al.


Recent studies document the burden malaria and other dis- global impact of antimicrobial resistance are hampered by the
eases place on the developing world [39]. However, in contrast lack of data on the impact of resistance outside of hospital
to the number of studies on the costs associated with VRE and settings. Estimates of the cost of treating a patient with MDR-
MRSA, little research has been performed on the impact of TB in Russia or Peru, for example, are not subject to the kind
resistance on treatment failure and its associated costs in ma- of scrutiny and review devoted to estimates of the cost of med-
laria, TB, or similar diseases. ical procedures in the United States. Even efforts to measure
The DOT treatment failure rate for patients with MDR-TB the economic costs of resistance to MRSA or VRE in US hos-
can be as high as 95% [40]. Treatment failure in TB is associated pitals have suffered from methodological problems and often
with use of hospital services and more expensive drugs and are of questionable validity. Finally, there has been little, if any,
increased mortality. In South Africa, treatment costs are $12,000 effort to assess the larger societal and macroeconomic costs of
per patient with MDR-TB versus $500 per patient with sus- resistance, especially in the developing world, related to lost
ceptible TB [41]. The spread of M. tuberculosis resistance in wages, the costs of caring for orphaned children, and the impact
Russia has corresponded to an increase from 9% to 30% in of increased infant and child mortality on fertility patterns and
mortality rates among those treated [40]. Patients with strains demographic growth, or the costs for surveillance and other
resistant to ⭓2 drugs can be especially difficult to treat. Farmer systemwide interventions of the type recommended by the
et al. [40] report that in Peru, it costs more than $8000 to treat WHO [45]. In short, although there is little doubt that anti-
a patient with a 5-drug–resistant strain compared with $277 to microbial resistance is increasing the global burden of disease,
treat a patient with a 2-drug–resistant strain. Extrapolating we are a long way from being able to quantify this burden.
these figures to the Russian Federation, Farmer et al. calculate
that the spread of 5-drug–resistant strains could increase treat-
Acknowledgment
ment costs by $100 million. One study estimated that care for
patients with strains resistant to first-line therapy in the United We thank Ralph Cordell of the Centers for Disease Control
States can be as high as $180,000 [42]. The resurgence of TB and Prevention for valuable advice and comments.
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- References
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