Relevance of Biomarkers and Clinical Predictors of Outcome in Unselected Population with Febrile Urinary Tract Infection at Primary Care and Emergency Department in a Prospective, Randomized Cohort Trial Comparing Short (7 days) Antibiotic Treatment with Conventional Treatment (14 days)

Patients with febrile urinary tract infection (fUTI) usually present with a
mild illness in primary care but may rapidly develop a life-threatening
condition, progressing into septic shock and multiple organ failure. The
overall mortality of patients with fUTI admitted to hospital amounts to about
7-8%. Given this spectrum of clinical presentation, disease severity and
outcome, this clinically well-recognizable disease represents an elegant model
to develop clinical scoring systems of disease severity, and characterize new
biomarkers of disease that will allow not only a timely diagnosis of urinary
tract infection and the etiologic microbial agent (and/or antibiotic
resistance), but also allow early identification of those patients who will
progress into more severe stages of the host inflammatory response, e.g.,
sepsis and septic shock with multiple organ failure. To date, a set of clinical
criteria to guide management of fUTI have not been established. Thus, the
general practitioner or emergency department specialist will decide to
hospitalize a patient or not guided by his personal perception of the patient*s
illness.
In the last decades hospitalization rates of patients with acute pyelonephritis
(AP) or fUTI has decreased from almost 100% to 10-30%. The outpatient
management of patients with fUTI has become popular as well as oral
antimicrobial treatment regiments and shortening of treatment duration.
However, as such approaches are only discovered in otherwise young health
non-pregnant women, the best management of fUTI in the elderly, men and
patients with co-morbidity remains elusive. Again, based on personal perception
of the attending physician antibiotic treatment, duration varies approximately
between 7-14 days. Facing the aging of the general population, it is urgent to
better define the optimal treatment for AP or fUTI in an unselected population
and to identify those at risk for treatment failure or poor outcome to guide
and optimize individual patient management and to prevent on the one hand
unnecessary long treatment duration and hospital admission and on the other
hand unsafe short duration or unsafe outpatient management.
In this study the efficacy and safety of a 7-day antimicrobial regimen compared
to a 14-day antimicrobial regimen will be evaluated in an unselected population
presenting with fUTI at primary care or emergency department and a clinical
and/or biomarker based scoring system of disease severity will be derived to
predict those at risk for treatment failure or poor outcome.

To assess clinical parameters and biomarkers in blood and urine in predicting
bacteremia, need for hospital admission, clinical and bacteriologic cure and
mortality in patients with fUTI.
To determine whether a 7-day duration of antibiotic treatment of fUTI is non
inferior to 14-day standard duration of treatment in unselected population
presenting at primary care or emergency department.
To asses the prevalence of pelvic floor dysfunction after recovery of fUTI ,
the occurrence of Clostridium difficile associated diarrhea (CDAD) and the
occurrence of fluoroquinolones resistant streptococci in the throat as side
effects of fUTI treatment

A multi-center double blind randomized placebo controlled non-inferiority trial
combined with prospective observational cohort study (for those who meet entry
criteria but cannot be randomized or receive study drugs). Five hundred
patients will be enrolled of which four hundred patients will be randomized to
either receive standard (14 days) or short (7 days) of antibiotic treatment.
Day 8 through 14 of treatment will be blinded; either oral placebo (b.i.d.) or
oral ciprofloxacin (500 mg b.i.d).

Either placebo or ciprofloxacin during the 8th through 14th day of
antimicrobial treatment.

The burden of study procedures is limited.
The risk of shorter antimicrobial treatment is minimal as this is already the
standard four young women without co-morbidity presenting with febrile urinary
tract infection (fUTI). It is reasonable to expect this also upholds the
elderly, men and people with underlying co-morbidity. Furthermore the risk of
longer (too long?) antimicriobial treatment should not be underestimated.
Safety is quaranteed as those subjects with a medical indication to treat fUTI
for longer than 7 days or other antimicrobials then the study drug, will NOT
receive the study drug but will be treated according to best clinical practice
as judged by the attending physician.