Epidemiology and In Vitro Activity of Ceftazidime/Avibactam, Meropenem/Vaborbactam and Imipenem/Relebactam against KPC-Producing K. pneumoniae Collected from Bacteremic Patients, 2018 to 2020

Abstract

The management of KPC-producing K. pneumoniae (KPC-Kp) in bloodstream infections (BSIs) represent a serious clinical challenge. In this study, the aim is to assess the incidence of resistance to novel β-lactams-β-lactamase inhibitor combinations (βL-βLICs), such as ceftazidime-avibactam (CAZ-AVI), meropenem-vaborbactam (MER-VAB) and imipenem-relebactam (IMI-REL), in KPC-Kp strains collected during a three-year period from patients with bacteremia. KPC-Kp strains resistant to βL-βLICs were selected for whole-genome sequencing. A total of 133 K. pneumoniae strains were isolated, and KPC-Kp strains were the most represented (87.2%). In 2018, resistance to CAZ-AVI and MER-VAB was 6.5% and 14.5%, respectively. In 2019, KPC-Kp resistance to CAZ-AVI and MER-VAB remained at low levels, with values of 12.9% and 3.2%, respectively. During 2020, CAZ-AVI resistance was detected in 2/23 of KPC-Kp strains (8.7%). IMI-REL was the most active βL-βLIC, inhibiting >98% of the isolates, while CAZ-AVI and MER-VAB inhibited 87–93% and 85–97% of the KPC producers, respectively. Correlations between genotypic traits and resistance to βL-βLICs showed that KPC-Kp strains resistant to CAZ-AVI harbored a mutation within the blaKPC-3 gene, while all KPC-Kp strains resistant to CAZ-AVI, MER-VAB and/or IMI-REL carried the blaKPC-3 gene. Moreover, genetic analysis of porin genes showed that 14/16 of KPC-Kp resistant isolates possessed a truncated OmpK35 and glycine (G) and aspartic acid (D) insertions at positions 134–135 within OmpK36, whereas 2/16 displayed truncated OmpK35 and OmpK36 porins. Novel βL-βLICs are promising agents against KPC-Kp infections; however, the emergence of resistance to these agents highlights the need for continuous surveillance and application of enhanced antimicrobial stewardship.

Synergistic Activity of Cefiderocol in Combination with Piperacillin-Tazobactam, Fosfomycin, Ampicillin-Sulbactam, Imipenem-Relebactam and Ceftazidime-Avibactam against Carbapenem-Resistant Gram-Negative Bacteria

“…In light of these considerations, CRE, P. aeruginosa and A. baumannii have been included by WHO among the most critical groups of MDR bacteria requiring urgent development of treatment options [3,22,25]. In recent years, new βL-βLICs have been approved in order to overcome resistance mechanisms in resistant pathogens [26], such as carbapenemases enzymes (e.g., KPCs group which is widely distributed in different countries) [24,27], lack of porin functionality and up regulation of the efflux system [12]. However, the emergence of resistance to these new agents has been recently described [5,12], presenting the significant impact in choosing between treatment options.…”

“…In recent years, new βL-βLICs have been approved in order to overcome resistance mechanisms in resistant pathogens [26], such as carbapenemases enzymes (e.g., KPCs group which is widely distributed in different countries) [24,27], lack of porin functionality and up regulation of the efflux system [12]. However, the emergence of resistance to these new agents has been recently described [5,12], presenting the significant impact in choosing between treatment options. Despite SULB having been proven to be effective against A. baumannii, probably owing to the binding to penicillin-binding proteins [28], CR-Ab infections are increasing due to a deficiency in therapeutic options against CR-Ab strains.…”

“…Despite βL-βLICs exhibiting strong in vitro and in vivo activity against CR bacteria producing β-lactamases, a growing number of strains are developing resistance to the novel combined drugs [5], posing serious limitations to these molecules. In particular, in Enterobacteriales, resistance to ceftazidime-avibactam (CAZ-AVI) was associated to mutations in KPC enzymes, coupled with alteration of cell permeability, while resistance to meropenem-vaborbactam (MER-VAB) and imipenem-relebactam (IMI-REL) was mainly associated with loss of porin expression, increase in bla KPC gene copies and activation of efflux pumps [5,12]. In 2019, the U.S. Food and Drug Administration (FDA) authorized the use of a novel cephalosporin, cefiderocol (CFD) [13,14], formerly S-649266, for the treatment of urinary tract infections (UTIs) and, subsequently, for the treatment of bacterial hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP).…”

Comparison of Broth Microdilution, Disk Diffusion and Strip Test Methods for Cefiderocol Antimicrobial Susceptibility Testing on KPC-Producing Klebsiella pneumoniae

“…Currently, CFD represents an effective antimicrobial agent for the treatment of infections caused by gram-negative bacteria in adults with limited treatment options available [ 5 ]. In particular, CFD is effective against gram-negative bacteria exhibiting resistance to carbapenem and could be considered for the treatment of difficult-to-treat (DTR) infections [ 12 , 13 ]. Although the BMD method is recommended by EUCAST as the reference method for the in vitro susceptibility assessment of CFD, other suitable and less laborious methods are available, such as the DD test and the strip test.…”

#AMRrounds: a systematic educational approach for navigating bench to bedside antimicrobial resistance

“…Alternatively, KPC may be suspected in cases where broad β-lactam resistance includes high-level resistance to CARBs and aztreonam, but susceptibility to ceftazidime/avibactam, meropenem/vaborbactam and imipenem/relebactam remains. 86 Meropenem/vaborbactam tends to have a lower MIC for KPC isolates than ceftazidime/avibactam. 87 , 88 This additional phenotypic clue can be helpful when deciding definitive therapy since resistance development has been more commonly reported with ceftazidime/avibactam than meropenem/vaborbactam.…”