Optimizing the treatment of cystitis using nitrofurantoin

Nitrofurantoin is an antibiotic used for the treatment of lower urinary tract
infections (cystitis) for more than 50 years. There has been a recent
resurgence of interest in this drug in the context of increasing multidrug
resistance amongst Gram-negative bacteria causing urinary tract infections.
Preliminary PK data demonstrates that urine concentrations of nitrofurantoin
(Furadantin ®) are highly variable between subjects after administration of 50
mg q6 hours and 100 mg q8 hours. This will have high consequences for the
effectivity of the therapy. These consequences are likely to be even higher for
the often prescribed dose of 100 mg q12 hours of the slow-release formulation
(Furabid ®) which is often used in the Netherlands. The question rises if this
dose (which is recommended in the Dutch national guideline SWAB (Stichting
Werkgroep Antbioticabeleid and the *NHG-standaard*) as first line treatment
option of cystitis together with the dose of 50 mg q6 hours) is effective and
indeed equivalent to the 50 mg q6 hour dose. (PK) Data to support this are
lacking. Additionally, while official guidelines advise to avoid the use of
nitrofurantoin in the elderly and those with moderate renal insufficiency, it
appears that clinicians are frequently prescribing this antibiotic tot both
populations in daily practice. These guidelines appear to be based mainly on
decades-old studies. Given the resurgence of its clinical use, there is an
urgent need to fill in these knowledge gaps regarding the effectivity and
safety of the current treatment of cystitis with nitrofurantoin in the general
patient population and/or patients with renal impairment.

Primary Objective:
To optimize the dosing regimen of nitrofurantoin in order to enhance the
effectivity and the safety of the treatment of cystitis with orally
administered nitrofurantoin in patients with suspected or proven cystitis.

Secondary Objectives:
(1) To determine the pharmacokinetic (PK) profile of orally administered
nitrofurantoin after administration of the normal-release formulation and the
slow-release formulation;
(2) To explore the influence of different covariates (e.g. renal function, age,
weight) on the this PK profile.
(3) To evaluate the effectivity of this treatment based on the minimum
inhibitory concentration (MIC) of the uropathogen and the clinical targets as
mentioned in guidelines by the European Committee on Antimicrobial
Susceptibility Testing (EUCAST).

This is a descriptive, prospective, pharmacokinetic study of nitrofurantoin in
60 female patients with suspected or proven active urinary tract infection.

This study will examine the pharmacokinetics of nitrofurantoin administered in
the dosing regimen, conform the Dutch national guideline SWAB (Stichting
Werkgroep Antibioticabeleid) of 50 mg four times daily (quarter in diem, qid)
or 100 mg two times daily (bis in die, bid) in steady state, using urine
samples.

This study will lead to an improved understanding of NFs properties and effects
and assist development of optimal dosing regimens to reduce clinical failure,
toxicity and emergence of resistance. The use of nitrofurantoin is standard for
the treatment of urinary tract infection. In this context, there is no
increased risk for the hospitalised patient. Therefore, the risk and burden of
participation in this study are minimal as compared to the potential value of
the study.