Fosmicin Mechanism of Action

Fosmicin is a sodium salt of fosfomycin and is given by IV administration. It is effective against infections due to Pseudomonas aeruginosa, Proteus sp, Serratia marcescens, E. coli and methicillin-resistant Staphylococcus aureus. 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 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, E. coli and methicillin-resistant Staphylococcus aureus.
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).
Pharmacokinetics: In Vivo Pharmacokinetic Behavior: Absorption and Excretion: In adult patients, IV injection of 1 g dissolved in 20 mL of 20% glucose solution produced a mean peak blood concentration of 74 mcg/mL at 30 min after injection, which gradually decreases to 8 mcg/mL by 6 hrs after injection. In healthy adult volunteers receiving 1-hr IV drip infusion of 2 g dissolved in 300 mL of 5% glucose solution, a mean peak blood concentration of 157.3 mcg/mL was attained at the time of completion of the infusion. This gradually decreased thereafter, reaching a level of 2.6 mcg/mL at 12 hrs after infusion. The serum half-life was 1.8 hrs.
The urinary recovery rate was 96% on an average within the first 12 hrs.
Tissue Concentrations: Distribution to the cerebrospinal fluid was 54% observed in patients with meningitis after IV drip infusion.
Clinical Data: The results of 3 comparative clinical tests and general clinical trials using 1021 patients were as follows:
Clinical Efficacy: The efficacy rate was: 80.77% (21/26 cases) for septicemia and bacteremia; 94.4% (17/18 cases) for burn, 90.9% (30/33 cases) for adnexitis, 87% (47/54) for intrauterine infection, 86.7% (13/15) for pelvic dead space inflammation, 66.7% (6/9) for parametritis and 77.8% (10/13) for bone and joint infections.
**Results of Post-Marketing Surveillance.
The results of 5-year post-marketing surveillance since July 1994 to March 1999 are as follows: 100, 230 clinical case reports were obtained from 4737 medical facilities nationwide. There were 562 cases (0.56%) of side effects.
The principal side effects developed were as shown in Table 2. (See Table 2.)

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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 no-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 when they administered the drug intraperitoneally or IV during the organogenesis, perinatal and lactation periods.
Antigenicity: No antigenicity of fosfomycin 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.