The results from two methodologically identical double-blind studies indicate that telavancin is noninferior to vancomycin based on clinical response in the treatment of hospital-acquired pneumonia due to Gram-positive pathogens.

The role of Panton-Valentine leukocidin (PVL) in determining the severity and outcome of complicated skin and skin structure infections (cSSSI) caused by methicillin (meticillin)-resistant Staphylococcus aureus (MRSA) is controversial. We evaluated potential associations between clinical outcome and PVL status by using MRSA isolates from patients enrolled in two large, multinational phase three clinical trials assessing telavancin for the treatment of cSSSI (the ATLAS program). MRSA isolates from microbiologically evaluable patients were genotyped by pulsed-field gel electrophoresis (PFGE) and PCR for pvl and 31 other putative virulence determinants. A single baseline pathogen of MRSA was isolated from 522 microbiologically evaluable patients (25.1%) among 2,079 randomized patients. Of these MRSA isolates, 83.2% (432/519) exhibited the USA300 PFGE genotype and 89.1% (465/522) were pvl positive. Patients with pvl-positive MRSA were more likely than those with pvl-negative MRSA to be young, to be North American, and to present with major abscesses (P < 0.001 for each). Patients were significantly more likely to be cured if they were infected with pvl-positive MRSA than if they were infected with pvl-negative MRSA (91.6% versus 80.7%; P ‫؍‬ 0.015). This observation remained statistically significant after adjustment for presence of abscess, fever, or leukocytosis; infection size; diabetes; patient age; and study medication received. The fnbA, cna, sdrC, map-eap, sed, seg, sei, sej, SCCmec type IV, and agr group II genes were also associated with clinical response (P < 0.05). This contemporary, international study demonstrates that pvl was not the primary determinant of outcome in patients with MRSA cSSSI.

Telavancin is a rapidly bactericidal antibiotic with multiple mechanisms of action against gram-positive bacteria. Preclinical and early clinical data suggested possible effects on cardiac repolarization requiring the conduct of a definitive evaluation of QT effects in healthy subjects. A total of 160 subjects were randomized into four groups to receive placebo (telavancin vehicle), telavancin at a dose of 7.5 mg/kg or 15 mg/kg, or moxifloxacin 400 mg (positive control). All medications were administered once daily for 3 days as 60-minute IV infusions. Sixteen ECGs were obtained over 24 hours following an infusion of D5W (baseline) and following Day 3 infusions of each medication. ECGs were analyzed digitally in a blinded fashion by a validated core ECG laboratory. The primary endpoint was QT data corrected for heart rate by the Fridericia formula (QTcF). Placebo-corrected mean changes in QTcF values for 7.5 mg/kg telavancin, 15 mg/kg telavancin, and moxifloxacin were 4.1 msec, 4.5 msec, and 9.2 msec, respectively. The mean change from baseline in QTcF for moxifloxacin, which served as the assay-sensitive positive control in the study, helped to establish that telavancin had a minimal effect on QT prolongation. No subject had a QTcF > or = 450 msec, and none experienced clinically significant ECG abnormalities. The telavancin treatment groups were not significantly different from each other. There was no correlation of the magnitude of change in QTc and plasma concentrations of telavancin. Telavancin has a < 5-msec mean effect on cardiac repolarization, with a flat-dose response over a two-fold exposure range.

The impact of Panton-Valentine leukocidin (PVL) on the outcome intested, (ii) presence of specific bacterial clone, (iii) levels of alphahemolysin, or (iv) delta-hemolysin production were identified. This study suggests that neither pvl presence nor in vitro level of alpha-hemolysin production is the primary determinant of outcome among patients with HAP caused by S. aureus. The Panton-Valentine leukocidin (PVL) is a bacteriophageassociated, bicomponent cytotoxin produced by some strains of Staphylococcus aureus. PVL induces host cell necrosis and apoptosis by producing pores in the cell membranes of neutrophils and other infected cells. The presence of PVL and the genetic elements coding for its production (two contiguous, cotranscribed genes, lukS and lukF, here referred to as pvl) has been strongly associated with a severe necrotizing pneumonia (13, 15). Although controversy persists, there is evidence that PVL is associated with severe disease in community-acquired pneumonia (CAP) due to S. aureus both in clinical reports (13, 15) and in some (10, 22), but not all (3,20,30,49), in vivo model systems. However, the studies on the association between PVL and clinical outcomes in hospitalacquired pneumonia (HAP), a distinct clinical entity from CAP, are limited.Hospital-acquired pneumonia is the leading cause of morbidity and mortality from nosocomial infections (9), and S. aureus is the leading cause of HAP in U.S. hospitals (12,28,34). In the current study, we tested the hypothesis that pvl presence in S. aureus isolates causing HAP was associated with a worse clinical outcome than the outcome of HAP caused by pvl-negative S. aureus counterparts. To test this hypothesis, we made use of a large international cohort of S. aureus isolates from patients with HAP. These isolates were collected in two identically designed phase III clinical trials for S. aureus HAP. MATERIALS AND METHODSPatients and study settings. The ATTAIN (Assessment of Telavancin for Hospital-Acquired Pneumonia) clinical trials were two identical phase III, randomized, double-blinded, parallel-group, multinational trials (ClinicalTrials.gov identifiers NCT00107952 and NCT00124020) studying the efficacy and safety of intravenous telavancin versus vancomycin for the treatment of hospital-acquired pneumonia (HAP) with a focus on patients with infections due to methicillin-resistant S. aureus (MRSA) (35). Following randomization, patients were treated for 7 to 21 days with the study drug. From January 2005 to June 2007, a total of 1,503 patients were enrolled from 235 clinical centers in 38 countries. Patients were included in the current study if all of the following criteria were met: (i) inclusion in the modified all treated (MAT) population (n ϭ 1,089), (ii) had monomicrobial infection with S. aureus at baseline, and (iii) had a clinical response of either "cure" or "failure" for the test-of-cure analysis. All patients or their legal guardian provided written informed consent. This study was approved by Duke University Medical Center Institutio...

BackgroundExisting data are not consistently supportive of improved clinical outcome when vancomycin dosing regimens aimed at achieving target trough levels are used. A retrospective, post hoc, subgroup analysis of prospectively collected data from the Phase 3 ATTAIN trials of telavancin versus vancomycin for treatment of nosocomial pneumonia was conducted to further investigate the relationship between vancomycin serum trough levels and patient outcome.MethodsStudy patients were enrolled in 274 study sites across 38 countries. A total of 98 patients had Staphylococcus aureus nosocomial pneumonia and vancomycin serum trough levels available. These patients were grouped according to their median vancomycin trough level; < 10 μg/mL, 10 μg/mL to < 15 μg/mL, and ≥ 15 μg/mL.ResultsClinical cure rates in the < 10 μg/mL, 10 μg/mL to < 15 μg/mL, and ≥ 15 μg/mL vancomycin trough level groups were 70% (21/30), 55% (18/33), and 49% (17/35), respectively (p = 0.09), and the frequencies of patient death were 10% (3/30), 15% (5/33), and 20% (7/35), respectively (p = 0.31). Renal adverse events were more frequent in the ≥ 15 μg/mL (17% [6/35]) than the < 10 μg/mL (0%) and 10 μg/mL to < 15 μg/mL (3% [1/33]) trough level groups (p < 0.01). When patients with acute renal failure or vancomycin exposure within 7 days prior to study medication were excluded, clinical cure rates in the < 10 μg/mL, 10 μg/mL to < 15 μg/mL, and ≥ 15 μg/mL vancomycin trough level groups (71% [12/17], 60% [9/15], and 27% [3/11], respectively; p = 0.04) and the number of deaths (12% [2/17], 20% [3/15], and 45% [5/11], respectively; p = 0.07) demonstrated a trend towards worse outcomes in the higher vancomycin trough level groups.ConclusionsThe findings of our study suggest that higher vancomycin trough levels do not result in improved clinical response but likely increase the incidence of nephrotoxicity.Trial registrationNCT00107952 and NCT00124020