What is the recommended dose adjustment of Fosfomycin for patients with Chronic Kidney Disease (CKD) and impaired renal function?

Fosfomycin Dosing in Chronic Kidney Disease

For patients with CKD, fosfomycin dosing should be adjusted based on creatinine clearance, with 15 g/day divided into three doses (5 g TID) recommended for normal to moderate renal impairment, and reduced to 12 g/day (4 g TID) for severe impairment or dialysis patients. 1, 2

Dosing Algorithm by Renal Function

Normal to Mild Renal Impairment (CrCl >60 mL/min)

• 15 g/day divided as 5 g three times daily (TID) achieves bacteriostatic activity against organisms with MIC ≤64 mg/L and provides 97.1% cumulative fraction of response against E. coli 1
• This represents a lower dose than historical practice but improves tolerability while maintaining efficacy 1

Moderate Renal Impairment (CrCl 30-60 mL/min)

• 12-15 g/day divided as 4-5 g TID is appropriate, with the lower end (12 g/day) preferred as kidney function declines 1, 2
• Creatinine clearance significantly influences fosfomycin clearance and must guide dosing decisions 1

Severe Renal Impairment (CrCl <30 mL/min)

• 12 g/day divided as 4 g TID achieves bactericidal activity (PTA ≥90%) at MIC 32 mg/L for most Gram-negative pathogens 2
• Despite severe impairment, urinary concentrations remain therapeutic (>100 mcg/mL) even with elevated plasma creatinine 3

End-Stage Renal Disease on Dialysis (CKRT or PIKRT)

• 12-24 g/day (4-8 g TID) is effective for critically ill patients undergoing continuous or prolonged-intermittent kidney replacement therapy 2
• Dialysis clearance is approximately 2.0 L/h, which must be factored into dosing calculations 2
• The dosage can remain relatively unchanged compared to non-dialysis patients due to fosfomycin's favorable safety profile and maintained urinary concentrations 3

Critical Pharmacokinetic Considerations

Elimination and Half-Life

• Fosfomycin is primarily renally eliminated, with serum levels and elimination time directly correlating with degree of renal insufficiency 4
• Plasma half-life increases in a parabolic fashion as renal function declines 3
• Body clearance averages 1.6 L/h in patients without dialysis 2

Target Attainment

• For bacteriostatic effect: AUC24-48/MIC ratio >22.7 or %T>MIC >69.0% 2
• For bactericidal effect: AUC24-48/MIC ratio >83.3 2
• Target MIC for Enterobacterales is ≤32 mg/L per EUCAST susceptibility breakpoints 1

Pathogen-Specific Efficacy

• E. coli: 15 g/day achieves 97.1% CFR, making it highly effective even with renal impairment 1
• K. pneumoniae: 15 g/day achieves 72.9% CFR, which may be suboptimal for severe infections 1
• P. aeruginosa: 15 g/day achieves 76.7% CFR; higher dosages may be needed but safety data are limited 1

Safety Profile in Renal Impairment

A critical advantage of fosfomycin is its absence of significant renal or systemic toxicity, allowing for consistent dosing even in severe renal insufficiency. 3

• Unlike many renally-cleared antibiotics, fosfomycin does not require dramatic dose reductions due to its favorable safety profile 3
• Monitoring renal function during treatment remains prudent, though dose-limiting nephrotoxicity is uncommon 1
• The primary dose-limiting factor is tolerability rather than toxicity, particularly at higher doses 1

Common Pitfalls to Avoid

• Do not use historical high-dose regimens (>24 g/day) in patients with normal renal function, as 15 g/day provides equivalent efficacy with better tolerability 1
• Do not assume dialysis removes all drug: Fosfomycin maintains therapeutic urinary concentrations even during dialysis 3
• Do not underdose in dialysis patients: 12-24 g/day remains appropriate and safe for CKRT/PIKRT patients 2
• Avoid using fosfomycin monotherapy for P. aeruginosa without susceptibility testing, as CFR is suboptimal even at 15 g/day 1