| Mode of action | The N-acetylmuramic acid component of the bacterial cell wall is derived from N-acetylglucosamine by the addition of a lactic acid substituent derived from phosphoenolpyruvate. Fosfomycin blocks this reaction by inhibiting the pyruvyl transferase enzyme involved. The antibiotic enters bacteria by utilizing active transport mechanisms for α-glycerophosphate and glucose-6-phosphate. Glucose-6-phosphate induces the hexose phosphate transport pathway in some organisms (notably Escherichia coli) and potentiates the activity of fosfomycin against these bacteria.
|
| Chemical Properties | Water-soluble crystals. |
| Originator | Fosfocin,Crinos,Italy,1977 |
| Uses | Antibacterial. |
| Definition | ChEBI: A phosphonic acid having an (R,S)-1,2-epoxypropyl group attached to phosphorus. |
| Manufacturing Process | (A) The preparation of [(1-chloroethoxy)chloromethyl]phosphonic acid:
Acetaldehyde (1.1 mol) and hydroxymethylphosphonic acid (1 mol) in 500 ml
of benzene are saturated with hydrogen chloride gas at 10°C to 15°C. The
mixture is aged at 25°C for 24 hr, the solvent distilled out in vacuo and the
residue flushed three times with benzene to remove all traces of hydrogen chloride. The residue is taken up in benzene (500 ml), treated with tert-butyl
hypochlorite (0.8 mol) and azobisisobutyronitrile (0.8 mm) at 40°C until
titration shows the absence of hypochlorite and the solution is then
evaporated to yield [(1-chloroethoxy)chloromethyl] phosphonic acid in the
form of an oil.
(B) The preparation of (cis-1,2-epoxypropyl)phosphonic acid: [(1-
chloroethoxy)chloromethyl] phosphonic acid (1.0 g) is added with stirring to
tetrahydrofuran (50 ml) to which has been added a crystal of iodine and a
zinc-copper couple (15.0 g). The mixture is then heated under reflux for 24 hr
and the resulting solution filtered to yield (cis-1,2-epoxypropyl)-phosphonic
acid.
There is also a fermentation route to Fosfomycin as noted by Kleeman and
Engel. |
| Therapeutic Function | Antibiotic |
| Clinical Use | Phosphomycin, introduced in 1972, inhibits enolpyruvial transferase, an enzyme catalyzing an early step in
bacterial cell wall biosynthesis. Inhibition results in reduced synthesis of peptidoglycan, an important
component in the bacterial cell wall. Phosphomycin is bactericidal against Escherichi a coli and Enterobacter
faecali s infections. |
| Drug interactions | Potentially hazardous interactions with other drugs
Metoclopramide: increases gastrointestinal motility
and therefore lowers the serum concentration and
urinary excretion of fosfomycin. |
| Metabolism | Fosfomycin undergoes no biotransformation and is
excreted mainly unchanged through the kidneys. This
results in very high urinary concentrations (up to 3
mg/mL) within 2-4 hours of a dose. Therapeutic
concentrations of 200-300 mcg/mL in urine are usually
maintained for at least 36 hours, and can last from 48-72
hours. |
