Re: ‘High interindividual variability in urinary fosfomycin concentrations in healthy female volunteers’ by Wijma et al.
Authors: C. Adembri, T. Cai, A. Novelli
Journal: Clinical Microbiology and Infection (2018)

We read with interest the paper by Wijma et al. [[1]Wijma R.X. Koch B.C.P. van Gelder T. Mouton J.W. High interindividual variability in urinary fosfomycin concentrations in healthy female volunteers.Clin Microbiol Infect. 2018; 24: 528-532Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar] 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. Fosfomycin trometamol PK variability has already been observed by some, but not all, kinetic studies that analysed the urinary concentrations after an oral dose [2Bergan 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 H.C. Williams J.D. New trends in urinary tract infections. Karger, Basel1988: 157-188Crossref Google Scholar, 3Fillastre J.P. Leroy A. Humbert G. Borsa F. Josse S. Comparative pharmacokinetics of fosfomycin in elderly subjects and uraemic patients.in: Neu H.C. Williams J.D. New trends in urinary tract infections. Karger, Basel1988: 143-156Google Scholar, 4Segre G. Bianchi E. Cataldi A. Zannini G. Pharmacokinetic profile of fosfomycin trometamol (Monuril).Eur Urol. 1987; 13: 56-63Crossref PubMed Scopus (52) Google Scholar]. Bergan et al. [[2]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 H.C. Williams J.D. New trends in urinary tract infections. Karger, Basel1988: 157-188Crossref Google Scholar] observed a high variation in urinary concentrations in nine healthy males (average age 22.5 years) even though the antibiotic had been given in the morning to overnight fasting participants who continued to fast until 3 h after the administration. Conversely, 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] observed a low inter-individual variability both in urinary concentrations and cumulative drug excretion in five male volunteers (mean age 36 years). Fosfomycin trometamol average cumulative urinary recovery observed by Wijma et al. [[1]Wijma R.X. Koch B.C.P. van Gelder T. Mouton J.W. High interindividual variability in urinary fosfomycin concentrations in healthy female volunteers.Clin Microbiol Infect. 2018; 24: 528-532Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar] over the initial 48-h period was 44.5%, a value similar to that observed by Bergan et al. (36.1%–41.2%), but lower than the one obtained in young volunteers by Segre et al. (50.4%) and also in five males with a CrCl of 127 ± 19.9 mL/min/1.73 m2 by Fillastre et al. (57%) [2Bergan 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 H.C. Williams J.D. New trends in urinary tract infections. Karger, Basel1988: 157-188Crossref Google Scholar, 3Fillastre J.P. Leroy A. Humbert G. Borsa F. Josse S. Comparative pharmacokinetics of fosfomycin in elderly subjects and uraemic patients.in: Neu H.C. Williams J.D. New trends in urinary tract infections. Karger, Basel1988: 143-156Google Scholar, 4Segre 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 27.5% urinary recovery obtained in eight elderly participants (mean age 71.8 = years, CrCl 48.8 ± 17.0 mL/min/1.73 m2) and the 31.6% urinary recovery in eight individuals with uraemia (CrCl 43.3 ± 32.5 mL/min/1.73 m2), confirmed that urinary excretion of fosfomycin trometamol is related to renal function [[3]Fillastre J.P. Leroy A. Humbert G. Borsa F. Josse S. Comparative pharmacokinetics of fosfomycin in elderly subjects and uraemic patients.in: Neu H.C. Williams J.D. New trends in urinary tract infections. Karger, Basel1988: 143-156Google Scholar]. However, Wijma et al. [[1]Wijma R.X. Koch B.C.P. van Gelder T. Mouton J.W. High interindividual variability in urinary fosfomycin concentrations in healthy female volunteers.Clin Microbiol Infect. 2018; 24: 528-532Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar] studied an almost homogeneous population when considering renal function, as the reported mean glomerular filtration rate of the 40 studied healthy women was 112.9 ml/min/1.73 m2. Therefore, a possible explanation for the high inter-individual differences in urinary concentrations in the Wijma et al. study [[1]Wijma R.X. Koch B.C.P. van Gelder T. Mouton J.W. High interindividual variability in urinary fosfomycin concentrations in healthy female volunteers.Clin Microbiol Infect. 2018; 24: 528-532Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar] may be better explained by the high variability in urinary output, ranging between 1850 and 6386 mL at 48 h. As the majority of total water intake occurs through drinking and the production of sweat accounts for approximately 20%–30% of water loss, there is a direct proportion between total fluid intake and 24-h urine volume. For an average daily urine volume of 1500 mL, a total daily fluid intake of almost 1.9–2.2 L is necessary [[5]Perrier E. Klein A. Guelinckx I. Armstrong L.E. Biological variation in urinary and salivary hydration biomarkers under conditions of ad-libitum fluid intake.Med Sci Sports Exerc. 2013; 45: 343Google Scholar]. Hence, the healthy women included in the study conducted by Wijma et al. [[1]Wijma R.X. Koch B.C.P. van Gelder T. Mouton J.W. High interindividual variability in urinary fosfomycin concentrations in healthy female volunteers.Clin Microbiol Infect. 2018; 24: 528-532Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar] had very variable daily water intake (some women drinking 20% more, and others more than the double the normal water intake). Nevertheless, in our opinion, the major issue of the Wijma et al. study [[1]Wijma R.X. Koch B.C.P. van Gelder T. Mouton J.W. High interindividual variability in urinary fosfomycin concentrations in healthy female volunteers.Clin Microbiol Infect. 2018; 24: 528-532Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar] is the sampling times after taking fosfomycin. Although a real-life research study cannot match all the requirements of a prospective study, the low number of samples within the first 12 h and, more importantly, the practical absence of samples in the first 2 h post-dose may really invalidate the results regarding the urinary peak concentration and the time necessary to reach the peak [[1]Wijma R.X. Koch B.C.P. van Gelder T. Mouton J.W. High interindividual variability in urinary fosfomycin concentrations in healthy female volunteers.Clin Microbiol Infect. 2018; 24: 528-532Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar]. Consequently, the authors obtained a urinary Cmax in the 2- to 4-h period only in 23.1% of cases, and within the sixth hour only in 46.2% of volunteers. Finally, in 17.9% of the cases they observed a peak concentration after 12 h. This is questionable, given the PK properties of fosfomycin, and it is also in contrast with the sentence included in the Results section that ‘Most fosfomycin (36.1%) was excreted during the first 6 h’ [[1]Wijma R.X. Koch B.C.P. van Gelder T. Mouton J.W. High interindividual variability in urinary fosfomycin concentrations in healthy female volunteers.Clin Microbiol Infect. 2018; 24: 528-532Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar]. If we compare the main PK parameters determined by both 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] and Bergan et al. [[2]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 H.C. Williams J.D. New trends in urinary tract infections. Karger, Basel1988: 157-188Crossref Google Scholar] with the ones reported by Wijma et al. [[1]Wijma R.X. Koch B.C.P. van Gelder T. Mouton J.W. High interindividual variability in urinary fosfomycin concentrations in healthy female volunteers.Clin Microbiol Infect. 2018; 24: 528-532Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar], we can observe that the urinary peak concentrations determined by both of those authors were 1.6 to 2.2 times higher than the value observed by Wijma et al. [[1]Wijma R.X. Koch B.C.P. van Gelder T. Mouton J.W. High interindividual variability in urinary fosfomycin concentrations in healthy female volunteers.Clin Microbiol Infect. 2018; 24: 528-532Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar]. Moreover, the mean Tmax in both the previous studies was 2.2 to 3.3 times shorter than in the Wijma et al.'s research (Table 1) [1Wijma R.X. Koch B.C.P. van Gelder T. Mouton J.W. High interindividual variability in urinary fosfomycin concentrations in healthy female volunteers.Clin Microbiol Infect. 2018; 24: 528-532Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar, 2Bergan 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 H.C. Williams J.D. New trends in urinary tract infections. Karger, Basel1988: 157-188Crossref Google Scholar, 4Segre G. Bianchi E. Cataldi A. Zannini G. Pharmacokinetic profile of fosfomycin trometamol (Monuril).Eur Urol. 1987; 13: 56-63Crossref PubMed Scopus (52) Google Scholar].Table 1Main pharmacokinetic parameters of fosfomycin trometamol observed in the urine of healthy volunteers after the administration of 3g or 50mg/kg in 3 different studiesStudyCmax (mg/L)Tmax (h)T1/2 (h)Bergan et al. [2]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 H.C. Williams J.D. New trends in urinary tract infections. Karger, Basel1988: 157-188Crossref Google Scholar4415.0 ± 10552.27.4Segre 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 Scholar3178.0 ± 958.73.489.54Wijma et al. [1]Wijma R.X. Koch B.C.P. van Gelder T. Mouton J.W. High interindividual variability in urinary fosfomycin concentrations in healthy female volunteers.Clin Microbiol Infect. 2018; 24: 528-532Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar1982.0 ± 1257.47.512.4 Open table in a new tab As a consequence, the pharmacodynamic profile related to the AUC/MIC values using the AUC0–48 h mean values, calculated on the urinary levels reported by both Segre et al. and Bergan et al., exceeds the reference EUCAST breakpoint value of 3994 for bacteriostasis for strains with MICs up to 8 mg/L [1Wijma R.X. Koch B.C.P. van Gelder T. Mouton J.W. High interindividual variability in urinary fosfomycin concentrations in healthy female volunteers.Clin Microbiol Infect. 2018; 24: 528-532Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar, 2Bergan 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 H.C. Williams J.D. New trends in urinary tract infections. Karger, Basel1988: 157-188Crossref Google Scholar, 4Segre G. Bianchi E. Cataldi A. Zannini G. Pharmacokinetic profile of fosfomycin trometamol (Monuril).Eur Urol. 1987; 13: 56-63Crossref PubMed Scopus (52) Google Scholar]. Moreover, when considering the peak concentrations, strains with MICs ≤ 32 mg/L would achieve a minimal average Cmax value of 138 (80.4–182.4) mg/L using Bergan et al.'s data and a value of 99.3 (78.4–150.6) using Segre et al.'s [2Bergan 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 H.C. Williams J.D. New trends in urinary tract infections. Karger, Basel1988: 157-188Crossref Google Scholar, 4Segre G. Bianchi E. Cataldi A. Zannini G. Pharmacokinetic profile of fosfomycin trometamol (Monuril).Eur Urol. 1987; 13: 56-63Crossref PubMed Scopus (52) Google Scholar]. In conclusion, studies on real-life populations are important to improve our knowledge of the use of antimicrobial drugs, even of those molecules that have been on the market for many years, such as fosfomycin trometamol. However, in this specific case, the absence/scarce data during the first hours after fosfomycin administration does not allow for a full perspective of the urinary PK profile of fosfomycin. No external funding was required.