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

Abstract

Objectives: To investigate the increase in the rates of OXA-48-like-producing isolates during 3 years of global surveillance.

Methods: Among 55?>162 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 β-lactam resistance mechanisms and MLST was performed in silico using WGS data.

Results: OXA-48-like-producing isolates increased from 0.5% (94/18 656) 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 blaCTX-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 β-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.

Figure 1 .

Increase in CRE and/or isolates carrying OXA-48-like genes in 2018 compared with 2016 and 2017.

Figure 2.

Distribution of OXA-48-like-encoding genes worldwide.

Figure 3.

MLST for K. pneumoniae isolates carrying OXA-48-like genes. The numbers in the circles represent the ST and the numbers in the lines represent the number of allele differences between groups of isolates. The lengths of the lines are not proportional to the number of differences. The colours indicate the origin of the isolates by country.

Figure 4.

Decrease in susceptibility rates of β-lactam agents due to co-production of ESBLs and/or presence of outer membrane protein alterations compared with the overall K. pneumoniae isolates without MBLs (n = 282).