Pharmacokinetics of fosfomycin in patients with prophylactic treatment for recurrent Escherichia coli urinary tract infection

Abstract

Objectives To evaluate the pharmacokinetics and clinical effectiveness of IV and oral fosfomycin treatment in patients with recurrent urinary tract infection (rUTI) with Escherichia coli. Patients and methods Patients with rUTI treated with 3 g of oral fosfomycin every 72 h for at least 14 days were included in a prospective open-label single-centre study. Serum samples were taken after oral and IV administration of fosfomycin. Urine was collected for 24 h on 3 consecutive days. Fosfomycin concentrations in serum and urine were analysed using validated LC–MS/MS. Pharmacokinetics were evaluated using a population model. EudraCT number 2018-000616-25. Results Twelve patients were included, of whom nine were also administered IV fosfomycin. Data were best described by a two-compartment model with linear elimination and a transit-absorption compartment. Median values for absolute bioavailability and serum half-life were 18% and 2.13 h, respectively. Geometric mean urine concentrations on Days 1, 2 and 3 were above an MIC of 8 mg/L after both oral and IV administration. Quality of life reported on a scale of 1–10 increased from 5.1 to 7.4 (P = 0.001). The average score of UTI symptoms decreased after fosfomycin dosing (by 3.1 points, 95% CI = −0.7 to 7.0, P = 0.10). Conclusions Oral fosfomycin at 3 g every 72 h provides plasma and urine concentrations of fosfomycin above the MIC for E. coli. This pharmacokinetic model can be used to develop optimal dosing regimens of fosfomycin in patients with UTI.

Population plasma and urine pharmacokinetics and the probability of target attainment of fosfomycin in healthy male volunteers

“…The model showed a good ability to characterise fosfomycin PK based on model diagnostics and validation. Most other recent studies also confirmed that the two-compartment model was the best fit to describe the fosfomycin plasma PK [17][18][19][20]. The second exponential decay suggests a distribution into deeper tissue, which leads to a slower release into plasma.…”

“…Although a number of studies on the population PK of fosfomycin have been conducted, most of these focused on plasma PK. Consequently, urinary PK is not fully understood [17][18][19][20]. Only a limited number of PK studies have evaluated plasma and urine samples simultaneously in healthy volunteers, utilising conventional PK analyses that did not include a covariate analysis [21][22][23].…”

Fosfomycin prophylaxis can reduce the risk of severe recurrent urinary tract infections requiring hospitalisation in children with complex urinary tract malformations

“…The available pharmacodynamic data show that the urinary concentrations of fosfomycin above the minimum inhibitory concentration (MIC) are maintained 24-48 hours after an oral therapeutic dose [26]. The daily dose of 1/3 of the therapeutic dose of fosfomycin resulted in a very good clinical effect and eradication of resistant pathogens.…”

Indications for medical antibiotic prophylaxis and potential targets for antimicrobial stewardship intervention: a narrative review

“…• Lack of evidence in elderly patients (harms may outweigh benefit) [95,96] • Role of antibiotic cycling strategies to reduce emergence of resistance and appropriate selection of antibiotic regimens for cycling [5,64,65] • Safety of prolonged (>1-2 year) AP duration [97][98][99][100] • Identification of patient groups that may benefit from AP around urinary catheter manipulations or short-term catheter bladder drainage [41-43,48,101 -103,103] • Optimal dosing strategy for AP with fosfomycin [104] • Role of AP in urodynamic studies [105][106][107][108] J o u r n a l P r e -p r o o f AP for spontaneous bacterial peritonitis…”