Fosfomycin, discovered in 1969 by a Spanish scientist, is a broad-spectrum bactericidal antibiotic that interferes with both gram-positive and negative cell wall synthesis. There are three different formulations depending on the salt, which it is formulated with: On the one hand calcium and tromethamine/trometamol for oral treatment and, on the other hand, disodium for intravenous treatment. Oral fosfomycin is mainly used for urinary tract infection (UTI) in women, mainly caused by Escherichia coli and Enterococcus faecalis.1 The two oral formulas are also used in recurrent UTI prophylaxis. The question is, whether both are equally appropriate for prophylaxis.
In February 2020 at the Alto Deba health organization (67,000 inhabitants) in Gipuzkoa (Spain), there were 21 patients with calcium fosfomycin (FC) with a prophylactic dose: 500mg/24–72h and 80 patients with fosfomycin trometamol (FT): 3g every 10 days, 15 days or weekly. Different national and international guidelines about recurrent UTI were reviewed without reference to FC. In fact, according to the Martindale Pharmacotherapaeutica Consultation Guide, FC is available or has been available in these countries: Spain, Italy, Mexico, Argentina, Japan and China.2 In Spain, the Fisterra guideline takes FC into account.
The recommended dose in the Fisterra guide (last access: 07/05/2020) for UTI prophylaxis is FC 500mg/day or FT 3g every 10 days. In reviewing literature consulted3–4 we notice that the authors refer only to the FT.
With the term “fosfomycin tromethamineOR trometamol” appear in PubMed (last access: 12/05/2020): 7740 articles, of which those published in the last 10 years are: 2413. “fosfomycin calcium”: 54 results and limited to the last 10 years: 16.
A study in 2016 analyzed the kinetics of both fosfomycin formulations. The oral bioavailability of FT is 34–58%, with absorption mainly in the small intestine. FT is absorbed 6 times more than the FC during the first 2h and 3–4 times more in the first 12h, the explanation may be because calcium salt is hydrolyzed and inactivated by gastric juices.5 Other studies compare the bioavailability of FT vs FC (40% vs 12%).6,7 Concentrations of a single dose of FT of 2g are 2–4 times higher than a single dose of 3g of FC.8
The justification for the usage of the single dose of FT is based on its pharmacokinetics. After administration of a single dose, a maximum concentration of 22–32g/ml is reached in about 2hours with an elimination half-life of 2.4–7.3h and an area under the curve of 145–228g/ml h. This achieves a high urinary concentration (1000–4000g/ml) by remaining >100g/ml for 30–48h.7
Taking into account the pharmacokinetic differences between the two salts, some author6 points out that they should not be treated as equivalent formulations. In addition, most studies of prophylaxis or treatment in UTI are based on trometamol salt and there is only one descriptive study9 noticing the effectiveness of FC in the treatment of uncomplicated cystitis. However, according to the comparative study of FT 2g versus FC 3g8 it seems logical to think that the calcium formulation of 500mg is not pharmacokinetically adequate for establishing doses of 500mg/day in prophylaxis. There should be a clear distinction in the clinical usefulness of both formulations. In fact, recently, in acute and chronic prostatitis, it is perceptible that, in enterobacteria resistant to fluorquinolones and cotrimoxazole, favorable results have been obtained with the use of FT 3g/day for one week, followed by 3g to alternate days for 6 weeks.10
Therefore, the absence on literature of use of FC in prophylaxis and its different pharmacokinetics compared to trometamol salt would justify the exclusion of FC from the protocol of antibiotic prophylaxis in recurrent UTI and, possibly, its progressive disappearance from routine clinical practice also in the treatment of UTI. After all, in terms of fosfomycins, salt is what really matters.
FundingThis manuscript is not funded by anyone.
Conflict of interestNone.
