Fosfomycin: Complete Pharmacokinetics, Pharmacodynamics, Drug Class, and Mechanism of Action
Drug Class and Mechanism of Action
Fosfomycin is a phosphonate antibiotic—the only one currently marketed—that irreversibly inhibits UDP-GlcNAc enolpyruvyl transferase (MurA), thereby blocking the first committed step in bacterial peptidoglycan cell wall synthesis. 1, 2
- Fosfomycin binds competitively to the MurA active site in place of the substrate phosphoenolpyruvate (PEP), then undergoes ring-opening nucleophilic attack by an active-site cysteine residue, resulting in irreversible covalent enzyme inactivation 2
- This unique mechanism of action results in no cross-resistance with β-lactams, aminoglycosides, or other antibiotic classes, making it valuable for multidrug-resistant pathogens 1, 3
- Fosfomycin also reduces bacterial adherence to uroepithelial cells, contributing to its efficacy in urinary tract infections 1
- The drug exhibits bactericidal activity in urine at therapeutic concentrations 1
Pharmacokinetics
Absorption and Bioavailability
- Oral fosfomycin tromethamine has poor bioavailability of <50%, limiting oral administration to single 3-gram doses for uncomplicated urinary tract infections 4
- Peak plasma concentration (Cmax) of approximately 26.1 mcg/mL is achieved 2 hours after a single 3-gram oral dose under fasting conditions 1
- High-fat meals delay absorption (peak at 6-8 hours instead of 2-4 hours) but do not alter total urinary excretion, so fosfomycin can be taken without regard to food 1
Distribution
- Volume of distribution approximates extracellular body water at 0.3 L/kg in healthy volunteers, but increases significantly in critically ill patients with bacterial infections 5
- Fosfomycin is not bound to plasma proteins 1, 5
- The drug demonstrates extensive tissue penetration, distributing to kidneys, bladder wall, prostate, seminal vesicles, CNS, soft tissues, bone, lungs, inflamed tissues, and abscess fluids 1, 4
- Mean bladder tissue concentration was 18.0 mcg/gram at 3 hours after a 50 mg/kg dose in surgical patients 1
- Fosfomycin crosses the placental barrier in both animals and humans 1
Metabolism
- Fosfomycin undergoes no hepatic metabolism and is excreted unchanged 1
Elimination
- Elimination is almost exclusively via glomerular filtration, with clearance directly dependent on renal function 1, 5
- Mean total body clearance (CLTB) is 16.9 (±3.5) L/hr following oral administration and 6.1 (±1.0) L/hr following IV administration 1
- Mean renal clearance (CLR) is 6.3 (±1.7) L/hr after oral dosing and 5.5 (±1.2) L/hr after IV dosing 1
- Approximately 38% of an oral 3-gram dose is recovered in urine and 18% in feces 1
- Mean elimination half-life (t½) is 5.7 (±2.8) hours in patients with normal renal function 1
Urinary Concentrations
- Mean urinary fosfomycin concentration of 706 (±466) mcg/mL is achieved within 2-4 hours after a single 3-gram oral dose under fasting conditions 1
- Urinary concentrations ≥100 mcg/mL are maintained for 26 hours after a single oral dose 1
- Mean urinary concentration remains at 10 mcg/mL in samples collected 72-84 hours post-dose 1
Special Populations
Renal Impairment
- In anuric patients undergoing hemodialysis, the elimination half-life extends to 40 hours 1
- In patients with creatinine clearances ranging from 54 mL/min to 7 mL/min, the t½ increases from 11 hours to 50 hours 1
- Urinary recovery decreases from 32% to 11% as renal function declines, indicating that renal impairment significantly reduces fosfomycin excretion 1
Geriatric Patients
- No differences in 24-hour urinary drug concentrations have been observed in elderly subjects, and no dosage adjustment is necessary based on age alone 1
Gender
- No gender differences exist in fosfomycin pharmacokinetics 1
Pharmacodynamics
PK/PD Targets
For Enterobacterales (including carbapenem-resistant strains), the optimal PK/PD targets are %T>MIC >70% and AUC₂₄/MIC >24 for bacteriostatic effect. 5
- For Pseudomonas aeruginosa, the target is AUC₂₄/MIC >15 for net bacterial stasis 5
- Monte Carlo simulations demonstrate that in critically ill patients with normal renal function, fosfomycin 4 g every 8 hours (or higher doses) infused over 30 minutes achieves >90% probability of target attainment (PTA) for Enterobacterales with MIC ≤32 mg/L 5
- For MIC of 64 mg/L, regimens of fosfomycin 6 g every 6 hours (30-minute infusion) or 8 g every 8 hours achieve PTA >90% 5
- No fosfomycin monotherapy regimen achieves adequate PK/PD targets for P. aeruginosa with MICs of 256-512 mg/L, necessitating combination therapy 5
Spectrum of Activity
- Fosfomycin demonstrates in vitro activity against vancomycin-resistant enterococci (VRE), methicillin-resistant S. aureus (MRSA), and extended-spectrum β-lactamase (ESBL)-producing gram-negative rods 6
- Susceptibility rates in carbapenem-resistant Klebsiella pneumoniae (CRKP) range widely from 39% to 99% depending on local epidemiology 7, 8
- For Pseudomonas aeruginosa, susceptibility is more variable (64.5% in one Greek study), and combination therapy is mandatory due to high risk of resistance development 7
Synergy and Combination Therapy
- The Infectious Diseases Society of America recommends fosfomycin-containing combination therapy for carbapenem-resistant Enterobacteriaceae (CRE) when the isolate is susceptible or demonstrates synergistic effects 7
- Fosfomycin combination therapy showed 114 fewer deaths per 1000 patients (RR=0.55,95% CI 0.28-1.10) compared to other combinations in observational studies, though evidence quality is very low 7
- Appropriate combination partners include tigecycline, polymyxin, carbapenems (at high doses), or aminoglycosides 7
- Gentamicin resistance mechanisms (aminoglycoside-modifying enzymes, reduced permeability) are completely unrelated to fosfomycin resistance pathways, supporting rational combination use 7
Critical Clinical Considerations
Mandatory Pre-Treatment Requirements
- Susceptibility testing is absolutely required before initiating fosfomycin therapy for gram-negative infections, as susceptibility testing is not routinely performed in many clinical laboratories 6, 7
- Antimicrobial synergy testing should be performed when possible to confirm synergistic effects in combination regimens 7
Contraindications
- Fosfomycin is contraindicated in patients with hypernatremia, cardiac insufficiency, and renal insufficiency due to the high sodium content of the IV formulation 7, 8
Adverse Effects Requiring Monitoring
- Severe, reversible hypokalemia occurred in 3 of 48 ICU patients (6.3%) receiving fosfomycin-based combinations; regular serum potassium monitoring is essential 7, 8
- In the FOREST trial, 8.6% of patients receiving IV fosfomycin developed heart failure versus 1.4% with meropenem; extra caution is needed for patients with existing cardiac risk factors 7
Resistance Considerations
- FosA-like resistance genes are increasingly prevalent in carbapenem-resistant strains, conferring fosfomycin resistance 7, 9
- Fosfomycin monotherapy should be avoided for serious infections due to rapid resistance development 4
- For Pseudomonas aeruginosa, fosfomycin must be used as part of combination therapy rather than monotherapy due to high resistance development risk 7
Route-Specific Guidance
- Oral fosfomycin tromethamine is approved only as a single 3-gram dose for uncomplicated urinary tract infections due to poor bioavailability 4
- The European Society of Clinical Microbiology and Infectious Diseases recommends intravenous fosfomycin for complicated UTI without septic shock based on the ZEUS trial 8
- IV fosfomycin-containing combination therapy is strongly recommended rather than oral monotherapy for complicated UTI or pyelonephritis caused by carbapenem-producing organisms 7