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Antimicrobial Agents and Chemotherapy, November 2003, p. 3442-3447, Vol. 47, No. 11
0066-4804/03/$08.00+0 DOI: 10.1128/AAC.47.11.3442-3447.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.
Division of Infectious Diseases, Department of Microbiology, and Intensive Care Unit, Centre Hospitalier Universitaire Vaudois, Lausanne,1 Division of Infectious Diseases and Intensive Care Unit, Hôpital Universitaire, Geneva, Switzerland,2 Smolensk Medical Academy, Smolensk, Russia,3 Intensive Care Unit, Szpital Gorniczy, Sosnowiec, Poland,4 Chaim Sheba Medical Center, Tel-Aviv University School of Medicine, Tel-Hashomer, Israel5
Received 23 June 2003/ Returned for modification 30 June 2003/ Accepted 22 July 2003
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ABSTRACT |
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INTRODUCTION |
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The adequacy of the initial antibiotic therapy is an independent predictor of both overall mortality and mortality attributable to pneumonia (1, 18, 22, 25). Since the causative pathogens are not usually known at the time of diagnosis, it is critical for an early empirical therapy to be active against the most common agents of nosocomial pneumonia in ICUs, such as Pseudomonas aeruginosa, members of the family Enterobacteriaceae, or Staphylococcus aureus (17). Several broad-spectrum antibiotics, including imipenem-cilastatin (7, 13, 15), piperacillin-tazobactam (15), ceftazidime (9, 14), and fluoroquinolones (13), were recently successfully used as monotherapy in this setting.
Cefepime is a "fourth-generation" cephalosporin (26) with good activity against most nosocomial gram-negative pathogens, as well as gram-positive cocci such as Streptococcus pneumoniae and methicillin-susceptible S. aureus (21). In contrast to other cephalosporins, cefepime is a weaker inductor of chromosomal ß-lactamases, and it shows good stability against both chromosomal and most plasmidic ß-lactamases (16). Cefepime is therefore an appealing option for monotherapy of nosocomial pneumonia. Several trials with relatively small sample sizes comparing cefepime with ceftazidime or cefotaxime suggested that cefepime is as effective as broad-spectrum cephalosporins for the treatment of community-acquired lower respiratory tract infections (2, 10, 19).
The present study was performed to compare cefepime with imipenem-cilastatin for monotherapy of nosocomial pneumonia in ICU patients with or without mechanical ventilation.
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MATERIALS AND METHODS |
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38°C; cough, sputum production, or tracheal secretions; leukocyte count, 10 x 109/liter or >15% band forms; hypoxemia (defined as a partial O2 pressure <70 mm Hg while the patient was breathing normal air or a decrease in the partial O2 pressure of 25% from an initial value); and rales and/or evidence of consolidation on pulmonary auscultation. Patients were excluded if they had hypersensitivity to carbapenems or ß-lactams; a neutrophil count <109/liter; were infected with human immunodeficiency virus; were infected with a microorganism known to be resistant to one of the study antibiotics; had a primary diagnosis of viral, fungal, or mycobacterial infection; had been treated with one of the study antibiotics within 4 weeks before randomization or with any investigational drug within 30 days before randomization; had hepatic failure; had a high likelihood of death within 48 h; or were pregnant or lactating.
All patients or their legally authorized representative gave written informed consent. The protocol was approved by the institutional review boards of all participating centers.
Study design and treatment. This was a randomized, controlled, open-label, evaluator-blind trial. Patients were assigned to receive one of the following regimens by using a centralized telephone randomization system: cefepime at 2 g three times a day (which is the recommended regimen for life-threatening infections) or imipenem-cilastatin at 500 mg four times a day. The dosages of both antibiotics were adjusted according to the patient's renal function when appropriate. The physician in charge of the patient determined the duration of therapy.
Assessment and monitoring. At the baseline, a complete history was obtained and a physical examination was performed by a local investigator in each participating center. The APACHE II score and the clinical pulmonary infection score (CPIS) (24) were determined. CPIS is based on body temperature, leukocyte count, the volume and character of tracheal secretions, arterial oxygenation, findings on the chest X-ray film, and Gram stain and culture of a tracheal aspirate. A good correlation between CPIS and quantitative bacteriology with samples obtained by invasive diagnostic methods has been described (24). The APACHE II score at the time of admission to the ICU was also calculated. Clinical data were then collected twice weekly and within 72 h after completion of study drug therapy. Blood chemistry and hematology evaluations were performed at the baseline and then twice weekly and within 48 h after the completion of study drug therapy. The baseline microbiological evaluation included two sets of blood cultures for all patients and a Gram stain and culture of tracheal secretions for mechanically ventilated patients. In patients without mechanical ventilation, a Gram stain and culture of sputum were performed when sputum was available. Collection of specimens by the use of invasive techniques was performed as deemed necessary by the physicians in charge of the patients. The microbiological evaluation was repeated between 48 and 96 h after the initiation of study drug therapy and within 72 h after the completion of study drug therapy. The evaluation included a new sampling of lower respiratory tract secretions, if available, and one set of blood cultures if the culture result for a previous blood sample was positive. Culture and antibiotic susceptibility testing were done at each participating center according to the recommendations of the American Society for Microbiology and the Kirby-Bauer method, respectively. The National Committee for Clinical Laboratory Standards recommendations for breakpoints (23) were used to define the antibiotic susceptibility levels of the pathogens isolated. Bacteria assessed as causative were sent to a central laboratory (the laboratory of J.B.) for confirmation of the identification. Their susceptibility profiles were confirmed by use of E-tests (AB Biodisk, Solna, Sweden). When confirmation by the central laboratory was not available, the results from the participating centers were reported.
Microbiological documentation of nosocomial pneumonia was considered definite if a pathogen was isolated from lung tissue or simultaneously from blood or pleural fluid and a respiratory tract specimen. Documentation was considered probable when >104 CFU of a possible pathogen per ml was isolated from bronchoalveolar lavage fluid or if Haemophilus influenzae, S. pneumoniae, or Legionella pneumophila was the predominant organism in respiratory tract secretions. Pneumonia was considered a possible microbiologically documented infection when a possible pathogen was semiquantitatively predominant in any lower respiratory tract specimen in the presence of more than 25 polymorphonuclear leukocytes and less than 10 squamous epithelial cells per magnification field (10 x 10).
End points. The primary end point of the study was comparison of the clinical response to cefepime with that to imipenem-cilastatin, as assessed blindly by the scientific coordinating committee (G.Z., G.G., and A.C.) according to guidelines on the evaluation of anti-infective drugs published by experts (3, 4, 6). This comparison was made for patients who have been treated according to the protocol (per-protocol analysis) after exclusion of those for whom circumstances precluded classification of treatment as a success or a failure. We also conducted a modified intent-to-treat analysis that included all patients who fulfilled the eligibility criteria, even if they had not been treated according to the protocol. Different from classical intent-to-treat analysis, randomized patients who were later found to violate the inclusion criteria were excluded. A therapeutic success was defined as either a cure (a complete resolution of symptoms and signs and an improvement or the lack of progression of abnormalities on the chest X-ray film) or an improvement (the same as for a cure, but with partial resolution of symptoms and signs). A minimal therapy duration of 5 days was required for assessment of the treatment as a success. The clinical response rate was defined as the number of patients whose clinical response was a success divided by the total number of patients included in the analysis. A treatment failure was defined as the absence of a response to treatment (a persistence or progression of signs and symptoms after 72 h of therapy, the development of new symptoms consistent with active infection, or the progression of radiographic abnormalities after 5 days of therapy), the documentation of a bacterium resistant to the allocated regimen resulting in the introduction of another antibiotic, a death due to pneumonia, or the inability to complete the study due to severe adverse effects. Patients who were not treated as required for efficacy assessment were also considered treatment failures in the modified intent-to-treat analysis, which avoided a biased comparison of the two groups in case they would differ regarding nonadherence to the protocol.
One secondary end point was comparison of the bacteriologic response obtained with each of the two drugs. Eradication was defined as the elimination of the causative organism(s) during or at the completion of therapy. When samples were not available for evaluation of the bacteriologic response because of clinical improvement (e.g., resolution of sputum production), the case was assessed as a presumed eradication. The bacteriologic response could also be classified as persistence (failure to eradicate the original causative organism from the sites previously listed), a relapse (recurrence of pulmonary infection with the same organism, i.e., an organism of the same genus and species and with the same antibiotic susceptibility profile, within 5 days after the discontinuation of treatment or during treatment after two consecutive cultures had been negative), a superinfection (a new lower respiratory tract infection during treatment or within 3 days after the completion of treatment due to an organism not previously recognized as causative), colonization (at least two cultures yielded a bacterium other than the primary causative isolate, in the absence of evidence of a new or progressive infection), and indeterminate (circumstances prevented classification of the response).
Finally, safety was assessed twice weekly until the end of treatment and within 72 h after the completion of treatment for all patients who received at least one dose of study medication.
Statistical analyses. We assumed that the proportion of patients with a favorable clinical response in the imipenem-cilastatin group would be 80%. The null hypothesis was that the absolute difference in the proportion of patients with a favorable clinical response between the imipenem-cilastatin and cefepime groups would exceed 15%. Noninferiority would be established in case of rejection of the null hypothesis, which required that the upper limit of the two-sided 95% confidence interval (CI) for the difference in clinical response rates was less than or equal to 15%. The choice of the 15% margin was recommended in 1992 by the U.S. Food and Drug Administration for trials of anti-infective therapy when the expected response rate was 80%. By using an alpha level of 5% and a power of 80% and assuming that 10% of the randomized patients would not be treated according to the protocol, a total of 250 patients were required. The sample size was increased to 280 patients during the study because a higher than expected proportion of patients were not evaluable for the primary efficacy analysis. The decision to increase the sample size was made before any comparison of the clinical responses of the two groups.
Clinical response rates were further compared after adjustment for predictors of clinical response. For that purpose, significant predictors at a 0.1 level of significance were candidates for inclusion in a logistic regression model that was built through a forward selection process.
Noninferiority of the bacteriological response to cefepime compared with that to imipenem-cilastatin was tested by using the method mentioned above for clinical efficacy.
Baseline characteristics in the two groups were compared by use of the two-sided Fisher exact test for proportions and the Wilcoxon rank-sum test for continuous and ordinal data. All tests were performed at a significance level of 5%.
Statistical analyses were performed with STATA statistical software (version 6.0; Stata Corp., College Station, Tex.).
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RESULTS |
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The two groups were balanced with respect to demographic and prestudy clinical characteristics (Table 1). The mean APACHE II score was nearly 15, and two-thirds of the patients in both groups were mechanically ventilated at the time of inclusion in the study.
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Among patients infected with an ESBL-producing causative pathogen, the clinical response rates were 9 of 13 (69%) patients in the cefepime group and 10 of 10 (100%) patients in the imipenem-cilastatin group. The reasons for failure in four patients treated with cefepime were an absence of improvement in two patients, death attributed to pneumonia in one patient, and early withdrawal because of the intermediate susceptibility of the organism to the antibiotic in one patient (although the reference laboratory later measured an MIC of 4 µg/ml for the organism from this patient; i.e., the MIC was below the breakpoint for in vitro susceptibility). The MICs of cefepime for the organisms from these four patients ranged from 2 to 4 µg/ml.
The all-cause 30-day mortality rates were 28 of 108 (26%) patients in the cefepime group and 19 of 101 (19%) patients in the imipenem-cilastatin group (P = 0.25). Pneumonia contributed to the deaths of 10 (9%) patients treated with cefepime and 4 (4%) patients treated with imipenem-cilastatin, including 3 and 1 patients, respectively, for whom death was considered the reason of treatment failure according to the protocol.
Microbiological efficacy. Antibiotic susceptibility to both study drugs was determined in 219 of the 226 causative pathogens (97%), which represented 143 of 148 pathogens from patients with microbiologically documented pneumonia. One hundred ninety-two of 219 (88%) pathogens were susceptible to cefepime at the baseline, and 204 of 219 (93%) pathogens were susceptible to imipenem-cilastatin at the baseline (P = 0.07). The causative pathogens from 121 of 143 (85%) patients were susceptible to cefepime, and the causative pathogens from 131 of 143 (92%) patients were susceptible to imipenem-cilastatin (P = 0.10). Eradication of the causative organism was proved or presumed in 47 (61%) of the 77 patients with microbiological documentation in the cefepime group and 38 of 71 (54%) patients in the imipenem-cilastatin group (95% CI for the difference in bacteriological response, -8 to 23%) (Table 4). The development of secondary resistance during cefepime therapy was observed in 6 of the 63 (10%) patients whose pathogens were initially susceptible to this drug, whereas the development of secondary resistance during imipenem-cilastatin therapy was observed in 10 of 61 (16%) patients (P = 0.29). Among patients with P. aeruginosa infections, resistance to the allocated regimen was initially present among the organisms from 2 of 27 patients in the cefepime group and 5 of 32 patients in the imipenem-cilastatin group. Secondary resistance was detected among the organisms from 3 of 25 patients during therapy with cefepime and 9 of 27 patients during therapy with imipenem-cilastatin. In total, primary resistance and secondary resistance were detected in the organisms from 5 of 27 patients (19%) treated with cefepime and 14 of 32 patients (44%) treated with imipenem (P = 0.05).
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DISCUSSION |
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The efficacy of cefepime for the therapy of nosocomial pneumonia is of interest in an era of increasing bacterial resistance that requires novel therapeutic options. Cefepime can also be administered less frequently on a daily basis than imipenem-cilastatin and showed interesting microbiological features. The causative organism was documented for 71% of the patients in the study. Of these organisms, 88 and 93% were susceptible to cefepime and imipenem-cilastatin, respectively. The bacteriological response to cefepime (61% of microbiologically documented infections) was not inferior to that of imipenem (54%). As is usually the case, P. aeruginosa was the most frequent pathogen and was found in 40% of patients with microbiological documentation of pneumonia. The propensity of P. aeruginosa to develop secondary resistance during therapy with imipenem-cilastatin has been reported previously (7, 15, 29), and this propensity was not reduced by the simultaneous use of aminoglycosides in one study (7). We confirmed that the resistance of P. aeruginosa prior to or during therapy was more frequent with imipenem-cilastatin than with cefepime. However, no difference in clinical outcome was observed among patients infected with this bacterium.
Another interesting characteristic of cefepime is its resistance to ß-lactamase hydrolysis in vitro, which is different from the case for broad-spectrum cephalosporins. Our study provided an opportunity to compare cefepime with imipenem-cilastatin for the treatment of pneumonia attributed to ESBL-producing bacteria. All ESBL-positive strains were susceptible to cefepime in vitro when a threshold of 8 µg/ml was used. Among the 13 patients in the cefepime group infected with an ESBL-positive pathogen, however, 1 died because of the pneumonia and 2 did not experience improvements with therapy. There were no such unfavorable outcomes among the 10 patients treated with imipenem-cilastatin. These data may be of poor generalizability, because 19 of the 23 ESBL-positive strains were K. pneumoniae isolates from a single center, which likely represented an epidemic cluster. While more data are needed before advice on the use of cefepime for the treatment of infections caused by ESBL-positive organisms can be provided, caution seems appropriate on the basis of our findings.
Adverse reactions possibly or probably attributable to a study drug were more frequently reported in patients treated with cefepime. We observed a slight excess of renal adverse events in the cefepime group, which was unexpected on the basis of existing data on the safety profile of the drug. The adverse events section of the product insert states that transient elevations in blood urea nitrogen and/or serum creatinine levels are observed in 0.5 to 1% of patients. This adverse event did not result either from an excessive dosage of cefepime or from a baseline imbalance in serum creatinine levels. Two of the five cases of renal adverse events reported in our study could also have been related to other predisposing factors. However, a study with an open-label design primarily aimed at a comparison of efficacy is not appropriate for investigation of this problem. We therefore recommend that this issue be addressed in future investigations of the drug. Treatment with imipenem-cilastatin, but not treatment with cefepime, was associated with symptomatic C. difficile infections in 4% of the patients. This difference may result from a more important alteration of the anaerobic flora with imipenem-cilastatin than with cefepime.
The absence of a prospectively required microbiological investigation at randomization and during follow-up was a limitation of the present study, resulting in a lack of a precise denominator for the results of follow-up cultures. However, the use of a clinical, poorly specific definition of nosocomial pneumonia mimics the real clinical situation, in which decisions must be made on an empirical basis (27), and several recent studies have stressed the importance of appropriate initial antibiotic coverage (1, 18, 22, 25). The two study drugs have shown comparable efficacies in this setting.
In conclusion, our study suggested but could not prove the similar clinical efficacies of cefepime and imipenem-cilastatin for monotherapy of nosocomial pneumonia in ICU patients. Therapy with imipenem-cilastatin, but not with cefepime, was complicated by C. difficile infection. The moderate renal failure associated with cefepime treatment in some patients deserves further consideration. Other observations from this study that require further evaluation include the higher rate of clinical failures in patients infected with an ESBL-producing organism in the cefepime group and the higher rate of resistant P. aeruginosa strains in the imipenem-cilastatin group.
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ACKNOWLEDGMENTS |
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Members of the Cefepime Study Group are as follows: A Mertens, J. Nagler, and P. Rogiers, Antwerp, Belgium; J. C. Preiser, J. P. Thys, and J. L. Vincent, Brussels, Belgium; E. Rubinstein and S. Segev, Tel Hashomer, Israel; W. Hustinx, Utrecht, The Netherlands; L. Krawczyk, Sosnowiec, Poland; J. Jastrzebski and J. Kacki, Warsaw, Poland; A. Grigoriev, Y. Grigoriev, and A. Sinopalnikov, Moscow, Russia; R. Koslov, V. Osipova, L. Strachunsky, and A. Zuzova, Smolensk, Russia; L. Matter, B. Regli, H. U. Rothen, and M. Taüber, Bern, Switzerland; J. Garbino, T. Kinge, D. Lew, and J. A. Romand, Geneva, Switzerland; D. Aymon, F. Bally, J. Bille, R. Chiolero, A. Cometta, M. P. Glauser, G. Greub, M. D. Shaller, and G. Zanetti, Lausanne, Switzerland; and M. Betschart, D. von Ow, and P. Vernazza, St. Gallen, Switzerland.
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FOOTNOTES |
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Members of the Cefepime Study Group are listed in the Acknowledgments.
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REFERENCES |
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