Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties
Pharmacotherapeutic group: Antibacterials for systemic use; Other antibacterials ATC-Code: J01XX01
Mechanism 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/pharmacodynamic relationship
Limited data indicate that fosfomycin most likely acts in a time-dependent manner.

Mechanism of resistance
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
Cross-resistance between fosfomycin and other antibiotic classes is not known.
Susceptibility testing breakpoints
Minimum inhibitory concentration (MIC) breakpoints established by the European Committee on Antimicrobial Susceptibility Testing are as follows (EUCAST breakpoint table version 10):
Species                             susceptible                   resistant Enterobacterales                    ≤ 32 mg/L                     > 32 mg/L Staphylococcus spp.                 ≤ 32 mg/L                     > 32 mg/L Susceptibility
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.
The information below gives only approximate guidance on the probability as to whether the micro-organism will be susceptible to fosfomycin or not.
Commonly susceptible species
Aerobic Gram-positive microorganisms
Staphylococcus aureus
Aerobic Gram-negative microorganisms
Citrobacter freundii
Citrobacter koseri
Escherichia coli
Haemophilus influenzae
Neisseria meningitidis
Salmonella enterica
Anaerobic microorganisms
Fusobacterium spp.
Peptococcus spp.
Peptostreptococcus spp.
Species in which acquired resistance may be a problem
Aerobic Gram-positive microorganisms
Staphylococcus epidermidis
Streptococcus pneumoniae
Enterococcus spp.
Aerobic Gram-negative microorganisms
Enterobacter cloacae
Klebsiella aerogenes
Klebsiella oxytoca

Klebsiella pneumonia
Proteus mirabilis
Pseudomonas aeruginosa
Serratia marcescens
Anaerobic Gram-positive microorganisms
Clostridium spp.
Inherently resistant species
Aerobic Gram-positive microorganisms
Staphylococcus saprophyticus
Streptococcus pyogenes
Aerobic Gram-negative microorganisms
Legionella pneumophila
Morganella morganii
Stenotrophomonas maltophilia
Anaerobic Gram-negative microorganisms
Bacteroides spp.
Other mikroorganisms
Chlamydia spp.
Chlamydophila spp.
Mycoplasma spp.

Pharmacokinetic Properties

5.2   Pharmacokinetic properties
Pharmacokinetics
A single intravenous infusion of 4 g and 8 g of fosfomycin in young healthy males resulted in maximum serum concentrations (Cmax) of approximately 200 and 400 micrograms/ml, respectively. The serum half-life was approximately 2 hours. In elderly and/or critically ill male and female subjects, single intravenous doses of 8 g of fosfomycin resulted in mean Cmax and half-lives in plasma of approximately 350–380 micrograms/ml and 3.6–3.8 h, respectively.
Distribution
The apparent volume of distribution of fosfomycin is approximately 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 approximately 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 12 hours after a single intravenous administration. A small amount of the antibiotic is found in faeces (0.075%). Fosfomycin is not metabolised, 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 section 4.2).
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 increased proportionally to the degree of renal insufficiency. Patients with creatinine clearance values of 40 ml/min or less require dose adjustments (see also section 4.2. “Renal impairment” 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.