Clin Infect Dis. 2006 Cosgrove S82 9

8/13/2019 Clin Infect Dis. 2006 Cosgrove S82 9

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S82 CID 2006:42 (Suppl 2) Cosgrove

S U P P L E M E N T A R T I C L E

The Relationship between Antimicrobial Resistance

and Patient Outcomes: Mortality, Length of HospitalStay, 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 inStaphylococcus 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 implicationsof 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 ([email protected]).

Clinical Infectious Diseases 2006;42:S829

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 [13]. 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


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

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

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-susceptibleS. aureus

(MSSA) bacteremia, was observed (OR, 1.93; ). In sub-P! .001

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, wereevaluated

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 significantS. aureusbacteremia (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; ) and hospital charges after S. aureusbac-Pp .045

teremia ($26,424 vs. $19,212; ). MRSA bacteremia wasPp .008

an independent predictor of increased length of hospitalization


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Table 2. Outcomes related to methicillin resistance in Staphylococcus aureussurgical site infections (SSIs) [21].

Comparison

Death Length of hospital stay after surgery Charges

Percentage

of subjects

who died OR P

Total no. of

d ays , m ea n ME

No. of days

attributable

to MRSA P

US$,

mean ME

US$

attributable

to MRSA P

Control vs. MRSA SSI 11.4 !.001 3.2 13.4 !.001 2.2 41,274 !.001Uninfected control subjects

(n p 193) 2.1 6.1 34,395

Patients with MRSA SSI

(n p 121) 20.7 29.1 118,414

MSSA SSI vs. MRSA SSI 3.4 .003 1.2 2.6 .11 1.2 13,901 .03

Patients with MSSA SSI

(n p 165) 6.7 13.2 73,165

Patients with MRSA SSI

(n p 121) 20.7 29.1 118,414

NOTE. ME, multiplicative effect; MRSA, methicillin-resistantS. aureus; MSSA, methicillin-susceptibleS. aureus.

(1.3-fold increase; ) and hospital charges (1.4-fold in-Pp .016

crease; ). A second study prospectively evaluated 105Pp .017

hemodialysis-dependent patients withS. aureusbacteremia who

were admitted to DukeUniversity 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 patients probability for having

MRSA bacteremia, based on demographics, comorbidities, andAPACHE 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; ) and the adjusted median costs higher for theP! .001

initial hospitalization ($21,251 vs. $13,978; ) and afterPp .012

12 weeks ($25,518 vs. $17,354; ) for patients infectedPp .015

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. aureussurgical site infectionsprimarily associated with cardiac or orthopedic procedures.

During 19942000, 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 ( ), andPp .003

by 11.4-fold, compared with the absence of infection (P!

) (table 2). Patients with MRSA infection had mean at-.001

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 childrenwith 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; ) and of hos-Pp .001

pital stay (14.5 vs. 12.7 days; ) were significantly longerPp .014

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; ). Also of note,S. aureusisolatesP! .001

containing the Panton-Valentine leukocidin gene were associ-ated with a greater proportion of complications (30.3% vs. 0%;

).Pp .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

[2527]. 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 ( ; 42% had VRE innp 233

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;

) without VRE colonization or infection who werenp 647

matched for length of hospital stay, hospital ward, and calendar


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Table 3. Outcomes related to resistance inPseudomonas aeru-ginosa,according to multivariate analysis.

Outcome

Patients with

resistance

at baseline

Patients with

emergence

of resistance

RR (95% CI) P RR (95% CI) P

Deatha

1.3 (0.62.8) .52 3.0 (1.27.8) .02

LOSb,c

1.0 (0.91.2) .71 1.7 (1.32.3) !.001

Daily hospital chargesc,d

1.0 (1.01.4) .41 1.1 (0.91.3) .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.

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; ),Pp .04

length of hospital stay (attributable excess hospitalization, 6.2

days; multiplicative effect, 1.73; ), and hospital costsP! .001(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-resistantStreptococcus pneu-

moniae. In distinct contrast to the results of studies of staph-

ylococci and enterococci, infection due to nonsusceptible S.

pneumoniaehas 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 withP. aeru-

ginosainfection 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-

line (table 3). In contrast, the emergence of resistance was

associated with a 3-fold greater risk of death ( ) and aPp .02

1.7-fold longer duration of hospital stay ( ). The esti-P! .001

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-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. Enterobacterspecies are common nosocomial

pathogens, with almost one-third of strains causing third-gener-

ation cephalosporinresistant 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 ( ) had an initial culturenp 46

that yieldedEnterobacterspecies susceptible to third-generationcephalosporins and a subsequent culture from which a resistant

strain was recovered. Reference patients from whom only sus-

ceptible Enterobacter strains were recovered ( ) werenp 113

matched to case patients on the basis of the site ofEnterobacter

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 inEnterobacterspecies 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-


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

Enterobacterspecies, according to multivariate analysis [33].

Outcome

Patients with

emergence

of resistance

Patients without

emergence

of resistance

Value attributable

to emergence

of resistance R R P

Death,a % of patients 26 13 5.02 .01

LOS,b

days 30 19 9 1.47c

!.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.

ble 4). The median attributable duration of hospital stay due

to emergence of resistance was 9 days, and the meanattributable

hospital charge was $29,379.

Extended-spectrumb-lactamaseproducing (ESBL)Esche-

richia coli andKlebsiella pneumoniae. ESBL E. coliand K.

pneumoniaewere initially reported as causes of outbreaks [34,

35] and have become endemic in recent years (causing 7%

of infections in ICU and non-ICU settings during 19981994)[24]. In a retrospective matched cohort study, Lautenbach et

al. [36] evaluated outcomes in patients with E. colior 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 nonESBL-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. colior K. pneumoniae (OR for each additional day of an-

timicrobial therapy, 1.1; ). Infection with ESBL-pro-Pp .006

ducingE. colior K. pneumoniaewas 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.

WHY DOES RESISTANCE AFFECT OUTCOMES?

Factors related to the host, the organism, and the treatment

may contribute to increases in mortality, length of hospitali-

zation, and costs associated with infection with resistant or-

ganisms. With regard to the host, severity of the underlying

disease may be synergistic with infection with resistant organ-

isms. Alternatively, some researchers argue that an inability to

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 virulentthan health careassociated 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 [4042], 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.


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Table 5. Outcomes for patients with infection due to extended-spectrumb-lac-tamaseproducingEscherichia coliandKlebsiella pneumoniae,according to mul-tivariate analysis [36].

Outcome

Case patients

(n p 33)

Control patients

(n p 66) RR (95% CI) P

Death,a

% of patients 15 9

LOS,b

median days 11 7 1.73 (1.142.65) .01

LOS,c median days 11 7 1.23 (0.811.87) .34

Charge,c

median US$ 66,590 22,231 1.71 (1.012.88) .04

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

OR, 1.91 (95% CI, 0.497.42); .Pp .35b

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 treatmentand

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; ) and was associated withPp .01

a longer duration of hospitalization after bacteremia (20 vs. 14

days; ). Methicillin resistance was the most significantPp .05

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 thestudy by Lautenbach et al. [36], time to effective therapy for

infections due to ESBL-producing strains was6-foldlonger than

that for infections caused by nonESBL-producing strains (72

vs. 11 h). In addition, in a study of 85 episodes of ESBL-pro-

ducingK. pneumoniaebacteremia, 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; ).Pp .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-resistantP. 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),

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; ). A second study of patients infectedPp .001

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; ).Pp .01

In conclusion, there is an association between the develop-

ment of resistance inS. 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.

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