Fosfomycin is a phosphate derivative that was first isolated from Streptococcus species in 1969 and could be synthesized artificially soon thereafter. Fosfomycin itself has poor oral absorption. Fosfomycin trometamol was artificially synthesized to increase oral bioavailability. The drug was launched in Europe in 1988 and in the United States in 1996. It is mainly used to treat uncomplicated urinary syndrome. Road infection.
Mechanism of action
Uridine diphosphate N-acetylglucosamine diphosphate (UDP.GlcNAc) enolpyruvyl transferase can catalyze the synthesis of uridine diphosphate N-acetylenolpyruvateglucosamine as an intermediate in the formation of peptidoglycan . Fosfomycin inhibits the activity of uridine diphosphate N-acetylglucose (UDP.GlcNAc) enolpyruvyltransferase (MurA) by binding to this enzyme, blocking the initial stage of cell wall formation and producing a bactericidal effect.
Fosfomycin is a concentration-dependent bactericide against Escherichia coli, Proteus mirabilis and Streptococcus pneumoniae, and a time-dependent bactericide against Staphylococcus aureus. At the same time, fosfomycin also has post-antibiotic effects. (Nikos Roussos)
Pharmacokinetic properties
Fosfomycin is absorbed in the small intestine after oral administration. Because it is easily hydrolyzed by the acidic environment in the digestive tract, the oral bioavailability of fosfomycin calcium salt is only 12-28%. Fosfomycin azatriol is absorbed after oral administration. Converted to fosfomycin, its oral bioavailability is 40%. Fosfomycin is not protein-bound in the blood. After oral administration of 3 g of fosfomycin tromethamine, the peak plasma concentration (Cmax) is 22-32 mg/L, the peak time is 2-2.5 hours, the elimination half-life is approximately 2.4-7.3 hours, and the area under the curve (AUC) is approximately 145-228mg/L, apparent volume of distribution (Vd) is 40-136L. Fosfomycin is almost completely eliminated unchanged through the kidneys through glomerular filtration, and no metabolites have been found.
In vitro antibacterial activity
Fosfomycin is a broad-spectrum antibacterial drug that is effective against aerobic Gram-negative bacteria such as Escherichia coli, Citrobacter coli, Citrobacter freundii, Haemophilus influenzae, Enterobacter aerogenes, and pneumonia. Klebsiella, Proteus mirabilis, and Serratia marcescens have good antibacterial activity against Gram-positive bacteria such as Staphylococcus aureus, Staphylococcus epidermidis, Enterococcus faecalis, Enterococcus faecium, Streptococcus pneumoniae, and Streptococcus pyogenes. , viridans streptococci, etc. also have good antibacterial activity.
Because it has a completely different mechanism of action from other antibacterial drugs, there is no cross-resistance, and it still has good antibacterial activity against many drug-resistant bacteria.
A Greek study on multi-drug-resistant Gram-negative bacteria showed that 30 strains of Klebsiella pneumoniae that produce both ESBLs and MBLs were 100% sensitive to fosfomycin, and the MIC90 of fosfomycin was 32 mg/ml. The sensitivity rate of 30 strains of ESBLs-producing Pseudomonas aeruginosa to fosfomycin was 90.0%, and the MIC90 was 128 mg/ml. (M.E. Falagas)
Another meta-study showed that the susceptibility of multidrug-resistant Enterobacteriaceae to fosfomycin exceeds 90%, and the susceptibility of ESBL-positive bacteria to fosfomycin also exceeds 90%. (Matthew E Falagas)
For Staphylococcus aureus, fosfomycin not only shows good antibacterial activity against MSSA, but also has good antibacterial activity against MRSA. Research in Austria shows that comparing the susceptibility to fosfomycin of Staphylococcus aureus isolated from 1994 to 2006, the sensitivity of MSSA to fosfomycin has always remained above 90%, and the sensitivity of MRSA isolated in different years to fosfomycin is 5 1.2% to 82.4%, and the sensitivity is related to the ST typing of the bacteria, rather than decreasing year by year. (C.Jebelean)
Fosfomycin also exhibits good antibacterial activity against vancomycin-resistant enterococci. The susceptibility of vancomycin-resistant Enterococcus faecalis was 100%, and the susceptibility of vancomycin-resistant Enterococcus faecium was 98.1%. (Mary Beth Peril)
Since fosfomycin tromethamine is mainly used to treat urinary tract infections, many scholars have observed the antibacterial activity of fosfomycin against bacteria isolated from urinary tract infections.
A Korean in vitro susceptibility study on Escherichia coli isolated from patients with urinary tract infection showed that the resistance rate to ciprofloxacin was 30.3%, the resistance rate to amoxicillin-clavulanic acid was 32.2%, and the resistance rate to gentamicin was 30.3%. The drug resistance rate was 22.8%, the drug resistance rate of co-trimoxazole was 43.0%, and the drug resistance rate of fosfomycin was only 0.3%. Among them, the sensitivity rate of ciprofloxacin-resistant Escherichia coli to fosfomycin was 100%, and the sensitivity rate of ESBL-positive strains to fosfomycin was also 100%. (Kwan Soo Ko)
A study in Switzerland showed that ESBL-positive bacteria isolated from patients with urinary tract infections were more than 95% sensitive to fosfomycin, while the sensitivity rate to furantantine was 79%. (Stephen P Hawser)
In the Netherlands from 2003 to 2004, 1,705 strains of Escherichia coli were isolated from patients with uncomplicated urinary tract infections across the country. The sensitivity rate to fosfomycin tromethamine was 99.35%. The MIC50 and MIC50 of fosfomycin tromethamine were The MIC90 are 1 mg/ml and 4 mg/ml respectively, and the sensitivity rates of nitrofurantoin and co-trimoxazole as first- and second-line therapeutic drugs are 98% and 77% respectively.
Although the clinical application of fosfomycin has been known for a long time, years of research have shown that the sensitivity of bacteria to fosfomycin has not changed much.
Spain compared the susceptibility of different bacteria to fosfomycin from 1973 to 2002. Among them, the susceptibility of Escherichia coli, Staphylococcus aureus, Salmonella and Serratia marcescens to fosfomycin has always remained At more than 80%, the sensitivity of the above-mentioned bacteria and Enterobacter, Klebsiella and Pseudomonas aeruginosa to fosfomycin has not been found.Changes appear instantaneously. (M.Gobernado) stated that no significant increase in drug resistance was found in the long-term application of fosfomycin.
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Clinical Application
There are 150 million urinary tract infections worldwide every year, 90% of which are uncomplicated urinary tract infections. The main pathogenic bacteria is Escherichia coli. Escherichia coli isolated from the urinary tract is very sensitive to ciprofloxacin, sulfonamides, The resistance rate of β-lactams and other antibiotics is increasing year by year, but the susceptibility rate of fosfomycin to Escherichia coli has remained around 99%. Fosfomycin tromethamine can be used orally, and the drug is mainly excreted in the urine as its prototype, with a high concentration in the urine. Therefore, it is widely used to treat uncomplicated urinary tract infections and prevent recurrent urinary tract infections. (G.C.Schito)
In a prospective study in Spain, a single oral dose of 3 g fosfomycin tromethamine in the treatment of community-acquired cystitis had a cure rate of 93%, while the control group of amoxicillin/clavulanic acid three times a day had a cure rate of 93%. Each dose is 625 mg, taken continuously for 5-7 days, and the cure rate is 84%. (Rodriguez·Bano J)
A randomized, double-blind study in Ukraine of fosfomycin tromethamine versus placebo showed that oral administration of 3 g of fosfomycin tromethamine every 10 days for 6 months was used to treat patients with recurrent urinary tract infections. After that, the time to the first episode of urinary tract infection was 38 days, compared with 6 days in the placebo group; the incidence rate of urinary tract infection within one year in the fosfomycin trometamol group was 0.14 times per patient, compared with 2.97 times in the placebo group. /patient. (Nikolay Rudenko)
Due to the high sensitivity of fosfomycin to ESBL-positive Gram-negative bacteria, fosfomycin tromethamine can be used to treat urinary tract infections caused by ESBL-positive bacteria.
Fosfomycin tromethamine is taken once every other day, 3g each time, for a total of three times to treat urinary tract infections caused by ESBL-positive Escherichia coli. All strains are resistant to ciprofloxacin and co-trimoxazole, and there are clinical The efficiency and bacterial removal rate were 94.3% and 78.5% respectively. (Husnu Pllukcu)
Administer 3 g of fosfomycin trometamol orally 3 hours before and 24 hours after a transurethral diagnostic or therapeutic operation. The incidence of urinary tract infection on the second postoperative day was 3.2%. The incidence of urinary tract infection on the seventh day was 3.6%, which was significantly lower than the incidence of urinary tract infection after amoxicillin and cefotaxime prophylaxis. (F.d high temperature resistant inorganic pigment i Silverio)
Patients with renal insufficiency require appropriate dose adjustment. Fosfomycin tromethamine can also be used when pregnant women have urinary tract infections. For asymptomatic bacteriuria during pregnancy, it is recommended to take a single dose of 3g fosfomycin tromethamine daily for treatment. In pediatric patients with urinary tract infection, the effective rate is 86% 5-7 days after a single dose of 2g, and the effective rate remains above 80% after 4-6 weeks of administration. (Patel SS)
Side effects
The incidence of side effects of fosfomycin tromethamine is very low, mainly including headache, diarrhea and nausea. The gastrointestinal discomfort is very mild and usually does not require discontinuation of the drug. Leukopenia has been reported.
Summary
With the long-term and large-scale application of antibacterial drugs, the phenomenon of bacterial resistance is becoming more and more serious. The unique mechanism of action of fosfomycin and chlorhexidine makes the drug rarely cross-resistance with other antibacterial drugs and maintains good antibacterial effect for a long time. Active and safe, it is a good choice for treating urinary tract infections.
