Treatment of Infections with OXA-48 producing Enterobacteriaceae [PublishAheadOfPrint]

Carbapenemase-producing Enterobacteriaceae (CPE) contribute significantly to the global public health threat of antimicrobial resistance. OXA-48, and its variants, are unique carbapenemases with low level hydrolytic activity toward carbapenems, but no intrinsic activity against expanded spectrum cephalosporins. bla_OXA-48 is usually located on a plasmid, but may also be integrated chromosomally, and these genes have progressively disseminated throughout Europe and the Middle East. Despite the inability of OXA-48-like carbapenemases to hydrolyse expanded spectrum cephalosporins, pooled isolates demonstrate high variable resistance to ceftazidime and cefepime, respectively, likely to represent high rates of extended-spectrum beta-lactamase (ESBL) co-production. In-vitro data from pooled studies suggests that avibactam is the most potent beta-lactamase inhibitor when combined with ceftazidime, cefepime, aztreonam, meropenem or imipenem. Resistance to novel avibactam combinations such as imipenem/avibactam or aztreonam/avibactam has not yet been reported in OXA-48 producers, although only few clinical isolates have been tested. Although combination therapy is thought to improve chances of clinical cure and survival in CPE infection, successful outcomes were seen in ~70% of patients with infections caused by OXA-48-producing Enterobacteriaceae treated with ceftazidime/avibactam monotherapy. A carbapenem in combination with either amikacin or colistin has achieved treatment success in a few case reports. Uncertainty remains over the best treatment options and strategies used to manage these infections. Newly available antibiotics such as ceftazidime/avibactam show promise, however recent reports of resistance are concerning. Newer choices of antimicrobial agents will likely be required to combat this problem.

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