Fosmicin Mechanism of Action

FOSMICIN is a sodium salt of fosfomycin and is given by intravenous administration. It is effective against infections due to Pseudomonas aeruginosa, Proteus sp., Serratia marcescens, and multidrug resistant strains of Staphylococcus aureus and Escherichia coli. Its mechanism of action is characteristic, and cross-resistance between fosfomycin and other antibiotics has not been demonstrated. Almost no binding to serum proteins has been reported. In animal studies, there has been no evidence of fosfomycin's possessing antigenicity.
Pharmacology: Antibacterial Activity: Fosfomycin acts bactericidally on gram-positive and gram-negative pathogens. It is especially highly active against Pseudomonas aeruginosa, Proteus sp., Serratia marcescens, and multidrug resistant strains of Staphylococcus aureus and E.coli.
Mechanism of Action: The mode of action of fosfomycin is very unique. It is taken into bacterial cells in high concentration via the active transport system against a concentration gradient, and inhibits the initial stage of cell wall synthesis (β-lactam antibiotics inhibit the final stage of cell wall synthesis).
Clinical Data: The results of 3 comparative clinical tests and general clinical trials using 1,021 patients were as follows.
Clinical Efficacy: The efficacy rate was: 37.5% (6/16 cases) for septicemia and bacteremia; 64.8% (107/165 cases) for pneumonia, bronchitis, etc., 67.6% (213/315 cases) for peritonitis, pyelonephritis and cystitis, 90.9% (30/33 cases) for adnexitis, 87.0% (47/54) for intrauterine infection, 86.7% (13/15) for pelvic dead space inflammation, 66.7% (6/9) for parametritis and 100% (15/15) for bartholinitis.
**Results of Postmarketing Surveillance.
The results of 6-year postmarketing surveillance in Japan are as follows: 33,711 clinical case reports were obtained from physicians at 2,618 institutions nationwide. There were 591 cases (1.75%) with 710 episodes of side effects .
The principal side effects developed were as follows. (See Table 2.)

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Pharmacokinetics: In Vivo Pharmacokinetic Behavior: Absorption and Excretion: In healthy adult volunteers receiving one-hour intravenous drip infusion of 2 g dissolved in 300 ml of 5% glucose solution, a mean peak blood concentration of 157.3 μg/ml was attained at the time of completion of the infusion. This gradually decreased thereafter, reaching a level of 2.6 μg/ml at 12 hours after infusion. The serum half-life was 1.8 hours.
The urinary recovery rate was 96% on an average within the first 12 hours.
Tissue Concentrations: Distribution to the cerebrospinal fluid was observed in patients with meningitis after continuous intravenous drip infusion.
Toxicology: Non-Clinical Tests: Acute Toxicity: See Table 3.

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Subacute and Chronic Toxicities: In subacute toxicity tests using rats and rabbits, the maximum non-effect dose was surmised to be 500 mg/kg/day in rats and 400 mg/kg/day in rabbits. In chronic toxicity tests using rats and dogs, the maximum non-effect dose was surmised to be 250 mg/kg/day for both animals.
Teratogenicity: Neither teratogenic effect, toxicity to the fetus nor influence on the growth of neonates was observed in tests using pregnant rats and rabbits administered the drug intraperitoneally or intravenously during the organogenesis, perinatal and lactation periods.
Antigenicity: No antigenicity of the drug was found in animal experiments using rabbits and mice and investigation for induction of IgG and IgE antibodies.
Mutagenicity: Ames and dominant lethal tests using mice showed that the drug possesses no mutagenicity.
Distribution: The drug efficiently transferred to the kidney, liver, lung, spleen, heart, thymus gland, aqueous humor, etc., after administering it at 40 mg/kg to rabbits.