Metronidazole

Metronidazole enters the microbial cell by simple diffusion, without a dedicated transporter. Once inside, its nitro group is reduced by an enzyme specific to anaerobic microorganisms and protozoa, pyruvate-ferredoxin oxidoreductase. This reduction generates highly reactive free radicals that break the strands of DNA and cause it to lose its helical structure. Deprived of intact DNA, the germ can no longer replicate and dies.

This activation only takes place in an environment with a low oxidation-reduction potential, that of anaerobic metabolism. Metronidazole therefore strikes anaerobic bacteria and protozoa, but has no effect on aerobic bacteria, which do not reduce its nitro group. Its mean elimination half-life is eight hours in a healthy subject, which sets the rhythm of the doses across the day.

Metronidazole covers several protozoal infections: trichomoniasis, amebiasis and giardiasis. It also treats bacterial vaginosis and infections caused by anaerobic bacteria, in particular intra-abdominal infections. Its range of action overlaps exactly with the germs that thrive in the absence of oxygen, where its mechanism can be activated.

Outside its marketing authorization, it is also used against Clostridioides difficile, an anaerobic bacterium responsible for diarrhea after antibiotic therapy. The doctor chooses the molecule according to the targeted germ and its location. The length of the course is set by the indication, and the treatment is carried through to the end.

The oral dose can be taken during a meal to limit stomach discomfort. Eating at the same time does not reduce the total amount of medicine absorbed: the meal only lowers the concentration peak and delays the moment when this peak is reached. Overall efficacy remains the same, and digestive comfort improves.

With a half-life of eight hours, taking the doses regularly keeps an active concentration stable. Metronidazole is transformed by the liver, through oxidation of its side chain and glucuronidation, and 60 to 80 % of the dose leaves in the urine. The course must be carried through to the end and not stopped on one’s own as soon as the signs ease off, at the risk of letting the infection return.

The most reported adverse effects are headaches, in about 18 % of people, and vaginitis, in 15 %. Next come nausea, from 10 to 12 %, and a characteristic metallic taste in 9 %. Genital itching affects around 5 %, dizziness and diarrhea each 4 %. The metallic taste and nausea are among the most frequent and can interfere with eating during treatment.

Rarer but serious neurological effects have been described: encephalopathy, peripheral neuropathy sometimes affecting the optic nerve, and seizures. The neurological risk increases with prolonged or repeated courses. When such signs appear, stopping the treatment may become necessary, and any new neurological symptom must be reported to the doctor without delay.

Alcohol is to be avoided throughout the treatment and for at least three days after the last dose, including products containing alcohol or propylene glycol. The combination triggers a disulfiram-like reaction, with flushing, tachycardia, nausea, vomiting and abdominal cramps. Concurrent use of disulfiram itself is not advised, since psychotic reactions have been reported in alcoholic patients taking both molecules together.

Metronidazole strengthens the effect of coumarin anticoagulants such as warfarin, with a lengthening of the prothrombin time and therefore an increased risk of bleeding. A short course has also been associated with a rise in lithium levels and, in a few cases, with signs of lithium toxicity. These two treatments call for particular vigilance when combined with metronidazole.

During prolonged or repeated courses, a complete blood count with white blood cell differential is recommended, because metronidazole can cause leukopenia and neutropenia. Neurological monitoring accompanies these long courses, in order to detect neuropathy or other signs of nervous system involvement early.

In people treated with warfarin, the prothrombin time, expressed by the INR, is checked throughout the combination. In those taking lithium, the lithium level is measured in the same way. These measurements adjust the doses and avert complications before they set in.