VA Class:AM900
Fosfomycin tromethamine, a phosphonic acid derivative,1 is a synthetic urinary antibacterial agent.1
Fosfomycin tromethamine is used orally for the treatment of uncomplicated urinary tract infections (acute cystitis) in women caused by susceptible Escherichia coli or Enterococcus faecalis (formerly Streptococcus faecalis ).1, 2, 3, 4, 5, 7, 9, 143
Some clinicians state that oral fosfomycin (single 3-g dose) is one of several preferred anti-infectives for empiric treatment of uncomplicated cystitis in women.7, 143 Fosfomycin is considered a good choice for empiric treatment of such infections since the incidence of fosfomycin resistance among uropathogens (e.g., E. coli ) is low to date and the single-dose regimen is well tolerated and has not been associated with selection of drug-resistant bacteria or colonization/infection with multidrug-resistant strains.7, 9, 143 Although some clinical studies suggest that the single-dose fosfomycin regimen is less effective than some other short-course anti-infective regimens used for the treatment of uncomplicated cystitis,1 results of a meta-analysis of published, randomized, controlled trials indicated that clinical and microbiologic success rates reported with a single dose of fosfomycin were similar to success rates reported with comparator anti-infective regimens.9
Oral fosfomycin (single dose or multiple doses†) has been used for the treatment of urinary tract infections caused by multidrug-resistant bacteria and some clinicians suggest that the drug may be a viable option for treatment of such infections;8, 11, 32, 33, 34 however, additional study is needed to evaluate efficacy and optimal fosfomycin regimens for treatment of urinary tract infections caused by multidrug-resistant bacteria.8, 11, 33, 34
Oral fosfomycin tromethamine should not be used for the treatment of pyelonephritis or perinephric abscesses.1, 143 Some clinicians state that oral fosfomycin should be avoided if there is diagnostic uncertainty regarding cystitis versus early pyelonephritis because the drug does not achieve adequate concentrations in renal tissue.143 Such diagnostic uncertainly may exist if cystitis symptoms are accompanied by subjective fever (not verified at the time of examination) and/or vague flank pain or tenderness or if cystitis symptoms have been present for longer than 5-7 days.143
Evidence from several controlled, double-blind, comparative studies in patients with uncomplicated lower urinary tract infections (acute cystitis) suggests that a single 3-g oral dose of fosfomycin is as effective as a 7-day regimen of oral nitrofurantoin (100 mg twice daily), but less effective than a 7-day regimen of oral ciprofloxacin (250 mg twice daily) or a 10-day regimen of oral trimethoprim (160 mg twice daily given as co-trimoxazole).1, 6 These studies enrolled patients with signs and symptoms of acute cystitis of less than 4 days duration, no manifestations of upper urinary tract infection (e.g., flank pain, chills, fever), no history of recurrent urinary tract infections (20% of patients had a prior episode of acute cystitis within the preceding year), no known structural abnormalities, no clinical or laboratory evidence of hepatic dysfunction, and no known or suspected CNS disorders (e.g., epilepsy) or other factors that predispose to seizures.1 In patients receiving fosfomycin, nitrofurantoin, ciprofloxacin, or co-trimoxazole, the microbiologic eradication rate 5-11 days after treatment was 82, 76, 98, or 98%, respectively, while the eradication rate on days 12-21 was 77, 76, 98, or 98%, respectively;1 clinical success rate (resolution of symptoms) was 70, 77, 96, or 94%, respectively.1
Results of a meta-analysis of 27 published, randomized, controlled trials indicated that clinical and microbiologic success rates reported with a single-dose regimen of oral fosfomycin were similar to success rates reported with comparator anti-infective regimens.9 Trials included in the meta-analysis involved patients of any age with microbiologically confirmed or clinical suspicion of cystitis who were randomized to receive treatment with fosfomycin (single-dose regimen) or another anti-infective (e.g., 3 or 7 days of ciprofloxacin, 7 days of nitrofurantoin, 3 days of co-trimoxazole, single dose or 5 days of trimethoprim, 5 days of cephalexin, 5 days of cefuroxime axetil, 5-7 days of fixed combination of amoxicillin and clavulanic acid, 3-7 days of norfloxacin [no longer available in the US], 5-7 days of pipemidic acid [not available in the US]).9 The primary effectiveness outcome for the meta-analysis was clinical success, defined as complete resolution (cure) and/or incomplete resolution (improvement) of symptoms at the end of treatment;9 microbiologic success (eradication), defined as a negative urine culture at the end of treatment, was a secondary effectiveness outcome.9
In a limited, retrospective review of 41 hospitalized adults with urinary tract infections caused by multidrug-resistant bacteria (e.g., E. coli , Klebsiella pneumoniae , Pseudomonas aeruginosa ), fosfomycin treatment (single- or multiple-dose regimen†) was associated with a microbiologic cure rate of 59% and a microbiologic failure rate of 41% (relapse or reinfection within 30 days).11 The average number of fosfomycin doses per treatment course was 3.3 doses in the microbiologic cure group and 2.4 doses in the microbiologic failure group.11 Some patients in each group received concomitant therapy with another anti-infective (e.g., tigecycline, an aminoglycoside, colistin, daptomycin, imipenem, fixed combination of piperacillin and tazobactam).11 Resistance to fosfomycin developed in 3 patients who were kidney transplant recipients with ureteral stents and were infected with carbapenem-resistant K. pneumoniae .11 (See Description: Resistance.)
Fosfomycin has been used in a limited number of men for the treatment of chronic prostatitis† caused by multidrug-resistant Enterobacteriaceae (e.g., E. coli ).16, 19, 20 There is evidence that fosfomycin is distributed into prostatic tissue following oral administration of fosfomycin tromethamine18 and clinical and microbiologic cure have been reported following oral fosfomycin treatment (e.g., 3 g every 48-72 hours for 6 weeks, 3 g once daily for 12 weeks or longer) in some men with prostatitis caused by multidrug-resistant Enterobacteriaceae that failed to respond to other anti-infectives (e.g., ciprofloxacin, co-trimoxazole, meropenem).16, 20 Fosfomycin has been effective when administered IV† (parenteral dosage form not available in the US) for the treatment of prostatic infections caused by E. coli resistant to fluoroquinolones and co-trimoxazole.19 However, treatment failures also have been reported and further study is needed to evaluate efficacy and safety of oral fosfomycin for the treatment of chronic prostatitis and to identify optimal dosage and duration of fosfomycin treatment for such infections.18, 20
Fosfomycin has been used for perioperative prophylaxis in men undergoing transrectal biopsy of the prostate†37 and for perioperative prophylaxis in men undergoing transurethral resection of the prostate†.17, 18 Results of a retrospective study in a limited number of men undergoing transrectal ultrasound-guided biopsy of the prostate indicated that a single-dose regimen of oral fosfomycin (single 3-g dose) can be effective and may be more effective than fluoroquinolones for such prophylaxis.37 Additional study is needed to evaluate efficacy and safety and optimal timing of fosfomycin for perioperative prophylaxis in men undergoing transrectal biopsy of the prostate or transurethral resection of the prostate†.17, 18, 37
Fosfomycin tromethamine is administered orally.1 Although fosfomycin has been administered IV†19, 25, 29 as the disodium salt,29 a parenteral formulation of the drug is not commercially available in the US.29
Fosfomycin tromethamine for oral administration is available as granules for oral solution that must be dissolved in water prior to administration.1 The drug should not be ingested as dry granules.1
The oral solution should be prepared by pouring the entire contents of a single-dose packet (sachet) containing 3 g of fosfomycin into 90-120 mL (3-4 ounces) of water and stirring until the granules dissolve.1 The entire oral solution should be ingested immediately after preparation.1 Hot water should not be used to dissolve fosfomycin tromethamine granules.1
Although food decreases oral bioavailability of fosfomycin tromethamine, the manufacturer states that the drug may be administered without regard to food since the cumulative amount of fosfomycin excreted in urine is similar whether the drug is given with or without food.1 (See Pharmacokinetics.)
Dosage of fosfomycin tromethamine is expressed in terms of fosfomycin.1
Uncomplicated Urinary Tract Infections
For the treatment of uncomplicated urinary tract infections (acute cystitis) in women 18 years of age and older, the usual oral dosage of fosfomycin is 3 g given as a single dose.1
Patients should be instructed to contact their clinician if cystitis symptoms do not improve within 2-3 days.1
The manufacturer states that no more than a single dose of oral fosfomycin should be used to treat an episode of acute cystitis since repeated daily doses of the drug do not improve clinical success or microbiologic eradication rates and may increase the incidence of adverse effects.1
The manufacturer does not provide any specific dosage recommendations for patients with hepatic impairment.1
Although fosfomycin pharmacokinetics may be altered in patients with renal impairment,1, 5 the manufacturer states that dosage adjustments are not necessary in such patients.1, 6
Dosage adjustments are not usually necessary in geriatric patients; however, dosage should be selected with caution because of the greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy.1 (See Geriatric Use under Warnings/Precautions: Specific Populations, in Cautions.)
Fosfomycin tromethamine is contraindicated in patients with known hypersensitivity to the drug.1
Superinfection/Clostridium difficile-associated Diarrhea and Colitis (CDAD)
Treatment with anti-infectives alters normal colon flora and may permit overgrowth of Clostridium difficile .1, 12, 14, 15 C. difficile infection (CDI) and C. difficile -associated diarrhea and colitis (CDAD; also known as antibiotic-associated diarrhea and colitis or pseudomembranous colitis) have been reported with nearly all anti-infectives, including fosfomycin, and may range in severity from mild diarrhea to fatal colitis.1, 12, 14, 15 C. difficile produces toxins A and B which contribute to development of CDAD;1, 12 hypertoxin-producing strains of C. difficile are associated with increased morbidity and mortality since they may be refractory to anti-infectives and colectomy may be required.1
CDAD should be considered in the differential diagnosis of patients who develop diarrhea during or after anti-infective therapy.1, 12, 14, 15 Careful medical history is necessary since CDAD has been reported to occur as late as 2 months or longer after anti-infective therapy is discontinued.1
If CDAD is suspected or confirmed, anti-infective therapy not directed against C. difficile should be discontinued whenever possible.1, 12 Patients should be managed with appropriate supportive therapy (e.g., fluid and electrolyte management, protein supplementation), anti-infective therapy directed against C. difficile (e.g., metronidazole, vancomycin), and surgical evaluation as clinically indicated.1, 12, 14, 15
Anaphylaxis, rash, and angioedema have been reported in patients receiving fosfomycin;1 a causal relationship to the drug has not been established.1
Other Warnings and Precautions
Selection and Use of Anti-infectives
When selecting or modifying anti-infective therapy, results of culture and in vitro susceptibility testing should be used.1
Prior to and after completion of fosfomycin therapy, urine specimens should be cultured and in vitro susceptibility tests performed.1 If persistence or recurrence of bacteriuria occurs after fosfomycin treatment, other antibacterial agents should be used.1
There are no adequate and well-controlled studies using fosfomycin in pregnant women.1 Fosfomycin should be used during pregnancy only if clearly needed.1
It is not known whether fosfomycin is distributed into milk.1
Because of the potential for serious adverse reactions in nursing infants, a decision should be made to discontinue nursing or not administer fosfomycin, taking into account the importance of the drug to the woman.1
Safety and efficacy of fosfomycin have not been established in children 12 years of age or younger.1
Clinical studies of fosfomycin did not include sufficient numbers of patients 65 years of age or older to determine whether geriatric patients respond differently than younger patients.1 Although other clinical experience has not identified age-related differences in response or tolerance, dosage for geriatric patients should be selected with caution and the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy in this age group should be considered.1
Adverse effects reported in more than 1% of patients receiving oral fosfomycin in clinical studies include adverse GI effects (diarrhea, nausea, dyspepsia), headache, dizziness, asthenia, and vaginitis.1
Drugs that Increase GI Motility
Concomitant use of fosfomycin tromethamine with drugs that increase GI motility may decrease serum and urine concentrations of fosfomycin.1
Concomitant use of cimetidine and fosfomycin tromethamine does not affect fosfomycin pharmacokinetics.1
There is some in vitro evidence that fosfomycin and meropenem may be synergistic against Escherichia coli .27
Concomitant use of metoclopramide and fosfomycin tromethamine decreases serum concentrations and urinary excretion of fosfomycin.1
Fosfomycin tromethamine is rapidly absorbed following oral administration and converted to fosfomycin (the free acid).1
Following a single 3-g oral dose under fasting conditions, mean peak serum concentrations of fosfomycin were 26 mcg/mL and were attained within 2 hours.1
In a study in healthy women, high interindividual variability in pharmacokinetic parameters was reported following a single 3-g oral dose of fosfomycin.30
Administration of fosfomycin tromethamine with food decreased oral bioavailability of the drug.1 Absolute oral bioavailability is 37% under fasting conditions or 30% under fed conditions.1
Following a single 3-g oral dose given with a high-fat meal, mean peak serum concentrations of fosfomycin were 17.6 mcg/mL and were attained within 4 hours.1
The cumulative amount of fosfomycin excreted in urine is similar whether the drug is given with or without food.1
The mean apparent steady-state volume of distribution of fosfomycin following oral administration of fosfomycin tromethamine is 136 L.1
Fosfomycin is distributed to the kidneys,1 bladder wall,1 prostate,1, 17, 18 and seminal vesicles.1
Following a single oral dose of 50 mg/kg of fosfomycin in patients undergoing urologic surgery for bladder carcinoma, the mean concentration of the drug in the bladder (sample taken at a distance from the neoplastic site) was 18 mcg/g of tissue at 3 hours after the dose.1
In otherwise healthy men undergoing transurethral resection of the prostate for benign prostatic hyperplasia who received a single 3-g oral dose of fosfomycin for perioperative prophylaxis†, the mean overall fosfomycin concentration in prostate tissue was 6.5 mcg/g (range: 0.7-22.1 mcg/g) and potentially therapeutic concentrations of the drug were detectable in prostate tissue up to 17 hours following the dose.18
Fosfomycin crosses the placenta in animals and humans.1
It is not known whether fosfomycin is distributed into milk.1
Fosfomycin is not bound to plasma proteins.1
Fosfomycin tromethamine is converted in vivo to fosfomycin, the microbiologically active form of the drug.1
Following an oral dose of fosfomycin tromethamine, 38% of the dose is excreted unchanged in urine and 18% of the dose is excreted unchanged in feces.1
The mean total body clearance and mean renal clearance of fosfomycin are 16.9 and 6.3 L/hour, respectively, after an oral dose.1
Following a single 3-g oral dose of fosfomycin given under fasting conditions, mean fosfomycin concentrations in urine 2-4 hours after the dose were 706 mcg/mL;1 in samples collected 72-84 hours after the dose, mean concentrations in urine were 10 mcg/mL.1
Although administration of fosfomycin tromethamine with food decreases oral bioavailability and rate of urinary excretion, the cumulative amount of fosfomycin excreted in urine is similar whether the drug is given with or without food.1 Following a 3-g oral dose administered with a high-fat meal, mean fosfomycin concentrations in urine were 537 mcg/mL 6-8 hours after the dose.1
Fosfomycin urinary concentrations of 100 mcg/mL or greater have been maintained for approximately 26 hours in patients who received a single oral dose of fosfomycin tromethamine given with or without food.1
Fosfomycin is removed by hemodialysis.1, 26
The mean elimination half-life of fosfomycin is 5.7 hours.1
Renal impairment decreases elimination of fosfomycin and prolongs the half-life of the drug.1 In patients with varying degrees of renal impairment (creatinine clearances ranging from 54 to 7 mL/minute), the mean elimination half-life of fosfomycin increased from 11 to 50 hours and the percentage of the drug recovered in urine decreased from 32 to 11%.1
Based on limited data regarding 24-hour urinary drug concentrations, pharmacokinetics of fosfomycin in geriatric adults are similar to pharmacokinetics reported in younger adults.1
Fosfomycin, a phosphonic acid derivative,5, 143 is a synthetic antibacterial agent.1 The drug is commercially available for oral administration as fosfomycin tromethamine;1 potency is expressed in terms of fosfomycin.1 Each single-dose packet (sachet) of granules for oral solution contains 5.631 g of fosfomycin tromethamine (equivalent to 3 g of fosfomycin).1
Fosfomycin usually is bactericidal in urine when administered in therapeutic doses.1, 5 The antibacterial activity of the drug results from interference with bacterial cell wall synthesis by inhibiting the enzyme enolpyruvyl transferase, which catalyzes the formation of uridine diphosphate- N -acetylmuramic acid in the first step of bacterial cell wall synthesis.1, 4, 5 In addition, fosfomycin reduces adherence of bacteria to uroepithelial cells.1, 5
Fosfomycin is active in vitro against a broad spectrum of gram-negative and gram-positive aerobic bacteria commonly associated with urinary tract infections.1, 4, 5, 21, 23
The drug is active in vitro1, 21, 22, 24, 31, 35, 36 and in clinical infections1 against Escherichia coli . Although safety and efficacy of fosfomycin for the treatment of clinical infections caused by other gram-negative aerobic bacteria have not been established in adequate and well-controlled studies to date,1 the drug is active in vitro against Citrobacter diversus ,1 C. freundii ,1 Enterobacter aerogenes ,1, 21 Klebsiella oxytoca ,1, 21, 31 K. pneumoniae ,1, 21, 31 Proteus mirabilis ,1, 21 P. vulgaris ,1, 21 Serratia marcescens ,1 and Pseudomonas aeruginosa .21, 35 Fosfomycin has been active in vitro against Enterobacteriaceae resistant to fluoroquinolones and generally has activity against extended-spectrum β-lactamase (ESBL)-producing strains resistant to extended-spectrum cephalosporins.21, 24, 36
Fosfomycin is active in vitro1, 21 and in clinical infections1 against Enterococcus faecalis 1, 21 and has been active in vitro against some vancomycin-resistant E. faecalis .21 Fosfomycin also has in vitro activity against some other gram-positive cocci, including E. faecium ;1 however, safety and efficacy of the drug for the treatment of clinical infections caused by these gram-positive bacteria have not been established in adequate and well-controlled studies to date.1
E. coli resistant to fosfomycin have been produced in vitro27 and clinical isolates of E. coli ,21, 32 K. pneumoniae ,21 P. mirabilis ,21 and Ps. aeruginosa 21 resistant to fosfomycin have been reported rarely.
E. cloacae 21 and E. faecalis resistant to fosfomycin have been reported.21
Resistance to fosfomycin in Enterobacteriaceae usually is related to the presence of the fos A gene, which can be encoded either on a chromosome (e.g., K. pneumoniae , Ps. aeruginosa ) or on a plasmid (e.g., E. coli ).28
Cross-resistance does not usually occur between fosfomycin and other antibacterial agents (e.g., β-lactams, aminoglycosides).1
Advise patients that fosfomycin tromethamine can be taken with or without food.1
Importance of diluting the granules with water ( not hot water) just prior to administration.1
Importance of contacting a clinician if symptoms of the urinary tract infection do not improve within 2-3 days after treatment.1
Advise patients that diarrhea is a common problem caused by anti-infectives and usually ends when the drug is discontinued.1 Importance of contacting a clinician if watery and bloody stools (with or without stomach cramps and fever) occur during or as late as 2 months or longer after the last dose.1
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.1
Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1
Importance of informing patients of other important precautionary information.1 (See Cautions.)
Additional Information
Overview® (see Users Guide). For additional information on this drug until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
1. Allergan USA, Inc. Monurol® (fosfomycin tromethamine) powder prescribing information. Irvine, CA; 2018 May.
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143. Gupta K, Hooton TM, Naber KG et al. International clinical practice guidelines for the treatment of acute uncomplicated cystitis and pyelonephritis in women: A 2010 update by the Infectious Diseases Society of America and the European Society for Microbiology and Infectious Diseases. Clin Infect Dis . 2011; 52:e103-20. Updates may be available at IDSA website at www.idsociety.org. [PubMed 21292654]