Uroday Mechanism of Action

Pharmacology: Pharmacodynamics: The structure of fosfomycin is analogous to that of p-enolpyruvate. This is why it inactivates the enzyme enolpyruvyl tranferase and thus the condensation of uridine diphosphate-Nacetylglucosamine with p-enolpyruvate is irreversible blocked, one of the first steps in the synthesis of the bacterial cell wall. Fosfomycin may also reduce bacterial adhesion to the bladder mucosa, which may be a predisposing factor for recurrent urinary tract infections. The susceptibility breakpoints established by the European Committee on Antimicrobial Susceptibility Testing are as follows (EUCAST breakpoint table version 11, 01.01 2021): (See table.)

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Prevalence of acquired resistance: 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 following table is based on data from surveillance programs and studies. It comprises relevant for the approved indications: Commonly susceptible species: Aerobic Gram-negative microorganisms; Escherichia coli.
Species in which acquired resistance may be a problem: Aerobic Gram-positive microorganisms; Enterococcus faecalis; Aerobic Gram-negative microorganisms; Klebsiella pneumonia; Proteus mirabilis.
Inherently resistant species: Aerobic Gram-positive microorganisms; Staphylococcus saprophyticus.
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.
The activity of Fosfomycin against the most common germs in case of urinary tract infection remained unchanged. Only a few bacteria can develop resistance.
The resistance rate of E.coli, which causes uncomplicated urinary tract infection is low.
Most resistant <<Multidrug>> E.coli and other Enterobacteriaceae, producing Extended Spectrum Beta-Lactamase (ESBL), are susceptible to Fosfomycin.
Most MRSA (Methicillin resistant Staph aureus) are also susceptible to Fosfomycin.
Cross-resistance: Cross-resistance between Fosfomycin and other antibiotic classes is not known. Cross-resistance should not be expected because the chemical structure of Fosfomycin is fundamentally different from that of all other antibiotics and Fosfomycin has unique mechanism of action.
Clinical efficacy: Fosfomycin has a broad antibacterial spectrum, which includes most of the gram-positive and gram-negative bacteria associated with urinary tract infections, as well as penicillinase producing strains.
In vivo, resistance has been observed in Enterobacter ssp., Klebsiella ssp., Enterococci, Proteus mirabilis, Staph. Aureus and Staph. Saprophyticus.
In addition, Uroday prevents the adhesion of bacteria to the bladder mucosa, which is predisposing factor for recurrent urinary tract infections.
Pharmacokinetics: General properties: Absorption: After a single-dose administration, fosfomycin trometamol has an absolute bioavailability of about 33-53%. Rate and extent of absorption are reduced by food, but the total amount of active substance excreted in the urine over the time is the same. Mean urinary Fosfomycin concentrations are maintained above an MIC threshold of 128 μg/ml for at least 24 h post 3 g oral dose in either the fasting or fed state, but the time to reach maximal concentrations in urine are delayed by 4 h. Fosfomycin trometamol undergoes enterohepatic recirculation.
After a single-dose administration of 3 g, tmax is 2-2.5 hours and Cmax is 22-32 μg/ml.
Distribution: Fosfomycin is distributed to tissues including the kidneys and bladder wall. Fosfomycin is not bound to plasma proteins. The volume of distribution is 136.1 l. Fosfomycin crosses the placental barrier and is excreted in human breast milk.
Elimination: Fosfomycin is excreted unchanged mainly via the kidneys by glomerular filtration (40-50% of the dose is found in the urine) with an elimination half-life of about 4 hours after oral use and to a lesser extent in faeces (18-28% of the dose). Even if food delays the drug absorption the total amount of the drug excreted in the urine over time is the same. After a single dose of 3 g fosfomycin trometamol, a urine concentration of fosfomycin of 1053-4415 μg/ml is reached after 2-4 hours. Therapeutically effective concentrations (>100 μg/ml) are still present up to 48 hours after administration.
Pharmacokinetics in special population: In patients with impaired renal function, the elimination half-life is increased proportionally to the degree of renal insufficiency. Urinary concentrations of fosfomycin in patients with impaired renal function remain effective for 48 hours after a usual dose if creatinine clearance is above 10 ml/min.
In older people fosfomycin clearance is reduced in line with the age-related reduction in renal function.
Metabolism: Fosfomycin does not appear to be metabolized.