In Vitro Synergy of Ceftazidime-Avibactam Plus Rifampin Against Pseudomonas aeruginosa

Abstract

Background: Pseudomonas aeruginosa is a major cause of nosocomial infections. An emerging concern is the increased prevalence of multidrug resistance that limits treatment options. Ceftazidime-avibactam (CZA), FDAapproved in February 2015, is a novel cephalosporin/non-b-lactam b-lactamase inhibitor coupling that demonstrates antipseudomonal activity. Despite its recent release, resistance to this agent has been reported. Rifampin (RI) has shown in vitro and in vivo synergistic activity when combined with b-lactams and polymyxins against P aeruginosa. The aim of this study was to investigate any antimicrobial synergistic activity of the combination of CZA and RI against CZAR P aeruginosa isolates. Methods: P aeruginosa isolates were prospectively collected from 193 consecutive patients during the last 5 months of 2015. Recovery sources were respiratory (45%), urinary (24%), wound (16%), bloodstream (9%), and other (6%) infections. Initial antimicrobial susceptibilities were determined by MicroScan. CZA and RI MICs (lg/mL) were determined by Etest. FDA MIC (lg/mL) interpretive guidelines for CZA are 8 susceptible and 16 resistant. There are no CLSI or FDA interpretive guidelines for testing RI against P aeruginosa. Rep-PCR analysis was used to determine that CZA-R isolates were genetically unique. MICs and synergy testing (MIC:MIC method) of CZA-R isolates were performed in triplicate. The summation fractional inhibitory concentration (PFIC) was calculated: synergy 0.5; additivity, >0.5-1. Results: A total of 9/193 (5%) P aeruginosa isolates were resistant to CZA, including 6/27 (22%) with multidrug resistance (resistant to 1 agent in 3 antimicrobial categories). In vitro synergy by Etest was detected in 5/9 (67%) isolates (PFICs 0.1-0.5) and additivity in 4 (PFIC 0.9-1.0). Conclusion: Even though ceftazidime-avibactam demonstrated excellent activity in the P aeruginosa isolates tested, resistance has already occurred. However, in vitro synergy or additivity was demonstrated against these CZA-R isolates with CZA plus RI. This combination should be further tested with additional isolates. In vitro synergy may not predict in vivo response.