High interindividual variability in urinary fosfomycin concentrations in healthy female volunteers – authors' response
Authors: R.A. Wijma, B.C.P. Koch, T. van Gelder, J.W. Mouton
Journal: Clinical Microbiology and Infection (2018)

We thank Adembri et al. [[1]Adembri C. Novelli A. Cai T. Re: ‘High interindividual variability in urinary fosfomycin concentrations in healthy female volunteers’ by Wijma et al.Clin Microbiol Infect. 2019; 25: 254-255Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar] for their valuable comments on our paper [[2]Wijma R.A. Koch B.C.P. van Gelder T. Mouton J.W. High interindividual variability in urinary fosfomycin concentratrions in healthy female volunteers.Clin Microbiol Infect. 2018; 24: 528-532Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar]. We are pleased to read that they also believe that urinary fosfomycin concentrations show a high interindividual variability (IIV). In their letter, Adembri et al. [[1]Adembri C. Novelli A. Cai T. Re: ‘High interindividual variability in urinary fosfomycin concentrations in healthy female volunteers’ by Wijma et al.Clin Microbiol Infect. 2019; 25: 254-255Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar] referred to the data of Bergan et al. [[3]Bergan T. Mastropaolo T. Di Mario F. Naccarato R. Pharmacokinetics of fosfomycin and influence of cimetidine and metoclopramide on the bioavailability of fosfomycin trometamol.in: Neu Williams New trends in urinary tract infections. 1988: 157-188Crossref Google Scholar] to support their view. Our results are in general similar to the results of Bergan et al. [[3]Bergan T. Mastropaolo T. Di Mario F. Naccarato R. Pharmacokinetics of fosfomycin and influence of cimetidine and metoclopramide on the bioavailability of fosfomycin trometamol.in: Neu Williams New trends in urinary tract infections. 1988: 157-188Crossref Google Scholar]. In that study, the authors studied the pharmacokinetics (PK) of fosfomycin in 12 healthy female volunteers and found maximum urinary concentrations ranging from 1053 to 3749 mg/L after ∼3 h and a mean fosfomycin recovery of 39% (over 72 hours). They also refer to the data of Segre et al. [[4]Segre G. Bianchi E. Cataldi A. Zannini G. Pharmacokinetic profile of fosfomycin trometamol (Monuril).Eur Urol. 1987; 13: 56-63Crossref PubMed Scopus (52) Google Scholar] from which they conclude that these authors did not demonstrate a high IIV of fosfomycin. However, Segre et al. [[4]Segre G. Bianchi E. Cataldi A. Zannini G. Pharmacokinetic profile of fosfomycin trometamol (Monuril).Eur Urol. 1987; 13: 56-63Crossref PubMed Scopus (52) Google Scholar] investigated the PK of fosfomycin in only five healthy male volunteers and it can hardly be expected that this represents a population. Segre et al. [[4]Segre G. Bianchi E. Cataldi A. Zannini G. Pharmacokinetic profile of fosfomycin trometamol (Monuril).Eur Urol. 1987; 13: 56-63Crossref PubMed Scopus (52) Google Scholar] found maximum concentrations of 2895 mg/L (SD 842) after 2–4 hours and a recovery of 32% (over 48 hours). Of note, the recovery in both these studies is significantly less than our findings. We found a mean Cmax of 1982.0 mg/L (SD 1257.4) after 7.5 hours (SD 4.2) with a total recovery of 47.0% (SD 10.4%) over 7 days and 44.5% (SD 12.6) over 48 hours [[2]Wijma R.A. Koch B.C.P. van Gelder T. Mouton J.W. High interindividual variability in urinary fosfomycin concentratrions in healthy female volunteers.Clin Microbiol Infect. 2018; 24: 528-532Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar]. It should also be mentioned that we also observed maximum concentrations of >3000 mg/L in many volunteers. However, because of the much higher number of study participants in our study (40 in our study compared with 12 in the study of Bergan et al. [[3]Bergan T. Mastropaolo T. Di Mario F. Naccarato R. Pharmacokinetics of fosfomycin and influence of cimetidine and metoclopramide on the bioavailability of fosfomycin trometamol.in: Neu Williams New trends in urinary tract infections. 1988: 157-188Crossref Google Scholar] and five in the study of Segre et al. [[4]Segre G. Bianchi E. Cataldi A. Zannini G. Pharmacokinetic profile of fosfomycin trometamol (Monuril).Eur Urol. 1987; 13: 56-63Crossref PubMed Scopus (52) Google Scholar]) the mean value we reported seems low, while the absolute range of Cmax values we found compared with the other studies by Bergan and Segre is not very different. Adembri et al. [[1]Adembri C. Novelli A. Cai T. Re: ‘High interindividual variability in urinary fosfomycin concentrations in healthy female volunteers’ by Wijma et al.Clin Microbiol Infect. 2019; 25: 254-255Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar] state that they also believe that urinary concentrations are closely related to the urinary output and therefore to the fluid intake of the volunteers. The highly variable fluid intake of our volunteers would therefore be a better explanation of the highly variable urinary concentrations we observed, rather than that these variable urinary concentrations are a PK property of fosfomycin. We fully agree with this statement and we also mention this in our paper as the most likely cause [[2]Wijma R.A. Koch B.C.P. van Gelder T. Mouton J.W. High interindividual variability in urinary fosfomycin concentratrions in healthy female volunteers.Clin Microbiol Infect. 2018; 24: 528-532Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar]. This observation highlights the importance of administering the drug before bedtime after emptying the bladder in order to optimize the residence time of fosfomycin in the bladder and to maximize the effect of the treatment. Their major comment in their letter is the low number of samples in a number of volunteers collected within the first 12 hours and the practical absence of samples in the first 2 hours after dosing [[1]Adembri C. Novelli A. Cai T. Re: ‘High interindividual variability in urinary fosfomycin concentrations in healthy female volunteers’ by Wijma et al.Clin Microbiol Infect. 2019; 25: 254-255Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar]. According to the authors, this resulted in Cmax concentrations which are too low and Tmax values which are too late. We mentioned that the purpose of our study was to describe the real-life situation because one should be more interested in real life data rather than data obtained in a laboratory/research setting [[2]Wijma R.A. Koch B.C.P. van Gelder T. Mouton J.W. High interindividual variability in urinary fosfomycin concentratrions in healthy female volunteers.Clin Microbiol Infect. 2018; 24: 528-532Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar]. We therefore did not put the volunteers on a preconceived voiding scheme, which would have required more fluid intake and artificial voiding. This might indeed have resulted in missing the ‘real’ Cmax, but it could also be argued that with artificial earlier voiding the Cmax would be too low because of the relationship between clearance and urinary concentrations. We would like to point out that the most important message of our paper was the high IIV in urinary concentrations, not only at the Cmax but also over time. Indeed, we clearly showed that some volunteers did not have measurable concentrations after already 48 hours. We refrain at this stage from replying to the statements with respect to EUCAST or CLSI breakpoints. We believe that at present there is not enough evidence to support these breakpoints as they are based on historical values rather than an abundance of (pre)clinical studies. In conclusion, we do not think that we would have drawn a different conclusion if we had used strict voiding schedules, which are artificial by nature. We think that it is important to realize that a single 3-g dose may not be sufficient to eradicate the uropathogen in a part of the population because of a fast clearance. The high IIV might therefore explain part of the observed treatment failures of fosfomycin [[5]Huttner A. Kowalczyk M.S. Turjeman A. Babich T. Brossier C. Eliakim-Raz N. et al.Effect of 5-day nitrofurantoin vs single-dose fosfomycin on clinical resolution of uncomplicated lower urinary tract infection in woman. A randomized clinical trial.JAMA. 2018; 319: 1781-1789Crossref PubMed Scopus (110) Google Scholar] in the randomized clinical trial published by Huttner et al. Re: ‘High interindividual variability in urinary fosfomycin concentrations in healthy female volunteers’ by Wijma et al.Clinical Microbiology and InfectionVol. 25Issue 2PreviewWe read with interest the paper by Wijma et al. [1] who found a considerable inter-individual pharmacokinetic (PK) variability in the urinary concentrations after a 3-g fosfomycin trometamol dose administered to 40 healthy women with normal renal function. Full-Text PDF Open ArchiveHigh interindividual variability in urinary fosfomycin concentrations in healthy female volunteersClinical Microbiology and InfectionVol. 24Issue 5PreviewFosfomycin is increasingly being prescribed for treatment of uncomplicated urinary tract infections in an era of emerging drug resistance. Surprisingly, little is known of the urinary concentrations of fosfomycin and its interindividual variation after the standard single 3-g oral dose. We aimed to gain more insight into urinary fosfomycin pharmacokinetics to evaluate its effectiveness. Full-Text PDF Open Archive