Elsevier

Clinical Therapeutics

Volume 34, Issue 8, August 2012, Pages 1667-1673.e1
Clinical Therapeutics

Pharmacotherapy
Original research
Clinical Efficacy of Oral Linezolid Compared With Intravenous Vancomycin for the Treatment of Methicillin-Resistant Staphylococcus aureus–Complicated Skin and Soft Tissue Infections: A Retrospective, Propensity Score–Matched, Case-Control Analysis

https://doi.org/10.1016/j.clinthera.2012.06.018Get rights and content

Abstract

Background

Linezolid is 100% bioavailable in oral and intravenous formulations. In a recent prospective, randomized, open-label, comparator-controlled, multicenter, phase 4 clinical trial in adults with complicated skin and soft tissue infections (cSSTIs) caused by methicillin-resistant Staphylococcus aureus (MRSA), linezolid achieved clinical and microbiologic success comparable to appropriately dosed intravenous vancomycin. Although patients were randomly assigned to receive linezolid or vancomycin, the protocol allowed patients to start therapy using oral or intravenous linezolid on the basis of investigator discretion and patient ability to tolerate oral medication.

Objective

The objective of this study was to assess the efficacy and tolerability of linezolid when administered orally in adults with cSSTI caused by MRSA. In this retrospective analysis, we examined data collected from the aforementioned trial to compare outcomes in patients who received either oral linezolid or intravenous vancomycin therapy.

Methods

This study analyzed outcomes in patients who received treatment for 7 to 14 days with either oral linezolid (600 mg q12h; n = 95) or intravenous vancomycin (15 mg/kg q12h, adjusted for creatinine clearance and trough concentration; n = 210). By design, these groups were not randomized. Propensity score matching on baseline variables was used to balance these groups by identifying a comparable group of patients who received vancomycin therapy and comparing them with patients who received oral linezolid therapy. Clinical and microbiologic success rates at the end of treatment and the end of the study (EOS) were then directly compared between the groups using matched-pair logistic regression. The tolerability of the 2 treatments (within this matched group) was also described.

Results

Ninety-two patients with well-matched baseline characteristics were included in each treatment group. At EOS, the odds ratio for clinical success of oral linezolid therapy vs intravenous vancomycin therapy was 4.0 (95% CI, 1.3–12.0; P = 0.01), and the odds ratio for microbiologic success at EOS was 2.7 (95% CI, 1.2–5.7; P = 0.01). Overall rates of adverse events in each group were consistent with reported safety profiles for each drug.

Conclusion

A favorable clinical cure rate was achieved with oral linezolid therapy when compared with intravenous vancomycin therapy in propensity score–matched patients with cSSTI proved to be caused by MRSA. ClinicalTrials.gov Identifier: NCT00087490.

Introduction

Skin and soft tissue infection (SSTI) is a common cause of morbidity in both the community and hospitals, and treatment is hampered by the increased frequency of methicillin-resistant Staphylococcus aureus (MRSA) in these settings.1 Surveillance data from Europe, North America, and Latin America have confirmed S aureus as the predominant cause of SSTI in all 3 geographic regions, and MRSA alone was responsible for 36% of infections in North America from 1998 to 2004.2 In the case of complicated SSTI (cSSTI), which is more likely to require hospitalization, the prevalence of MRSA may be even higher.3

Vancomycin has been the first-line treatment of choice for suspected MRSA-related cSSTI. However, vancomycin is available only for intravenous administration for this indication, and its use is complicated by the need for serum trough concentration monitoring and the potential for ototoxicity and nephrotoxicity.4 The oxazolidinone linezolid is an alternative to vancomycin, providing effective MRSA coverage and providing excellent tissue penetration5 and equivalent bioavailability in both oral and intravenous formulations.6 One-on-one studies of patients with suspected or proved MRSA-related cSSTI have reported comparable or superior rates of clinical success in patients who received linezolid therapy compared with those who received vancomycin therapy.7, 8 Furthermore, compared with use of vancomycin, use of linezolid has been reported to significantly reduce length of hospital stay, duration of intravenous therapy, and treatment costs.8, 9, 10, 11

In a recent, prospective, randomized, open-label, comparator-controlled, multicenter, phase 4 clinical trial of treatment of cSSTI caused by culture-proved MRSA, linezolid in both oral and intravenous formulations achieved clinical and microbiologic success comparable to that with appropriately dosed intravenous vancomycin.12 Only patients with culture-proved MRSA continued in the study and were included in the efficacy analyses. Although patients were randomly assigned to receive linezolid or vancomycin, the protocol allowed patients to start therapy with oral or intravenous linezolid on the basis of investigator discretion and patient ability to tolerate oral medication. The objective of this retrospective subgroup analysis was to assess the outcomes in patients in that study who initiated and continued therapy with oral linezolid compared with those who received intravenous vancomycin therapy, using propensity score matching.13, 14

Section snippets

Study Design, Patients, and Treatment

Patients aged ≥18 years with culture-confirmed MRSA-related cSSTI were randomized to undergo treatment for 7 to 14 days with either oral or IV linezolid, 600 mg q12h (with the option to switch from intravenous to oral formulation at any time) or IV vancomycin, 15 mg/kg q12h (with dose adjustment as needed and at investigator discretion on the basis of vancomycin trough concentration and estimated creatinine clearance). The primary end point in the original study was the clinical success rate in

Results

Baseline characteristics of all patients in the oral linezolid and intravenous vancomycin groups are given in Table I. The logistic regression model for building the propensity scores initially included weight, baseline temperature, diagnosis of diabetic ulcer, diagnosis of wound infection, hospitalization status, hospitalization before day 1, geographic region, and mean number of signs and symptoms because these factors were found to differentiate patients receiving oral linezolid therapy from

Discussion

In this propensity-matched analysis, patients treated with oral linezolid or intravenous vancomycin had comparable responses for clinical outcome at EOT. Furthermore, compared with intravenous vancomycin, oral linezolid was associated with significantly better clinical and microbiologic outcomes at EOS. These findings support the consideration of oral linezolid as a reasonable option for initial therapy for cSSTI caused by MRSA in patients who are able to tolerate oral medication.

As with any

Conclusions

In this retrospective analysis, compared with intravenous vancomycin, oral linezolid had comparable efficacy at EOT and superior efficacy at EOS for treatment of cSSTI caused by MRSA. On the basis of these findings, linezolid may be an option for the initial therapy of cSSTI caused by MRSA in patients who are able to tolerate oral medication.

Conflicts of Interest

This study was funded by Pfizer Inc (the sponsor). The execution of the design, data collection and medical monitoring was conducted by the sponsor or its designated representatives. The analysis, interpretation of the data, preparation, review and approval of this manuscript was performed by all authors and supported by the sponsor. Dr. Itani has received institutional research support from Pfizer Inc, Merck & Co, Inc, and Trius Therapeutics, Inc. Dr. Biswas, Ms. Reisman, and Dr. Bhattacharyya

Acknowledgments

This study was funded by Pfizer Inc. The authors thank Drs. Dan Meyer and Jack Mardekian for their insightful suggestions on the statistical methods and Dr. H. Preston Holley for helpful comments on an earlier version of this manuscript. Drs. Itani and Baruch designed and executed the protocol for the original study (NCT00087490) and formulated the clinical hypotheses and analyses in this article. Dr. Bhattacharyya, Ms. Reisman and Dr. Biswas designed and implemented the protocol of the study

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