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Antimicrobial Agents and Chemotherapy, June 2006, p. 2192-2196, Vol. 50, No. 6
0066-4804/06/$08.00+0     doi:10.1128/AAC.00060-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Differential Effects of Levofloxacin and Ciprofloxacin on the Risk for Isolation of Quinolone-Resistant Pseudomonas aeruginosa

Duke University Medical Center, Durham, North Carolina,¹ University of Chicago Medical Center, Chicago, Illinois,² Beth Israel Deaconess Medical Center, Boston, Massachusetts³

Received 16 January 2006/ Returned for modification 20 February 2006/ Accepted 6 April 2006

	ABSTRACT

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Due to the greater in vitro activity of ciprofloxacin than that of levofloxacin against Pseudomonas aeruginosa, the likelihood of isolating a clinical strain of quinolone-resistant (QR) P. aeruginosa might be greater after exposure to levofloxacin than ciprofloxacin. We examined the risk of isolating QR P. aeruginosa in association with prior levofloxacin or ciprofloxacin exposure. A case-case-control study was conducted. Two groups of cases, one with nosocomial QR P. aeruginosa infections and one with nosocomial quinolone-susceptible (QS) P. aeruginosa infections, were compared to a control group of hospitalized patients without P. aeruginosa infections. Bivariable and multivariable analyses were used to determine risk factors for isolation of QR P. aeruginosa and QS P. aeruginosa. One hundred seventeen QR P. aeruginosa and 255 QS P. aeruginosa cases were identified, and 739 controls were selected. Exposures to ciprofloxacin were similar among all three groups (8% for controls, 9.4% for QR P. aeruginosa cases, and 7.5% for QS P. aeruginosa cases; P 0.6). Levofloxacin use was more frequent in the QR P. aeruginosa cases than in the controls (35.9% and 22.1%, respectively; odds ratio [OR] = 2.0; 95% confidence interval [CI] = 1.3 to 3.0) and less frequent in QS P. aeruginosa cases (14.1% of QS P. aeruginosa cases; OR = 0.6; 95% CI = 0.4 to 0.9). In multivariable analysis, levofloxacin, but not ciprofloxacin, was a significant risk factor for isolation of QR P. aeruginosa (OR for levofloxacin = 1.7 [95% CI = 1.0 to 2.9]; OR for ciprofloxacin = 1.2 [95% CI = 0.6 to 2.5]). Levofloxacin was associated with a reduced risk of isolation of QS P. aeruginosa (OR = 0.6; 95% CI = 0.4 to 0.9), whereas ciprofloxacin had no significant effect (OR = 1.0; 95% CI = 0.6 to 1.8). In conclusion, the use of levofloxacin, but not ciprofloxacin, was associated with isolation of QR P. aeruginosa.

	INTRODUCTION

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Pseudomonas aeruginosa continues to be a major pathogen in nosocomial infections, ranking fifth among all organisms isolated and first among organisms causing infections in medical intensive care units (ICUs) in the United States (17, 23). P. aeruginosa causes a wide range of infections, some life threatening, such as bacteremia and pneumonia. In recent years, this organism has become increasingly resistant to various antimicrobial agents (6, 7).

Among the fluoroquinolones, ciprofloxacin has been most commonly used for the treatment of infections caused by P. aeruginosa. Levofloxacin, a newer member of the quinolone class, also has activity against P. aeruginosa, albeit usually to a lesser degree, as evidenced by higher MICs than those of ciprofloxacin (5, 16, 22, 24, 27). With the widespread use of quinolones both in the hospital and in the community setting, resistance to ciprofloxacin and levofloxacin among P. aeruginosa isolates has emerged and continues to rapidly escalate (3, 4). However, data quantifying the impact of fluoroquinolone use on the risk of isolation of quinolone-resistant (QR) P. aeruginosa are limited and based largely on population studies (1, 18, 22, 30). Furthermore, at the level of individual patients, no studies to our knowledge have compared the impact of the newer (respiratory) fluoroquinolones and that of ciprofloxacin on the risk of isolation of quinolone-resistant P. aeruginosa.

In addition to being intrinsically resistant to several antibiotics, P. aeruginosa can acquire resistance traits during therapy through an array of mechanisms (9, 15, 21, 26, 28, 29). For example, resistance to fluoroquinolones can develop through mutations in the bacterial target enzymes encoded by the gyrA, gyrB, parC, and parE genes or through the elaboration of efflux pumps, such as mexR and nfxB (8, 14).

In this study, we examined the differential risk of subsequent isolation of QR P. aeruginosa imparted by prior levofloxacin and ciprofloxacin exposure. In addition, we identified independent risk factors for the isolation of QR P. aeruginosa. We hypothesized that, due to its less favorable in vitro activity against P. aeruginosa, levofloxacin exposure would result in a higher risk of emergence of QR P. aeruginosa than ciprofloxacin exposure.

(This paper was presented as a poster at the 44th Interscience Conference on Antimicrobial Agents and Chemotherapy, Washington, D.C., October 2004.)

	MATERIALS AND METHODS

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Study location. The study was conducted at Beth Israel Deaconess Medical Center (BIDMC), a tertiary-care teaching hospital in Boston, Massachusetts, that consists of approximately 450 beds. During the study period, extending from December 1999 to October 2002, levofloxacin and ciprofloxacin were both approved antimicrobial agents on the hospital formulary.

Study design and patient population. A retrospective case-case-control study design was used (11, 13). The first group of cases consisted of patients with nosocomial isolation of QR P. aeruginosa, and the second group included patients with nosocomial isolation of quinolone-susceptible (QS) P. aeruginosa. The organism was considered to be nosocomially acquired if it was isolated 48 h after hospital admission. Cases were classified as QR P. aeruginosa or QS P. aeruginosa based on the susceptibility of the first P. aeruginosa isolate; thus, if more than one P. aeruginosa isolate was cultured from the same patient, only the initial isolate was included. The control group was defined as patients who had been hospitalized for 3 days and who were not infected or colonized with P. aeruginosa during their hospital stay. Only adult patients (>18 years of age) were included in the study.

Variable definitions. All information was obtained from hospital records, and variable definitions were established prior to data collection. Susceptibility testing for all organisms was performed using the Vitek II system. Ciprofloxacin susceptibility was used as a surrogate marker for fluoroquinolone susceptibility. Variables analyzed as risk factors for isolation of P. aeruginosa included patient demographics, patient comorbid conditions, antibiotic exposures, and other hospital exposure factors, including surgery, stay in an ICU, and time-at-risk (TAR) period. TAR was defined as the interval between hospital admission and isolation of P. aeruginosa from culture. For controls, TAR spanned the entire duration of the hospital stay. The presence or absence of risk factors was determined for study patients only during the TAR period. Treatment with antibiotics was defined as receipt of at least one dose of an antimicrobial agent during the TAR period. During the study period, the dose of levofloxacin used for patient treatment was 500 mg, given either intravenously or orally.

Analysis plan and statistical analysis. The objective of this case-case-control study was to identify variables associated specifically with the isolation of QR P. aeruginosa. Two different analyses were conducted. In the first, risk factors for isolation of QR P. aeruginosa were determined by comparing patients with QR P. aeruginosa to uninfected controls. In the second analysis, risk factors for isolation of QS P. aeruginosa were identified by comparing patients with QS P. aeruginosa to the same group of uninfected controls. By comparing and contrasting these two models, variables uniquely associated with the isolation of QR P. aeruginosa were determined (6, 7, 11-13).

Data were entered into a Microsoft Office Access 2003 database, and analysis was performed using SAS 8.02 (SAS Institute, Cary, NC). Bivariable analyses were performed using Fisher's exact test or the ² test for categorical variables and the independent-samples t test or the Wilcoxon signed-rank test for continuous variables.

Using logistic regression, two multivariable models were constructed, one including predictors of nosocomial isolation of QR P. aeruginosa and the other including predictors of nosocomial isolation of QS P. aeruginosa. The primary objective of these multivariable analyses was to assess the independent impact of ciprofloxacin and levofloxacin on the risk of isolation of QR P. aeruginosa and QS P. aeruginosa while controlling for potential confounders. The secondary objective of these analyses was to identify other independent predictors of QR P. aeruginosa or QS P. aeruginosa. In addition to ciprofloxacin and levofloxacin use, the candidate variables for inclusion in the logistic models included all variables with P values of <0.20 in bivariable analyses. A stepwise selection procedure was used to select variables for inclusion in the final model. The final selected model was tested for confounding variables. If a covariate affected the ß coefficient of levofloxacin or ciprofloxacin or another selected variable in the model by >10%, then the confounding variable was maintained in the multivariable model. All P values were two-sided.

Ethical considerations. The study was approved by the Institutional Review Board at BIDMC. Because no direct patient contact was anticipated and no follow-up interviews were conducted, the requirement for informed consent was waived. All data collected for the purpose of this study were kept anonymous and confidential.

	RESULTS

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Totals of 117 QR P. aeruginosa cases and 255 QS P. aeruginosa cases were identified during the study period. Seven hundred thirty-nine uninfected hospitalized subjects were randomly selected as controls. The overall cohort of 1,111 patients had a mean age of 63.5 years and a male-to-female ratio of 0.86:1. Quinolone exposure in the study population amounted to 8.0% for ciprofloxacin and 21.7% for levofloxacin.

The results of bivariable analyses for cases with QR P. aeruginosa and QS P. aeruginosa infection, each compared to the same group of control patients, are shown in Tables 1 and 2, respectively. The most common sites of isolation of P. aeruginosa in both QR P. aeruginosa and QS P. aeruginosa cases were respiratory tract (32.5% and 33.7%, respectively), urine (23.9% and 24.7%, respectively), and wound specimens (24.8% and 22.7%, respectively). There was no difference among the results for the three groups with respect to age or gender.

Treatment with various classes of antimicrobial agents, including penicillins, expanded-spectrum cephalosporins, carbapenems, aminoglycosides, and glycopeptides, was significantly more common for QR P. aeruginosa cases than for controls (P < 0.05). However, there was no difference in the proportions of QR P. aeruginosa cases and controls exposed to ciprofloxacin (9.4% and 8.0%, respectively [OR = 1.2; 95% CI = 0.6 to 2.3]). In contrast, levofloxacin exposure occurred more commonly in the QR P. aeruginosa group than in the control group (35.9% and 22.1%, respectively [OR = 2.0; 95% CI = 1.3 to 3.0]).

(ii) Multivariable results. Comparison to results for patients who did not receive antibiotics revealed that exposure to levofloxacin was an independent predictor of QR P. aeruginosa isolation (OR = 1.7; 95% CI = 1.0 to 2.9) but that exposure to ciprofloxacin was not associated with isolation of QR P. aeruginosa (OR = 1.2; 95% CI = 0.6 to 2.6) (Table 3). Patients who received antibiotics other than a quinolone were at increased risk for isolation of QR P. aeruginosa (OR = 2.2; 95% CI = 1.3 to 3.8). Other independent predictors of isolation of QR P. aeruginosa included stay in an ICU (OR = 3.3; 95% CI = 2.1 to 5.1), the presence of three or more comorbid conditions (OR = 1.7; 95% CI = 1.1 to 2.8), and a TAR of >6 days (OR = 1.8; 95% CI = 1.1 to 2.8). This model was controlled for the confounding effects of an age of >64 years and transfer from another institution.

Treatment with various classes of antimicrobial agents, including penicillins, expanded-spectrum cephalosporins, carbapenems, aminoglycosides, and glycopeptides, was significantly more predominant for QS P. aeruginosa cases than for controls. There was no difference in the proportions of controls and QS P. aeruginosa cases exposed to ciprofloxacin (7.5% and 8.0%, respectively [OR = 0.9; 95% CI = 0.5 to 1.6]). However, fewer patients in the QS P. aeruginosa group were exposed to levofloxacin than were control patients (14.1% and 22.1%, respectively [OR = 0.6; 95% CI = 0.4 to 0.9]).

(ii) Multivariate results. Levofloxacin was found to be associated with a reduced risk of QS P. aeruginosa isolation when results were compared with results for controls (OR = 0.6; 95% CI = 0.4 to 0.9), whereas ciprofloxacin had no effect on isolation of QS P. aeruginosa (OR = 1.0; 95% CI = 0.6 to 1.8). Other independent predictors of isolation of QS P. aeruginosa included ICU stay (OR = 3.7; 95% CI = 2.7 to 5.1), treatment with other antibiotics (OR = 2.1; 95% CI = 1.5 to 3.0), the presence of three or more comorbid conditions (OR = 1.6; 95% CI = 1.1 to 2.3), and an age of >65 years (OR = 1.4; 95% CI = 1.0 to 2.0). This model was controlled for the confounding effect of TAR.

	DISCUSSION

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There is mounting evidence demonstrating that resistance rates among P. aeruginosa isolates are steadily increasing. Recent data from the multicenter Intensive Care Unit Surveillance Study (19) in the United States indicate that the proportion of P. aeruginosa isolates susceptible to the routinely tested antipseudomonal agents decreased from 60.4% in 1996 to 48.9% in 2001 and 2002. The rise in the rate of antimicrobial resistance to a specific antibiotic was greatest for ciprofloxacin (16% absolute increase) (4). In addition, among the 23 facilities participating in Project ICARE (Intensive Care Antimicrobial Resistance Epidemiology), the prevalence of ciprofloxacin-resistant P. aeruginosa increased significantly from 1996 and 1997 to 1998 and 1999 for isolates recovered from ICUs as well as from non-ICU hospital environments and in the outpatient setting (3).

Studies that analyze the impact of antibiotic treatment on antimicrobial resistance must account for the effect of confounding by indication (2, 25). This effect describes a phenomenon where patients at increased risk for infection due to nosocomial pathogens (such as Pseudomonas spp.) are more likely to be prescribed an antibiotic that provides broad coverage against nosocomial pathogens than an antibiotic that has less activity against nosocomial pathogens. For example, because ciprofloxacin was used primarily for empirical therapy for pseudomonal infection during the study period, one would expect that due to confounding by indication, the results of this study would be biased towards identifying ciprofloxacin as a risk factor for isolation of QR P. aeruginosa. Furthermore, because levofloxacin was used primarily at the study institution to treat community-acquired respiratory infections and not Pseudomonas, one would expect that our results would be biased towards not identifying levofloxacin as a risk factor for isolation of QR P. aeruginosa. Thus, the fact that this study identified levofloxacin exposure, but not ciprofloxacin exposure, as a risk factor for isolation of QR P. aeruginosa is particularly notable. In fact, due to confounding by indication, the impact of levofloxacin on the increased likelihood of isolation of QR P. aeruginosa is probably underestimated in this study.

The differential effects of ciprofloxacin and levofloxacin on the risk of isolating QR P. aeruginosa that were reported in this study might be related to the greater intrinsic in vitro activity of ciprofloxacin against P. aeruginosa than that of levofloxacin. With higher MICs against P. aeruginosa, levofloxacin might have been more likely than ciprofloxacin to select for colonization or infection with QR P. aeruginosa. Interestingly, population studies have demonstrated a similar association between an increase in levofloxacin prescriptions and an increase in rates of QR P. aeruginosa recovered in hospitals (1, 19).

We also noted that exposure to levofloxacin, but not ciprofloxacin, was associated with a decreased risk of isolation of QS P. aeruginosa. These differential effects of levofloxacin and ciprofloxacin on isolation of QS P. aeruginosa might reflect confounding by indication: the protective effect of levofloxacin on isolation of QS P. aeruginosa might be a reflection of levofloxacin being prescribed to a population at low risk for infection with P. aeruginosa. In addition, the lack of protective effect of ciprofloxacin against isolation of QS P. aeruginosa may relate to bias associated with the use of ciprofloxacin for patients at increased risk for pseudomonal infection.

Additional independent predictors for isolation of QR P. aeruginosa and QS P. aeruginosa were similar and included markers of severity of illness, hospital exposures, and exposure to antimicrobial agents other than the quinolones. These variables have been described previously as risk factors for isolation of P. aeruginosa (6, 7, 10, 19, 20). Thus, levofloxacin was the only variable that was a risk factor for isolation for QR P. aeruginosa but not for QS P. aeruginosa.

Attempts to implicate the fluoroquinolones as risk factors for QR P. aeruginosa resistance have previously been made by other investigators. Hsu et al. performed a case-control study comparing 91 cases with QR P. aeruginosa infection to 86 controls with QS P. aeruginosa infection and reported quinolone use as the strongest independent predictor of QR P. aeruginosa isolation (10). In addition, Neuhauser et al. had demonstrated that the increasing incidence of ciprofloxacin resistance among gram-negative bacilli coincided with increased national consumption of fluoroquinolones (18). Additional studies have investigated the differential effects of various quinolones on risk for QR P. aeruginosa and have identified levofloxacin as a stronger risk factor than ciprofloxacin (1, 22). The results from these population studies were based on overall antimicrobial expenditures and total defined daily doses of quinolones, suggesting the possibility of an ecological association. These population studies did not address the relationship between quinolone therapy and subsequent isolation of QR P. aeruginosa at the level of the individual patient. The case-case-control design that was used in the current study allowed an accurate analysis of the effects of different types of quinolone exposures on the risk of isolation of QR P. aeruginosa at the level of the individual patient.

One limitation of this study is that controls were not actively screened for colonization with P. aeruginosa, potentially leading to the misclassification of some cases as controls. However, this type of misclassification bias would only serve to make the case and control groups more similar and thus underestimate the true risk imparted by the exposure to quinolones and would not otherwise bias our results. In addition, this was a single-institution study, and some of the results might be specific to the study institution. These results should be confirmed in additional study settings. As no outbreaks of P. aeruginosa infections were identified during the study period, molecular typing of the organisms was not performed. Finally, the potential impact of using doses of levofloxacin greater than 500 mg per day was not assessed in this study.

At the level of the individual patient, exposure to levofloxacin, but not to ciprofloxacin, was associated with increased risk of subsequent isolation of QR P. aeruginosa. Antimicrobials which favor the nosocomial isolation of the resistant phenotype of an organism may be particularly harmful to the microbial ecology of an institution by promoting the emergence and dissemination of antimicrobial-resistant strains. For hospitals where QR P. aeruginosa is an important pathogen, the epidemiologies of both QR P. aeruginosa isolation and quinolone prescribing should be examined. In addition, the effects of treatment with different quinolones on antimicrobial resistance should be considered for Pseudomonas and other organisms, such as methicillin-resistant Staphylococcus aureus. Decisions regarding which fluoroquinolones should be included on a hospital's formulary might take into account the differential effects of levofloxacin and ciprofloxacin on isolation of QR P. aeruginosa. The intrinsically weak activity of ciprofloxacin against important gram-positive pathogens should also be considered when making such decisions. The results of this study indicate that ciprofloxacin is more appropriate than levofloxacin for empirical therapy for suspected pseudomonal infections.

	ACKNOWLEDGMENTS

 
Keith S. Kaye was supported by grant K23 AG23621-01A1 from the National Institute of Aging.

	FOOTNOTES

 
* Corresponding author. Mailing address: Division of Infectious Diseases, Duke University Medical Center, Box 3152, Durham, NC 27710. Phone: (919) 668-5158. Fax: (919) 684-8474. E-mail: kaye0001{at}mc.duke.edu.

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