ホスホマイシン

Pharmaceuticals -> Antibiotics

Pharmaceuticals -> Listed in ZINC15

Pharmaceuticals -> Used in Switzerland

This chemical does not meet GHS hazard criteria for 100% (4 of 4) of all reports.

Not Classified

Aggregated GHS information provided per 4 reports by companies from 1 notifications to the ECHA C&L Inventory.

Serum aminotransferase elevations occur in a small proportion of patients after a single oral dose of fosfomycin (1-2%), but at rates similar to those with comparator antibiotics. Nevertheless, serum enzyme elevations are mentioned as potential adverse events in the product label for fosfomycin. In addition, a small number of cases of clinically apparent liver injury attributed to fosfomycin have been published. The time to onset has been short, within one week of a single oral dose or within the first week of intravenous therapy, and the pattern of liver enzyme elevations has been mixed or hepatocellular. The injury has typically been mild and self-limited, and no cases of fatal acute liver failure, chronic hepatitis or vanishing bile duct syndrome have been convincingly linked to fosfomycin. The number of cases described has been too few to establish a typical clinical pattern, but immunoallergic features and autoimmune markers appear to be uncommon.

Drug-Induced Liver Injury Severity and Toxicity (DILIst)

fosfomycin

DILI Positive

Oral

DOI:10.1016/j.drudis.2019.09.022

Fosfomycin

69.9

295.9

The recommended dosage for women 18 years of age and older for uncomplicated urinary tract infection (acute cystitis) is one sachet (3 g of fosfomycin).

Data used to generate the benchmarks include the following: Lowest Daily Dose (LDD): 3000 mg/day, Lowest Therapeutic Dose (LTD): 37.5 mg/kg-day, and Screening Dose: 0.01 mg/kg-day.

24-Oct-19

J01XX01

J - Antiinfectives for systemic use

S - Sensory organs

QJ - Antiinfectives for systemic use

QS - Sensory organs

Although used primarily to treat urinary tract infections, fosfomycin has been shown to act synergistically with other antibiotics against clinically relevant bacteria. There is also growing interest in the potential of fosfomycin to treat more complex infections since it has retained activity against many difficult-to-treat strains of bacteria including methicillin-resistant _Staphylococcus aureus_ (MRSA) and multidrug-resistant enterobacteria. Further, since fosfomycin has a unique and singular mechanism of action, the risk of cross-resistance with other antibiotics is low. Fosfomycin also demonstrates immunomodulating properties. For example, the antibiotic may influence components of the acute inflammatory cytokine response and enhances neutrophil phagocytic destruction of pathogens. Fosfomycin penetrates biofilms effectively and is capable of not only reducing or eliminating microorganisms in biofilms but can also alter the biofilm structure.

Fosfomycin exerts its bactericidal effects by binding covalently to a cysteine in the active site of the UDP-N-acetylglucosamine enolpyruvyl transferase (MurA) enzyme, rendering it inactive. By preventing MurA from catalyzing the condensation of phosphoenolpyruvate (PEP) with UDP-N-acetylglucosamine (UNAG), fosfomycin inhibits the production of the peptidoglycan precursor UDP N-acetylmuramic acid (UDP-MurNAc). Ultimately, the first step of bacterial cell wall synthesis is disrupted. In _Escherichia coli_, fosfomycin gains entry into bacterial cells via two mechanisms: the L-alpha-glycerophosphate system and the hexose-6-phosphate transporter system. Fosfomycin also has important effects on cell adhesion. For example, the adhesion of bacterial cells to urinary epithelial cells is reduced in the presence of fosfomycin. The adhesion of _Streptococcus pneumoniae_ and _Haemophilus influenzae_ to respiratory epithelial cells is also reduced

Fosfomycin is a low molecular weight and hydrophilic drug. When administered orally, fosfomycin is rapidly absorbed in the small intestine and distributed widely to the tissues. The oral bioavailability ranges from 34-58%. Co-administration of fosfomycin with food decreases gastrointestinal absorption to approximately 30%. The reported AUC = 145-228 mg x h/L, while the reported Cmax = 26.1 (∓9.1) mcg/mL.

Fosfomycin is excreted almost entirely by the kidneys. Factors including administration with food, impaired renal function, and older age may reduce the rate of fosfomycin elimination.

In healthy subjects, the volume of distribution (Vd) of fosfomycin is approximately 0.3 L/Kg. Due to changes in the vascular endothelium, the Vd can be up to 50% higher in critically ill patients.

In one study, the reported CL/F of fosfomycin in healthy volunteers was 17 ∓ 4.7 L/hour.