RECRUITINGPhase 3INTERVENTIONAL

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

Fosfomycin Versus Standard of Care in Children With Antibiotic-resistant Urinary Tract Infections: A Non-inferiority, Pragmatic, Multi-centre Adaptive Trial to Evaluate the Safety, Tolerability, Efficacy and Pharmacokinetics of Oral Fosfomycin in Children With Antibiotic-resistant Urinary Tract Infections.

About This Trial

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?

Who May Be Eligible (Plain English)

Who May Qualify: Children aged ≥6 months to \<18 years with: 1. Symptoms consistent with a clinical diagnosis of a UTI (as per the treating clinician); AND 2. 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 3. 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 4. 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 5. The patient has not yet received \>48 hours of antibiotics with in vitro activity against the urinary pathogen prior to enrolment. Who Should NOT Join This Trial: 6. Evidence of bacteraemia due to the same uropathogen within the same clinical illness; OR 7. Evidence of infection at a secondary site (such as meningitis or endocarditis); OR 8. Children with features suggestive of sepsis (defined as requiring inotropic support, or \>20ml/kg fluid bolus); OR 9. Children who are unable to tolerate or absorb oral antibiotics; OR 10. Children with severe renal unsifficiency (creatinine clearance \<10ml/minute/1.73m\^2); OR 11. Known allergy to fosfomycin; OR 12. A decision by the primary treating physician that enrolment in the trial is not in the child's best interest. Always talk to your doctor about whether this trial is right for you.

Original Eligibility Criteria

View original clinical language

Inclusion Criteria: Children aged ≥6 months to \<18 years with: 1. Symptoms consistent with a clinical diagnosis of a UTI (as per the treating clinician); AND 2. 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 3. 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 4. 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 5. The patient has not yet received \>48 hours of antibiotics with in vitro activity against the urinary pathogen prior to enrolment. Exclusion Criteria: 6. Evidence of bacteraemia due to the same uropathogen within the same clinical illness; OR 7. Evidence of infection at a secondary site (such as meningitis or endocarditis); OR 8. Children with features suggestive of sepsis (defined as requiring inotropic support, or \>20ml/kg fluid bolus); OR 9. Children who are unable to tolerate or absorb oral antibiotics; OR 10. Children with severe renal unsifficiency (creatinine clearance \<10ml/minute/1.73m\^2); OR 11. Known allergy to fosfomycin; OR 12. A decision by the primary treating physician that enrolment in the trial is not in the child's best interest.

Treatments Being Tested

DRUG

Fosfomycin

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 ≥ 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.

DRUG

Standard of care antibiotics

Standard of care antibiotics will be chosen by the treating clinician according to institutional prescribing practices, local antibiograms and medication availability.

Locations (5)

Sydney Childrens Hospital

Sydney, New South Wales, Australia

The Children's Hospital at Westmead

Sydney, New South Wales, Australia

Queensland Children's Hospital

Brisbane, Queensland, Australia

Royal Childrens Hospital

Melbourne, Victoria, Australia

Perth Children's Hospital

Perth, Western Australia, Australia