Colistin Versus Ceftazidime-Avibactam in the Treatment of Infections Due to Carbapenem-Resistant Enterobacteriaceae

Abstract

Background: The efficacy of ceftazidime-avibactam-a cephalosporin-β-lactamase inhibitor combination with in vitro activity against Klebsiella pneumoniae carbapenemase-producing carbapenem-resistant Enterobacteriaceae (CRE)-compared with colistin remains unknown.

Methods: Patients initially treated with either ceftazidime-avibactam or colistin for CRE infections were selected from the Consortium on Resistance Against Carbapenems in Klebsiella and other Enterobacteriaceae (CRACKLE), a prospective, multicenter, observational study. Efficacy, safety, and benefit-risk analyses were performed using intent-to-treat analyses with partial credit and the desirability of outcome ranking approaches. The ordinal efficacy outcome was based on disposition at day 30 after starting treatment (home vs not home but not observed to die in the hospital vs hospital death). All analyses were adjusted for confounding using inverse probability of treatment weighting (IPTW).

Results: Thirty-eight patients were treated first with ceftazidime-avibactam and 99 with colistin. Most patients received additional anti-CRE agents as part of their treatment. Bloodstream (n = 63; 46%) and respiratory (n = 30; 22%) infections were most common. In patients treated with ceftazidime-avibactam versus colistin, IPTW-adjusted all-cause hospital mortality 30 days after starting treatment was 9% versus 32%, respectively (difference, 23%; 95% bootstrap confidence interval, 9%-35%; P = .001). In an analysis of disposition at 30 days, patients treated with ceftazidime-avibactam, compared with those treated within colistin, had an IPTW-adjusted probability of a better outcome of 64% (95% confidence interval, 57%-71%). Partial credit analyses indicated uniform superiority of ceftazidime-avibactam to colistin.

Conclusions: Ceftazidime-avibactam may be a reasonable alternative to colistin in the treatment of K. pneumoniae carbapenemase-producing CRE infections. These findings require confirmation in a randomized controlled trial.

Keywords: Klebsiella pneumoniae; benefit-risk; carbapenem-resistant Enterobacteriaceae; ceftazidime-avibactam; colistin.

Figure 1.

Inverse probability of treatment weighting (IPTW)–adjusted efficacy: disposition over time (n = 137; IPTW-adjusted probability estimates of hospital mortality and discharge status). A, Ceftazidime-avibactam group (n = 38). B, Colistin group (n = 99).

Figure 2.

Inverse probability of treatment weighting (IPTW)–adjusted safety over time: renal failure (n = 72; restricted to patients at risk for incident renal failure, without renal failure at treatment initiation). A, Ceftazidime-avibactam group (n = 26). B, Colistin group (n = 46).

Figure 3.

Inverse probability of treatment weighting (IPTW)–adjusted partial credit analysis. A, Safety: estimated between-treatment difference (ceftazidime-avibactam minus colistin) in mean scores and associated 95% confidence bands, as a function of the partial credit assigned to those not observed to die with renal failure (more details in Section 5.25–5.45). B, Benefit-risk: estimated between-treatment difference (ceftazidime-avibactam minus colistin) in mean scores as a function of the partial credits assigned to those alive in the hospital or discharged not to home, with or without incident renal failure (more details in Section 5.85–6.45).