FOSFOMYCIN GRNL,RCNST-ORAL

Clinical Criteria Summary

FDA approved for treatment of uncomplicated urinary tract infections (acute cystitis) in women due to susceptible strains of Escherichia coli and Enterococcus faecalis.
Not indicated for pyelonephritis or perinephric abscess.
Off-label uses include management of cystitis in males, acute and chronic prostatitis, pre-operative prophylaxis (e.g., pre-transrectal prostate biopsy), and rarely as chronic suppressive therapy for recurrent symptomatic cystitis.

CLSI breakpoint (≤ 64 ug/mL) applies only to E. coli and Enterococcus faecalis in urine cultures.
Susceptibility testing is not routinely performed; must be specifically requested.
Approved testing methods are disk diffusion and agar dilution MIC method (agar media supplemented with 25 ug/mL glucose-6-phosphate); broth microdilution MIC should not be performed.
Breakpoints apply only to E. coli urinary tract isolates and should not be extrapolated to other Enterobacterales species.
IDSA guidance recommends limiting oral fosfomycin to E. coli cystitis due to the intrinsic fosA gene in other gram-negative organisms (moderate to high risk of AmpC production), which may lead to clinical failure.
Clinical data indicate worse outcomes and higher emergence of resistance with non-E. coli gram-negative isolates, particularly Klebsiella pneumoniae and Pseudomonas aeruginosa.

FDA approved regimen: Single 3-gram dose dissolved in water for uncomplicated cystitis.
Off-label dosing varies by clinical scenario:
• Cystitis in males: 3 grams every 24–72 hours for 3–4 doses (1–3 weeks total).
• Prostatitis: 3 grams daily for one week, followed by 3 grams every 48 hours OR 3 grams orally every 48–72 hours for 2–4 weeks (acute) or 4–6 weeks or longer (chronic).
• Pre-transrectal prostate biopsy prophylaxis: Single 3-gram dose.
Oral dosing does not achieve systemic concentrations required for upper urinary tract infections or systemic manifestations.

Diarrhea is the most frequently reported adverse event (9% in prescribing information; up to 18% in longer treatment case series), occasionally necessitating discontinuation, dose interval prolongation, or dietary modification.
Other reported adverse events include vaginitis, nausea, headache, dizziness, asthenia, and dyspepsia.
One case of C. difficile infection was reported; no other studies noted it.
Indiscriminate use may result in treatment failure, adverse events (especially diarrhea), and emergence of resistance.

Ideal use is for lower urinary tract infections (e.g., cystitis) without signs of upper tract infection or systemic signs (e.g., fever, leukocytosis) caused by ESBL-producing E. coli resistant to other oral options.
Appropriate when other oral agents are unavailable or inappropriate due to resistance, allergy, or route of administration.
Aims to prevent hospital admission or outpatient parenteral antibiotic therapy.
Most studies excluded patients with fever, leukocytosis, and upper tract infection symptoms; pharmacokinetic data does not support efficacy for systemic or upper urinary tract infections.
Male sex has been identified as an independent risk factor for treatment failure in at least one study.
Susceptibility testing is often unavailable at therapy initiation, and few VA laboratories routinely test for fosfomycin susceptibility.

Treatment of systemic infections beyond the urinary tract or prostate
History of hypersensitivity reaction to fosfomycin
Pyelonephritis or perinephric abscess
Asymptomatic bacteriuria unless the patient is scheduled to undergo significant urinary manipulation or is pregnant
Inclusion Criteria (At least one must be fulfilled)
Cystitis with Escherichia coli or Enterococcus spp. in urine culture which is non-susceptible to other appropriate oral agents (e.g., nitrofurantoin, beta-lactams, trimethoprim-sulfamethoxazole) OR have a severe allergy or contraindication to other susceptible oral agents
Acute/chronic prostatitis with Escherichia coli or Enterococcus spp. in culture which is non-susceptible to other appropriate oral agents (e.g., trimethoprim-sulfamethoxazole, doxycycline, fluoroquinolones) OR have a severe allergy or contraindication to other susceptible oral agents
Other locally-approved indication or patient situation

Acute uncomplicated cystitis in females (FDA-approved): 3 grams orally once with or without food
Complicated cystitis in females or males: 3 grams orally once every 2-3 days for 3 doses (utilized for multi-drug resistant UTI)
Acute/chronic prostatitis (off-label): 3 g orally daily for one week, followed by 3 g orally every 48 hours; OR 3 g orally every 48 to 72 hours. Durations: acute – 2 to 4 weeks, chronic – 4 to 6 weeks

FDA-approved for Escherichia coli and Enterococcus faecalis uncomplicated UTI (by definition excludes males), but likely safe and efficacious for complicated UTI in males only involving the bladder
ESBL E. coli fosfomycin resistance rates are low (susceptibility rates 81-100%)
Reserve for E. coli; avoid for other gram-negative organisms (Klebsiella spp., Enterobacter spp., Serratia marcescens, Pseudomonas aeruginosa) due to intrinsic fosA gene leading to hydrolysis and clinical failure
Does not achieve adequate concentration in the renal parenchyma; avoid for pyelonephritis and complicated UTI
May be considered (off-label) for bacterial prostatitis, but fluoroquinolones are generally preferred if susceptible due to more robust evidence for chronic prostatitis