Clinical Trial Details
— Status: Terminated
Administrative data
| NCT number |
NCT05254808 |
| Other study ID # |
NL75841.041.20 |
| Secondary ID |
|
| Status |
Terminated |
| Phase |
Phase 3
|
| First received |
|
| Last updated |
|
| Start date |
September 6, 2021 |
| Est. completion date |
February 14, 2022 |
Study information
| Verified date |
February 2022 |
| Source |
UMC Utrecht |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
Cystitis is the most frequent reason for women to visit their general practitioner. More than
600.000 women suffer from urinary tract infections in The Netherlands each year. Currently,
the 1st choice treatment for uncomplicated cystitis is nitrofurantoin (NIT) for 5 days. The
second choice is 3 gram fosfomycin-trometamol (FT) in a single dose. FT is increasingly
prescribed because it has few side-effects and it has a patient-friendly dosing scheme.
Previous research did not show significant difference in efficacy between fosfomycin and
nitrofurantoin, but a clinical trial from 2018 claims a single dose of FT might be inferior
to 5 days of nitrofurantoin. Pharmacodynamic and pharmacokinetic research suggests that a
single dose of FT may be insufficient to cure cystitis. Overall, it remains unknown whether a
single gift of FT is as efficacious as 5 days of nitrofurantoin for uncomplicated cystitis
with regard to clinical cure and if an additional gift of FT would overcome this. A clinical
trial is therefore warranted.
Objective: To investigate the comparative effectiveness and side-effects of 5 days of
nitrofurantoin, single dose FT, and extended use of FT in uncomplicated cystitis in primary
care.
Study design: An open-label randomized non-inferiority / superiority study with 3 arms.
Study population: 777 non-pregnant women with symptoms of uncomplicated cystitis, with 259
subjects in each study arm.
Intervention: (A) FT in a single dose of 3000mg on day 1; (B) extended dosing of 3000mg FT on
day 1 and 3 (C) nitrofurantoin 100mg bid (slow release) for 5 days.
Main study parameters/endpoints: primary: days of absence of cystitis symptoms within 28
days. Secondary: clinical failure on day 28, microbiological failure on day 28, incidence of
side-effects, cost-effectiveness Burden and risks associated with participation, benefit and
group relatedness: A potential risk of participation is that the treatment arm to which the
patient is allocated is either less efficacious, has more adverse events or higher recurrence
rate than the other treatment arms. However, NIT and FT are both frequently used for urinary
tract infections and considered safe and effective compounds for uncomplicated cystitis.
According to previous studies, a second dose of FT is well tolerated. The potential risks of
participation on severe adverse events is expected to be negligible as the risk of severe
clinical failure after cystitis treatment is only 1% according to previous studies and
differences between NIT and FT have not been observed previously. A potential benefit of
participating to this study is that a more patient friendly treatment scheme is equally
effective. For future patients the guidelines could be improved and become more
patient-friendly. The burden of participation is considered low. Study participants need to
complete a short daily questionnaire on a mobile application up to 28 days.
Description:
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.
In summary, the current recommendation for Dutch GPs is to treat uncomplicated cystitis
with a 5-day course of nitrofurantoin (2x100mg or 4x50mg daily). It is unknown whether a
single dosage might be equally effective and if the efficacy of FT could be improved by
an additional dosage on day 3. Efficacy reflects the rapidity in which complaints
disappear and the likelihood of not developing a relapse or recurrence cystitis or
pyelonephritis within 28 days.
We, therefore, designed a non-inferiority/superiority trial for the treatment of
uncomplicated cystitis in the Dutch community, in which the investigators compare a
1-day and 3-day regimen of FT to a 5-day regimen of nitrofurantoin to investigate the
effect on time to resolution of symptoms and the occurrence of recurrence/relapse within
28 days.
2. OBJECTIVES
2.1. Primary Objective:
To investigate the effect of the different treatment arms on:
- the number of days with full resolution of cystitis symptoms within the period of 28
days 2.2. Secondary Objective(s):
- Rate of clinical failure within 28 days, irrespective the causing organism
- Rate of microbiological failure at day 28
- Rate of relapses at day 28,
- Rate of reinfections at day 28
- Rate of aggravation to pyelonephritis or urosepsis at day 28
- Rate of hospital admission at day 28
- Rate of mortality at day 28
- Incidence of (severe) adverse events (including fever, diarrhea, nausea, vaginitis,
headache, dizziness) on day 7
- Self-reported therapy adherence on day 7
- Satisfaction with the treatment received after 28 days
- The number of days of absenteeism (from payed work or volunteer work)
- Correlation between in vivo and in vitro activity for the investigational treatments
- If funding permits:
- A pharmacodynamic evaluation of in vitro activity measurement of fosfomycin for E.
coli and Klebsiella spp.
- Micro-organisms associated with clinical failure as identified with molecular
microbiological methods
- Develop novel approaches to identify human antibodies recognizing E. coli
2.3. Hypotheses
The investigators will test the following hypotheses related to the primary objective:
1. Fosfomycin in a single dose is non-inferior to nitrofurantoin,
2. Fosfomycin in two dosages on day 1 and 3 is non-inferior to nitrofurantoin
3. Fosfomycin in two dosages on day 1 and 3 is superior to fosfomycin in a single dose.
3. STUDY DESIGN
An open-label non-inferiority/superiority randomized clinical trial. Patients will be
randomized in a 1:1:1 ratio to either of:
A) Fosfomycin in a single dose on day one (FT1) B) Extended use of fosfomycin during three
days with a dose given on day one and three (FT1+3); C) Nitrofurantoin for 5 consecutive days
(2 times daily 100mg in slow release form (Furabid®) (NIT1-5)*
In case of treatment failure the treating physician will act according to their medical
standards. In general this implicates that study medication will be ceased and other
antibiotics will be started according to the professional judgment of the physician.
4. STUDY POPULATION 4.1 Population (base) The study population consists of non-pregnant adult
(>=18 years of age) women with cystitis. 5-10 general practices will participate. An average
general practice performs about 8966 consulting moments a year (NIVEL) which implies at least
165 UTIs in women per general practice yearly. Of all eligible patients an inclusion rate of
25-30% is assumed.
4.4 Sample size calculation The investigators performed sample size calculation for both
duration of symptoms and clinical failure using sample size calculations for non-inferiority.
The sample size was driven by clinical failure. Assumptions for duration of symptoms were a
standard deviation of 2.2 days10, clinically relevant non-inferiority margin of 0.8 days,
two-sided alpha of 0.017, power of 90%, and 20% loss of efficiency due to skewness of the
outcome parameter and potentially missing outcome data, which yielded a total sample size of
741 (247 per arm).
Assumptions for clinical failure were a failure rate at day 28 of 7.5% based on data provided
by the Julius Huisartsen Netwerk, clinically relevant non-inferiority margin of 7.5%,
two-sided alpha of 0.017, and power of 80%, which yielded a total sample size of 777 (259 per
arm).
Hence the investigators aim to enroll 777 patients in total. The investigators did not take
into account missing outcome data for this endpoint since these data will be derived from the
GP medical records with a short follow-up period. The sample size has been calculated for the
non-inferiority analyses, and ensures sufficient power for the superiority analyses.
6. INVESTIGATIONAL PRODUCT
6.1 Name and description of investigational product(s) 6.1.1 Fosfomycin Fosfomycin is a
phosphoenolpyruvate (PEP) analogue that is produced by Streptomyces spp.. It has a
bactericidal action, primarily by inhibiting bacterial cell wall (peptidoglycan) synthesis.
In the Netherlands, Fosfomycin is orally available as fosfomycin-trometamol (Monuril).
Fosfomycin-trometamol is identical to fosfomycin-tromethamine. Fosfomycin-trometamol is a
phosphoric acid derivative of fosfomycin, available in a single dose sachet containing white
granules. One sachet contains 5.63 g of fosfomycin-trometamol, corresponding with 3000mg
fosfomycin.
6.1.2 Nitrofurantoin Nitrofurantoin belongs to the group of nitrofuranes. Both nitrofurantoin
and its metabolites have antibacterial activity, which is enhanced under acidic conditions.
Nitrofurantoin is reduced to (active) metabolites by bacterial enzymes. These metabolites
inhibit bacterial enzymes that are essential for energy metabolism and inhibit bacterial
protein synthesis by binding to ribosomes. Active therapeutic concentrations are only reached
in urine and not in other tissues. Several manufacturers produce generic nitrofurantoin in
the solid oral form. Three different formulations exist: a macrocrystalized form,
nitrofurantoin monohydrate (microcrystals) and a mixture of macrocrystals (75%) and
monohydrate 25%) contained in a delayed-release gel matrix (Furabid®) In this trail only
Furabid® will be used. Macrocrystals are slower dissolved and absorbed in comparison to the
monohydrate.
6.4 Summary of known and potential risks and benefits 6.4.1 Fosfomycin Fosfomycin is
contraindicated in patients with known hypersensitivity, but is generally considered safe.
The allergic risk is very low.19 Mild and self-limiting gastro-intestinal disturbances, such
as diarrhoea, nausea, abdominal pain and dyspepsia are the most common. Headaches, dizziness,
upper respiratory tract infections, vaginitis, bacterial and fungal superinfections have been
reported. Transient laboratory alterations concerns all blood series (neutropenia,
eosinophilia, anaemia, low platelet count, increased liver enzymes, bilirubin), but no renal
insufficiency.20 A full list of adverse reactions can be found in the SPC and investigator
brochure.
6.4.2 Nitrofurantoin Nitrofurantoin is contra-indicated in patients with renal impairment
(creatinine clearance <30 mL/min), a history of lung or liver reaction or peripheral
neuropathy, hypersensitivity of nitrofuranen, acute porphyria, G6PD-deficiency, newborns
(<3mnd). Common side-effects include superinfection by fungus or resistant bacteria in
urogenital tract, benign intracranial hypertension and (temporary) alopecia. A full list of
possible side effects can be found in the SPC.
6.5 Description and justification of route of administration and dosage 6.5.1 Fosfomycin In
the Netherlands FT has been registered as an oral single dose for symptomatic UTI, on 29
march 1990.21 Before registration, 3 clinical trials on fosfomycin-tromethamine (=fosfomycin
trometamol) were performed in the US, demonstrating safety and efficacy.22 Fosfomycin has
been marketed as fosfomycin-calcium previously, but as a result of low bio-availability, it
is not registered in the Netherlands nor internationally.23 Fosfomycin is also registered as
an intravenous administration, fosfomycin-disodium (in the Netherlands registered as Fomicyt)
for the treatment of complicated UTI, osteomyelitis, nosocomial infections, lower airway
infections, bacterial meningitis, or bacteremia in conjunction with one of the above
infections. It is only indicated when it is deemed inappropriate to use the commonly used
antibiotics or when these antibiotics have failed.24 6.5.2 Nitrofurantoin In the Netherlands,
nitrofurantoin is available in 1) a slow-release formulation in capsules of 100mg, 2) in
macrocrystalline form in capsules of 50mg and 100mg and 3) in a suspension of 10mg/mL (100mL
per dose).
7. NON-INVESTIGATIONAL PRODUCT
Not applicable.
8. METHODS
8.2 Randomisation, blinding and treatment allocation
Participants will be randomized to fosfomycin FT1:FT1+3:NF1-5 in a 1:1:1 ratio. Randomization
will be performed by the UMCU study team after obtainment of informed consent. Randomization
will be done centrally and computer generated via the eCRF. The randomization sequence is
created by computer software using block randomization with unequal block size.
8.3 Study procedures
The patient's GP will verify the eligibility criteria. Eligible patients interested in
participation in the study will receive from the GP, the study's patient information form as
well as a link to an information video. Eligible patients will receive a telephone call from
the UMCU study team for the informed consent procedure. If the u to the pharmacy to obtain
the study medication. If co-medication is used and the study pharmacist is not the patient's
regular pharmacist, the study pharmacist will request a medication overview from her regular
pharmacist. The patient is asked for consent to do so. If no consent to participate in the
study is obtained, the patient will receive antibiotics in accordance to the GPs
prescription.
If the patient consents to study participation, the UMCU study team will perform the
following study procedures:
- Randomize the patient
- Notify the GP, the pharmacist and Saltro laboratory about participation and allocation,
and request GP to send urine samples to Saltro laboratory.
- Fill in the eCRF
- Register the participant for the mobile application
Follow-up data will be collected by a research application for mobile phones. A daily
notification will be sent to participants in the subsequent 28 days with three additional
questionnaires on day 0, day 7 (adverse events and treatment adherence) and day 28
(absenteeism, treatment satisfaction, hospital admission). For participants not able to use
the mobile application, the alternative of a paper diary will be provided including the same
questions and with weekly phone contacts to obtain the follow-up data. The content of the
mobile application and tasks per day is provided in attachment 1. Secondary endpoints and
SAE's that cannot be reported (timely) with the mobile application, will be collected by the
GP (e.g. mortality, hospital admission, pyelonephritis).
8.4 Withdrawal of individual subjects Participants can leave the study at any time for any
reason if they wish to do so without any consequences. Participants will be asked to provide
the reason for withdrawal but are not obliged to disclose it. Participants that want to
withdraw from the study will be asked permission to obtain follow-up data from the medical
records for secondary endpoints. The investigator can decide to withdraw a participant from
treatment for urgent medical reasons. Urgent medical reasons include: an AE that requires
immediate change of study medication (e.g. allergic reaction) or a medical complication (e.g.
pyelonephritis, urosepsis) that requires a change of study medication. In these cases the
participant is however still requested to participate in the daily completion of the
questionnaires.
8.4.1 Specific criteria for withdrawal (if applicable) No specific criteria applicable 8.4.2
Replacement of individual subjects after withdrawal Withdrawn participants will not be
replaced as the sample size calculation already incorporates this.
9. SAFETY REPORTING 9.1. Temporary halt for reasons of subject safety It is highly unlikely
that for reasons of subject safety the trial needs to be halted. If this is however the case,
then in accordance to section 10, subsection 4, of the WMO, the sponsor will suspend the
study if there is sufficient ground that continuation of the study will jeopardise subject
health or safety. The sponsor will notify the accredited METC without undue delay of a
temporary halt including the reason for such an action. The study will be suspended pending a
further positive decision by the accredited METC. The investigator will take care that all
participants are kept informed.
9.5. Safety Committee This study is performed in a (generally) healthy population in primary
care. There is extensive experience in the population with both nitrofurantoin and
fosfomycin. Both compounds are considered safe. For these reasons a DSMB is not necessary.
Instead an annual safety report will be sent to the accredited METC and competent authority
(see 9.3)
10. STATISTICAL ANALYSIS
10.1. Primary study parameter(s) Duration of absence of cystitis symptoms will be analyzed
using linear regression analysis, adjusted for stratification variable GP practice. Putative
violations of the homoscedasticity assumption will be corrected using robust standard errors.
Differences in duration of cystitis symptoms with corresponding 98.3% confidence intervals
(to account for multiple testing) will be calculated for each comparison. Non-inferiority
will be tested for single-dose FT vs. nitrofurantoin and double-dose FT vs. nitrofurantoin,
using a non-inferiority margin of 0.8 day, and superiority will be tested for double-dose FT
vs. single-dose FT. Hence a two-sided alpha will be used. Two different populations will be
analysed: the intention-to-treat (ITT) population and the microbiologically evaluable,
per-protocol population. The ITT population includes all patients who were enrolled in the
study. The per-protocol analysis excludes patients with a negative urine culture immediately
prior to starting antibiotic treatment and patients that have received a new antibiotic
treatment since the investigational treatment.
10.2. Secondary study parameter(s) The rates of clinical failure, microbiological failure,
relapses, reinfections, complete self-reported therapy adherence, aggravation to
pyelonephritis or urosepsis, hospital admission or mortality will be analyzed using
generalized linear models, adjusted for stratification variable GP practice, using a binomial
identify link function and will be reported as risk difference with 98.3% confidence
interval. Differences in duration of adverse events, the days of absenteeism, within the
population that is employed (including voluntarily work) or studies, and the degree of
satisfaction with the received treatment on a scale from 1 to 5 will be calculated for each
comparison and will be reported with corresponding 98.3% confidence intervals. The incidence
and nature of severe adverse events will be described.
Correlation between in vivo and in vitro activity will be reported as categorical and
essential agreements, which is done separately for the investigational treatments.
10.3. Other study parameters Incremental differences in costs and health outcomes (days with
complaints) will be compared among the 3 different treatments and plotted in a
cost-effectiveness plane / cost-effectiveness frontier. Uncertainty analysis will be
performed with a bootstrap procedure.
10.4. Interim analysis (if applicable) Not applicable. No interim analysis will be performed.
10.5. Missing data Missing observations due to loss to follow-up will be examined to
determine both its extent and whether it is missing at random or has a structural underlying
reason. If data are missing, the use of appropriate multiple imputation techniques will be
considered. Data management processes will include checking for data outliers and unusual
data patterns.
11. ETHICAL CONSIDERATIONS
11.1 Regulation statement The trial will be conducted according to the principles of the
Declaration of Helsinki 64th WMA General Assembly, Fortaleza, Brazil, October 2013, ICH GCP
E6(R2) Guideline, and in accordance with the Medical Research Involving Human Subjects Act
(WMO).
11.2 Recruitment and consent
Assistants in participating general practices are instructed to inform patients about the
EXFOCY study when a woman seeks help for cystitis.
During the appointment the GP checks if patient meets inclusion criteria and no exclusion
criteria are present. The GP asks if the patient would like to participate in principle and
prescribes a study medication prescription which is sent digitally to the central pharmacy or
printed and given to the patient.
While waiting for the dipstick result at home, information about the study can be read
(patient letter and informed consent form), and an information video about the study can be
viewed. Waiting time is usually a couple of hours.
Eligible patients will be called by the UMCU study team for the informed consent procedure.
After signing the informed consent the patient will be assigned to one of the three arms
randomly and given a study number. Under supervision of the UMCU study team the mobile
research application is downloaded and together they check if it works properly. The patient
is then referred to the pharmacy to obtain the study medication.
If the patient initially agreed to participate, but has second thoughts and does not want to
participate when arriving at the pharmacy the study medication prescription will be
interpreted as a nitrofurantoin prescription (current 1st choice for cystitis).
11.3 Objection by minors or incapacitated subjects (if applicable) Not applicable.
11.4 Benefits and risks assessment, group relatedness The investigators are investigating 3
arms. Both fosfomycin and nitrofurantoin are already frequently used for cystitis so risks
are small, but benefits for FT1+3 arm could be great.
Benefits for NIT1-5 are that it is currently first choice. Benefits for FT1 are that this is
the most patient friendly dosing scheme with few side-effects and possibly non-inferior to
NIT1-5.
Benefits for FT1+3 are that it is still a patient-friendly dosing scheme with few
side-effects and is possibly superior to FT1.
Risks for NIT1-5 are side-effects and a higher risk of forgetting a pill due to the high
number to be taken (N=10).
Risks for FT1 are side-effects and potentially a lower efficacy than NIT1-5. Risks for FT1+3
are a higher risk of side effects compared to FT1.
12.6 Public disclosure and publication policy Prospective Trial registration will be
performed before inclusion of the first patient in order to comply with requirements from the
The International Committee of Medical Journal Editor.
When the study is finished the results will be published in a peer-reviewed journal.
All findings are of interest on a national and international level considering the debate
about a single dose of fosfomycin and considering cystitis is such a frequently seen problem.
The study resembles current clinical practice in the Netherlands as much as possible and
therefore findings can be easily interpreted and placed into national context.
Before initiation of this study the NHG will be informed about the trial. The findings of
this study will actively be communicated to GPs and will help shape an updated Dutch
NHG-guidelines on UTIs.
13. STRUCTURED RISK ANALYSIS
13.1 Potential issues of concern See section 13.2 Synthesis
13.2. Synthesis Nitrofurantoin is the current 1st choice antibiotic and fosfomycin is the
current 2nd choice for uncomplicated cystitis. Both compounds are frequently prescribed in
primary care in the Netherlands and both are in general considered safe for the population
studied.
From an effectiveness perspective a single dose of fosfomycin has been considered
non-inferior to nitrofurantoin with equal effectiveness in treatment of uncomplicated UTI
based on trials with some quality issues. In 2018 it was claimed by Huttner et al. 2018 that
fosfomycin is inferior to nitrofurantoin, but it is unknown whether this finding would also
apply to the Dutch primary care setting. Therefore a reevaluation and possible optimization
of fosfomycin treatment for UTI is warranted.
All study arms have particular benefits and possible disadvantages. FT1: Based on PK/PD
studies a single dose FT may be insufficient. The pharmacodynamic parameter most strongly
linked to effectiveness is the area under the curve / minimal inhibitory concentration
(AUC/MIC) ratio. For this reason it is possible that extended or higher dosing of FT improves
outcomes. Additionally, 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. It is
however a very patient friendly due to its simple dosing and limited side-effects which might
explain why FT is increasingly used for treatment of uncomplicated UTI.
FT1+3: An extended dose of fosfomycin could have a higher efficacy than a single dose of FT
for above mentioned reason, but also have a higher chance of side-effects.
NIT1-5: Is the 1st choice and possibly has the highest efficacy, but it is also the longest
treatment with most pills.
Resistance rates for fosfomycin and nitrofurantoin are similar and low (1% and 2% resistance
rate in primary care in 2018) and does not favour fosfomycin nor nitrofurantoin.
In summary, the current recommendation for Dutch GPs is to treat uncomplicated cystitis with
a 5-day course of nitrofurantoin (at least 10 pills), and it is unknown whether a single
dosage or 2 dosages of FT in 3 days might be equally effective.
