Linezolid in methicillin-resistant Staphylococcus aureus nosocomial pneumonia: a randomized, controlled study.

BACKGROUND: Post hoc analyses of clinical trial data suggested that linezolid may be more effective than vancomycin for treatment of methicillin-resistant Staphylococcus aureus (MRSA) nosocomial pneumonia. This study prospectively assessed efficacy and safety of linezolid, compared with a dose-optimized vancomycin regimen, for treatment of MRSA nosocomial pneumonia. METHODS: This was a prospective, double-blind, controlled, multicenter trial involving hospitalized adult patients with hospital-acquired or healthcare-associated MRSA pneumonia. Patients were randomized to receive intravenous linezolid (600 mg every 12 hours) or vancomycin (15 mg/kg every 12 hours) for 7-14 days. Vancomycin dose was adjusted on the basis of trough levels. The primary end point was clinical outcome at end of study (EOS) in evaluable per-protocol (PP) patients. Prespecified secondary end points included response in the modified intent-to-treat (mITT) population at end of treatment (EOT) and EOS and microbiologic response in the PP and mITT populations at EOT and EOS. Survival and safety were also evaluated. RESULTS: Of 1184 patients treated, 448 (linezolid, n = 224; vancomycin, n = 224) were included in the mITT and 348 (linezolid, n = 172; vancomycin, n = 176) in the PP population. In the PP population, 95 (57.6%) of 165 linezolid-treated patients and 81 (46.6%) of 174 vancomycin-treated patients achieved clinical success at EOS (95% confidence interval for difference, 0.5%-21.6%; P = .042). All-cause 60-day mortality was similar (linezolid, 15.7%; vancomycin, 17.0%), as was incidence of adverse events. Nephrotoxicity occurred more frequently with vancomycin (18.2%; linezolid, 8.4%). CONCLUSIONS: For the treatment of MRSA nosocomial pneumonia, clinical response at EOS in the PP population was significantly higher with linezolid than with vancomycin, although 60-day mortality was similar.

Efficacy and safety of linezolid versus vancomycin for the treatment of complicated skin and soft-tissue infections proven to be caused by methicillin-resistant Staphylococcus aureus.

BACKGROUND: This open-label study compared oral or intravenous linezolid with intravenous vancomycin for treatment of complicated skin and soft-tissue infections (cSSTIs) caused by methicillin-resistant Staphylococcus aureus (MRSA). METHODS: Patients with proven MRSA cSSTI were randomized to receive linezolid or vancomycin. Clinical and microbiologic outcomes, duration of antimicrobial therapy, length of hospital stay, and safety were assessed. RESULTS: In the per-protocol population, the rate of clinical success was similar in linezolid- and vancomycin-treated patients (P = .249). The rate of success was significantly higher in linezolid-treated patients in the modified intent-to-treat population (P = .048). The microbiologic success rate was higher for linezolid at the end of treatment (P < .001) and was similar at the end of the study (P = .127). Patients receiving linezolid had a significantly shorter length of stay and duration of intravenous therapy than patients receiving vancomycin. Both agents were well tolerated. Adverse events were similar to each drug's established safety profile. CONCLUSIONS: Linezolid is an effective alternative to vancomycin for the treatment of cSSTI caused by MRSA.

Complicated skin and skin-structure infections and catheter-related bloodstream infections: noninferiority of linezolid in a phase 3 study.

BACKGROUND: Catheter-related bloodstream infection (CRBSI) causes substantial morbidity and mortality, but few randomized, controlled studies have been conducted to guide therapeutic interventions. METHODS: To determine whether linezolid would be noninferior to vancomycin in patients with CRBSI, we conducted an open-label, multicenter, comparative study. Patients with suspected CRBSI were randomized to receive linezolid or vancomycin (control group). The primary end point was microbiologic outcome at test of cure 1-2 weeks after treatment, as assessed by step-down procedure. The first analysis population was complicated skin and skin structure infection (cSSSI) in patients with suspected CRBSI; patients with CRBSI were analyzed if noninferiority criteria (lower bound of the 95% confidence interval [CI] not outside -15%) were met. RESULTS: Noninferiority criteria were met for cSSSI (microbiologic success rate for linezolid recipients, 89.6% [146 for 163 patients]; for the control group, 89.9% [134 of 149]; 95% CI, -7.1 to 6.4) and CRBSI (for linezolid recipients, 86.3% [82 of 95]; for the control group, 90.5% [67 of 74]; 95% CI, -13.8 to 5.4). The frequency and severity of adverse events were similar between groups. Mortality rates were 10.4% for linezolid recipients (28 of 269 patients) and 10.1% for control subjects (26 of 257) in the modified intent-to-treat population (i.e., all patients with gram-positive baseline culture) through test of cure, and they were 21.5% for linezolid recipients (78 of 363) and 16.0% for the control group (58 of 363; 95% CI, -0.2 to 11.2) for all treated patients through poststudy treatment day 84. CONCLUSIONS: Linezolid demonstrated microbiologic success rates noninferior to those for vancomycin in patients with cSSSIs and CRBSIs caused by gram-positive organisms. Patients with catheter-related infections must be carefully investigated for the heterogeneous underlying causes of high morbidity and mortality, particularly for infections with gram-negative organisms.

Linezolid versus vancomycin for Staphylococcus aureus bacteraemia: pooled analysis of randomized studies.

OBJECTIVES: To compare outcomes in patients with Staphylococcus aureus bacteraemia treated with linezolid with those of vancomycin-treated patients. METHODS: We pooled and analysed five randomized studies comparing linezolid with vancomycin, focusing on the 144 adults with S. aureus bacteraemia, which was secondary in >70% of patients. Efficacy variables were clinical cure of primary infection, microbiological success (eradication of S. aureus from blood or presumed eradication based on clinical cure of primary infection), survival, and outcome predictors identified by multivariate logistic regression. RESULTS: Of 99 clinically evaluable patients, primary infection was cured in 28 (55%) of 51 linezolid recipients and 25 (52%) of 48 vancomycin recipients [odds ratio (OR) for cure with linezolid versus vancomycin, 1.12; 95% confidence interval (CI), 0.51-2.47]. There were no between-group differences in the meta-analysis (OR, 1.16; 95% CI, 0.5-2.65). Of 53 evaluable patients with methicillin-resistant S. aureus (MRSA) bacteraemia, clinical cure occurred in 14 (56%) of 25 linezolid recipients and 13 (46%) of 28 vancomycin recipients (OR, 1.47; 95% CI, 0.50-4.34). Microbiological success occurred in 41 (69%) of 59 linezolid recipients and 41 (73%) of 56 vancomycin recipients (OR, 0.83; 95% CI, 0.37-1.87). Fifty-five (74%) of 74 linezolid recipients survived versus 52 (74%) of 70 vancomycin recipients (OR, 1.00; 95% CI, 0.47-2.12). In the multivariate analysis, treatment group was not a significant predictor of clinical cure or survival. CONCLUSIONS: Linezolid was associated with outcomes that were not inferior to those of vancomycin in patients with secondary S. aureus bacteraemia.