Oral Fosfomycin Formulation in Bacterial Prostatitis: New Role for an Old Molecule-Brief Literature Review and Clinical Considerations

Abstract

Bacterial prostatitis infections are described as infections that are difficult-to-treat, due to prostate anatomic characteristics along with clinical difficulty in terms of diagnosis and management. Furthermore, the emergence of multidrug resistant (MDR) bacteria, such as extended-spectrum beta-lactamase (ESBL) producer Escherichia coli, also representing the main causative pathogen in prostatitis, poses major problems in terms of antibiotic management and favorable clinical outcome. Oral fosfomycin, an antibiotic commonly used for the treatment of uncomplicated urinary tract infections (UTIs), has been recently evaluated for the treatment of bacterial prostatitis due to its favorable pharmacokinetic profile, its activity against MDR gram-positive and gram-negative bacteria, safety profile, and multiple synergic effect with other antibiotics as well as the low resistance rate. This review addresses fosfomycin pharmacokinetics and pharmacodynamics and discusses the latest clinical evidence on its clinical use to treat acute and chronic bacterial prostatitis in hospitalized patients and in outpatients. As described in several reports, oral fosfomycin may represent a valid therapeutic option to treat susceptible germs commonly causing prostatitis, such as E. coli and other Enterobacterales as well as Enterococcus faecium, even as a first-line regimen in particular clinical settings (patients with previous treatment failure, with allergies or outpatients). Stronger data from further studies, including randomized controlled trials, would be helpful to establish the proper dosage and specific indications.

Keywords: bacterial prostatitis; oral fosfomycin; urinary tract infections.

Figure 1

Molecular structures of (A) fosfomycin; (B) fosfomycin disodium; (C) fosfomycin calcium; (D) fosfomycin tromethamine. Created with BioRender.com; accessed on 2 August 2022.

Figure 2

Fosfomycin accesses into the bacterial wall by two transport uptake systems, GlpT and UhpT. In the cytoplasm, fosfomycin covalently binds to the active site of MurA enzyme, preventing the reaction between PEP and UNAG and avoiding UDPMurNAc synthesis, resulting in peptidoglycan building interruption and causing bacterial-cell death. Abbreviations: F, fosfomycin; GlpT, L-alpha- glycerophosphate transport system; UhpT, hexose-6-phosphate transport system; PEP, phosphoenolpyruvate; UNAG, UDP-N-acetylglucosamine; MurA, UDP-N-acetylglucosamine enolpyruvyl transferase; P, phosphate; UDPMurNAc, UDP N-acetylmuramic acid. Created with BioRender.com; accessed on 3 August 2022.

Figure 3

The majority of fosfomycin resistance mechanisms are chromosomally mediated, interfering with the antibiotic transport into bacteria. Mutations of the glpT transporter gene cause reduced fosfomycin permeability. The functional G6P-inducible UhpT transport system overrules resistance, maintaining fosfomycin permeability. Cysteine/aspartate substitution in the active site of MurA provokes conformational modification that prevents fosfomycin binding. Fos enzymes inactivate fosfomycin by modifying its molecular structure. Abbreviations: F, fosfomycin; GlpT, L-alpha-glycerophosphate transport system; UhpT, hexose-6-phosphate transport system; G6P, glucose-6-phosphate; PEP, phosphoenolpyruvate; UNAG, UDP-N-acetylglucosamine; MurA, UDP-N-acetylglucosamine enolpyruvyl transferase; P, phosphate; UDPMurNAc, UDP N-acetylmuramic acid; Fos, fos enzymes. Created with BioRender.com; accessed on 4 August 2022.