In vitro activity of zidebactam/cefepime (WCK 5222), a β-lactam enhancer/ β-lactam combination against carbapenem- and colistin-resistant Klebsiella pneumoniae isolates

Objectives: In vitro activity of β-lactam enhancer/β-lactam combination zidebactam/cefepime was evaluated against carbapenem- and colistin-resistant Klebsiella pneumoniae isolates.

Methods: Non duplicate K. pneumoniae (n=185), resistant to colistin as well as non-susceptible to carbapenems were collected (2018-2019) at two large tertiary care hospitals in India. Colistin resistance-conferring genes mcr1 and mcr3 were screened among 123 of 185 randomly-selected isolates. These isolates were also subjected to multi-locus sequence typing (MLST). Additionally, alterations in mgrB were screened in 109 of these 123 isolates. All the study isolates were screened for presence of carbapenemases genes. MICs of zidebactam/cefepime, colistin, carbapenems, ceftazidime/avibactam, imipenem/relebactam, amikacin and piperacillin/tazobactam were determined by reference CLSI broth dilution method.

Results: Among the isolates, 65.4% (121/185) carried bla_OXA-48-like gene and 27.6% isolates (51/185) carried dual carbapenemase genes; bla_OXA-48-like and bla_NDM. Of the remainder, 8 isolates carried bla_NDM and 5 isolates lacked carbapenemases gene despite being carbapenem-resistant. None of the isolates showed presence of mcr1 and mcr3. Out of 109 isolates analysed for mgrB, 36 showed mutational changes. The MLST profile revealed at least 14 unique sequence types with ST231 being the dominant clone. All the isolates showed colistin MICs >2 mg/L and were non-susceptible to carbapenems. Zidebactam/cefepime demonstrated potent activity with MIC₅₀ and MIC₉₀ of 1 and 2 mg/L, respectively. MIC₉₀s of amikacin, ceftazidime/avibactam and imipenem/relebactam were >32 mg/L.

Conclusion: Zidebactam/cefepime combination was highly active against multi-clonal, carbapenem-non-susceptible and colistin-resistant K. pneumoniae isolates producing OXA-48-like (Ambler class D) or/and NDM (Ambler class B) carbapenemases, thus potentially offering a valuable treatment options for infections caused by such pan-drug resistant resistotypes. Though, zidebactam is not an inhibitor of class B and D β-lactamases, potent activity of zidebactam/cefepime combination is attributable to β-lactam enhancer mechanism.