Ronald N. Jones

Volume 62, no. 1, e01323-17, 2018, [https://doi.org/10.1128/AAC.01323-17][1]. Cristopher A. Mazo's name is incorrect in the byline of the original article. The correct byline is shown above. [1]: /lookup/doi/10.1128/AAC.01323-17

Gepotidacin, a novel triazaacenaphthylene antibacterial agent, is the first in a new class of type IIA topoisomerase inhibitors with activity against many biothreat and conventional pathogens, including Neisseria gonorrhoeae. To assist ongoing clinical studies of gepotidacin to treat gonorrhea, a multilaboratory quality assurance investigation determined the reference organism (N. gonorrhoeae ATCC 49226) quality control MIC range to be 0.25 to 1 μg/ml (88.8% of gepotidacin MIC results at the 0.5 μg/ml mode).

Fusidic acid (FA) activity was evaluated against 2,002 clinical staphylococcal isolates collected in U.S. hospitals during 2014. FA (MIC _50/90 , 0.12/0.12 μg/ml) inhibited 99.8% of Staphylococcus aureus isolates at ≤1 μg/ml. Only four S. aureus isolates displayed FA values of >2 μg/ml (three strains with fusC and one with an L461K substitution in fusA ), and they were isolated from patients in four states. In conclusion, FA demonstrated sustained, potent activity against this recent collection of U.S. staphylococci.

Dalbavancin, a novel lipoglycopeptide, was approved in 2014 by regulatory agencies in the United States (USA) and Europe for the treatment of skin and skin structure infections. The activity of dalbavancin was also widely assessed against Streptococcus pneumoniae clinical isolates collected from patients on six continents monitored during two time intervals (2011-2013 and 2014). A total of 18,186 pneumococci were obtained from 49 nations and submitted to a monitoring laboratory as part of the SENTRY Antimicrobial Surveillance Program for reference susceptibility testing. Dalbavancin potency against S. pneumoniae was consistent across the monitored years with a MIC_50/90 of 0.015/0.03 μg/ml and all isolates were inhibited at ≤ 0.12 μg/ml. The activity for dalbavancin was not adversely influenced by non-susceptibility to β-lactams (ceftriaxone or penicillin), macrolides, clindamycin, fluoroquinolones, tetracyclines or multidrug-resistance (MDR). Regional variations of dalbavancin activity was not detected, but S. pneumoniae isolated in the Asia-Pacific region were more likely to be non-susceptible to penicillin and ceftriaxone as well as being MDR, compared to North or South America and Europe. Direct comparisons of potency illustrated dalbavancin (MIC_50/90 of 0.015/0.03 μg/ml) to be 16-fold or more active than vancomycin (MIC₅₀, 0.25 μg/ml), linezolid (MIC₅₀, 1 μg/ml), levofloxacin (MIC₅₀, 1 μg/ml), ceftriaxone (MIC₉₀, 1 μg/ml), and penicillin (MIC₉₀, 2 μg/ml). In conclusion, dalbavancin had potent and consistent activity against this contemporary (2011-2014) collection of S. pneumoniae isolates.

Measurement of vancomycin susceptibility has been shown to be highly predictive as a surrogate measure of oritavancin susceptibility among clinically indicated Gram-positive species. Results of studying over 30,000 pathogens (from 2011 to 2014) by cross-susceptibility analysis and determining the poor reproducibility of oritavancin-nonsusceptible results showed nearly perfect surrogate testing accuracy (99.86 to 99.94%). Any isolate of an indicated organism species with locally reproducible oritavancin-nonsusceptible results (extremely rare) should be referred to a reference laboratory for confirmation of the results and determination of the resistance mechanism.

Ceftazidime-avibactam is a broad-spectrum-β-lactamase inhibitor combination in late-stage clinical development for the treatment of serious infections. In preparation for clinical microbiology laboratory use, a validation experiment was initiated to evaluate a commercial broth microdilution product (Sensititre dried MIC susceptibility system) compared to reference panels using 525 recent clinical isolates. Among 11 pathogen groups, all had Sensititre MIC/reference MIC ratios predominantly at 1 (47.5% to 97.5%), and automated and manual endpoint results did not differ. Enterobacteriaceae MIC comparisons showed a modest skewing of Sensititre MIC results toward an elevated MIC (33.9%), but the essential agreement was 98.9% with 100.0% reproducibility. In conclusion, Sensititre panels produced accurate ceftazidime-avibactam MIC results, allowing quality MIC guidance for therapy following regulatory approvals.

Oritavancin is a recently approved lipoglycopeptide antimicrobial agent with activity against Gram-positive pathogens. Its extended serum elimination half-life and concentration-dependent killing enable single-dose treatment of acute bacterial skin and skin structure infections. At the time of regulatory approval, new agents, including oritavancin, are not offered in the most widely used susceptibility testing devices and therefore may require application of surrogate testing using a related antimicrobial to infer susceptibility. To evaluate vancomycin as a predictive susceptibility marker for oritavancin, 26,993 recent Gram-positive organisms from U.S. and European hospitals were tested using reference MIC methods. Organisms included Staphylococcus aureus , coagulase-negative staphylococci (CoNS), beta-hemolytic streptococci (BHS), viridans group streptococci (VGS), and enterococci (ENT). These five major pathogen groups were analyzed by comparing results with FDA-approved susceptible breakpoints for both drugs, as well as those suggested by epidemiological cutoff values and supported by pharmacokinetic/pharmacodynamic analyses. Vancomycin susceptibility was highly accurate (98.1 to 100.0%) as a surrogate for oritavancin susceptibility among the indicated pathogen species. Furthermore, direct MIC comparisons showed high oritavancin potencies, with vancomycin/oritavancin MIC ₉₀ results of 1/0.06, 2/0.06, 0.5/0.12,1/0.06, and >16/0.06 μg/ml for S. aureus , CoNS, BHS, VGS, and ENT, respectively. In conclusion, vancomycin demonstrated acceptable accuracy as a surrogate marker for predicting oritavancin susceptibility when tested against the indicated pathogens. In contrast, 93.3% of vancomycin-nonsusceptible enterococci had oritavancin MIC values of ≤0.12 μg/ml, indicating a poor predictive value of vancomycin for oritavancin resistance against these organisms. Until commercial oritavancin susceptibility testing devices are readily available, isolates that when tested show vancomycin susceptibility can be inferred to be susceptible to oritavancin by using FDA-approved breakpoints.