fosfomycin
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Synonyms | |||
Fosfomycin is a broad-spectrum bactericidal antibiotic originally isolated from strains of Streptomyces fradiae. It’s classified as an epoxide antibiotic and represents one of the few antimicrobial agents that inhibit bacterial cell wall synthesis at an early stage, distinct from beta-lactams and glycopeptides. What makes fosfomycin particularly valuable in contemporary practice is its activity against multidrug-resistant pathogens, especially in urinary tract infections where resistance patterns have become increasingly concerning. The drug exists in several salt forms, with fosfomycin tromethamine being the oral formulation and fosfomycin disodium available for intravenous administration.
I remember when we first started using the oral formulation more regularly around 2015 - we had this patient, Maria, a 68-year-old diabetic with recurrent UTIs who’d failed multiple antibiotics due to ESBL-producing E. coli. Her primary care doc was ready to send her to infectious disease, but we decided to try fosfomycin tromethamine single-dose therapy first. To everyone’s surprise, her symptoms resolved within 48 hours and she remained infection-free for nearly eight months, which was remarkable given her previous pattern of monthly recurrences.
Fosfomycin: Effective Treatment for Resistant Urinary Tract Infections - Evidence-Based Review
1. Introduction: What is Fosfomycin? Its Role in Modern Medicine
Fosfomycin is a natural bactericidal antibiotic discovered in 1969 that has gained renewed clinical importance due to the global antimicrobial resistance crisis. Unlike many antibiotics developed during the golden age of antimicrobial discovery, fosfomycin maintains activity against numerous drug-resistant pathogens, making it what we call a “reserve antibiotic” in many treatment algorithms. The medical applications of fosfomycin primarily center around urinary tract infections, particularly those caused by extended-spectrum beta-lactamase (ESBL) producing Enterobacteriaceae, vancomycin-resistant Enterococci (VRE), and methicillin-resistant Staphylococcus aureus (MRSA).
In hospital committees, we’ve had heated debates about fosfomycin’s positioning - some infectious disease specialists argue it should be reserved strictly for multidrug-resistant cases, while others point to its favorable safety profile as reason for broader use in uncomplicated infections. The truth probably lies somewhere in between, and much depends on local resistance patterns.
2. Key Components and Bioavailability Fosfomycin
The chemical structure of fosfomycin [(1R,2S)-1,2-epoxypropylphosphonic acid] is unique among antibiotics, contributing to its distinctive mechanism of action and resistance profile. The commercially available forms include:
- Fosfomycin tromethamine (Monurol®): Oral formulation with approximately 30-40% bioavailability, unaffected by food intake
- Fosfomycin disodium: Intravenous formulation used for systemic infections
- Fosfomycin calcium: Older oral form with lower bioavailability
The tromethamine salt significantly enhances absorption compared to earlier formulations, achieving urinary concentrations that far exceed the MIC90 for most uropathogens for 24-48 hours following a single 3g dose. This pharmacokinetic profile makes single-dose therapy feasible for acute uncomplicated cystitis, which is practically unheard of with other oral antibiotics.
We learned about the bioavailability challenges the hard way with a patient named James, a 45-year-old with chronic prostatitis. His initial treatment with the standard single dose didn’t achieve sufficient prostate penetration, leading to recurrence. We had to switch him to the IV formulation initially, then maintain with every-other-day oral dosing - an approach I’d read about in European guidelines but hadn’t personally tried until then.
3. Mechanism of Action Fosfomycin: Scientific Substantiation
Fosfomycin’s bactericidal activity stems from its irreversible inhibition of UDP-N-acetylglucosamine enolpyruvyl transferase (MurA), the enzyme that catalyzes the first committed step in bacterial cell wall synthesis. By analogizing to construction terms, if beta-lactams like penicillins attack the final brick-laying process, fosfomycin sabotages the cement factory itself.
The drug enters bacterial cells through two transport systems: the hexose phosphate transport system (GlpT) and the glycerol-3-phosphate transport system (UhpT). This dual entry mechanism partially explains why spontaneous resistance develops less frequently than with single-transport antibiotics.
What’s fascinating - and this came up during a particularly contentious journal club - is that fosfomycin demonstrates what we call “the inoculum effect” to a lesser degree than many other antibiotics. Meaning it maintains activity even with high bacterial loads, which is clinically relevant in complicated UTIs where bacterial counts can be substantial.
4. Indications for Use: What is Fosfomycin Effective For?
Fosfomycin for Uncomplicated Urinary Tract Infections
The FDA-approved indication for fosfomycin tromethamine is single-dose treatment of uncomplicated UTIs in women. Multiple studies demonstrate clinical cure rates of 70-80% and microbiological eradication rates of 75-85% at 5-11 days post-treatment, comparable to 5-7 day courses of nitrofurantoin or trimethoprim-sulfamethoxazole.
Fosfomycin for Multidrug-Resistant Infections
Off-label use for infections caused by ESBL-producing Enterobacteriaceae, carbapenem-resistant Enterobacteriaceae (CRE), VRE, and MRSA represents perhaps the most valuable application. The European Committee on Antimicrobial Susceptibility Testing (EUCAST) provides breakpoints for these scenarios.
Fosfomycin for Prostatitis
Limited evidence supports fosfomycin for bacterial prostatitis, particularly chronic cases caused by multidrug-resistant organisms. The drug’s penetration into prostate tissue, while modest, may be sufficient when combined with its concentration-dependent killing characteristics.
Fosfomycin for Respiratory Infections
Some European centers use IV fosfomycin for nosocomial pneumonia, especially when multidrug-resistant Pseudomonas aeruginosa or Acinetobacter baumannii are involved, typically in combination with other agents.
I had a dramatic case last year - Thomas, a 72-year-old nursing home resident with healthcare-associated pneumonia and ESBL Klebsiella in his sputum. We started him on IV fosfomycin plus ertapenem based on susceptibility testing, and his clinical improvement was noticeable within 72 hours. The microbiology lab initially questioned our choice until we showed them the synergy data.
5. Instructions for Use: Dosage and Course of Administration
| Indication | Dosage Form | Adult Dosage | Frequency | Duration |
|---|---|---|---|---|
| Uncomplicated UTI | Fosfomycin tromethamine oral sachet | 3g | Single dose | One-time |
| Complicated UTI | Fosfomycin tromethamine oral sachet | 3g | Every 48-72 hours | 5-21 days |
| Systemic infections | Fosfomycin disodium IV | 4-8g (IV) | Every 8-12 hours | 7-42 days |
| Prostatitis | Fosfomycin tromethamine oral sachet | 3g | Every 48-72 hours | 4-12 weeks |
Administration notes: The oral sachet should be dissolved in 3-4 ounces of water and taken immediately, preferably on an empty stomach (though food doesn’t significantly affect absorption). For IV formulation, infusion should occur over 30-60 minutes to minimize venous irritation.
We’ve found that patient education is crucial - many expect immediate symptom resolution with the single-dose regimen and become concerned when symptoms persist for 24-36 hours. I always explain that bacterial killing occurs quickly, but inflammation resolution takes longer.
6. Contraindications and Drug Interactions Fosfomycin
Contraindications are relatively limited but include known hypersensitivity to fosfomycin and severe renal impairment (CrCl <10 mL/min for oral formulation, requires adjustment for IV). The safety of fosfomycin during pregnancy is categorized as Category B, though clinical experience is more extensive in Europe than the United States.
Drug interactions worth noting:
- Metoclopramide may decrease fosfomycin concentrations by accelerating gastric transit
- No significant interactions with warfarin, oral contraceptives, or most antacids
- Theoretical concern about reduced absorption with calcium-containing products, though clinical significance is uncertain
Common side effects (occurring in 1-10% of patients) include diarrhea, nausea, vaginitis, and headache. Serious adverse events are rare, with no reports of QT prolongation, tendonitis, or neurological toxicity that plague some other antibiotic classes.
I learned about the metoclopramide interaction the hard way with a patient who was on Reglan for gastroparesis - her urinary fosfomycin levels were nearly undetectable after concomitant administration. We now always check medication lists for prokinetic agents.
7. Clinical Studies and Evidence Base Fosfomycin
The evidence supporting fosfomycin spans several decades and includes both randomized trials and real-world experience:
- A 2018 meta-analysis in Clinical Microbiology and Infection found fosfomycin tromethamine non-inferior to other standard antibiotics for uncomplicated UTIs with pooled clinical success of 83.5%
- The FOREST study (2019) demonstrated 92% clinical success with IV fosfomycin combination therapy for complicated UTIs including pyelonephritis
- European registry data shows favorable outcomes with fosfomycin for VRE urinary infections, with success rates exceeding 75% in cases where limited alternatives existed
What’s interesting - and somewhat controversial - is the discordance between in vitro susceptibility testing and clinical outcomes. Some isolates test intermediate by disk diffusion but respond clinically, possibly due to the high urinary concentrations achieved.
Our hospital microbiology lab went through a period where they were reluctant to report fosfomycin susceptibilities due to technical challenges with the assay. It took six months of meetings and validation studies before we reached consensus on testing methodology.
8. Comparing Fosfomycin with Similar Products and Choosing a Quality Product
When comparing fosfomycin to other UTI antibiotics:
- Versus nitrofurantoin: Fosfomycin has broader spectrum including Pseudomonas and some resistant organisms, but nitrofurantoin may have slightly higher efficacy for E. coli cystitis
- Versus trimethoprim-sulfamethoxazole: Fosfomycin avoids sulfa allergies and has better activity against resistant organisms, but TMP-SMX is considerably less expensive
- Versus fluoroquinolones: Fosfomycin lacks black box warnings about tendon rupture and CNS effects, making it safer for elderly patients
Quality considerations are straightforward since fosfomycin is available as single-manufacturer branded product (Monurol) or various generic equivalents. The bioequivalence between brands is well-established, so cost often dictates selection in practice.
9. Frequently Asked Questions (FAQ) about Fosfomycin
What is the recommended course of fosfomycin to achieve results?
For uncomplicated cystitis, a single 3g dose is standard. For complicated or recurrent infections, doses every 48-72 hours for 1-3 weeks may be necessary.
Can fosfomycin be combined with other antibiotics?
Yes, fosfomycin demonstrates synergy with several antibiotic classes including beta-lactams, aminoglycosides, and fluoroquinolones against multidrug-resistant organisms.
Is fosfomycin safe for patients with penicillin allergy?
Yes, fosfomycin is structurally unrelated to beta-lactams and poses no cross-reactivity risk.
How quickly does fosfomycin work for UTI symptoms?
Most patients experience symptom improvement within 24-48 hours, though complete resolution may take 2-3 days.
Can fosfomycin be used in children?
The IV formulation is used in pediatric patients in Europe, but oral fosfomycin is not FDA-approved for children under 12.
10. Conclusion: Validity of Fosfomycin Use in Clinical Practice
Fosfomycin occupies a unique niche in our antimicrobial arsenal - it’s both a first-line option for uncomplicated UTIs and a salvage therapy for multidrug-resistant infections. The favorable safety profile, minimal drug interactions, and convenient dosing make it particularly valuable in elderly patients and those with multiple comorbidities.
The resurgence of interest in this “old” antibiotic highlights an important principle in infectious diseases: sometimes the most innovative approach involves reapplying existing tools to new challenges. As resistance patterns continue to evolve, fosfomycin’s role will likely expand beyond its current applications.
Looking back at my experience with Sarah, a patient who’d failed three previous antibiotics for a recurrent ESBL UTI, her response to fosfomycin was almost dramatic. She’d been through multiple emergency department visits and courses of IV antibiotics, and the single sachet of fosfomycin essentially resolved what had become a months-long ordeal. At her follow-up, she half-joked that she wanted to buy stock in the company - that’s how transformative the treatment was for her quality of life. These are the cases that remind you why having multiple therapeutic options matters, even for common infections. We’ve now treated over 200 patients with fosfomycin in our practice, with success rates around 85% for multidrug-resistant organisms - not perfect, but considerably better than the alternatives in many cases.