fr-264205 and Respiratory-Tract-Infections

Antimicrobial resistance is one of the top 10 global public-health threats. Especially high rates of resistance have been reported for isolates from ICU patients, requiring expanded treatment options in this setting. We evaluated the activity of ceftolozane/tazobactam and comparators against Gram-negative isolates collected from patients with lower respiratory tract infections (LRTIs) in ICUs in seven Asian countries.. In 2017-2019, up to 100 consecutive, aerobic Gram-negative LRTI isolates were collected per year at each of 37 hospitals. MICs were determined using the Clinical and Laboratory Standards Institute reference broth microdilution method.. Overall, ceftolozane/tazobactam was active against 72% of 1408 Enterobacterales and 86% of 761 Pseudomonas aeruginosa isolates. Susceptibility to the non-carbapenem β-lactam comparators, including piperacillin/tazobactam, was 52-67% among Enterobacterales isolates, and the activity of all β-lactam comparators, including meropenem, was 57-70% among P. aeruginosa. Ceftolozane/tazobactam maintained activity against 61% of meropenem-nonsusceptible and 64% of piperacillin/tazobactam-nonsusceptible P. aeruginosa. At the country-level, ceftolozane/tazobactam activity ranged from >90% against Enterobacterales from Hong Kong and South Korea to <64% in Thailand and Vietnam, and from >90% against P. aeruginosa from South Korea, Malaysia, Philippines and Taiwan to <75% in Thailand and Vietnam. Correspondingly, the proportions of carbapenemase-positive isolates among Enterobacterales and P. aeruginosa isolates were highest in Thailand and Vietnam.. Ceftolozane/tazobactam provides a potential treatment option for ICU patients in Asia, which is especially important considering the reduced activity of commonly used β-lactams against the studied ICU isolates. Knowledge of local resistance patterns should inform empirical therapy decision-making.

Topics: Anti-Bacterial Agents; Cephalosporins; Drug Resistance, Multiple, Bacterial; Humans; Intensive Care Units; Meropenem; Piperacillin, Tazobactam Drug Combination; Pseudomonas aeruginosa; Pseudomonas Infections; Respiratory Tract Infections; Tazobactam; Thailand

Biofilm growth, mucoid phenotype and proficient resistance development by hypermutable strains dramatically limit the efficacy of current therapies for Pseudomonas aeruginosa chronic respiratory infection (CRI) in cystic fibrosis (CF) patients. We evaluated the activity of the new cephalosporin CXA-101, ceftazidime, meropenem and ciprofloxacin against biofilms of wild-type PAO1 and its mucoid (mucA), hypermutable (mutS) and mucoid-hypermutable derivatives, and analysed the capacity of these strains to develop resistance during planktonic and biofilm growth.. MICs and MBCs were determined by microdilution, and mutant frequencies were determined at 4x and 16x the MICs. Biofilms were formed using a modified Calgary device and were incubated for 24 h with 0x, 1x, 4x or 16x the MIC of each antibiotic. Biofilms were plated, and total cells and resistant mutants enumerated.. CXA-101 showed concentration-independent biofilm bactericidal activity, being the most potent agent tested at 1x the MIC for wild-type, mucoid and hypermutable strains. The spontaneous mutant frequencies for CXA-101 were extremely low (<5 x 10(-11)), even for the hypermutable strain at low concentrations (4x the MIC), in sharp contrast to the other antipseudomonal agents. Accordingly, mutants resistant to 4x the MIC of CXA-101 did not emerge in biofilms for any of the strains/concentrations tested.. These data strongly suggest that resistance to CXA-101 (at least 4x the MIC) cannot be driven by single-step mutations, either in planktonic or in biofilm growth. CXA-101 shows encouraging properties for the treatment of CRI by P. aeruginosa, which need to be further evaluated in animal models and pertinent clinical trials.

Topics: Anti-Bacterial Agents; Biofilms; Cephalosporins; Colony Count, Microbial; Drug Resistance, Bacterial; Humans; Microbial Sensitivity Tests; Microbial Viability; Mutation; Phenotype; Pseudomonas aeruginosa; Pseudomonas Infections; Respiratory Tract Infections