The presence of vancomycin-resistant enterococci (VRE) was looked for in fecal samples from 104 healthy volunteers (3 with hospital exposure), 100 selected hospitalized patients, and various environmental sources (44 commercial chickens, 5 farm-raised chickens, 3 turkeys, and 2 chicken farm lagoon slurries). Five probiotic preparations were also studied. No VRE with vanA or vanB genes were isolated from the healthy volunteers without hospital exposure, environmental sources, or probiotic preparations. VRE with vanB were found in the stools of 16% of the high-risk hospitalized patients and in one volunteer with hospital contact. All VRE examined could be classified into one of two clones by pulsed-field gel electrophoresis. VRE from 11 of the colonized patients were quantified and ranged from 10 3 to 10 6 CFU/g of stool. This study, in contrast to findings in Europe, failed to find evidence of VanA-or VanB-type VRE in the community or environmental sources in Houston, Texas, and suggests that these settings are not a likely source of VRE in hospitals in this geographic area.

No abstract

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...

In June 2017, The National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health, organized a workshop entitled “Pharmacokinetics-Pharmacodynamics (PK/PD) for Development of Therapeutics against Bacterial Pathogens” to discuss details and critical parameters of various PK/PD methods and identify approaches for linking human pharmacokinetic (PK) data and drug efficacy analyses. The workshop participants included individuals from academia, industry, and government. This and the accompanying minireview on nonclinical PK/PD summarize the workshop discussions and recommendations. It is important to consider how information like PK/PD can support the clinical effectiveness of new antibacterial drugs, as PK/PD data have become central to antibacterial drug development programs. Key clinical considerations for antibacterial dose selection and clinical PK/PD characterization discussed in this minireview include a robust assessment of PK in the patient population of interest, critical considerations for assessing drug penetration in the lung for the treatment of pneumonia, and an emphasis on special populations, including patients with renal impairment and augmented renal function, as well as on dosing in obese and pediatric patients. Successful application of such approaches is now used to provide a more informative drug development package to support the approval of new antibiotics.

SPR741 is a novel polymyxin B derivative, with minimal intrinsic antibacterial activity and reduced nonclinical nephrotoxicity compared to levels with polymyxin B, that interacts with the outer membrane of Gram-negative bacteria, enhancing penetration of coadministered antibiotics. The safety, tolerability, and pharmacokinetics (PK) of SPR741 were evaluated in two studies, after single and multiple intravenous (i.v.) doses in healthy adult subjects and after coadministration with partner antibiotics. In the single and multiple ascending-dose study, SPR741 or placebo was administered as a 1-h infusion at single doses of 5 to 800 mg and in multiple doses of 50 to 600 mg every 8 h (q8h) for 14 days. In the drug-drug interaction study, a single 400-mg i.v. dose of SPR741 was administered alone and in combination with piperacillin-tazobactam, ceftazidime, and aztreonam. PK parameters for SPR741 and partner antibiotics were determined using noncompartmental analysis. After single doses, a dose-linear and proportional increase in mean maximum concentration in plasma (Cmax) and area under the concentration-time curve (AUC) was observed. At doses of 100 to 800 mg, >50% of the dose was excreted in the urine in the first 4 h postdose. After multiple doses, the mean half-life was 2.2 h on day 1 and up to 14.0 h on day 14, with no evidence of accumulation after 14 days of dosing up to 400 mg. The PK profile of SPR741 and partner antibiotics was unchanged with coadministration. SPR741 was generally well tolerated at doses up to 1,800 mg/day. These data support further clinical development of SPR741 for treating serious infections due to resistant bacteria. (These studies have been registered at ClinicalTrials.gov under identifiers NCT03022175 and NCT03376529.)

SummaryFrom a public health perspective, new antibacterial agents should be developed before widespread resistance to existing agents emerges. Anticipatory drug development based on noninferiority trials offers a path to making safe and efficacious antibiotics available ahead of epidemic resistance.

Treatment with phospholipid emulsion did not reduce 28-day all-cause mortality, or reduce the onset of new organ failure in patients with suspected or confirmed Gram-negative severe sepsis.

Pulsed-field gel electrophoresis (PFGE) and multilocus enzyme electrophoresis (MLEE) were compared in this study of 65 Enterococcus faecalis isolates recovered over a 20-year period from diverse geographic sources. Clonal relationships recognized by PFGE were also recognized by MLEE; however, MLEE recognized a greater number of isolates as belonging to clonal groups than did PFGE. Both techniques were reproducible and discriminatory, but MLEE more readily recognized relationships among large numbers of isolates. MLEE confirmed the previously reported clonal spread of ␤-lactamase-producing E. faecalis to six hospitals in five states. MLEE provided a useful population framework of the E. faecalis isolates in this sample, while PFGE was able to differentiate among isolates within some MLEE clonal groups.