Fosfomycin for the Treatment of Uncomplicated Urinary Tract Infections
Fosfomycin for the Treatment of Uncomplicated Urinary Tract Infections
By Jessica C. Song, MA, PharmD, Assistant Professor of Pharmacy Practice, University of the Pacific, Stockton, CA, and Pharmacy Clerkship and Coordinator, Santa Clara Valley Medical Center, is Associate Editor for Infectious Disease Alert
Jessica Song reports no consultant, stockholder, speaker’s bureau, research, or other financial relationships with companies having ties to this field of study.
Uncomplicated Urinary Tract Infections (UTI) are the most frequent bacterial infections in women, as evidenced by lifetime risks in excess of 50%. Overall expenditures in the United States for the treatment of UTI in women (outpatient prescription expenditures excluded) approached 2.5 billion dollars in 2000.1 The 1999 IDSA (Infectious Diseases Society of America) meta-analysis showed that trimethoprim-sulfamethoxazole (TMP-SMX) for 3 days represented the best option for the empiric treatment of acute, uncomplicated cystitis. Fluoroquinolones given for 3 days were recommended as an alternative first-line therapeutic option in communities with high rates (ie, > 10%-20%) of resistance to TMP-SMX. The IDSA review found that single-dose therapy was inferior in efficacy to longer durations of treatment with the same antimicrobial, and that other agents such as nitrofurantoin (given for 7 days), -lactams (given for 3 days), and single-dose fosfomycin tromethamine should be categorized as second-line agents.2 Fosfomycin is a synthetic broad-spectrum phosphonic acid derivative that exerts its bactericidal effects through inhibiting pyruvyl transferase, an enzyme crucial for the initial step in bacterial cell wall synthesis.3
Since 1999, gatifloxacin has been added to the category of agents that have been approved by the Food and Drug Administration (FDA) for use in single-dose therapy for uncomplicated cystitis.4 However, in contrast to fosfomycin tromethamine, single-dose gatifloxacin has been shown to be as effective as 3-day regimens with ciprofloxacin or gatifloxacin.5 Recently, Hooton and colleagues conducted a study (n = 370 females) comparing the efficacy of a 3-day regimen of amoxicillin-clavulanate (500 mg/125 mg twice daily) to that of a 3-day regimen of ciprofloxacin (250 mg twice daily) in the treatment of acute cystitis.6 The clinical cure rate for amoxicillin-clavulanate-treated females was nearly 25% lower than the rate reported for ciprofloxacin-treated females (P < 0.001). Given that the prevalence of resistance to TMP-SMX among uropathogens is increasing,7 and that amoxicillin-clavulanate has been shown to be not as effective as ciprofloxacin for the treatment of acute uncomplicated cystitis, it is anticipated that fluoroquinolones will be increasingly used first-line for the management of cystitis. In light of the concern of fluoroquinolone resistance in uropathogens, the place of fluoroquinolone-sparing antibiotics such as fosfomycin tromethamine in the treatment of acute uncomplicated cystitis should be re-assessed. This article will: 1) review the pharmacology, pharmacokinetics, and FDA indications of fosfomycin tromethamine, 2) review its drug interactions, dosage, and resistance patterns, and 3) review the safety and efficacy of fosfomycin tromethamine.
Pharmacologic/Other Clinical Properties of Fosfomycin Tromethamine
Table 1 summarizes the mechanism of action, spectrum of activity, FDA indications, pharmacokinetics, dosing/administration, contraindications, adverse effects, drug interactions, resistance patterns, and cost of fosfomycin tromethamine.
| Table | ||||||||
| Pharmacologic, Pharmacokinetic, Clinical Properties of Fosfomycin Tromethamine | ||||||||
| Brand/Generic3 | Monurol® (Fosfomycin Tromethamine) | |||||||
| Classification8 | Synthetic broad-spectrum antibiotic (phosphonic acid derivative), miscellaneous category | |||||||
| Mechanism of Action9 | Exerts bactericidal effects secondary to blocking cell wall synthesis via inhibition of pyruvyl transferase, an enzyme crucial for the initial step in bacterial cell wall synthesis. | |||||||
| Spectrum of Activity10 | Spectrum of activity may include isolates of Citrobacter spp., Escherichia coli, Enterobacter spp., Enterococcus spp., Klebsiella spp., Proteus spp., Providencia spp., Pseudomonas aeruginosa, and Staphylococcus spp. | |||||||
| FDA Indications3 | Treatment of uncomplicated urinary tract infections caused by susceptible isolates of E. coli and E. faecalis | |||||||
| Pharmacokinetics3,11-13 | Half-life | Oral bioavailability | Duration (urine level > 128 mg/L | Tmax | Vd | Protein Bound | Hepatic metabolism | Recovered unchanged in urine 48 hours) |
| 5.7h | 34-41% | 24-48hours | 2-2.5 h | 140 | 3% | < 1% | 38-60% | |
| How Supplied3 | Powder for solution (3 gram packet, Forest Pharmaceuticals) | |||||||
| Dosage3 | One single 3 gram dose of fosfomycin tromethamine (adult women 18 years and older) Note: Safety and efficacy in children ≤ 12 years of age have not been established. | |||||||
| Dosage Adjustment3,11 | Renal The elimination half-life of fosfomycin is significantly longer in renally insufficient patients (up to 50 h with CrCl < 10 mL/min). Hepatic No dosage adjustment required. |
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| Storage/Administration3 | Storage Store medication at room temperature (59°F to 85°F) away from heat, moisture, and direct light Administration •Orange-flavored powder should be mixed with 4 ounces (1/2 cup) of water (don’t use hot water) until the powder has dissolved. Drink the medicine immediately. •Can be taken with or without food. |
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| Contraindications3 | Previously hypersensitivity to fosfomycin | |||||||
| Adverse Effects14 | Most frequently reported in US trials: •Diarrhea (9%) •Vaginitis (5.5%) •Nausea (4.1%) •Headache (3.9%) •Dizziness (1.3%) •Dyspepsia (1.1%) |
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| Drug Interactions14 | •Metoclopramide decreases the absorption and urinary concentrations of fosfomycin •Concomitant administration with other prokinetic agents such as cisapride should be avoided |
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| Pregnancy category3 | •Pregnancy category B | |||||||
| Resistance14,15 | Resistance rates of outpatient urine isolates of E. coliand E. faecalisin the United States rarely exceed 1%. Cross-resistance to other antibiotics unlikely, as one investigation showed that 70% of strains resistant to ampicillin, sulfamethoxazole, or trimethoprim retained sensitivity to fosfomycin. | |||||||
| Cost | Accessed from www.drugstore.com on July 10, 2005: $39.66 for one packet of fosfomycin tromethamine (Monurol) | |||||||
Clinical Efficacy of Fosfomycin-Tromethamine
At present, clinically useful published data comparing fosfomycin tromethamine with antimicrobial agents is sparse, as most trials used inappropriate comparator regimens, such as other antimicrobials as single-dose therapy, or the trials enrolled an insufficient number of subjects.2 In a meta-analysis of 2 trials in which single-dose fosfomycin was compared with a norfloxacin 400 mg twice daily (5-7 days) regimen, fosfomycin was shown to have similar eradication and recurrence rates (fosfomycin: 97%, 31%; norfloxacin: 93%, 29%; P = nonsignificant), but a significantly higher rate of adverse events (fosfomycin 26%; norfloxacin 11%; P = 0.004).2 Single-dose fosfomycin was compared with a 7-day course of nitrofurantoin 100 mg given twice daily in another study of acute cystitis in 749 females.16 Bacteriologic cure rates (~7 days post-treatment) observed with single-dose fosfomycin and multiday nitrofurantoin were 78% and 81% (P = 0.5), respectively. Clinical cure rates (~7 days post-treatment) reported for fosfomycin-treated patients and nitrofurantoin-treated patients were 82% and 84% (P = 0.3), respectively. Adverse event rates were similar, as 5.3% of patients who received fosfomycin tromethamine and 5.6% of patients who received nitrofurantoin reported adverse effects that were temporally related to study medication (p-value not reported). Another comparative trial demonstrated that single-dose fosfomycin tromethamine was comparable to a 5-day course of trimethoprim 200 mg twice daily in eradicating bacteriuria in acute cystitis (fosfomycin 83.0%; trimethoprim 83.3%; p-value not reported).17 Finally, data presented to the US FDA Anti-Infective Drugs Advisory Committee revealed that among a total of 1025 patients, fosfomycin single-dose therapy was significantly less effective in eradicating bacteriuria (86% to 93%), compared with TMP-SMX for 10 days or ciprofloxacin for 7 days (83% to 97%). Interestingly, these same studies showed similar cure rates for fosfomycin tromethamine and TMP-SMX/ciprofloxacin.14
At present, 2 antimicrobial agents, fosfomycin tromethamine and gatifloxacin, are FDA-approved for use as single-dose treatment options for acute cystitis patients. Single-dose therapy of uncomplicated UTI offers several advantages over multidose therapy, including better patient compliance and reduced selective pressure for resistant uropathogens. Of note, unlike TMP-SMX and fluoroquinolones, fosfomycin tromethamine has little or no tendency to induce or select for resistant strains, as resistance rates in the United States rarely exceed 1%. Overall, published and unpublished data with fosfomycin suggest that it is inferior to first-line agents (TMP-SMX, fluoroquinolones) currently available for the management of acute uncomplicated UTI. Although the bacteriologic cure rates, overall clinical success rates, and adverse effect profiles were similar for single-dose fosfomycin tromethamine and 7-day nitrofurantoin, fosfomycin tromethamine is considerably more expensive than nitrofurantoin, as it is not marketed as a generic agent. In summary, fosfomycin tromethamine should be considered as an alternative treatment option for women with a history of noncompliance with multidose treatment regimens, those with UTI due to resistant pathogens, and those unable to take other oral antimicrobials due to allergy.
References
- Griebling TL. Urologic Diseases in America Project: Trends in Resource Use for Urinary Tract Infections in Women. J Urol. 2005;173:1281-1287.
- Warren JW, et al. Guidelines for Antimicrobial Treatment of Uncomplicated Acute Bacterial Cystitis and Acute Pyelonephritis in Women. Clin Infect Dis. 1999;29:745-758.
- Fosfomycin Tromethamine (Monurol ) Prescribing Information. St. Louis, MO: Forest Pharmaceuticals, Inc.; 1997 December.
- Gatifloxacin (Tequin ) Prescribing Information. Princeton, NJ: Bristol-Myers Squibb Company; 2005 May.
- Richard GA, et al. Single-Dose Fluoroquinolone Therapy of Acute Uncomplicated Urinary Tract Infection in Women: Results from a Randomized, Double-Blind, Multicenter Trial Comparing Single-Dose to 3-Day Fluoroquinolone Regimens. Urology. 2002;59:334-339.
- Hooton TM, et al. Amoxicillin-Clavulanate vs Ciprofloxacin for the Treatment of Uncomplicated Cystitis in Women: A Randomized Trial. JAMA. 2005;293:949-955.
- Gupta K, et al. Antimicrobial Resistance Among Uropathogens That Cause Community-Acquired Urinary Tract Infections in Women: A Nationwide Analysis. Clin Infect Dis. 2001;33:89-94.
- Fosfomycin, in McEvoy GK (ed). AHFS Drug Information. Baltimore, MD, American Society of Health-System Pharmacists, Inc., 2004, p. 868.
- Kahan FM, et al. The Mechanism of Action of Fosfomycin. Ann N Y Acad Sci. 1974;235:364-386.
- Barry AL, Brown SD. Antibacterial Spectrum of Fosfomycin Trometamol. J Antimicrob Chemother. 1995;35:228-230.
- Patel SS, et al. Fosfomycin Tromethamine: A Review of Its Antibacterial Activity, Pharmacokinetic Properties and Therapeutic Efficacy as a Sngle-Dose Oral Treatment for Acute Uncomplicated Lower Urinary Tract Infections. Drugs. 1997;53:637-656.
- Bergan T. Degree of Absorption, Pharmacokinetics of Fosfomycin Trometamol and Duration of Urinary Antibacterial Activity. Infection. 1990;18(suppl 2):s65-699.
- Reeves DS. Fosfomycin Trometamol. J Antimicrob Chemother. 1994;34:853-858.
- Stein GE. Single-Dose Treatment of Acute Cystitis with Fosfomycin Tromethamine. Ann Pharmacother. 1998;32:215-219.
- Fuchs PC, et al. Fosfomycin Tromethamine Susceptibility of Outpatient Urine Isolates of Escherichia coli and Enterococcus faecalis from Ten North American Medical Centres by Three Methods. J Antimicrob Chemother. 1999;43:137-140.
- Stein GE. Comparison of Single-Dose Fosfomycin and a 7-day Course of Nitrofurantoin in Female Patients with Uncomplicated Urinary Tract Infection. Clin Ther 1999;21:1864-72.
- Minassian MA, et al. A Comparison Between Single-Dose Fosfomycin Trometamol (Monuril) and a 5-Day Course of Trimethoprim in the Treatment of Uncomplicated Lower Urinary Tract Infection in Women. Int J Antimicrob Agents. 1998;10:39-47.
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