Fosfomycin

Fosfomycin is a phosphonic acid derivative, the only member of its class, with bactericidal activity against many Gram-positive and Gram-negative bacteria. It has no cross-resistance with other classes, which makes it useful against ESBL-producing and some carbapenem-resistant organisms. Oral fosfomycin trometamol is a single-dose treatment for uncomplicated cystitis. Intravenous fosfomycin disodium is used as part of combination therapy for serious infection.

Mechanism. Irreversible inhibition of MurA (UDP-N-acetylglucosamine enolpyruvyl transferase), blocking the first committed step of peptidoglycan synthesis. Entry occurs through the glycerol-3-phosphate and hexose phosphate transporters, which are upregulated by glucose-6-phosphate, so culture testing is done with added glucose-6-phosphate.

Pharmacokinetics. Oral bioavailability of the trometamol salt is 30 to 40 percent; excreted unchanged in urine, giving high urinary concentrations for 48 hours or longer. IV: low protein binding, wide tissue distribution including bone, CSF and abscess; half-life 4 to 8 hours; almost entirely renal elimination.

Spectrum. E. coli (including ESBL), Enterococcus faecalis, MSSA and MRSA, many Enterobacter and Citrobacter. Less reliable against Klebsiella (fosA gene), Serratia, Pseudomonas aeruginosa and Acinetobacter. Resistance can emerge during monotherapy.

• Fosfomycin trometamol (oral sachet): cystitis and prostatitis.
• Fosfomycin disodium (IV): combination therapy for bone and joint infection, bacteraemia, endocarditis, meningitis and resistant Gram-negative infection.

Adult regimens (normal renal function).

• Uncomplicated cystitis: fosfomycin trometamol 3 g orally as a single dose, dissolved in water, taken on an empty stomach at bedtime after emptying the bladder. For complicated or ESBL infection, 3 g every 48 to 72 hours for 3 doses.
• Chronic bacterial prostatitis: 3 g every 48 to 72 hours for 3 to 6 weeks in specialist practice.
• IV fosfomycin: 12 to 24 g daily in 3 or 4 divided doses (for example 4 to 8 g every 8 hours), always with a second active agent, for bone and joint infection, MRSA bacteraemia (with daptomycin) and carbapenem-resistant infection.
• Children over 12 years: oral 3 g single dose. Younger children are dosed by weight and age under specialist advice.

Selection. Single-dose oral therapy for uncomplicated cystitis when first-line agents are unsuitable or resistance is present. Not for pyelonephritis as single-agent oral therapy. IV use is reserved for resistant infection and always in combination.

Contraindications. Hypersensitivity; severe renal impairment (creatinine clearance under 10 mL/min) for oral therapy; IV use in heart failure or hypernatraemia without adjustment.

Serious and common effects. Oral: diarrhoea, nausea, headache, vaginitis. IV: large sodium load (hypernatraemia, hypokalaemia, fluid overload, worsening heart failure), phlebitis, transaminase elevation, rarely marrow suppression and QT prolongation.

Interactions. Metoclopramide lowers absorption of oral fosfomycin; probenecid reduces urinary excretion.

Monitoring. IV: sodium, potassium, creatinine, liver tests and fluid status at least every 2 to 3 days.

Special groups. Pregnancy: oral single dose acceptable for cystitis; breastfeeding: acceptable. Renal impairment: IV dose reduced stepwise as creatinine clearance falls (about 50 percent at 40 to 60 mL/min, with longer intervals at lower clearance). Older adults: sodium load needs attention. Region: availability is limited in East Africa.