Pneumonia and renal replacement therapy are risk factors for ceftazidime-avibactam treatment failures and resistance among patients with carbapenem-resistant Enterobacteriaceae infections [PublishAheadOfPrint]

Ceftazidime-avibactam was used to treat 77 patients with carbapenem-resistant Enterobacteriaceae (CRE) infections at our center. Thirty- and 90-day survival rates were 81% and 69%, respectively; rates were higher than predicted by SAPS II and SOFA scores at the onset of infection. Clinical success was achieved in 55% of patients, but varied by site of infection. Success rates were lowest for pneumonia (36%) and higher for bacteremia (75%) and urinary tract infections (88%). By multivariate analysis, pneumonia (P=0.045) and receipt of renal replacement therapy (RRT; P=0.046) were associated with clinical failure. Microbiologic failures occurred in 32% of patients, and occurred more commonly among patients infected with KPC-3-producing than KPC-2-producing CRE (P=0.002). Pneumonia was an independent predictor of microbiologic failures (P=0.007). Ceftazidime-avibactam resistance emerged in 10% of patients, including 14% infected with Klebsiella pneumoniae and 32% with microbiologic failures. RRT was an independent predictor for the development of resistance (P=0.009). Resistance was identified exclusively among K. pneumoniae harboring variant KPC-3 enzymes. Upon phylogenetic analysis of whole genome sequences, resistant isolates from 87.5% (7/8) of patients clustered within a previously defined sequence type (ST)258, clade II sub-lineage; resistant isolates from one patient clustered independently from other ST258, clade II isolates. In conclusion, our report offers new insights into the utility and limitations of ceftazidime-avibactam across CRE infection types. Immediate priorities are to identify ceftazidime-avibactam dosing and therapeutic regimens that improve upon the poor outcomes among patients with pneumonia, and in those receiving RRT.

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