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Can fosfomycin be used to treat urinary tract infections caused by multidrug-resistant pathogens?

Fosfomycin is a phosphonic acid derivative that has bactericidal activity due to the irreversible inhibition of the formation of molecules that make up the bacterial cell wall. It has a broad spectrum of antimicrobial activity against many Gram-negative bacteria, including Escherichia coli, Enterobacter, Serratia marcescens, Pseudomonas aeruginosa and Klebsiella pneumoniae, with the exception of Acinetobacter baumannii. Fosfomycin is also active against Gram-positive microorganisms such as Staphylococcus aureus and enterococci (including methicillin-resistant strains S. aureus and resistant isolates vancomycin Enterococcus).

The salt for administration of fosfomycin trometamol is the only drug registered in the United States; the disodium salt of fosfomycin for parenteral administration is not available. Fosfomycin trometamol is a small lipophilic molecule with bioavailability when ingested from 30 to 37% and an average volume of 136 liters. This medication is particularly well distributed in the kidneys, bladder wall and prostate, and creates high concentrations in the urine for 4 hours, which remain high (more than 128 mg / l) up to 48 hours after a single dose. of 3 g of drug. It is mainly excreted unchanged in the urine, with an average half-life of 5.7 hours. When used with metoclopramide, a decrease in serum and urinary concentrations has been demonstrated, so this appointment should be avoided.

Fosfomycin trimethamol is approved by the United States Food and Drug Administration (FDA) for oral administration in a single dose of 3 g as a powder dissolved in cold water for the treatment of urinary tract infections (UTIs) ) uncomplicated caused by E. faecalis or E. coli, in women. Adverse events occurring while taking the drug were generally mild and manifested by the gastrointestinal tract, while diarrhea was the most common. Fosfomycin is not recommended for the treatment of pyelonephritis.

According to the recommendations of the American Infectious Diseases Society of America (IDSA), fosfomycin is included in the list of possible drugs for the treatment of acute uncomplicated cystitis, although it is noted that this drug may be less effective to other standard treatment regimens. However, a meta-analysis showed no difference in clinical or microbiological efficacy in the treatment of acute cystitis between fosfomycin and other antibiotics. Comparable microbiological efficacy has also been observed in a limited number of clinical studies in children and pregnant women. Fosfomycin belongs to category B according to the FDA classification and can be used as an alternative therapy in patients who have limitations for the appointment of other antibiotics.

The emergence of multi-resistant microorganisms such as E. coli, resistant to fluoroquinolones, bacteria which synthesize extended spectrum beta-lactamases (BLRS) and K. pneumoniae, resistant to carbapenems, has led to an overestimation of the value of non-traditional antibiotics, such as phosphomycin, as well as studies to study its effectiveness in the treatment of urinary tract infections and systemic infections from another location. Although the only indication for prescribing fosfomycin is lower urinary tract infections, its study was conducted to treat uncomplicated and complicated urinary tract infections caused by multidrug-resistant uropathogens. In addition, parenteral phosphomycin has been used worldwide to treat various infections at doses from 1 g / day to 16 g / day, divided into 3 to 4 administrations.

Among the BLRSs which produce microorganisms of the Enterobacteriaceae family, the antimicrobial activity of phosphomycin is more pronounced for E. coli, with a total sensitivity of 96 , 8% and 81.3% for K. pneumoniae isolates using the marginal value of the minimum inhibitory concentration (MIC) to determine a sensitivity of 64 mg / l or less. Scientists assessed the efficacy of fosfomycin in 52 patients with a urinary tract infection caused by BLRS-producing strains of E. coli, however, in the absence of leukocytosis or fever. Fosfomycin was prescribed 3 g overnight for 3 days. The microbiological efficacy was 78.5%, the clinical efficacy 94.3%. The total treatment efficiency rate was 93.8% according to the results of 2 studies on urinary tract infections caused by isolates producing BLRS E. coli, despite an indicator of more microbiological efficacy low.

Scientists have evaluated the microbiological results of treatment with phosphomycin UTI caused by strains of multidrug-resistant microorganisms, including 13 strains of K. pneumoniae resistant to carbarpenem. The in vitro sensitivity to fosfomycin was 92%, microbiological healing was achieved in 46% (6/13 patients).

The emergence of resistance is considered to be an important issue in the evaluation of the role of fosfomycin for clinical purposes. Despite its high propensity for mutations under in vivo conditions, such a trend has not been observed in clinical practice. The use of a single dose regimen for the treatment of urinary tract infections and the acidic environment of urine reduces the likelihood of resistant strains of uropathogens.

A recent meta-analysis of the efficacy and safety of fosfomycin has not revealed the emergence of resistance from clinical trials evaluating the efficacy of the treatment of urinary tract infections. However, the use of fosfomycin for the treatment of infections from another place (non-UTI) is more conducive to the development of resistance. For example, a resistance level of 2.3 to 6.7% was observed in a study on the use of oral and parenteral fosfomycin in the treatment of respiratory infections and osteomyelitis. Resistance is notable, in particular, in the treatment of infections caused by P. aeruginosa.

Thus, fosfomycin is an adequate choice in the treatment of uncomplicated urinary tract infections, comparable in clinical efficacy with other first-line drugs, nitrofurantoin and trimethoprim / sulfamethoxazole. When prescribing the drug inside, sufficient concentrations in the urine are created once. This scheme is practical and effective. Given the wide range of in vitro activities of fosfomycin, it is worth resuming studies on the use of fosfomycin for the treatment of infections caused by multidrug-resistant pathogens. Given the low level of resistance to this drug and evidence of its effectiveness, fosfomycin may be an adequate option for the oral treatment of infections caused by multidrug-resistant uropathogens. Additional studies are needed to investigate the most appropriate dosing regimen and duration of treatment for fosfomycin urinary tract infections caused by such problematic pathogens.