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Previous Article | Next Article 
Antimicrobial Agents and Chemotherapy, June 1999, p. 1379-1382, Vol. 43, No. 6
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
Emergence of Antibiotic-Resistant Pseudomonas
aeruginosa: Comparison of Risks Associated with Different
Antipseudomonal Agents
Yehuda
Carmeli,*
Nicolas
Troillet,
George M.
Eliopoulos, and
Matthew H.
Samore
Division of Infectious Diseases, Beth Israel
Deaconess Medical Center, and Harvard Medical School, Boston,
Massachusetts
Received 24 November 1998/Returned for modification 13 January
1999/Accepted 17 March 1999
 |
ABSTRACT |
Pseudomonas aeruginosa is a leading cause of nosocomial
infections. The risk of emergence of antibiotic resistance may vary with different antibiotic treatments. To compare the risks of emergence
of resistance associated with four antipseudomonal agents, ciprofloxacin, ceftazidime, imipenem, and piperacillin, we conducted a
cohort study, assessing relative risks for emergence of resistant P. aeruginosa in patients treated with any of these drugs.
A total of 271 patients (followed for 3,810 days) with infections due to P. aeruginosa were treated with the study agents.
Resistance emerged in 28 patients (10.2%). Adjusted hazard ratios for
the emergence of resistance were as follows: ceftazidime, 0.7 (P = 0.4); ciprofloxacin, 0.8 (P = 0.6); imipenem, 2.8 (P = 0.02); and piperacillin, 1.7 (P = 0.3). Hazard ratios for emergence of resistance
to each individual agent associated with treatment with the same agent
were as follows: ceftazidime, 0.8 (P = 0.7); ciprofloxacin, 9.2 (P = 0.04); imipenem, 44 (P = 0.001); and piperacillin, 5.2 (P = 0.01). We concluded that there were evident differences among
antibiotics in the likelihood that their use would allow emergence of
resistance in P. aeruginosa. Ceftazidime was associated with the lowest risk, and imipenem had the highest risk.
| |
INTRODUCTION |
Pseudomonas aeruginosa is
a leading cause of nosocomial infections, ranking second among the
gram-negative pathogens reported to the National Nosocomial Infection
Surveillance System. There are a limited number of antimicrobial agents
with reliable activity against P. aeruginosa, including
antipseudomonal penicillins and cephalosporins, carbapenems, and
fluoroquinolones, particularly ciprofloxacin. Aminoglycosides are
frequently used as part of combination regimens for treatment of
serious pseudomonal infections but are generally not recommended as
single drugs. For each of these agents, emergence of resistance during
therapy has been described and has been recognized as a cause of
treatment failure (4, 6, 8, 10, 12, 13). Yet comparative
analyses of the frequency of emergence of resistance associated with
different classes of antipseudomonal drugs are lacking, even though
knowledge about the relative risks of emergence of resistance with
different antibiotics could be useful in helping to guide therapeutic
choices. Ideally, the information regarding risks of emergence of
resistance associated with individual regimens should come from a
large-scale prospective randomized study with multiple treatment
groups. Unfortunately, the costs associated with such a study would be
prohibitive. Therefore, we performed an observational study to compare
the relative risks for emergence of resistant P. aeruginosa
associated with four individual antipseudomonal agents.
In order to directly compare the overall effect of each antibiotic, we
examined emergence of resistance to any antipseudomonal antibiotic. In a secondary analysis, individual antibiotic
resistances were studied as separate and distinct endpoints,
focusing on the association between emergence of resistance to a
specific agent and exposure to that agent.
| |
MATERIALS AND METHODS |
Hospital setting, data collection, and microbiology.
The
Deaconess Hospital is a 320-bed urban tertiary-care teaching hospital
in Boston, Mass. It utilizes 24 intensive-care unit (ICU) beds and has
approximately 11,000 patients admitted per year.
The study was designed as a historical cohort study of data
prospectively collected in the hospital repository. Data were collected
from administrative, pharmacy, and laboratory computerized databases by
using a relational database management system (Access; Microsoft Corp.,
Redmond, Wash.). The presence of infections was confirmed by reviewing
the medical records and laboratory, pathology, and radiology results.
P. aeruginosa had been identified from clinical specimens
submitted to the microbiology laboratory by using Gram-Negative Identification Panel Type II (Dade International Inc., West Sacramento, Calif.). Susceptibility had been determined by microdilution broth testing (MicroScan; Dade International Inc.).
Definitions and study design.
Four antipseudomonal drugs
used frequently in our hospital were studied: ceftazidime,
ciprofloxacin, imipenem, and piperacillin. Piperacillin-tazobactam was
used infrequently for treating pseudomonal infections and was grouped
with piperacillin.
Criteria for entry into the study population were as follows: (i)
admission between 1 August 1994 and 31 July 1996 with a hospital stay
of at least 2 days; (ii) recovery of P. aeruginosa from
clinical culture; (iii) susceptibility of the first pseudomonal isolate
to at least one of the four antibiotics listed above; (iv) subsequent
treatment with at least one of these drugs; and (v) confirmation of
clinical infection on the basis of Centers for Disease Control and
Prevention definitions for infection (modified to include community
infections and with exclusion of asymptomatic bacteriuria)
(7). The patients were followed from the date of detection
of their baseline isolate until discharge or until the detection of the
emergence of resistance in a subsequent clinical isolate of P. aeruginosa.
The emergence of resistance to individual antibiotics was also studied.
Patients were included in each of these analyses according to the
susceptibility of their baseline isolate to the study drug. The
follow-up periods were defined as described above, except that the
endpoint was considered to be the emergence of resistance to the
specific antibiotic that defined the cohort; e.g., for the cohort
defined by baseline susceptibility to ceftazidime, the outcome was the
emergence of resistance to ceftazidime.
The MICs determining susceptibility thresholds for the different drugs
were as follows: 
64 µg/ml for piperacillin, <16 µg/ml for
ceftazidime, < 8 µg/ml for imipenem, and < 2 µg/ml for
ciprofloxacin. Isolates with intermediate susceptibility were
considered resistant in order to match better treatment decisions in
clinical settings. The emergence of resistance was defined as the
clinical detection of resistant P. aeruginosa with a minimum
fourfold increase (two dilutions) in MIC compared to that of the
baseline isolate (the first isolate for each admission), which resulted
in a change in the interpretive criteria.
To explore confounding factors, the following variables were analyzed
in addition to the study drugs: age, gender, underlying diseases and
weighted comorbidities (Charlson comorbidity score) (3),
culture site, surgical procedures, ICU stays, time interval between
hospital admission and the detection of the baseline isolate, number of
initial antibiotic resistances in the baseline isolate, average number
of nursing hours per day (calculated from nursing administrative
records), administration of more than one study drug, and concomitant
administration of aminoglycosides. A score was constructed in order to
adjust for the intensity of clinical culturing by calculating the
average number of cultures obtained per day during the follow-up period.
All available pairs of isolates from patients in whom resistance
emerged were studied by pulsed-field gel electrophoresis (PFGE) as
previously described (5). Isolates from before and after the
emergence of resistance were compared.
Statistical analysis.
Statistical analyses were performed
with SAS (SAS Institute Inc., Cary, N.C.) and Stata (Stata Corp.,
College Station, Tex.) software. Survival analysis was performed in
order to allow for different follow-up periods.
Crude and multivariable Cox proportional-hazard models were used to
address the emergence of resistance. Thus, for each day of follow-up,
comparisons were made only among individuals who were still in the
hospital on that day. Treatment courses with the study antibiotics were
analyzed as time-dependent variables. The measure of relative risk in
Cox proportional-hazard regression is the hazard ratio (HR), which in
this study represents the risk ratio per unit of time for emergence of
resistance, comparing "exposed" and "unexposed" patients (e.g.,
patients who received ceftazidime versus patients who did not receive ceftazidime).
Variables with a P value of <0.2 in the crude analysis were
considered candidates for multivariable analysis and added to a model
that included the study drugs. In addition, variables were tested for
confounding by adding them one at a time to the model and examining
their effects on the beta coefficients of the study drugs. Variables
which caused substantial confounding (a change in the beta coefficient
of greater than 10%) were included in the final model. Effect
modification between antibiotics was examined by using interaction
terms. The proportional-hazard assumption was tested for every analyzed variable.
All statistical tests were two tailed. A P value of <0.05
was considered significant.
| |
RESULTS |
Emergence of resistance (to any of four antipseudomonal
drugs).
Two hundred and seventy-one patients satisfied the
criteria for entry in the study cohort; 162 were males. The single most common site of infection was a wound. The average age of the patients was 62 (range, 24 to 94). The susceptibility pattern of the baseline isolates was as follows: 15 (5%) were resistant to piperacillin, 19 (7%) were resistant to ceftazidime, 36 (13%) were resistant to
imipenem, and 58 (21%) were resistant to ciprofloxacin. One hundred
and eighty-five (68%) of the baseline isolates were susceptible to all
four study drugs, 56 (20%) were resistant to one agent, 27 (10%) were
resistant to two agents, and 6 (2%) were resistant to three agents.
The patients were followed for a total of 3,810 days. The median
follow-up period was 11 days (range, 2 to 72 days). The number of
patients receiving each of the study antibiotics was as follows:
imipenem, n = 37 (14%); ciprofloxacin, n = 98 (36%); piperacillin, n = 91 (33%);
ceftazidime, n = 125 (46%). Sixty-six patients
received more than one study agent. Seventy-seven patients received an
aminoglycoside in addition to a study agent. The median duration of
aminoglycoside therapy was 6 days.
P. aeruginosa resistant to at least one of the study agents
emerged in 28 patients (10.2%), an incidence of 7.4 per 1,000 patient-days. Pairs of isolates (before and after resistance emerged) from nine of these patients were available and were typed by PFGE. Typing patterns before and after the emergence of resistance were identical in each of the patients, confirming that resistance emerged
in a susceptible isolate. The median time to emergence of resistance
was 14 days (range, 2 to 65 days). Characteristics and exposures in
these patients are summarized in Table 1
along with HRs. Imipenem treatment was associated with a
2.9-fold-higher hazard of emergence of resistance. In the crude
analysis, other factors significantly associated with emergence of
resistance were the frequency of microbiological culturing and the
length of the hospital stay before entry into the cohort.
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|
TABLE 1.
Clinical and microbiological characteristics, exposures,
and Cox proportional HRs for the emergence of resistance to any of
the four study drugs
|
|
The multivariable analysis included the four study antibiotics, other
variables that were independently significant (e.g., frequency of
microbiological culturing), and factors which were considered
clinically significant and which were putative confounders (e.g.,
aminoglycoside use and ICU exposure) (Table
2). Treatment with imipenem was still
significantly associated with the emergence of resistance (adjusted
HR = 2.8; P = 0.02).
Combination therapy with an aminoglycoside did not appear to prevent
the emergence of resistance (P = 0.8 in the
multivariable model). The relatively infrequent use of aminoglycosides
in this study reflected a reluctance by clinicians to prescribe
aminoglycosides for patients whose risk for aminoglycoside-induced
nephrotoxicity was high because of age and underlying comorbidities,
such as preexisting renal disease. The analysis showed that there was confounding of the effect of aminoglycosides because of preferential use of aminoglycosides in patients who were at higher risk for emergence of resistance. This confounding was manifested by the decrease in relative risk for aminoglycoside exposure from 1.3 in the
crude analysis to 0.8 in the adjusted model.
We also examined the emergence of resistance to each individual drug,
first by examining crude relative risks and then by adjusting for
aminoglycoside use and culturing score. The crude and adjusted relative
risks were very similar. Resistance to ceftazidime was detected in 14 patients, 6 of whom had been treated with ceftazidime and 8 of whom had
been treated with other antipseudomonal agents (association between
ceftazidime treatment and ceftazidime resistance, adjusted HR = 0.8 [P = 0.7]). Resistance to ciprofloxacin developed in 12 patients, 11 of whom had been treated with ciprofloxacin and 1 had been treated with other antipseudomonal agents (association between
ciprofloxacin treatment and ciprofloxacin resistance, adjusted HR = 9.2 [P = 0.04]). Emergence of resistance to
imipenem occurred in eight patients, seven of whom had been treated
with imipenem (association between imipenem treatment and imipenem resistance, adjusted HR = 44 [P = 0.001]).
Emergence of resistance to piperacillin occurred in 11 patients, 7 of
whom had been treated with piperacillin (association between
piperacillin treatment and piperacillin resistance, adjusted HR = 5.2 [P = 0.01]).
| |
DISCUSSION |
Resistance to antimicrobial agents is an increasing clinical
problem and is a recognized public health threat. P. aeruginosa shows a particular propensity for the development of
resistance. The emergence of resistance in P. aeruginosa
also limits future therapeutic choices and is associated with increased
rates of mortality and morbidity and higher costs (2, 8).
Therefore, we conducted this study to assess resistance arising during
treatment with different antibiotics, first by examining the overall
effect of each antibiotic on emergence of resistance and second by
examining the emergence of resistance to individual agents.
We found that emergence of resistance to at least one antibiotic
occurred in 10.2% of the patients (7.4 cases per 1,000 patient-days). This proportion should be considered a minimum estimate of the risk of
emergence of resistance during antipseudomonal therapy, since it is
based solely on clinical cultures and includes follow-up only during
the index hospitalization. Resistance emerged during treatment with
each class of antibiotic and did not appear to be significantly
prevented by the use of combination therapy with aminoglycosides.
However, the latter issue needs to be further examined in studies that
include larger number of patients on aminoglycosides.
Important differences between antibiotics were evident. First, imipenem
was associated with a significantly higher overall risk of emergence of
resistance (HR, 2.8; P = 0.02) and had the strongest
association with emergence of resistance to itself in the analysis of
individual antibiotics (HR, 44; P = 0.001). In contrast, ceftazidime had the lowest risk for emergence of resistance in the combined analysis (HR, 0.7), and showed no association with
emergence of resistance to itself (i.e., to ceftazidime) (HR, 0.8;
P = 0.7). The relative risk for ciprofloxacin in the combined analysis was also low, but in contrast to ceftazidime, ciprofloxacin was distinctly associated with emergence of resistance to
itself (HR, 9.2; P = 0.04).
The finding that imipenem carries a higher risk of emergence of
pseudomonal resistance is consistent with the results of other studies.
The clinical emergence of resistant P. aeruginosa has been
described during imipenem therapy, ranging from 14 to 53% and
occasionally leading to treatment failures (4, 6, 9, 13,
14). In two randomized clinical trials, these rates were significantly higher for imipenem than for ciprofloxacin or
piperacillin-tazobactam (6, 9). Moreover, imipenem
resistance in P. aeruginosa became widespread in some
hospitals soon after the introduction of this agent (1). In
this study more patients with P. aeruginosa infections were
included than in the randomized trials, and adjustment for possible
confounding was performed. Moreover, this study allowed direct
comparison of four different antipseudomonal agents while accounting
for differences in follow-up periods by using survival analysis.
Although treatment with imipenem could result more often in the
emergence of resistant P. aeruginosa than treatments with other antipseudomonal agents, this tendency may not translate into a
higher prevalence of imipenem resistance among hospital isolates.
Ciprofloxacin resistance, for instance, is more common than imipenem
resistance in P. aeruginosa isolated from inpatients at our
institution (15 versus 9%) (14). This apparent discrepancy might be related to differences in the frequency of use of various agents and to the different likelihoods of persistence of resistant strains.
An observational study such as this has a number of limitations,
including the potential for confounding due to the lack of randomization and the use of more than one study antibiotic in some
patients. However, multivariable analysis allowed us to adjust for
confounding variables and to assess the independent effects of each antibiotic.
Follow-up was continued only during the hospital stay, and not until
the resolution of infection. We used survival analysis to avoid the
potential bias relating to differences in follow-up. Using these
methods, the risks for patients with the same follow-up were compared
to each other. All of the patients had follow-up cultures, but the
frequency of culturing differed among patients. Although we adjusted
for the differences in culturing density by adjusting for the culturing
score, the confounding related to it may not have been fully controlled
for. Our study also did not specifically address the mechanisms by
which resistance occurred (11). We typed only a limited
number of organisms by PFGE to show that resistance emerged in a
susceptible strain. Knowledge of the specific means by which resistant
microorganisms emerge is likely to be useful for designing effective
prevention measures.
One should always remember that the spread of resistant organisms from
patient to patient can be reduced by appropriate infection control
measures. The results of this study are not generalizable to organisms
other than P. aeruginosa. In other gram-negative pathogens,
such as Enterobacter spp., emergence of resistance to
broad-spectrum cephalosporins, including ceftazidime, may occur frequently, while resistance to imipenem is extremely rare.
In conclusion, the present study is important from a practical point of
view. We believe that the use of imipenem for treatment of P. aeruginosa should be reserved for situations where the infection is polymicrobial, particularly when anaerobic bacteria are present, or
for pseudomonal isolates resistant to other antibiotics. In cases where
imipenem is selected as the antipseudomonal antibiotic, the potential
for emergence of resistance should be anticipated, and in appropriate
circumstances, routine culturing and susceptibility testing should be
performed to detect the emergence of resistance P. aeruginosa as soon as possible.
| |
FOOTNOTES |
*
Corresponding author. Mailing address: Division of
Infectious Diseases, Tel Aviv Medical Center, 6 Weizman St., Tel Aviv
64239, Israel. Phone: (972) 3 697-3317. Fax: (972) 3 697-4996. E-mail: ycarmeli{at}mailexcite.com.
| |
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Antimicrobial Agents and Chemotherapy, June 1999, p. 1379-1382, Vol. 43, No. 6
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
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Abstract
Introduction
