The study was performed at the Hospital of the University of Pennsylvania (HUP), a 725-bed tertiary-care center, and Penn Presbyterian Medical Center (PPMC), a 344-bed urban community hospital. Each hospital is located in Philadelphia, Pennsylvania, USA, and is part of the University of Pennsylvania Health System. The study was reviewed and approved by the University of Pennsylvania Institutional Review Board.

During the study period, culture results were positive for P. aeruginosa , and cefepime susceptibility was tested for 2,529 patients. Median patient age was 61 years (95% CI 60–62), and 1,439 (56.9%) patients were male. Regarding race and/or ethnicity, 1,116 (44.4%) were white, 848 (33.7%) were African American, 30 (1.2%) were Asian, 29 (1.2%) were Hispanic, and the rest were identified as other or unknown. Among all participants, 1,984 (78.5%) were hospitalized at HUP and 545 (21.6%) were hospitalized at PPMC.

P. aeruginosa isolates came from the following anatomic sites: respiratory tract (247 [35.5%]), urine (763 [30.2%]), wound (467 [18.5%]), blood (248 [9.8%]), tissue (120 [4.7%]), and other (35 [1.3%]). Among the 2,529 isolates, 213 (8.4%) exhibited cefepime resistance and 339 (13.4%) exhibited multidrug resistance. Annual prevalence of P. aeruginosa cefepime resistance over time showed no significant trend (p = 0.99; Figure).

Using bivariate analysis to compare exposures, we found several differences between cefepime-resistant and cefepime-susceptible P. aeruginosa (Table 1). Specifically, participants with cefepime-resistant P. aeruginosa were more likely to have received an extended-spectrum cephalosporin, extended-spectrum penicillin, or quinolone. Multivariate analysis indicated that prior use of an extended-spectrum cephalosphorin had the strongest association with cefepime-resistant P. aeruginosa (adjusted OR 2.18, 95% CI 1.57–3.04; p<0.001) (Table 2). Independently associated with cefepime-resistant P. aeruginosa were prior use of an extended-spectrum penicillin or a quinolone and transfer from an outside facility (Table 2). No substantive differences were found in the final model when analyses were limited to blood isolates.

The overall mortality rate among participants was 13.8% (348/2,529). The mortality rate for participants with cefepime-resistant P. aeruginosa was 20.2% (43/213) and for participants with cefepime-susceptible P. aeruginosa was 13.2% (305/2,316) (relative risk [RR] 1.53, 95% CI 1.15– 2.04; p = 0.007). After controlling for significant confounders in the multivariate analysis, cefepime-resistant P. aeruginosa was no longer associated with death (Table 3). However, the association between cefepime-resistant P. aeruginosa and death varied significantly, depending on whether the isolate was from the blood or elsewhere. When analyses were restricted to blood isolates, a significant independent association between cefepime-resistant P. aeruginosa and death was found (RR 15.55, 95% CI 3.10–77.89; p = 0.001] (Table 4).

We found the following to be significant factors independently associated with isolation of a cefepime-resistant P. aeruginosa strain in culture of a clinical sample in the hospital setting: prior use of extended-spectrum cephalosphorins, extended-spectrum penicillins, or fluoroquinolones; and transfer from an outside facility. We also demonstrated that cefepime-resistant P. aeruginosa was independently associated with increased deaths among patients hospitalized for >30 days but only for those for whom P. aeruginosa was isolated from blood.

Past studies have found an association between use of an antipseudomonal agent and emergence of resistance to that same agent (19,31,32). Past studies have also demonstrated that P. aeruginosa resistance to 1 class of antimicrobial drugs is often associated with resistance to other classes (11,33). The tendency for health care–acquired P. aeruginosa to become resistant to drugs from multiple classes is well known, and several molecular mechanisms for its intrinsic and acquired resistance have been suggested (10). Our findings not only suggest that prior treatment with cefepime in itself is associated with subsequent emergence of cefepime-resistant P. aeruginosa but that even prior exposure to certain antipseudomonal agents in other classes is associated. Our results emphasize that to devise strategies that prevent further emergence of cefepime-resistant P. aeruginosa, recent prior use of antipseudomonal agents within the same class and from certain other classes must be recognized. The effect of curtailing use of non–β-lactam agents (i.e., fluoroquinolones) on cefepime-resistant P. aeruginosa prevalence should be formally assessed.

We also found that transfer from an outside facility was associated with cefepime-resistant P. aeruginosa infection. Because transferred patients potentially came from another hospital or from a long-term care facility, these patients might have been more likely to already be colonized with cefepime-resistant P. aeruginosa at the time of admission. That antimicrobial drug resistance is common in long-term care facilities is well known (34). Further work focusing specifically on antimicrobial drug–resistant P. aeruginosa infections in long-term care settings is warranted.

The significant association between cefepime-resistant P. aeruginosa infection and increased mortality rates (limited to those patients with P. aeruginosa bacteremia) may result from the fact that bacteremia is a more serious infection than, for example, a urinary tract infection. Alternatively, these results might be explained by noting that a blood isolate is more likely to represent a true infection than is an isolate from other anatomic sites, where isolates are more likely to represent colonization. Nonetheless, our results emphasize the potential serious effect of cefepime-resistant P. aeruginosa infection and the need for strategies to combat its further emergence.

This study has several potential limitations. The first is the ongoing, and appropriate, debate regarding the selection of the control group for case–control studies investigating the association between prior antimicrobial drug use and resistance. Like Harris and et al., we believe that selection of the control group depends on the study question (29,35). In our study, the main question was “What are the risk factors for cefepime resistance among all clinical isolates of P. aeruginosa in the hospital setting?” Thus, we selected patients with cefepime-susceptible P. aeruginosa infection as controls.

Another potential limitation is selection bias, which is always a concern in case–control studies. We believe that any such bias was minimized by the fact that every patient with a P. aeruginosa isolate was eligible for inclusion. Furthermore, all isolates were identified in the clinical microbiology laboratory at HUP, which processes all inpatient cultures at the participating study sites.

Misclassification bias is also a concern in case–control studies. However, the categorization of case-patients and controls and their exposure status was based entirely on preexisting clinical data from the clinical microbiology laboratory. The antimicrobial drug–susceptibility profiles were determined before study initiation, so determination of case and control status did not influence these profiles. Furthermore, case-patients and controls were selected without knowledge of their status regarding risk factors of interest. Thus, we believe any differential misclassification bias was unlikely.

Identification of participants in this study was based solely on clinical cultures. As such, that all of these cultures represented true infection is unlikely. For this reason, we performed additional analyses, focusing only on P. aeruginosa blood isolates because these would be expected to meet Centers for Disease Control and Prevention criteria for infection. The results of these secondary analyses did not differ substantively from the primary analyses investigating risk factors for cefepime-resistant P. aeruginosa. Finally, all patients in this study were admitted to either HUP or PPMC. Thus, our findings can only be generalized to similar academic centers. One must also keep in mind the differing resistance profiles at any given institution.

In conclusion, cefepime-resistant P. aeruginosa will negatively affect clinical outcomes, and strategies to counter its emergence are needed. Recognizing recent prior use of antipseudomonal agents, both within the same class and from certain other classes, is needed for devising successful interventions.

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1. You are seeing a 61-year-old man admitted for pneumonia. His blood culture is now growing Pseudomonas aeruginosa, and you are concerned regarding the possibility of antimicrobial resistance of this organism.What was the approximate rate of resistance to cefepime among isolates of P. aeruginosa in the current study?A. Less than 1%B. 8%C. 22%D. 47%2. Which of the following variables independently increased the risk for P. aeruginosa resistance to cefepime in the current study?A. Male sexB. Diagnosis of pneumoniaC. Higher Charlson index scoreD. Transfer from another facility3. The patient was treated with antibiotics as an outpatient prior to hospital admission. Prior treatment with which classes of antibiotics was found to increase the risk for cefepime-resistant P. aeruginosa (CRPA) in the current study?A. Aminoglycosides onlyB. Extended-spectrum cephalosporins onlyC. Extended-spectrum cephalosporins, extended-spectrum penicillins, and quinolonesD. Aminoglycosides, extended-spectrum penicillins, and macrolides4. The patient is diagnosed with CRPA. What does the current study suggest regarding the effect of CRPA vs. cefepime-sensitive P. aeruginosa on the risk for mortality?A. CRPA did not confer a higher risk for mortality in any analysisB. Only older patients with CRPA were at a higher risk for deathC. Only patients with blood isolates for CRPA were at a higher risk for deathD. Any infection with CRPA was associated with a higher risk for death