Evaluation of pooled human urine and synthetic alternatives in a dynamic bladder infection in vitro model simulating oral fosfomycin therapy.

The impact of the bladder environment on fosfomycin activity and treatment response is uncertain. Standard laboratory media does not reflect the biomatrix of urine, where limited nutritional factors are important for growth and antimicrobial kill rates. We compared fosfomycin activity against Enterobacteriaceae in laboratory media, human urine and synthetic alternatives. Sixteen clinical isolates (8-Escherichia coli, 4-Enterobacter cloacae, 4-Klebsiella pneumoniae) were studied with broth microdilution (BMD) susceptibility, static time-kill assays and dynamic testing in a bladder infection model simulating a 3 g oral fosfomycin dose. Mueller-Hinton broth (MHB) with and without 25 mg/L glucose-6-phosphate (G6P), pooled midstream urine (MSU), pooled 24 h urine collection (24 U), artificial urine medium (AUM) and synthetic human urine (SHU) were compared. BMD susceptibility, bacterial growth and response to static fosfomycin concentrations in urine were best matched with SHU and were distinctly different when tested in MHB with G6P. Fosfomycin exposure in the bladder infection model was accurately reproduced (bias 4.7 ± 6.2%). Under all media conditions, 8 isolates (2-E. coli, 2-E. cloacae, 4-K. pneumoniae) re-grew and 4 isolates (4-E. coli) were killed. The remaining isolates (2-E. coli, 2-E. cloacae) re-grew variably in urine and synthetic media. Agar dilution MIC failed to predict re-growth, whereas BMD MIC in media without G6P performed better. Emergence of resistance was restricted in synthetic media. Overall, SHU provided the best substitute for urine for in vitro modelling of antimicrobial treatment of uropathogens, and these data have broader utility for improved preclinical testing of antimicrobials for urinary tract infections.

Phase I Study To Evaluate the Pharmacokinetics, Safety, and Tolerability of Two Dosing Regimens of Oral Fosfomycin Tromethamine in Healthy Adult Participants.

The pharmacokinetics (PK), safety, and tolerability of two repeated dosing regimens of oral fosfomycin tromethamine were evaluated in 18 healthy adult subjects. Subjects received 3 g every other day (QOD) for 3 doses and then every day (QD) for 7 doses, or vice versa, in a phase I, randomized, open-label, two-period-crossover study. Serial blood (n = 11) and urine (n = 4 collection intervals) samples were collected before and up to 24 h after dosing on days 1 and 5, along with predose concentrations on days 3 and 7. PK parameters were similar between days 1 and 5 within and between dosing regimens. The mean (± standard deviation [SD]) PK parameters for fosfomycin in plasma on day 5 during the respective QOD and QD dosing regimens were as follows: maximum concentration of drug in serum (Cmax) = 24.4 ± 6.2 versus 23.8 ± 5.6 µg/ml, time to Cmax (Tmax) = 2.2 ± 0.7 versus 2.0 ± 0.4 h, apparent volume of distribution (V/F) = 141 ± 67.9 versus 147 ± 67.6 liters, apparent clearance (CL/F) = 21.4 ± 8.0 versus 20.4 ± 5.3 liters/h, renal clearance (CLR) = 7.5 ± 4.1 versus 7.3 ± 3.5 liters/h, area under the concentration-time curve from 0 to 24 h (AUC0-24) = 151.6 ± 35.6 versus 156.6 ± 42.5 µg · h/ml, and elimination half-life (t1/2) = 4.5 ± 1.1 versus 5.0 ± 1.7 h. Urine concentrations peaked at approximately 600 µg/ml through the 0- to 8-h urine collection intervals but displayed significant interindividual variability. Roughly 35 to 40% of the 3-g dose was excreted in the urine by 24 h postdose. No new safety concerns were identified during this study. The proportion of diarrhea-free days during the study was significantly lower with the QD regimen than with the QOD regimen (61% versus 77%; P < 0.0001). Further studies to establish the clinical benefit/risk ratio for repeated dosing regimens of oral fosfomycin tromethamine are warranted. (This trial is registered at ClinicalTrials.gov under registration no. NCT02570074.).

A fast and sensitive LC-MS/MS method for the quantification of fosfomycin in human urine and plasma using one sample preparation method and HILIC chromatography.

Fosfomycin is an old antibiotic that is increasingly prescribed because of emergence of the antibiotic resistance and the growing incidence of multi-drug resistant infections. Surprisingly, little is known about its pharmacokinetics (PK) and the pharmacodynamics (PD). Quantification of fosfomycin in both urine and plasma provides insight into the PK/PD characteristics of fosfomycin, which is crucial for the optimization of the therapy and the prevention of the emergence of resistance. An analytical method is therefore needed for the quantification of fosfomycin in both urine and plasma. A fast and sensitive tandem mass spectrometry method in combination with HILIC chromatography for the quantification of fosfomycin with a universal sample preparation method for urine and plasma was developed and validated according to FDA guidelines. The universal sample preparation method only requires 100µL of a sample, the addition of the internal standard fosfomycin-13C3 benzylamine and an ultrafiltration step. The method is applicable for the concentration range of 0.75-375mg/L (R2 of 0.9998 in both matrices) encompassing the clinically relevant concentration range based on the susceptibility of possible (uro)pathogens in the clinical setting. The validation results for urine and plasma for all QC levels, were <2.1% and <3.2% for accuracy, <1.5% and <1.7% for within day precision and <5.0% and <3.8% for between day precision, respectively. No matrix effects were encountered and the total recovery in urine and plasma was high (102.5% and 99.4%). Prepared samples were stable at 4°C and 15°C for at least 72h and stored samples at -80°C were stable for at least 6 months. Selectivity and sensitivity were confirmed and no carry-over was observed. The method was successfully applied in two pharmacokinetic studies in healthy volunteers and patients respectively.

A simple LC-MS/MS method using HILIC chromatography for the determination of fosfomycin in plasma and urine: application to a pilot pharmacokinetic study in humans.

A high performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) method, using hydrophilic interaction liquid chromatography (HILIC) chromatography for the analysis of fosfomycin in human plasma and urine, has been developed and validated. The plasma method uses a simple protein precipitation using a low volume sample (10 µL) and is suitable for the concentration range of 1 to 2000 µg/mL. The urine method involves a simple dilution of 10 µL of sample and is suitable for a concentration range of 0.1 to 10 mg/mL. The plasma and urine results, reported, respectively, are for recovery (68, 72%), inter-assay precision (≤9.1%, ≤8.1%) and accuracy (range -7.2 to 3.3%, -1.9 to 1.6%), LLOQ precision (4.7%, 3.1%) and accuracy (1.7% and 1.2%), and includes investigations into the linearity, stability and matrix effects. The method was used in a pilot pharmacokinetic study of a critically ill patient receiving i.v. fosfomycin, which measured a maximum and minimum plasma concentration of 222 µg/mL and 172 µg/mL, respectively, after the initial dose, and a maximum and minimum plasma concentration of 868 µg/mL and 591µg/mL, respectively, after the fifth dose. The urine concentration was 2.03 mg/mL after the initial dose and 0.29 mg/mL after the fifth dose.

A high-throughput colorimetric-based bioassay method for determination of fosmidomycin in plasma and urine and application for pharmacokinetic study.

INTRODUCTION: Fosmidomycin is a phosphonic acid derivative originally isolated as a natural antibiotic from Streptomyces lavendulae. It was originally used as an antibiotic, and later on as an antimalarial drug. A simple, sensitive, selective and reproducible bioassay based on colorimetric method was developed for the determination of fosmidomycin in human plasma and urine. METHODS AND RESULTS: Enterobacter cloacae ATCC 23355 strain was used as a test organism. Inhibition of bacterial growth was assessed using MTT assay. Calibration curves were prepared from concentration response curves in plasma (0, 0.5, 1, 2.5, 5, 12.5, 25, 50 ng/microl) and urine (0, 0.5, 1, 2.5, 5, 12.5, 25, 50 and 100 ng/microl) and were all linear with correlation coefficients better than 0.990. The precision of the method based on within-day repeatability and reproducibility (day-to-day variation) was below 10% (% coefficient of variations: % C.V.) Good accuracy was observed for both the intra-day and inter-day assays, as indicated by the minimal deviation of mean values found between the measured samples and the theoretical values (below +/-10%). Limit of quantification (L.O.Q.) was accepted as 0.5 ng using 20 microl plasma or 10 microl urine sample. The mean recovery for fosmidomycin was greater than 99%. The method was free from interference from other commonly used antibiotics. DISCUSSION: The analytical method established in this study meets the criteria of high sensitivity, accuracy and reproducibility for routine use in pharmacokinetic studies. The method has advantages over the recently developed bioassay in its simplicity, accuracy, short analysis time, good sensitivity, and the requirement for smaller volumes of samples. The method appears to be robust and has been applied to a pharmacokinetic study to determine the plasma and urinary excretion of fosmidomycin in a total of 24 Thai patients with acute uncomplicated falciparum malaria following oral doses of 1800 fosmidomycin given every 10 h for 3 days.

Coste biológico asociado a la resistencia a la fosfomicina en aislamientos de Escherichia coli de orina / Biological cost associated with fosfomycin resistance in Escherichia coli isolates from urinary tract infections

La resistencia a la fosfomicina surge rápidamente en condiciones experimentales, pero aunque su uso es frecuente en las infecciones del tracto urinario, la resistencia de Escherichia coli, el principal uropatógeno, es muy baja (1% a 3%) y ha permanecido así por muchos años. El objetivo de este estudio fue evaluar si las cepas de E. coli resistentes a la fosfomicina tienen menos competitividad (fitness) que las sensibles, y por tanto tenderían a desaparecer al competir con las cepas sensibles en ausencia de antibióticos. Se utilizaron cepas resistentes a la fosfomicina (n=11) con diferentes fenotipos de resistencia a otros antibióticos, y cepas sensibles a la fosfomicina (n=15) con los mismos fenotipos de resistencia al resto de los antibióticos que algunas de las cepas resistentes, pero con el patrón opuesto de fermentación de la lactosa. Se realizaron 33 experimentos de competición por pares en caldo nutriente. Se utilizaron cantidades iguales de cada cepa (50%-50%) durante cuatro días, con cambio diario a un nuevo medio. Se hicieron cinco recuentos diferenciales, los días 0, 1, 2, 3 y 4. En 20 experimentos (60,6%) hubo un incremento relativo de la cepa sensible a la fosfomicina. En seis experimentos (18,2%) hubo un incremento relativo de la cepa resistente a la fosfomicina. En siete experimentos (21,2%) ninguna cepa mostró un incremento relativo. Cuando los datos de los 26 experimentos en que había cambios se analizaban por X2 había una diferencia estadísticamente significativa (p=0.044). La resistencia a la fosfomicina puede suponer un coste de competitividad para la mayoría de las cepas de E. coli probadas

Resistance to fosfomycin develops rapidly in experimental conditions, although despite its frequent use in UTI, resistance in E. coli, the main uropathogen, is very low (1-3%), and has remained so for many years. The objective of this study was to ascertain whether E. coli fosfomycin- resistant strains have less fitness than those that are fosfomycin-sensitive in competing, and would therefore tend to disappear in their competition with fosfomycin-sensitive strains in the absence of antibiotics. Fosfomycin-resistant strains (n=11) with different phenotypes of resistance to other antibiotics were used. All but one were lactose (+). Fosfomycin-susceptible strains (n=15) that had the same phenotypes of resistance to other antibiotics as the resistant strains and which had the opposite pattern of lactose fermentation were also used. Thirty-three (33) competition experiments by pairs of strains were conducted in nutrient broth. Equal amounts of the strains were challenged (approx. 50% and approx. 50%) for 4 days, with a daily change to a new medium. Five differential counts were performed on days 0, 1, 2, 3 and 4. In 20 experiments (60.6%) there was a relative increase in the fosfomycin-sensitive strain. In 6 experiments (18.2%) there was a relative increase in the fosfomycin-resistant strain. In 7 experiments (21.2%), on the fourth day none of the strains reached 60%. When the data of the 26 (20+6) experiments in which there were changes were analyzed by the X2 test there was a statistically significant difference (p=0.044). Resistance to fosfomycin could entail a biological cost (less fitness) for the majority of the E. coli strains assayed

Bioassay for determination of fosmidomycin in plasma and urine: application for pharmacokinetic dose optimisation.

A simple, sensitive, selective and reproducible method based on agar diffusion disk assay was developed for the determination of fosmidomycin and clindamycin in human plasma and urine. A disk diffusion technique was used, essentially as previously described but utilising the assay organism Enterobacter cloacae ATCC 23355 strain to seed the agar assay plates. Calibration curves were prepared from concentration response curves in plasma (0, 1, 2.5, 5, 7.5, 10, 25, 50 ng/microl) and urine (0, 10, 25, 50, 75, 100, 250 and 500 microg/microl) were all linear with correlation coefficients better than 0.990. The precision of the method based on within-day repeatability and reproducibility (day-to-day variation) was below 5% (% coefficient of variations: %C.V.). Good accuracy was observed for both the intra-day or inter-day assays, as indicated by the minimal deviation of mean values found with measured samples from that of the theoretical values (below +/-5%). Limit of quantification (L.O.Q.) was accepted as 1 ng using 40-microl plasma or 7.5-microl urine sample. The mean recovery for fosmidomycin was greater than 99%. The method was free from interference from other commonly used antibiotics including clindamycin, carbenicillin, cephalothin, chloramphenicol, kanamycin, methicillin, penicillin, erythromycin, lincomycin, tetracycline and paromomycin. The method appears to be robust and has been applied to a pharmacokinetic study in plasma and urinary excretion of fosmidomycin in a patient with malaria following oral doses of clindamycin at 1200 mg given every 8 h for 7 days.

[Fosfomycin trometamol: multiple-dose regimen for the treatment of lower urinary tract infections]. / Fosfomicina trometamol. Dosis múltiples como pauta larga en el tratamiento de las infecciones urinarias bajas.

INTRODUCTION: A short antibiotic regimen is recommended for the treatment of uncomplicated lower urinary tract infection. Nevertheless, the treatment to follow in other situations is not so clearly defined. When the person affected by lower urinary tract infection is not a young woman, it is recommended to treat at least 7 days, and quinolones or cotrimoxazole are the antibiotics most often used. However, because of the frequency of drug resistance in this type if infection, it is advisable to apply antibiotics with lower rates of resistance, such as fosfomycin trometamol, for longer treatment periods than the often-used single dose. METHODS: Using the data on urinary elimination of fosfomycin after a single dose obtained in a prior study in healthy volunteers, we simulated the urinary concentrations of this antibiotic following administration of two doses. In addition, we calculated the interval of administration required to achieve urinary concentrations greater than 16 mg/L, the critical concentration of sensitivity for Escherichia coli, one of the most commonly implicated microorganisms in these infections. RESULTS: Fosfomycin concentrations in urine persisted above the defined cut-off for 161 hours after administration of two 3-g doses of fosfomycin trometamol, 72 hours apart. This implied an efficacy time of 66% in a period of 7 days. CONCLUSION: From the pharmacokinetic viewpoint, the optimum dosage of fosfomycin trometamol to achieve appropriate urinary concentrations along 7 days is administration of two 3-g doses, 72 hours apart.

Determination of fosmidomycin in human serum and urine by capillary electrophoresis.

A capillary electrophoresis method with direct UV detection was developed for the determination of fosmidomycin, a promising new anti-malarial drug, in human serum and urine. Optimization of the separation parameters resulted in a buffer system adjusted to pH 10.8 containing a cationic reagent and an organic modifier. Under these conditions, the migration time of fosmidomycin was 5.2 min with serum and 7.4 min with urine samples. Validation of the method revealed good recoveries, precision and accuracy. The limit of quantification was 0.5 microg/ml in serum and 10 microg/ml in urine. The determination of fosmidomycin in serum was linear over a range of 0.1-150 microg/ml. Short and long-term stability tests resulted in no significant loss of fosmidomycin. The described technique will provide a fast and accurate analytical method for future pharmacokinetic studies.

Flow injection spectrophotometric determination of the antibiotic fosfomycin in pharmaceutical products and urine samples after on-line thermal-induced digestion.

A new flow injection (FI) method for the precise and rapid spectrophotometric determination of the antibiotic fosfomycin (FMC) in urine and pharmaceutical samples is described. The method is based on the on-line quantitative thermal-induced digestion of the analyte prior to injection into the FI system. Ammonium persulfate was used as the oxidation reagent. The resulting orthophosphate ions were determined spectrophotometrically (lambda(max) = 690 nm) using the molybdenum blue approach. Chemical and FI variables that affected on-line oxidation were studied and optimized. The proposed method is very precise (s(r) = 1.2% at 1.0 x 10(-4) mol L(-1) FMC, n = 12), offers a high sampling rate of 60 h(-1), and allows for the determination of the analyte in the range 3.0 x 10(-6) to 3.0 x 10(-4) mol L(-1) with a satisfactory 3sigma detection limit of 1.0 x 10(-6) mol L(-1). Application of the proposed method to urine and pharmaceutical samples yielded accurate results with percentage recoveries in the range 96.4-102.5%.

Cisplatin-induced nephrotoxicity and the protective effect of fosfomycin on it as demonstrated by using a crossover study of urinary metabolite levels.

BACKGROUND: Cisplatin induces nephrotoxicity and this study evaluated the protective effect of fosfomycin on it in 11 gynecological cancer patients. METHODS: The N-acetyl-beta-D-glucosaminidase (NAG), beta 2-microglobulin (beta 2MG), creatinine (uCr) and total protein (TP) levels in a 24-hour urine specimen as well as the blood urea nitrogen (BUN) and serum creatinine (sCr) were measured before and after CAPF chemotherapy alone (control) or with fosfomycin. RESULTS: The results were statistically analyzed by using the t-test. NAG, beta 2MG, uCr and TP levels increased significantly after chemotherapy in the control patients, but BUN and sCr levels did not change significantly. The NAG level in the control group was twice as high as in the fosfomycin group 8 days after chemotherapy (p < 0.01). The uCr and TP in control patients increased significantly after chemotherapy when compared to those in patients coad-ministered fosfomycin. There were no significant changes in beta 2MG, BUN and sCr levels. CONCLUSIONS: Cisplatin affected the levels of NAG, beta 2MG, uCr and TP without influencing BUN and sCr levels. Fosfomycin, therefore, may be useful as a supplemental treatment for reducing cisplatin nephrotoxicity, especially proximal tubular damage.

Urinary concentrations of fosfomycin after a single 3 g dose of fosfomycin to elderly nursing-home patients.

The urinary concentrations of fosfomycin in 7 elderly patients with impaired renal function (mean creatinine clearance 40 ml/min) were studied after a single oral dose of 3 g fosfomycin as the trometamol salt. Urine samples were collected as 12 h portions for 84 h. Urinary concentrations of fosfomycin were 1,383 mg/l (range 314 to 4,200 mg/l) in the first 12 h and gradually declined to 165 mg/l (range 65 to 365 mg/l) between 36 and 48 h. 37% of the oral dose was recovered in the urine unchanged after 84 h, but a wide range (15-60%) in urinary recovery was observed. The elimination half-lives in the patients (estimated from the renal excretion profile of fosfomycin) ranged between 7 and 24 h. These data suggest that the urinary levels obtained in this patient population exceed the minimum inhibiting concentration of the usual pathogens involved in uncomplicated cystitis for at least 48 h. After 24 h the urinary concentrations of fosfomycin are higher than those reported for healthy young subjects.

Pharmacokinetic profile of fosfomycin trometamol.

The pharmacokinetics of fosfomycin trometamol has been assessed in 12 healthy volunteers given oral doses of 2, 3, and 4 g of fosfomycin and 3 g intravenously of fosfomycin as fosfomycin sodium, all in the fasting state. The assay was microbiological (Proteus mirabilis ATCC 21100). There was a gradual rise in both peak serum concentrations and total area under the curve by rising oral doses, from 16.0 mg/l and 106.7 mg x h/l, after 2 g to 30.9 mg/l and 189.7 mg x h/l after 4 g respectively. The serum half-life was 4 h after the oral doses and 2.1 h after the intravenous dose. After the oral doses, the amounts excreted in urine in the active form ranged from 36 to 40% compared to 93% after the intravenous dose. The bioavailability was slightly below 40%. Concentrations in urine covers the usual urinary tract pathogens after oral doses of 2, 3, and 4 g.

[A study of the absorption and excretion of fosfomycin sodium in children].

Fosfomycin sodium (FOM-Na, Forocyle-S) was administered at 25 mg/kg or 50 mg/kg to 15 children between the ages of 3 and 15 through intravenous injection or through 1 hour intravenous drip infusion, and concentrations in blood serum and excretion through urine were examined and a pharmacokinetic analysis was carried out using the one-compartment model. 1. Average concentrations in the blood serum after injections with 25 mg/kg and 50 mg/kg were 55.3 +/- 6.3 micrograms/ml and 118.8 +/- 31.1 micrograms/kg 30 minutes after injection, respectively, and their half-lives were 1.04 +/- 0.15 hours and 0.98 +/- 0.17 hours, respectively. Six hours after injection, the levels were 2.7 +/- 1.6 micrograms/kg and 6.2 +/- 5.5 micrograms/kg, respectively. With 1 hour intravenous drip infusion of 25 mg/kg and 50 mg/kg, average concentrations the blood serum were 34.2 +/- 14.9 micrograms/ml and 89.7 +/- 6.7 micrograms/ml, respectively, and their half-lives were 0.87 +/- 0.24 hour and 0.69 +/- 0.10 hour, respectively. Six hours after the administration, the levels were 2.7 +/- 1.8 micrograms/ml and 6.7 +/- 0.8 micrograms/ml. There was a clear dose response in the concentration levels in the blood in those given the drug at 25 mg/kg and 50 mg/kg in either method of administration. 2. Average levels in urine after injection of 25 mg/kg and 50 mg/kg were 5,778 +/- 2,257 micrograms/ml and 6,268 +/- 3,329 micrograms/ml 0-2 hours after administration, respectively, and average levels at 4-6 hours were 701 +/- 765 micrograms/ml and 1,588 +/- 1,324 micrograms/ml, respectively. Average excretion, rates into the urine were 72.8 +/- 11.0 and 73.9 +/- 11.1%, respectively. In case of 1 hour drips infusion of 25 mg/kg and 50 mg/kg, average concentrations in the urine 0-2 hours after administration were 3,570 +/- 1,540 micrograms/ml and 11,800 micrograms/ml, respectively, and averages for 4-6 hours were 211 +/- 124 micrograms/ml and 1,300 micrograms/ml. Average rates of excretion into the urine for the first group was 57.9 +/- 16.3% and the second group was 78.4%. Clear dose response was observed in changes of drug concentration levels in the urine with 25 mg/kg and 50 mg/kg doses through either administration method, and in terms of excretion into the urine, no noticeable differences were observed between the different amounts administered or different administration methods.(ABSTRACT TRUNCATED AT 400 WORDS)

Pharmacokinetic comparison between fosfomycin and other phosphonic acid derivatives.

The pharmacokinetic comparison of phosphonic acid derivatives is based upon a survey of available literature on the whole group of compounds and on our own studies on fosfomycin. All three clinically used compounds, fosfomycin, fosmidomycin, and alafosfalin, are available for both oral and parenteral administration. The highest bioavailability is observed for the trometamol derivative of fosfomycin (37-44%); the calcium salt of fosfomycin is 2-2.5 times less absorbed and fosmidomycin has a bioavailability of 20-30%. The peak serum concentration of fosfomycin when given as the trometamol salt is about 2 times higher than the one reached with fosfomycin calcium or fosmidomycin. Urine recovery of unchanged drug is comparable after intravenous doses of fosfomycin and fosmidomycin, 80-95%, whereas the figure is only 10-20% for alafosfalin because it is extensively metabolized. After oral administration, urine recovery is highest for fosfomycin trometamol, 35-60%, compared to approximately 25% (range 18-29%) for fosfomycin calcium, 26% for fosmidomycin, and 6-17% for alafosfalin. The serum half-life of fosfomycin is 2-4 h (higher, up to 5.5 h, for some formulations of the calcium salt), 1.5-2.0 h for fosmidomycin, and about 1 h for alafosfalin. Thus, among available phosphonic acid derivatives and formulations, the trometamol derivative of fosfomycin has the most favourable characteristics. This applies to both bioavailability and urinary recovery, while at the same time the medium long half-life renders moderate fluctuation of concentrations whereby longer dosage intervals are possible.(ABSTRACT TRUNCATED AT 250 WORDS)

Relative bioavailability of fosfomycin and of trometamol after administration of single dose by oral route of fosfomycin trometamol in fasting conditions and after a meal.

The pharmacokinetics of fosfomycin and trometamol after single oral dose of fosfomycin trometamol (Z 1282) was studied in healthy volunteers in fasting conditions and immediately after standard meal. The dose was of 1.876 g (equivalent to 1.0 g of fosfomycin). The parameters considered were: serum apparent elimination half-life (t1/2), maximum serum concentration (Cmax), time to Cmax (tmax), area under the curve of the serum concentrations from time 0 (zero) to infinity (AUC0-infinity) and urinary recovery in the first 48 h. The results confirm that fosfomycin trometamol allows high bioavailability of fosfomycin. The absorption and elimination rates of fosfomycin and trometamol in the serum were similar. A statistically significant difference was found between the Cmax values of fosfomycin in the 2 experimental conditions. Means +/- SE of Cmax (micrograms/ml) were 12.1 +/- 0.6 in fasting conditions and 7.8 +/- 1.6 after a meal. Urinary recovery of the antibiotic was high in both experimental conditions. The fraction of the dose recovered (the dose being taken as equal to 1) was on the average 0.58 in the first condition and 0.52 in the second. Urinary recoveries of trometamol in the 2 different conditions were similar.

Antibacterial activity in human urine of fosfomycin trometamol in an in vitro model of the urinary bladder.

The urinary concentrations of fosfomycin trometamol, norfloxacin, pipemidic acid and cotrimoxazole were studied at various times after oral administration of drugs in healthy volunteers. Using the same urine, the bactericidal activity of four antimicrobial agents against Escherichia coli, Proteus mirabilis and Klebsiella pneumoniae in an in vitro model simulating the treatment of bacterial cystitis was also evaluated. The results obtained show that very high concentrations of the drugs were achieved in urine particularly after the oral administration of the fosfomycin trometamol. In the bladder model bactericidal activity of fosfomycin trometamol, norfloxacin and pipemidic acid were higher than that of cotrimoxazole; no resistant mutants to drugs were selected over a period of 24 h.

[Fosfomycin-trometamol (monuril): pharmacokinetics and food-drug interactions]. / La fosfomycine-trométamol (monuril): pharmacocinétique et interaction aliment-médicament.

A new water soluble monobasic salt of fosfomycin with trometamol has been recently developed for oral administration. The objective of this study was to evaluate the pharmacokinetics of trometamol-fosfomycin (monuril) in serum and urine in 10 healthy volunteers after oral administration of one single dose (50 mg/kg). In the volunteers, the concentrations of fosfomycin were measured before and after food absorption in serum and urine samples taken at t = 0, 2, 4, 6, 8, 24 h after the dose (plus 0.5 hand 1 h for serum samples). The measurement of fosfomycin levels was carried out by means of a microbiological procedure using Proteus mirabilis ATCC 21100 as test organism. The results indicated at 2 h after oral administration of the antibiotic, a mean serum peak level of 21.04 +/- 6.88 micrograms/ml. The urine concentrations reached 2,000 to 2,750 micrograms/ml at the 2nd hour, with high levels (mean: 1,876 +/- 709 micrograms/ml) till the 8th hour and persistence of noticeable concentrations at 24 h (334 +/- 210 micrograms/ml). The influence of food absorption, even variable, decreased significantly the rate of absorption with lower serum and urine levels. Taking into account this factor influencing the bioavailability and the distribution of the drug, the results of the study confirm that a high proportion of the oral dose of trometamine salt of fosfomycin is well absorbed; the extremely high urinary recovery of the drug could certainly allow short course therapy in the treatment of uncomplicated urinary tract infection.