Research Paper on OXA-48-Like-Expressing Klebsiella pneumoniae In-Vitro Selection of Ceftazidime/Avibactam Resistance: In-Vitro and In-Vivo Fitness, Genetic Basis, and Activities of -Lactam Plus Novel -Lactamase Inhibitor or -Lactam Enhancer Combinations

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Title: OXA-48-Like-Expressing Klebsiella pneumoniae In-Vitro Selection of Ceftazidime/Avibactam Resistance: In-Vitro and In-Vivo Fitness, Genetic Basis, and Activities of -Lactam Plus Novel -Lactamase Inhibitor or -Lactam Enhancer Combinations

Abstract: Uniquely, ceftazidime/avibactam exhibits activity against Enterobacterales that express both KPC and OXA-48-like carbapenemase. In-vitro resistance studies predicted clinical resistance to ceftazidime/avibactam in KPC-producers. Here, using a serial transfer approach, we evaluated the resistance selection propensity of ceftazidime/avibactam in K. pneumoniae expressing OXA-48-like -lactamases (n = 10). After 15 daily-sequential transfers, ceftazidime/avibactam MICs (0.25–4 mg/L) increased to 16–256 mg/L. The whole genome sequence analysis of the terminal mutants revealed changes in the proteins involved in efflux (AcrB/AcrD/EmrA/Mdt), permeability of the outer membrane (OmpK36), and/or pathways for the stress response (CpxA/EnvZ/RpoE). All of the ftazidime/avibactam-selected mutants’ in-vitro growth characteristics were on par with those of their respective parents, and they all still had the capacity to infect neutropenic mice’s lungs. We investigated the effects of various mixtures of -lactams (ceftazidime or cefepime) with structurally different -lactamase inhibitors or a -lactam enhancer, zidebactam, against these mutants. Zi debactam was able to overcome ceftazidime/avibactam resistance (MIC range 0.5-8 mg/L) when combined with either cefepime or ceftazidime, while cefepime/avibactam came in second (MIC: 0.5-16 mg/L) in terms of producing lower MICs. The current study demonstrated the potential for ceftazidime/avibactam resistance in K. pneumoniae that is similar to OXA-48 through mutations in efflux and/or porin-related proteins without concurrent fitness cost, necessitating careful monitoring of ceftazidime/avibactam resistance among OXA-48 genotypes.

Keywords: ceftazidime/avibactam; β-lactams; β-lactamase inhibitor; multi-drug resistance

Paper Quality: SCOPUS / Web of Science Level Research Paper

Subject: Antibiotics

Writer Experience: 20+ Years

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