Fosfomycin Tromethamine

Abstract

Fosfomycin tromethamine is a phosphonic acid bactericidal agent with in vitro activity against most urinary tract pathogens. It is particularly active against Escherichia coli, and Citrobacter, Enterobacter, Klebsiella, Serratia and Enterococcus spp. There appears to be little cross-resistance between fosfomycin and other antibacterial agents, possibly because it differs from other agents in its general chemical structure and site of action. In its new formulation as the oral tromethamine salt, fosfomycin has 34 to 41% oral bioavailability, has a mean elimination half-life of 5.7 hours, and is primarily excreted unchanged in the urine. Following a single 3g oral dose, peak urinary concentrations occur within 4 hours and remain high (>128 mg/L) for 24 to 48 hours, which is sufficient to inhibit most urinary tract pathogens. In clinical trials in patients with acute uncomplicated lower urinary tract infection, single-dose fosfomycin tromethamine therapy was effective, and comparable with several other antibacterial agents given either as single-dose or multiple-dose treatments [e.g. β-lactam and fluoroquinolone agents, cotrimoxazole (trimethoprim-sulfamethoxazole), nitrofurantoin and pipemidic acid]. Bacteriological eradication rates of 75 to 90% were achieved 5 to 11 days after therapy, with eradication rates of 62 to 93% 4 to 6 weeks after therapy. In 3 large double-blind comparisons with ciprofloxacin, cotrimoxazole and nitrofurantoin, 99% of fosfomycin tromethamine recipients and 100% of patients receiving comparator agents were considered clinically cured or improved after therapy. Fosfomycin tromethamine is well tolerated, with a low incidence of adverse events. These comprise mainly gastrointestinal symptoms that are transient, mild and self-limiting. Thus, fosfomycin tromethamine achieves high clinical and bacteriological cure rates in patients with acute uncomplicated lower urinary tract infection and is well tolerated. The single-dose administration regimen and favourable US pregnancy category rating of fosfomycin tromethamine should also encourage its use in this indication. Fosfomycin tromethamine is a bactericidal phosphonic acid derivative which acts primarily by inhibiting bacterial cell wall (peptidoglycan) synthesis. It has antibacterial activity against many pathogenic and opportunistic Gram-positive and Gram-negative bacteria isolated from patients with lower urinary tract infections (UTI). According to conventional in vitro susceptibility tests, fosfomycin has good activity against Escherichia coli, Staphylococcus aureus, and Serratia, Klebsiella, Citrobacter, Enterococcus and Enterobacter spp. Minimum inhibitory concentrations active against 90% of isolates (MIC₉₀ values) for some other important pathogens are relatively high, but are well within the urinary concentrations of fosfomycin achieved during treatment with the drug. In vitro studies modelling bladder fill and voiding (to simulate fluctuations of fosfomycin concentrations) indicate that sufficiently high concentrations of fosfomycin are achieved after a single 3g dose to attain >99% kill rates against common urinary pathogens. Bacterial adhesiveness to uroepithelial mucosa is reduced within 1 hour after exposure to fosfomycin 1000 mg/L. Bacterial resistance to fosfomycin can be either chromosomal or, more rarely, plasmid-mediated. The frequency of in vitro fosfomycin-resistant mutants is low, and there appears to be little cross-resistance between fosfomycin and other antibacterial agents. Small changes to the faecal flora of healthy volunteers generally occur 2 to 4 days after administration but usually return to baseline levels within 2 to 3 weeks. Following a single oral dose of fosfomycin tromethamine (≡3g fosfomycin), mean peak plasma concentrations (C_max) range from 22 to 32 mg/L and are reached between 2 and 2.5 hours (t_max). The bioavailability of a single 3g oral dose ranges from 34 to 41%, and from 54 to 65% when expressed as a proportion of the oral dose recovered in the urine. The mean terminal elimination half-life (t_1/2β) of fosfomycin is 5.7 hours. The drug is primarily excreted unchanged in the urine; 128 mg/L, which are sufficient to inhibit most urinary pathogens, are maintained for 24 to 48 hours after a single 3g oral dose. In patients with renal impairment (creatinine clearance max of fosfomycin is increased, t_max and t_1/2β are prolonged and urinary elimination is reduced. Comparative nonblind and double-blind studies in patients (predominantly women) with acute uncomplicated lower UTI indicate that a single 3g oral dose of fosfomycin tromethamine is as bacteriologically effective as single oral doses of amoxicillin, cotrimoxazole (trimethoprim-sulfamethoxazole), norfloxacin, ofloxacin or pefloxacin. Single-dose fosfomycin tromethamine is also as effective as multiple-dose regimens of amoxicillin-clavulanic acid, cefalexin, nitrofurantoin, norfloxacin, pipemidic acid or shorter (3-day) cotrimoxazole therapy. It was slightly less effective than ciprofloxacin 250mg twice daily for 7 days and a longer (10-day) cotrimoxazole regimen. In double-blind studies, a single 3g oral dose of fosfomycin tromethamine produced bacteriological cure after 5 to 11 days in 75 to 90% of patients with lower UTI (compared with 76 to 97% of patients receiving comparator agents) and 62 to 93% of patients after 4 to 6 weeks (compared with 65 to 96% of patients receiving comparator agents). Reinfection rates were 8 to 13% in fosfomycin tromethamine recipients and 6 to 16% in control treatment groups. In 3 large double-blind comparisons with ciprofloxacin, cotrimoxazole and nitrofurantoin (237 to 273 evaluable patients per treatment arm), 99% of fosfomycin tromethamine recipients and 100% of patients receiving...