Fosfomycin for injection may show promise and noninferiority compared with standard treatment for the treatment of complicated urinary tract infections (UTIs) and acute pyelonephritis, according to a poster presented at American Society of Microbiology (ASM) Microbe 2019, held June 20 to 24, 2019 in San Francisco, California.
At this time, intravenous (IV) fosfomycin is being pursued for United States registration for the treatment of complicated UTI and acute pyelonephritis. By binding to MurA, fosfomycin disrupts cell wall synthesis and also has in vitro bactericidal activity vs multidrug-resistant (MDR) pathogens. The ZEUS study has been underway to compare IV fosfomycin and piperacillin-tazobactam for treating complicated UTIs and acute pyelonephritis.
However, phases 2 and 3 of ZEUS were conducted according to the 2015 FDA Guidance for complicated UTI/acute pyelonephritis, which was updated in 2018. The 2018 FDA Guidance reduced the microbial eradication threshold from <104 to <103 CFU/mL. Therefore, this study reported ZEUS efficacy that was reanalyzed according to the 2018 FDA Guidance and by baseline piperacillin-tazobactam susceptibility.
Hospitalized patients with complicated UTI or acute pyelonephritis received either 6 g IV fosfomycin every 8 hours for 7 days or 4.5 g IV piperacillin-tazobactam at the same frequency and duration. The primary endpoint was the overall success in the microbiologic modified intent-to-treat population at test of cure. Overall success was defined as clinical cure plus microbiologic eradication at the test of cure (days 19-21).
In the original analysis, IV fosfomycin was shown to be noninferior to piperacillin-tazobactam, based on the prespecified 15% noninferiority margin (64.7% vs 54.5%, respectively). Reanalysis of the primary endpoint, following the updated 2018 FDA Guidance, showed similar results with a greater treatment difference that favored fosfomycin. In patients in whom piperacillin-tazobactam-resistant pathogens were uncommon at baseline, the overall success at test of cure was 78.6% for patients in the fosfomycin group and 33.3% for patients in the piperacillin-tazobactam group. Further, in patients with baseline piperacillin-tazobactam-susceptible pathogens, the overall success at test of cure was 64.7% for patients in the fosfomycin group and 56.7% for patients in the piperacillin-tazobactam group.
Overall, the study authors concluded that, “If approved, [fosfomycin] may provide a useful treatment option for [complicated UTI/ acute pyelonephritis], including cases caused by piperacillin-tazobactam-resistant and MDR pathogens.”
Ellis-Grossee EJ, Skarinsky D, Manvelian K, Eckburg PB, Das A, Kaye KS. Fosfomycin for injection (FOS) versus (vs) piperacillin-tazobactam (PIP-TAZ) for treating complicated urinary tract infections (cUTI) and acute pyelonephritis (AP): further analyses of the ZEUS study. Presented at: ASM Microbe 2019; June 20-24, 2019; San Francisco, California. Poster P404.