Fosfomycin

Fosfomycin is a phosphonic acid antibiotic given as a single oral dose (trometamol salt) for uncomplicated cystitis, and intravenously (disodium salt) as a combination partner in multidrug-resistant infection. It keeps activity against many ESBL-producing Enterobacterales and has no cross-resistance with other classes.

Classification. Phosphonic acid derivative.

Mechanism. Inhibits MurA enzyme (UDP-N-acetylglucosamine enolpyruvyl transferase), blocking the first step of cell wall peptidoglycan synthesis; bactericidal.

Spectrum. Escherichia coli (including ESBL and many carbapenemase producers), Enterococcus faecalis, Staphylococcus aureus including MRSA, Klebsiella (variable), Proteus, Pseudomonas aeruginosa (limited, used only IV and in combination). Weaker against Klebsiella and Enterobacter in monotherapy because of heteroresistance.

Pharmacokinetics. Oral bioavailability about 40% (reduced by food); urinary levels stay therapeutic for 48 to 72 hours after 3 g. Half-life 4 to 8 hours. IV drug distributes widely, including bone, CSF and abscess. Excreted unchanged in urine.

IV maximum 24 g daily.

Adults, oral. - Uncomplicated cystitis in women: fosfomycin trometamol 3 g as a single dose, in a sachet dissolved in water. - Complicated lower urinary tract infection, including ESBL-producing Escherichia coli: 3 g every 48 to 72 hours for 2 to 3 doses. - Chronic bacterial prostatitis (specialist): 3 g every 48 to 72 hours for 2 to 4 weeks. - Preoperative prophylaxis before transrectal prostate biopsy: 3 g once, 3 hours before.

Adults, IV (fosfomycin disodium; always with a second active drug). - 12 to 24 g daily in 3 to 4 divided doses (4 g every 6 hours or 6 to 8 g every 8 hours), infused over 30 minutes to 1 hour. - Multidrug-resistant bacteraemia, bone and joint infection, ventilator-associated pneumonia, meningitis (specialist): usual course 2 to 6 weeks, with oral step-down when possible.

Children. - Oral: 12 years and over 3 g single dose. Under 12 years specialist use only (limited data). - IV: 100 to 200 mg/kg/day divided every 6 to 8 hours (up to 300 mg/kg/day in severe infection; maximum 12 g daily in children); neonates 100 mg/kg/day divided every 8 to 12 hours.

Alternatives. Nitrofurantoin, trimethoprim, pivmecillinam, cephalexin (oral); carbapenems, amikacin, colistin, ceftazidime avibactam (IV).

Contraindications. Hypersensitivity; oral form when creatinine clearance is under 10 mL/min; fosfomycin IV with severe sodium or fluid overload (relative).

Adverse effects. Diarrhoea, nausea, headache, vaginitis, rash. IV use: hypokalaemia, hypernatraemia and fluid overload (sodium load), infusion-site phlebitis, raised transaminases. Rare: anaphylaxis, cholestatic hepatitis, optic neuritis, Clostridioides difficile infection.

Interactions. Metoclopramide (lowers urinary levels); other drugs that increase gastric emptying; warfarin (INR rise, rare); diuretics and drugs causing hypokalaemia (with IV use).

Common prescribing errors. Single IV drug in serious infection (resistance emerges), no sodium and potassium monitoring with IV doses, repeating oral doses at 24 hours, and use in pyelonephritis without a systemic agent.

Special groups. - Pregnancy: oral single dose acceptable when needed; IV use only when no alternative.

Breastfeeding: acceptable (low milk levels). - Older adults: usual dose; check kidney function and sodium load. - Kidney impairment (IV): reduce the daily dose by creatinine clearance, to about 70% at 40 to 60 mL/min, 60% at 30 to 40 mL/min, 40% at 20 to 30 mL/min, 20% at 10 to 20 mL/min, and 12 to 24 g once on dialysis days in specialist units.

Oral single dose is acceptable at creatinine clearance 10 mL/min or more, with a longer interval. - Liver impairment: no adjustment. - Region: oral sachets are available in some East African markets; IV supply is limited.

Preparation. Oral: dissolve the sachet in half a glass of water and drink at once, on an empty stomach, preferably at bedtime after emptying the bladder. IV: reconstitute each 4 g vial with 20 mL of sterile water and dilute in 100 to 250 mL of 5% glucose or 0.9% sodium chloride; infuse over 30 to 60 minutes. Each 4 g contains about 14 mmol of sodium.

Baseline and monitoring. - Baseline: creatinine, sodium, potassium, fluid status, urine culture. - IV: sodium, potassium, creatinine and liver tests at least twice weekly; weight and fluid balance.

Stop rules. Stop for anaphylaxis, severe hypokalaemia not corrected, heart failure from sodium load, or hepatitis.

Referral and escalation. Infectious diseases consultation for IV use and multidrug-resistant infection.