Mechanism of Action and Selectivity
Fosfomycin belongs to the class of murein monomer synthesis inhibitors. Its primary target is the initial assembly stage of the peptidoglycan bacterial cell wall.
Chemically, the drug is a structural analogue of phosphoenolpyruvate (PEP). Its biochemical action involves the irreversible blockade of enzymatic condensation. The antibiotic induces covalent modification of the active site of the enzyme UDP-N-acetylglucosamine-3-enolpyruvyltransferase (shortly, MurA). This process reliably blocks the formation of UDP-N-acetylmuramic acid (UDP-NAM) from its precursor, uridine diphosphate-N-acetylglucosamine (UDP-NAG). Without this step, murein monomers are simply not formed.
An important property of the drug is its selective toxicity. It does not affect human enzymes (enolase, pyruvate kinase, or carboxykinase), making it relatively non-toxic to the human host.
Transport and Antibacterial Spectrum
To reach its target, the antibiotic must enter the microbial cell. Fosfomycin achieves this via active transport, utilizing bacterial nutrient uptake systems—specifically the glycerophosphate or glucose-6-phosphate transporters.
Fosfomycin exerts a bactericidal effect and possesses a broad spectrum of activity:
- Gram-negative bacteria (primary target): Escherichia coli, Klebsiella spp., Proteus mirabilis, Proteus vulgaris, as well as Citrobacter, Enterobacter, Serratia, and Morganella morganii.
- Gram-positive bacteria: Staphylococci, streptococci, and enterococci. However, efficacy against them is lower because a number of Gram-positive microorganisms lack the selective transporters required for drug uptake into the cell.
Pharmacokinetics and Clinical Application
The key pharmacokinetic feature of fosfomycin is its excretion profile. It is excreted renally in an entirely unchanged form, achieving extremely high concentrations within the urinary tract.
This provides a tremendous clinical advantage: for uncomplicated urinary tract infections (cystitis, urethritis) caused by susceptible flora, a single oral dose (3 g) is sufficient. This single dose is equivalent to a multi-day course of other antibiotics.
- Prevention and treatment of infectious complications during surgical procedures and transurethral diagnostics.
- Treatment of pregnant women (serving as a safe alternative to fluoroquinolones, which are contraindicated during pregnancy).
Dosage regimens depend on the route of administration. Orally, it is administered once daily. Parenteral administration requires intravenous use every 6–8 hours or intramuscular use twice daily.
Side Effects and Related Compounds
The drug is generally well tolerated. Adverse effects are rare (occurring in 1–10% of patients) and are typically limited to headache, nausea, or diarrhea.
When prescribed orally, it is important to consider drug interactions that can reduce the absorption of the antibiotic. These include:
- Antacids.
- Calcium salts.
- Agents that increase gastrointestinal motility (e.g., metoclopramide).
The murein monomer inhibitor class also includes a related compound, fosmidomycin. It is also a PEP analogue and shares a similar mechanism of action. However, clinical practice with fosmidomycin has revealed issues with resistance development. Resistance mechanisms include mutations in transport systems (glycerophosphate or glucose-6-phosphate transporters) and active drug efflux via specific pump proteins, as described in E. coli strains. Fosmidomycin is not used clinically in many regions.