Antimicrobial Activity of Ceftazidime-Avibactam and Comparators against Pathogens Harboring OXA-48 and AmpC Alone or in Combination with Other ß-Lactamases Collected from Phase 3 Clinical Trials and an International Surveillance Program.

In vitro activities of ceftazidime-avibactam (CAZ-AVI) and key comparators against AmpC-overproducing Enterobacterales and Pseudomonas aeruginosa isolates from four Phase 3 clinical trials and against OXA-48-producing Enterobacterales with multiple resistance mechanisms from the Antimicrobial Testing Leadership and Surveillance (ATLAS) program were evaluated. Susceptibility to CAZ-AVI and comparators was determined by reference broth microdilution methods. Clinical response at test of cure (TOC) was assessed in patients from Phase 3 trials with baseline OXA-48-producing Enterobacterales or AmpC-overproducing Enterobacterales and P. aeruginosa treated with CAZ-AVI or comparators. Against 77 AmpC-overproducing Enterobacterales isolates from Phase 3 trials, meropenem-vaborbactam (98.7% susceptible [S]), CAZ-AVI (96.1% S), and meropenem (96.1% S) had similar in vitro activity and were more active than ceftolozane-tazobactam (24.7% S). Clinical cure rates in patients with baseline AmpC-overproducing Enterobacterales were 80.7% (n = 21/26) and 85.0% (n = 17/20) for CAZ-AVI and comparators. Against 53 AmpC-overproducing P. aeruginosa isolates from Phase 3 trials, CAZ-AVI (73.6% S) was more active in vitro than ceftolozane-tazobactam (58.5% S) and meropenem (37.7% S). Clinical cure rates in patients with baseline AmpC-overproducing P. aeruginosa were 85.7% (n = 12/14) and 75.0% (n = 9/12) for CAZ-AVI and comparators, respectively. Of 113 OXA-48-producing isolates from the ATLAS program, 99.1% were susceptible to CAZ-AVI. Four patients with baseline OXA-48-producing Klebsiella pneumoniae isolates treated with CAZ-AVI in Phase 3 trials were clinical cures at TOC and had favorable microbiological response. CAZ-AVI was among the most active agents against AmpC-overproducing P. aeruginosa and Enterobacterales and had greater in vitro activity against OXA-48-producing Enterobacterales than meropenem-vaborbactam, meropenem, ceftolozane-tazobactam, and other comparators.

Antimicrobial Activity of Ceftazidime-Avibactam Against Contemporary Pathogens From Urinary Tract Infections and Intra-abdominal Infections Collected From US Children During the 2016-2019 INFORM Surveillance Program.

BACKGROUND: Antibacterial activity of ceftazidime-avibactam (CAZ-AVI) was evaluated against bacterial isolates from children in the United States with a urinary tract infection (UTI) or intra-abdominal infection (IAI) during the 2016-2019 International Network for Optimal Resistance Monitoring program. Prevalence of isolates and susceptibility to CAZ-AVI in pediatric and adult patients were compared. METHODS: Bacterial isolates were collected from children with a UTI or IAI at 70 US medical centers from 2016 to 2019. The antimicrobial activity of CAZ-AVI and comparator agents was tested by broth microdilution methods. RESULTS: The most prevalent Enterobacterales pathogens in children with UTIs were Escherichia coli (62.5%), Klebsiella pneumoniae (12.1%) and Proteus mirabilis (6.2%). Minimum inhibitory concentration 90% values for CAZ-AVI against Enterobacterales (0.25 µg/mL) and Pseudomonas aeruginosa (4 µg/mL) were identical for children and adults. The most prevalent Enterobacterales pathogens in children with IAIs were E. coli (57.4%), K. pneumoniae (11.1%) and Enterobacter cloacae species complex (9.3%). All isolates of Enterobacterales from pediatric patients with UTI and IAI were susceptible to CAZ-AVI, including extended-spectrum ß-lactamase phenotypes. Susceptibility of P. aeruginosa isolates to CAZ-AVI was 96.2% in children and 98.4% in adults with a UTI: for IAI it was 100% and 97.2%, respectively. CONCLUSIONS: Contemporary UTI and IAI pathogens collected from US children from 2016 to 2019 exhibited similar prevalence and susceptibilities as isolates collected from adult patients. CAZ-AVI exhibited potent activity against these pathogens.

Microbiological Profile of Sarecycline, a Novel Targeted Spectrum Tetracycline for the Treatment of Acne Vulgaris.

Sarecycline is the first narrow-spectrum tetracycline-class antibiotic being developed for acne treatment. In addition to exhibiting activity against important skin/soft tissue pathogens, sarecycline exhibits targeted antibacterial activity against clinical isolates of Cutibacterium acnes In the current study, sarecycline was 16- to 32-fold less active than broad-spectrum tetracyclines-such as minocycline and doxycycline-against aerobic Gram-negative bacilli associated with the normal human intestinal microbiome. Also, reduced activity against Escherichia coli was observed in vivo in a murine septicemia model, with the 50% protective doses, or the doses required to achieve 50% survival, being >40 mg/kg of body weight and 5.72 mg/kg for sarecycline and doxycycline, respectively. Sarecycline was also 4- to 8-fold less active than doxycycline against representative anaerobic bacteria that also comprise the normal human intestinal microbiome. Additionally, C. acnes strains displayed a low propensity for the development of resistance to sarecycline, with spontaneous mutation frequencies being 10-10 at 4 to 8 times the MIC, similar to those for minocycline and vancomycin. When tested against Gram-positive pathogens with defined tetracycline resistance mechanisms, sarecycline was more active than tetracycline against tet(K) and tet(M) strains, with MICs ranging from 0.125 to 1.0 µl/ml and 8 µl/ml, respectively, compared with MICs of 16 to 64 µl/ml and 64 µl/ml for tetracycline, respectively. However, sarecycline activity against the tet(K) and tet(M) strains was decreased compared to that against the wild type, which demonstrated MICs ranging from 0.06 to 0.25 µl/ml, though the decrease in the activity of sarecycline against the tet(K) and tet(M) strains was not as pronounced as that of tetracycline. These findings support sarecycline as a narrow-spectrum tetracycline-class antibiotic that is effective for the treatment of acne, and further investigation into the potential reduced effects on the gut microbiome compared with those of other agents is warranted.