JAC Advance Access originally published online on December 12, 2005
Journal of Antimicrobial Chemotherapy 2006 57(2):176-189; doi:10.1093/jac/dki448
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Systematic review |
Empirical antibiotic monotherapy for febrile neutropenia: systematic review and meta-analysis of randomized controlled trials
1 Department of Medicine E, Rabin Medical Center, Beilinson Campus, 49100 Petah-Tiqva, Israel; 2 Sackler Faculty of Medicine, Tel-Aviv University, Tel Aviv, Israel
* Corresponding author. Tel: +972-3-9376501; Fax: +972-3-9376512; E-mail: pil1pel{at}zahav.net.il
Received 16 June 2005; returned 15 September 2005; revised 10 November 2005; accepted 12 November 2005
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Abstract |
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Objectives: Early, empirical broad-spectrum antibiotic treatment is the established practice for febrile neutropenia. Several ß-lactams are accepted for monotherapy. We asked whether patients' outcomes are influenced by the chosen ß-lactam.
Methods: Systematic review and meta-analysis of randomized controlled trials comparing anti-pseudomonal ß-lactams administered as empirical monotherapy for febrile neutropenia, with or without vancomycin. The search included The Cochrane Library, PubMed, Embase, Lilacs databases, bibliography, conference proceedings, trial registries and FDA new drug approvals. Two reviewers independently applied selection criteria, performed quality assessment and extracted the data. Trials assessing the same ß-lactam were pooled using the fixed effect model. Relative risks (RRs) with 95% confidence intervals (CIs) were calculated. The primary outcome assessed was all-cause mortality.
Results: Thirty-three trials fulfilled inclusion criteria. Cefepime was associated with higher all-cause mortality at 30 days than other ß-lactams (RR 1.44, 95% CI 1.06–1.94, 3123 participants). Carbapenems were associated with fewer treatment modifications, including addition of glycopeptides, than ceftazidime or other comparators. Adverse events were significantly more frequent with carbapenems, specifically pseudomembranous colitis (RR 1.94, 95% CI 1.24–3.04, 2025 participants). All-cause mortality was unaltered. Piperacillin/tazobactam was compared only with cefepime and carbapenems, in six trials. No significant differences were demonstrated with paucity of data for all-cause mortality.
Conclusions: The use of cefepime for febrile neutropenia is associated with increased mortality and should be carefully considered pending further analysis. Empirical use of carbapenems entails fewer treatment modifications, but an increased rate of pseudomembranous colitis. Ceftazidime, piperacillin/tazobactam, imipenem/cilastatin and meropenem appear to be suitable agents for monotherapy.
Keywords: ß-lactams , cefepime , ceftazidime , piperacillin/tazobactam , carbapenems
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Background |
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Febrile neutropenia is a common complication of cancer treatment associated with significant morbidity and mortality. Early institution of broad-spectrum antibiotic treatment reduces mortality.1
Monotherapy using a broad-spectrum ß-lactam is as effective and safer than the classical combination of a ß-lactam and an aminoglycoside.2 Current guidelines propose ‘cefepime or ceftazidime or imipenem or meropenem’, empirically, as single ß-lactams, with or without vancomycin.3 The potential of piperacillin/tazobactam is pointed at, stipulating further experience.
Common to all monotherapies is an in vitro spectrum of coverage including Pseudomonas aeruginosa. Differences exist with regard to the spectrum of coverage against Gram-positive bacteria and multidrug-resistant Gram-negative bacteria. Ceftazidime, with the longest experience in clinical trials, provides broad-spectrum coverage against Gram-negative bacteria. Comparatively, cefepime, piperacillin/tazobactam and carbapenems offer better coverage in vitro against methicillin-susceptible Staphylococcus aureus, Streptococcus viridans and Streptococcus pneumoniae.4 Cefepime and piperacillin/tazobactam provide enhanced activity against certain extended spectrum ß-lactamases (ESBLs),5 whereas carbapenems are the treatment of choice for ESBL-producing Gram-negative bacteria.6
Antibiotic-related adverse events may also differ, affecting morbidity, cancer treatment schedule and ultimately patients' prognosis. Significant adverse events include pseudomembranous colitis, colonization with resistant bacteria or fungi and resultant superinfections.
We speculated whether these differences result in different clinical outcomes. We performed a systematic review with meta-analysis of randomized controlled trials that compared these antibiotic monotherapies for febrile neutropenia.
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Methods |
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Our objective was to assess whether there is an advantage to one of the ß-lactam monotherapies recommended for the empirical treatment of febrile neutropenia.3 We included randomized controlled trials comparing ceftazidime, cefepime, carbapenems or piperacillin/tazobactam with any different ß-lactam for the empirical treatment of febrile neutropenia. We restricted the antibiotics assessed to anti-pseudomonal ß-lactams. We regarded ceftazidime, the first established monotherapy for febrile neutropenia, as reference and compared other monotherapies with it when relevant. Only the addition of a glycopeptide to both study arms was permitted, since monotherapy is recommended in current guidelines with or without a glycopeptide.3 The primary outcome assessed was all-cause mortality, 30 days following end of treatment. When unavailable, mortality at end of study follow-up was used. Secondary outcomes included treatment failure, defined as non-resolved infection, treatment modification or death owing to infection; infection-related mortality; treatment modifications assessing specifically the need to add glycopeptides and antifungals; microbiological failure, defined as failure to eradicate causative pathogen/s; superinfection; and adverse events. We planned to compare the duration of hospital stay, development of resistance among pre-treatment isolates and the rate of colonization with resistant bacteria. However, these outcomes were not assessed in all included studies.
We searched The Cochrane Library, Medline, Embase and Lilacs databases using specific antibiotic names combined with the terms (neutrop?en* OR granulocytop?en*) and a filter for randomized trials.7 Unpublished trials were sought in references of all included studies; relevant conference proceedings; trial registries and ongoing trial databases; new drug application (NDA) documents of the US Food and Drug Administration; and through personal contact with the authors and sponsoring pharmaceutical companies of included studies. No language or date restrictions were imposed. The last search was performed in February 2005.
Two reviewers independently performed the search, applied inclusion criteria and extracted the data. Whenever mortality data or randomization methods were not reported in the primary reference we contacted the authors and the sponsor requesting these data. Quality assessment was performed using the individual component approach assessing allocation sequence generation, allocation concealment, blinding, intention to treat analysis and number of patients excluded from outcome assessment. Allocation concealment and generation were graded as adequate (A), unclear (B) or inadequate (C) using criteria suggested in the Cochrane handbook. To assess the effect of study quality on outcomes we performed sensitivity analyses by individual components. We regarded primarily the quality of allocation concealment that has been shown to correlate with bias.8,9
Relative risks (RRs) and 95% confidence intervals (CI) were calculated for individual studies. Studies comparing the same ß-lactam were combined using the fixed effect model to obtain the combined RR of that ß-lactam versus comparators. Within each comparison studies were subgrouped by the comparator. Heterogeneity in the results of the trials was assessed using a 
2 test of heterogeneity and the I2 measure of inconsistency quantified according to Higgins et al.10 Analyses were conducted using RevMan 4.2 software. A funnel plot and Egger's test of the intercept were used to assess small study effect (publication bias or other).11
The full search strategy and detailed methodology are available in The Cochrane Library.12
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Results |
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The trial flow is depicted in Figure 1. Thirty-three trials fulfilled inclusion criteria (Table 1).13–47 The monotherapies assessed were ceftazidime (19 trials); cefepime (18 trials); imipenem (12 trials); meropenem (8 trials); and piperacillin/tazobactam (7 trials). Single trials compared piperacillin13 or ticarcillin/clavulanate18 with ceftazidime and three trials compared cefoperazone/sulbactam with imipenem.16,19,47 Vancomycin was added in both study arms to all patients in four trials,13,14,18,19 and as needed in two trials.33,40 Most studies were conducted during the last decade. The primary outcome assessed in all studies was treatment failure. Data regarding all-cause mortality were reported in the primary reference in 20 studies and obtained from the authors in eight additional studies. The adjusted mean all-cause mortality rate at end of study follow-up was 3.9% for adults (23 studies, 4938 patients) and 1.2% for children (4 studies, 605 patients). Seven trials are unpublished—three were found in the NDA application for cefepime14,33,41 and four in conference proceedings.22–24,28,39,43
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Cefepime versus comparators
Cefepime was assessed in 17 trials, comparing it with ceftazidime in eight trials, imipenem in four, piperacillin/tazobactam in three and meropenem in two. Data regarding all-cause mortality were obtained for all studies. All-cause mortality was significantly higher with cefepime compared with other ß-lactams (RR 1.44, 95% CI 1.06–1.94, P = 0.02), with no heterogeneity (I2 = 0%, Figure 2). The corresponding funnel plot was symmetric (intercept –0.262, 95% CI –1.350 to 0.825, P = 0.61, Figure 3).
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Sensitivity analyses (Figure 4) show a larger mortality difference with adequate versus inadequate allocation concealment (adequate concealment RR 1.81, 95% CI 1.22–2.70), adequate versus inadequate allocation generation, among studies reporting mortality by intention to treat and in published versus unpublished studies. Four studies recruited only children and mortality was higher with cefepime when compared with ceftazidime (RR 2.28, 95% CI 0.53–9.79, 3 studies,27,34,38 263 children) and equal when compared with meropenem (1 study35). The effect estimate was higher among studies that used less than the registered recommended dose for cefepime in febrile neutropenia (2 g three times daily or 50 mg/kg three times daily for adults and children, respectively), but did not reach statistical significance (RR 2.01, 95% CI 0.87–5.08). Mortality difference remained significant in studies using the full-recommended dose with adequate allocation concealment (RR 1.73, 95% CI 1.12–2.66).
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No significant differences were detected between cefepime and comparators with regard to all secondary efficacy outcomes (Table 2). Treatment failure, as defined, was assessed in 16 trials (RR 1.03, 95% CI 0.96–1.10, I2 = 0.1%). With adequate allocation concealment the RR for failure was 1.06 (95% CI 0.97–1.15), and with unclear concealment 0.96 (95% CI 0.85–1.07). Infection-related mortality was assessed in 13 trials (RR 1.24, 95% CI 0.78–1.97). Microbiological failure and need for drug modifications were equal. Bacterial superinfections occurred more frequently in the cefepime arm (RR 1.70, 95% CI 0.94–3.09).
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Adverse events, overall, were less frequent with cefepime owing to an advantage when compared with carbapenems (RR 0.68, 95% CI 0.52–0.89). When compared with ceftazidime no difference was seen. Adverse events requiring discontinuation occurred more frequently with cefepime (RR 1.48, 95% CI 0.89–2.46). More patients in the cefepime arm discontinued treatment owing to infections. Discontinuation owing to treatment failure was not assessed separately.
Carbapenems versus comparators (Table 2)
Imipenem was compared with ceftazidime and cefepime in four trials each, with cefoperazone/sulbactam in three trials and with piperacillin/tazobactam in one trial. Meropenem was compared with ceftazidime in five trials, cefepime in two and piperacillin/tazobactam in one trial.
All-cause mortality did not differ significantly between carbapenems and comparators (RR 0.93, 95% CI 0.68–1.29, I2 = 0%, Figure 5). The major comparison was with ceftazidime (RR 0.91, 95% CI 0.54–1.54, 8 studies, 2028 participants).
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An advantage for carbapenems was observed with regard to treatment failure (Figure 6), any antibiotic modification and glycopeptide addition. Moderate heterogeneity was present in these comparisons (I2 = 25–50%). Again the major comparison was with ceftazidime and the corresponding effect estimates were RR 0.86 (95% CI 0.80–0.94), I2 = 0% for failure, RR 0.86 (95% CI 0.79–0.94), I2 = 32% for any modifications, and RR 0.70 (95% CI 0.57–0.86), I2 = 0% for glycopeptide addition. Addition of antifungals was more common with carbapenems, but the difference was not significant (RR 1.14, 95% CI 0.94–1.38). No significant advantage was observed with regard to infection-related mortality (RR 0.85, 95% CI 0.51–1.41), microbiological failure (RR 0.98, 95% CI 0.88–1.09) and superinfections (RR 0.89, 95% CI 0.71–1.12). Meta-analysis of the three trials comparing imipenem with cefoperazone/sulbactam was consistent with the overall comparison, except for failure with modification, which was non-significantly more frequent with imipenem (RR 1.19, 95% CI 0.99–1.43).
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Imipenem was associated with more frequent adverse events when compared with other ß-lactams, RR 1.72, 95% CI 1.45–2.04 for any adverse event (8 studies, 1419 participants) and RR 2.78, 95% CI 1.00–7.76 for seizures (7 studies, 1885 participants). Carbapenems were associated with significantly more frequent pseudomembranous colitis than cephalosporins (RR 1.94, 95% CI 1.24–3.04, Figure 7). All but one trial31 in this comparison assessed imipenem (RR 2.07, 95% CI 1.28–3.34).
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Sensitivity analysis showed that the advantage to carbapenems with regard to treatment failure was present in studies with unclear allocation concealment (RR 0.90, 95% CI 0.83–0.98, 9 trials, 2094 participants), but not in studies with adequate allocation concealment (RR 1.02, 95% CI 0.92–1.13, 9 trials, 2099 participants). All-cause mortality results were unaffected. No advantage to carbapenems with regard to failure was observed when dropouts were counted as failures in studies conducted per protocol (RR 0.95, 95% CI 0.90–1.01). The RRs for clinical and microbiological failure did not decrease in recent years, as might be expected with increasing prevalence of ESBL-positive Gram-negative bacteria.
Piperacillin/tazobactam versus comparators (Table 2)
Six trials assessed piperacillin/tazobactam comparing it with imipenem and meropenem, (one trial each), and more recently with cefepime (four trials).
All-cause mortality was available in four trials (RR 0.62, 95% CI 0.34–1.13) and infection-related mortality in four (RR 0.52, 95% CI 0.22–1.23). Both favour piperacillin/tazobactam but CIs are wide owing to the small number of trials and participants.
Treatment failure was similar (RR 0.93, 95% CI 0.84–1.03, I2 = 64%, both by intention to treat and per protocol), with heterogeneity originating in a disparity between studies favouring piperacillin/tazobactam when compared with cefepime (RR 0.87, 95% CI 0.77–1.00, I2 = 0%), but not when compared with carbapenems (RR 1.08, 95% CI 0.93–1.25, I2 = 0%). Other secondary outcomes were not significantly different. None of these studies provided data regarding superinfection rates or aetiology. A single study reported adverse event rates.30
Lack of data regarding trials' methodology precluded sensitivity analyses for study quality. A single study with inadequate allocation concealment showed an advantage to cefepime with regard to treatment failure.43
No study comparing piperacillin/tazobactam with ceftazidime monotherapy was identified. Two older studies compared other penicillins with ceftazidime. Piperacillin was found significantly inferior to ceftazidime with regard to failure,13 RR 0.54, 95% CI 0.38–0.78, and ticarcillin/clavulanate was not significantly different.18
Quality assessment (supplementary data are available at JAC Online)
The methods for allocation generation and concealment were unclear in 12 and 17 of the 33 trials, respectively. Two trials were quasi-randomized, using alternation34 or patients' room assignment43 for allocation. Outcome assessors were blinded in eight trials, patients and carers in two, whereas the remaining were open. All-cause mortality was reported by intention to treat in 13 of 28 trials. Follow-up time for mortality assessment was variable, ranging between end of treatment and 30 days following end of treatment. Different lengths of follow-up may introduce bias. Patients were included in the analysis more than once in 26 of 33 trials. This is methodologically incorrect since the statistical tests used assume independence between the observations. Unclear or inadequate allocation concealment was associated with exaggerated treatment effects for failure.
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Discussion |
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ß-Lactams alone, with or without vancomycin, are commonly used for the empirical treatment of febrile neutropenia.3 These ß-lactams have been assessed comparatively prior to and following their introduction into clinical use. We hypothesized that different ß-lactams may be associated with different clinical outcomes. To assess this hypothesis, we assembled all randomized studies comparing different anti-pseudomonal ß-lactams.
The review included 33 trials. ß-Lactams assessed in more than one trial were ceftazidime, cefepime, imipenem, meropenem, piperacillin/tazobactam and cefoperazone/sulbactam. Ceftazidime was assessed most frequently and we compared other ß-lactams with it.
Cefepime was associated with a higher all-cause mortality rate than its comparators (RR 1.44, 95% CI 1.06–1.94). The difference was statistically significant. Infection-related mortality, bacterial superinfections and discontinuation of the allocated treatment were more common with cefepime, whereas no differences were observed regarding other secondary outcomes.
Carbapenems were associated with an advantage with regard to treatment failure when compared with ceftazidime. The advantage disappeared in studies with proper allocation concealment and originated from a lower rate of treatment modifications, including significantly less use of glycopeptides in the carbapenem arm. Use of antifungals, however, was not reduced. All-cause mortality and microbiological eradication rates were similar to ceftazidime and other comparators. Carbapenems were associated with a significantly higher rate of pseudomembranous colitis compared with cephalosporins, with an RR of 1.94 denoting a nearly 2-fold risk. Imipenem (used 2 g/day most commonly) was associated with a 3-fold risk of seizures.
Piperacillin/tazobactam has not been compared with ceftazidime monotherapy. Its comparison with cefepime and carbapenems shows no significant differences with regard to clinical and microbiological success. A further study showed similar results for piperacillin/tazobactam monotherapy versus ceftazidime + amikacin.48 The mortality comparison is favourable to piperacillin/tazobactam, but currently available data for this and other outcomes are limited.
The adverse ecological impact of the different antibiotics was infrequently assessed. None of the trials reported on surveillance sampling, thus colonization rates with resistant microorganisms are unknown.
All-cause mortality was defined in our protocol as the primary outcome for this review.12 Undoubtedly the most significant outcome for the patient, all-cause mortality encompasses the many outcomes related to treatment of infections: efficacy, adverse events and superinfections. We extracted mortality at end of treatment and up to 30 days after end of treatment. Most fatal cases within this period are related to the infectious episode, but adequate randomization should ensure an equal distribution of non-infection-related deaths between the study groups. While primary studies are not powered to assess differences in mortality, meta-analyses may detect previously unsuspected trends.49,50
The observation that all-cause mortality is higher with cefepime is unexpected. Ceftazidime and cefepime are both advanced oxyimino-cephalosporins targeting a similar spectrum of Gram-negative bacteria.51 Cefepime was introduced as a ‘fourth generation’ cephalosporin, offering a broader in vitro spectrum of coverage than ceftazidime against Gram-positive bacteria, resistance to some of the ESBLs that inactivate ceftazidime and a lower propensity for selection of resistant (derepressed) mutants.6,51,52 We believe our search identified all randomized trials comparing cefepime with other single ß-lactams for febrile neutropenia (6 of 17 studies unpublished). Despite under-reporting of all-cause mortality in the original publications, we obtained these data from the primary investigators in all studies. Adequate randomization methods and adherence to intention to treat analysis accentuated cefepime's disadvantage. Adequate allocation concealment assures against selection of sicker patients to an ‘attractive’ treatment arm.53 Analysis by intention to treat protects against unequal exclusion of cases by evaluators. No heterogeneity was detected within the comparison, attesting to similarity of effect estimates across studies. Finally, the difference persisted when analysis was limited to published studies. Overall, selection bias was minimized and sensitivity analyses support the validity of the comparison of mortality for cefepime.
We could not define the reason for increased all-cause mortality with cefepime within the secondary outcomes assessed. The trends observed with other efficacy outcomes point towards reduced efficacy. The mortality rates we observed were low (mean 3.1%). Comparatively, in-hospital mortality rates in contemporary observational studies range between 5 and 9% in a non-selected population54–56 and 13% in high-risk patients.54 Thus, randomized trials tend to recruit rather low-risk patients and our analysis may underestimate differences between treatment regimens.
Implications for practice and further research
Pending further analysis, the increased mortality rate observed in febrile neutropenic patients treated with cefepime should serve as a strong caveat against its use for febrile neutropenia. Further trials are not warranted until individual patient assessment (patient data meta-analysis) of the time and cause of death in existing trials is conducted. Its efficacy for other indications should be re-assessed.
Ceftazidime, piperacillin/tazobactam, imipenem/cilastatin and meropenem appear as suitable agents for monotherapy. Local epidemiology and susceptibility patterns should serve to select the optimal of these agents. Further trials assessing piperacillin/tazobactam are needed.
Empirical use of carbapenems entails fewer treatment modifications than ceftazidime, but adverse events occur more frequently and mortality is similar. In our opinion, the increased adverse events rate, especially pseudomembranous colitis, offsets the advantage in treatment modifications. Bearing in mind that carbapenems are drugs of last resort for multidrug-resistant Gram-negative bacteria, their empirical use should be restricted. To limit glycopeptide overuse with comparators, glycopeptides should not be added empirically for persistent fever alone.57
To permit evidence-based antimicrobial treatment of febrile neutropenia randomized controlled trials should adhere to standard methodology. Allocation must ensure a truly random sequence, patients should not be included more than once and outcomes should be reported by intention to treat. Reporting of all-cause mortality must be mandatory to permit patients' safety assessment.
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None declared. Complementary data were requested from the pharmaceutical companies that sponsored the studies included. None of the companies provided additional data.
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Supplementary data |
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Supplementary data are available at http://jac.oxfordjournals.org.
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Acknowledgements |
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We thank all the authors who provided complementary data for their studies (Table 1). In addition, we thank Alice Baruch (Pfizer) and John F. Tomayko (GlaxoSmithKline) for conducting independent searches for additional studies. This work was supported in part by an EC 5th framework IST grant (TREAT project, grant no. 1999-11459). Preliminary results were presented at the Fifteenth European Congress of Clinical Microbiology and Infectious Diseases, 2004. The protocol for this review is published in The Cochrane Library,12 where the complete review will be published and updated.
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References |
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