Ceftazidime

AIM: Comparative study of antibiotics resistance and VNTR-typing of Vibrio cholerae non O1/ non O139 strains, isolated on the territory of Rostov region in 2014.

Ceftazidime is one of the few cephalosporins with activity againstPseudomonas aeruginosa Using whole genome comparative analysis, we set out to determine the prevalent mechanism(s) of resistance to ceftazidime using a set of 181 clinical isolates. These isolates represented various multi-locus sequence types that consisted of both ceftazidime susceptible and resistant populations. A presumptive resistance mechanism against ceftazidime was identified in 88% of the non-susceptible isolates using this approach.

β-Lactams inhibit penicillin-binding proteins (PBPs) and serine β-lactamases by acylation of a nucleophilic active site serine. Avibactam is approved for clinical use in combination with ceftazidime, and is a breakthrough non β-lactam β-lactamase inhibitor also reacting via serine acylation. Molecular dynamics (MD) and quantum chemical calculations on avibactam-mediated inhibition of a clinically relevant cephalosporinase reveal that recyclisation of the avibactam derived carbamoyl complex is favoured over hydrolysis. In contrast, we show that analogous recyclisation in β-lactam mediated inhibition is disfavoured. Avibactam recyclisation is promoted by a proton shuttle, a 'structural' water protonating the nucleophilic serine, and stabilization of the negative charge developed on aminocarbonyl oxygen. The results imply the potential of calculations for distinguishing between bifurcating pathways during inhibition and in generating hypotheses for predicting resistance.

BACKGROUND: The Clinical Laboratory Standards Institute (CLSI) and the European Committee on Antimicrobial Susceptibility Testing (EUCAST) guidelines are the most popular breakpoint guidelines used in antimicrobial susceptibility testing worldwide. The EUCAST guidelines are freely available to users while CLSI is available for non-members as a package of three documents for US $500 annually. This is prohibitive for clinical microbiology laboratories in resource poor settings. We set out to compare antibiotic susceptibility determined by the two guidelines to determine whether adoption of EUCAST guidelines would significantly affect our susceptibility patterns.