Molecular epidemiology of cefotaxime-resistant but ceftazidime-susceptible Enterobacterales and evaluation of the in vitro bactericidal activity of ceftazidime and cefepime

Abstract

Extended-spectrum β-lactamases (ESBL) production is the main resistance mechanism to third generation cephalosporins (TGCs) in gram-negative bacilli. In Argentina, there is a high prevalence of cefotaximase-type ESBLs (CTX-M). For this reason, dissociated resistance phenotype (DRP) displaying a profile of resistance to cefotaxime (CTX) and susceptibility to ceftazidime (CAZ) might be detected. The aims of this study were to determine the prevalence of DRP in Enterobacterales clinical isolates, to characterize the mechanisms responsible for this phenotype and to evaluate the in vitro behaviour against different antibiotics.Sixty Enterobacterales resistant to any TGC were studied and, among them, 25% displayed a DRP. The β-lactamases associated with DRP were 5/11 CTX-M-2, 4/11 CTX-M-14, 1/11 CTX-M-15 and 1/11 CMY-2 in E. coli, 2/3 CTX-M-2, and 1/3 CMY-2 in P. mirabilis, and 1/1 CTX-M-14 in K. pneumoniae. Furthermore, CTX-M-2 and CTX-M-14 were related with DRP in both wild-type isolates and the corresponding transconjugants. Time-kill experiments showed CAZ bactericidal activity on CTX-M-2-and CTX-M-14-producing strains and bacterial regrowth in those CMY-2 producers. An opposite behaviour was evident when cefepime (FEP) was used. However, CAZ and gentamicin combination showed a synergistic effect against the CMY-2 producers.We concluded that Enterobacterales with DRP responded differently to CAZ or FEP depending on the type of β-lactamase they possess, suggesting that these cephalosporins could be a therapeutic option. Therefore, the characterization of the involved resistance mechanism might contribute to define the appropriate antibiotic treatment.