Abstract
Ceftazidime/avibactam uniquely demonstrates activity against both KPC and OXA-48-like carbapenemase-expressing Enterobacterales. Clinical resistance to ceftazidime/avibactam in KPC-producers was foreseen in in-vitro resistance studies. Herein, we assessed the resistance selection propensity of ceftazidime/avibactam in K. pneumoniae expressing OXA-48-like β-lactamases (n = 10), employing serial transfer approach. Ceftazidime/avibactam MICs (0.25–4 mg/L) increased to 16–256 mg/L after 15 daily-sequential transfers. The whole genome sequence analysis of terminal mutants showed modifications in proteins linked to efflux (AcrB/AcrD/EmrA/Mdt), outer membrane permeability (OmpK36) and/or stress response pathways (CpxA/EnvZ/RpoE). In-vitro growth properties of all the ceftazidime/avibactam-selected mutants were comparable to their respective parents and they retained the ability to cause pulmonary infection in neutropenic mice. Against these mutants, we explored the activities of various combinations of β-lactams (ceftazidime or cefepime) with structurally diverse β-lactamase inhibitors or a β-lactam enhancer, zidebactam. Zidebactam, in combination with either cefepime or ceftazidime, overcame ceftazidime/avibactam resistance (MIC range 0.5–8 mg/L), while cefepime/avibactam was the second best (MIC: 0.5–16 mg/L) in yielding lower MICs. The present work revealed the possibility of ceftazidime/avibactam resistance in OXA-48-like K. pneumoniae through mutations in proteins involved in efflux and/or porins without concomitant fitness cost mandating astute monitoring of ceftazidime/avibactam resistance among OXA-48 genotypes.
Highlights
The OXA-48-like-expressing K. pneumoniae isolates utilized in this study were susceptible to ceftazidime/avibactam as shown in Table 1 (MICs 0.25 to 4 mg/L; susceptibility breakpoint 8 mg/L)
The launch of ceftazidime/avibactam in 2015 aptly generated a high anticipation among the clinicians owing to its activity against challenging resistance mechanisms expressed in Enterobacterales; AmpC, OXA-48-like and Klebsiella pneumoniae carbapenemases (KPCs) β-lactamases, which are not amenable to available β-lactam/β-lactamase-inhibitor combinations
Within years of ceftazidime/avibactam’s clinical use, several disturbing reports, revealing its vulnerability to on-therapy resistance selection in KPC-expressing pathogens, began appearing [16,24,25]. Corroborating this trend, in-vitro resistance selection studies published earlier have pointed towards the risk of clinical resistance to ceftazidime/avibactam, signifying the relevance of such in-vitro resistance selection studies [20,22]
Summary
Compared to the other two carbapenemases in the triad, OXA-48-like β-lactamases possess a weaker carbapenemase activity; when they co-exist with impermeability, extended-spectrum β-lactamases (ESBLs) and/or AmpC, a clinically-relevant resistance to carbapenems is observed [1,2,3,4]. Such a multiplicity of resistance mechanisms, usually prevalent in K. pneumoniae harboring OXA-48-like, presents a therapeutic challenge to diverse antibiotic classes [1,5,6]
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