In vivo development of resistance to novel β-lactam/β-lactamase inhibitor combinations in KPC-producing Klebsiella pneumoniae infections: a case series.

Introduction: Understanding the dynamics that may characterize the emergence of KPC variants with resistance to novel β-lactam/β-lactamase inhibitor combinations (βL/βLICs) represents a challenge to be overcome in the appropriate use of recently introduced antibiotics.

Methods: Retrospective case series describing development of multiple resistance to novel βL/βLICs in patients with KPC-producing Klebsiella pneumoniae (KPC-Kp) infections treated with these drugs. Clinical-microbiological investigation and characterization of longitudinal strains by Whole-Genome Sequencing were performed.

Results: Four patients with KPC-Kp bloodstream infections were included. Most frequent clinical features were kidney disease, obesity, cardiac surgery as reason for admission, ICU stay, treatment with ceftazidime/avibactam, and pneumonia and/or acute kidney injury needing renal replacement therapy as KPC-Kp sepsis-associated complications. The development of resistance to ceftazidime/avibactam was observed in four longitudinal strains (three of which were co-resistant to aztreonam/avibactam and cefiderocol) following treatments with ceftazidime/avibactam (n = 3) or cefiderocol (n = 1). Resistance to meropenem/vaborbactam and imipenem/cilastatin/relebactam was observed in one case after exposure to ceftazidime/avibactam and imipenem/cilastatin/relebactam. Resistome analysis showed that resistance to novel βL/βLICs was related to specific mutations within bla_KPC carbapenemase gene (D179Y mutation [KPC-33]; deletion Δ242-GT-243 [KPC-14]) in three longitudinal strains, while porin loss (truncated OmpK35 and OmpK36 porins) was observed in one case.

Conclusion: Therapy with novel βL/βLICs or cefiderocol may lead to the selection of resistant mutants in the presence of factors influencing the achievement of PK/PD targets. KPC variants are mainly associated with resistance to ceftazidime/avibactam, and some of them (e.g. KPC-14) may also be associated with reduced susceptibility to aztreonam/avibactam and/or cefiderocol. Loss of function of the OmpK35 and OmpK36 porins appears to play a role in the development of resistance to meropenem/vaborbactam and/or imipenem/relebactam, but other mechanisms may also be involved.