Pharmacokinetic/Pharmacodynamic Determinants of Vancomycin Efficacy in Enterococcal Bacteremia.

While pharmacokinetic-pharmacodynamic targets for vancomycin therapy are recognized for invasive methicillin-resistant Staphylococcus aureus infections, scant data are available to guide therapy for other Gram-positive infections. A retrospective single-center cohort of patients with Enterococcus bacteremia hospitalized between 1 January 2009 and 31 May 2015 were studied. The average vancomycin AUC0-24 was computed using a Bayesian approach. The MIC was determined by gradient diffusion (Etest; bioMérieux), and the average AUC0-24/MIC value over the initial 72 h of therapy was calculated. We assessed 30-day all-cause mortality as the primary outcome. Classification and regression tree analysis (CART) was used to identify the vancomycin AUC0-24/MIC value associated with 30-day mortality. Fifty-seven patients with enterococcal bacteremia (32 E. faecium, 21 E. faecalis, and 4 other Enterococcus spp.) were studied. The median vancomycin MIC was 0.75 mg/liter (range, 0.38 to 3 mg/liter). All-cause 30-day mortality occurred in 10 of 57 patients (17.5%). A CART-derived vancomycin AUC/MICEtest value of ≥389 was associated with reduced mortality (P = 0.017); failure to achieve this independently predicted 30-day mortality (odds ratio, 6.83 [95% confidence interval = 1.51 to 30.84]; P = 0.01). We found that a vancomycin AUC/MICEtest value of ≥389 achieved within 72 h was associated with reduced mortality. Larger, prospective studies are warranted to verify the vancomycin pharmacodynamic targets associated with maximal clinical outcomes and acceptable safety.

Clinical and Molecular Correlates of Escherichia coli Bloodstream Infection from Two Geographically Diverse Centers in Rochester, Minnesota, and Singapore.

Escherichia coli bacteremia is caused mainly by sequence type complex 131 (STc131) and two clades within its fluoroquinolone-resistance-associated H30 subclone, H30R1 and H30Rx. We examined clinical and molecular correlates of E. coli bacteremia in two geographically distinct centers. We retrospectively studied 251 unique E. coli bloodstream isolates from 246 patients (48 from the Mayo Clinic, Rochester, MN [MN], and 198 from Tan Tock Seng Hospital, Singapore [SG]), from October 2013 through March 2014. Isolates underwent PCR for phylogroup, STc, blaCTX-M type, and virulence gene profiles, and medical records were reviewed. Although STc131 accounted for 25 to 27% of all E. coli bacteremia isolates at each site, its extended-spectrum-ß-lactamase (ESBL)-associated H30Rx clade was more prominent in SG than in MN (15% versus 4%; P = 0.04). In SG only, patients with STc131 (versus other E. coli STc isolates) were more likely to receive inactive initial antibiotics (odds ratio, 2.8; P = 0.005); this was true specifically for patients with H30Rx (odds ratio, 7.0; P = 0.005). H30Rx comprised 16% of community-onset bacteremia episodes in SG but none in MN. In SG, virulence scores were higher for H30Rx than for H30R1, non-H30 STc131, and non-STc131 isolates (P < 0.02 for all comparisons). At neither site did mortality differ by clonal status. The ESBL-associated H30Rx clade was more prevalent and more often of community onset in SG, where it predicted inactive empirical treatment. The clonal distribution varies geographically and has potentially important clinical implications. Rapid susceptibility testing and clonal diagnostics for H30/H30Rx might facilitate earlier prescribing of active therapy.

Design and synthesis of sarolaner, a novel, once-a-month, oral isoxazoline for the control of fleas and ticks on dogs.

Over the last decade, the isoxazoline motif has become the intense focus of crop protection and animal health companies in their search for novel pesticides and ectoparasiticides. Herein we report the discovery of sarolaner, a proprietary, optimized-for-animal health use isoxazoline, for once-a-month oral treatment of flea and tick infestation on dogs.

In Vitro Activities of Ceftazidime-Avibactam, Aztreonam-Avibactam, and a Panel of Older and Contemporary Antimicrobial Agents against Carbapenemase-Producing Gram-Negative Bacilli.

Among 177 carbapenemase-producing Gram-negative bacilli (108 KPC, 32 NDM, 11 IMP, 8 OXA-48, 4 OXA-181, 2 OXA-232, 5 IMI, 4 VIM, and 3 SME producers), aztreonam-avibactam was active against all isolates except two NDM producers with elevated MICs of 8/4 and 16/4 mg/liter; ceftazidime-avibactam was active against all KPC-, IMI-, SME-, and most OXA-48 group-producing isolates (93%) but not metallo-ß-lactamase producers. Among older and contemporary antimicrobials, the most active were colistin, tigecycline, and fosfomycin, with overall susceptibilities of 88%, 79%, and 78%, respectively.

Solution phase parallel synthesis and evaluation of MAPK inhibitory activities of close structural analogues of a Ras pathway modulator.

A solution phase parallel synthesis approach was undertaken to rapidly explore the structure-activity relationship of an inhibitor of the Ras/Raf protein interaction identified from a small molecule compound library. Evaluation of the MAPK pathway signaling inhibitory activity of the synthesized analogues as well as their antiproliferative activity and ability to inhibit soft agar growth were performed.