Presence of Genes Encoding Panton-Valentine Leukocidin Is Not the Primary Determinant of Outcome in Patients with Hospital-Acquired Pneumonia Due to Staphylococcus aureus

Abstract

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...

Characterization of Alpha-Toxin hla Gene Variants, Alpha-Toxin Expression Levels, and Levels of Antibody to Alpha-Toxin in Hemodialysis and Postsurgical Patients with Staphylococcus aureus Bacteremia

“…Only 3 of the 197 isolates encoding hla had RBC lysis activity with no detectable alpha-toxin detected by ELISA, whereas 32 of the 197 hla-positive isolates had detectable alpha-toxin by ELISA but not by the RBC lysis assay. These data suggest that previous reports using the RBC lysis assay may have underreported the prevalence of alpha-toxin in different S. aureus isolates (43). We observed that 89% of hemodialysis and 84% of postsurgical isolates produced alpha-toxin in vitro, suggesting that the potential for alpha-toxin expression is highly conserved.…”

“…Assessment of in vitro alpha-toxin production was done by quantitative analysis of rabbit red blood cell (RBC) lysis as previously described by our group (43) and others (44,45). Briefly, 10 ml of tryptic soy broth (TSB; Becton Dickinson, Sparks, MD) in a 50-ml Falcon tube was inoculated with a loopful of culture from a fresh plate of each strain and incubated at 37°C and 220 rpm for overnight culture.…”

Pneumonia Caused by Methicillin-Resistant Staphylococcus aureus: Does Vancomycin Heteroresistance Matter?

“…In the current study, there was a strong association between PVL positivity and increased mortality. The presence of PVL has been inconsistently associated with mortality (48,49). In fact, in the study by Haque et al, PVL negativity was associated with increased mortality on univariate analysis but was not an independent predictor of mortality (25).…”

Predictors of Clinical Success Among a National Veterans Affairs Cohort With Methicillin-Resistant Staphylococcus aureus Pneumonia

“…35 Furthermore, we were unable to molecularly classify the MRSA isolates; molecular differences in MRSA strains have been shown to affect clinical results. [14][15][16] Susceptibility data and trough data were not available, and therefore it is not known if subjects reached therapeutic levels of the treatment agent.…”

“…[9][10][11]13,14 There are multiple differences among MRSA strains on a molecular level, including staphylococcal cassette chromosome mec (SCCmec) type, presence of the toxin Panton-Valentine leukocidin, and minimum inhibitory concentration, which can affect clinical outcomes. [14][15][16] MRSA pneumonia is a complex disease associated with significant morbidity and mortality. Despite the large public health impact of MRSA pneumonia, there are limited published data examining clinical predictors of success or failure.…”