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© 2003 American Society for Clinical Oncology Reappraisal With Meta-Analysis of the Addition of Gram-Positive Prophylaxis to Fluoroquinolone in Neutropenic Patients
From the Center of Preventive Medicine, Verona; and the Institute of Microbiology, University of Padua, Padua, Italy. Address reprint requests to Mario Cruciani, MD, Center of Preventive Medicine/HIV Outpatient Clinic, ULSS 20, V Germania, 20-37135 Verona, Italy; e-mail: crucianimario{at}virgilio.it.
Purpose: Past reports and meta-analyses indicate that fluoroquinolones are highly effective in preventing Gram-negative infections in neutropenic cancer patients, but offer inadequate coverage for Gram-positive infections. We evaluated by meta-analysis the efficacy of the addition of antimicrobial agents with enhanced Gram-positive activity to prophylaxis with quinolones. Materials and Methods: Randomized trials comparing fluoroquinolones alone (ciprofloxacin, ofloxacin, pefloxacin, or norfloxacin) with fluoroquinolone in combination with Gram-positive prophylaxis (rifampin, vancomycin, amoxicillin, roxithromycin, or penicillin) were retrieved. We pooled relative risks (RRs) using a fixed-effects model. Results: Nine trials (1,202 patients) published between 1993 and 2000 meet inclusion criteria. Compared with fluoroquinolone alone, Gram-positive prophylaxis reduced total bacteremic episodes (RR, 1.54; 95% CI, 1.26 to 1.88), streptococcal infections (RR, 2.20; 95% CI, 1.44 to 3.37), coagulase-negative staphylococcal infections (RR, 1.46; 95% CI, 1.04 to 2.04), and rate of febrile patients (RR 1.08; 95% CI, 1.00 to 1.16). Occurrence of clinically documented infections, unexplained fever, and infectious mortality was similar in the two groups. The addition of Gram-positive prophylaxis, however, significantly increased side effects (RR, 0.46; 95% CI, 0.28 to 0.76). Rifampin use resulted in a higher incidence of undesirable effects. Conclusion: Considering the lack of cut-clear benefit on some parameters of morbidity and mortality, routine use of Gram-positive prophylaxis is not advisable. This strategy, however, should be particularly valuable in subgroups of patients at high risk of streptococcal infection (eg, those with severe and prolonged neutropenia or mucositis, and those receiving cytarabine). Problems of tolerability and the potential for the emergence of resistant microorganisms should be considered when prescribing prophylaxis with enhanced Gram-positive activity to neutropenic patients.
THE EFFICACY of fluoroquinolones in preventing Gram-negative infection in neutropenic cancer patients is well documented.1–3 Conversely, the beneficial effects of fluoroquinolone prophylaxis on mortality and on other parameters of morbidity are debatable. Moreover, concerns about the long-lasting efficacy of fluoroquinolones in preventing Gram-negative infections became apparent after studies reporting the emergence of fluoroquinolone-resistant Gram-negative bacilli.4–6 Nevertheless, in those centers in which resistance has not emerged, prophylaxis with fluoroquinolones is still widely in use. Gram-positive organisms, predominantly viridans streptococci and coagulase-negative staphylococci, have emerged as the most commonly isolated pathogens responsible for infections among neutropenic patients receiving fluoroquinolones.7–10 This is not surprising, given that viridans streptococci and coagulase-negative staphylococci generally are resistant to fluoroquinolones, and use of these agents would select for colonization with these microorganisms. Early reports have found that the benefit of quinolone prophylaxis can be improved by adding agents with enhanced Gram-positive activity.11,12 Consequently, strategies to reduce Gram-positive infections by combining Gram-positive coverage with fluoroquinolone prophylaxis have been widely explored. A number of controlled clinical trials have evaluated the efficacy of prophylaxis with oral fluoroquinolone in combination with antimicrobial agents active against Gram-positive bacteria.9,13–26 Indeed, these studies are somewhat heterogeneous with regard to design, patient selection, antimicrobial agent used, and outcomes investigated. Moreover, the benefit of prophylaxis with enhanced Gram-positive coverage has been substantiated in some of these studies, whereas other studies failed to demonstrate consistent advantages. In this study, we evaluated by systematic review and meta-analyses the randomized studies investigating the efficacy of the addition of antimicrobial agents with enhanced Gram-positive activity to a fluoroquinolone-based prophylactic regimen in neutropenic cancer patients.
Literature Search The medical literature was searched for relevant studies published between 1984 and October 2002. The search was carried out on Medline, CancerLit database, Database of Abstracts of Reviews of Effects, and on Cochrane Library. Medical subject heading terms used were neutropenia or agranulocytosis and bacterial infections. The bibliographies from the articles retrieved were consulted to supplement the computer search. Where possible, we contacted the authors of publications for missing or incomplete information.
Study Selection
Outcome Measures
Quality Assessment
Statistical Analysis Sensitivity analysis was performed to determine if quantitative results differed with the exclusion of individual studies.
Assessment of Publication Bias The procedure of Rosenthal35 and Klein,36 which is based on estimation of the minimum number of negative (or null) studies required to lead the results of the meta-analysis to a statistically nonsignificant level, was also applied.
Heterogeneity Assessment
We retrieved 2,269 articles dealing with neutropenia and bacterial infections. Fifteen comparative published trials of fluoroquinolones combined with Gram-positive prophylaxis were identified as being appropriate for inclusion in our analysis on the basis of the predetermined inclusion and exclusion criteria.13–26 Of these, four randomized studies were excluded because they compared fluoroquinolones combined with Gram-positive agents to oral nonabsorbable antibiotics,23,24 placebo,25 or no treatment.26 One study that evaluated ofloxacin plus rifampin was excluded because it was not randomized and included a historical control group receiving norfloxacin or no antibiotic prophylaxis.22 We also excluded another case-control study in which patients receiving quinolone alone were compared with matched patients receiving a quinolone plus penicillin.9
The main characteristics of the nine randomized studies13–21 that met the inclusion criteria are shown in Table 1
Quality Assessment The mean Jadad score was 2.8 ± 1.2. Two double-blind studies had a score of 5.16,21 Of the remaining studies with open assessment, two had a score of 3, and five had a score of 2. Using the 15-item criteria for classification, the mean quality score was 11.4 (standard deviation, 1.4; range, 9.5 to 14). The quality criteria most often absent were calculation of CIs (absent in eight of nine studies), blinding of patients (absent in seven of nine studies), documentation of study dates (absent in six of nine studies), and estimation of study power (absent in four of nine studies).
Results of the Meta-Analysis
Table 2  shows the cumulative relative risks (RRs), related 95% CIs, and pooled rates for each of the study outcomes. Table 3 shows percentage of risk reduction, number of patients that needed to be treated to prevent one event, and publication bias assessed by the procedure of Rosenthal35 and Klein.36
The addition of Gram-positive prophylaxis to fluoroquinolones significantly reduced total episodes of bacteremia, staphylococcal and streptococcal infections, and febrile morbidity. The RRs in favor of Gram-positive prophylaxis were 2.20 (95% CI, 1.44 to 3.37) for streptococcal infections, 1.54 (95% CI, 1.26 to 1.88) for total bacteremic episodes, 1.46 (95% CI, 1.04 to 2.04) for staphylococcal infections, and 1.08 (95% CI, 1.00 to 1.16) for febrile patients. Almost all of the episodes of staphylococcal bacteremia were sustained by coagulase-negative staphylococci: 69 of 72 episodes in recipients of quinolones, and 46 of 48 episodes in the group receiving Gram-positive prophylaxis. Thus, only five episodes of Staphylococcus aureus bacteremia (three in the quinolone group and two in the Gram-positive prophylaxis group) were reported among 1,202 patients (0.4%) in the nine studies examined.
The occurrence of clinical documented infections, Gram-negative infections, unexplained episodes of fever, and infectious mortality, was similar in the two groups (Table 2 In sensitivity analysis, after exclusion of two studies with rifampin18,20 and one study with roxithromycin as Gram-positive prophylaxis, the difference in the occurrence of side effects was no longer statistically significant. Exclusion of the study by Gomez-Martin et al20 yielded the largest change (RR, 0.66; 95% CI, 0.37 to 1.16). For the other outcomes analyzed, the exclusion of any single study yielded only minimal change on the effect size and did not change statistical significance. Moreover, subgroup analyses after removal of coagulase-negative staphylococcal bacteremia or streptococcal bacteremia from total episodes of bacteremia did not alter the effect of Gram-positive prophylaxis.
Publication Bias Assessment
For the outcome staphylococcal infection, the asymmetric appearance of the funnel plots and the Egger test (P = .017) suggest that publication bias may be present. After adjusting for missing studies using the trim and fill approach, the estimate RR changed from an original value favoring Gram-positive prophylaxis to a value that was not statistically significant (Fig 4  ). However, the correlation test of Begg and Mazudmar was not statistically significant, thus suggesting that asymmetry of funnel plots might be due to factors other than publication bias.
Heterogeneity Assessment
A continuous debate surrounds the issue of the adequacy of fluoroquinolones in preventing bacterial infections in neutropenic patients. Without a doubt, prophylaxis with fluoroquinolones has led to a decrease in the occurrence of Gram-negative infections in neutropenic patients. When quinolones are used as prophylaxis, the rate of Gram-negative bacteremia is reduced to 1% to 2%.38 Three meta-analyses of clinical trials examining the benefit of fluoroquinolone prophylaxis in neutropenic patients have been published.1–3 Since that time, however, there has been a continuous interest in the use of quinolone prophylaxis, and a number of trials investigating the efficacy of fluoroquinolones alone or in combination with Gram-positive prophylaxis have been carried out. One of the drawbacks to prophylaxis with fluoroquinolones is represented by the emergence of resistant strains. Reports of fluoroquinolone-resistant Escherichia coli causing bacteremia among cancer patients are a matter of concern.4–6 Given that prophylaxis with fluoroquinolones has, until now, led to a remarkable reduction in the occurrence of Gram-negative infections during neutropenia in many centers, generalized statements against its use still seem inappropriate. Rather, the potential disadvantages of quinolone prophylaxis should be weighed against the established benefits. Part of the limited overall effectiveness of fluoroquinolone prophylaxis, however, is related to the inadequate coverage for Gram-positive bacteria. Infection with viridans streptococci has recently became a major problem in neutropenic patients; the organisms can cause sepsis and pneumonia.9,10 It is generally recognized that viridans streptococci infections in a neutropenic host may progress rapidly to septic shock and acute respiratory distress syndrome.10,39,40 Moreover, viridans streptococci that are resistant to various beta-lactams, macrolides, tetracycline, and trimethoprim-sulfamethoxazole are increasingly reported.41–43 Oral prophylaxis with the older quinolones is unlikely to be effective in preventing Gram-positive infections. Furthermore, breakthrough bacteremia caused by viridans streptococci has been reported in neutropenic patients receiving fluoroquinolone prophylaxis.39,44,45 It is likely that the selective pressure of prophylaxis would select for viridans streptococci colonization by strains that express a high level of resistance to quinolone. Attempts to overcome this problem with the use of newer quinolones, such as levofloxacin, has led to worrisome results.46,47 It has been shown that levofloxacin has a suboptimal in vitro activity against viridans streptococci, and exposure to this drug in neutropenic patients has produced mutations in the A subunit of DNA gyrase, which is also one of the preferential targets for other quinolones with enhanced activity against Gram-positive organisms.46–50 Two recent reports from the United States demonstrate that prophylaxis with levofloxacin in neutropenic patients is associated with the selection of viridans streptococci with diminished susceptibility to levofloxacin and to quinolones with enhanced activity against Gram-positive organisms, namely moxifloxacin and gatifloxacin.46,47 Other strategies to reduce Gram-positive infections consist of the addition of antimicrobial agents with enhanced activity against Gram-positive organisms to fluoroquinolones. Evidence from early reports and open studies suggested that prophylaxis with vancomycin, penicillins, macrolide, or rifampin may reduce Gram-positive infections in neutropenic patients.11,12,51–58 Soon after these observations, several investigators have evaluated the efficacy of the addition of Gram-positive prophylaxis to quinolones by means of controlled clinical trials.9,13–26 Some of these studies have shown a beneficial effect of Gram-positive coverage on certain parameters of morbidity,9,14–17,22–25 whereas others have failed to confirm these observations.13,18–21,26 The results of these trials are often difficult to interpret separately or to generalize because of the relatively small numbers of patients enrolled onto most of the studies. Therefore, we undertook a systematic review and meta-analysis of randomized studies comparing prophylactic regimens that were based on fluoroquinolone combined with drugs specifically acting against Gram-positive bacteria, with a control arm in which subjects were given fluoroquinolone alone. Overall, nine randomized studies met selection criteria and were included in this meta-analysis of 1,202 neutropenic cancer patients. A significant effect of the addition of Gram-positive coverage (penicillins, macrolide, rifampin, or vancomycin) to fluoroquinolone prophylaxis (ciprofloxacin, ofloxacin, pefloxacin, or norfloxacin) was evident on some parameters of infectious morbidity, but not on mortality. Our quantification of heterogeneity showed no intertrial heterogeneity for the outcomes analyzed. Compared with patients who received fluoroquinolone alone, patients who received Gram-positive prophylaxis experienced 11.1% fewer bacteremic episodes (from 29.5% to 18.4%), as a result of a decrease in streptococcal and coagulase-negative staphylococcal infections. There also was limited evidence for a reduction of febrile morbidity in patients receiving prophylaxis with fluoroquinolones. This reduction translated into decreases of 6.7% (from 78.5 to 71.7%) in the number of febrile patients, but the unexplained episodes of fever and the first day of fever were comparable between groups. Moreover, there was no significant effect of the addition of Gram-positive prophylaxis to quinolone in terms of infectious mortality (RR, 0.95; 95% CI, 0.53 to 1.71). On the contrary, side effects were significantly less common among recipients of fluoroquinolone alone than among patients receiving fluoroquinolone combined with Gram-positive prophylaxis (RR, 0.46; 95% CI, 0.28 to 0.76; P = .003). In sensitivity analysis, however, the effects of rifampin (two studies) and macrolide (one study) on side effects were marked: After exclusion of these single studies, the pooled RR was no longer statistically significant.14,18,20 Publication bias is a significant threat to the validity of meta-analysis. In this meta-analysis, evidence of publication bias with graphic and statistical methods was not detectable for the outcomes overall bacteremia, streptococcal infections, rates of febrile patients, unexplained episodes of fever, and side effects. Evidence also existed for the robustness of some of these conclusions. For the outcome staphylococcal infections, there was evidence of publication bias with the regression asymmetry test of Egger et al.32 This was not confirmed when the rank correlation test was applied.33 Moreover, the results of the Begg and Mazumdar test were consistent for all of the end points analyzed. Thus, a false-positive test for bias with the former test cannot be excluded. Quality assessment is of absolute relevance to systematic reviews.27 Methodologic problems with trials involving neutropenic patients have been reported.59 These observations have prompted the Immunocompromised Host Society and, more recently, the Immunocompromised Host Society in conjunction with the Multinational Associations for Supportive Care in Cancer, to produce a set of guidelines on methodologic issues for clinical trials in neutropenic patients.60,61 On average, the quality of the studies included in this analysis was not ideal. Many studies did not pay attention to statistical issues, such as calculation of CIs and estimation of study power. Among the nine studies included in this analysis, five described methods of randomization and two were blinded. Generally, however, there was uniformity in patient selection criteria, settings, definition of outcomes assessed, and characteristics of the patients included in the trials. Clinicians will have to decide whether fluoroquinolone prophylaxis of bacterial infections is still worthwhile in neutropenic patients with cancer. The efficacy of quinolone prophylaxis in preventing Gram-negative infections has ultimately emerged in recent reports from European cancer centers, and shows a striking rebound of Gram-negative bacteremias after discontinuation of prophylaxis with fluoroquinolones.62,63 Data from Switzerland show an increase of the proportion of Gram-negative bacteremias from 25% to 85% of all bloodstream infections.62 However, the shift was recorded concomitantly with a decrease of Gram-positive bacteremias. Our data confirm the continuous efficacy of quinolone prophylaxis in preventing Gram-negative infection. The pooled incidence of Gram-negative infection was approximately 4% in both groups. S aureus was isolated from blood in a negligible proportion (0.4%) of patients. In contrast, coagulase-negative staphylococci were by far the leading cause of bacteremia, with 135 episodes reported among 1,202 patients (11.2%). Given that the increase in coagulase-negative staphylococci bacteremia is related strictly to the increasing use of indwelling intravenous catheters, strategies aimed at an optimal management of intravascular devices, including insertion and maintenance, should prevent these infections more efficiently than the use of systemic antibiotic prophylaxis.64 Straightforward conclusions from the results of this meta-analysis, however, are not easy to reach. Overall, the results of our meta-analysis do not support the routine use of Gram-positive coverage in combination with quinolone prophylaxis in neutropenic patients. Considering the lack of clear benefit in terms of some parameters of morbidity and mortality, it probably makes sense to use Gram-positive coverage in particular subgroups of neutropenic patients. We found that prophylaxis with enhanced Gram-positive coverage is uniformly effective in reducing streptococcal infections. Risk factors for streptococcal infection that have been identified include severe neutropenia, oral mucositis, bone marrow transplantation, and administration of high-dose cytarabine.9,10,65 According to these observations, such a prophylactic strategy should be of particular efficacy in neutropenic patients at high risk of streptococcal infection. In contrast, prophylaxis should be avoided in those patients for whom neutropenia is expected to be short and mucositis uncommon (eg, solid tumor patients or patients with certain lymphomas). Problems with tolerability should be taken into account when prescribing prophylaxis. As our meta-analysis supports, rifampin use could result in higher incidence of undesirable effects. Oral vancomycin and penicillin have been found to be at least as effective as rifampin but are better tolerated, and should be preferred in this setting. In this case, however, the potential for the emergence of penicillin-resistant streptococci and vancomycin-resistant enterococci has to be monitored strictly and weighed against the benefits of treatment.
The authors indicated no potential conflicts of interest.
Part of this study was presented at the 42nd Interscience Conference on Antimicrobial Agents and Chemotherapy, San Diego, CA, September 27–30, 2002.
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
.05. Pooled rates were assessed to calculate the number of patients that needed to be treated to prevent one event.
