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Antimicrobial Agents and Chemotherapy, May 2006, p. 1910-1911, Vol. 50, No. 5
0066-4804/06/$08.00+0 doi:10.1128/AAC.50.5.1910-1911.2006
| LETTER TO THE EDITOR |
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LETTER |
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The study was designed to prove superiority of linezolid over vancomycin with respect to the primary end point of clinical cure, with a power of 0.90 and a significance level of 0.05 for a two-sided test. The primary outcome result was not statistically significant based on the trial design (intent-to-treat [ITT] population clinical cure for linezolid, 92.2%, and for vancomycin, 88.5%; 95% confidence interval, –0.11%, 7.47%).
A subgroup analysis based on the microbiological outcomes was performed, and the authors reached the conclusion that linezolid is "... superior to vancomycin in the treatment of CSSTIs due to MRSA" (2). This was based on the methicillin-resistant Staphylococcus aureus (MRSA) subgroup analysis, in which the direct comparison yielded a significantly higher proportion of microbiological outcomes in the linezolid arm than in the vancomycin arm. Baseline characteristics within each MRSA subgroup that could have biased the results in either arm were not provided. In addition, an interaction test to understand if there was a difference in the magnitude of the effect based on the type of microorganism was also not provided. This is not in accordance with the CONSORT guidelines (1) for clinical trial reporting. We performed this analysis with the published data and found no significant treatment by microorganism (MRSA versus non-MRSA organism) interaction for either the MRSA modified intent-to-treat (MITT) (P = 0.24) or MRSA microbiologically evaluable (ME) (P = 0.07) subgroups, indicating that there was not a differential treatment effect based on microorganism type.
Also, it was surprising that we could not find the "clinical response" analysis (the primary end point of the study) with respect to this same MRSA subgroup in the published paper. This is of paramount importance. For a microbiological cure to be meaningful, it has to be accompanied by a clinical cure. Due to its obvious importance, the clinical response outcome (cured, improved, failed, or indeterminate) should have been reported within the MRSA subgroup, and results (similar to those of Table 4 [2]) should be presented along with baseline characteristics and interaction tests, as suggested above for the "microbiological outcomes" analysis.
In addition, we are concerned with the safety conclusion: "Drug-related adverse events were reported in similar numbers in both the linezolid and the vancomycin arms of the trial" (2). However, this is not appropriate, since thrombocytopenia (P < 0.001), diarrhea (P = 0.0006), and nausea (P = 0.006) were highly statistically significantly more frequent in the linezolid than in the vancomycin arm.
In conclusion, this study failed to prove linezolid's superiority over vancomycin in the CSSTI population. The rate of "microbiological cure" (secondary outcome) in the MRSA subgroup was higher with linezolid, but the rate of "clinical cure" (primary outcome) was not presented. Moreover, the absence of significant interaction suggests that the treatment effect was not influenced by the type of microorganism. Another trial needs to be done to confirm the results from the MRSA subgroup analysis. Finally, the paper's conclusion should also state that the rates of thrombocytopenia, diarrhea, and nausea were statistically significantly higher with linezolid than with vancomycin.
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Andre C. Kalil*
Section of Infectious Diseases University of Nebraska Medical Center Omaha, NE 68198-5400,1
Susan Puumala
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| * Phone: (402) 559-8650, Fax: (402) 559-5581, E-mail: akalil{at}unmc.edu |
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We also created a number of multivariate (logistic regression) models to account for the effect of prognostic variables, including MRSA, on clinical and microbiologic success at the test-of-cure visit for the MITT and ME populations, where a pathogen was required for evaluating outcomes. Treatment regimen (linezolid or vancomycin) was a significant predictor for both outcomes even after adjusting for other explanatory variables, such as severity of illness and type of complicated soft tissue infection. MRSA at baseline was consistently an important predictor of clinical and microbiological outcome and is a significant predictor of both outcomes for the vancomycin-treated subjects. As seen in this study (6) and others (2), response rates for MRSA-infected patients for vancomycin are lower than that seen with MSSA. Patients with MRSA at baseline may have organisms displaying defects in accessory gene regulators that interfere with autolysis or other killing mechanisms (4). Also, some strains of MRSA may exhibit heteroresistance to vancomycin (3), and linezolid may have an effect on reducing toxin production (5).
With regard to safety, Table 6 (6) clearly shows the overall numbers of drug-related adverse events in both arms of the study. Nausea, diarrhea, and thrombocytopenia were more frequent in the linezolid group, and rash, anaphylaxis, and phlebitis were more frequent in the vancomycin group. We also elaborate on the careful monitoring of hematological parameters in the discussion.
Finally, we agree that it is important to confirm important findings in additional clinical trials, and we are currently conducting a large prospective multicenter trial with patients with complicated skin infections caused by MRSA.
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John Weigelt
Medical College of Wisconsin Milwaukee, Wisconsin,2
Kamal Itani
Dennis Stevens
Charles Knirsch
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