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Fosfomycin Tromethamine

Class: Urinary Anti-infectives
VA Class: AM900
Chemical Name: (1R,2S)-(1,2-Epoxypropyl)phosphonic acid, compound with 2-amino-2-(hydroxymethyl)-1,3-propanediol (1:1)
Molecular Formula: C3H7O4P•C4H11N O13
CAS Number: 78964-85-9
Brands: Monurol

Medically reviewed on Dec 17, 2018

Introduction

Antibacterial; phosphonic acid derivative.1

Uses for Fosfomycin Tromethamine

Urinary Tract Infections (UTIs)

Treatment of uncomplicated UTIs (acute cystitis) in women caused by susceptible Escherichia coli or Enterococcus faecalis (formerly Streptococcus faecalis).1 2 3 4 5 7 9 143

Oral fosfomycin (single 3-g dose) is one of several preferred anti-infectives for empiric treatment of uncomplicated cystitis in women.7 143 Considered a good choice for such infections since 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

Has been used (single dose or multiple doses) for treatment of UTIs caused by multidrug-resistant bacteria and some clinicians suggest it may be a viable option for treatment of such infections;8 11 32 33 34 however, additional study needed.8 11 33 34

Do not use for treatment of pyelonephritis or perinephric abscesses.1 143 Avoid if diagnostic uncertainty exists regarding cystitis versus early pyelonephritis (e.g., cystitis symptoms accompanied by subjective fever [not verified at time of examination] and/or vague flank pain or tenderness, cystitis symptoms present for >5–7 days).143

Prostatitis

Has been effective when used in a limited number of men for treatment of chronic prostatitis caused by multidrug-resistant Enterobacteriaceae (e.g., E. coli).16 19 20 However, treatment failures also reported and further study needed to evaluate efficacy and safety of oral fosfomycin for treatment of chronic prostatitis and to identify optimal dosage and duration of fosfomycin treatment for such infections.18 20

Perioperative Prophylaxis

Has been effective when used for perioperative prophylaxis in men undergoing transrectal biopsy of the prostate.37

Has been effective when used for perioperative prophylaxis in men undergoing transurethral resection of the prostate for benign prostatic hyperplasia.17 18

Additional study needed to evaluate efficacy and safety and optimal timing for perioperative prophylaxis in men undergoing transrectal biopsy of the prostate or transurethral resection of the prostate.17 18 37

Fosfomycin Tromethamine Dosage and Administration

Administration

Administer orally as fosfomycin tromethamine.1

Has been administered IV19 25 29 as disodium salt;29 parenteral formulation not available in US.29

Oral Administration

Granules for oral solution must be dissolved in water prior to administration;1 do not ingest as dry granules.1

Prepare oral solution by adding entire contents of single-dose packet (sachet) containing 3 g of the drug to 90–120 mL (3–4 ounces) of water;1 do not use hot water.1 After stirring to dissolve granules, immediately ingest entire oral solution.1

May be taken with or without food.1

Dosage

Available as fosfomycin tromethamine;1 dosage expressed in terms of fosfomycin.1

Adults

Urinary Tract Infections (UTIs)
Uncomplicated UTIs
Oral

Acute cystitis in women ≥18 years of age: 3 g as a single dose.1

Contact clinician if cystitis symptoms do not improve within 2–3 days.1

Do not give additional doses;1 repeated doses do not improve clinical success or microbiologic eradication rates and may increase incidence of adverse effects.1

Prescribing Limits

Adults

Uncomplicated UTIs
Oral

Acute cystitis in women: Single dose.1

Special Populations

Hepatic Impairment

No specific dosage recommendations.1

Renal Impairment

Dosage adjustment not necessary.6 (See Pharmacokinetics.)

Geriatric Patients

Dosage adjustment not necessary.1 Select dosage with caution because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.1 (See Geriatric Use under Cautions.)

Cautions for Fosfomycin Tromethamine

Contraindications

  • Known hypersensitivity to fosfomycin.1

Warnings/Precautions

Warnings

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) 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

Consider CDAD if diarrhea develops during or after anti-infective treatment and manage accordingly.1 12 14 15 Obtain careful medical history since CDAD may occur as late as ≥2 months after anti-infective therapy is discontinued.1

If CDAD is suspected or confirmed, anti-infectives not directed against C. difficile should be discontinued.1 Manage moderate to severe cases with fluid, electrolyte, and protein supplementation, anti-infective therapy active against C. difficile (e.g., oral metronidazole or vancomycin), and surgical evaluation when clinically indicated.1 12 14 15

Sensitivity Reactions

Hypersensitivity Reactions

Anaphylaxis, rash, and angioedema reported;1 causal relationship to the drug not established.1

Other Warnings and Precautions

Selection and Use of Anti-infectives

Use results of culture and in vitro susceptibility testing when selecting or modifying anti-infective therapy.1

Obtain urine specimens for culture and in vitro susceptibility testing before and after completion of therapy.1

If persistence or recurrence of bacteriuria occurs after fosfomycin treatment, use other antibacterial agents.1

Specific Populations

Pregnancy

No adequate and well-controlled studies in pregnant women;1 use during pregnancy only if clearly needed.1

Lactation

Not known whether distributed into milk.1

Because of potential for serious adverse reactions in nursing infants, discontinue nursing or do not administer drug, taking into account importance of the drug to the woman.1

Pediatric Use

Safety and efficacy not established in children ≤12 years of age.1

Geriatric Use

Insufficient experience in those ≥65 years of age to determine whether they respond differently than younger adults.1 No evidence of substantial differences in safety and efficacy relative to younger adults.1

Although dosage adjustment not usually necessary, select dosage with caution because of age-related decreases in hepatic, renal, and/or cardiac function and potential for concomitant disease and drug therapy.1

Common Adverse Effects

Diarrhea, nausea, dyspepsia, headache, dizziness, asthenia, vaginitis.1

Interactions for Fosfomycin Tromethamine

Drugs that Increase GI Motility

May decrease serum and urine concentrations of fosfomycin.1

Specific Drugs

Drug

Interaction

Cimetidine

Pharmacokinetics of fosfomycin not affected1

Meropenem

In vitro evidence of synergistic antibacterial activity against E. coli27

Metoclopramide

Decreased serum concentrations and decreased urinary excretion of fosfomycin1

Fosfomycin Tromethamine Pharmacokinetics

Absorption

Bioavailability

Fosfomycin tromethamine is rapidly absorbed following oral administration and converted to fosfomycin (the free acid).1

Following single 3-g oral dose of fosfomycin under fasting conditions, peak serum concentrations of 26 mcg/mL were attained within 2 hours.1

High interindividual variability in pharmacokinetics reported in healthy women following single 3-g oral dose.30

Food

Food decreases oral bioavailability;1 bioavailability is 37% or 30% under fasting or fed conditions, respectively.1

Cumulative amount of drug excreted in urine is similar whether given with or without food.1

Distribution

Extent

Distributed to kidneys,1 bladder wall,1 prostate,1 17 18 and seminal vesicles.1

Crosses placenta in animals and humans.1

Not known whether distributed into milk.1

Plasma Protein Binding

Not bound to plasma proteins.1

Elimination

Metabolism

Converted in vivo to fosfomycin, the microbiologically active form of the drug.1

Elimination Route

Eliminated as unchanged fosfomycin in urine (38% of an oral dose) and feces (18% of an oral dose).1

Following 3-g oral dose given with a high-fat meal, mean fosfomycin concentrations in urine were 537 mcg/mL 6–8 hours after the dose.1

Fosfomycin urinary concentrations ≥100 mcg/mL have been maintained for approximately 26 hours in patients who received a single oral dose of fosfomycin with or without food.1

Removed by hemodialysis.1 26

Half-life

5.7 hours.1

Special Populations

Renal impairment: Decreased elimination and prolonged half-life.1 Half-life increased from 11 to 50 hours in patients with varying degrees of renal impairment (Clcr ranging from 54 to 7 mL/minute).1

Geriatric adults: Pharmacokinetics similar to that reported in younger adults (based on 24-hour urinary drug concentrations).1

Stability

Storage

Oral

Powder

25°C (may be exposed to 15–30°C).1

Actions and Spectrum

  • Phosphonic acid derivative,5 143 synthetic antibacterial agent.1

  • Usually bactericidal in urine when administered in therapeutic doses.1 5

  • Antibacterial activity 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 Also reduces adherence of bacteria to uroepithelial cells.1 5

  • Active in vitro against a broad spectrum of gram-negative and gram-positive bacteria commonly associated with uncomplicated UTIs.1 4 5 21 23

  • 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

  • Gram-negative bacteria: Active in vitro1 21 22 24 31 35 36 and in vivo in clinical infections1 against Escherichia coli.1 21 22 24 31 35 36 Although clinical importance unknown, has in vitro activity 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

  • Gram-positive bacteria: Active in vitro1 21 and in vivo in clinical infections1 against Enterococcus faecalis.1 21 Has been active in vitro against some vancomycin-resistant E. faecalis.21 Although clinical importance unknown, has in vitro activity against some other gram-positive cocci, including E. faecium.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. aeruginosa21 resistant to fosfomycin reported rarely. Fosfomycin-resistant E. cloacae21 and E. faecalis reported.21

  • Fosfomycin resistance in Enterobacteriaceae usually related to presence of the fosA gene, which can be chromosome-mediated (e.g., K. pneumoniae, Ps. aeruginosa) or plasmid-mediated (e.g., E. coli).28

  • Cross-resistance does not usually occur between fosfomycin and other antibacterials (e.g., β-lactams, aminoglycosides).1

Advice to Patients

  • Advise patients that fosfomycin may 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 UTI symptoms 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 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.)

Preparations

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.

Fosfomycin Tromethamine

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Granules, for solution

3 g (of fosfomycin) per packet

Monurol

Allergan

AHFS DI Essentials™. © Copyright 2019, Selected Revisions December 17, 2018. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

1. Allergan USA, Inc. Monurol (fosfomycin tromethamine) powder prescribing information. St. Louis, MO; 2018 May.

2. Elhanan G, Tabenkin H, Yahalom R et al. Single-dose fosfomycin trometamol versus 5-day cephalexin regimen for treatment of uncomplicated lower urinary tract infections in women. Antimicrob Agents Chemother. 1994; 38:2612-4. http://www.ncbi.nlm.nih.gov/pubmed/7872756?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=188250&blobtype=pdf

3. Selvaggi FP, Ditonno P, Traficante A et al. Fosfomycin trometamol (Monuril) versus norfloxacin in single dose for adult female uncomplicated UTIs: multicenter randomized, double-blind study. Chemotherapy. 1990; 36(Suppl 1):31-3. http://www.ncbi.nlm.nih.gov/pubmed/2085986?dopt=AbstractPlus

4. Reeves DS. Fosfomycin trometamol. J Antimicrob Chemother. 1994; 34:853-8. http://www.ncbi.nlm.nih.gov/pubmed/7730229?dopt=AbstractPlus

5. Patel SS, Balfour JA, Bryson HM. Fosfomycin tromethamine: a review of its antibacterial activity, pharmacokinetic properties and therapeutic efficacy as a single-dose oral treatment for acute uncomplicated lower urinary tract infections. Drugs. 1997; 53:637-56. http://www.ncbi.nlm.nih.gov/pubmed/9098664?dopt=AbstractPlus

6. Forest Pharmaceuticals, Inc, St. Louis, MO: Personal communication.

7. Grigoryan L, Trautner BW, Gupta K. Diagnosis and management of urinary tract infections in the outpatient setting: a review. JAMA. 2014 Oct 22-29; 312:1677-84. http://www.ncbi.nlm.nih.gov/pubmed/25335150?dopt=AbstractPlus

8. Walker E, Lyman A, Gupta K et al. Clinical Management of an Increasing Threat: Outpatient Urinary Tract Infections Due to Multidrug-Resistant Uropathogens. Clin Infect Dis. 2016; 63:960-5. http://www.ncbi.nlm.nih.gov/pubmed/27313263?dopt=AbstractPlus

9. Falagas ME, Vouloumanou EK, Togias AG et al. Fosfomycin versus other antibiotics for the treatment of cystitis: a meta-analysis of randomized controlled trials. J Antimicrob Chemother. 2010; 65:1862-77. http://www.ncbi.nlm.nih.gov/pubmed/20587612?dopt=AbstractPlus

10. Qiao LD, Zheng B, Chen S et al. Evaluation of three-dose fosfomycin tromethamine in the treatment of patients with urinary tract infections: an uncontrolled, open-label, multicentre study. BMJ Open. 2013; 3:e004157. http://www.ncbi.nlm.nih.gov/pubmed/24309172?dopt=AbstractPlus

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14. Fekety R for the American College of Gastroenterology Practice Parameters Committee. Guidelines for the diagnosis and management of Clostridium difficile-associated diarrhea and colitis. Am J Gastroenterol. 1997; 92:739-50. http://www.ncbi.nlm.nih.gov/pubmed/9149180?dopt=AbstractPlus

15. American Society of Health-System Pharmacists Commission on Therapeutics. ASHP therapeutic position statement on the preferential use of metronidazole for the treatment of Clostridium difficile-associated disease. Am J Health-Syst Pharm. 1998; 55:1407-11. http://www.ncbi.nlm.nih.gov/pubmed/9659970?dopt=AbstractPlus

16. Grayson ML, Macesic N, Trevillyan J et al. Fosfomycin for Treatment of Prostatitis: New Tricks for Old Dogs. Clin Infect Dis. 2015; 61:1141-3. http://www.ncbi.nlm.nih.gov/pubmed/26063723?dopt=AbstractPlus

17. Rhodes NJ, Gardiner BJ, Neely MN et al. Optimal timing of oral fosfomycin administration for pre-prostate biopsy prophylaxis. J Antimicrob Chemother. 2015; 70:2068-73. http://www.ncbi.nlm.nih.gov/pubmed/25802286?dopt=AbstractPlus

18. Gardiner BJ, Mahony AA, Ellis AG et al. Is fosfomycin a potential treatment alternative for multidrug-resistant gram-negative prostatitis?. Clin Infect Dis. 2014; 58:e101-5. http://www.ncbi.nlm.nih.gov/pubmed/24170195?dopt=AbstractPlus

19. Hagiya H, Ninagawa M, Hasegawa K et al. Fosfomycin for the treatment of prostate infection. Intern Med. 2014; 53:2643-6. http://www.ncbi.nlm.nih.gov/pubmed/25400191?dopt=AbstractPlus

20. Los-Arcos I, Pigrau C, Rodríguez-Pardo D et al. Long-Term Fosfomycin-Tromethamine Oral Therapy for Difficult-To-Treat Chronic Bacterial Prostatitis. Antimicrob Agents Chemother. 2015; 60:1854-8. http://www.ncbi.nlm.nih.gov/pubmed/26666924?dopt=AbstractPlus

21. Keepers TR, Gomez M, Celeri C et al. Fosfomycin and Comparator Activity Against Select Enterobacteriaceae, Pseudomonas, and Enterococcus Urinary Tract Infection Isolates from the United States in 2012. Infect Dis Ther. 2017; 6:233-243. http://www.ncbi.nlm.nih.gov/pubmed/28285420?dopt=AbstractPlus

22. Johnson JR, Drawz SM, Porter S et al. Susceptibility to alternative oral antimicrobial agents in relation to sequence type ST131 status and Coresistance phenotype among recent Escherichia coli isolates from U.S. veterans. Antimicrob Agents Chemother. 2013; 57:4856-60. http://www.ncbi.nlm.nih.gov/pubmed/23877695?dopt=AbstractPlus

23. Garau J. Other antimicrobials of interest in the era of extended-spectrum beta-lactamases: fosfomycin, nitrofurantoin and tigecycline. Clin Microbiol Infect. 2008; 14 Suppl 1:198-202. http://www.ncbi.nlm.nih.gov/pubmed/18154548?dopt=AbstractPlus

24. Sardar A, Basireddy SR, Navaz A et al. Comparative Evaluation of Fosfomycin Activity with other Antimicrobial Agents against E.coli Isolates from Urinary Tract Infections. J Clin Diagn Res. 2017; 11:DC26-DC29. http://www.ncbi.nlm.nih.gov/pubmed/28384863?dopt=AbstractPlus

25. Parker SL, Frantzeskaki F, Wallis SC et al. Population Pharmacokinetics of Fosfomycin in Critically Ill Patients. Antimicrob Agents Chemother. 2015; 59:6471-6. http://www.ncbi.nlm.nih.gov/pubmed/26239990?dopt=AbstractPlus

26. Schmidt JJ, Bode-Böger SM, Wilhelmi M et al. Pharmacokinetics and total removal of fosfomycin in two patients undergoing intermittent haemodialysis and extended dialysis: prescription needs to avoid under-dosing. J Antimicrob Chemother. 2016; 71:2673-4. http://www.ncbi.nlm.nih.gov/pubmed/27272722?dopt=AbstractPlus

27. Docobo-Pérez F, Drusano GL, Johnson A et al. Pharmacodynamics of fosfomycin: insights into clinical use for antimicrobial resistance. Antimicrob Agents Chemother. 2015; 59:5602-10. http://www.ncbi.nlm.nih.gov/pubmed/26124169?dopt=AbstractPlus

28. Klontz EH, Tomich AD, Günther S et al. Structure and dynamics of FosA-mediated fosfomycin resistance in Klebsiella pneumoniae and Escherichia coli. Antimicrob Agents Chemother. 2017; 61:1-13. http://www.ncbi.nlm.nih.gov/pubmed/28874374?dopt=AbstractPlus

29. Wenzler E, Ellis-Grosse EJ, Rodvold KA. Pharmacokinetics, Safety, and Tolerability of Single-Dose Intravenous (ZTI-01) and Oral Fosfomycin in Healthy Volunteers. Antimicrob Agents Chemother. 2017; 61 http://www.ncbi.nlm.nih.gov/pubmed/28630194?dopt=AbstractPlus

30. Wijma RA, Koch BCP, van Gelder T et al. High interindividual variability in urinary fosfomycin concentrations in healthy female volunteers. Clin Microbiol Infect. 2017; http://www.ncbi.nlm.nih.gov/pubmed/28867662?dopt=AbstractPlus

31. Mischnik A, Baumert P, Hamprecht A et al. In vitro susceptibility to 19 agents other than β-lactams among third-generation cephalosporin-resistant Enterobacteriaceae recovered on hospital admission. J Antimicrob Chemother. 2017; 72:1359-1363. http://www.ncbi.nlm.nih.gov/pubmed/28108677?dopt=AbstractPlus

32. Senol S, Tasbakan M, Pullukcu H et al. Carbapenem versus fosfomycin tromethanol in the treatment of extended-spectrum beta-lactamase-producing Escherichia coli-related complicated lower urinary tract infection. J Chemother. 2010; 22:355-7. http://www.ncbi.nlm.nih.gov/pubmed/21123160?dopt=AbstractPlus

33. Pullukcu H, Tasbakan M, Sipahi OR et al. Fosfomycin in the treatment of extended spectrum beta-lactamase-producing Escherichia coli-related lower urinary tract infections. Int J Antimicrob Agents. 2007; 29:62-5. http://www.ncbi.nlm.nih.gov/pubmed/17189097?dopt=AbstractPlus

34. Giancola SE, Mahoney MV, Hogan MD et al. Assessment of Fosfomycin for Complicated or Multidrug-Resistant Urinary Tract Infections: Patient Characteristics and Outcomes. Chemotherapy. 2017; 62:100-104. http://www.ncbi.nlm.nih.gov/pubmed/27788499?dopt=AbstractPlus

35. Hirsch EB, Raux BR, Zucchi PC et al. Activity of fosfomycin and comparison of several susceptibility testing methods against contemporary urine isolates. Int J Antimicrob Agents. 2015; 46:642-7. http://www.ncbi.nlm.nih.gov/pubmed/26498988?dopt=AbstractPlus

36. Hirsch EB, Zucchi PC, Chen A et al. Susceptibility of Multidrug-Resistant Gram-Negative Urine Isolates to Oral Antibiotics. Antimicrob Agents Chemother. 2016; 60:3138-40. http://www.ncbi.nlm.nih.gov/pubmed/26883704?dopt=AbstractPlus

37. Ongün S, Aslan G, Avkan-Oguz V. The effectiveness of single-dose fosfomycin as antimicrobial prophylaxis for patients undergoing transrectal ultrasound-guided biopsy of the prostate. Urol Int. 2012; 89:439-44. http://www.ncbi.nlm.nih.gov/pubmed/23006631?dopt=AbstractPlus

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. http://www.ncbi.nlm.nih.gov/pubmed/21292654?dopt=AbstractPlus

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