Fosfomycin: A New Single-Dose Antibiotic
By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD
A new single-dose antibiotic has been approved by the FDA for the treatment of uncomplicated urinary tract infections (UTI)in women. UTIs are one of the most common reasons for outpatient visits, with an estimated prevalence of 35-45 cases per 1000 women annually. Fosfomycin tromethamine (Monurol, Forest Labs) represents the first in a new class of antibiotics, derivatives of phosphonic acid. The drug is bactericidal against a wide range of common urinary tract pathogens and is well absorbed orally. A single dose results in high serum levels, which provides concentrations above the MIC for common urinary pathogens to the urinary tract for up to 3.5 days. Fosfomycin is supplied as a package of soluble granules that is mixed with water.
Indications
Fosfomycin is indicated for the treatment of uncomplicated UTIs (acute cystitis) in women that are caused by susceptible strains of Escherichia coli and Enterococcus faecalis.
Potential Advantages
Fosfomycin is the first antibiotic approved for single-dose treatment of uncomplicated UTIs. It has been reported to provide urine concentrations above MlC90 for E. coli for up to 3.5 days and is bactericidal against common urinary pathogens at usual urine concentrations. There is generally little cross resistance between fosfomycin and other antibiotics.1 Fosfomycin received a Pregnancy category B classification (i.e., no evidence of risk in humans)the same as amoxicillin and nitrofurantoin, while TMP/SMX and quinolones are in category C (i.e., risk cannot be ruled out). The drug has been extensively used in Europe since 1988.
Potential Disadvantages
The most common side effect of fostomycin is diarrhea (9%). The average duration of diarrhea is about two days.2 In vitro data suggest that Staphylococcus saprophyticus, a common urinary pathogen particularly in young women, is resistant to fosfomycin.3 The bacteriologic eradication rate with fosfomycin (82%) is inferior to that of a seven-day course of ciprofloxacin (98%) and a 10-day course of TMP/SMX (98%).1 Metoclopramide lowers the serum concentration and urinary excretion of fosfomycin. The coadministration of these drugs is not recommended. Fostomycin is not approved for uncomplicated UTIs in men.1
Dosing Information
Fosfomycin is supplied in orange-flavored granules for solution (3 g of fosfomycin). The granules are dissolved in 3-4 ounces of water taken as a single dose. It should not be mixed with hot water. Repeated daily doses do not appear to improve clinical success but do increase the incidence of adverse events. Fosfomycin may be taken without regard to food.1
Comments
Fosfomycin is a new synthetic antibiotic with a novel mechanism of action. It inhibits cell synthesis by inactivating the enzyme enolpyruvyl transferase, which catalyzes one of the the early steps in cell wall synthesis.
The bacteriological cure rate for fosfomycin generally ranges between 69% to 96% when assessed 5-11 days post-treatment. In comparative clinical trials, fosfomycin was found to be less effective than seven days of ciprofloxacin (250 mg bid) and 10 days of TMP/SMX (960 mg daily) but was comparable to a seven-day course of nitrofurantoin (Macrodantin 100 mg bid).1,3
A small, nonblinded study (N = 36) suggests that fosfomycin may be more effective than low-dose TMP/SMX (960 mg) given for three days.4 ln a large single blind study (N =308), fosfomcyin was comparable to a single dose of TMP/SMX (1.92 g) and a single dose of ofloxacin (200 mg) in terms of bacteriologic cure, with bacteriologic cure rates of 69%, 85%, and 71%, respectively.5 Single-dose or short-term (e.g., 3 days) treatment of UTIs offers advantages of compliance, side effects, and lower risk of alteration of the vaginal and colonic flora.
While fosfomycin is the only FDA-approved single-dose regimen, clinical data indicate that it is no more effective than a single-dose of two double-strength TMP/SMX. A regimen of three-day treatment with TMP/SMX (1 DS tablet bid ´ 3 days) is often considered to be optimal treatment due to effectiveness and relapse rates.6,7
Comparative studies between this regimen and fosfomycin have not been reported. Other regimens include trimethoprim 100 mg bid for three days, ciprofloxacin 100 mg bid for three days, and cephalexin 250-500 mg qid for three days.
Fosfomycin is expensive ($21.04 per treatment) and should be reserved for patients in whom TMP/SMX is not appropriate (e.g., sulfa allergy, bacterial resistance, and third trimester of pregnancy).
Clinical Implications
Fosfomycin offers an alternative to standard therapy for UTIs in women. Although no better in terms of cure rates than standard therapy, even standard single-dose therapy, it may be useful for those with multiple drug allergies or patients who are compliance risks. Fosfomycin should probably be reserved for patients in whom other, more standard drugs are not appropriate, since the drug is 10 times more expensive than a three-day course of TMP/SMX. (Dr. Elliott is Chair, Regional Pharmacy and Therapeutics Committee at Kaiser of Northern California, and Assistant Clinical Professor of Medicine at University of California-San Francisco. Dr. Chan is the Head of Drug Information at Kaiser Permanente, California.) v
References
1. Monurol Product Information. Forest Pharmaceuticals, Inc. January 1997.
2. F-D-C ReportsThe Pink Sheet. December 23, 1996.
3. Patel SS, et al. Drugs 1997;53(4):637-656.
4. Crocchiolo P, et al. Chemotherapy 1990; 36 Suppl 1:37-40.
5. Naber KG, et al. Infection 1990;18 Suppl 2:S70-76.
6. Stamm WE, et al. N Engl J Med 1993;329:1328-1334.
7. The Medical Letter 1996;38:25-34.
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