Urinary tract infections (UTIs) are among the most common bacterial infections in children. Up to 50% of UTI's are caused by multi-drug resistant ESBL-producing gram negative bacteria that do not respond to treatment with oral penicillin's or cephalosporins. Instead, children often require hospital admission to receive broad-spectrum intravenous antibiotics when they may otherwise be safely managed at home; resulting in prolonged hospital stays and an increased use of health resources. Fosfomycin is a broad-spectrum antibiotic discovered in 1969 that remains susceptible to a large number of organisms due to its low international use. Fosfomycin can be prepared as an oral solution with an orange/tangerine flavour and is currently approved for use in females \>12 years old. Despite extensive evidence of its efficacy in adults and safety in neonates, the use of fosfomycin in children remains limited and fosfomycin is not currently licensed for use in children \<12 years old in Australia.
The aim of this clinical trial is to compare the use of oral fosfomycin against standard of care antibiotics for the treatment of antibiotic resistant urinary tract infections in children. The main questions the trial aims to answer are:
1. Is oral fosfomycin non-inferior in efficacy to the current standard of care for the treatment of antibiotic-resistant urinary tract infections in children? 2. Is oral fosfomycin a safe and well-tolerated antibiotic in children? 3. What is the best dosing regimen of oral fosfomycin for the treatment of antibiotic-resistant UTIs in children?
Symptoms consistent with a clinical diagnosis of a UTI (as per the treating clinician); AND
Microbiological confirmation: Defined as a urine culture revealing a predominant growth of a bacterial uropathogen [≥10^6 CFU/L, or ≥10^3 CFU/mL] together with ≥10x10^6 white blood cells on microscopy; AND
The bacterial uropathogen is a non-pseudomonal gram-negative organism likely to cause urinary tract infections in children; being one of either: Escherichia coli, Proteus spp., Klebsiella spp., Enterobacter spp., Serratia spp., or Citrobacter spp., AND
The uropathogen has in vitro evidence of resistance to all oral penicillins and oral first- and second- generation cephalosporins (or is presumed to be resistant based on the pattern of phenotypic testing); AND
Evidence of bacteraemia due to the same uropathogen within the same clinical illness; OR
Evidence of infection at a secondary site (such as meningitis or endocarditis); OR
Children with features suggestive of sepsis (defined as requiring inotropic support, or >20ml/kg fluid bolus); OR
Children who are unable to tolerate or absorb oral antibiotics; OR
Parallel
Fosfomycin
DrugFosfomycin trometamol is a white crystalline powder which is very soluble in water. The granules are mixed with 90ml of cool water for the constitution to dissolve and will be administered soon after reconstitution. Each 30ml will contain 1g fosfomycin base. * Children ≥ 6 months to \<1 year old will be administered 30ml (=1g fosfomycin base) of dissolved solution and the remainder discarded for each dose. * Children ≥ 1 to 11 years will be administered 60ml (=2g fosfomycin base) of dissolved solution and the remainder discarded for each dose. * Children ≥12 and \<18 years will be administered the entire 90ml solution (= 3g fosfomycin base) for each dose.
Standard of care antibiotics
DrugStandard of care antibiotics will be chosen by the treating clinician according to institutional prescribing practices, local antibiograms and medication availability.
Treatment failure within 28 days after enrolment between patients treated with standard of care versus oral fosfomycin.
Treatment failure is defined as: 1. Persistent or recurrent (clinical and microbiologically-confirmed) diagnosis of a UTI between 7 and 28 days after enrolment, with the same uropathogen; or 2. Decision to switch to an alternative antibiotic due to perceived treatment failure; or 3. Isolation of the same pathogenic organism from a new sterile site between 7 and 28 days after enrolment;
Occurrence of treatment-related adverse events to Day 28
Occurrence of serious adverse events attributable to UTI to Day 28
Evidence of primary treatment failure, defined as: a) Persistent fever (>38.0C) attributable to UTI at 72h after enrolment; and/or b) Failure to return to baseline health at 28 days after enrolment
Evaluation of the cost of hospital resources in the first 28 days of enrolment in children receiving standard of care versus oral fosfomycin; including: a) Cost of prescribed drugs b) Cost of hospital services (inpatient and outpatient)
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