Oral fosfomycin for treatment of acute bacterial prostatitis caused by multidrug-resistant Enterobacterales.

To assess the feasibility of oral fosfomycin-tromethamine (FT) for the management of acute bacterial prostatitis (ABP) caused by multidrug-resistant (MDR) Enterobacterales. An observational study of adult patients diagnosed with ABP from Vall d'Hebron University Hospital (Barcelona, Spain), treated with oral FT. The primary outcome was clinical cure defined as symptom relief at the control visit, 2-4 weeks post-end of treatment. Secondary outcomes included microbiological cure, relapse, and adverse events related to the treatment. Eighteen patients with ABP caused by Enterobacterales (15 Escherichia coli and three Klebsiella pneumoniae) were included. Microorganisms were MDR bacteria [14 extended-spectrum beta-lactamase (ESBL) producers and two carbapenemase producing K. pneumoniae]. Patients received treatment with FT 3 g/48 hours during a median of 14 days (Q25-Q75, 12-17.75). Fifteen patients received a lead-in phase of intravenous suitable antimicrobial during a median of 7 days (Q25-Q75, 3.75-8). No patient had to stop treatment due to adverse events, and the only side effect reported in two patients was diarrhea. Clinical cure was achieved in all (18/18) patients and microbiological cure in 11/12 patients. After a median of follow-up of 5 months (Q25-Q75, 2-11), 2/18 patients relapsed with an orchitis and a new episode of ABP. FT is an attractive step-down therapy for ABP in patients with resistance or side effects to first-line drugs. The availability of oral treatment could reduce the use of the carbapenems, with a benefit in the quality of life of the patient, health costs, and an ecological impact. IMPORTANCE We present a brief but largest and interesting experience in which we use fosfomycin-tromethamine (FT) for the treatment of acute bacterial prostatitis (ABP) due to multiresistant bacteria. Our study provides new data that help to consider FT as a plausible alternative for treating ABP in patients with resistance or side effects to first-line drugs. The availability of an alternative oral treatment to avoid the use of the carbapenems could have important benefits in terms of quality of life of the patient, health costs, and an ecological impact.

Plasma and Urine Pharmacokinetics of Oral Fosfomycin Tromethamine in Dogs.

Fosfomycin is a broad-spectrum, bactericidal antibiotic with low toxicity. It has been used in human medicine and is a promising candidate for treating infections in veterinary medicine. Different Fosfomycin salts exhibit various degrees of bioavailability. Tromethamine salt is the most commonly used oral form due to its improved bioavailability. However, information regarding its use with dogs is limited. Therefore, this study aimed to investigate the pharmacokinetics of oral Fosfomycin tromethamine in canine plasma and urine using liquid chromatography tandem mass spectrometry (LC-MS/MS). Six healthy male beagles underwent a three-period three-treatment study: treatment 1 and 2 with single oral Fosfomycin tromethamine at 40 and 80 mg/kg (the total doses with tromethamine salt were 75 and 150 mg/kg, respectively), and treatment 3 with intravenously Fosfomycin disodium at 57 mg/kg (the total dose with disodium salt was 75 mg/kg). Dogs receiving oral Fosfomycin tromethamine at 75 and 150 mg/kg, maximal drug concentration (Cmax) in plasma produced results of 34.46 ± 12.52 and 66.40 ± 12.64 µg/mL, oral bioavailability (F) was approximately 38 and 45%, while urine Cmax was 4463.07 ± 2208.88 and 8784.93 ± 2303.46 µg/mL, respectively. No serious adverse effects were reported, except loose stool in some dogs. The tremendously high urine Fosfomycin concentrations indicate that oral Fosfomycin tromethamine is suitable as an alternative treatment for bacterial cystitis in dogs.

Comparison of single-dose fosfomycin tromethamine and other antibiotics for lower uncomplicated urinary tract infection in women and asymptomatic bacteriuria in pregnant women: A systematic review and meta-analysis.

INTRODUCTION: This systematic review and meta-analysis investigated the efficacy and safety of single-dose fosfomycin tromethamine (FT) versus other antibiotic agents in women suffering from lower uncomplicated urinary tract infection (uUTI) and pregnant women with uUTI or asymptomatic bacteriuria (ASB). METHODS: MEDLINE, EMBASE and the Cochrane library were searched to identify relevant literature. Twenty-one studies were identified. Nine of the 21 studies enrolled 21 22 patients and were used to compare the clinical resolution of uUTI between non-pregnant and pregnant women. Given that uUTI and ASB are assessed using similar microbiological evaluation methods, all 3103 patients in the identified 21 studies were pooled to determine microbiological resolution between uUTI or ASB patients. Safety outcomes of the treatments were analysed in 15 studies. RESULTS: The results showed that single-dose FT was comparable with other antibiotic agents in clinical resolution of uUTI (OR 0.89; 95% CI 0.71-1.10; P = 0.41) in non-pregnant (P = 0.32) and pregnant women (P = 0.64). Moreover, single-dose FT was equal to other antibiotics in microbiological resolution, and there was no difference in overall microbiological resolution (OR 1.11; 95% CI 0.92-1.34; P = 0.29) among non-pregnant women with uUTI (P = 0.48), pregnant women with uUTI (P = 0.81) and pregnant women with ASB (P = 0.30). There were no serious fosfomycin-related adverse events and most frequent adverse events were mainly gastrointestinal. CONCLUSION: This meta-analysis suggests that single-dose fosfomycin tromethamine produces equivalent clinical outcomes to comparator antibiotics in terms of clinical efficacy and microbiological efficacy. It is therefore clinically effective and safe for women with uUTI and pregnant women with uUTI or ASB, and has higher patient compliance.

Antibacterial effect of fosfomycin tromethamine on the bacteria inside urinary infection stones.

OBJECTIVE: This study sought to evaluate the antibacterial effect of fosfomycin tromethamine (FT) on the bacteria inside urinary infection stones. METHODS: The internal structures of urinary stones were observed via scanning electron microscopy to verify the presence of internal bacteria. We randomly assigned equal numbers of patients with kidney stones who met the inclusion criteria into two groups in a prospective study and treated them with different perioperative antibiotics. One group (experimental group) was treated with FT, and the other (control group) was treated with cefuroxime sodium. All stone specimens were collected via percutaneous nephrolithotomy (PCNL). The primary infection stones were screened via a stone component analysis, 30 cases in the experimental group and 31 cases in the control group. High-performance liquid chromatography (HPLC)-mass spectrometry was used to measure the drug concentration inside the stones, the bacterial count was calculated via stone culture, and the clinical infection index were monitored for between-group comparisons. RESULTS: Compared with the control group, the experimental group had a higher internal drug concentration, a higher drug sensitivity against various pathogenic bacteria, a lower bacterial colony count in the stone culture, and a lower incidence of postoperative clinical infection. CONCLUSIONS: FT is more effective than cefuroxime, which is commonly used during the perioperative period of urinary stones, and exerts a high antibacterial effect on these internal bacteria, and effectively reduces the probability of infection and sepsis after urinary stone surgery. FT can be used as an antibiotic during the perioperative period of urinary stones.

Fosfomycin tromethamine activity on biofilm and intracellular bacterial communities produced by uropathogenic Escherichia coli isolated from patients with urinary tract infection.

Fosfomycin tromethamine (FT), an old antibiotic revived as a new strategy to overcome antibiotic resistance, is an excellent option for the treatment of lower urinary tract infection (UTI). During UTI, Escherichia coli produces biofilms and could invade the bladder epithelial cells, developing intracellular bacterial communities (IBC). The present work aimed to evaluate the activity of FT on biofilms and IBC from clinical isolates of E. coli. A total of 38 E. coli clinical UTI isolates previously characterized as biofilm and IBC producers were studied. FT susceptibility was evaluated and its activity on 48 h biofilm was determined by microtiter plate-based biofilm assay comparing three different antibiotic concentrations. Two UPEC strains were selected to evaluate FT activity on IBC in vitro using T24 bladder cells. The survival percentage of intracellular bacteria after 24 h exposure to FT was calculated and compared to the percentage of intracellular bacteria without antibiotic. All the strains were susceptible to FT. FT produced a significant reduction of biofilms at the three concentrations tested, compared to the control. However, no statistically effect on IBC was observed after 24 h of fosfomycin exposure in cell culture. FT is a good option for bacterial biofilm reduction within UTI. However, it does not affect IBC.

[Fosfomycin tromethamine inhibits the expressions of TNF-α, IL-8 and IL-6 in the prostate tissue of rats with chronic bacterial prostatitis].

OBJECTIVE: To investigate the effects of fosfomycin tromethamine (FT) on the expressions of tumor necrosis factor-α (TNF-α), interleukin-8 (IL-8), and interleukin-6 (IL-6) in the prostate tissue of the rats with chronic bacterial prostatitis (CBP). METHODS: We randomly divided 70 male SD rats into 7 groups of equal number: blank control, CBP model control, positive control, 14 d low-dose FT, 7 d low-dose FT, 14 d high-dose FT, and 7 d high-dose FT. The CBP model rats in the latter five groups were treated intragastrically with levofloxacin at 100 mg/kg/d for 30 days and FT at 200 mg/kg/d for 14 and 7 days and at 300 mg/kg/d for 14 and 7 days, respectively. Then we collected the prostate tissue from the animals for determination of the levels of TNF-α, IL-8 and IL-6 by ELISA. RESULTS: Compared with the blank controls, the CBP model rats showed significantly increased levels of TNF-α (ï¼»19.83 ± 6.1ï¼½ vs ï¼»32.93 ± 6.21ï¼½ ng/g prot, P <0.01), IL-8 (ï¼»8.26 ± 0.52ï¼½ vs ï¼»16.2 ± 2.84ï¼½ ng/g prot, P <0.01) and IL-6 (ï¼»1.55 ± 0.11ï¼½ vs ï¼»2.51 ± 1.06ï¼½ ng/g prot, P <0.05) in the prostate tissue. In comparison with the CBP model controls, the levels of TNF-α and IL-8 were remarkably decreased in the groups of positive control (ï¼»20.54 ± 5.78ï¼½ ng/g prot, P <0.01; ï¼»12.43 ± 4.02ï¼½ ng/g prot, P <0.05), 14 d low-dose FT (ï¼»21.95 ± 6.48ï¼½ ng/g prot, P <0.01; ï¼»11.11 ± 2.86ï¼½ ng/g prot, P <0.01), 7 d low-dose FT (ï¼»23.8 ± 6.93ï¼½ ng/g prot, P <0.05; ï¼»12.43 ± 4.02ï¼½ ng/g prot, P <0.05), 14 d high-dose FT (ï¼»19.97 ± 2.58ï¼½ ng/g prot, P <0.01; ï¼»8.83 ± 1.32ï¼½ ng/g prot, P <0.01), and 7 d high-dose FT (ï¼»21.97 ± 3.38ï¼½ ng/g prot, P <0.01; ï¼»12.68±1.97ï¼½ ng/g prot, P <0.05). No statistically significant differences were observed between the positive control and FT groups in the contents of TNF-α, IL-8 or IL-6 (P >0.05). The expression of IL-6 was markedly reduced in the 14 d high-dose FT group as compared with the model controls (ï¼»1.76 ± 0.46ï¼½ vs ï¼»2.51 ± 1.06ï¼½ ng/g prot, P<0.05) but exhibited no significant difference between the CBP model control and the other groups (P >0.05). CONCLUSIONS: Fosfomycin tromethamine inhibits the expressions of TNF-α, IL-8 and IL-6 in the prostate tissue, suppresses its inflammatory reaction, promotes the repair of damaged prostatic structure, and thus contributes to the treatment of chronic bacterial prostatitis in rats.

Fosfomycin as a potential therapy for the treatment of systemic infections: a population pharmacokinetic model to simulate multiple dosing regimens.

Fosfomycin has emerged as a potential therapy for multidrug-resistant bacterial infections. In most European countries, the oral formulation is only approved as a 3 g single dose for treatment of uncomplicated cystitis. However, for the treatment of complicated systemic infections, this dose regimen is unlikely to reach efficacious serum and tissue concentrations. This study aims to investigate different fosfomycin-dosing regimens to evaluate its rationale for treatment of systemic infections. Serum concentration-time profiles of fosfomycin were simulated using a population pharmacokinetic model based on published pharmacokinetic parameter values, their uncertainty, inter-individual variability and covariates. The model was validated on published data and used to simulate a wide range of dosing regimens for oral and intravenous administration of fosfomycin. Finally, based on the minimum inhibitory concentration for E. coli, surrogate pharmacodynamic indices were calculated for each dosing regimen. This is the first population pharmacokinetic model to describe the oral pharmacokinetics of fosfomycin using data from different literature sources. The model and surrogate pharmacodynamic indices provide quantitative evidence that a dosing regimen of 6-12 g per day divided in 3 doses is required to obtain efficacious exposure and may serve as a first step in the treatment of systemic multi-drug-resistant bacterial infections.

Evaluation of perioperative prophylaxis with fosfomycin tromethamine in ureteroscopic stone removal: an investigator-driven prospective, multicenter, randomized, controlled study.

PURPOSE: To compare efficacy, safety, and cost-effectiveness of fosfomycin tromethamine with other standard-of-care antibiotics in patients undergoing ureteroscopic lithotripsy. METHODS: This study was a prospective, multicenter, randomized, controlled trial. Eligible patients scheduled for ureteroscopic lithotripsy were randomly assigned to receive either fosfomycin (fosfomycin group, N = 101 patients) or standard-of-care antibiotic therapy as prophylaxis (control group, N = 115 patients). The incidence of infectious complications and adverse events was analyzed between the two groups, as well as the cost-benefit analysis. RESULTS: The incidence of infections following lithotripsy was 3.0% in the fosfomycin group and 6.1% in the control group (p > 0.05). Only asymptomatic bacteriuria was reported in fosfomycin group. In the control group was reported asymptomatic bacteriuria (3.5%), fever (0.9%), bacteremia (0.9%), and genitourinary infection (0.9%). The rate of adverse events was very low, with no adverse event reported in the fosfomycin group and only one in the control group (forearm phlebitis). The average cost per patient of antibiotic therapy with fosfomycin was 151.45 ± 8.62 yuan (22.7 ± 1.3 USD), significantly lower compared to the average cost per patient of antibiotics used in the control group 305.10 ± 245.95 yuan (45.7 ± 36.9 USD; p < 0.001). CONCLUSIONS: Two oral doses of 3 g fosfomycin tromethamine showed good efficacy and safety and low cost in perioperative prophylaxis of infections following ureteroscopic stone removal.

Fosfomycin tromethamine inhibits the expressions of TNF-α, IL-8 and IL-6 in the prostate tissue of rats with chronic bacterial prostatitis / 中华男科学杂志

<p><b>Objective</b>To investigate the effects of fosfomycin tromethamine (FT) on the expressions of tumor necrosis factor-α (TNF-α), interleukin-8 (IL-8), and interleukin-6 (IL-6) in the prostate tissue of the rats with chronic bacterial prostatitis (CBP).</p><p><b>METHODS</b>We randomly divided 70 male SD rats into 7 groups of equal number: blank control, CBP model control, positive control, 14 d low-dose FT, 7 d low-dose FT, 14 d high-dose FT, and 7 d high-dose FT. The CBP model rats in the latter five groups were treated intragastrically with levofloxacin at 100 mg/kg/d for 30 days and FT at 200 mg/kg/d for 14 and 7 days and at 300 mg/kg/d for 14 and 7 days, respectively. Then we collected the prostate tissue from the animals for determination of the levels of TNF-α, IL-8 and IL-6 by ELISA.</p><p><b>RESULTS</b>Compared with the blank controls, the CBP model rats showed significantly increased levels of TNF-α (［19.83 ± 6.1］ vs ［32.93 ± 6.21］ ng/g prot, P <0.01), IL-8 (［8.26 ± 0.52］ vs ［16.2 ± 2.84］ ng/g prot, P <0.01) and IL-6 (［1.55 ± 0.11］ vs ［2.51 ± 1.06］ ng/g prot, P <0.05) in the prostate tissue. In comparison with the CBP model controls, the levels of TNF-α and IL-8 were remarkably decreased in the groups of positive control (［20.54 ± 5.78］ ng/g prot, P <0.01; ［12.43 ± 4.02］ ng/g prot, P <0.05), 14 d low-dose FT (［21.95 ± 6.48］ ng/g prot, P <0.01; ［11.11 ± 2.86］ ng/g prot, P <0.01), 7 d low-dose FT (［23.8 ± 6.93］ ng/g prot, P <0.05; ［12.43 ± 4.02］ ng/g prot, P <0.05), 14 d high-dose FT (［19.97 ± 2.58］ ng/g prot, P <0.01; ［8.83 ± 1.32］ ng/g prot, P <0.01), and 7 d high-dose FT (［21.97 ± 3.38］ ng/g prot, P <0.01; ［12.68±1.97］ ng/g prot, P <0.05). No statistically significant differences were observed between the positive control and FT groups in the contents of TNF-α, IL-8 or IL-6 (P >0.05). The expression of IL-6 was markedly reduced in the 14 d high-dose FT group as compared with the model controls (［1.76 ± 0.46］ vs ［2.51 ± 1.06］ ng/g prot, P<0.05) but exhibited no significant difference between the CBP model control and the other groups (P >0.05).</p><p><b>CONCLUSIONS</b>Fosfomycin tromethamine inhibits the expressions of TNF-α, IL-8 and IL-6 in the prostate tissue, suppresses its inflammatory reaction, promotes the repair of damaged prostatic structure, and thus contributes to the treatment of chronic bacterial prostatitis in rats.</p>

Evaluation of the in vitro activity of fosfomycin tromethamine against Gram-negative bacterial strains recovered from community- and hospital-acquired urinary tract infections in Turkey.

OBJECTIVES: The aim of this study was to evaluate the in vitro activities of antimicrobial agents including fosfomycin tromethamine against Gram-negative isolates recovered from urine samples. METHODS: A total of 2334 strains (1562 Escherichia coli, 509 Klebsiella spp, 85 Proteus spp, 75 Pseudomonas spp, 45 Enterobacter spp, 37 Acinetobacter baumannii, 8 Citrobacter spp, 7 Morganella morganii, and 6 Serratia spp) were identified by VITEK 2 during the study period, November 2008 to June 2012. Antimicrobial susceptibilities of the strains were also evaluated using the Kirby-Bauer disk diffusion method, in accordance with the Clinical and Laboratory Standards Institute guidelines. RESULTS: Overall, 2160 (92.5%) of the isolates tested were susceptible to fosfomycin tromethamine. Higher resistance rates were observed among inpatients compared to outpatients. Resistance rates by strain were: 2.0% for E. coli, 4.4% for Enterobacter spp, 6.9% for Klebsiella spp, 9.4% for Proteus spp, 48.6% for A. baumannii, 56.0% for Pseudomonas spp, and 100% for Morganella morganii. All Serratia spp and Citrobacter spp strains were susceptible. Extended-spectrum beta-lactamase (ESBL)-producing isolates displayed higher fosfomycin resistance rates than negative strains (19.2% vs. 2.9%). The highest in vitro activity was detected for amikacin, piperacillin-tazobactam, and imipenem for all strains including ESBL-producers. CONCLUSIONS: Regardless of ESBL production, the excellent activity of fosfomycin against E. coli, Enterobacter spp, Serratia spp, and Citrobacter spp, indicates that the drug is a valuable therapeutic option for urinary tract infections, even those with co-trimoxazole- and ciprofloxacin-resistant isolates, but not in ESBL-producing Klebsiella spp, Pseudomonas spp, A. baumannii, and Proteus spp. Further studies should be carried out to determine the in vivo drug activity among Enterobacteriaceae other than E. coli.