Background: PLZ is a next-generation aminoglycoside with structural modifications that protect it from aminoglycoside-modifying enzymes (AMEs) and in vitro activity against multidrug-resistant (MDR) Enterobacteriaceae, including aminoglycoside- and carbapenem-resistant strains. In the CARE study, PLZ was associated with improvement in 28-day all-cause mortality vs CST in pts with CRE BSI. We report the microbiological outcomes in the CARE study by pathogen and key resistance mechanism.
Methods: CARE was a multinational, open-label trial that enrolled BSI pts with documented or presumed CRE into 2 cohorts. Pts in the randomized cohort received PLZ (15 mg/kg q24h IV) or CST (300-mg load [CST base activity] then 5 mg/kg/d IV) plus adjunctive tigecycline or meropenem. Pts in the observational cohort received PLZ plus investigators choice of adjunctive agent. Treatment duration was 7-14 days. Isolate identification and susceptibility testing were conducted by a central laboratory. Whole-genome sequencing was used to identify AME and carbapenemase genes. Microbiological outcomes were assessed in pts with confirmed CRE who received ≥1 dose of study drug (mMITT population).
Results: Of 45 BSI pts enrolled, 43 had confirmed CRE (mMITT), including Klebsiella pneumoniae (n = 42) and Enterobacter aerogenes (n = 1). Against CRE, PLZ MICs ranged from 0.12 to >128 µg/mL; 25/28 (89.3%) isolates from PLZ-treated pts had a PLZ MIC ≤4 µg/mL, while 3 had a PLZ MIC ≥128 µg/mL and a confirmed 16S ribosomal methyltransferase gene. CST MICs ranged from 0.25 to >128 µg/mL; 6/16 (37.5%) isolates from CST-treated pts had an MIC >2 µg/mL. There were 47 distinct Enterobacteriaceae pathogens isolated from 43 patients, and of these, AME genes were detected in 43/47 (91.5%), most commonly aac(6)-Ib (n = 29). Carbapenemase genes were detected in 45/47 (95.7%) isolates, most commonly blaKPC (n = 33). PLZ demonstrated higher microbiological eradication rates than CST against CRE, including AME- and carbapenemase-producing isolates (Table).
Conclusion: The results provide evidence of the efficacy of PLZ-based therapy for pts with BSI due to MDR Enterobacteriaceae, including AME- and carbapenemase-producing organisms.
A. W. Serio,
K. M. Krause, Achaogen, Inc.: Employee , Salary .
I. Galani, Achaogen, Inc.: Scientific Advisor , Research funding and honoraria . MSD: Scientific Advisor , Honoraria .
A. C. Gales, MSD: Consultant and Speaker , Consulting fee . Pfizer: Consultant and Speaker , Consulting fee . BD: Consultant , Consulting fee . Bayer: Consultant , Consulting fee .
A. Jubb, Achaogen, Inc.: Employee and Shareholder , Salary .
L. E. Connolly, Achaogen, Inc.: Consultant , Consulting fee .