Genetic characterization of Vga ABC proteins conferring reduced susceptibility to pleuromutilins in Staphylococcus aureus.

Retapamulin MICs of > or =2 microg/ml were noted for 6 of 5,676 S. aureus recent clinical isolates evaluated. The ABC proteins VgaAv and VgaA were found to be responsible for the reduced susceptibility to pleuromutilins exhibited by these six isolates.

Molecular epidemiology of methicillin-resistant and methicillin-susceptible Staphylococcus aureus isolates from global clinical trials.

Determining the genetic characteristics of Staphylococcus aureus is important for better understanding of the global and dynamic epidemiology of this organism as we witness the emergence and spread of virulent and antibiotic-resistant clones. We genotyped 292 S. aureus isolates (105 methicillin resistant and 187 methicillin susceptible) using a combination of pulsed-field gel electrophoresis, multilocus sequence typing, and SCCmec typing. In addition, S. aureus isolates were tested for the presence of the Panton-Valentine leukocidin (PVL) genes. Isolates were recovered from patients with uncomplicated skin infections in 10 different countries during five phase III global clinical trials of retapamulin, a new topical antibiotic agent. The most common methicillin-resistant clone had multilocus sequence type 8, pulsed-field type USA300, and SCCmec type IV and possessed the PVL genes. This clone was isolated exclusively in the United States. The most common PVL-positive, methicillin-susceptible clone had multilocus sequence type 121 and pulsed-field type USA1200. This clone was found primarily in South Africa and the Russian Federation. Other clones were found at lower frequencies and were limited in their geographic distribution. Overall, considerable genetic diversity was observed within multilocus sequence type clonal complexes and pulsed-field types.

A geographic variant of the Staphylococcus aureus Panton-Valentine leukocidin toxin and the origin of community-associated methicillin-resistant S. aureus USA300.

BACKGROUND: The majority of recent community-associated methicillin-resistant Staphylococcus aureus (MRSA) infections in the United States have been caused by a single clone, USA300. USA300 secretes Panton-Valentine leukocidin (PVL) toxin, which is associated with highly virulent infections. METHODS: We sequenced the PVL genes of 174 S. aureus isolates from a global clinical sample. We combined phylogenetic reconstruction and protein modeling methods to analyze genetic variation in PVL. RESULTS: Nucleotide variation was detected at 12 of 1726 sites. Two PVL sequence variants, the R variant and the H variant, were identified on the basis of a substitution at nt 527. Of sequences obtained in the United States, 96.7% harbor the R variant, whereas 95.6% of sequences obtained outside the United States harbor the H variant; 91.3% of MRSA isolates harbor the R variant, and 91.3% of methicillin-susceptible strains harbor the H variant. A molecular model of PVL shows 3 mechanisms by which the amino acid substitution may affect PVL function. CONCLUSIONS: All sampled PVL genes appear to share a recent common ancestor and spread via a combination of clonal expansion and horizontal transfer. US isolates harbor a variant of PVL that is strongly associated with MRSA infections. Protein modeling reveals that this variant may have functional significance. We propose a hypothesis for the origin of USA300.

Topical retapamulin ointment, 1%, versus sodium fusidate ointment, 2%, for impetigo: a randomized, observer-blinded, noninferiority study.

BACKGROUND: Retapamulin is a novel pleuromutilin antibacterial developed for topical use. OBJECTIVE: To compare the efficacy and safety of retapamulin ointment, 1% (twice daily for 5 days), with sodium fusidate ointment, 2% (3 times daily for 7 days), in impetigo. METHODS: A randomized (2:1 retapamulin to sodium fusidate), observer-blinded, noninferiority, phase III study in 519 adult and pediatric (aged > or = 9 months) subjects. RESULTS: Retapamulin and sodium fusidate had comparable clinical efficacies (per-protocol population: 99.1 and 94.0%, respectively; difference: 5.1%, 95% confidence interval: 1.1-9.0%, p = 0.003; intent-to-treat population: 94.8 and 90.1%, respectively; difference: 4.7%, 95% confidence interval: -0.4 to 9.7%, p = 0.062). Bacteriological efficacies were similar. Success rates in the small numbers of sodium-fusidate-, methicillin- and mupirocin-resistant Staphylococcus aureus were good for retapamulin (9/9, 8/8 and 6/6, respectively). Both drugs were well tolerated. CONCLUSION: Retapamulin is a highly effective and convenient new treatment option for impetigo, with efficacy against isolates resistant to existing therapies.

Topical retapamulin ointment (1%, wt/wt) twice daily for 5 days versus oral cephalexin twice daily for 10 days in the treatment of secondarily infected dermatitis: results of a randomized controlled trial.

BACKGROUND: New antibacterial agents with activity against pathogenic strains resistant to established antibiotics are needed to treat patients with secondarily infected dermatitis (SID). OBJECTIVE: We sought to determine the clinical safety and efficacy of topical retapamulin ointment 1% versus oral cephalexin for the treatment of SID. METHODS: Patients with SID were randomly assigned to retapamulin ointment 1% (twice daily [bid]) for 5 days, or oral cephalexin (500 mg bid) for 10 days. The primary efficacy end point was clinical response at follow-up. Secondary outcomes included microbiologic response at follow-up, safety, and compliance. RESULTS: Retapamulin was as effective as cephalexin (clinical success rates at follow-up: 85.9% and 89.7%, respectively). Microbiologic success rates at follow-up were 87.2% for retapamulin and 91.8% for cephalexin. Retapamulin was well tolerated and the topical formulation was preferred over the oral drug. LIMITATIONS: An imbalance existed in the number of patients with the clinical outcome "unable to determine" (15 retapamulin, 2 cephalexin), mainly because of their failure to attend the study visit. If those who failed to attend visits (who did not withdraw as a result of drug-related events) are removed from the analysis, the clinical success rates are 89.9% for retapamulin and 89.7% for cephalexin. CONCLUSIONS: Retapamulin ointment 1% (bid) for 5 days was as effective as oral cephalexin (bid) for 10 days in treatment of patients with SID, and was well tolerated.

Retapamulin ointment twice daily for 5 days vs oral cephalexin twice daily for 10 days for empiric treatment of secondarily infected traumatic lesions of the skin.

INTRODUCTION: Retapamulin is a novel, topical antibacterial of the pleuromutilin class in development for the treatment of secondarily infected traumatic lesions of the skin. METHODS: The efficacy, safety, and tolerability of topical retapamulin ointment, 1% for 5 days twice daily was evaluated in 2 identical, randomized, double-blind, double-dummy, multicenter studies vs oral cephalexin, 500 mg twice daily for 10 days, in 1904 patients with secondarily infected traumatic lesions. RESULTS: Clinical success rates were 89.5% in protocol-adherent patients receiving retapamulin compared with 91.9% for cephalexin (treatment difference, -2.5% [95% confidence interval, -5.4% to 0.5%]). In patients with Staphylococcus aureus or Streptococcus pyogenes at baseline, clinical success was 89.2% (365/409) for retapamulin and 92.6% (63/68) for cephalexin. Safety and tolerability were similar between treatments. Noncompliance (defined as using or taking <80% of doses) was recorded in 8.0% (51/636) of patients taking cephalexin compared with 0.39% (5/1268) of patients receiving retapamulin. CONCLUSIONS: Retapamulin offers a novel, effective, and convenient topical treatment for secondarily infected traumatic lesions.