What are the indications, dosing regimens, pharmacokinetics, adverse effects, renal dose adjustments, and alternative therapies for oral fosfomycin (fosfomycin tromethamine or calcium) and intravenous fosfomycin?

Fosfomycin: Comprehensive Clinical Guide

Oral Fosfomycin (Fosfomycin Tromethamine)

FDA-Approved Indication and Dosing

Oral fosfomycin is indicated exclusively for acute uncomplicated cystitis in women, administered as a single 3-gram dose mixed with water. 1

• The single dose provides therapeutic urinary concentrations (>128 mg/L) for 24-48 hours, sufficient to eradicate most uropathogens 2, 1
• Must be mixed with water before ingesting; never take in dry form 1
• Can be taken with or without food, though food reduces peak concentration from 26.1 mcg/mL (fasting) to 17.6 mcg/mL (fed) without affecting total urinary excretion 1

Pharmacokinetics

• Absorption: 37% oral bioavailability (fasting), reduced to 30% with high-fat meals 1
• Distribution: Volume of distribution 136.1 L; not protein-bound; distributes to kidneys, bladder wall, prostate, and seminal vesicles 1, 3
• Peak urinary concentrations: 706 mcg/mL at 2-4 hours (fasting), maintained >100 mcg/mL for 26 hours 1
• Elimination: 38% excreted unchanged in urine, 18% in feces; half-life 5.7 hours in normal renal function 1

Renal Dose Adjustments

No dose adjustment is required for eGFR ≥30 mL/min/1.73 m². 2

• In anuric patients on hemodialysis, half-life increases from 5.7 hours to 40 hours 1
• In severe renal impairment (CrCl 7-54 mL/min), half-life increases from 11 to 50 hours with urinary recovery dropping from 32% to 11% 1
• Avoid in patients with eGFR <30 mL/min/1.73 m² due to inadequate urinary concentrations 2

Clinical Efficacy for Uncomplicated Cystitis

Fosfomycin achieves 91% clinical cure rates and 78-83% microbiological eradication at 5-9 days post-treatment. 2

• Comparable clinical efficacy to 3-day trimethoprim-sulfamethoxazole (93% cure) or fluoroquinolones (90% cure), despite slightly lower bacteriological efficacy 2
• Recommended as first-line therapy when TMP-SMX resistance exceeds 20% in the community 2
• E. coli resistance to fosfomycin remains low at 2.6% in initial infections and 5.7% at 9 months 2

Spectrum of Activity

Fosfomycin demonstrates broad-spectrum bactericidal activity against both gram-positive and gram-negative uropathogens. 1, 3

• Gram-negative: E. coli, Klebsiella pneumoniae, Klebsiella oxytoca, Proteus mirabilis, Enterobacter aerogenes, Citrobacter spp., Serratia marcescens 1
• Gram-positive: Enterococcus faecalis, Enterococcus faecium 1
• Active against multidrug-resistant pathogens including ESBL-producing E. coli, VRE, and MRSA 2
• No cross-resistance with beta-lactams or aminoglycosides due to unique mechanism (inhibits MurA enzyme, blocking cell wall synthesis) 1, 4

Critical Contraindications and Limitations

Oral fosfomycin must NOT be used for pyelonephritis, complicated UTIs, upper tract infections, or UTIs in men. 5, 2

• Insufficient efficacy data for these conditions; use fluoroquinolones or beta-lactams instead 5, 2
• Contraindicated in patients with hypernatremia, cardiac insufficiency, or severe renal insufficiency (eGFR <30 mL/min) 2, 6
• Not recommended for asymptomatic bacteriuria except in pregnant women 2

Adverse Effects

Common adverse effects include diarrhea, nausea, vomiting, and headache, occurring in 5.6-28% of patients. 2

• Generally well-tolerated with no serious drug-related adverse events in clinical trials 2
• Minimal disruption to intestinal flora compared to fluoroquinolones and cephalosporins, reducing C. difficile risk 2
• Pregnancy Category B; safe for use in pregnant women with asymptomatic bacteriuria 2, 4

Drug Interactions

• Metoclopramide: Lowers serum concentrations and urinary excretion of fosfomycin; avoid concurrent use 1
• Cimetidine: No effect on fosfomycin pharmacokinetics 1

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Intravenous Fosfomycin (Fosfomycin Disodium)

Indications (Not FDA-Approved in US; Available in Europe/Asia)

IV fosfomycin is recommended for complicated UTIs (cUTI) without septic shock and as combination therapy for carbapenem-resistant gram-negative infections. 5, 6

• ZEUS trial: IV fosfomycin 6 grams every 8 hours for 7 days (14 days if bacteremic) was noninferior to piperacillin-tazobactam for cUTI and acute pyelonephritis 5, 7
• Superior microbiological eradication against ESBL-producing E. coli, Klebsiella spp., and carbapenem-resistant Enterobacterales 7
• FOREST trial: IV fosfomycin noninferior to meropenem for bacteremic cUTI caused by E. coli 5

Dosing Regimens

Standard IV dosing: 6 grams every 8 hours (18 grams/day) for 7 days; extend to 14 days if concurrent bacteremia. 7

• For carbapenem-resistant Klebsiella pneumoniae (CRKP) infections: Use in combination with tigecycline, polymyxin, or carbapenems 5
• Susceptibility rates for CRKP range from 39-99% depending on local epidemiology; always confirm susceptibility 5, 6

Pharmacokinetics

• Distribution: Achieves clinically relevant concentrations in kidneys, bladder, prostate, lungs, bone, CSF, abscess fluid, and heart valves 3
• Elimination: Following IV administration, mean total body clearance 6.1 L/hr and renal clearance 5.5 L/hr 8
• Half-life: 5.7 hours in normal renal function; increases to 40-50 hours in anuric patients 2, 8

Renal Dose Adjustments for IV Fosfomycin

In severe renal impairment or anuria, the elimination half-life increases dramatically from 5.7 hours to 40-50 hours. 2, 8

• Specific IV dosing adjustments for renal impairment are not well-established in guidelines; use with extreme caution in eGFR <30 mL/min 2
• Monitor electrolytes closely due to sodium load and risk of hypernatremia 2, 6

Efficacy in Resistant Infections

Fosfomycin-containing combination therapy for CRKP infections reduced mortality by 114 deaths per 1000 patients (RR 0.55,95% CI 0.28-1.10), though evidence quality is very low. 5

• In ICU patients with CRKP/CRPA infections, fosfomycin combinations achieved 54.2% treatment efficacy, 56.3% bacterial eradication, and 37.5% 28-day mortality 5
• Demonstrates synergistic in vitro activity against CRKP when combined with other agents 5

Adverse Effects and Monitoring

IV fosfomycin is generally safe with mild adverse reactions; the most significant risk is reversible severe hypokalemia. 5

• Hypokalemia occurred in 3 of 48 ICU patients (6.3%) receiving IV fosfomycin combinations 5
• FOREST trial safety concern: 8.6% (6/70) of patients developed heart failure with IV fosfomycin versus 1.4% (1/73) with meropenem 5
• Monitor electrolytes: Hypokalemia, hypocalcemia, hypomagnesemia, and hypernatremia can occur 2
• Contraindicated in patients with cardiac insufficiency, hypernatremia, or severe renal insufficiency 2, 6

Critical Limitations

IV fosfomycin should not be used as monotherapy for serious infections; always use in combination with other active agents. 5, 6

• Resistance genes (FosA-like) are increasingly prevalent in CRKP; always confirm susceptibility before use 5, 6
• Avoid in patients at risk for heart failure based on FOREST trial data 5

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Alternative Therapies by Clinical Scenario

For Uncomplicated Cystitis (When Fosfomycin Unsuitable)

First-line alternatives: Nitrofurantoin 100 mg twice daily for 5 days or TMP-SMX 160/800 mg twice daily for 3 days (if local resistance <20%). 2

• Nitrofurantoin: 93% clinical cure, 88% microbiological eradication 2
• TMP-SMX: 93% clinical cure, 94% microbiological eradication 2
• Second-line: Fluoroquinolones (ciprofloxacin 250 mg twice daily or levofloxacin 250 mg once daily for 3 days) reserved for resistant pathogens 2

For Pyelonephritis or Upper UTI

Fluoroquinolones (ciprofloxacin or levofloxacin) for 5-7 days or beta-lactams for 7 days are preferred; oral fosfomycin is NOT recommended. 5, 2

• Ciprofloxacin/levofloxacin: 5-day regimens comparable to 7-day courses 5
• Beta-lactams: 7-day regimens recommended based on RCT data 5

For Complicated UTI or Bacteremic UTI

IV fosfomycin 6 grams every 8 hours for 7-14 days (if available) or carbapenems are preferred. 5, 7

• Aminoglycosides (gentamicin, amikacin) for 5-7 days are acceptable for bacteremic UTI of urinary source 5
• Avoid aminoglycosides beyond 7 days due to nephrotoxicity risk 5

For Carbapenem-Resistant Gram-Negative Infections

Combination therapy with IV fosfomycin plus tigecycline, polymyxin, or carbapenem (if MIC permits) is recommended. 5

• Ceftazidime-avibactam plus fosfomycin showed no mortality difference but reduced secondary infections compared to ceftazidime-avibactam plus other agents 5
• Always confirm fosfomycin susceptibility; resistance rates vary widely (39-99% for CRKP) 5, 6

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Common Pitfalls and How to Avoid Them

Pitfall 1: Using Oral Fosfomycin for Pyelonephritis

Never use oral fosfomycin for upper UTI or pyelonephritis; insufficient efficacy data and high failure rates. 5, 2

• Solution: Use fluoroquinolones (5-7 days) or beta-lactams (7 days) for pyelonephritis 5

Pitfall 2: Prescribing Fosfomycin in Severe Renal Impairment

Avoid oral fosfomycin when eGFR <30 mL/min; inadequate urinary concentrations and prolonged half-life (up to 50 hours). 2, 1

• Solution: Use nitrofurantoin (if eGFR ≥30 mL/min) or TMP-SMX; avoid nitrofurantoin if eGFR <30 mL/min 2

Pitfall 3: Using IV Fosfomycin Monotherapy for Serious Infections

IV fosfomycin should never be used alone for CRKP or serious infections; resistance develops rapidly. 5, 6

• Solution: Always combine with tigecycline, polymyxin, or carbapenem (if susceptible) 5

Pitfall 4: Ignoring Cardiac Risk with IV Fosfomycin

IV fosfomycin caused heart failure in 8.6% of patients in the FOREST trial; avoid in patients with cardiac insufficiency. 5, 6

• Solution: Screen for heart failure risk factors; monitor closely if IV fosfomycin is necessary 5

Pitfall 5: Failing to Monitor Electrolytes with IV Fosfomycin

Hypokalemia, hypernatremia, and other electrolyte disturbances occur with IV fosfomycin, especially in ICU patients. 5, 2

• Solution: Monitor potassium, sodium, calcium, and magnesium during and after IV fosfomycin therapy 2

Pitfall 6: Co-Administering Metoclopramide with Oral Fosfomycin

Metoclopramide reduces fosfomycin serum and urinary concentrations, potentially causing treatment failure. 1

• Solution: Avoid metoclopramide during fosfomycin therapy; use alternative antiemetics if needed 1