Choosing Ceftazidime/Avibactam and Ceftolozane/Tazobactam as Empiric Therapies against Pseudomonas aeruginosa (Pa) using Rapid Molecular Diagnostics (RMDs): PRIMERS IV

Abstract

Background. Overcoming β-lactam resistance in Pa is a major clinical challenge as diverse mechanisms (bla genes, porin changes, efflux pump overexpression, changes in PBPs, etc.) produce this phenotype. Novel therapeutics are available [ceftazidime/avibactam (taz/avi) and ceftolozane/tazobactam (tol/tazo)] that may overcome many of these resistance mechanisms. We investigated whether representative RMDs can inform the empiric use of tol/tazo and taz/avi against multidrug-resistant (MDR) Pa. Methods. Three RMD platforms [Nanosphere, PCR/ESI-MS, and Molecular Beacons (MBs)] were employed to identify genes potentially conferring resistance/susceptibility to taz/avi and tol/tazo in Pa. The absence or presence of blaNDM, -VIM, -IMP, and blaKPC genes was queried against the reference standard of MIC determinations. A worldwide collection of 197 archived clinical MDR Paisolates were tested. Analytical methods employing susceptibility and resistance sensitivities were estimated with 95% confidence intervals. Predictive values for susceptibility and resistance were also estimated as a function of susceptibility prevalence using an adjusted logit transformation. Results. In this collection, 27% (n = 53) of the isolates were resistant to tol/tazo and 23% (n = 45) were resistant to taz/avi by MICs. Susceptibility sensitivity was >99% for both combination antibiotics. However, resistance sensitivities were lower: tol/tazo (62% to 66%) and taz/avi (31% to 33%). Assuming 95% prevalence of susceptibility for both combinations, the susceptibility predictive value was >97% across all platforms. In contrast, the resistance predictive values (RPVs) of MBs were 62% (34, 84) for tol/tazo and 48% (22, 75) for taz/avi. Estimated RPVs of nanosphere and PCR/ ESI-MS were similar: 72% (39, 92) and 60% (26, 86) for tol/tazo and taz/avi, respectively (figure). Conclusion. Using taz/avi and tol/tazo empiric therapy against Pa can be assisted by results of RMDs. Clinicians need to be mindful of the benefits and risks of resistance gene detection in Pathat impacts these novel agents, especially when the prevalence of resistance is still undefined and likely to change (Figure Presented) .