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A single 1200-mg dose of oritavancin was noninferior to 7–10 days of vancomycin for treatment of acute bacterial skin and skin structure infections (ABSSSIs) caused by gram-positive pathogens. Oritavancin provides a single-dose alternative to multi-dose therapies for ABSSSI.Background. Oritavancin is a lipoglycopeptide antibiotic with rapid bactericidal activity against gram-positive bacteria. Its concentration-dependent activity and long half-life allow for single-dose treatment.Methods. In a randomized, double-blind trial, adults with acute bacterial skin and skin structure infections (ABSSSIs) received either a single intravenous 1200-mg dose of oritavancin or 7–10 days of twice-daily vancomycin. Three efficacy endpoints were tested for noninferiority: (1) primary composite endpoint at 48–72 hours (cessation of spreading or reduction in lesion size, absence of fever, and no rescue antibiotic); (2) investigator-assessed clinical cure 7–14 days after end of treatment; and (3) ≥20% reduction in lesion area at 48–72 hours.Results. A total of 503 and 502 patients comprised the modified intent-to-treat population for oritavancin and vancomycin, respectively. All 3 efficacy endpoints met the 10% noninferiority margin: the primary composite endpoint (80.1% vs 82.9%; 95% confidence interval [CI], −7.5 to 2.0), investigator-assessed clinical cure (82.7% vs 80.5%; 95% CI, −2.6 to 7.0), and proportion of patients attaining ≥20% reduction in lesion area (85.9% vs 85.3%; 95% CI, −3.7 to 5.0) for oritavancin vs vancomycin, respectively. Efficacy outcomes by pathogen, including methicillin-resistant Staphylococcus aureus and the frequency of adverse events, were similar between treatment groups.Conclusions. A single 1200-mg dose of oritavancin was noninferior to 7–10 days of vancomycin in treating ABSSSIs caused by gram-positive pathogens, and was well tolerated. Oritavancin provides a single-dose alternative to multidose therapies for the treatment of ABSSSIs.Clinical Trials Registration. NCT01252732. [ABSTRACT FROM PUBLISHER]

A letter to the editor is presented which discusses the in vitro activity of oritavancin and other lipoglycopeptides against vancomycin-susceptible and -resistant Enterococcus faecalis.

Bacteriophages have evolved specific mechanisms that redirect bacterial metabolic pathways to the bacteriophage reproduction cycle. In this study, we characterized the bactericidal mechanism of two polypeptides from bacteriophages Twort and G1 that target the DNA sliding clamp of Staphylococcus aureus. The DNA sliding clamp, which tethers DNA polymerase to its template and thereby confers processivity upon the enzyme, was found to be essential for the viability of S. aureus. Expression of polypeptides TwortORF168 and G1ORF240 in S. aureus selectively inhibited DNA replication which in turn resulted in cell death. Both polypeptides specifically inhibited the S. aureus DNA replicase that was reconstituted in vitro but not the corresponding replicase of Streptococcus pyogenes. We demonstrated that inhibition of DNA synthesis is multifaceted and occurs via binding the DNA sliding clamp: TwortORF168 and G1ORF240 bound tightly to the DNA sliding clamp and prevented both its loading onto DNA and its interaction with DNA polymerase C. These results elucidate the impact of bacteriophage polypeptide expression upon DNA replication in the growing cell. [ABSTRACT FROM AUTHOR]

Over evolutionary time bacteriophages have developed unique proteins that arrest critical cellular processes to commit bacterial host metabolism to phage reproduction. Here, we apply this concept of phage-mediated bacterial growth inhibition to antibiotic discovery. We sequenced 26 Staphylococcus aureus phages and identified 31 novel polypeptide families that inhibited growth upon expression in S. aureus. The cellular targets for some of these polypeptides were identified and several were shown to be essential components of the host DNA replication and transcription machineries. The interaction between a prototypic pair, ORF104 of phage 77 and DnaI, the putative helicase loader of S. aureus, was then used to screen for small molecule inhibitors. Several compounds were subsequently found to inhibit both bacterial growth and DNA synthesis. Our results suggest that mimicking the growth-inhibitory effect of phage polypeptides by a chemical compound, coupled with the plethora of phages on earth, will yield new antibiotics to combat infectious diseases. [ABSTRACT FROM AUTHOR]

Background Oritavancin is a lipoglycopeptide used in the treatment of acute bacterial skin and skin structure infections (ABSSSIs) in adults. To characterize its use in patients in the postapproval setting, a patient registry was developed. Methods Data collected in an ongoing retrospective observational registry are used to evaluate the utilization, outcomes, and adverse events (AEs) associated with oritavancin for the treatment of infections presumed or confirmed to be caused by gram-positive (GP) bacteria in clinical practice. Results Data for 112 patients from 8 sites were collected. All patients received a single 1200-mg dose of oritavancin mostly in an infusion center. Infection type included cellulitis (67.0%), cutaneous abscess (21.4%), and wound (4.5%). Most patients (72.3%) received 1 or more antimicrobial agents for the index GP infection within 28 days prior to oritavancin treatment. Of positive cultures obtained prior to oritavancin administration, methicillin-resistant Staphylococcus aureus was the predominant pathogen (78.4%). A positive clinical response was observed in 92.8% of patients, and microbial eradication was observed in 90.0% of patients with post-therapy cultures. Within 28 days following oritavancin administration, 4 (3.6%) patients were hospitalized for failure of treatment of the index infection. Five (4.5%) patients experienced 1 or more possible drug-related AEs, which were consistent with types previously reported. There were no drug-related serious AEs reported. Conclusions Clinical and microbiologic outcomes and safety of single-dose oritavancin 1200 mg were similar in this older patient population with multiple comorbid conditions to those observed in the phase 3 SOLO trials. [ABSTRACT FROM AUTHOR]

A correction to the article "Competition of Bacteriophage Polypeptides With Native Replicase Proteins for Binding to the DNA Sliding Clamp Reveals a Novel Mechanism for DNA Replication in Staphylococcus Aureus," in the 2006 issue is presented.