Drug profile Fosfomycin Block 1 Class Generic name Brand Formulation Dose Content Mfg date -Expire date Block 2 Mechanism of action Pharmacology Pk and pd Route of administration Uses Adverse drug reaction Mild, Moderate, Severe (5 Examples in each category) Drug durg interaction Mild, Moderate, Severe (5 Examples in each category) Source-
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DRUG PROFILE: FOSFOMYCIN
BLOCK 1 - IDENTIFICATION & FORMULATION
| Parameter | Details |
|---|---|
| Drug Class | Phosphonic acid antibiotic - unique structural class unrelated to any other antibiotic family |
| Generic Name | Fosfomycin (also: Fosfomycin Tromethamine / Fosfomycin Disodium) |
| Brand Names | Monurol (oral, USA) - Infectofos (IV, Europe) - Fosmicin (Japan/Korea) - Urixin - Urizone - Fosfocin |
| Formulations | - Oral powder for solution: Fosfomycin tromethamine 5.61 g sachet (= 3 g fosfomycin base), dissolved in water before ingestion - IV powder for solution (outside USA): Fosfomycin disodium 2 g, 4 g, 8 g vials - Tablets (some countries): 500 mg, 1 g fosfomycin calcium |
| Approved Dose | - Uncomplicated cystitis (women): Single oral dose of 3 g (one sachet) - Complicated UTI (off-label oral): 3 g every 48 h x 3 doses - UTI prophylaxis (oral): 3 g every 10 days - Systemic infections (IV, outside USA): 200-300 mg/kg/day in 3-4 divided doses; typical adult dose 4-8 g IV every 8 h (max up to 16-24 g/day in severe infections) |
| Content (per sachet) | Fosfomycin tromethamine 5.61 g equivalent to fosfomycin 3 g; excipients: saccharin, orange flavor, sucrose |
| Mfg / Expiry Date | Printed on each individual sachet/vial. Shelf life: typically 3 years from manufacturing date when stored at room temperature (20-25°C / 68-77°F), protected from moisture. Reconstituted IV solution: stable for 12 hours at room temperature. |
BLOCK 2 - CLINICAL PHARMACOLOGY
Mechanism of Action
Fosfomycin exerts bactericidal activity through a unique, two-step mechanism:
-
Uptake into bacteria: Fosfomycin enters gram-negative bacteria via the glycerophosphate transporter (GlpT) and the glucose-6-phosphate transporter (UhpT). This active transport is inducible by glucose-6-phosphate (which is why susceptibility testing requires glucose-6-phosphate supplementation in culture media).
-
Irreversible inhibition of MurA (UDP-N-acetylglucosamine enolpyruvyl transferase): Fosfomycin covalently and irreversibly inhibits MurA, the enzyme that catalyzes the first committed step in peptidoglycan biosynthesis - specifically the transfer of the enolpyruvyl moiety from phosphoenolpyruvate (PEP) to UDP-N-acetylglucosamine (UDP-GlcNAc). This blocks synthesis of UDP-N-acetylmuramic acid (UDP-MurNAc), a critical precursor for the bacterial cell wall.
Since no other antibiotic class targets MurA, cross-resistance with other antibiotics is rare. Additionally, fosfomycin has been shown to reduce bacterial adhesion to uroepithelial cells, contributing to its efficacy in UTIs.
- Sources: Goodman & Gilman's Pharmacological Basis of Therapeutics; Lippincott Illustrated Reviews Pharmacology; Harrison's Principles of Internal Medicine 22E; PMC review 2025 PMID 40127436
Pharmacology
| Property | Detail |
|---|---|
| Chemical class | Phosphonic acid derivative; synthetic analogue of phosphoenolpyruvate |
| Spectrum | Broad - gram-positive AND gram-negative |
| Gram-positive activity | S. aureus (including MRSA), Enterococcus faecalis, VRE (E. faecium), S. saprophyticus, S. epidermidis |
| Gram-negative activity | E. coli (excellent), Proteus mirabilis, Klebsiella pneumoniae (variable), Enterobacter spp. (variable), Serratia marcescens, P. aeruginosa (variable, IV only), ESBL-producing Enterobacterales (mostly susceptible) |
| Resistant organisms | Acinetobacter baumannii, Burkholderia spp., Pseudomonas (oral formulation insufficient) |
| Bactericidal type | Time-dependent killing (T > MIC predictive of efficacy for systemic use); concentration-dependent characteristics also noted |
| Activity pH | Greater activity in acidic environments (favorable for urine) |
Pharmacokinetics (PK) and Pharmacodynamics (PD)
Pharmacokinetics
| Parameter | Oral (Tromethamine) | IV (Disodium) |
|---|---|---|
| Bioavailability | ~34-40% | 100% |
| Tmax | 2-2.5 hours | End of infusion |
| Cmax (3g oral) | ~26 mg/L plasma | Much higher |
| Urinary concentration | 1,000-4,000 µg/mL | Very high |
| Protein binding | None (0%) | None (0%) |
| Volume of distribution | ~136-158 L | ~136-158 L |
| Metabolism | Not metabolized (excreted unchanged) | Not metabolized |
| Elimination half-life (t½) | 5-8 hours | 4-8 hours |
| Elimination route | Renal (glomerular filtration), 100% excreted unchanged in urine | Renal |
| Urinary antibacterial activity duration | Up to 24-48 hours after single oral dose | Sustained with dosing |
| Tissue penetration | Bone, lung, CSF (IV formulation); poor systemic levels with oral dose |
Absorption note: Oral fosfomycin is absorbed via a saturable, carrier-mediated phosphate transport system in the small intestine. Food may delay but not significantly reduce absorption.
Pharmacodynamics
- PK/PD index: Time above MIC (T>MIC) for systemic infections; AUC/MIC also correlates with efficacy.
- For oral single-dose cystitis: the very high urinary concentrations (1,000-4,000 µg/mL) far exceed MICs of susceptible pathogens for over 24 hours, justifying single-dose therapy.
- PK/PD simulations suggest total daily IV doses of 6-12 g for organisms with MIC ≤8 mg/L provide optimal target attainment.
Route of Administration
| Route | Formulation | Indication |
|---|---|---|
| Oral | Powder dissolved in water (single sachet) | Uncomplicated UTI/cystitis |
| Intravenous (IV) | IV infusion over 30-60 minutes (outside USA) | Systemic infections: bacteremia, osteomyelitis, pneumonia, CNS infections |
| Intrathecal/intravitreal | Investigational | Refractory CNS/eye infections |
Uses / Indications
FDA-Approved:
- Uncomplicated urinary tract infections (acute cystitis) in women, caused by susceptible strains of E. coli and E. faecalis
Off-Label / Established Clinical Uses:
- Complicated UTIs and recurrent UTIs (including in men)
- ESBL-producing organism infections (UTI)
- VRE (Vancomycin-Resistant Enterococcus) urinary infections
- MRSA infections (IV, combination therapy)
- Osteomyelitis (IV combination)
- Nosocomial pneumonia (IV combination)
- Hospital-acquired bacteremia (IV combination)
- Surgical prophylaxis (some countries)
- Cystitis in pregnancy (considered safe)
- Pyelonephritis (IV formulation only - oral is insufficient)
- Clostridioides difficile infection (some evidence)
Adverse Drug Reactions (ADRs)
MILD (5 examples)
| # | ADR | Details |
|---|---|---|
| 1 | Nausea | Most common GI effect; occurs in ~6.5% of patients; self-limiting |
| 2 | Headache | Mild, transient; reported in <5% of patients |
| 3 | Diarrhea (mild) | Loose stools, not bloody; occurs without Clostridioides colitis |
| 4 | Vaginitis / vaginal itching or discharge | Reported in ~0.5-1% of women; likely secondary to altered flora |
| 5 | Dizziness / vertigo | Occasional; resolves after treatment ends |
MODERATE (5 examples)
| # | ADR | Details |
|---|---|---|
| 1 | Abdominal pain / GI distress | Cramping, bloating, dyspepsia, especially with higher doses |
| 2 | Rash / skin eruptions | Urticaria, maculopapular rash; requires monitoring |
| 3 | Elevated liver enzymes (transaminitis) | Transient ALT/AST elevation, especially with IV use; resolves after stopping |
| 4 | Back pain / musculoskeletal discomfort | Reported in some patients; mechanism unclear |
| 5 | Sodium overload (IV disodium salt only) | Each gram of IV fosfomycin disodium contains ~330 mg Na+; clinically relevant in heart failure, hypertension, or renal failure patients |
SEVERE (5 examples)
| # | ADR | Details |
|---|---|---|
| 1 | Anaphylaxis / severe hypersensitivity | Angioedema, urticaria, bronchospasm; rare but potentially life-threatening |
| 2 | Clostridioides difficile-associated diarrhea (CDAD) | Pseudomembranous colitis with watery/bloody diarrhea; can occur weeks after treatment |
| 3 | Cholestatic jaundice / hepatic necrosis | Post-marketing reports; rare; may require drug discontinuation |
| 4 | Aplastic anemia / hematologic toxicity | Very rare; includes hemolytic anemia (especially in G6PD-deficient patients and neonates), agranulocytosis |
| 5 | Severe hypernatremia with IV formulation | High sodium content of IV disodium form; can cause fluid overload, hypertension, pulmonary edema, especially in patients with compromised renal or cardiac function |
Drug-Drug Interactions (DDIs)
MILD (5 examples)
| # | Drug | Interaction | Mechanism |
|---|---|---|---|
| 1 | Metoclopramide (oral) | Reduces fosfomycin oral bioavailability and urinary concentrations | Accelerates GI motility, shortening contact time for absorption |
| 2 | Biotin (Vitamin B7) | Theoretical competition at intestinal transporters | Minor; clinical significance low |
| 3 | Pantothenic acid (Vitamin B5) | Minor interaction at absorption level | Low clinical significance |
| 4 | Pyridoxine (Vitamin B6) | Possible mild absorption competition | Rarely clinically significant |
| 5 | Thiamine (Vitamin B1) | Minor transporter competition | Rarely clinically significant |
MODERATE (5 examples)
| # | Drug | Interaction | Mechanism |
|---|---|---|---|
| 1 | Digoxin | Fosfomycin may alter gut flora affecting digoxin metabolism; may increase digoxin toxicity risk | Disruption of Eggerthella lenta bacteria that metabolize digoxin in the gut |
| 2 | Estrogens (oral contraceptives, HRT - conjugated estrogens, estradiol, estropipate) | May reduce contraceptive efficacy | Antibiotic disruption of enterohepatic recirculation of estrogen by altering gut bacteria; additional contraception may be warranted |
| 3 | Sodium picosulfate/magnesium oxide/citric acid (bowel prep solutions) | Altered GI motility and electrolyte changes may affect fosfomycin absorption and sodium load | GI motility and absorption interaction |
| 4 | Immunosuppressants (tacrolimus, cyclosporine) - IV fosfomycin | Potential additive nephrotoxicity with high-dose IV fosfomycin; monitor renal function | Pharmacodynamic synergy in nephrotoxicity |
| 5 | Antacids / proton pump inhibitors | May reduce oral absorption by altering gastric pH and GI transit | Pharmacokinetic - absorption reduction |
SEVERE (5 examples)
| # | Drug | Interaction | Clinical Concern |
|---|---|---|---|
| 1 | Live BCG vaccine | Fosfomycin (antibacterial) may inactivate live attenuated BCG vaccine | Pharmacodynamic antagonism - antibiotic kills the live bacterial vaccine, rendering it ineffective; avoid concurrent use |
| 2 | Oral typhoid vaccine (Ty21a) | Same mechanism as BCG - antibiotic inactivates live bacterial vaccine | Avoid fosfomycin within 24-72 hours of live typhoid vaccine; may result in vaccine failure and unprotected patient |
| 3 | Oral cholera vaccine (live) | Antibiotic activity may impair immunogenicity of live bacterial cholera vaccine | Same mechanism; schedule fosfomycin and vaccine at least 72 hours apart |
| 4 | Aminoglycosides (IV combination - high-dose) | Potential additive nephrotoxicity and risk of acute kidney injury with prolonged IV fosfomycin + aminoglycosides | Pharmacodynamic synergy for nephrotoxicity; monitor renal function closely in combined use |
| 5 | Drugs prolonging QT interval (in context of hypokalemia induced by fosfomycin sodium overload) | High-dose IV fosfomycin disodium causing hypernatremia and hypokalemia can amplify QT prolongation from drugs like antiarrhythmics, fluoroquinolones, macrolides | Indirect electrolyte-mediated pharmacodynamic interaction; risk of arrhythmia |
Sources
- Goodman & Gilman's The Pharmacological Basis of Therapeutics (pp. 1651-1662) - Mechanism of Action, Pharmacology, Toxicity, Therapeutic Uses
- Harrison's Principles of Internal Medicine, 22nd Edition (2025, McGraw Hill) (p. 1222) - FOSFOMYCIN section
- Lippincott Illustrated Reviews: Pharmacology (p. 1046) - Cell wall synthesis inhibitors; Fosfomycin for cystitis
- Merck Manual Professional Edition (Reviewed May 2024, Updated Apr 2025) - Full entry
- PMC Review: Fosfomycin: Pharmacological, Clinical and Future Perspectives - PMC5745467
- PubMed: Kim & Lees (2025). Molecular Pharmacology of Fosfomycin. Biochemistry. PMID 40127436
- PubMed: Falagas et al. (2025). IV Fosfomycin for Gram-Negative and Gram-Positive Infections. Antibiotics. PMID 41463696
- PubMed: Trailokya & Tiwaskar (2025). Fosfomycin Tromethamine: A Urinary Antibiotic. JAPI. PMID 41100332
- RxList Drug Profile - Adverse effects and drug interaction database
- FDA Prescribing Information (Fosfomycin tromethamine, Amneal Pharmaceuticals, April 2024)
Clinical Pearl: Fosfomycin is one of the few oral antibiotics that remains effective against ESBL-producing E. coli and VRE in the urinary tract, making it an important agent in the era of multidrug-resistant infections. Its single-dose oral regimen (3 g) offers an excellent compliance advantage. The IV formulation (available outside the USA) is increasingly used in combination for serious resistant infections including MRSA and carbapenem-resistant Enterobacterales (CRE).
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