EXtended Use of FOsfomycin for the Treatment of CYstitis in Primary Care

1. INTRODUCTION AND RATIONALE

Cystitis is the most common problem in primary care in the Netherlands for women (3.7% of all consultations in women).0 Women are disproportionally affected with about 70/1000 new lower urinary tract infections (UTIs) per year, compared to 10/1000 new UTIs per year for men.1 In the Netherlands this implies more than 600,000 women suffer from a UTI every year.

Empiric treatment of lower urinary tract infection (UTI) targets Enterobacterales and in particular E.coli, the most prevalent causative pathogen. In the Netherlands, the current first choice treatment for uncomplicated cystitis is nitrofurantoin for 5 days (four times daily 50mg or twice daily 100mg in slow release form, mainly depending on availability at the pharmacy), the second choice is fosfomycin-trometamol (FT) in a single dose and the third choice is trimethoprim for 3 days.1 FT is increasingly prescribed, probably because it is easy to administer, well tolerated and patient friendly due to its shorter treatment duration. In a large database of prescribed drugs in primary care (Utrecht region) there is a clear increase in FT use since (in 2013) FT became 2nd choice for the treatment of uncomplicated cystitis, at the expense of nitrofurantoin (NIT) (now 1st choice) and trimethoprim (now 3rd choice). FT as a second choice is much more frequently used than trimethoprim as a second choice in 2013 (see figure 1, below)

In two randomized controlled trials, performed more than 20 years ago, efficacy (based on participant reported symptoms) between a single gift of FT compared to nitrofurantoin four times 50mg or twice daily 100mg for 7 days did not differ statistically significant.4,5 Yet, one of these studies did not meet the necessary number of inclusions and was thus underpowered 4 and the other was performed in a population in which causative pathogens had higher levels of resistance to nitrofurantoin than is usual in the Netherlands. 5 A recent open-label randomized controlled trial suggests that a single gift of FT is less effective compared to thrice daily 100mg nitrofurantoin for 5 days for uncomplicated cystitis in non-pregnant women.3 Compared to the Dutch recommendation they applied a higher dose of nitrofurantoin, reported nitrofurantoin adherence was very high, and the study also included hospitalized patients (7,4% of study population) whereas in the Netherlands nitrofurantoin for uncomplicated cystitis is almost exclusively prescribed to outpatients.3 This implies that the findings of this study may not be fully generalizable to the Dutch situation, and call for a reevaluation and possible optimization of fosfomycin treatment for UTI.

Although usually prescribed in a single dose, the optimal dose of FT for cystitis is still unknown.3 The pharmacodynamic parameter most strongly linked to effectiveness is the area under the curve / minimal inhibitory concentration (AUC/MIC) ratio. High inter-individual variability in urinary FT concentrations in healthy female volunteers were observed after a single-gift FT with fosfomycin concentrations in urine below the EUCAST breakpoint in two-thirds of the volunteers after 72 hours.8 Moreover, in vitro bladder models have shown that a single dose of oral FT 3000mg is insufficient to kill E.coli strains with a minimal inhibitory concentration (MIC)>4mg/L in urine. Consequently, a single dose FT may be insufficient and it is suspected that extended dosing of FT improves outcomes.8,7 Besides, in vitro activity of a single dose of FT for cystitis correlates badly to in vivo bacteriological efficacy, even when using agar dilution, a reference standard for susceptibility testing.3,9 For that reason, dose-finding studies in clinical patients such as in our trial are indispensable for cystitis.