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Fosfomycin is an older epoxide antibiotic initially discovered in the 1960s by the collaborative research efforts of Merck Institute of Therapeutic Research and Compañía Española de Penicilina y Antibióticos (CEPA) (1). The compound (originally called phosphonomycin) was produced by strains of Streptomyces spp. (i.e.,Streptomyces fradiae, Streptomyces viridochromogenes and Streptomyces wedmorensis) isolated in broth screening cultures of soil samples. Subsequently, fosfomycin was manufactured synthetically and has been available as an intravenous formulation (fosfomycin disodium) and two oral formulations (fosfomycin calcium and fosfomycin tromethamine [also known as fosfomycin trometamol]) (2).
The intravenous formulation of fosfomycin has been available in Europe since 1971, and has been used for the treatment of hospitalized patients with serious bacterial infections including UTI, pneumonia, bone and joint, and bacteremia. In contrast, the oral formulations of fosfomycin have mainly been used for the treatment of UTIs in outpatients (3). The increasing concerns of multidrug-resistant (MDR) and extensively drug-resistant Gram-negative and Gram-positive bacteria has led to an increased use of intravenous fosfomycin, either as monotherapy or in combination regimens with other antibiotics (2-6). However, most the clinical experiences in these serious infections have come from retrospective case series or small randomized controlled trials (2 ,6).
The oral formulation of fosfomycin tromethamine has been commercially available in the USA since 1996 (7). The US FDA approved the 3-gram sachet (Monurol® ) as a single-dose treatment of uncomplicated urinary tract infections caused by Escherichia coli and Enterococcus faecalis in women. Similar to several other countries, the intravenous formulation of fosfomycin is not available in the USA.
This review provides an overview of the microbiology, clinical pharmacology and initial clinical experiences of the intravenous fosfomycin product (ZTI-01; Contepo™ [formerly referred to as Zolyd™]) which is undergoing clinical development in the USA for the treatment of complicated urinary tract infections (cUTIs) and acute pyelonephritis (AP). A single, randomized, double-blind Phase II/III clinical trial (ZEUS™) has demonstrated the safety and efficacy of intravenous fosfomycin 6 g every 8h as noninferior to piperacillin-tazobactam in overall success (clinical cure and microbiologic eradication) for the treatment of hospitalized patients with cUTIs or AP (8 ,9). The sponsor (Nabriva Therapeutics, PA, USA) has submitted a 505b.(2) new drug application (NDA) to the FDA as a drug approval pathway of intravenous...