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MRSA VAP: Vancomycin or Linezolid?
Abstract & Commentary
By Andrew M. Luks, MD, Pulmonary and Critical Care Medicine, University of Washington, Seattle. Dr. Luks reports no financial relationship to this field of study. This article originally appeared in the February 2009 issue of Critical Care Alert. It was edited by David J. Pierson, MD, and peer reviewed by William Thompson, MD.
Synopsis: This open-label, multicenter trial showed that treatment of MRSA ventilator-associated pneumonia with linezolid was associated with non-statistically significant improvements in microbiologic cure, clinical cure, survival, duration of mechanical ventilation, and ICU length of stay when compared to therapy with vancomycin.
Source: Wunderink RG, et al. Early microbiological response to linezolid vs vancomycin in ventilator-associated pneumonia due to methicillin-resistant Staphylococcus aureus. Chest. 2008;134:1200-1207.
Methicillin-resistant staphylococcus aureus (MRSA) is a common cause of ventilator-associated pneumonia (VAP). Several studies have shown that linezolid is associated with higher clinical cure and survival rates when compared with vancomycin in the treatment of MRSA nosocomial pneumonia.1,2 Wunderink et al sought to build on these data and determine if treatment with linezolid was also associated with a faster microbiologic response than vancomycin for patients with MRSA VAP.
They conducted a prospective, randomized, open-label, multicenter study at 36 sites over a three-year period. Patients were eligible for inclusion if they were ≥ 18 years of age with suspected VAP based on the presence of purulent sputum, fever or hypothermia, hypotension, or leukocytosis, leukopenia, or bandemia. Patients had to have been in the hospital > 5 days, have been on mechanical ventilation for at least 48 hours, and be expected to need mechanical ventilation for at least 72 hours following enrollment. Patients were excluded if they had received antimicrobial agents with activity against the patient's MRSA isolate for ≥ 48 hours prior to enrollment. Bronchoalveolar lavage (BAL) was performed anywhere from 24-72 hours post-study enrollment, and patients were deemed to have MRSA VAP if the quantitative culture yielded > 104 cfu/mL of the organism.
Patients were randomized to receive linezolid 600 mg IV every 12 hours or vancomycin 1 g every 12 hours for 7-14 days. Seventy-two to 96 hours later, a repeat BAL was performed from the same lung subsegment as in the initial collection. After four days or following the second bronchoscopy, patients receiving linezolid could be switched to oral therapy (600 mg every 12 hours). Patients were withdrawn from the study due to non-compliance or protocol violations, if it was deemed medically necessary, or if the baseline quantitative cultures yielded < 104 cfu/mL for MRSA. Using intention-to-treat analysis, the authors examined differences in microbiologic cure rates between linezolid- and vancomycin-treated patients with microbiologic cure defined as a repeat BAL containing < 102 cfu/mL for MRSA. Secondary outcomes included clinical outcome, mortality, the duration of mechanical ventilation, and hospital and ICU length of stay.
Wunderink et al identified only 50 patients (30 linezolid and 20 vancomycin) who had a MRSA concentration of 104 cfu/mL on the baseline BAL sample. Of these patients, only 23 linezolid patients and 19 vancomycin patients underwent follow-up BAL at 72-96 hours. Patients treated with linezolid had a non-statistically significantly higher microbiologic cure rate than patients treated with vancomycin (56.5% vs 47.4%). None of the 10 linezolid patients with microbiologic treatment failure died, as compared with five of 10 patients with microbiologic failure in the vancomycin group. Regarding the secondary outcomes, patients treated with linezolid had higher clinical response rate (66.7% vs 52.9%), greater survival at the end of the study (86.7% vs 70%), fewer days on mechanical ventilation (10.4 days vs 14.3 days), shorter hospitalization (18.8 days vs 20.1 days), and shorter ICU length of stay (12.2 days vs 16.2 days), but none of these differences reached statistical significance. The incidence of treatment-related adverse events was similar between the two groups.
Vancomycin has long been the standard treatment for MRSA VAP. While it is generally effective in this regard, the entire course of therapy must be administered intravenously, which usually mandates central or PICC line placement. Linezolid offers a potential advantage in this respect, as an oral form of the medication is available and patients can be switched to this route after several days on the intravenous form. Clinical use of the medication is not as widespread as is vancomycin, however, and one plausible reason might be the lack of randomized, prospective trials establishing its efficacy relative to vancomycin for VAP. The earlier studies of these two agents all examined patients with nosocomial pneumonia, not just patients with VAP, and several were retrospective in nature.
By focusing on patients with VAP and collecting data in a prospective manner, this study attempts to address these issues and puts forth some intriguing results. However, the study has some methodological issues, the most important of which is the very low number of patients who completed the study protocol. Given the prevalence of MRSA and of VAP, it is unclear how a multicenter study conducted at 36 sites over a three-year period could only enroll 50 patients. As a result, the study was clearly underpowered, and none of the results reached statistical significance. The study was also open-label, although blinding a study in which the dose and frequency of administration of one of the medications must be adjusted based on drug-levels is admittedly difficult. It is also not clear to me that Wunderink et al's definition of microbiologic cure (repeat BAL with < 102 cfu/mL at 72-96 hours) is a valid endpoint that has any correlation with meaningful clinical outcomes.
Finally, it is noteworthy that the lead author, who is also the lead author on several other studies comparing linezolid with vancomycin, is a paid consultant for Pfizer, Inc., the maker of linezolid, while all but two of the other authors are either employees of or consultants to the company. In fact, there are surprisingly few studies in the literature comparing these two agents in adults that are not authored by the lead author in this study, and one of the few studies in adults for which he is not an author has similar issues with relationships between the paper's authors and linezolid's manufacturer.3
The question of which medication is the better option for patients with MRSA VAP is an important one. The existing literature suggests that linezolid may be as effective as, if not more effective than, vancomycin, but before we make wholesale changes in our practice and adopt linezolid as the treatment of choice for this problem, we need larger, prospective trials conducted with less influence from the company with a stake in the outcome of the study.
1. Wunderink RG, et al. Linezolid versus vancomycin: Analysis of two double-blinded studies of patients with methicillin-resistant Staphylococcal aureus nosocomial pneumonia. Chest 2003;124:1789-1797.
2. Rubinstein E, et al. Linezolid (PNU-100766) versus vancomycin in the treatment of hospitalized patients with nosocomial pneumonia: A randomized, double-blind, multi-center study. Clin Infect Dis 2001;32:402-412.
3. Kohno S, et al. Linezolid versus vancomycin for the treatment of infections caused by methicillin-resistant Staphylococcal aureus in Japan. J Antimicrob Chemother 2007;60:1361-1369.]