Fosfomycin Versus Standard of Care in Children With Antibiotic-resistant Urinary Tract Infections (FosUTI)

The aim of this clinical trial is to determine, in children with multi-drug resistant urinary tract infections, whether oral fosfomycin is noninferior to standard of care antibiotics in achieving a cure without recurrence within 30 days of treatment. The The main questions the trial aims to answer are: Is oral fosfomycin inferior in efficacy to the current standard to care for multi-drug resistant UTIs in children as defined by the recurrence of a UTI within 30 days of completion of therapy? Is fosfomycin a safe and well-tolerated antibiotic in children? Participants aged ≥1 to <18 years of age with a clinical diagnosis of antibiotic-resistant urinary tract infections will be recruited and randomised after informed consent is obtained via computer generated randomisation into standard of care or intervention (treatment with oral fosfomycin) arms. For children randomised into the standard of care arm: Management will be as per physician preference based on institutional prescribing practices and local antibograms. For children randomised into the intervention arm: a single dose of oral fosfomycin trometamol will be prescribed (with dosage determined based on age). Both groups will complete a tolerability questionnaire and be subject to physical examination, pathology investigations and other clinical interventions tailored to their needs as per routine standard of care. Clinical observations and results of the investigation will be recorded on a case report form via an electronic database. A follow-up safety review will be performed 10 and 28 days after enrollment.

A single dose of oral fosfomycin trometamol (Monurol), dosed as: ≥ 1 to <12 years of age: 2 grams (of fosfomycin base) as a single dose Children ≥ 12 years and <18 years of age: 3 grams (of fosfomycin base) as a single dose For children who have persistent fevers at 48 hours, the dose of oral fosfomycin may be repeated every 48 hours, to a maximum of 3 doses. For a subset of 30 children aged 1-12 years (inclusive) at the primary recruitment sites (RCH, SCH and CHW) two blood samples will be taken after the first oral fosfomycin dose to determine plasma fosfomycin concentrations. The timing of these samples after the oral fosfomycin dose are as follows, with participants being randomly allocated to one of the two sampling groups: Sample 1 Sample 2 Group 1 (n=15) 20 minutes to 180 minutes post dose 4-12 hours post dose Group 2 (n=15) 120 to 240 minutes post dose 12 to 18 hours post dose

Management as per physician preference based on institutional prescribing practices and local antibiograms. For participants administered an oral antibiotic in the Standard of Care arm, a tolerability questionnaire will be administered at the time of the first dose.

A single dose of oral fosfomycin trometamol, dosed as: ≥ 1 to <12 years of age: 2 grams (of fosfomycin base) as a single dose Children ≥ 12 years and <18 years of age: 3 grams (of fosfomycin base) as a single dose For children who have persistent fevers at 48 hours, the dose of oral fosfomycin may be repeated every 48 hours, to a maximum of 3 doses. Fosfomycin 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 ≥ 1 to 11 years will be administered 60ml (=2g fosfomycin base) of dissolved solution and the remainder discarded. Children ≥12 and <18 years will be administered the entire 90ml dose ( = 3g fosfomycin base).

Treatment failure will be defined as: Recurrent (clinical and microbiologically-confirmed) UTI within 28 days of enrolment, with the same uropathogen; or Decision to switch to an alternative antibiotic due to perceived treatment failure; or Isolation of the same pathogenic organism from a new sterile site within 28 days after enrolment; whereby microbiological confirmation might only include the evidence of pyuria (in the absence of epithelial cells) and may or may not include a positive urine culture.

To compare, between the two treatment arms, the proportion of children with: Treatment-related adverse effects and serious adverse effects; Severe complications attributable to their UTI (as judged by the clinician), including: Admission to intensive care; or The development of UTI complications (abscess, sepsis, meningitis); Persistent symptoms attributable to their urinary tract infection at 10 days after enrolment; Re-presentation with a UTI within 28 days of enrolment; The use of hospital resources in children receiving SOC versus oral fosfomycin; The tolerability of fosfomycin versus other oral antibiotics; and Quality of life indicators for children prescribed SOC versus oral fosfomycin.

Inclusion Criteria: Children aged ≥1 to <18 years with: Symptoms suggestive of a clinical diagnosis of a UTI (as per the treating clinician); AND Microbiological confirmation: Defined as a urine culture revealing pure growth of a single bacterial uropathogen [≥106 CFU/L, or ≥103 CFU/mL] together with ≥10 white blood cells [WBCs] per high power field in centrifuged urine on microscopy, or ≥10 WBCs/mm3 in uncentrifuged urine]; AND The bacterial uropathogen is one of: Escherichia coli, Proteus spp., Klebsiella spp., Enterobacter spp., Serratia spp., or Citrobacter spp., AND The uropathogen has evidence of resistance to all oral penicillins and cephalosporins AND The patient has not yet received ≥48 hours of antibiotics effective against the urinary pathogen prior to enrolment. Exclusion Criteria: Evidence of bacteraemia due to the same uropathogen within the same clinical illness; OR Evidence of infection at a secondary site (such as CNS infection 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 Creatinine clearance <40ml/minute; OR Known allergy to fosfomycin.

Efficacy and AEs/SAEs will be summarised and pooled. Deidentified individual data will be shared with the DSMB and ethics for SAEs only. Investigators have the protocols and the ICFs. SAP will be available for all investigators once authored. Reports and analytical code will be shared when approved by trial statisticians.