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 PVLpositive, 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.

e GSK2251052, a novel leucyl-tRNA synthetase (LeuRS) inhibitor, was in development for the treatment of infections caused by multidrug-resistant Gram-negative pathogens. In a phase II study (study LRS114688) evaluating the efficacy of GSK2251052 in complicated urinary tract infections, resistance developed very rapidly in 3 of 14 subjects enrolled, with >32-fold increases in the GSK2251052 MIC of the infecting pathogen being detected. A fourth subject did not exhibit the development of resistance in the baseline pathogen but posttherapy did present with a different pathogen resistant to GSK2251052. Whole-genome DNA sequencing of Escherichia coli isolates collected longitudinally from two study LRS114688 subjects confirmed that GSK2251052 resistance was due to specific mutations, selected on the first day of therapy, in the LeuRS editing domain. Phylogenetic analysis strongly suggested that resistant Escherichia coli isolates resulted from clonal expansion of baseline susceptible strains. This resistance development likely resulted from the confluence of multiple factors, of which only some can be assessed preclinically. Our study shows the challenges of developing antibiotics and the importance of clinical studies to evaluate their effect on disease pathogenesis. (These studies have been registered at ClinicalTrials.gov under registration no. NCT01381549 for the study of complicated urinary tract infections and registration no. NCT01381562 for the study of complicated intra-abdominal infections.) A pproximately 5% of patients admitted to hospitals in the United States develop nosocomial infections that increase not only patient mortality (1) but also hospitalization time and cost of treatment (2, 3). In the United States, Gram-negative bacterial pathogens, such as Escherichia coli, Klebsiella pneumoniae/Klebsiella oxytoca, Pseudomonas aeruginosa, and Acinetobacter baumannii, are responsible for 35% of the most common hospitalacquired infections (HAIs) or conditions, including urinary tract infections (UTIs), pneumonia, and surgical site and bloodstream infections. Furthermore, Ͼ70% of the bacteria causing HAIs are resistant to at least one of the most commonly used antibiotics (4-6). The continuing emergence of resistance has compromised treatment options for Gram-negative bacterial pathogens and forced the use of polymyxins (7), an old antibiotic class with nephrotoxicity issues. Despite the clear need for alternatives to treat these multidrug-resistant life-threatening pathogens, a review of the antibacterial pipeline reveals a scarcity of new antibiotic candidates (8).Aminoacyl-tRNA synthetases (AaRSs) play an essential role in protein synthesis (9) and have been clinically validated to be antibacterial targets of mupirocin (10), an inhibitor of isoleucyltRNA synthetase that has been successfully used since 1985 in the topical treatment of Gram-positive bacterial skin infections (11). Their ubiquitous nature, high degree of conservation within a broad spectrum of bacterial species, and considerable divergence...

Objectives: Dolutegravir/lamivudine (DTG/3TC) is indicated for treatment-naive and experienced people with HIV; however, questions remain about its utility in a test-and-treat setting because of potential transmitted resistance and baseline hepatitis B virus (HBV) co-infection. We present feasibility and efficacy of DTG/3TC in newly diagnosed individuals in a test-and-treat setting. Design: The single-arm STAT study evaluated DTG/3TC in a US test-and-treat setting. Methods: Eligible adults initiated DTG/3TC 14 days or less after HIV-1 diagnosis without availability of baseline laboratory results. If baseline testing indicated DTG or 3TC resistance, HBV co-infection, or creatinine clearance less than 30 ml/min per 1.73 m 2 , participants remained on study with treatment modification. Efficacy endpoints included proportions of participants with HIV-1 RNA less than 50 copies/ml at Week 24, regardless of antiretroviral regimen, among all participants (intention-to-treat exposed) and those with available HIV-1 RNA data (observed). Results: Of 131 participants enrolled, 8% were female and 50% were non-white. Through Week 24, treatment was modified in eight participants [five with HBV co-infection, one with baseline M184V, one for adverse event (rash), one participant decision]. At Week 24, 78% (102/131) of all participants and 92% (102/111) of those with available data achieved HIV-1 RNA less than 50 copies/ml. Incidence of drug-related adverse events was low (7%); no drug-related serious adverse events occurred. Conclusion: These data demonstrate the feasibility, efficacy, and safety of using DTG/3TC as a first-line regimen in a test-and-treat setting, with therapy adjustments for baseline resistance or HBV co-infection occurring safely via routine clinical care as needed [ClinicalTrials.gov, NCT03945981; see Supplemental Digital Content 1, video abstract (Video abstract summarizing the STAT study design and results)].

Retapamulin offers a novel, effective, and convenient topical treatment for secondarily infected traumatic lesions.

Clinical success rates were higher with retapamulin versus placebo in the treatment of patients with secondarily infected traumatic lesions, but the difference between treatment groups was not significant. Retapamulin was well tolerated.