By Stan Deresinski, MD, FACP, FIDSA

Clinical Professor of Medicine, Stanford University

Dr. Deresinski reports no financial relationships relevant to this field of study.

SYNOPSIS: Ceftazidime-avibactam therapy was non-inferior to meropenem treatment in a double-blind, randomized trial that included patients with nosocomial pneumonia, including those with ventilator-associated pneumonia.

SOURCE: Torres A, Zhong N, Pachl J, et al. Ceftazidime-avibactam versus meropenem in nosocomial pneumonia, including ventilator-associated pneumonia (REPROVE): A randomised, double-blind, phase 3 non-inferiority trial. Lancet Infect Dis 2017 Dec 15. pii: S1473-3099(17)30747-8. doi: 10.1016/S1473-3099(17)30747-8. [Epub ahead of print].

In the double-blind non-inferiority REPROVE study, 879 patients with hospital-acquired pneumonia at 136 hospitals in 23 countries were randomized to treatment with either ceftazidime-avibactam (CAv) or meropenem. CAv (2,000 mg/500 mg) was infused over two hours, while meropenem (1,000 mg) was infused over 30 minutes. Each was administered every eight hours for 7-14 days, and dosing was adjusted for altered renal function. Randomization was stratified by presence or absence of ventilator-associated pneumonia (VAP) and by geographic region. The study had a > 85% power to reject non-inferiority with a lower margin of difference of -12.5%.

Of the patients with identified baseline pathogens (the microbiological modified intent-to-treat population) for whom a Gram-negative bacillus was found in respiratory culture, the most frequently identified were Klebsiella pneumoniae (37%) and Pseudomonas aeruginosa (30%). Among these baseline isolates, 11 (two K. pneumoniae and nine P. aeruginosa) were resistant to CAv and 37 (five K. pneumoniae, one Serratia marcescens, and 31 P. aeruginosa) were non-susceptible to meropenem. Ten isolates (two K. pneumoniae and eight P. aeruginosa) were resistant to both CAv and meropenem. S. aureus was recovered in 15%. Approximately 5% in each treatment group were bacteremic.

There was no statistically significant difference in clinical cure rates between the treatment arms in either the clinically modified intent-to-treat (ITT) or the clinically evaluable population. In the former population, clinical cure was achieved in 245 (68.6%) of 356 CAv recipients and 270 (73.0%) of 370 patients randomized to receive meropenem (difference -4.2% [95% confidence interval [CI], -10.8 to 2.5]). Clinical cure in the clinically evaluable cohort was achieved in 199 (77.4%) of 257 CAv and 211 (78.1%) of 270 meropenem recipients (difference -0.7% [95% CI, -7.9 to 6.4]). Crude mortality was low in each group at 8% and 7%, respectively.

Microbial persistence of isolates with the same genotype with a greater than fourfold increase in minimum inhibitory concentration occurred in only one pair of isolates from CAv recipients but in 11 from meropenem recipients. Seventy-five (19%) CAv recipients and 54 (13%) meropenem recipients experienced serious adverse events, with four (all in the ceftazidime group) considered treatment-related.

COMMENTARY

CAv initially received approval from the Food and Drug Administration in February 2015. Avibactam is a non-beta-lactam beta-lactamase inhibitor whose spectrum includes several carbapenemases, most notably KPC. The study by Torres and colleagues reviewed here demonstrates the statistical non-inferiority of CAv to meropenem therapy in patients with hospital-acquired pneumonia, including those with ventilator-associated pneumonia. However, the major deficit in this study is that meropenem was put at a disadvantage as a result of its dosing at 1 gram given over 30 minutes. It has become clear that extended duration infusion is more likely to achieve pharmacodynamic targets with this and other beta-lactam antibiotics.

A concern regarding CAv was raised last year when Shields et al reported bacteriologic failure in 10 (27%) of 37 patients with infection due to carbapenem-resistant Enterobacteriaceae (CRE).1 Furthermore, in three of the 10 microbiological failures, the organism had become resistant to CAv as a consequence in blaKPC3. However, in REPROVE only one isolate became resistant to CAv. In contrast, this occurred with isolates from 11 meropenem recipients. One could speculate that this was the consequence of inadequate exposure related to 1 gram doses infused over only 30 minutes.

REFERENCES

  1. Shields RK, Potoski BA, Haidar G, et al. Clinical outcomes, drug toxicity, and emergence of ceftazidime-avibactam resistance among patients treated for carbapenem-resistant Enterobacteriaceae infections. Clin Infect Dis 2016;63:1615-1618.