Fosfomycin is an oral antibiotic used for the treatment of uncomplicated urinary tract infections (UTIs) caused by either E. coli or Enterococcus faecalis. Fosfomycin is structurally similar to phosphoenolpyruvate, one of the precursors involved in the synthesis of peptidoglycan. Unlike beta-lactams, fosfomycin disrupts the building of bacterial cell walls by blocking formation of cell wall precursors rather than blocking peptide cross-linking. The combination of fosfomycin and a beta-lactam may be synergistic. Fosfomycin was originally discovered in 1969 and may be listed as "phosfomycin" in some US references. It has been available in Europe since 1988. Since it sustains effective urinary concentrations for over 3 days, fosfomycin is approved for single-dose treatment of uncomplicated urinary tract infection, however, efficacy as a single dose agent appears to be less than that for fluoroquinolones or co-trimoxazole. In vitro data suggest that fosfomycin may also be effective for other UTIs caused by gram-negative rods, however, no clinical data are available at this time to support using fosfomycin in UTIs involving these pathogens. Fosfomycin was FDA approved December 18, 1996 and is currently available in 19 foreign countries.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Oral Administration
-Fosfomycin is administered orally without regard to meals.
Oral Liquid Formulations:
-Do not administer dry powder. Pour the entire contents of a sachet containing the equivalent of 3 g of fosfomycin into 3-4 oz (1/2 cup) of water; do not use hot water. Stir to dissolve. Take immediately after dissolving.
Gastrointestinal adverse events reported during fosfomycin clinical trials included diarrhea (9-10.4%), nausea (4.1-5.2%), dyspepsia (1.1-1.8%), and abdominal pain (2.2%). Other GI symptoms occurring at a rate of < 1% included abnormal stools, anorexia, constipation, xerostomia, flatulence, and vomiting. Toxic megacolon was noted in post-marketing experience.
Elevated hepatic enzymes (SGPT) were reported in < 1% of patients during fosfomycin clinical trials. Serious adverse reactions to fosfomycin during post-marketing surveillance outside the United States were reported rarely and included cholestatic jaundice and hepatic necrosis.
Microbial overgrowth and superinfection can occur with antibiotic use. C. difficile-associated diarrhea (CDAD) or pseudomembranous colitis has been reported with fosfomycin. If pseudomembranous colitis is suspected or confirmed, ongoing antibacterial therapy not directed against C. difficile may need to be discontinued. Institute appropriate fluid and electrolyte management, protein supplementation, C. difficile-directed antibacterial therapy, and surgical evaluation as clinically appropriate. Vaginitis (5.5% to 7.6%) has been reported. Influenza syndrome and infection have been noted in less than 1% of patients during trials.
Nervous system adverse events reported during fosfomycin clinical trials include headache (3.9-10.3%), dizziness (1.3-2.3%), and asthenia (1.1-1.7%). Other adverse events reported in < 1% of patients during trials include insomnia, migraine, paresthesias, nervousness, and somnolence (drowsiness). Unilateral optic neuritis occurred in 1 patients and may be possibly related to fosfomycin therapy.
Rhinitis (4.5%) and pharyngitis (2.5%) were reported during fosfomycin clinical trials. Asthma exacerbation was noted in post-marketing reports.
Back pain (3%) and myalgia (< 1%) were reported during clinical trials with fosfomycin.
Dysmenorrhea (2.6%), dysuria (< 1%), hematuria (< 1%), and menstrual disorder (< 1%) were noted in clinical trials with fosfomycin.
Unspecified pain (2.2%), fever (< 1%), and lymphadenopathy (< 1%) were reported during clinical trials with fosfomycin.
Rash (unspecified) was reported in 1.4% of patients during fosfomycin clinical trials. Unspecified skin disorder and pruritus were reported in < 1% of patients during trials. Angioedema and anaphylactoid reactions have been noted in post-marketing reports.
Unspecified ear disorder was reported during fosfomycin clinical trials. Hearing loss has been noted in post-marketing reports.
Aplastic anemia was noted in post-marketing reports with fosfomycin.
Limited data indicate that fosfomycin produces low levels in milk. The manufacturer recommends that the use of fosfomycin in breast-feeding mothers should be undertaken with caution. In 2 women, after 1-2 grams of fosfomycin given by injection, colostrum concentrations were 4.8 mg/L and milk concentrations were 3.6 mg/L. Cephalexin, nitrofurantoin, or sulfamethoxazole; trimethoprim may be potential alternatives to consider during breast-feeding. However, site of infection, patient factors, local susceptibility patterns, and specific microbial susceptibility should be assessed before choosing an alternative agent. Trimethoprim (in combination with sulfamethoxazole) and nitrofurantoin are considered to be usually compatible with breast-feeding by the AAP. Cephalosporins, such as cephalexin, are generally considered to be compatible with breast-feeding. If fosfomycin is used, alterations to the infants' gut flora may be altered; monitor appropriately. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.
The safe and effective use of fosfomycin in neonates, infants, and children under 12 years of age has not been established in adequate and well-controlled studies.
Fosfomycin crosses the placental barrier. The FDA labeling suggests that fosfomycin should be used during pregnancy only if clearly needed. While there are no adequate and well-controlled studies with fosfomycin in pregnant women, observational data suggest that the single-dose use during pregnancy may be well tolerated during pregnancy.
Consider pseudomembranous colitis in patients presenting with diarrhea after antibacterial use. Careful medical history is necessary as pseudomembranous colitis has been reported to occur over 2 months after the administration of antibacterial agents. Almost all antibacterial agents, including fosfomycin, have been associated with pseudomembranous colitis or C. difficile-associated diarrhea (CDAD) which may range in severity from mild to life-threatening. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.
Because fosfomycin is given in a single-dose regimen, no particular dose adjustments have been recommended for geriatric patients. Repeated daily doses do not improve the clinical success or microbiological eradication rates compared to single dose therapy, but do increase the incidence of adverse events. Diarrhea is a particularly common side effect. The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents (e.g., geriatric adults) of long-term care facilities (LTCFs). According to OBRA, use of antibiotics should be limited to confirmed or suspected bacterial infections. Antibiotics are non-selective and may result in the eradication of beneficial microorganisms while promoting the emergence of undesired ones, causing secondary infections such as oral thrush, colitis, or vaginitis. Any antibiotic may cause diarrhea, nausea, vomiting, anorexia, and hypersensitivity reactions.
Per the manufacturer, this drug has been shown to be active against most strains of the following microorganisms either in vitro and/or in clinical infections: Citrobacter diversus, Citrobacter freundii, Enterococcus faecalis, Enterococcus faecium, Escherichia coli, Klebsiella aerogenes, Klebsiella oxytoca, Klebsiella pneumoniae, Proteus mirabilis, Proteus vulgaris, Serratia marcescens
NOTE: The safety and effectiveness in treating clinical infections due to organisms with in vitro data only have not been established in adequate and well-controlled clinical trials.
For the treatment of asymptomatic bacteriuria*, prostatitis* due to infections with difficult-to-treat resistance, and lower urinary tract infection (UTI), such as cystitis, including infections with difficult-to-treat resistance:
NOTE: Fosfomycin is not indicated for the treatment of pyelonephritis or perinephric abscess.
-for the treatment of asymptomatic bacteriuria*:
Oral dosage:
Adults: 3 g PO as a single dose.
-for the treatment of uncomplicated lower UTI, such as cystitis, including infections with difficult-to-treat resistance:
Oral dosage:
Adults: 3 g PO as a single dose.
Adolescents 16 to 17 years*: 3 g PO as a single dose.
-for the treatment of complicated lower UTI*:
Oral dosage:
Adults: 3 g PO as a single dose, or alternatively, 3 g PO every 48 hours for 3 doses.
-for the treatment of prostatitis* due to infections with difficult-to-treat resistance:
Oral dosage:
Adults: 3 g PO once daily for 1 week, then 3 g PO every 48 hours for 6 to 12 weeks as an alternative for ESBL-producing E. coli.
For urinary tract infection (UTI) prophylaxis* for recurrent infections:
Oral dosage:
Adults: 3 g PO every 10 days. The duration of prophylaxis is variable and should be assessed routinely. Generally 3 to 12 months is suggested; however, longer durations have been used.
Maximum Dosage Limits:
-Adults
Women: 3 g PO as a single dose.
Men: Safety and efficacy have not been established.
-Elderly
Women: 3 g PO as a single dose.
Men: Safety and efficacy have not been established.
-Adolescents
Safety and efficacy have not been established.
-Children
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.
Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available. The half-life of fosfomycin increases and urinary excretion decreases as renal impairment progresses.
*non-FDA-approved indication
Bethanechol: (Moderate) Bethanechol increases gastrointestinal motility and may decrease the systemic absorption of fosfomycin when the drugs are coadministered. This may result in lower fosfomycin serum concentrations and urinary excretion. Since fosfomycin is given as a single dose, separating times of administration may limit the interaction.
Cisapride: (Moderate) Cisapride may decrease the systemic absorption of fosfomycin due to the prokinetic action of cisapride. This may result in lower fosfomycin serum concentrations and urinary excretion. Monitor for evidence of clinical effectiveness of fosfomycin. Since fosfomycin is given as a single dose, separating times of administration may limit the interaction.
Metoclopramide: (Moderate) When coadministered with fosfomycin, metoclopramide, a drug which increases gastrointestinal motility, lowers the serum concentration and urinary excretion of fosfomycin. Other drugs that increase gastrointestinal motility may produce similar effects. Monitor for evidence of clinical effectiveness of fosfomycin. Since fosfomycin is given as a single dose, separating times of administration may limit the interaction.
Prucalopride: (Moderate) Prucalopride may decrease the systemic absorption of fosfomycin due to the prokinetic action of prucalopride. This may result in lower fosfomycin serum concentrations and urinary excretion. Monitor for evidence of clinical effectiveness of fosfomycin. Since fosfomycin is given as a single dose, separating times of administration may limit the interaction.
Fosfomycin inhibits one of the first steps in the synthesis of peptidoglycan. After transport into bacterial cells via glycerol-3-phosphate or glucose-6-phosphate transport systems, fosfomycin, through its epoxide group, irreversibly inactivates the enzyme enolpyruvyl transferase by taking the place of phosphoenolpyruvate. Inactivation of this enzyme blocks the condensation of uridine diphosphate-N-acetylglucosamine with p-enolpyruvate, a key first step in bacterial cell wall synthesis. Fosfomycin also binds other p-enolpyruvate dependent enzymes, but irreversible inactivation does not occur. Inhibition of peptidoglycan synthesis results in accumulation of the nucleotide precursors and subsequent death and bacterial cell lysis. Fosfomycin is bactericidal in the urine at therapeutic doses. Clinicians are advised to consult susceptibility data at the institution in which they practice to determine fosfomycin activity.
Fosfomycin is administered orally as fosfomycin tromethamine. In the systemic circulation, fosfomycin is not bound to plasma proteins. The drug is distributed to the kidneys, bladder wall, prostate, and seminal vesicles. Fosfomycin has been shown to cross the placenta. Fosfomycin is not metabolized and excretion occurs via both urine and feces. Approximately 38% of a dose is recovered from urine and 18% from feces. A mean urinary concentration of 706 +/- 466 mcg/mL was attained within 2-4 hours after a single 3-gram oral dose under fasting conditions. After a high-fat meal, a mean urinary concentration of 537 +/- 252 mcg/mL was achieved within 6-8 hours. The cumulative amount of fosfomycin excreted in the urine was the same under fed and fasting conditions. Urinary concentrations >= 100 mcg/mL were maintained for 26 hours. The mean elimination half-life is 5.7 +/- 2.8 hours.
-Route-Specific Pharmacokinetics
Oral Route
Following administration, fosfomycin tromethamine is rapidly absorbed and converted to the free acid, fosfomycin. The absolute oral bioavailability under fasting conditions is 37% and is reduced to 30% under fed conditions. Following a single 3-gram oral dose, mean maximum serum concentrations were achieved within 2 hours or 4 hours on an empty stomach or with a high-fat meal, respectively.