Previous ciprofloxacin exposure is associated with resistance to b-lactam antibiotics in subsequent Pseudomonas aeruginosa bacteremic isolates Miguel Lo´pez-Dupla, MD,a Jose´-Antonio Martı´nez, MD,b Francesc Vidal, MD,a Manuel Almela, MD,b Alex Soriano, MD,b Francesco Marco, MD,b Josefina Lo´pez, MD,b Montserrat Olona, MD,a and Josep Mensa, MDb Tarragona and Barcelona, Spain
Background: Pseudomonas aeruginosa cross-resistance to ceftazidime, imipenem, meropenem, piperacillin, and fluoroquinoles has been shown in experimental studies, but information regarding its impact in the clinical setting is scarce and inconsistent. The aim of this study was to assess whether previous exposure to ciprofloxacin influences on the sensitivity of those antibiotics in subsequent P aeruginosa bacteremic isolates. Methods: Patients with P aeruginosa bacteremia were recorded from a blood culture surveillance program (1997-2007). Demographic characteristics, underlying diseases, setting of the infection, source of infection, previous antibiotic exposure, and antibiotic sensitivity were analyzed. Results: We studied 572 cases of P aeruginosa bacteremia. There were 327 men (57.2%), and the mean age was 61.2 6 18 years. The bacteremia was nosocomial in 62.4% of episodes. Resistance rates of P aeruginosa isolates were 15.5% for ceftazidime, 16.7% for imipenem, 11.2% for meropenem, 12.3% for piperacillin-tazobactam, and 23.1% for ciprofloxacin. Exposure to ciprofloxacin during the previous 30 days was an independent predictor of resistance to ceftazidime (odds ratio [OR], 3; 95% confidence interval [CI]: 1.7-5.3; P , .001), imipenem (OR, 2; 95% CI: 1.1-3.7; P 5 .02), meropenem (OR, 2.7; 95% CI: 1.4-5.3; P 5 .004), piperacillintazobactam (OR, 2.4; 95% CI: 1.3-4.7; P 5 .007), ciprofloxacin (OR, 2.9; 95% CI: 1.7-4.9; P , .001), and multidrug resistance (OR, 2.5; 95% CI: 1.2-5.2; P 5 .02). Conclusion: P aeruginosa bacteremic isolates from patients who have been exposed to ciprofloxacin during the 30 days prior to the development of bacteremia have an increased risk of being resistant to ceftazidime, imipenem, meropenem, piperacillin-tazobactam, or ciprofloxacin and to have multidrug resistance. Key Words: Pseudomonas aerugonosa; bacteremia; ciprofloxacin; ceftazidime; piperacillin-tazobactam; imipenem; meropenem; resistance. Copyright ª 2009 by the Association for Professionals in Infection Control and Epidemiology, Inc. (Am J Infect Control 2009;37:753-8.)
The incidence of antibiotic resistance in isolates of Pseudomonas aeruginosa is increasing.1-4 Recognized risk factors for colonization or infection by drug-resistant P aeruginosa include prolonged hospital stay, admittance to an intensive care unit, prolonged central venous or urinary catheterization, nasogastric tube feeding, and previous exposure to antipseudomonal antibiotics.5-9 The
From the Hospital Universitari de Tarragona Joan XXIII, IISPV, Universitat Rovira i Virgili, Tarragona, Spaina; and Hospital Clı´nic IDIBAPS, Barcelona, Spain.b Address correspondence to Miguel Lopez-Dupla, MD, Servei de Medicina Interna, Hospital Universitari de Tarragona Joan XXIII, C/Dr. Mallafre´ Guasch, 4, 43007 Tarragona, Spain. E-mail: [email protected]
Supported in part by a grant from the Fundacio´n Ma´ximo Soriano Jime´nez. Conflicts of interest: None to report. 0196-6553/$36.00 Copyright ª 2009 by the Association for Professionals in Infection Control and Epidemiology, Inc. doi:10.1016/j.ajic.2009.02.003
predisposition of P aeruginosa to develop resistance is thought to be due to the multiple mechanisms of resistance that can be activated when it is exposed to antimicrobial drugs.10 Some of these mechanisms, mainly the activation of the membrane MexAB-OprM efflux pump system, can determine concomitant cross-resistance to different groups of antibiotics such as ceftazidime, piperacillin, meropenem, and fluoroquinolones. Furthermore, exposure to drugs either individually or in combination can activate the efflux pump system and enable multidrug-resistant P aeruginosa isolates to be selected.11,12 It should be pointed out that imipenem is affected by the activation of the MexEF-OprN system, not by the up-regulation of MexAB-OprM system. Although this is well established in the experimental laboratory,13,14 there is very little information available about the importance of selecting P aeruginosa strains resistant to some of these antibiotics in daily clinical practice, mainly in terms of outcome and costs.15,16 The few studies that have evaluated how previous treatment with ciprofloxacin affects the resistance of subsequent P aeruginosa infections to 753
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b-lactam antibiotics provide inconsistent information.7,17-21 We therefore designed a case-control study with the primary aim to assess the effect of previous ciprofloxacin exposure on the resistance pattern to ceftazidime, imipenem, meropenem, piperacillin-tazobactam, and ciprofloxacin in subsequent P aeruginosa bacteremic episodes. As a secondary aim, we assessed the effect of previous ceftazidime, imipenem, meropenem, and piperacillin-tazobactam exposure on the resistance pattern to these antibiotics and to ciprofloxacin in subsequent P aeruginosa bacteremic episodes.
MATERIALS AND METHODS Design and setting This was a case-control study. Patients were collected through a blood culture surveillance program between 1997 and 2007. The main characteristics of our database and cohorts studied have been reported elsewhere.22-25 Patients aged over 14 years with P aeruginosa bacteremia were included. Patients with more than 1 episode of P aeruginosa bacteremia were included only once, and the episode included was the first one. The study was conducted at the Hospital Clı´nic Universitari in Barcelona and the Hospital Universitari Joan XXIII in Tarragona, Spain. These are university-affiliated hospitals with 900 and 350 beds, respectively, and provide broad medical, surgical, and intensive care. There is no burn unit in either hospital.
Microbiology P aeruginosa isolates were identified using standard bacteriologic methods and an automated system (MicroScan Baxter Healthcare, Sacramento, CA). Susceptibility to ceftazidime, imipenem, meropenem, piperacillin-tazobactam, and ciprofloxacin was assessed with the microdilution method (minimum inhibitory concentration), in accordance with the National Committee for Clinical Laboratory Standards method.26 Isolates were categorized as susceptible, intermediate, or resistant. These last 2 categories were considered to be resistant to analysis. A strain of P aeruginosa was considered multidrug resistant if resistance to ceftazidime, imipenem, piperacillin-tazobactam, and ciprofloxacin were present.27
Definitions The following information was recovered from medical records and included prospectively in the database: primary site of infection; underlying diseases (diabetes mellitus, chronic obstructive lung disease, chronic liver disease, heart failure, chronic renal failure, solid neoplasia, malignant lymphoma, leukemia, HIV infection, among others); conditions associated with immunosuppression (bone marrow transplantation, solid organ
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transplantation, treatment with steroids, neutropenia); and other data such as mechanical ventilation, nosocomial infection, hospital admittance during the previous 30 days, admission to intensive care unit at the time when the bacteremia developed, previous antibiotic treatment, shock, and death. The prognosis of the underlying diseases was categorized according to the McCabe and Jackson criteria.28 The definitions used for underlying diseases, source of bacteremia, neutropenia, treatment with steroids, severe sepsis, septic shock, and others have been reported elsewhere.22-25 The criteria for previous antimicrobial exposure to antibiotics that share the MexAB-OprM and MexEFOprN efflux pump systems were all the following: (1) antimicrobial drugs were given within the 30-day period prior to the bacteremic episode, (2) antimicrobial drugs were given for at least 48 hours, and (3) antimicrobial drugs were prescribed at the currently recommended doses and patterns of administration. The antibiotics considered were ceftazidime, imipenem, meropenem, piperacillin-tazobactam, and ciprofloxacin. Patients were followed up until in-hospital death or discharge. An episode of bacteremia detected within the first 72 hours of admission or before hospitalization was considered to be community acquired. It was considered to be nosocomial if it occurred $72 hours after admission, if the patient had been hospitalized within the 2 weeks previous to the current admission, and/or if the patient came from a long-term care facility.29
Statistical analysis To compare resistant and nonresistant P aeruginosa bacteremia episodes for each antibiotic studied, univariate analysis was performed using the x2 test and Fisher exact test when necessary. The variables recorded at baseline for the univariate analysis were sex, age, previous admission, nosocomial origin, McCabe and Jackson prognosis criteria,28 different previous antibiotic exposures, different underlying conditions, and sources of bacteremia as risk factor variables. Shock and crude mortality were assessed as prognostic variables. The sample size was based on a statistical estimate, which showed that a 20% difference between previously exposed and nonexposed to ciprofloxacin in resistant and nonresistant P aeruginosa isolates to ceftazidime, imipenem, meropenem, piperacillin-tazobactam, and ciprofloxacin would be discovered on a 95% probability level with 80% power. Logistic regression test was performed to assess the independent risk factors for resistance to each antibiotic studied. In the multivariate analysis, we included all variables that had a P value ,.2 in the univariate analysis. A P value ,.05 was considered significant. All calculations were made with the SPSS statistical package for Windows (version 11.5; SPSS Inc, Chicago, IL).
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RESULTS Characteristics of the patients studied The study group was made of 572 patients with P aeruginosa bacteremia. The main demographic and clinical characteristics are shown in Table 1. An underlying condition was present in 84%, and half of patients had ultimately or rapidly fatal diseases. Previous antibiotic therapy is showed in Table 1. Ciprofloxacin was the only fluoroquinolone given previously. P aeruginosa isolates showed resistance to ceftazidime in 87 of 563 tested (15.5%), imipenem in 94 of 562 (16.7%), meropenem in 63 of 563 (11.2%), piperacillin-tazobactam in 69 of 560 (12.3%), and ciprofloxacin in 131 of 567 (23.1%). Multidrug-resistant P aeruginosa isolates were recovered in 47 cases (8.2%). The antibiograms with regard to P aeruginosa isolates were similar in the 2 hospitals participating in the study.
P aeruginosa resistance patterns Univariate analysis. We performed univariate analyses to assess the risk factors for resistance of P aeruginosa bacteremic isolates to ceftazidime, imipenem, meropenem, piperacillin-tazobactam, ciprofloxacin, and multidrug resistance. We provide here only the significant associations; the full data are available on request. Ceftazidime resistance was associated with nosocomial origin (odds ratio [OR], 1.9; 95% confidence interval [CI]: 1.13.1; P 5 .02), absence of neutropenia (OR, 3.3; 95% CI: 1.1-10; P 5 .02), chronic liver disease (OR, 2.2; 95% CI: 1-4.8; P , .01), leukemia (OR, 0.3; 95% CI: 0.1-1; P , .01), solid organ transplantation (OR, 2.2; 95% CI: 1.2-4; P 5 .01), chronic renal failure (OR, 2.2; 95% CI: 1.2-4.2; P 5 .01), and previous ciprofloxacin therapy (OR, 3.1; 95% CI: 1.8-5.4; P , .01). Male sex (OR, 1.8; 95% CI: 1.2-3; P , .01), nosocomial origin (OR, 1.8; 95% CI: 1.1-3; P 5 .01), absence of neutropenia (OR, 2.5; 95% CI: 1.1-10; P 5 .03), solid organ transplantation (OR, 1.9; 95% CI: 1.1-3.5; P 5 .03), mechanical ventilation (OR, 1.8; 95% CI: 1.1-3.2; P 5 .03), previous treatment with imipenem (OR, 2.8, 95% CI 1.5-5.1; P , .01), and previous ciprofloxacin therapy (OR, 2.3; 95% CI: 1.3-4.1; P , .01) were the variables associated with resistance of P aeruginosa isolates to imipenem. Male sex (OR, 2.7; 95% CI: 1.5-4.9; P , .01) and previous ceftazidime (OR, 4; 95% CI: 1.6-10.3; P , .01) and ciprofloxacin (OR, 2.8; 95% CI: 1.5-5.1; P , .01) therapy were associated with meropenem resistance. Piperacillin-tazobactam resistance was exclusively associated with chronic renal failure (OR, 2.7; 95% CI: 1.4-5.3; P , .01) and previous ciprofloxacin treatment (OR, 2.4; 95% CI: 1.3-4.4; P , .01). Absence of neutropenia (OR, 2; 95% CI: 1-5; P 5 .03), heart failure (OR, 3; 95% CI: 1.1-8.5; P 5 .03), urinary tract source (OR, 1.8; 95% CI: 1.1-3; P 5 .02),
Table 1. Characteristics and main data of the 572 patients with P aeruginosa bacteremia n (%) Sex (male/female) Age, yr (mean 6 SD; range) Previous admission Intensive unit care admission Nosocomial origin Ultimately fatal prognosis Rapidly fatal prognoses Underlying diseases or conditions Neutropenia Chronic liver disease Leukemia Solid organ neoplasia Malignant lymphoma Bone marrow transplantation Solid organ transplantation Heart failure Diabetes mellitus COPD Chronic renal failure HIV infection Steroid therapy Mechanical ventilation Polytraumatism None Source of bacteremia Abdominal Central venous device Urinary tract Respiratory tract Skin and soft tissues Articular Other Unknown Previous antibiotic therapy Ceftazidime Imipenem Meropenem Piperacillin-tazobactam Ciprofloxacin Shock Death
327/245 61.2 6 18; 15-102 154 (26.9) 115 (20.1) 357 (62.4) 270 (47.2) 36 (6.3) 69 (12.1) 36 (6.3) 64 (11.2) 105 (18.4) 27 (4.7) 28 (4.9) 66 (11.5) 15 (2.6) 96 (16.8) 73 (12.8) 58 (10.1) 25 (4.4) 211 (36.9) 85 (14.9) 16 (2.8) 92 (16.1) 54 (9.4) 130 (22.7) 85 (14.9) 115 (20.1) 30 (5.2) 1 (0.2) 20 (3.4) 137 (24) 22 (3.8) 58 (10.1) 31 (5.4) 51 (8.9) 78 (13.6) 114 (19.9) 99 (17.3)
COPD, Chronic obstructive pulmonary disease; SD, standard deviation.
and previous treatment with ciprofloxacin (OR, 2.7; 95% CI 1.7-4.5; P , .01) increased the chance that an isolate of P aeruginosa would be resistant to ciprofloxacin. Multidrug-resistant P aeruginosa was associated with chronic renal failure (OR, 3.1; 95% CI: 1.5-6.5; P , .01), urinary tract source (OR, 2.1; 95% CI: 1.1-4.3; P 5 .03), and previous ciprofloxacin therapy (OR, 2.4; 95% CI: 1.2-4.8; P 5 .01). Multivariate analyses. Table 2 shows the factors that were independent predictors of resistance to ceftazidime, imipenem, meropenem, piperacillin-tazobactam, and ciprofloxacin in multivariate analysis. As shown, previous exposure to ciprofloxacin was independently associated with ceftazidime, imipenem,
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Table 2. Independent predictors of resistance to the antibiotics assessed: multivariate analysis Odds ratio (95% CI) Ceftazidime resistance Previous ciprofloxacin therapy Imipenem resistance Male sex Previous imipenem therapy Previous ciprofloxacin therapy Meropenem resistance Male sex Previous ciprofloxacin therapy Previous ceftazidime therapy Piperacillin tazobactam resistance Previous ciprofloxacin therapy Chronic renal failure Ciprofloxacin resistance Previous ciprofloxacin therapy Multidrug resistance Male sex Previous ciprofloxacin therapy
Table 3. Clinical characteristics of patients with and without previous treatment with ciprofloxacin expressed as a percentage Previous No previous therapy with therapy with ciprofloxacin, ciprofloxacin, P n 5 78 (%) n 5 494 (%) value
1.7 (1.1-2.9) 2.3 (1.2-4.5) 2 (1.1-3.7)
.03 .01 .02
2.3 (1.2-4.4) 2.7 (1.4-5.3) 3.7 (1.3-10.6)
.009 .004 .01
2.4 (1.3-4.7) 2.1 (1-4.3)
2.2 (1.1-4.5) 2.5 (1.2-5.2)
CI, Confidence interval.
meropenem, piperacillin-tazobactam, ciprofloxacin, and multidrug resistance. Chronic renal failure was an independent predictor of piperacillin-tazobactam resistance. Previous imipenem and ceftazidime therapy were independent predictors of resistance to imipenem and meropenem, respectively. Male sex predisposed to both imipenem and meropenem and multidrug resistance.
Characteristics of patients previously exposed to ciprofloxacin Ciprofloxacin had previously been given to 78 patients (Table 3). Some of them had also received other antibiotics at the same time, but these associations did not have any influence on the antibiotic resistance pattern (data not shown, available on request). Most patients who had received ciprofloxacin had acquired nosocomial infections (76.9% vs 60.1%, respectively, P 5 .004), were bone marrow transplant recipients (11.5% vs 3.8%, respectively, P 5 .008), and/or had an infected intravenous device as source of infection (32.1% vs 21.3%, respectively, P 5 .03). Most of them had received ciprofloxacin because of antibiotic prophylaxis.
DISCUSSION This study shows that exposure to ciprofloxacin within the previous 30 days is associated with an increased risk of resistance to ceftazidime, imipenem, meropenem, piperacillin-tazobactam, or ciprofloxacin or were multidrug resistant in isolates of subsequent P aeruginosa bacteremia. We also confirm a predisposition to a greater resistance to imipenem18,21,30 and
Sex (male/female) (%) Previous admission Nosocomial origin Underlying diseases Neutropenia Chronic liver disease Leukemia Solid organ neoplasia Malignant lymphoma Bone marrow transplantation Solid organ transplantation Chronic renal failure COPD HIV infection Steroid therapy Mechanical ventilation Source of bacteremia Abdominal Central venous device Urinary tract Respiratory tract Shock Death
61.5/38.5 35.9 76.9
56.5/43.5 25.5 60.1
.4 .06 .004
14.1 7.7 10.3 20.5 9 11.5 11.5 10.3 10.3 1.3 46.2 17.9
11.7 6.1 11.3 18 4 3.8 11.5 10.1 13.2 4.9 35.2 14.4
.6 .6 .8 .6 .08 .008 1 1 .5 .2 .07 .4
12.8 32.1 15.4 14.1 17.9 17.9
8.9 21.3 14.8 21.1 20.2 17.2
.3 .03 .9 .2 .6 .9
COPD, Chronic obstructive pulmonary disease.
ciprofloxacin31,32 if these antibiotics have been used previously. However, previous therapy with ceftazidime, meropenem, or piperacillin-tazobactam does not predispose to resistance to themselves. In addition, meropenem and piperacillin-tazobactam do not predispose to cross-resistance with any of the antibiotics assessed. Experimental research has demonstrated that fluoroquinolones can select P aeruginosa strains resistant to b-lactam antibiotics such as ticarcillin, cefsulodin, aztreonam, and cefepime.13,14 This is thought to be mainly due to mutations that up-regulate the membrane efflux pump systems MexAB-OprM and, less frequently, to the activation of MexEF-OprN system in combination with a decrease in the porin OprD expression.11 Whether this is important in the daily clinical setting is still a matter of debate. Although our results do not establish cause-effect, they do show that ciprofloxacin can induce the mechanisms that produce cross-resistance to ceftazidime, imipenem, meropenem, and piperacillin-tazobactam. Some studies have assessed the relationship between the previous use of fluoroquinolones and the emergence of resistance to ceftazidime,7,19,20 piperacillin-tazobactam,17 or imipenem7,18,20,21,33 in subsequent P aeruginosa infections in the clinical setting, but only imipenem and piperacillin resistance was shown to be modulated by
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the previous use of ciprofloxacin.7,20,33 Also, like the data presented here, some case-control studies in intensive care unit patients showed that the incidence of drug-resistant P aeruginosa isolates from specimens of patients with colonization or infection was associated with previous use of fluoroquinolones, long-term use of fluoroquinolones, or concomitant resistance to fluoroquinolones.6,7,20,34 As well as individual exposure to fluoroquinolones, environmental fluoroquinolone pressure has been shown to increase the chance of P aeruginosa infections because of fluoroquinolone nonsusceptible strains.35 None of these reports, however, found a modulatory effect of prior ciprofloxacin exposure on individual b-lactam drug resistance, such as ceftazidime, piperacillin-tazobactam, or meropenem. Other investigations, using different definition criteria of multidrug-resistant P aeruginosa than we have used, have found that previous use of fluoroquinolones also predispose to multidrug-resistant P aeruginosa.8,27,36 Our findings agree with these data. On the contrary, Schwaber et al,37 in a small case-control study, even reported that fluoroquinolone use tended to protect against the emergence of resistance to ceftazidime in P aeruginosa isolates from nosocomial infections. With respect to the molecular mechanisms that might explain our findings, it is known that these different groups of antibiotics share the same resistance mechanisms. Membrane MexAB-OprM efflux pump system up-regulation can cause cross-resistance to cephalosporins, penicillins, ciprofloxacin, and meropenem but not to imipenem, and MexEF-OprN activation in association with decreased porin OprD expression shows cross-resistance to fluoroquinolones and imipenem.38 In accordance to our results, both MexAB-OprM and MexEFOprN derepression may have been the main mechanism induced by previous exposure to ciprofloxacin, as has been demonstrated experimentally for other cephalosporins.13,14 The question arises as to what the reasons are for the different results among clinical studies. These discrepancies may be partly due to the differences in the design and differences in the type of patients and infection studied. Our study also provided evidence that previous use of ceftazidime, meropenem, and piperacillin-tazobactam had little ability to induce resistance to themselves and also meropenem and piperacillin-tazobactam to induce cross-resistance to the other studied antibiotics in subsequent P aeruginosa bacteraemia isolates, whereas previous use of imipenem was a strong independent predictor of further imipenem resistance, as was the case of ciprofloxacin. Similar findings have been reported,7,19,20,34,39 although inconsistencies do also exist.40 Our study has some limitations. First, the design is retrospective. Despite this, our results are supported by the large number of patients assessed and show interesting statistical associations. Second, we made no
genotyping studies of the MexAB-OprM and MexEFOprN efflux pump system of P aeruginosa isolates pre- and postexposure to ciprofloxacin to confirm this clinical association with antibiotic resistance. We were unable to do so because P aeruginosa samples were only available when the infection was diagnosed. Experimental reports that correlate in the laboratory our clinical data do exist13,14 and hence support the clinical findings of the present study. It would also have been interesting to know how long the previous treatment with ciprofloxacin lasted and the interval of time between this treatment and the appearance of the P aeruginosa bacteremia. Third, the number of patients previously exposed to ceftazidime and meropenem was low; hence, statistical analysis may be underpowered. Fourth, because previous exposure to ciprofloxacin was associated with nosocomial acquisition, a well-established risk factor for resistance, our findings may have been affected by known or unknown confounders. Finally, this investigation has been performed in university teaching hospitals, and our data reflect the hospital-based and not those from population-based P aeruginosa bloodstream infections resistance patterns (which usually are much lower); hence, there may be a referral bias in our study. Our findings may also have important consequences in terms of infection control practice. Given that a limited number of new antimicrobial agents are being developed to treat drug-resistant P aeruginosa infections, rigorous infection control measures are advocated to prevent the spread of this microorganism.41-43 Also, to assess the effect of strategies to minimize the exposure to ciprofloxacin in patients at risk for developing P aeruginosa bacteremia would be of interest. In conclusion, patients who developed an episode of P aeruginosa bacteremia and who had been exposed to ciprofloxacin within the previous 30 days have a greater chance of being infected by a strain resistant to ceftazidime, imipenem, meropenem, piperacillin-tazobactam, or ciprofloxacin or, even, of being multidrug resistant. Because drug-resistant P aeruginosa represents an important threat in nosocomial infections, infection control professionals should be aware of this association. The authors thank the 3 anonymous reviewers whose constructive comments and criticisms greatly helped us to improve the manuscript.
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