Is fosfomycin safe to use in a patient with an estimated glomerular filtration rate of approximately 21 mL/min/1.73 m²?

Fosfomycin Safety in Severe Renal Impairment (GFR 21 mL/min/1.73 m²)

Fosfomycin can be used with caution in a patient with GFR 21 mL/min/1.73 m², but expect significantly prolonged elimination, reduced urinary concentrations, and increased systemic accumulation that may require dose adjustment or extended dosing intervals.

Pharmacokinetic Considerations in Severe Renal Impairment

The FDA label clearly documents that fosfomycin elimination is critically dependent on renal function, with dramatic changes in patients with severe impairment:

• In anuric patients on hemodialysis, the elimination half-life extends to 40 hours (compared to 5.7 hours in normal renal function) 1
• In patients with creatinine clearances ranging from 7-54 mL/min, the half-life increases from 11 to 50 hours 1
• Urinary recovery decreases from 32% to only 11% in severe renal impairment, indicating that the primary route of elimination is substantially compromised 1

At a GFR of 21 mL/min/1.73 m² (CKD stage G4), your patient falls into the severe renal impairment category where fosfomycin clearance is markedly reduced 1.

Urinary Concentration and Efficacy Concerns

A critical issue is whether adequate urinary concentrations can be achieved for treating urinary tract infections:

• In elderly patients with impaired renal function (mean creatinine clearance 40 mL/min), urinary fosfomycin concentrations after a single 3g dose were 1,383 mg/L in the first 12 hours and 165 mg/L at 36-48 hours, which still exceeded MIC thresholds for common uropathogens 2
• The elimination half-life in these patients ranged from 7-24 hours, substantially longer than in healthy subjects 2
• Urinary recovery was highly variable (15-60%) but averaged 37% over 84 hours 2

However, these data are from patients with moderate impairment (CrCl ~40 mL/min), not severe impairment at GFR 21. The urinary concentrations would be expected to be lower in your patient.

Dosing Recommendations for GFR 21 mL/min/1.73 m²

For oral fosfomycin (3g single dose for uncomplicated UTI):

• The standard 3g single dose may still achieve therapeutic urinary concentrations for 24-48 hours, though lower than in patients with normal renal function 2
• Consider extending the observation period beyond the typical 24-48 hours, as the prolonged half-life means the drug will persist longer in both urine and serum 1, 2
• Monitor for signs of systemic accumulation if repeat dosing is contemplated, as the drug is not effectively cleared 1

For intravenous fosfomycin (if used for systemic infections):

• Recent data in critically ill patients suggest that 12-24 g/day divided into three daily doses can achieve bactericidal targets even in patients on kidney replacement therapy 3
• At GFR 21 mL/min/1.73 m², body clearance would be approximately 1.6 L/h (based on population PK modeling), substantially reduced from normal 3
• Dose reduction or interval extension is prudent to avoid accumulation 1, 3

Safety Monitoring

Key monitoring parameters include:

• Assess baseline renal function and avoid further nephrotoxic agents (NSAIDs, aminoglycosides) that could acutely worsen GFR 4
• Monitor for neurological symptoms (confusion, seizures) that may indicate drug accumulation, particularly if high doses or prolonged therapy is used 5
• Check electrolytes, as patients with GFR <30 mL/min/1.73 m² are at higher risk for metabolic disturbances 4
• Temporarily suspend or reduce dosing if acute illness, dehydration, or contrast exposure further compromises renal function 5

Clinical Context

The evidence base for fosfomycin dosing in severe renal impairment (GFR 15-29 mL/min/1.73 m²) is limited. The FDA label does not provide specific dose adjustments but documents the pharmacokinetic changes 1. The available data from elderly patients with moderate impairment suggest efficacy is maintained despite reduced urinary excretion 2, but extrapolation to GFR 21 requires caution.

For a single 3g oral dose treating uncomplicated cystitis, the risk-benefit ratio favors use, as therapeutic urinary concentrations are likely achievable and systemic accumulation from a single dose is manageable 2. For repeated dosing or intravenous therapy, dose reduction or interval extension is necessary to prevent accumulation 1, 3.