Linezolid for Nosocomial MRSA Pneumonia: A Better Option?
By Brian Blackburn, MD, Clinical Assistant Professor of Medicine, Division of Infectious Diseases and Geographic Medicine at Stanford University School of Medicine, is Associate Editor for Infectious Disease Alert.
Dr. Blackburn reports no financial relationships related to this field of study.
Synopsis: Linezolid was non-inferior to vancomycin in patients with nosocomially-acquired MRSA pneumonia. Although mortality was similar among linezolid- and vancomycin-treated patients, several outcomes (such as clinical cure and microbiological cure) favored linezolid.
Source: Wunderink RG, et. al. Linezolid in Methicillin-Resistant Staphylococcus aureus nosocomial pneumonia: A randomized, controlled study. Clin Infect Dis 2012;54:621-9.
The treatment of MRSA pneumonia is often regarded as problematic, with unacceptably high morbidity and mortality rates among affected patients. Two recent prospective, randomized, double-blind trials found that linezolid was non-inferior to vancomycin for the treatment of nosocomial pneumonia.1,2 In addition, post-hoc analysis of pooled data from these two trials found that survival (80% vs. 63%) and clinical cure (59% vs. 36%) significantly favored linezolid in the MRSA pneumonia subgroup.3 However, the post-hoc nature of this subgroup analysis could have introduced bias, and vancomycin dosing was not optimized in these trials, leading to calls for a prospective, randomized, double-blind trial to verify these findings.
The authors thus undertook such a study comparing linezolid to vancomycin. Adult patients with radiographically documented nosocomial pneumonia (including those with both HAP [hospital acquired pneumonia; 84% of the cohort] and HCAP [health care associated pneumonia; 16% of the cohort]) and a respiratory culture positive for MRSA were randomized to receive either linezolid 600 mg every 12 hours or vancomycin 15 mg/kg every 12 hours. Dosing of the latter was subsequently adjusted based on serum vancomycin levels. Patients were treated for 7-14 days, although those with bacteremia were treated for 21 days. All patients received an antibiotic with Gram-negative (but without anti-MRSA) activity, which was discontinued if no Gram-negative pathogens were identified.
Although 1,225 patients were randomized to receive the study drug, only 448 (37%) were included in the modified intent-to-treat (mITT) analysis, with most patients excluded because MRSA was not identified in cultures. Only 348 patients were included in the per-protocol analysis. This population had a median age of 61 years, and 64% had ventilator-associated pneumonia. Median vancomycin serum troughs (µg/mL) were 12 at day 3, 15 at day 6, and 16 at day 9. Eleven percent of patients in the vancomycin arm had bacteremia, compared to 5% in the linezolid arm; slightly more patients in the vancomycin arm received mechanical ventilation than in the linezolid arm.
In the per-protocol population, clinical cure at the end-of-study assessment occurred in 95 (58%) of the 165 linezolid-treated patients, and in 81 (47%) of the 174 vancomycin-treated patients (P = .042). Microbiological cure occurred in nearly the same proportion of patients in both arms at the end-of-study analysis. All-cause mortality at the end-of-study analysis did not differ significantly - 28% in the linezolid arm and 26% in the vancomycin arm.
Renal failure occurred twice as frequently in the vancomycin arm (7.3%) as in the linezolid (3.7%) arm. The frequency of cytopenias did not differ between groups.
Commentary
This prospective, randomized, double-blind trial seems to confirm the earlier post hoc subgroup analysis which suggested that linezolid may be superior to vancomycin for the treatment of nosocomial MRSA pneumonia. Although mortality did not differ between groups in this trial, linezolid was associated with higher clinical and microbiological cure rates than vancomycin. These results were consistent in most subgroups analyzed in the study, including among patients with mixed infections, among those who received mechanical ventilation, and among those who received systemic corticosteroids.
The apparent superiority of linezolid may have resulted from better intrinsic antimicrobial activity, better lung penetration, and more complete bacterial eradication. These findings are more robust than the previous post-hoc study, given the prospective, randomized, double-blind nature of this study, and that vancomycin dosing was optimized in this study based on serum levels. Linezolid also appeared safer than vancomycin, with less nephrotoxicity and no increase in hematologic toxicity, another compelling point in favor of linezolid (especially given that renal failure is a significant predictor of mortality in this setting).
Mortality was not lower among linezolid-treated patients, possibly in part because a lower-than-expected mortality was observed among vancomycin-treated patients. This might have been a result of the intensive dose optimization by serum drug level monitoring for vancomycin, but whether this is applicable to many real-world settings is unclear from this study.
Limitations of the study included the large number of patients excluded after randomization, which could have introduced bias. In addition, while the requirement of a positive culture for MRSA was a strength in terms of confirming the role of linezolid in patients with known MRSA pneumonia, it also introduces a limitation for real-world use, given that antibiotics are usually started empirically in patients with nosocomial pneumonia. It is common that no etiologic diagnosis is ever made in this setting, and this trial does not address the efficacy of linezolid in this situation. Another limitation was the slightly higher proportion of patients with bacteremia and mechanical ventilation in the vancomycin arm, which could have biased the results against vancomycin. Finally, even with linezolid, the clinical cure rates observed were relatively low, suggesting that we still do not have an optimal drug for this serious and difficult-to-treat condition.
Despite these limitations, this study provides compelling evidence to bolster the notion that linezolid may be superior to vancomycin for nosocomial MRSA pneumonia. If these findings result in enthusiastic demand for linezolid in this setting, careful stewardship is of paramount importance, given that widespread use of linezolid in this setting could prove very expensive, and might promote resistance to this drug. If linezolid does become the first-line anti-Gram positive agent for nosocomial pneumonia, perhaps limiting use to clinically and microbiologically well-documented cases of nosocomial MRSA pneumonia would be prudent, with empiric use limited to a short course if MRSA is not subsequently recovered from respiratory cultures.
References
- Rubinstein E, et. al. Linezolid Nosocomial Pneumonia Study Group. Linezolid (PNU-100766) versus vancomycin in the treatment of hospitalized patients with nosocomial pneumonia: a randomized, double-blind, multicenter study. Clin Infect Dis 2001; 32:402–12.
- Wunderink RG, et.al. Linezolid Nosocomial Pneumonia Study Group. Continuation of a randomized, double-blind, multicenter study of linezolid versus vancomycin in the treatment of patients with nosocomial pneumonia. Clin Ther 2003;25:980–92.
- Wunderink RG, et.al. Linezolid vs. vancomycin: analysis of two double-blind studies of patients with methicillin-resistant Staphylococcus aureus nosocomial pneumonia. Chest 2003; 124:1789–97.
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