Fosfomycin

Fosfomycin is an antibiotic that blocks the building of the bacterial wall from its very first step. It irreversibly inactivates an enzyme called enolpyruvyl transferase, or MurA. This enzyme launches the synthesis of peptidoglycan, the rigid mesh that surrounds the bacterium, by condensing UDP-N-acetylglucosamine with phosphoenolpyruvate. By neutralising MurA, fosfomycin cuts off this production at the source, and the bacterium can no longer build its envelope.

The block depends on the way the molecule attaches: it binds covalently to a conserved cysteine in the active site of MurA, which puts the enzyme out of service for the long term. Fosfomycin still has to get inside the bacterium. To do this it uses one of two transporters, the glycerol-3-phosphate system (GlpT) or the hexose-phosphate system (UhpT). Mutations in the glpT or uhpT genes close these entry points, reduce the antibiotic’s penetration and make the strain resistant.

Fosfomycin trometamol, the form that is swallowed, targets a precise situation: acute uncomplicated cystitis in women. It treats infections caused by susceptible strains of Escherichia coli and Enterococcus faecalis, the two bacteria most often responsible for a lower urinary tract infection. Its value lies in its simple intake and its targeted action on the bladder.

Its indication stops at the bladder. Oral fosfomycin is not suitable for treating pyelonephritis, the infection that affects the kidney itself, nor a perinephric abscess. These deeper conditions call for other treatments. The diagnosis therefore guides the prescription: the same molecule does not answer to all urinary tract infections.

The oral form has a rare feature: it is taken as a single 3 g dose. The sachet dissolves in 90 to 120 mL of water at room temperature, about half a glass, and is drunk right away, with or without food. This single intake is enough for the targeted cystitis; there is no treatment to continue over the following days.

After this intake, fosfomycin stays in the body long enough to act: its plasma half-life is 5.7 hours on average, with a variation of plus or minus 2.8 hours from one person to another. It is eliminated unchanged in the urine and stools, which concentrates it where it must work, in the urinary tract. A single intake is followed to the letter: the dose is calculated for one administration, it is not doubled and not repeated on one’s own initiative.

The adverse effects of the oral form were measured in clinical trials. The most common is diarrhoea, in 9.0% of people. Then come vaginitis in 5.5%, nausea in 4.1% and headache in 3.9%.

Other effects appear more rarely: dizziness in 1.3% of people, tiredness, or asthenia, in 1.1%, and difficult digestion, or dyspepsia, in 1.1%. Diarrhoea, the most frequent, invites care with food for a few days.

A medicine can change the effectiveness of fosfomycin by altering its route through the body. Metoclopramide, used against nausea, lowers the serum concentrations of fosfomycin and the amount eliminated in the urine. Other medicines that speed up gastrointestinal motility, that is, transit, can have the same effect: by moving the digestive contents along faster, they leave the antibiotic less time to pass into the blood.

During pregnancy, the rule is caution: fosfomycin should be used only if it is clearly necessary. This decision rests with the doctor, who weighs the expected benefit against each person’s situation. Reporting a pregnancy or a wish to become pregnant at the time of prescription is therefore part of the useful dialogue.

There is a second form, fosfomycin disodium, given intravenously in hospital for more severe infections. It has a constraint of its own: a high sodium load, with 330 mg of sodium per gram of fosfomycin, or 1,980 mg of sodium per vial. This sodium can raise blood sodium and, at the same time, lower potassium, calcium and phosphorus. A low-sodium diet is recommended during this treatment.

Laboratory monitoring frames this intravenous form. In one trial, the abnormalities observed were hypokalaemia, potassium below 3.0 mEq/L, in 9.9% of patients, hypernatraemia in 3.4%, hypocalcaemia in 3.9% and hypophosphataemia in 2.1%. Sodium, potassium, calcium, magnesium and phosphorus are therefore monitored, along with hydration status, with heightened vigilance in cases of heart failure, kidney failure, cirrhosis, hypertension or pulmonary oedema.