1 Department of Medicine E, Rabin Medical Center, Beilinson Campus, 49100 Petah-Tiqva; 2 Sackler Faculty of Medicine, Tel-Aviv University, Ramat-Aviv, Tel Aviv, Israel
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Abstract |
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Methods: Systematic review and meta-analysis of randomized controlled trials comparing antibiotics with anti-Gram-positive spectrum to control or placebo, in addition to the same baseline antibiotic regimen in both arms. We searched MEDLINE, EMBASE, LILACS, the Cochrane Library, conference proceedings, and references. No restrictions on inclusion were imposed. Two reviewers independently applied selection criteria, carried out quality assessment, and extracted the data. Relative risks with 95% confidence intervals were pooled using the fixed effect model. The primary outcome assessed was all-cause mortality.
Results: Thirteen studies met inclusion criteria, including 2392 participants. Glycopeptides were assessed in nine trials. Empirical anti-Gram-positive antibiotics were assessed for the initial treatment in 11 studies, and for persistent fever in two. No significant difference in all-cause mortality was seen [RR 0.86 (0.581.26), seven studies, 852 participants]. Overall failure at end of therapy occurred equally [RR 1.00 (0.791.27), six studies, 943 participants]. Failure associated with treatment modifications was more frequent in the control arm when empirical initial glycopeptides were assessed [RR 0.70 (0.610.80), five studies, 1178 participants]. Bacterial superinfections, mainly Gram-positive, were detected less frequently in the intervention arm. Adverse events were significantly more common with the additional antibiotic, and nephrotoxicity was significantly more common with additional glycopeptides [RR 1.88 (1.103.22), six studies, 1282 participants]. No significant heterogeneity was present in these comparisons.
Conclusions: The use of glycopeptides can be safely deferred until the documentation of a resistant Gram-positive infection.
Keywords: glycopeptides , neutropenic fever , vancomycin , Staphylococcus aureus
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Introduction |
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In the last few decades, the aetiology of infection among cancer patients has shifted from predominance of Gram-negative to that of Gram-positive bacteria. In multicentre trials conducted by the EORTC, the rate of Gram-positive infections increased from 29% of single-organism bacteraemias in 1973 to 69% in 1993.3,4 Increased use of indwelling catheters, quinolone prophylaxis, and mucositis induced by more intensive chemotherapy are implicated in these changes.5 Currently used ß-lactams do not provide adequate coverage for the majority of these Gram-positive infections.
Empirical antibiotic treatment was shown to reduce mortality when Gram-negative infections predominated, infections known to be rapidly fatal.1 Empirical ß-lactam monotherapy, holding broad-spectrum Gram-positive coverage, is currently considered safe despite the rising prevalence of resistant Gram-positive infections. Such practice must rely on evidence showing that mortality is not increased. We carried out a systematic review and meta-analysis of randomized trials assessing the empirical addition of antibiotics with specific activity against staphylococci and other Gram-positive bacteria.
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Materials and methods |
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We included randomized controlled trials comparing a standard antibiotic regimen (standard) with or without the addition of an antibiotic with activity against Gram-positive bacteria (intervention). These were defined as: glycopeptides, 1st generation cephalosporins, penicillinase-resistant penicillins, clindamycin, quinupristin/dalfopristin, and linezolid. Any standard regimen was permitted as long as the same combination or monotherapy was used in both study arms. We included studies assessing empirical intervention, both initially (initial therapy) and at the time of reassessment for persistent fever (persistent fever). Studies reporting efficacy analysis with a dropout rate after randomization above 30% were excluded. Studies are labelled by the first author and year of publication.
Search strategy
We used the search string: (neutrop?en* OR granulop?en* OR granulocytop?en* OR immune-supres* OR cancer* OR neoplasm* OR malignan* OR tumor* OR leukem* OR lymphom*), combined with specific antibiotic names and classes as defined above, and restricted to clinical trials.6 Databases searched included CENTRAL (Cochrane Library Issue 1, 2004), MEDLINE, EMBASE, and LILACS, all up to March 2004. In addition, we searched conference proceedings (Interscience Conference on Antimicrobial Agents and Chemotherapy 1995 to 2003, American Society of Hematology 2001 to 2002, Japan Society of Clinical Oncology), on-going clinical trial databases, and all references of included studies. Two reviewers inspected relevant articles and applied inclusion criteria.
Outcomes
The primary outcome assessed was all-cause mortality at end of follow-up. Pre-defined secondary outcomes included overall failure disregarding treatment modifications; failure with modifications and the specific addition of amphotericin; durations of fever, treatment, and hospitalization. We extracted data on the development of resistance as well as the rates of bacterial and fungal superinfection and colonization. We extracted all adverse events and those resulting in treatment discontinuation or fatality.
Data extraction
Two reviewers independently extracted data from included trials. Missing data were sought for all trials and obtained for five. Outcomes were extracted by intention to treat, including all individuals randomized in the outcome assessment. When unavailable, data for available cases were used for the main comparisons, and their effect was assessed through sensitivity analysis.
Quality assessment
Two reviewers independently extracted randomization procedures, blinding, re-entries, intention-to-treat and the number of patients excluded from outcome assessment in studies reporting efficacy analysis. Allocation generation and concealment were classified as A (adequate); B (unclear); C (inadequate), using criteria suggested in the Cochrane handbook.7 We carried out sensitivity analyses for allocation concealment, based on evidence showing overestimation of effects with inadequate allocation concealment.8,9
Data analysis
Relative risks (RRs) with 95% confidence intervals are reported. Treatment effects across studies were combined using the fixed effect model. The Z statistic was used to test for a significant pooled estimate (i.e. significantly different than 1 at a 95% confidence level). The fixed effect model assumes a common effect for all studies. Heterogeneity was assessed using a 2 test for heterogeneity (Cochran's Q test), and the I2 statistic.10
The I2 statistic estimates the percentage of the variability in effect estimates that is due to heterogeneity rather than chance alone, with values > 50% indicating substantial heterogeneity. We carried out subgroup analyses of patients with documented Gram-positive infections. While studies report rates of Gram-positive bacteraemia, outcomes for these patients are usually not reported. We therefore used meta-regression to assess the association between the incidence of Gram-positive bacteraemia and individual study effect estimates (STATA 8 software). Regression coefficients are the estimated increase in the log risk ratio per unit-increase in the covariate, in this case the incidence of Gram-positive bacteraemia. Relative risk ratios (RRR) with 95% confidence intervals are reported. A funnel plot (standard error plotted against odds ratios) was examined to estimate potential selection bias (publication or other), or discrepancies between large and small studies.
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Results |
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All-cause mortality
No significant difference in all-cause mortality was seen with the addition of antibiotics against Gram-positive infections [RR 0.86 (0.581.26), values < 1 favouring the intervention, Figure 2]. Seven studies and 852 participants were assessed. Two studies assessed initial glycopeptides, two assessed their addition for persistent fever, and three trials examined the initial addition of other anti-Gram-positive antibiotics. No difference was seen for each sub-category. Heterogeneity was observed between the two studies assessing additional glycopeptides for persistent fever (P=0.15, I2=50.7%), but the overall comparison was non-heterogeneous (P=0.83, I2=0%).
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Four studies were not included in the mortality analyses. Three provided no information,41,43,46 and the authors of one reported no significant difference in mortality without providing data.40
Only four studies reported all-cause mortality for patients with documented Gram-positive infections. No significant difference was detected [RR 2.15 (0.568.25), 107 participants]. Comparative data for other subgroups were scarce (Gram-positive bacteraemia, one study, 26 participants; Staphylococcus aureus infections, two studies, 15 participants; streptococcal infections, three studies, 53 participants), and no significant difference was found for any of the comparisons.
There was no association between the rate of single-agent Gram-positive bacteraemia and the relative risk for mortality.
Treatment failure
Overall failure was equivalent in both study arms [RR 1.00 (0.791.27)], and in all sub-categories (Figure 3). Ten trials reported failure including treatment modifications in the definition of failure. Significantly more failures were observed in the control arm, the difference originating from studies assessing glycopeptides initially (Figure 4). Amphotericin was added more commonly to the intervention arm in non-blinded trials [RR 1.51 (0.802.83), I2=70%, three trials, 976 participants], but not in double-blind studies [RR 0.99 (0.751.33), I2=0%, two studies, 225 participants].
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Superinfections
The administration of glycopeptides resulted in a significant reduction in the rate of bacterial superinfections [RR 0.38 (0.240.59), I2=28%, eight studies, 1628 participants] and Gram-positive superinfection [RR 0.21 (0.110.37), Figure 5]. Documented fungal superinfections did not differ between the study groups [RR 1.10 (0.69, 1.77), I2=7%, nine studies, 1637 patients].
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Adverse events
Addition of anti-Gram-positive treatment resulted in significantly more adverse events (Table 2), mostly dermatological. Glycopeptides were associated with increased nephrotoxicity resulting in harm caused to one of every 37 patients given a glycopeptide.
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Repeating the analyses for all-cause mortality and treatment failure using only studies with adequate allocation concealment did not affect results (data not shown). No significant difference in all-cause mortality was seen when analysis was restricted to studies reporting mortality by intention to treat [RR 0.74 (0.481.16), five studies]. Intention to treat for failure with modification was carried out for seven studies imputing failure for all dropouts. The treatment effect estimate was smaller than the main comparison [RR 0.85 (0.730.99)].
A funnel plot (not shown) showed a symmetric distribution of the studies.
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Discussion |
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The empirical addition of antibiotics against Gram-positive infections did not reduce all-cause mortality [RR 0.86 (0.581.26)]. In unblinded studies, more treatment modifications were made in the control arm, but overall success was equally achieved. Infection-related mortality did not differ between the study groups. More Gram-positive superinfections were detected in the control arm, but the effects of additional glycopeptides on colonization with resistant microorganisms or selection of resistance could not be assessed. Adverse events were more frequent in the intervention arm, which included an increased rate of nephrotoxicity when the additional antibiotic was a glycopeptide. Thus, no advantage to empirical use of antibiotics against Gram-positive infections was detected, but for a lower rate of Gram-positive superinfections with inadequate data to assess the overall effect of empirical glycopeptides on future resistance.
To maximize our power to detect a significant difference, we merged studies assessing both the initial and the later addition of glycopeptides, and studies assessing other antibiotics with Gram-positive spectra. All studies are empirical in that the intervention was implemented before detection of a causative pathogen. All compared a standard antibiotic regimen to the same regimen, combined with specific antibiotics against Gram-positive infections. These changed throughout the years mirroring changes in the prevalence of resistant Gram-positive infections. Currently, only 51.6% of Gram-positive infections among febrile neutropenic patients are susceptible to ß-lactams in different cancer centres in the USA.52 Thus, the antibiotics chosen nowadays for which our results apply are glycopeptides.
The relative risk for mortality favours additional anti-Gram-positive treatment, but the 95% confidence intervals include equivalence and superiority of the control regimen. Figure 2 shows that the advantage to the intervention largely originates from earlier studies using non-glycopeptide antibiotics. To further assess the existence of a possible benefit for additional anti-Gram-positive antibiotics, we repeated outcome analyses for patients in whom Gram-positive infections were subsequently documented. No advantage was detected in these patients as well. Neither did we find a significant relationship between increasing rates of Gram-positive bacteraemia and improved outcomes.
The major limitation of this study is the rather small number of studies identified, some of which did not provide comparative data for all-cause mortality. Only two studies assessed the empirical addition of glycopeptides for persistent fever, and their results regarding mortality point in opposite directions. Five trials permitted patient re-inclusion referring to febrile episodes instead of patients. This is methodologically incorrect since the statistical tests used assume independence between observations. Finally, our study cannot exclude the possibility that selected patients may benefit from empirical glycopeptides.
Elting et al. analysed 909 episodes of bacteraemia using primary data from 10 randomized clinical trials of initial empirical therapy for febrile neutropenia.19 The presence of septic shock at onset and clinically documented infections were associated with a significantly higher mortality rate due to infection (P < 0.0001 for both in multivariate analysis). Septic shock complicated only 1% of bacteraemias due to Gram-positive organisms compared with 5% of Gram-negative bacteraemias, but mortality of patients with septic shock reached 59%, with only two of 22 patients for whom initial therapy failed surviving long enough to permit modification of therapy. Empirical glycopeptides are recommended for these patients.2 Patients with clinically documented infections faired poorly. Intensive aetiological investigation should be carried out in these patients to direct therapy, including the need for additional glycopeptides.
In the same study, the initial administration of vancomycin was not associated with improved ultimate outcome for patients with Gram-positive bacteraemia (418 patients), with the exception of Streptococcus viridans bacteraemia (117 patients). In these patients, initial administration of vancomycin was associated with a 14% absolute reduction in mortality (P=0.004). This study and current guidelines2 suggest that centres in which these Gram-positive bacteria are common causes of serious infections, or are commonly associated with penicillin resistance, should consider empirical use of glycopeptides. Other risk factors for viridans streptococcal bacteraemia identified by multivariate analyses in different trials include profound neutropenia, oral mucositis, high dose cytosine arabinoside therapy, prophylaxis with trimethoprim/sulfamethoxazole or fluoroquinolones, and use of antacids or histamine type 2 blockers.53 The presence of one or more of these factors should prompt a careful assessment for the need of empirical glycopeptide therapy.
Catheter-related infections and skin/soft-tissue infections are most commonly caused by Gram-positive bacteria. Centres in which resistance to ß-lactams is prevalent should use glycopeptides empirically for these infections.2
In summary, currently available evidence from randomized controlled trials does not support the need for empirical glycopeptides initially or for persistent fever. Withholding specific treatment against Gram-positive infections pending growth of a resistant Gram-positive organism is safe. Despite more frequent treatment modifications, such practice is associated with fewer adverse events.
Cancer centres need to monitor pathogen prevalences to guide empirical treatment. Future trials assessing empirical glycopeptides are warranted if the spectrum of infections in cancer patients progresses further towards Gram-positive infections. Such trials should adhere to recommendations for their design, analysis and reporting.54,55
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Acknowledgements |
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Transparency declaration |
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References |
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