Background: PLZ is a next-generation aminoglycoside (AG) that is structurally protected from common AG-modifying enzymes (AMEs) in Enterobacteriaceae and with in vitro activity against multidrug-resistant Enterobacteriaceae, including ESBL-producing, AG-resistant, and carbapenem-resistant isolates. We report microbiological outcomes in the EPIC study, including outcomes for resistant pathogens and by the PLZ MIC.
Methods: EPIC was a multinational, randomized, double-blind study in hospitalized pts with cUTI or AP. Pts received IV PLZ (15 mg/kg q24h) or IV MEM (1 g q8h) for 4-7 days, followed by optional oral therapy, for a total of 7-10 days of therapy. The extended mMITT population included pts with ≥1 qualifying baseline pathogen (≥105 CFU/mL urine) who received study drug. Microbiological outcomes were assessed at TOC (day 15-19). Isolate identification and susceptibility testing were conducted by a central laboratory. Whole-genome sequencing was used to identify AME and β-lactamase genes.
Results: Of 609 pts enrolled, 407 (66.8%) were included in the extended mMITT population. The most common uropathogen was Escherichia coli (63.4%) followed by Klebsiella pneumoniae (19.7%). PLZ and MEM MIC50/90 for Enterobacteriaceae were 0.5/2 μg/mL (range: ≤0.06->128 mg/mL) and 0.015/0.06 mg/mL (range: ≤0.004-128 mg/mL), respectively. ESBL and AG-NS phenotypes were found in 29% and 27% of isolates, respectively. Genotyping detected β-lactamase and AME genes in 32.5% and 36.8% of isolates, respectively, most commonly blaCTX-M-15 (n = 98), blaOXA-1/OXA-30 (n = 82), aac(6`)Ib-cr (n = 79), and aac(3)-IIa (n = 56). Rates of microbiological eradication are shown in Table 1. All Enterobacteriaceae in the PLZ group with a PLZ MIC of 4 µg/mL (6/6) were eradicated at TOC (Table 2). Across 49 pts with concurrent bacteremia, 100% (27/27) and 96% (24/25) of Enterobacteriaceae were cleared from the blood at TOC in the PLZ and MEM groups, respectively.
Conclusion: PLZ demonstrated comparable or higher microbiological eradication rates compared to MEM for common gram-negative uropathogens, including resistant pathogens. The results support PLZ as a potential treatment option for cUTI, including AP, caused by Enterobacteriaceae with PLZ MICs of ≤4 mg/mL.
T. R. Keepers,
D. J. Cloutier, Achaogen, Inc.: Employee and Shareholder , Salary .
A. Komirenko, Achaogen, Inc.: Employee and Shareholder , Salary .
L. Connolly, Achaogen, Inc.: Consultant , Consulting fee .
K. Krause, Achaogen, Inc.: Employee , Salary .