Meta-Analysis: Antibiotic Prophylaxis Reduces Mortality in Neutropenic Patients

Context Bacterial infections cause clinically significant illness and death in neutropenic patients. Contribution This meta-analysis summarizes 95 randomized trials of antibiotic prophylaxis in 9283 afebrile neutropenic patients with conditions such as hematologic cancer. Fluoroquinolone prophylaxis, evaluated in 55 trials, reduced the risk for fever, infections, and all-cause and infection-related mortality. Increased risks for adverse events and harboring drug-resistant bacteria were not statistically significant. Cautions Some trials did not report mortality outcomes. The benefit of antibiotics was lower in higher quality trials. Implications The benefits of antibiotic prophylaxis with a fluoroquinolone probably outweigh the harms in some patients with hematologic cancer and neutropenia. The Editors Patients with cancer are subject to infections resulting mainly from neutropenia induced by chemotherapy. Without preventive measures, 48% to 60% of febrile neutropenic patients have an infection, while 16% to 20% of profoundly neutropenic patients (neutrophil counts < 0.1 109 cells/L) develop bacteremia (1-3). Studies evaluating prophylaxis with trimethoprimsulfamethoxazole (TMP-SMZ) demonstrated a reduced infection rate for patients treated with TMP-SMZ when compared with placebo or no treatment (4, 5). Since their introduction into clinical practice, fluoroquinolones are an attractive option for prophylactic use in neutropenic patients with cancer, mainly because of their broad antimicrobial spectrum (6, 7). Studies have suggested that fluoroquinolones are more effective than placebo or no treatment, oral nonabsorbable antibiotics, or TMP-SMZ in reducing infections (6). However, most of these studies were underpowered to detect a statistically significant effect on survival. Because of concerns about the emergence of drug- resistant bacteria and the lack of convincing evidence that prophylaxis reduces mortality, current guidelines for antibiotic treatment in neutropenic patients with cancer (8) recommend avoiding routine antibiotic prophylaxis. We undertook a systematic review and meta-analysis of randomized, controlled trials to test whether antibiotic prophylaxis reduces mortality in neutropenic patients, focusing on fluoroquinolone prophylaxis. Methods Data Sources We searched the Cochrane Cancer Network register of trials (December 2004), The Cochrane Library (Issue 4, 2004), EMBASE (January 1980 to December 2004), and MEDLINE (January 1966 to December 2004). The terms neutropenia and similar, antibiotic and similar, and prophylaxis and similar were crossed (9). We scanned references of all included trials and reviews identified for additional studies. Study Selection We included all randomized, controlled trials comparing antibiotic therapy with placebo, no intervention, or other antibiotics for prophylaxis of bacterial infections in neutropenic patients. We included trials regardless of publication status and language. Two reviewers independently inspected each reference identified by the search and applied the inclusion criteria. For possibly relevant articles or in cases of disagreement between the 2 reviewers, we obtained and independently inspected the full article. Data Extraction and Quality Assessment Two reviewers independently extracted the data of included trials. In case of any disagreement between the 2 reviewers, a third reviewer extracted the data. We discussed data extraction, documented decisions, and contacted the authors of trials for missing data when necessary. Two independent reviewers assessed trials for methodologic quality. We individually assessed the following components: allocation concealment, generation of the allocation sequence, and blinding. We graded allocation concealment and generation as adequate, unclear, or inadequate. We defined adequate allocation concealment as the use of central randomization, numbered or coded bottles or containers, drugs prepared by the pharmacy, serially numbered and sealed opaque envelopes, or other convincing measures. We defined adequate allocation generation as the use of a random number table, a random number generator, computer generation, coin-tossing, or shuffling. We also collected data on exclusions after randomization and whether the primary analysis was performed according to the intention-to-treat principle or per protocol. Data Synthesis and Analysis The primary outcome was all-cause mortality by the end of follow-up, as defined in each study. Secondary outcomes included infection-related death, febrile episodes, clinically documented infection, microbiologically documented infection, bacteremia, adverse effects, and emergence of resistant bacteria. We analyzed data by calculating the relative risk for each trial with uncertainty expressed with 95% CIs (Review Manager [RevMan], version 4.2 for Windows, The Cochrane Collaboration, Oxford, United Kingdom). For the main outcome, all-cause mortality, we performed a modified intention-to-treat analysis in which we included all known events in both nominator and denominator, even if excluded in the trial's original analysis. We used a fixed-effect model by using the MantelHaenszel method for dichotomous data for pooling trial results throughout the review unless statistically significant heterogeneity was found, in which case, we chose a random-effects model by using the DerSimonian and Laird method. We assessed heterogeneity of trial results by inspecting graphical presentations and calculating a chi-square test of heterogeneity and the I2 measure of inconsistency. We predefined significant heterogeneity as a chi-square test P value less than 0.1 or an I2 measure greater than 50% (10). We explored potential sources of heterogeneity through subgroup and sensitivity analyses. We performed subgroup analyses through meta-regression by using STATA software, version 8.0 (Stata Corp., College Station, Texas). Meta-regression tests whether trial attributes are associated with trial results. We used this type of analysis to assess the effect of the percentage of exclusions after randomization, percentage of patients with hematologic cancer, percentage of patients who underwent bone marrow transplantation, proportion of study days with profound neutropenia (neutrophil count < 0.1 109 cells/L), time of prophylaxis initiation (at start of chemotherapy vs. beginning of neutropenia), administration of growth factors, study size (trial population size > median population size vs. median population size), and the year in which the trial was initiated on all-cause mortality. We performed sensitivity analyses to assess the effect of the quality of allocation concealment, allocation generation, and blinding on trial results. We examined funnel plots for all-cause mortality (1 SE plotted against relative risks) to estimate small study effects (publication or other). We formally tested funnel plot asymmetry by using the Begg-adjusted rank correlation test (11). Role of the Funding Sources This work was supported by a research grant from Rabin Medical Center and a European Commission fifth framework International Society Technologies grant (TREAT project, grant no. 1999-11459). The funding sources had no role in the collection, analysis, or interpretation of the data or in the decision to submit the manuscript for publication. Results We included 95 studies performed between 1973 and 2004 in our review (12-106) (Figure 1). (Excluded trials can be found in the Appendix.) The trials randomly assigned 9283 patients, mostly adults. Fifty trials compared a prophylactic antibiotic with placebo or no intervention, of which 17 trials evaluated fluoroquinolones (Table 1; Appendix Table 1 and Appendix Table 2). Forty-five studies compared different prophylactic regimens, of which 30 trials compared fluoroquinolones with other antibiotics and 5 trials compared different types of fluoroquinolones (ciprofloxacin, ofloxacin, norfloxacin, or pefloxacin) in the 2 study groups. Sixty-four trials included only patients with hematologic malignant conditions: mostly acute leukemia but also lymphoma, chronic myelocytic leukemia in blast crisis, and multiple myeloma. Nine trials included more than 80% patients with solid tumors (breast, lung, ovary, and germ cell tumors). Twenty-seven studies included patients who underwent bone marrow transplantation. Patients were hospitalized for the duration of prophylaxis in 77 trials, 2 trials included both outpatients and inpatients, and 10 trials included only outpatients. The remaining 6 trials did not report the trial setting. Figure 1. Publications identified for study and exclusions. Table 1. Characteristics of Included Studies Prophylaxis was initiated either when the patient became neutropenic (17 trials) or with the initiation of chemotherapy (78 trials). In all but 2 trials (73, 101), prophylaxis was continued until the peripheral granulocyte count reached more than 0.5 109 cells/L or more than 1.0 109 cells/L, fever or remission developed, or the patient received a maximum of 6 weeks of treatment. Most trials did not report the duration of prophylaxis. In 14 trials, the mean duration ranged from 10 days to 151 days. In 7 trials, the median duration ranged from 8 days to 37.5 days. Most studies did not report adherence. Twenty-one trials reported full intention-to-treat analysis for mortality and infection, and 6 trials reported full intention-to-treat analysis for mortality alone. In 12 trials, the number of patients evaluated was the same as the number of randomly assigned patients, with no mention of loss to follow-up. The remaining studies did not perform intention-to-treat analysis. Any Antibiotic Versus Placebo or No Treatment Primary Outcome: All-Cause Mortality Overall, antibiotic prophylaxis significantly decreased the risk for death (relative risk, 0.67 [95% CI, 0.55 to 0.81]) (Figure 2). Meta-regression demonstrated no association between the studies' relative risk