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Linezolid versus vancomycin for Staphylococcus aureus bacteraemia: pooled analysis of randomized studies |
Shorr A F, Kunkel M J, Kollef M |
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CRD summary The review assessed the use of linezolid and vancomycin for adults whose bloodstreams were infected with Staphylococcus aureus. The authors concluded that linezolid is not inferior to vancomycin. The review was not conducted or reported sufficiently well to be confident that all relevant studies were included or that the results are reliable. The authors' conclusion might not be impartial.
Authors' objectives To compare linezolid and vancomycin for Staphylococcus aureus (S. aureus) bacteraemia in terms of clinical outcomes and safety.
Searching PubMed was searched; the search terms were reported but not the dates. Abstracts from the Infectious Diseases Society of America, Interscience Conference on Antimicrobial Agents and Chemotherapy, and the European Congress of Clinical Microbiology and Infectious Diseases were handsearched for the previous 5 years.
Study selection Study designs of evaluations included in the reviewRandomised controlled trials (RCTs) were eligible for inclusion.
Specific interventions included in the reviewStudies that compared linezolid with vancomycin were eligible for inclusion. The patients in the included studies received 600 mg linezolid or 1 g vancomycin every 12 hours. Linezolid was given intravenously for at least 7 days, with the option of oral administration thereafter. Adjustment of the vancomycin dose was permitted. Concurrent aztreonam was used in studies of patients with pneumonia. Azireonam or gentamicin was allowed in the other studies. Vancomycin could be changed to a penicillinase-resistant penicillin in one study if the S. aureus causing skin and soft tissue infection was found to be susceptible to methicillin. The duration of treatment was predefined in the included studies: it ranged from a minimum of 7 days for urinary tract infection to a maximum of 28 days for bacteraemia of unknown origin.
Participants included in the reviewStudies in patients with a positive blood culture for S. aureus were eligible for inclusion. The included studies were conducted in adults with either nosocomial pneumonia (signs and symptoms 48 hours after admission to hospital), complicated skin and soft tissue infections, or methicillin-resistant S. aureus (MRSA) infections susceptible to the study drugs. S. aureus infection was confirmed by a central laboratory. Secondary bacteraemia was defined as bacteraemia in a patient with a documented primary infection elsewhere. Almost 90% of the patients in the included studies had secondary bacteraemia. The primary infection was pneumonia in 42% of the patients, skin and soft tissue infection in 30%, bacteraemia in 11%, urinary tract infection in less than 2% and unspecified for 16%. The mean ages of patients treated with linezolid and vancomycin were 63.5 years (standard deviation, SD=17.1) and 59.3 years (SD=18.9), respectively. Overall, 64% of the included patients were men and 51% had MRSA infection.
Outcomes assessed in the reviewThe primary outcome was clinical cure of the primary infection at the end of treatment (follow-up ranged from a minimum of 7 days to a maximum of 35 days). Clinical cure was defined in the included studies as the resolution of baseline signs and symptoms with improvement, or the lack of progression of radiographic, laboratory or other objective findings. Clinical failure was defined as the persistence or progression of signs and symptoms. The patients had to receive at least 5 days and 10 doses of study drug to be assessed for clinical cure, and at least 2 days and 4 doses to be assessed for clinical failure; they would otherwise be designated as having indeterminate clinical outcome. Microbiological success and overall survival were secondary outcomes. Microbiological success was defined as documented eradication of S. aureus bacteraemia or, in the absence of repeat blood culture, presumed eradication based on clinical cure of the primary infection. Microbiological failure was defined as documented persistence of S. aureus bacteraemia or, in the absence of repeat blood culture, presumed persistence based on clinical failure. Overall survival was determined at the final follow-up, which ranged from 15 to 98 days.
Safety was assessed on the basis of standard reporting of adverse clinical events and platelet counts determined by a central laboratory. Adverse events were designated as serious or not serious, as determined by the trial investigators. Thrombocytopenia was defined as a decrease from baseline of 1.50E11 platelets per L or more. The baseline count and at least one follow-up count were required for inclusion in the analysis, and patients had to receive at least one day of treatment.
How were decisions on the relevance of primary studies made?Study selection possibly involved two authors, although this was unclear due to poor reporting.
Assessment of study quality The authors reported using the quality grading system developed by Jadad et al. However, they appeared to have used an intermediate version as the total possible score was 8 and not 5, which is the maximum attainable score using the final version of the Jadad instrument. The criteria assessed probably included the description of randomisation, double-blinding and withdrawals (the three items in the final instrument), and possibly also the definition of objectives, outcomes, and the inclusion and exclusion criteria in each study. Two reviewers graded the studies; no further details of the procedure were reported.
Data extraction The authors did not state how the data were extracted for the review, or how many reviewers performed the data extraction.
Data extracted included the number of events for each outcome in each treatment group, and the number of patients evaluated, in each study. Patient characteristics extracted included race, mean APACHE II (Acute Physiology and Chronic Health Evaluation) score and SD, numbers on mechanical ventilation and with comorbidities, site of primary infection, and numbers with MRSA and methicillin-susceptible S. aureus (MSSA) infection.
Methods of synthesis How were the studies combined?For the outcome clinical cure, the studies were combined in a formal meta-analysis using a random-effects model to calculate a weighted pooled odds ratio (OR) and 95% confidence interval (CI).
Event rates were also summed across studies for each of the two treatments to calculate apparently unweighted ORs and 95% CIs for clinical cure, microbiological success and survival for linezolid versus vancomycin. The rates of clinical cure were recalculated by 'intention-to-treat', including patients with missing or indeterminate results as treatment failures.
How were differences between studies investigated?Statistical heterogeneity in the meta-analysis was assessed using the chi-squared statistic (p<0.05 indicated statistical significance). The authors also reported using Galbraith plots but these were not shown or mentioned thereafter.
Clinical cure and survival event rates were reported for the subset of patients with MRSA bacteraemia.
Multivariate logistic regression analysis was conducted using a random-effects model to identify predictors of clinical cure and survival. All 144 patients were included; patients with missing clinical cure data were coded as failures. The explanatory variables included in the model were treatment (linezolid, vancomycin), pathogen (MRSA, MSSA), gender, race (white, other), age (under 65 years, 65 years and older), nosocomial pneumonia (present, absent), skin and soft tissue infections, diabetes, congestive heart failure, renal insufficiency (creatinine 1.5 mg/L or less, >1.5 mg/L), active malignancy, and any co-morbidity. Missing data were not imputed. The APACHE II score was analysed separately using simple logistic regression.
Demographic data were combined across studies for each of the two treatments, then compared using Student's t-test and the chi-squared test.
Results of the review Five studies were included. Of the total trial population of 3,228 patients, 144 treated with linezolid or vancomycin for S. aureus bacteraemia were included in the review.
The median quality score was 7 out of a possible 8 points (range: 6 to 8).
Clinical cure.
The meta-analysis showed no statistically significant difference in clinical cure between linezolid and vancomycin (OR 1.16, 95% CI: 0.50, 2.65), based on 99 patients in 5 trials. There was no statistically significant heterogeneity between the studies.
The OR calculated from the unweighted sum of event rates gave similar results (OR 1.12, 95% CI: 0.15, 2.47). The inclusion of patients with missing or indeterminate results as treatment failures did not change the findings. The number of patients with MRSA bacteraemia and known clinical outcome who achieved clinical cure was similar in each group.
The multivariate regression analysis found congestive heart failure to be a significant predictor of clinical cure.
Microbiological success.
The OR calculated from the unweighted sum of event rates showed no significant difference between the two treatments (OR 0.83, 95% CI: 0.37, 1.87), based on 115 patients.
Survival.
The OR calculated from the unweighted sum of event rates showed no difference between the two treatments (OR 1.00, 95% CI: 0.47, 2.12). The result was similar in the subset of 73 patients with MRSA bacteraemia.
The multivariate regression analysis found any co-morbidity, absence of malignancy and absence of congestive heart failure to be significant predictors of survival. Using simple regression, the APACHE II score was a significant predictor of survival.
Safety.
There was no statistically significant difference between the treatment groups in the incidence of adverse events, serious adverse events, discontinuation of treatment, or in the mean change in platelet count from baseline. Significantly more patients in the linezolid group had new onset thrombocytopenia (13% versus 0%, p=0.02).
Authors' conclusions Linezolid is associated with clinical, microbiological and survival outcomes that are not inferior to vancomycin in patients with secondary S. aureus bacteraemia.
CRD commentary The review question was not entirely clear with regard to primary and secondary bacteraemia; the focus appeared to be on the latter. The search for relevant studies was limited in the sources searched and the terms used. Poor reporting failed to clarify whether steps were taken to minimise bias in the study selection process. All of the included trials were published (two as meetings abstracts) in English and were supported by grants from Pfizer (the manufacturer of linezolid). Although study quality was assessed systematically it was not adequately reported, which precluded independent judgment of the potential for bias in the individual studies. The process of data extraction was not described although the authors acknowledged that they had access to all data.
The characteristics of the individual studies were not reported in sufficient detail to allow a qualitative comparison across studies. The reporting of the analysis methods and results was not sufficiently clear to allow independent judgement of the validity of the methods, or to provide reassurance of the absence of outcome reporting bias in the review. There was no pre-definition of inferiority reported for either the review or the individual included studies. The authors' conclusion went beyond the evidence presented, in favour of linezolid. All three authors declared a conflict of interest related to Pfizer.
Implications of the review for practice and research Practice: The authors stated that blood cell counts should be monitored during linezolid treatment. Vigilance for adverse effects should be increased during prolonged treatment and in the presence of risk factors for myelosuppression.
Research: The authors stated that more studies are needed to confirm their findings.
Bibliographic details Shorr A F, Kunkel M J, Kollef M. Linezolid versus vancomycin for Staphylococcus aureus bacteraemia: pooled analysis of randomized studies. Journal of Antimicrobial Chemotherapy 2005; 56(5): 923-929 Indexing Status Subject indexing assigned by NLM MeSH Acetamides /adverse effects /pharmacology /therapeutic use; Aged; Anti-Bacterial Agents /adverse effects /pharmacology /therapeutic use; Bacteremia /drug therapy /microbiology; Female; Humans; Linezolid; Male; Middle Aged; Multivariate Analysis; Odds Ratio; Oxazolidinones /adverse effects /pharmacology /therapeutic use; Randomized Controlled Trials as Topic; Retrospective Studies; Staphylococcal Infections /drug therapy /microbiology; Staphylococcus aureus /drug effects; Survival Analysis; Treatment Outcome; Vancomycin /adverse effects /pharmacology /therapeutic use AccessionNumber 12005002209 Date bibliographic record published 31/05/2007 Date abstract record published 31/05/2007 Record Status This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn. |
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