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 (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 ( = 0.045) and receipt of renal replacement therapy (RRT) ( = 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 ( = 0.002). Pneumonia was an independent predictor of microbiologic failure ( = 0.007). Ceftazidime-avibactam resistance emerged in 10% of patients, including 14% of those infected with and 32% of those with microbiologic failure. RRT was an independent predictor of the development of resistance ( = 0.009). Resistance was identified exclusively among 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.

Meropenem-Vaborbactam as Salvage Therapy for Ceftazidime-Avibactam-Resistant Klebsiella pneumoniae Bacteremia and Abscess in a Liver Transplant Recipient

“…Solid-organ transplant recipients are frequently subjected to broad-spectrum antimicrobials, lengthy hospital admissions, and periods of heightened immunosuppression, all of which may add to the likelihood of treatment-emergent resistance. Lastly, the case patient's initial infection was pneumonia, which has been recently identified as an independent predictor of ceftazidime-avibactam microbiologic failure (17). Although some associations are speculative and based on a limited sample size, risk factors for ceftazidimeavibactam treatment failure merit further study as additional reports are compiled.…”

Challenges in the Diagnosis and Management of Bacterial Lung Infections in Solid Organ Recipients: A Narrative Review

“…Ceftazidime/avibactam inhibits the activity of class A and D carbapenemases, including KPC and OXA 48, but it is not active against class B carbapenemases. Ceftazidime/avibactam is approved for hospital-acquired and ventilator-associated pneumonia, although recent studies recognized pneumonia as a risk factor for microbiologic failure and ceftazidime/avibactam resistance among patients with carbapenem-resistant Enterobacteriaceae infections [89]. Although there is no evidence to support recommending the use of ceftazidime/avibactam in association with other antimicrobials, combination treatment seems strongly reasonable given the recent report of resistances and the high mortality associated with infections due to carbapenem-resistant Enterobacteriaceae [89].…”

Beware of broad-spectrum generalizations: ceftazidime-avibactam compared to meropenem for the treatment of gram-negative pneumonia

“…The exclusions were unfortunate because these populations represent the highest at risk individuals for MDR-GNR infections in general and CRE infections in particular (2). Notably, the study also excluded patients with a creatinine clearance (CrCl) less than 16 mL/min and those receiving hemodialysis (HD) or other renal support, which are also populations of key interest since CA resistance has been documented to occur in patients receiving renal replacement (3,4). Additionally, patients previously treated with CA were excluded, but there was no such exclusion for MERO.…”

“…Thus far, only a limited number of reports have emerged (4,9,10). In a 2017 paper from University of Pittsburg looking at blood stream infections from carbapenem-resistant Klebsiella pneumoniae , CA was compared to alternative therapies (9).…”

“…Overall, patients receiving CA did relatively well, achieving a higher rate of clinical success compared to the alternative regimens (P=0.02), but there were only three patients in the CA group with pneumonia. In a 2018 paper from the same group, 77 patients with CRE infections were analyzed to better understand risk factors associated with treatment failure and the development of resistance to CA (4). Nearly half of the treated patients in this study had pneumonia (43%), and 26% had bacteremia.…”