Pneumonia and Renal Replacement Therapy Are Risk Factors for Ceftazidime-Avibactam Treatment Failures and Resistance among Patients with Carbapenem-Resistant Enterobacteriaceae Infections

Abstract

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; these rates were higher than those predicted by SAPS II and SOFA scores at the onset of infection. Clinical success was achieved for 55% of patients but differed by the 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 CRE than among those infected with KPC-2-producing CRE (P = 0.002). Pneumonia was an independent predictor of microbiologic failure (P = 0.007). Ceftazidime-avibactam resistance emerged in 10% of patients, including 14% of those infected with Klebsiella pneumoniae and 32% of those with microbiologic failure. RRT was an independent predictor of the development of resistance (P = 0.009). Resistance was identified exclusively among K. pneumoniae bacteria 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 258 (ST258) clade II sublineage; 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 on the poor outcomes among patients with pneumonia and those receiving RRT.

Keywords: CRE; Klebsiella pneumoniae; ceftazidime-avibactam; failure; outcomes; pneumonia; renal replacement therapy.

FIG 1

Phylogenetic comparison of ST258 clade II K. pneumoniae isolates from our center and others in the United States. The phylogenetic tree, based on core genome SNP analysis, was generated with the use of the maximum-likelihood optimality criterion. Branch lengths are proportional to the number of evolutionary changes, and all nodes had 100% bootstrap support. Twenty-three K. pneumoniae isolates from the present study and 22 isolates collected from hospitals in New York, New Jersey, Pennsylvania, Maryland, and Michigan in previous studies (41–43) were included. Isolates from our medical center are indicated by red lines. The colored ovals indicate the previously defined ST258 clade II sublineage associated with ceftazidime-avibactam resistance (orange) (3), the reference ST258 clade II lineage (green), and two distinct isolates from a single patient who developed ceftazidime-avibactam resistance (blue).