Old means for new ends : Optimizing the treatment of urinary tract infections

Urinary tract infections (UTIs) are common bacterial infections that are at most inconvenient for some patients while they seriously impede health for others. The first part of this thesis addresses the antibiotic treatment of cystitis in general practice. Its high incidence makes it a relevant topic and an attractive object for epidemiological research. We found that the effectiveness and safety of the antibiotic nitrofurantoin is determined by the dose that is given. This applies to the treatment of cystitis as well as to the daily prophylaxis for recurrent UTI. The guideline makes no distinction between the doses that we investigated. Furthermore, we found that the antibiotic fosfomycin appears to be more effective than nitrofurantoin for treatment of cystitis in patients with impaired renal function, while nitrofurantoin is currently the first choice. Bacterial resistance to antibiotics complicates the treatment of UTI in the hospital. In the second part we investigate this problem. The main finding is that fosfomycin is efficacious for the targeted treatment of UTI in hospitalized women, caused by the bacterium Escherichia coli. Due to low resistance percentages to fosfomycin among Escherichia coli, a new treatment option is created for patients, as an alternative to parenteral antibiotics. In other chapters, we investigated the use of fosfomycin for UTIs in renal transplant patients, the reliability of susceptibility tests against fosfomycin, the acquisition of resistance of Escherichia coli to fosfomycin, the duration of carriage of multidrug resistant gut bacteria and the effectiveness of antibiotics for UTIs caused by multidrug resistant bacteria

Oral fosfomycin versus ciprofloxacin in women with E.coli febrile urinary tract infection, a double-blind placebo-controlled randomized controlled non-inferiority trial (FORECAST)

BACKGROUND: Febrile Urinary Tract Infection (FUTI) is frequently treated initially with intravenous antibiotics, followed by oral antibiotics guided by clinical response and bacterial susceptibility patterns. Due to increasing infection rates with multiresistant Enterobacteriaceae, antibiotic options for stepdown treatment decline and patients more frequently require continued intravenous antibiotic treatment for FUTI. Fosfomycin is an antibiotic with high bactericidal activity against Escherichia coli and current resistance rates are low in most countries. Oral Fosfomycin-Trometamol 3000 mg (FT) reaches appropriate antibiotic concentrations in urine and blood and is considered safe. As such, it is a potential alternative for stepdown treatment. METHODS: The FORECAST study (Fosfomycin Randomized controlled trial for E.coli urinary tract infections as Alternative Stepdown Treatment) is a randomized, double-blind, double-dummy, non-inferiority trial in which 240 patients will be randomly allocated to a stepdown treatment with FT or ciprofloxacin (standard of care) for FUTI, caused by Escherichia coli with in vitro susceptibility to both antibiotics. The study population consists of consenting female patients (≥18 years) with community acquired E. coli FUTI. After intravenous antibiotic treatment during at least 48 (but less than 120) hours, and if eligibility criteria for iv-oral switch are met, patients receive either FT (3 g every 24 h) or ciprofloxacin (500 mg every 12 h) for a total antibiotic duration of 10 days. The primary endpoint is clinical cure (resolution of symptoms) 6-10 days post-treatment. Secondary endpoints are microbiological cure 6-10 days post-treatment, clinical cure, mortality, ICU admittance, relapse, reinfection, readmission, additional antibiotic use for UTI, early study discontinuation, adverse events, days of hospitalization and days of absenteeism within 30-35 days post-treatment. The sample size is based on achieving non-inferiority on the primary endpoint, applying a non-inferiority margin of 10%, a two-sided p-value of < 0.05 and a power of 80%. DISCUSSION: The study aims to demonstrate non-inferiority of oral fosfomycin, compared to oral ciprofloxacin, in the stepdown treatment of E. coli FUTI. TRIAL REGISTRATION: Registered at the Nederlands trial register (Dutch trial register) on 4-10-2017. TRIAL REGISTRATION NUMBER: NTR6449 . Secondary ID (national authority): NL60186.041.17

Oral fosfomycin versus ciprofloxacin in women with E.coli febrile urinary tract infection, a double-blind placebo-controlled randomized controlled non-inferiority trial (FORECAST)

BACKGROUND: Febrile Urinary Tract Infection (FUTI) is frequently treated initially with intravenous antibiotics, followed by oral antibiotics guided by clinical response and bacterial susceptibility patterns. Due to increasing infection rates with multiresistant Enterobacteriaceae, antibiotic options for stepdown treatment decline and patients more frequently require continued intravenous antibiotic treatment for FUTI. Fosfomycin is an antibiotic with high bactericidal activity against Escherichia coli and current resistance rates are low in most countries. Oral Fosfomycin-Trometamol 3000 mg (FT) reaches appropriate antibiotic concentrations in urine and blood and is considered safe. As such, it is a potential alternative for stepdown treatment. METHODS: The FORECAST study (Fosfomycin Randomized controlled trial for E.coli urinary tract infections as Alternative Stepdown Treatment) is a randomized, double-blind, double-dummy, non-inferiority trial in which 240 patients will be randomly allocated to a stepdown treatment with FT or ciprofloxacin (standard of care) for FUTI, caused by Escherichia coli with in vitro susceptibility to both antibiotics. The study population consists of consenting female patients (≥18 years) with community acquired E. coli FUTI. After intravenous antibiotic treatment during at least 48 (but less than 120) hours, and if eligibility criteria for iv-oral switch are met, patients receive either FT (3 g every 24 h) or ciprofloxacin (500 mg every 12 h) for a total antibiotic duration of 10 days. The primary endpoint is clinical cure (resolution of symptoms) 6-10 days post-treatment. Secondary endpoints are microbiological cure 6-10 days post-treatment, clinical cure, mortality, ICU admittance, relapse, reinfection, readmission, additional antibiotic use for UTI, early study discontinuation, adverse events, days of hospitalization and days of absenteeism within 30-35 days post-treatment. The sample size is based on achieving non-inferiority on the primary endpoint, applying a non-inferiority margin of 10%, a two-sided p-value of < 0.05 and a power of 80%. DISCUSSION: The study aims to demonstrate non-inferiority of oral fosfomycin, compared to oral ciprofloxacin, in the stepdown treatment of E. coli FUTI. TRIAL REGISTRATION: Registered at the Nederlands trial register (Dutch trial register) on 4-10-2017. TRIAL REGISTRATION NUMBER: NTR6449 . Secondary ID (national authority): NL60186.041.17

A semi-supervised decision support system to facilitate antibiotic stewardship for urinary tract infections

Urinary Tract Infections (UTIs) are among the most frequently occurring infections in the hospital. Urinalysis and urine culture are the main tools used for diagnosis. Whereas urinalysis is sufficiently sensitive for detecting UTI, it has a relatively low specificity, leading to unnecessary treatment with antibiotics and the risk of increasing antibiotic resistance. We performed an evaluation of the current diagnostic process with an expert-based label for UTI as outcome, retrospectively established using data from the Electronic Health Records. We found that the combination of urinalysis results with the Gram stain and other readily available parameters can be used effectively for predicting UTI. Based on the obtained information, we engineered a clinical decision support system (CDSS) using the reliable semi-supervised ensemble learning (RESSEL) method, and found it to be more accurate than urinalysis or the urine culture for prediction of UTI. The CDSS provides clinicians with this prediction within hours of ordering a culture and thereby enables them to hold off on prematurely prescribing antibiotics for UTI while awaiting the culture results