Impact of anticancer chemotherapy on the extension of beta-lactamase spectrum: an example with KPC-type carbapenemase activity towards ceftazidime-avibactam

Claire Amaris Hobson,Thomas Storme,Didier Hocquet,Stéphane Bonacorsi,Catherine Doit,Olivier Tenaillon,André Baruchel,Mony Fahd,Raksamy Tang,André Birgy

doi:10.1038/s41598-020-57505-w

Abstract

Through their action on DNA replication, anticancer chemotherapies could increase the basal mutation rate in bacteria and increase the risk of selecting antibiotic resistant mutants. We investigated the impact of several drugs on a beta-lactamase model using KPC-type carbapenemase-producing Enterobacteriaceae. We studied the impact of anticancer chemotherapies used in pediatric hematologic malignancies on 7 clinical isolates of Enterobacteriaceae producing KPC-type carbapenemases. We compared the mutation rates from cultures with/without chemotherapy on ceftazidime-avibactam, rifampicin and ceftazidime-avibactam combined with meropenem media. Mechanisms of ceftazidime-avibactam resistance were explored on a subset of mutants. After exposure to some cytotoxic molecules, the bacterial mutation rates leading to ceftazidime-avibactam and to rifampicin resistance increased up to 104-fold while we observed no emergence of resistant mutants (frequency of <10−10) on a meropenem combined with ceftazidime-avibactam media. Compared to the parental strains, an increased susceptibility to meropenem was observed in the ceftazidime-avibactam resistant mutants. The blaKPC genes of ceftazidime-avibactam mutants harbored either mutations, deletions or insertions, especially in the region encoding the Ω-loop of the KPC-type carbapenemase. Anticancer chemotherapy can increase the mutation rates of bacteria accelerating the extension of KPC-type carbapenemases towards ceftazidime-avibactam, one of the last resort antimicrobial chemotherapy.

Highlights

Patients treated with anticancer chemotherapy drugs (ACD) are vulnerable to infectious diseases due to immunosuppression and to the direct impact of ACD on their intestinal microbiota[1,2]
The frequency of emergence of CZA-resistant mutants from E. cloacae RD26 significantly increased after incubation with azacitidine (p = 0.0006), dacarbazine (p = 0.003), and mitoxantrone (p = 0.008)
Azacitidine had the highest impact on mutation rates with an increase up to 103-fold

Summary

Introduction

Patients treated with anticancer chemotherapy drugs (ACD) are vulnerable to infectious diseases due to immunosuppression and to the direct impact of ACD on their intestinal microbiota[1,2]. The growing carriage of Carbapenem-Resistant Enterobacteriaceae (CRE) increases the risk of invasive infections with these resistant bacteria responsible for a mortality rate over 30%8. Klebsiella pneumoniae carbapenemase (KPC) was described for the first time in 19969 It is a common carbapenem resistance mechanism among Enterobacteriaceae in the USA, Israel, Asia, Latin America, and South Europe, reaching a prevalence rate of 66.5% among K. pneumoniae isolated in Greece[10,11]. CZA demonstrates excellent in vitro activity against CRE of KPC-type, and is associated with a decreased mortality rate in treated patient[8,15]. It has been showed in vitro that anticancer chemotherapy drugs could enhance the emergence of antibiotic-resistant pathogenic bacteria, mostly through activation of the SOS response[2,19]. We hypothesized that ACD treatment could accelerate the modification of beta-lactamase spectrum and the emergence of CZA-resistant mutant in KPC-producing Enterobacteriaceae.

Methods

Results

Conclusion