SUPPLEMENT ARTICLE

The Relationship between Antimicrobial Resistance

and Patient Outcomes: Mortality, Length of Hospital

Downloaded from https://academic.oup.com/cid/article/42/Supplement_2/S82/377684 by Karolinska Institutet Library user on 08 July 2021

Stay, and Health Care Costs
Sara E. Cosgrove
Division of Infectious Diseases, The Johns Hopkins Medical Institutions, Baltimore, Maryland

There is an association between the development of antimicrobial resistance in Staphylococcus aureus, enter-
ococci, and gram-negative bacilli and increases in mortality, morbidity, length of hospitalization, and cost of
health care. For many patients, inadequate or delayed therapy and severe underlying disease are primarily
responsible for the adverse outcomes of infections caused by antimicrobial-resistant organisms. Patients with
infections due to antimicrobial-resistant organisms have higher costs (∼$6,000–$30,000) than do patients with
infections due to antimicrobial-susceptible organisms; the difference in cost is even greater when patients
infected with antimicrobial-resistant organisms are compared with patients without infection. Strategies to
prevent nosocomial emergence and spread of antimicrobial-resistant organisms are essential.

Awareness of the prevalence of antimicrobial resistance
is growing among the medical community and the gen-
eral public, and the impact of antimicrobial resistance
on clinical and economic outcomes is the subject of
ongoing investigation. An awareness of the effect of
antimicrobial resistance on outcomes has several po-
tential benefits. First, knowledge about the implications
of resistance with regard to patient outcomes may
prompt hospitals and health care providers to begin
and support initiatives to prevent such infections (e.g.,
infection-control programs and antimicrobial agent
management programs). Second, data can be used to
influence health care providers to follow guidelines
about isolation and to make rational choices with re-
gard to the use of antimicrobial agents. Third, data can
guide policy makers who make decisions about the
funding of programs to track and prevent the spread
of antimicrobial-resistant organisms. Fourth, such
knowledge may stimulate interest in developing new
antimicrobial agents and therapies. Finally, information
Reprints or correspondence: Dr. Sara E. Cosgrove, Div. of Infectious Diseases,
The Johns Hopkins Medical Institutions, Osler 425, 600 N. Wolfe St., Baltimore,
MD 21287 (scosgro1@jhmi.edu).
Clinical Infectious Diseases 2006; 42:S82–9
 2005 by the Infectious Diseases Society of America. All rights reserved.
1058-4838/2006/4202S2-0004$15.00
about resistance may be important in defining the prog-
nosis for individual patients with infection. In the pres-
ent article, methodological issues that influence the re-
sults of studies of antimicrobial resistance outcomes will
be acknowledged, and associations between resistance
in specific pathogens and adverse outcomes, including
increased mortality, length of hospital stay, and cost,
will be reviewed.
METHODOLOGICAL ISSUES IN STUDIES
OF ANTIMICROBIAL RESISTANCE
OUTCOMES
Various methodological issues can influence the con-
duct and results of studies of antimicrobial resistance
outcomes, as discussed in detail elsewhere [1–3]. The
types of outcomes examined, the perspective of the
study, the reference groups within the study, adjust-
ments for confounding factors, and the type of eco-
nomic assessment are among the factors that should
be considered (table 1) [2].
With regard to outcomes, morbidity and cost, rather
than mortality, may be the most sensitive measures with
which to quantify the impact of antimicrobial resis-
tance. The perspective of an outcome study determines
the end points measured and affects how the economic
impact of infection with resistant organisms is esti-
mated. The cost for individual patients (relevant to the

S82 • CID 2006:42 (Suppl 2) • Cosgrove

Table 1. Influences on studies assessing the impact of infection with antimicrobial-resistant bacteria.

Methodologic issue, factor Aspects

Outcome
Mortality In hospital, attributable to infection; in hospital and after discharge, all-cause
Morbidity Length of hospitalization, need for ICU care, need for surgery or other procedures,
activity level at discharge, and loss of functional status (loss of work)
Economic Hospital costs, hospital charges, resource utilization, total health care costs, skilled
nursing, and other outpatient costs

Downloaded from https://academic.oup.com/cid/article/42/Supplement_2/S82/377684 by Karolinska Institutet Library user on 08 July 2021

Outcome perspective
Hospital Inpatient morbidity, mortality, and/or costs
Third-party payer Inpatient and outpatient health care costs
Patient Decreased functional status, loss of work, and fewer antimicrobial agent options
Societal Total health care costs of antimicrobial resistance and loss of antimicrobial classes
Choice of reference group
Patients infected with susceptible strains …
Uninfected patients …
Patients colonized with resistant strains …
Confounding factors
Length of hospital stay APACHE score, McCabe/Jackson score, and Charlson comorbidity scorea
Underlying severity of illness …
Comorbid conditions …

NOTE. ICU, intensive care unit. Adapted and reprinted with permission from Cosgrove and Carmeli [2].
a
APACHE is a severity of disease classification system that uses a point score based on initial values of 12 routine physiologic measurements, age, and
previous health status. It is a validated tool to predict mortality for patients in the ICU. The McCabe/Jackson score uses a simple 3-category score to predict
mortality for patients with bacteremia due to gram-negative organisms. The Charlson comorbidity score is a simple, readily applicable, and valid method of
estimating risk of death from comorbid disease.

perspective of the hospital or third-party payers) pales in the
face of the societal impact, which was estimated to be in the
billions of dollars a decade ago [4]. Some of the most important
influences on the patient and society, such as the gradual loss
of efficacy of antimicrobial classes, are difficult to measure. It
is essential to select the appropriate reference group (i.e., in-
dividuals infected with susceptible strains, colonized with re-
sistant strains, or uninfected), control for the length of hospital
stay, and adjust for the severity of the underlying illness and
comorbidities before infection, because each of those factors
can have a significant effect on outcomes measures.
OUTCOMES OF INFECTIONS WITH
ANTIMICROBIAL-RESISTANT GRAM-POSITIVE
PATHOGENS
Methicillin-resistant Staphylococcus aureus (MRSA). The
impact of methicillin resistance on mortality rates among pa-
tients infected with S. aureus has been studied primarily in
patients with bacteremia, and results of studies have varied [5–
17]. To further address this issue, we conducted a meta-analysis
of studies with relevant mortality data published between 1980
and 2000 [18]. When data from all studies (31 cohort studies
including 3963 patients [34% of whom were infected with
methicillin-resistant strains]) were pooled with a random-ef-
fects model, a significant increase in mortality associated with
MRSA bacteremia, relative to methicillin-susceptible S. aureus
(MSSA) bacteremia, was observed (OR, 1.93; P ! .001 ). In sub-
group analyses conducted to explore heterogeneity in the
pooled analysis, mortality associated with MRSA infection was
consistently higher, with minimal or no significant heteroge-
neity in each group. These analyses included studies adjusted
for potential confounding variables, versus nonadjusted studies;
studies with a high proportion of cases of nosocomial bacter-
emia (⭓70%) versus a low proportion (!70%); studies per-
formed in an outbreak versus nonoutbreak setting; studies with
a high proportion of catheter-associated infections (⭓40%)
versus a low proportion (!40%); and studies with a high pro-
portion of patients with endocarditis (⭓45%) versus a low
proportion (!45%).
Length of hospital stay and costs related to MRSA bacteremia,
compared with those related to MSSA bacteremia, were evaluated
in 2 recently published cohort studies [19, 20]. In a study by
our group, 346 patients admitted to the Beth Israel Deaconess
Medical Center (Boston, MA) with clinically significant S. aureus
bacteremia (96 case patients with MRSA infection and 252 con-
trol patients with MSSA infection) between 1997 and 2000 were
evaluated. Among survivors, methicillin resistance was associated
with significant increases in the median length of hospital stay
after acquisition of infection (9 vs. 7 days for patients with MSSA
bacteremia; P p .045) and hospital charges after S. aureus bac-
teremia ($26,424 vs. $19,212; P p .008). MRSA bacteremia was
an independent predictor of increased length of hospitalization

Antimicrobial Resistance and Patient Outcome • CID 2006:42 (Suppl 2) • S83

(1.3-fold increase; P p .016) and hospital charges (1.4-fold in-
crease; P p .017). A second study prospectively evaluated 105
hemodialysis-dependent patients with S. aureus bacteremia who
were admitted to Duke University Medical Center (Durham, NC)
between 1996 and 2001 [20]. Thirty-four patients with MRSA
infection were compared with 70 patients with MSSA infection.
A propensity score for each patient’s probability for having
MRSA bacteremia, based on demographics, comorbidities, and
APACHE II scores, was estimated using logistic regression and
was used to adjust for confounding. Results for this population
of patients undergoing hemodialysis were similar to those for
the inpatient population at Beth Israel Deaconess Medical Center,
with the adjusted median length of hospital stay longer (11 vs.
7 days; P ! .001) and the adjusted median costs higher for the
initial hospitalization ($21,251 vs. $13,978; P p .012) and after
12 weeks ($25,518 vs. $17,354; P p .015) for patients infected
with MRSA.
Engemann et al. [21] evaluated clinical and economic out-
comes attributable to methicillin resistance in a retrospective
cohort study of patients with S. aureus surgical site infections
primarily associated with cardiac or orthopedic procedures.
During 1994–2000, 121 patients with a surgical site infection
due to MRSA and 165 patients with a surgical site infection
due to MSSA were identified, and another 193 uninfected pa-
tients, matched by type and year of surgical procedure, were
selected. The investigators controlled for underlying severity of
illness by use of the National Nosocomial Infection Surveillance
risk index variables (American Society of Anesthesiologists
score, duration of surgery, and wound class). The authors re-
ported an independent contribution of methicillin resistance
toward increased mortality, prolonged length of hospitalization,
and increased hospital costs, which is consistent with the find-
ings for bacteremia. The presence of MRSA in a surgical wound
increased the adjusted 90-day postoperative mortality risk by
3.4-fold, compared with the presence of MSSA (P p .003), and
by 11.4-fold, compared with the absence of infection (P !
Table 2. Outcomes related to methicillin resistance in Staphylococcus aureus surgical site infections (SSIs) [21].
Death
Percentage
of subjects
Comparison who died OR P days, mean
Control vs. MRSA SSI 11.4 !.001
Uninfected control subjects
(n p 193) 2.1
Patients with MRSA SSI
(n p 121) 20.7
MSSA SSI vs. MRSA SSI 3.4 .003
Patients with MSSA SSI
(n p 165) 6.7
Patients with MRSA SSI
(n p 121) 20.7
NOTE. ME, multiplicative effect; MRSA, methicillin-resistant S. aureus; MSSA, methicillin-susceptible S. aureus.
S84 • CID 2006:42 (Suppl 2) • Cosgrove
.001) (table 2). Patients with MRSA infection had mean at-
tributable excess hospital charges of $13,901 and $41,274, com-
pared with patients with MSSA infection and patients without
infection, respectively. The design of this study shows the im-
pact of choice of control groups on results.
Data on outcomes for patients with community-associated
MRSA infection are limited. Martinez-Aguilar et al. [22] re-
ported their findings from a retrospective study of 59 children
Downloaded from https://academic.oup.com/cid/article/42/Supplement_2/S82/377684 by Karolinska Institutet Library user on 08 July 2021
with musculoskeletal infections (e.g., osteomyelitis, septic ar-
thritis, and pyomyositis) caused by community-associated S.
aureus (31 with MRSA infection and 28 with MSSA infection).
The durations of fever (4.9 vs. 1.5 days; P p .001) and of hos-
pital stay (14.5 vs. 12.7 days; P p .014) were significantly longer
in the children infected with MRSA than in children infected
with MSSA. The Panton-Valentine leukocidin gene, which en-
codes for a toxin of the same name that has been associated
with leukocyte destruction and tissue necrosis, was found more
frequently among the MRSA strains (87% of MRSA strains vs.
24% of MSSA strains; P ! .001). Also of note, S. aureus isolates
containing the Panton-Valentine leukocidin gene were associ-
ated with a greater proportion of complications (30.3% vs. 0%;
P p .002).
Vancomycin-resistant enterococci (VRE). VRE were first
isolated almost 2 decades ago [23] and have since become
important nosocomial pathogens for which there are limited
treatment options [24]. VRE infections have been shown to
have a negative impact on mortality and cost of hospitalization
[25–27]. For example, in a retrospective, cohort study of pa-
tients hospitalized between 1993 and 1997, Carmeli et al. [28]
compared the health and economic outcomes of patients col-
onized or infected with VRE (n p 233; 42% had VRE in
wounds, 31% had VRE in urine, 17% had VRE in intra-ab-
dominal sites, and 9% has VRE in blood) with those of control
subjects (percentages do not total 100 because of rounding;
n p 647) without VRE colonization or infection who were
matched for length of hospital stay, hospital ward, and calendar
Length of hospital stay after surgery Charges
No. of days US$
Total no. of attributable US$, attributable
ME to MRSA P mean ME to MRSA P
3.2 13.4 !.001 2.2 41,274 !.001
6.1 34,395
29.1 118,414
1.2 2.6 .11 1.2 13,901 .03
13.2 73,165
29.1 118,414
date (within 7 days). A propensity score was calculated to adjust
for the risk of having VRE infection or colonization and was
included in a multivariate analysis of each outcome. Compared
with a similar but uninfected hospitalized cohort, patients with
VRE infection had increased mortality (adjusted attributable
mortality rate, 6%; adjusted relative risk [RR], 2.1; P p .04),
length of hospital stay (attributable excess hospitalization, 6.2
days; multiplicative effect, 1.73; P ! .001), and hospital costs
(attributable cost, $12,766; multiplicative effect, 1.4; P ! .001).
Morbidity was also significantly higher among patients infected
with VRE (e.g., 2.7-fold increased odds of undergoing a major
surgical procedure and 3.5-fold increased odds of being ad-
mitted to an intensive care unit [ICU]).
Penicillin- and cephalosporin-resistant Streptococcus pneu-
moniae. In distinct contrast to the results of studies of staph-
ylococci and enterococci, infection due to nonsusceptible S.
pneumoniae has not been shown to adversely affect outcomes
in most studies. For instance, in a prospective, international,
observational study of 844 hospitalized patients with blood
cultures positive for S. pneumoniae, discordant therapy (i.e.,
use of an antimicrobial agent that was classified as inactive in
vitro) with penicillins, cefotaxime, and ceftriaxone did not re-
sult in a higher mortality rate, a longer time to defervescence,
or more-frequent suppurative complications [29]. In studies of
patients with cefotaxime-resistant pneumococcal meningitis
[30] and bacteremic pneumonia [31], there were no differences
in mortality, length of hospitalization, or need for admission
to an ICU among case patients relative to matched control
patients infected with susceptible isolates. Aggressive empirical
use of vancomycin, favorable pharmacodynamics (i.e., most
isolates had a cefotaxime MIC !4 mg/mL, a level reached or
exceeded by cefotaxime in CSF and lung tissue), and com-
munity-acquired infection in otherwise healthy patients may
explain these results.
OUTCOMES OF INFECTIONS WITH RESISTANT
GRAM-NEGATIVE PATHOGENS
Antimicrobial-resistant Pseudomonas aeruginosa. Carmeli
et al. [32] published one of the first studies to address outcomes
associated with antimicrobial resistance in gram-negative path-
ogens. The study population included 489 patients with P. aeru-
ginosa infection who were hospitalized between 1994 and 1996;
at baseline, 144 (29%) had an isolate resistant to ceftazidime,
ciprofloxacin, imipenem, and/or piperacillin, and 30 (6%) de-
veloped resistance during therapy. For 37% of the patients, the
isolate recovered at baseline was nosocomially acquired. Culture
specimens were obtained from wounds (41%), urine (23%),
the respiratory tract (22%), effusion (5%), blood (5%), and
tissue (4%). There were no differences in mortality or length
of hospital stay between patients infected with a resistant isolate
at baseline and those infected with a susceptible isolate at base-
Antimicrobial Resistance and Patient Outcome • CID 2006:42 (Suppl 2) • S85
line (table 3). In contrast, the emergence of resistance was
associated with a 3-fold greater risk of death (P p .02) and a
1.7-fold longer duration of hospital stay (P ! .001). The esti-
mated mean adjusted increase in duration of hospitalization
was 5.7 days. The emergence of resistance was also associated
with an increased risk of secondary bacteremia (14% vs. 1.4%
in patients without emergence of resistance; RR, 9.0; P ! .001).
The investigators found no differences in hospital charges be-
Downloaded from https://academic.oup.com/cid/article/42/Supplement_2/S82/377684 by Karolinska Institutet Library user on 08 July 2021
tween any of the groups. The results of this study underscore
the impact of emergence of resistance on patient outcomes.
Enterobacter species resistant to third-generation
cephalosporins. Enterobacter species are common nosocomial
pathogens, with almost one-third of strains causing third-gener-
ation cephalosporin–resistant infections in patients in the ICU
[24]. In a nested, matched cohort study of patients admitted
to Beth Israel Deaconess Medical Center between 1994 and
1997 [33], our research group evaluated the impact of emer-
gence of resistance to third-generation cephalosporins on pa-
tient outcomes. Case patients (n p 46 ) had an initial culture
that yielded Enterobacter species susceptible to third-generation
cephalosporins and a subsequent culture from which a resistant
strain was recovered. Reference patients from whom only sus-
ceptible Enterobacter strains were recovered (n p 113) were
matched to case patients on the basis of the site of Enterobacter
infection (including respiratory tract [44% of total], wounds
[20%], effusion [18%], blood [13%], and urine [5%]) and
length of hospitalization prior to isolation of the susceptible
strain, with control patients required to have a length of hospital
stay of at least the same duration as the time to isolation of a
resistant strain for the matched case patients. Emergence of
antimicrobial resistance in Enterobacter species resulted in sig-
nificantly increased mortality (RR, 5.02), length of hospital stay
(1.5-fold increase), and hospital charges (1.5-fold increase) (ta-
Table 3. Outcomes related to resistance in Pseudomonas aeru-
ginosa, according to multivariate analysis.
Patients with Patients with
resistance emergence
at baseline of resistance
Outcome RR (95% CI) P RR (95% CI) P
a
Death 1.3 (0.6–2.8) .52 3.0 (1.2–7.8) .02
LOSb,c 1.0 (0.9–1.2) .71 1.7 (1.3–2.3) !.001
Daily hospital chargesc,d 1.0 (1.0–1.4) .41 1.1 (0.9–1.3) .43
NOTE. Adapted and reprinted with permission from Carmeli et al. [32].
LOS, length of hospital stay; RR, relative risk.
a
The following variables were included in the model: intensive care unit
(ICU) stay, female sex, and Charlson comorbidity score.
b
The following variables were included in the model: ICU stay, intensity of
culturing, no. of days in hospital before baseline culture, and the presence of
P. aeruginosa in urine.
c
RR for this outcome is the multiplicative effect.
d
The following variables were included in the model: ICU stay, nosocomial
isolate, and major surgery.
ble 4). The median attributable duration of hospital stay due WHY DOES RESISTANCE AFFECT OUTCOMES?
to emergence of resistance was 9 days, and the mean attributable
Factors related to the host, the organism, and the treatment
hospital charge was $29,379.
may contribute to increases in mortality, length of hospitali-
Extended-spectrum b-lactamase–producing (ESBL) Esche-
zation, and costs associated with infection with resistant or-
richia coli and Klebsiella pneumoniae. ESBL E. coli and K.
ganisms. With regard to the host, severity of the underlying
pneumoniae were initially reported as causes of outbreaks [34,
disease may be synergistic with infection with resistant organ-
35] and have become endemic in recent years (causing ∼7%
isms. Alternatively, some researchers argue that an inability to
of infections in ICU and non-ICU settings during 1998–1994)

Downloaded from https://academic.oup.com/cid/article/42/Supplement_2/S82/377684 by Karolinska Institutet Library user on 08 July 2021

[24]. In a retrospective matched cohort study, Lautenbach et
al. [36] evaluated outcomes in patients with E. coli or K. pneu-
moniae infection who were hospitalized at the University of
Pennsylvania Medical Center (Philadelphia, PA) during 1997–
1998. The study population included 33 case patients (i.e., pa-
tients infected with ESBL-producing isolates) and 66 control
patients (i.e., patients infected with non–ESBL-producing iso-
lates), who were matched to case patients on the basis of the
species of the infecting organism (for case patients, 76% of
isolates were K. pneumoniae), the anatomical site of infection
(for case patients, 52% of infections were in the urinary tract,
15% were in wounds, 12% were in catheters, 9% were in blood,
9% were in the respiratory tract, and 3% were in abdominal
sites), and the date of isolation. Exposure to antimicrobial
agents was the only independent predictor of ESBL-producing
E. coli or K. pneumoniae (OR for each additional day of an-
timicrobial therapy, 1.1; P p .006). Infection with ESBL-pro-
ducing E. coli or K. pneumoniae was an independent predictor
of higher median hospital charges subsequent to infection (1.7-
fold increase), a higher mortality rate, and a longer length of
hospital stay (table 5). Although mortality and length of hos-
pitalization were greater for patients with ESBL-producing or-
ganisms, these 2 outcome measures did not reach the level of
statistical significance because of the small sample size. These
findings suggest that resistance need not increase mortality to
have a dramatic impact on the cost of care.
properly control for severity of the underlying illness may lead
to the observed differences in outcomes.
Although increased virulence could explain the adverse im-
pact of resistant pathogens on clinical outcomes, to date, no
studies have demonstrated such an association, except for com-
munity-acquired MRSA. No existing evidence suggests that
VRE strains are more virulent than vancomycin-susceptible
strains, and resistance in gram-negative bacilli may actually
reduce their fitness [37]. Similarly, in studies of health care–
associated infection, MRSA has not been shown to be more
virulent than MSSA [38, 39]. In contrast, there is some evidence
to suggest that community-acquired MRSA is more virulent
than health care–associated MRSA, on the basis of its shorter
doubling time and the higher proportion of isolates with Pan-
ton-Valentine leukocidin gene and other exotoxin genes [38,
39]. Given the influence of antimicrobial resistance in the com-
munity on that in hospitals, the increased virulence of com-
munity-acquired MRSA is worthy of concern and certainly
requires further study.
Treatment factors may contribute to adverse outcomes in
patients infected with a resistant pathogen. These factors in-
clude (1) decreased effectiveness [40–42], increased toxicity
[43], and/or improper dosing [44] of antimicrobial agents avail-
able for treatment; (2) a delay in treatment with or the absence
of microbiologically effective antimicrobials; and (3) an in-
creased need for surgery and other procedures as a result of
these infections.

Table 4. Outcomes for patients with emergence of third-generation cephalosporin-resistant

Enterobacter species, according to multivariate analysis [33].

Patients with Patients without Value attributable

emergence emergence to emergence
Outcome of resistance of resistance of resistance RR P
a
Death, % of patients 26 13 … 5.02 .01
LOS,b days
c
30 19 9 1.47 !.001
Hospital charges,d $US 79,323 40,406 29,379 1.51c !.001

NOTE. LOS, length of hospital stay; RR, relative risk.

a
The following variables were included in the model: McCabe score, no. of comorbidities, and intensive care
unit (ICU) stay.
b
The following variables were included in the model: McCabe score, ICU stay, and transfer from another
hospital.
c
The RR for this outcome is also the multiplicative effect.
d
The following variables were included in the model hepatic disease, McCabe score, ICU stay, major surgery,
and transfer from other hospital.

S86 • CID 2006:42 (Suppl 2) • Cosgrove

 Table 5. Outcomes for patients with infection due to extended-spectrum b-lac-
tamase–producing Escherichia coli and Klebsiella pneumoniae, according to mul-
tivariate analysis [36].
Case patients
Outcome (n p 33)
a
Death, % of patients 15
b
LOS, median days 11
LOS,c median days 11
Charge,c median US$ 66,590
NOTE. LOS, length of hospital stay; RR, relative risk.
a
OR, 1.91 (95% CI, 0.49–7.42); P p .35.
b
Controlling for APACHE II score at the time of infection.
c
Controlling for APACHE II score and LOS before infection.
Mortality rates are higher among patients with ventilator-as-
sociated pneumonia who receive inappropriate empirical treat-
ment (i.e., mismatch between the in vitro activity of the agent
and the subsequent susceptibility results of the infecting path-
ogen) [45]. This association between inappropriate treatment and
increased mortality has also been observed with other infections.
For example, in a study of 167 patients with nosocomial S. aureus
bacteremia during 1999 to 2001, Lodise et al. [46] found that,
compared with prompt treatment, delayed treatment was an in-
dependent predictor of infection-related mortality (mortality
rate, 33.3% vs. 19.3%; OR, 3.8; P p .01) and was associated with
a longer duration of hospitalization after bacteremia (20 vs. 14
days; P p .05). Methicillin resistance was the most significant
predictor of delayed appropriate treatment (OR, 8.3; P ! .001).
The same group of investigators found that receipt of inappro-
priate treatment also explained the increased length of hospital
stay for patients with VRE bacteremia [47]. Similar associations
have been observed for resistant gram-negative infections. In the
study by Lautenbach et al. [36], time to effective therapy for
infections due to ESBL-producing strains was ∼6-fold longer than
that for infections caused by non–ESBL-producing strains (72
vs. 11 h). In addition, in a study of 85 episodes of ESBL-pro-
ducing K. pneumoniae bacteremia, Paterson et al. [48] observed
that failure to treat with an appropriate antimicrobial agent (i.e.,
one with in vitro activity against ESBL-producing K. pneumoniae)
resulted in a significantly greater mortality rate (64% vs. 14%
for patients who received an appropriate antimicrobial agent;
OR, 10.7; P p .001).
Longer length of hospital stay and higher costs of care for
patients infected with a resistant organism may also result from
an increased frequency of surgical interventions required to
control infection. Several groups of investigators have docu-
mented an increased need for surgery among patients infected
with resistant organisms [28, 49, 50]. In a case series of 22
patients without cystic fibrosis who were infected with multi-
drug-resistant P. aeruginosa, Harris et al. [49] found that 89%
of patients with clinical infection required surgery (e.g., de-
bridement of infected tissue with or without revascularization),
Antimicrobial Resistance and Patient Outcome • CID 2006:42 (Suppl 2) • S87
Control patients
(n p 66) RR (95% CI) P
9 … …
7 1.73 (1.14–2.65) .01
7 1.23 (0.81–1.87) .34
Downloaded from https://academic.oup.com/cid/article/42/Supplement_2/S82/377684 by Karolinska Institutet Library user on 08 July 2021
22,231 1.71 (1.01–2.88) .04
and 30% of patients required amputation. In the study by
Carmeli et al. [28], patients with wound or abdominal infec-
tions caused by VRE were significantly more likely to require
surgery, compared with patients without VRE infection (ad-
justed RR, 2.7; P p .001). A second study of patients infected
with Enterococcus faecium also demonstrated that invasive in-
terventions for intra-abdominal and intrathoracic infections
were required more frequently in the cohort infected with a
vancomycin-resistant strain (76% vs. 49% of the patients in-
fected with a vancomycin-susceptible strain; P p .01).
In conclusion, there is an association between the develop-
ment of resistance in S. aureus, enterococci, and gram-negative
bacilli and increases in mortality, length of hospitalization, and
costs of health care. This association is likely the result of in-
adequate or delayed therapy and may be related to the degree
of severity of the underlying disease (with the exception of
community-acquired MRSA). Patients with infections due to
antimicrobial-resistant organisms have higher costs (∼$6,000–
$30,000) than do patients with infections due to antimicrobial-
susceptible organisms; the difference in cost is even greater
when patients infected with antimicrobial-resistant organisms
are compared with patients without infection. Thus, strategies
to prevent the nosocomial emergence and spread of antimi-
crobial-resistant organisms are essential.
Acknowledgments
Potential conflicts of interest. S.E.C. has served on a scientific review
panel for Cubist Pharmaceuticals.
References
1. Schulgen G, Kropec A, Kappstein I, Daschner F, Schumacher M. Es-
timation of extra hospital stay attributable to nosocomial infections:
heterogeneity and timing of events. J Clin Epidemiol 2000; 53:409–17.
2. Cosgrove SE, Carmeli Y. The impact of antimicrobial resistance on
health and economic outcomes. Clin Infect Dis 2003; 36:1433–7.
3. Kaye KS, Engemann JJ, Mozaffari E, Carmeli Y. Reference group choice
and antibiotic resistance outcomes. Emerg Infect Dis 2004; 10:1125–8.
4. Impact of antibiotic-resistant bacteria: thanks to penicillin—he will
come home! Publication OTA-H-629. Washington, DC: Office of Tech-
nology Assessment, Congress, 1995.
 5. Conterno LO, Wey SB, Castelo A. Risk factors for mortality in Staph-
ylococcus aureus bacteremia. Infect Control Hosp Epidemiol 1998; 19:
32–7.
6. Craven DE, Kollisch NR, Hsieh CR, Connolly MG Jr, McCabe WR.
Vancomycin treatment of bacteremia caused by oxacillin-resistant
Staphylococcus aureus: comparison with b-lactam antibiotic treatment
of bacteremia caused by oxacillin-sensitive Staphylococcus aureus. J In-
fect Dis 1983; 147:137–43.
7. French GL, Cheng AF, Ling JM, Mo P, Donnan S. Hong Kong strains
of methicillin-resistant and methicillin-sensitive Staphylococcus aureus
have similar virulence. J Hosp Infect 1990; 15:117–25.
8. Gonzalez C, Rubio M, Romero-Vivas J, Gonzalez M, Picazo JJ. Bac-
teremic pneumonia due to Staphylococcus aureus: a comparison of
disease caused by methicillin-resistant and methicillin-susceptible or-
ganisms. Clin Infect Dis 1999; 29:1171–7.
9. Harbarth S, Rutschmann O, Sudre P, Pittet D. Impact of methicillin
resistance on the outcome of patients with bacteremia caused by Staph-
ylococcus aureus. Arch Intern Med 1998; 158:182–9.
10. Hershow RC, Khayr WF, Smith NL. A comparison of clinical virulence
of nosocomially acquired methicillin-resistant and methicillin-sensitive
Staphylococcus aureus infections in a university hospital. Infect Control
Hosp Epidemiol 1992; 13:587–93.
11. Lewis E, Saravolatz LD. Comparison of methicillin-resistant and meth-
icillin-sensitive Staphylococcus aureus bacteremia. Am J Infect Control
1985; 13:109–14.
12. Marty L, Flahault A, Suarez B, Caillon J, Hill C, Andremont A. Re-
sistance to methicillin and virulence of Staphylococcus aureus strains
in bacteremic cancer patients. Intensive Care Med 1993; 19:285–9.
13. McClelland RS, Fowler VG Jr, Sanders LL, et al. Staphylococcus aureus
bacteremia among elderly vs. younger adult patients: comparison of
clinical features and mortality. Arch Intern Med 1999; 159:1244–7.
14. Mylotte JM, Aeschlimann JR, Rotella DL. Staphylococcus aureus bac-
teremia: factors predicting hospital mortality. Infect Control Hosp Ep-
idemiol 1996; 17:165–8.
15. Roghmann MC. Predicting methicillin resistance and the effect of in-
adequate empiric therapy on survival in patients with Staphylococcus
aureus bacteremia. Arch Intern Med 2000; 160:1001–4.
16. Romero-Vivas J, Rubio M, Fernandez C, Picazo JJ. Mortality associated
with nosocomial bacteremia due to methicillin-resistant Staphylococcus
aureus. Clin Infect Dis 1995; 21:1417–23.
17. Selvey LA, Whitby M, Johnson B. Nosocomial methicillin-resistant
Staphylococcus aureus bacteremia: is it any worse than nosocomial
methicillin-sensitive Staphylococcus aureus bacteremia? Infect Control
Hosp Epidemiol 2000; 21:645–8.
18. Cosgrove SE, Sakoulas G, Perencevich EN, Schwaber MJ, Karchmer
AW, Carmeli Y. Comparison of mortality associated with methicillin-
resistant and methicillin-susceptible Staphylococcus aureus bacteremia:
a meta-analysis. Clin Infect Dis 2003; 36:53–9.
19. Cosgrove SE, Qi Y, Kaye KS, Harbarth S, Karchmer AW, Carmeli Y.
The impact of methicillin resistance in Staphylococcus aureus bacter-
emia on patient outcomes: mortality, length of stay, and hospital
charges. Infect Control Hosp Epidemiol 2005; 26:166–74.
20. Reed SD, Friedman JY, Engemann JJ, et al. Costs and outcomes among
hemodialysis-dependent patients with methicillin-resistant or methi-
cillin-susceptible Staphylococcus aureus bacteremia. Infect Control
Hosp Epidemiol 2005; 26:175–83.
21. Engemann JJ, Carmeli Y, Cosgrove SE, et al. Adverse clinical and eco-
nomic outcomes attributable to methicillin resistance among patients
with Staphylococcus aureus surgical site infection. Clin Infect Dis
2003; 36:592–8.
22. Martinez-Aguilar G, Avalos-Mishaan A, Hulten K, Hammerman W,
Mason EO Jr, Kaplan SL. Community-acquired, methicillin-resistant
and methicillin-susceptible Staphylococcus aureus musculoskeletal in-
fections in children. Pediatr Infect Dis J 2004; 23:701–6.
23. Uttley AH, Collins CH, Naidoo J, George RC. Vancomycin-resistant
enterococci. Lancet 1988; 1:57–8.
S88 • CID 2006:42 (Suppl 2) • Cosgrove
24. National Nosocomial Infection Surveillance System. National Noso-
comial Infections Surveillance (NNIS) system report, data summary
from January 1992 through June 2004. Am J Infect Control 2004; 32:
470–85.
25. Edmond MB, Ober JF, Dawson JD, Weinbaum DL, Wenzel RP. Van-
comycin-resistant enterococcal bacteremia: natural history and attrib-
utable mortality. Clin Infect Dis 1996; 23:1234–9.
26. Stosor V, Peterson LR, Postelnick M, Noskin GA. Enterococcus faecium
bacteremia: does vancomycin resistance make a difference? Arch Intern
Med 1998; 158:522–7.
Downloaded from https://academic.oup.com/cid/article/42/Supplement_2/S82/377684 by Karolinska Institutet Library user on 08 July 2021
27. Bhavnani SM, Drake JA, Forrest A, et al. A nationwide, multicenter,
case-control study comparing risk factors, treatment, and outcome for
vancomycin-resistant and -susceptible enterococcal bacteremia. Diagn
Microbiol Infect Dis 2000; 36:145–58.
28. Carmeli Y, Eliopoulos G, Mozaffari E, Samore M. Health and economic
outcomes of vancomycin-resistant enterococci. Arch Intern Med
2002; 162:2223–8.
29. Yu VL, Chiou CC, Feldman C, et al. An international prospective study
of pneumococcal bacteremia: correlation with resistance, antibiotics
administered, and clinical outcome. Clin Infect Dis 2003; 37:230–7.
30. Fiore AE, Moroney JF, Farley MM, et al. Clinical outcomes of men-
ingitis caused by Streptococcus pneumoniae in the era of antibiotic re-
sistance. Clin Infect Dis 2000; 30:71–7.
31. Moroney JF, Fiore AE, Harrison LH, et al. Clinical outcomes of bac-
teremic pneumococcal pneumonia in the era of antibiotic resistance.
Clin Infect Dis 2001; 33:797–805.
32. Carmeli Y, Troillet N, Karchmer AW, Samore MH. Health and eco-
nomic outcomes of antibiotic resistance in Pseudomonas aeruginosa.
Arch Intern Med 1999; 159:1127–32.
33. Cosgrove SE, Kaye KS, Eliopoulous GM, Carmeli Y. Health and eco-
nomic outcomes of the emergence of third-generation cephalosporin
resistance in Enterobacter species. Arch Intern Med 2002; 162:185–90.
34. Rice LB, Willey SH, Papanicolaou GA, et al. Outbreak of ceftazidime
resistance caused by extended-spectrum b-lactamases at a Massachu-
setts chronic-care facility. Antimicrob Agents Chemother 1990; 34:
2200–9.
35. Quale JM, Landman D, Bradford PA, et al. Molecular epidemiology
of a citywide outbreak of extended-spectrum b-lactamase–producing
Klebsiella pneumoniae infection. Clin Infect Dis 2002; 35:834–41.
36. Lautenbach E, Patel JB, Bilker WB, Edelstein PH, Fishman NO. Ex-
tended-spectrum b-lactamase-producing Escherichia coli and Klebsiella
pneumoniae: risk factors for infection and impact of resistance on
outcomes. Clin Infect Dis 2001; 32:1162–71.
37. Bjorkman J, Andersson DI. The cost of antibiotic resistance from a
bacterial perspective. Drug Resist Updat 2000; 3:237–45.
38. Baba T, Takeuchi F, Kuroda M, et al. Genome and virulence deter-
minants of high virulence community-acquired MRSA. Lancet 2002;
359:1819–27.
39. Naimi TS, LeDell KH, Como-Sabetti K, et al. Comparison of com-
munity- and health care-associated methicillin-resistant Staphylococcus
aureus infection. JAMA 2003; 290:2976–84.
40. Small PM, Chambers HF. Vancomycin for Staphylococcus aureus en-
docarditis in intravenous drug users. Antimicrob Agents Chemother
1990; 34:1227–31.
41. Gentry CA, Rodvold KA, Novak RM, Hershow RC, Naderer OJ. Ret-
rospective evaluation of therapies for Staphylococcus aureus endocar-
ditis. Pharmacotherapy 1997; 17:990–7.
42. Fowler VG Jr, Kong LK, Corey GR, et al. Recurrent Staphylococcus
aureus bacteremia: pulsed-field gel electrophoresis findings in 29 pa-
tients. J Infect Dis 1999; 179:1157–61.
43. Levin AS, Barone AA, Penco J, et al. Intravenous colistin as therapy
for nosocomial infections caused by multidrug-resistant Pseudomonas
aeruginosa and Acinetobacter baumannii. Clin Infect Dis 1999; 28:
1008–11.
44. Rodman DP, McKnight JT, Rogers T, Robbins M. The appropriateness
of initial vancomycin dosing. J Fam Pract 1994; 38:473–7.
45. Niederman MS. Use of broad-spectrum antimicrobials for the treat-
ment of pneumonia in seriously ill patients: maximizing clinical out-
comes and minimizing selection of resistant organisms. Clin Infect Dis
2006; 42(Suppl 2):S72–81 (in this supplement).
46. Lodise TP, McKinnon PS, Swiderski L, Rybak MJ. Outcomes analysis
of delayed antibiotic treatment for hospital-acquired Staphylococcus
aureus bacteremia. Clin Infect Dis 2003; 36:1418–23.
47. Lodise TP, McKinnon PS, Tam VH, Rybak MJ. Clinical outcomes for
patients with bacteremia caused by vancomycin-resistant enterococcus
in a level 1 trauma center. Clin Infect Dis 2002; 34:922–9.
Antimicrobial Resistance and Patient Outcome • CID 2006:42 (Suppl 2) • S89
48. Paterson DL, Ko WC, Von Gottberg A, et al. Antibiotic therapy for
Klebsiella pneumoniae bacteremia: implications of production of ex-
tended-spectrum b-lactamases. Clin Infect Dis 2004; 39:31–7.
49. Harris A, Torres-Viera C, Venkataraman L, DeGirolami P, Samore M,
Carmeli Y. Epidemiology and clinical outcomes of patients with mul-
tiresistant Pseudomonas aeruginosa. Clin Infect Dis 1999; 28:1128–33.
50. Linden PK, Pasculle AW, Manez R, et al. Differences in outcomes for
patients with bacteremia due to vancomycin-resistant Enterococcus fae-
cium or vancomycin-susceptible E. faecium. Clin Infect Dis 1996; 22:
663–70.
Downloaded from https://academic.oup.com/cid/article/42/Supplement_2/S82/377684 by Karolinska Institutet Library user on 08 July 2021