Effectiveness of fosfomycin versus nitrofurantoin in Dutch risk groups with cystitis: a pilot study (Uri-weg study)

More and more urinary tract infections in general practitioner patients are
caused by extended-spectrum beta lactamases (ESBLs). In 2013, 3% of all
(E.coli) urine isolates reported in ISIS-AR (GP patients) was ESBL positive.
Observational studies have previously shown a significant increase in ESBL (E.
coli) prevalence in urine samples from GP patients with cystitis (0.1% in 2006
to 1.0% in 2009). Currently, no longer trimethoprim but nitrofurantoin is
prescribed as the first choice treatment in healthy non-pregnant women (over 12
years) with cystitis (without tissue invasion). Fosfomycin and trimethoprim are
now prescribed respectively as second and third choice treatment. In patients
with an increased risk of complicated cystitis the first and second choice
antibiotic treatment is nitrofurantoin and amoxicillin / clavulanic acid (in
pregnant women) or trimethoprim (in other risk groups) respectively. Fosfomycin
is not included in the empirical antibiotic policy in risk groups despite its
low resistance and good cure rates, partly because there is little scientific
support for risk groups. In a recent review, the effect (microbiological
eradication) of fosfomycin compared to other antibiotics (including
fluoroquinolones, trimethoprim, and nitrofurantoin), was already demonstrated
in patients with cystitis from a non-risk group. It was shown that fosfomycin
compared to nitrofurantoin (and other antibiotics) showed comparable
microbiological eradication rates with fewer side effects. The same effect was
seen within risk groups (including pregnant women and males). Unfortunately,
the quality of these studies was low and the effect was not compared to
nitrofurantoin, which is currently empirically prescribed as first antibiotic
treatment in the Netherlands. To address this knowledge gap in Dutch risk
groups a randomized controlled trial is necessary.

To determine the microbiological and clinical cure rate after 14 days.

This study will be designed as a pilot study (open-label randomized clinical
trial). The study population consists of patients who present to their GP with
signs of a urinary tract infection without signs of tissue invasion and belong
to a NHG-defined risk group. NHG risk groups are: men, pregnant women, patients
with diabetes mellitus or impaired immune systems, patients with an indwelling
urinary catheter and those with preexisting abnormalities of kidney or urinary
tract. When these patients with symptoms of uncomplicated UTI (painful or
burning urination, increased urinary frequency, false urgency, hematuria,
abdominal pain) present to their general practitioner and are diagnosed with an
urinary tract infection with the standard recommended procedure by the NHG (
dipstick test, dip slide, (water) complaints, sediment and / or culture) will
be asked to participate in the study. Three GP practices will participate in
this study (all based in one location) and asking the patient informed consent.
Participating patients will be randomized into one of two treatment arms.
Urinary voiding symptoms, test results and demographic data are registered by
the GP (online CRF). Also a urine sample is sent to the microbiology laboratory
for a classic urine culture. Patients are treated with fosfomycin (1 time
daily, 3 grams) of nitrofurantoin (7 days, 2 times daily 100 mg) on the basis
of the randomization results. The doctor writes this prescription and the
medication is picked up at a pharmacy of choice. Over 14 days, the patients
will keep a daily diary in which they describe their (voiding) symptoms and
side effects. If the symptoms worsen in these 14 days, it is recommended to
contact the patients GP. In the case of side effects or worsening of symptoms
and in any other situation, the physician has the ability to prescribe a
treatment of choice. These situations will be defined as 'failures'. After 14
days, the patient will return to general practice and urine is sent to the
microbiology laboratory for a classic urine culture as control. Also a brief
questionnaire about the urinary problems at that time will be performed (online
CRF). During the 14 days of patient updates will be registered by the GP. The
details of patients' lost-to-follow-up will also be recorded. Also is asked the
practitioners to register the number of patients that decide not to participate
in the study, without recording personal data. The microbiological and clinical
cure of both treatment arms will be compared after 14 days.

Fosfomycin (1 day, 1 time 3 gram) or nitrofurantoin (7 days; 2 times a day 100
mg) based on randomization

Complications can never be ruled out completely. However, both groups are
treated with antibiotics that are registered for the indication (uncomplicated
UTI). By setting the exclusion criteria as an attempt is made to keep the
complications as small as possible.
Exclusion criteria:
Patients with known renal dysfunction(s) (MDRD< 60 ml/min).
Patient is known with an uropathogen isolated in the past 12 months with
resistance towards nitrofurantoin and/or fosfomycin.
Patient is known with complications towards nitrofurantoin and/or fosfomycin
such as allergic reactions, peripheral neuropathy and/or lung and liver
reactions.
Patients who are known hypersensitive towards nitrofurantoin, fosfomycin and /
or one of the excipients.
Patients known with Glucose-6-phosphate dehydrogenase deficiency.
Patients with known fructose intolerance, glucose-galactose malabsorption or
sucrase-isomaltase insufficiency.
Patients with known acute porphyria.
Patients with known gout.
Patients receiving hemodialysis.
Patients using other antibiotics.
Patients using alkalizing agents.
For pregnant women:
Is in the first trimester of pregnancy (week 1 to 13).
Is in the period of delivery (after the first contractions).
Patients who refuse or are unable to give informed consent.

In addition, outside the Netherlands sufficient experience is gained with
fosfomycin in risk groups (including men and pregnant women). A recent review
carried out [Falagas, 2010) concluded that side effects in pregnant women were
significantly lower when treated with fosfomycin relative to the comparators
(including cefuroxime, pipemidic acid, ceftibuten and amoxicillin / clavulanic
acid). Additionally, the latest issue of drugs in pregnancy and lactation
concludes that fosfomycin can be used in all trimesters of pregnancy without
harming both fetus and child, and can therefore be classified as low risk for
pregnant women. In addition, the microbiological eradication is comparable in
comparison with the comparators in the mentioned review.

Completing the diary and the submission of the control urine (other than
standard) takes minimal time and is not seen as a major drawback for the
patient. This study provides insight into the effectiveness (both clinical and
microbiological) of fosfomycin. With rising resistance rates, it is important
to have sufficient reserve antibiotics as well as effective first-line agents.