Increasing frequency of OXA-48-producing Enterobacterales worldwide and activity of ceftazidime/avibactam, meropenem/vaborbactam and comparators against these isolates

Objectives: To investigate the increase in the rates of OXA-48-like-producing isolates during 3years of global surveillance. Methods: Among 55162 Enterobacterales isolates, 354 carbapenem-resistant isolates carried genes encoding OXA-48-like enzymes. Isolates were susceptibility tested for ceftazidime/avibactam and comparators by broth microdilution methods. Analysis of beta-lactam resistance mechanisms and MLST was performed in silico using WGS data. Results: OXA-48-like-producing isolates increased from 0.5% (94/18656) in 2016 to 0.9% (169/18 808) in 2018. OXA-48 was the most common variant; isolates primarily were Klebsiella pneumoniae (318/354 isolates) from Europe and adjacent countries. MLST analysis revealed a diversity of STs, but K. pneumoniae belonging to ST395, ST23 and ST11 were observed most frequently. Thirty-nine isolates harboured MBLs and were resistant to most agents tested. The presence of bla(CTX-M-15) (258 isolates), OmpK35 nonsense mutations (232) and OmpK36 alterations (316) was common among OXA-48 producers. Ceftazidime, cefepime and aztreonam susceptibility rates, when applying CLSI breakpoints, were 12%-15% lower for isolates carrying ESBLs alone and with either or both OmpK35 stop codons and OmpK36 alterations. Meropenem and, remarkably, meropenem/vaborbactam were affected by specific OmpK36 alterations when a deleterious mutation also was observed in OmpK35. These mechanisms caused a decrease of 12%-42% in the susceptibility rates for meropenem and meropenem/vaborbactam. Ceftazidime/avibactam susceptibility rates were >98.9%, regardless of the presence of additional beta-lactam resistance mechanisms. Conclusions: Guidelines for the treatment of infections caused by OXA-48-producing isolates are scarce and, as the dissemination of these isolates continues, studies are needed to help physicians understand treatment options for these infections.