Fosfomycin Trometamol Compared With an Alternative Active Antibiotic as Step-down Therapy for the Treatment of Acute Pyelonephritis Due to Escherichia Coli in Elderly Women : a Randomized, Multicenter, Non-inferiority Trial (FOSFOLD)

Fosfomycine trométamol comparé à un Autre Traitement Antibiotique Actif en Relais Pour le Traitement Des pyélonéphrites aiguës à Escherichia Coli Chez Les Femmes âgées : Essai randomisé, Multicentrique de Non infériorité

Acute pyelonephritis (APN) is among the most common bacterial infections in older women. Oral step-down antibiotic therapy may potentially be associated with toxicity, particularly with fluoroquinolones or trimethoprim-sulfamethoxazole, espcially in geriatric patients. The emergence of resistant strains reduces the choice of oral step-down treatment, thereby increasing the risk of nosocomial complications related to intravenous access and prolonged hospitalization.

Fosfomycin trometamol (FT) has broad activity against Enterobacterales, including resistant strains. It has an excellent safety profile and moderate ecological impact, and has been used for several years to treat cystitis. Recent studies have demonstrated its efficacy as an oral step-down therapy for the treatment of E.coli APN in younger women. Its efficacy in a geriatric population remains to be demonstrated.

The primary objective is to demonstrate the non-inferiority, in terms of clinical cure, of FT compared with an alternative active antibiotic as step-down therapy for E. coli APN in older women.

FOSFOLD is a national, multicenter, randomised, comparative, phase 3, non-inferiority trial (1:1), open-label with two parallel treatment groups. After 3 or 4 days of appropriate empirical antibiotic therapy, women aged 75 or over with E.coli APN will be randomised to receive either 3g of FT once daily or an alternative antibiotic treatment in accordance with current french guidelines, for a total of 10 days.

The primary endpoint is clinical cure at Day 17, i.e. 10 days after completion of antibiotic therapy.

If non-inferiority of FT is confirmed, it could provide a new therapeutic approach for oral step-down therapy in the older patients with APN. Its favorable tolerability profile could help prevent common geriatric complications, such as delirium, falls and malnutrition. Ultimately, it could help prevent some of the iatrogenic functional decline associated with hospitalisation.

Study Overview

• Status: Not yet recruiting
• Conditions: Elderly Women; Pyelonephritis; Escherichia Coli Infection; Antibiotherapy
• Intervention / Treatment: Drug: Fosfomycin-trometamol (FT); Drug: Alternative antibiotic treatment

• Study Type: Interventional
• Enrollment (Estimated): 312
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Jérôme Lambert, MD PhD; Phone Number: +33 +33 1 42 49 97 42; Email: jerome.lambert@u-paris.fr
• Study Contact Backup: Name: Clara Pouchelon, MD; Phone Number: +33 +33 1 40 36 73 67; Email: clara.pouchelon@ght-gpne.fr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 75 years and older (Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

1. Female.
2. Age ≥ 75 years.
3. Body temperature ≥ 38°C on at least once during the 72 hours preceding diagnosis.
4. At least one new symptom among the following : urinary urgency, dysuria, increased urinary frequency, gross hematuria, burning on urination, spontaneous of provoked flank or suprapubic pain or urinary incontinence.
5. Positive urine culture collected before initiation of antibiotic therapy defined as : ≥ 10,000 leukocytes/mL and monomicrobial culture with Escherichia coli ≥ 103 CFU/mL and susceptibility to FT,the empirical antibiotic,and at least one alternative antibiotic (active and not contraindicated), administered either orally (fluoroquinolone, amoxicillin, amoxicillin-clavulanic acid, or trimethoprim-sulfamethoxazole or, in the absence of an oral alternative, intravenously.
6. Ability to reveive oral medication
7. Favorable clinical course after 3 or 4 days of effective empirical antibiotic therapy, defined as resolution of fever (temperature < 38°C) and regression or reduction in the intensity and/or frequency of the clinical sign(s) present at the time of APN diagnosis, without the occurrence of any new symptoms.

Exclusion Criteria:

1. Presence of an infectious focus other than the urinary tract.
2. Severe infection and/or initial infectious complications, including septic shock, requirement for an emergency upper urinary tract intervention, or renal abscess.
3. Indwelling urinary catheter, including bladder, ureteral, or nephrostomy catheters.
4. Inability to take oral medication.
5. Immunosuppression, including sold-organ transplant, ongoing immunosuppressive therapy, ongoing chemotherapy.
6. Hypersensitivity to fosfomycin trometamol or to any of the excipients of the study medication
7. End-stage chronic kidney disease with an estimated glomerular filtration rate (eGFR) < 15 mL/min/1.73 m2.
8. Lack of health insurance coverage.
9. Patient under legal protection or guardianship.
10. Absence of written informed consent from the patient or, if the patient is unable to provide consent, absence of agreement from the designated trusted person or a close relative.
11. Participation in another interventional clinical research protocole

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Fosfomycin-trometamol (FT)	Drug: Fosfomycin-trometamol (FT); One sachet (3g), once daily, orally for 6 or 7 days, following 4 or 3 days, respectivelly of effective antibiotic therapy, for a total of 10 days of effective antibiotic treatment.
Active Comparator: Alternative antibiotic treatment	Drug: Alternative antibiotic treatment; Treatment will be selected at the investigator's discretion, in accordance with the 2017 recommandations of the French Society for Infectious Diseases (SPILF) and the 2025 French National Authority for Health (HAS) guidelines. Therapy will be administrated for 6 or 7 days (Day 1 - Day 6/7), following 4 or 3 days, respectively of effective antibiotic therapy. The total duration of effective antibiotic therapy will be 10 days. Injection antibiotic therapy will be offered in the absence of an active oral antibiotic option.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinical resolution	Clinical cure defined as : Body temperature < 38 °C and resolution of all urinary symptoms present at the time of the APN diagnosis, with no occurrence of new clinical signs (urinary urgency, dysuria, increased urinary frequency, gross hematuria, painful/burningurination, flank pain [spontaneous or provoked], suprapubic pain, or urinary incontinence) between treatment discontinuation and assessment of the primary endpoint at Day 17, except for a temperature ≥ 38°C unrelated to a urinary tract condition; No resumption of antibiotic therapy active against the causative pathogen responsible for the APN following completion of the antibiotic treatment course	Day 17

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Occurence of antibiotic-related adverse events	Occurrence, nature, and severity of antibiotic-related adverse events, assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) scale.	Up to 37 days
Occurence of geriatric complications	Occurrence of delirium, defined according the Confusion Assessment Method (CAM); Fall(s) (one or more episodes); Weight loss, assessed as the percentage change between admission body weight and discharge body weight or Day 17 weight if the patient remains hospitalized; Occurrence of pressure ulcers, staged according to the National Pressure Ulcer Advisory Panel (NPUAP) pressure ulcer staging classification (HAS Guidelines, Prevention and Treatment of Pressure Ulcers in Adults and Older Persons, 2001)	Up to 37 days
Functional autonomy	According to the Activities of Daily Living (ADL) scale: score ranges from 0 (complete dependence) to 6 (complete independence), with higher scores indicating greater independence in basic daily activities such as bathing, dressing, toileting, transferring and eating.	Up to 37 days
Incidence of Infectious and urological complications	Renal abscess (yes/no); Need for urinary drainage; Transfer to an continuous care unit or intensive care unit due to the infection At the end of antibiotic treatment (Day 7)	Up to day 7
Cumulative incidence of recurrent febrile or non-febrile urinary tract infectious (UTIs) (relapse or reinfection)	Cystitis : recurrence of urinary symptoms in the absence of fever, associated with a positive urine culture.; Acute pyelonephritis :; recurrence of urinary symptoms with fever and a positive urine culture.; Reinfection : new infection caused by a microorganism different from that isolated during the initial episode.; Relapse : recurrence of infection due to the same microorganism as that isolated during the initial episode.	From Day 17 to Day 37
Rate of hospitalization or rehospitalization following treatment for APN		Up to day 37
Length of hospital stay following randomization		Up to day 37
All-cause mortality		Up to day 37
Rate of rectal colonization with antibiotic-resistant Enterobacterales	fluoroquinolones, trimethoprim-sulfamethoxazole, fosfomycin, and third-generation cephalosporins	Up to day 37

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris

Study record dates

Study Major Dates

• Study Start (Estimated): December 1, 2026
• Primary Completion (Estimated): January 17, 2030
• Study Completion (Estimated): February 15, 2030

Study Registration Dates

• First Submitted: October 29, 2026
• First Submitted That Met QC Criteria: November 5, 2026
• First Posted (Actual): November 10, 2026

Study Record Updates

• Last Update Posted (Actual): November 10, 2026
• Last Update Submitted That Met QC Criteria: November 5, 2026
• Last Verified: October 1, 2026

More Information

Terms related to this study

• Keywords: kidney; bacterial infection; Escherichia coli; pyelonephritis; Antibiotherapy; Elderly women; geriatry; fosfomycin-trometamol
• Additional Relevant MeSH Terms: Urogenital Diseases; Male Urogenital Diseases; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Infections; Bacterial Infections and Mycoses; Gram-Negative Bacterial Infections; Nephritis; Enterobacteriaceae Infections; Nephritis, Interstitial; Pyelitis; Escherichia coli Infections; Bacterial Infections; Pyelonephritis; Organic Chemicals; Organophosphorus Compounds; Organophosphonates; Fosfomycin
• Other Study ID Numbers: APHP240802

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No