Pharmacotherapeutic group: Antibiotics for systemic use, other antibacterials. ATC-Code: J01XX01.
Pharmacology: Pharmacodynamics: Mode of action: Fosfomycin exerts a bactericidal effect on proliferating pathogens by preventing the enzymatic synthesis of the bacterial cell wall. Fosfomycin inhibits the first stage of intracellular bacterial cell wall synthesis by blocking peptidoglycan synthesis.
Fosfomycin is actively transported into the bacterial cell via two different transport systems (the sn-glycerol-3-phosphate and hexose-6 transport systems).
Pharmacokinetic (PK)/pharmacodynamic (PD) relationship: Limited data indicate that fosfomycin most likely acts in a time-dependent manner.
Resistance mechanism: Main mechanism of resistance is a chromosomal mutation causing an alteration of the bacterial fosfomycin transport systems. Further resistance mechanisms, which are plasmid- or transposon-borne, cause enzymatic inactivation of fosfomycin by binding the molecule to glutathione or by cleavage of the carbon-phosphorus-bond in the fosfomycin molecule, respectively.
Cross-resistance: The mode of action of fosfomycin differs from that of all other antibiotic classes. Fosfomycin was generally found to be active in-vitro against clinical isolates of methicillin-resistant staphylococci, vancomycin-resistant enterococci, penicillin and erythromycin-resistant streptococci and multiresistant Pseudomonas.
Antimicrobial spectrum of fosfomycin (in vitro): The data predict only the probability of micro-organism susceptibility to fosfomycin.
For intravenous fosfomycin, the susceptibility breakpoints established by the European Committee on Antimicrobial Susceptibility Testing are as follows (EUCAST breakpoint table version 5.0, 2015). (See Table 1.)
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The prevalence of acquired resistance of individual species may vary geographically and over time. Local information about the resistance situation is therefore necessary, particularly in order to ensure appropriate treatment of severe infections.
In-vitro activity spectrum of fosfomycin and resistance: The following table is based on the breakpoint according to EUCAST and comprises organisms relevant for the approved indications: See Table 2.
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The physiologically important apathogenic anaerobic species, Lactobacillus and Bifidobacterium, are not susceptible to fosfomycin.
Pharmacokinetics: A single intravenous infusion of 4 g of fosfomycin in young healthy males resulted in maximum serum concentration (Cmax) of approx. 200 μg/ml. The serum half-life was approx. 2 hours.
Distribution: The apparent volume of distribution of fosfomycin is approx. 0.30 l/kg body weight. Fosfomycin is distributed well to tissues. High concentrations are reached in eyes, bones, wound secretions, musculature, cutis, subcutis, lungs and bile. In patients with inflamed meninges, cerebrospinal fluid concentrations reach approx. 20-50% of the corresponding serum levels. Fosfomycin passes the placental barrier. Low quantities were found in human milk (about 8% of the serum concentrations). The plasma protein binding is negligible.
Metabolism: Fosfomycin is not metabolised by the liver and does not undergo enterohepatic circulation. No accumulation is therefore to be expected in patients with hepatic impairment.
Elimination: 80-90% of the quantity of fosfomycin administered to healthy adults is eliminated renally within 10 hours after a single intravenous administration. Fosfomycin is not metabolized, i.e. the biologically active compound is eliminated. In patients with normal or mildly to moderately impaired renal function (creatinine clearance ≥ 40 ml/min), approximately 50-60% of the overall dose is excreted within the first 3-4 hours.
Linearity: Fosfomycin shows linear pharmacokinetic behaviour after intravenous infusion of therapeutically used doses.
Special populations: Very limited data are available in special populations.
Elderly: No dose adjustment is necessary based on age alone. However, renal function should be assessed and the dose should be reduced if there is evidence of renal impairment (see Dosage & Administration).
Paediatric population: The pharmacokinetics of fosfomycin in children and adolescents aged 3-15 years as well as in term newborns with normal renal function are generally similar to those of healthy adult subjects. However, in renally healthy neonates and infants up to 12 months, the glomerular filtration rate is physiologically decreased compared to older children and adults. This is associated with a prolongation of the elimination half-life of fosfomycin in dependence on the stage of renal maturation.
Renal insufficiency: In patients with impaired renal function, the elimination half-life is increase proportionally to the degree of renal insufficiency. Patients with creatinine clearance values of 40 ml/min or less require dose adjustments (see also Dosage in renal insufficiency under Dosage & Administration for further details).
In a study investigating 12 patients under CVVHF customary polyethylene sulfone haemofilters with a membrane surface of 1.2 m2 and a mean ultrafiltration rate of 25 ml/min were employed. In this clinical setting, the mean values of plasma clearance and elimination half-life in plasma were 100 ml/min, and 12h, respectively.
Hepatic insufficiency: There is no requirement for dosage adjustments in patients with hepatic insufficiency since the pharmacokinetics of fosfomycin remains unaffected in this patient group.
Toxicology: Preclinical Safety data: Subacute and chronic toxicity: The toxicity of Fosfomycin following repeated administration for up to 6 months was evaluated in rats, dogs, rabbits and monkeys. At high intra-peritoneal doses of Fosfomycin (> 500 mg/kg/day), rats developed respiratory arrest, tetanic cramps, anemia, a reduction of blood protein levels, increased serum cholesterol and reduced blood glucose. Furthermore, dogs and monkeys experienced diarrhea due to antibiotic-related changes in the intestinal flora following intravenous administration of doses higher than 250 mg/kg/day and 500 mg/kg/day, respectively. In the rabbit, no toxicity was observed following intravenous administration of 400 mg/kg/day for a period of 1 month.
Reproductive toxicity: Fertility: In male and female rats, following repeated administration (via a pharyngeal tube) of up to 1400 mg/kg/day reduced fertility was observed at the maximum dose tested.
Teratogenicity: Fosfomycin was administered to mice, rats and rabbits via pharyngeal tube at maximum doses of 2 x 120 mg/kg/day, 1400 mg/kg/day and 420 mg/kg/day, respectively or intravenously to mice and rabbits at 55.3 mg/kg/day, and up to 250 mg/kg/day, respectively. There was no evidence of embryotoxicity or teratogenicity.
Perinatal and postnatal toxicity: In rats, a maximum dose of 2800 mg/kg/day was administered via a pharyngeal tube. There was no evidence of fetal or peri- and postnatal toxicity.
Mutagenicity: In vitro tests were performed to test the alkylating capacity and the mutagenic effect of Fosfomycin. Fosfomycin showed no alkylating effect. In the Ames test, no mutagenic effect was seen in test strains of Salmonella typhimurium (TA 98, TA 100, TA 1535, TA 1537 and TA 1538, with and without addition of rat-liver homogenate) after exposure Fosfomycin at up to 1600 μg/ml.