SEARCH

SEARCH BY CITATION

Keywords:

  • Fosfomycin;
  • fosfomycin–trometamol;
  • urinary tract infections

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Chemical Structure
  5. Classifications
  6. Pharmacokinetics of Fosfomycin–Trometamol
  7. Mechanism of Action of FOM
  8. Antibacterial Activity
  9. Indications
  10. Adverse Effects
  11. Conclusion
  12. Transparency Declaration
  13. References

Clin Microbiol Infect 2012; 18: 4–7

Abstract

Fosfomycin is a broad-spectrum antibiotic discovered in Spain in 1969. It has bactericidal activity against a wide range of bacteria, including gram-negative micro-organisms and some gram-positive bacteria, such as staphylococci. Initially fosfomycin was administered parenterally and only to patients with severe infections. Today it is often dispensed as fosfomycin–trometamol, an oral formula recommended in the treatment of urinary tract infections. Fosfomycin–trometamol in a single dose is indicated for the treatment of women with uncomplicated urinary tract infections.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Chemical Structure
  5. Classifications
  6. Pharmacokinetics of Fosfomycin–Trometamol
  7. Mechanism of Action of FOM
  8. Antibacterial Activity
  9. Indications
  10. Adverse Effects
  11. Conclusion
  12. Transparency Declaration
  13. References

The increasing antimicrobial drug resistance of bacterial pathogens, together with the relative shortage of new antimicrobial agents, call for a new look at the therapeutic options. One of the alternative treatments for multidrug-resistant pathogens is fosfomycin.

Fosfomycin was first discovered in Spain in 1969 from cultures of the Streptomyces species and was originally named ‘fosfomycin’. It is currently available as a systemic antibiotic that has no structural relationship with other known classes of agents.

It has a broad antibacterial spectrum, targeting bacteria with mucopeptide synthesis by inhibiting phosphoenolpyruvate transferase, the first enzyme involved in the synthesis of peptidoglycan [1]. There is no cross-resistance, and fosfomycin can be administered in combination with a number of other antimicrobial agents.

Chemical Structure

  1. Top of page
  2. Abstract
  3. Introduction
  4. Chemical Structure
  5. Classifications
  6. Pharmacokinetics of Fosfomycin–Trometamol
  7. Mechanism of Action of FOM
  8. Antibacterial Activity
  9. Indications
  10. Adverse Effects
  11. Conclusion
  12. Transparency Declaration
  13. References

Fosfomycin is a relatively small hydrophilic agent with negligible serum protein binding. It is excreted unchanged in urine, achieving high concentrations for a prolonged period [2].

Fosfomycin distributes well into the tissues, achieving clinically relevant concentrations in sites such as serum, soft tissues, lung, bone, cerebrospinal fluid and heart valves.

Classifications

  1. Top of page
  2. Abstract
  3. Introduction
  4. Chemical Structure
  5. Classifications
  6. Pharmacokinetics of Fosfomycin–Trometamol
  7. Mechanism of Action of FOM
  8. Antibacterial Activity
  9. Indications
  10. Adverse Effects
  11. Conclusion
  12. Transparency Declaration
  13. References

Fosfomycin belongs to the class of phosphonic antibiotics: three phosphonic antibiotics in parenteral use are known: fosfomycin, fosmidomycin and alafosfalin, the last of which was abandoned. Initially, for many years fosfomycin–disodium was administered parenterally to patients with serious infections, including meningitis [3]. More recently, it has been produced in an oral form, fosfomycin–trometamol, which is a monobasic hydrosoluble fosfomycin salt used specifically in the treatment of urinary tract infections. With the exception of fosfomycin–trometamol salt the data on the other products is limited [1].

In some European countries, fosfomycin–disodium is occasionally administered for the treatment of patients with sepsis and soft-tissue infections [4].

Despite the fact that in most European countries fosfomycin–disodium has been used for many years, it has become available for clinical use only recently for example in Turkey. In the USA, the Food and Drug Administration has approved fosfomycin–trometamol only for the treatment of patients with uncomplicated cystitis [3].

The use of fosfomycin for treating multidrug-resistant bacterial infections and in the treatment of paediatric cancer patients with fever and neutropenia in combinations with other antibiotics has drawn attention to this agent [3].

Fosfomycin has a rapid bactericidal effect and a wide antibacterial spectrum including methicillin-resistant Staphylococcus aureus, vancomycin-resistant enterococci and a large number of gram-negative pathogens [5–7].

Fosfomycin has the smallest molecular mass (138 Da) of existing antibiotics, which ensures extensive diffusibility. It is reasonably soluble in water [1] and the drug substance is stable under normal storage conditions (2–3 years). Fosfomycin is also strongly polar and hence is a very soluble molecule. The product is unstable in an acidic medium and so has poor oral bioavailability in the form of the disodium salt, which is reserved for the parenteral route [1]. However, fosfomycin–trometamol is a hydrosoluble product, which allows oral administration. After absorption, fosfomycin–trometamol releases fosfomycin by hydrolysis. The molecular weight of fosfomycin–trometamol is 259.2 Da, and the product is presented in the form of a white crystalline powder.

Pharmacokinetics of Fosfomycin–Trometamol

  1. Top of page
  2. Abstract
  3. Introduction
  4. Chemical Structure
  5. Classifications
  6. Pharmacokinetics of Fosfomycin–Trometamol
  7. Mechanism of Action of FOM
  8. Antibacterial Activity
  9. Indications
  10. Adverse Effects
  11. Conclusion
  12. Transparency Declaration
  13. References

The concentrations in serum are higher when the compound is administered before food intake. Pharmacokinetic parameters indicate that absorption is significantly reduced after food intake. Fifty-eight per cent of the administered dose is found in the urine within 24 h [7–9].

Urinary concentrations are high and may exceed 2000 mg/L after administration of a single dose. Urinary levels remain high for a prolonged period (over 24 h) constituting an argument in favour of its use in the treatment of common urinary tract infections [10].

Mechanism of Action of FOM

  1. Top of page
  2. Abstract
  3. Introduction
  4. Chemical Structure
  5. Classifications
  6. Pharmacokinetics of Fosfomycin–Trometamol
  7. Mechanism of Action of FOM
  8. Antibacterial Activity
  9. Indications
  10. Adverse Effects
  11. Conclusion
  12. Transparency Declaration
  13. References

Fosfomycin inhibits bacterial cell wall biosynthesis by acting on the initial stages in the synthesis of peptidoglycan procedures [11].

Antibacterial Activity

  1. Top of page
  2. Abstract
  3. Introduction
  4. Chemical Structure
  5. Classifications
  6. Pharmacokinetics of Fosfomycin–Trometamol
  7. Mechanism of Action of FOM
  8. Antibacterial Activity
  9. Indications
  10. Adverse Effects
  11. Conclusion
  12. Transparency Declaration
  13. References

Fosfomycin is a broad-spectrum antibiotic, with moderate activity against numerous bacterial species. Its activity depends on its transportation into the bacterial cell by 1-α-glycerophosphate transport system and hexose monophosphate systems involving the presence of glucose-6-phosphate. For this reason the antibacterial activity of fosfomycin in vitro requires the addition of glucose-6-phosphate to the medium to determine MIC [1,12,13].

The antibacterial spectrum of fosfomycin includes staphylococci, Haemophilus sp. and most of the enteric gram-negative bacteria, but with a considerably higher MIC for Klebsiella sp., Enterobacter sp. and Serratia sp. Fosfomycin is moderately active against Pseudomonas aeruginosa with variable MICs ranging from 4 to >512 mg/L. Acinetobacter sp. is not susceptible to fosfomycin (MIC from 16 to 128 mg/L). Falagas et al. [6] reported 17 antimicrobial susceptibility studies, including 5057 clinical isolates of Enterobacteriaceae, 4448 of them were positive for extended spectrum beta-lacatamase (ESBL); 11 of the 17 studies reported that at least 90% of the isolates were susceptible to fosfomycin, using a MIC breakpoint of 64 mg/L or less, 1604 (96.8%) of 1657 Escherichia coli producing ESBL were susceptible to fosfomycin, and 608 (81.3%) of 748 Klebsiella pneumoniae isolates were susceptible to fosfomycin. Fosfomycin has a rapid bactericidal effect and a wide antibacterial spectrum, including methicillin-resistant Staphylococcus aureus, glycopeptide-susceptible and glycopeptide-resistant enterococci and a large number of gram-negative pathogens.

Peak plasma levels of 22–32 mg/L occur 2–2.5 h after a single oral dose of fosfomycin [14]. The drug is not bound to plasma proteins. It does not undergo metabolism in the body and is primarily excreted unchanged in the urine by glomerular filtration. Peak urinary concentrations occur within 4 h of dosing. After a single 3-g oral dose, urine fosfomycin levels >128 mg/L are maintained for at least 36–48 h. These levels are sufficient to inhibit most urinary pathogens. It has good penetration of the kidneys, bladder wall, prostate and seminal vesicles. Urinary fosfomycin levels are not compromised by mild degrees of renal insufficiency. Cerebrospinal fluid penetration is about 25%.

It has a long serum half-life and high concentrations in urine after oral administration, so fosfomycin–trometamol deserves further consideration for single-dose treatment of urinary tract infections [15–17]. Fosfomycin–trometamol has c. 40% oral bioavailability and is primarily excreted in the urine. The substance is active against gram-positive and gram-negative bacteria but shows decreased activity against Morganella morganii, Porphyromonas vulgaris, P. aeruginosa and Enterococcus faecium.

Despite its being in use for many years, fosfomycin–trometamol continues to have a low incidence of E. coli resistant strains (1–3%) worldwide. Fosfomycin–trometamol has retained its activity against quinolone-resistant strains of E. coli and cross-resistance with other classes of antibiotics is at present not a problem. It is less active, however, against coagulase-negative staphylococci. The effect of fosfomycin–trometamol on the intestinal flora after the intake of a single 3-g dose has not been well established. However, because of limited exposure the effect is probably minor.

Oteo et al. [18] showed in Spain a parallel increase in the use of fosfomycin in the community and resistance to fosfomycin in ESBL-producing E. coli.

We checked in unpublished data the susceptibility to fosfomycin–trometamol of 374 community-acquired uropathogens in northern Israel. Susceptibility was measured by disk sensitivity (200 mg/L). A bacterium was confirmed as sensitive when the inhibition zone was greater than 16 mm.

From 374 community isolates, 264 were E. coli, 44 were K. pneumoniae and 31 were Proteus sp.

Ninety-nine per cent of the E. coli, 82% of the Klebsiella sp. and 90% of the Proteus were sensitive to fosfomycin–trometamol. However, the sensitivity was found to be lower in Enterobacter sp. (50%) and M. morganii (17%). The 4.6% of Enterobacteriaceae that were ESBL-producers were sensitive to fosfomycin–trometamol .

The ARESC (Antimicrobial Resistance Epidemiological Survey on Cystitis) study group [19] collected clinical data from 4264 eligible patients. A positive urine culture was found in 74.6%, and E. coli was most frequent (76.7%) with the highest rate of susceptibility to fosfomycin (98.1%). In all countries, a susceptibility rate of E. coli above 90% was found only for fosfomycin, mecillinam and nitrofurantoin. The conclusions of the ARESC study were that fosfomycin, mecillinam and nitrofurantoin have preserved their in vitro activity in all countries investigated, representing good options for empiric therapy of female patients with uncomplicated cystitis. Falagas et al. [20] published a meta-analysis of 27 randomized controlled trials (eight were blind) on fosfomycin versus other antibiotics for the treatment of cystitis. The conclusion was that in an era with high drug resistance rates, even among community-acquired uropathogens, fosfomycin may provide a valuable alternative option for the treatment of cystitis in women (non-pregnant and pregnant) and in elderly and paediatric patients.

Indications

  1. Top of page
  2. Abstract
  3. Introduction
  4. Chemical Structure
  5. Classifications
  6. Pharmacokinetics of Fosfomycin–Trometamol
  7. Mechanism of Action of FOM
  8. Antibacterial Activity
  9. Indications
  10. Adverse Effects
  11. Conclusion
  12. Transparency Declaration
  13. References

De Cueto et al. [21] present more data regarding the susceptibility of fosfomycin–trometamol to ESBL-producing Enterobacteriaceae. They found that from 428 ESBL-producing isolates, 417 (87.4%) were susceptible to fosfomycin–trometamol (MIC ≤64 mg/mL). Fosfomycin shows maintained activity against ESBL-producing strains and does not present co-resistance with other antimicrobial groups [21].

Fosfomycin–trometamol in a 3-g single-dose can be used to treat women, including pregnant women, with uncomplicated urinary tract infections.

For empiric therapy of frequent uncomplicated cystitis fosfomycin–trometamol together with nitrofurantoin is recommended as first-line antibiotics [22].

It has been used successfully to treat recalcitrant prostatitis caused by a vancomycin-resistant enterococcus in a patient who wished to avoid intravenous therapy. In this instance, it was administered orally once every 3 days for 3 weeks, based on the fact that therapeutic levels of the drug are known to be present in the urine for at least 36–48 h after a single oral dose [14]. Fosfomycin–trometamol has not been approved in all European countries for use in pregnant women.

In males (prostatitis): we suggest an oral 3 g every 2–3 days for a total of 21 days, but this requires more clinical evaluation [14,23].

Adverse Effects

  1. Top of page
  2. Abstract
  3. Introduction
  4. Chemical Structure
  5. Classifications
  6. Pharmacokinetics of Fosfomycin–Trometamol
  7. Mechanism of Action of FOM
  8. Antibacterial Activity
  9. Indications
  10. Adverse Effects
  11. Conclusion
  12. Transparency Declaration
  13. References

Fosfomycin is very well tolerated and the adverse effects range is in 1–10% of patients [23].

Only minor, self-limiting adverse effects were observed: rash, headache, nausea, rhinitis, vaginitis, etc. In Japan, only one case of pseudomembranous colitis was noted in a post-marketing study involving 35 481 patients over a 6-year period [14].

Conclusion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Chemical Structure
  5. Classifications
  6. Pharmacokinetics of Fosfomycin–Trometamol
  7. Mechanism of Action of FOM
  8. Antibacterial Activity
  9. Indications
  10. Adverse Effects
  11. Conclusion
  12. Transparency Declaration
  13. References

Fosfomycin–trometamol could have an increased role as a therapeutic option against multidrug-resistant community-acquired pathogens, including those in pregnant women.

Further research is required to evaluate the potential utility of the agent as a systemic antibiotic.

A panel of international experts was convened by the Infectious Diseases Society of America (IDSA) in collaboration with the European Society for Microbiology and Infectious Diseases (ESCMID) to update the Clinical Practice Guidelines for the treatment of acute uncomplicated cystitis and pyelonephritis from 1999. They all agreed that the optimal treatment for acute uncomplicated cystitis is nitrofurantoin followed by trimethoprim–sulfamethoxazole. If the resistance rate is >20% fosfomycin is an appropriate choice for therapy but it appears to have inferior efficacy [19,23].

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Chemical Structure
  5. Classifications
  6. Pharmacokinetics of Fosfomycin–Trometamol
  7. Mechanism of Action of FOM
  8. Antibacterial Activity
  9. Indications
  10. Adverse Effects
  11. Conclusion
  12. Transparency Declaration
  13. References
  • 1
    Fosfomycin and derivatives by E. Bergogne-Berezin in antimicrobial agents. Bryskier A, ed. Washington, DC: ASM press, chapter 37 page 972.
  • 2
    Rousson N, Karageorgopoulos DE, Samonis G, Falagas ME. Clinical significance of the pharmacokinetic and pharmacodynamic characteristics of fosfomycin for the treatment of patients with systemic infections. Int J Antimicrob Agents 2009; 34: 506515.
  • 3
    Baylan O. Fosfomycin: past, present and future. Mikrobiyol Bul 2010; 44: 311321.
  • 4
    Popovic M, Steinort D, Pillai S, Joukhadar C. Fosfomycin: an old, new friend? Eur J Clin Microbiol Infect Dis 2010; 29: 127142.
  • 5
    Falagas ME, Kastoris AC, Kapaskelis AM, Karageorgopoulos DE. Fosfomycin for the treatment of multidrug-resistant, including extended-spectrum beta-lactamase producing, Enterobacteriaceae infections: a systematic review. Lancet Infect Dis 2010; 10: 4350.
  • 6
    Falagas ME, Kastoris AC, Karageorgopoulos DE, Rafailidis PI. Fosfomycin for the treatment of infections caused by multidrug-resistant non-fermenting Gram-negative bacilli: a systematic review of microbiological, animal and clinical studies. Int J Antimicrob Agents 2009; 34: 111120.
  • 7
    Falagas ME, Roussos N, Gkegkes ID, Rafailidis PI, Karageorgopoulos DE. Fosfomycin for the treatment of infections caused by Gram-positive cocci with advanced antimicrobial drug resistance: a review of microbiological, animal and clinical studies. Expert Opin Investig Drugs 2009; 18: 921944.
  • 8
    Bergogne-Berezin E, Muller-Serieys C, Joly-Guillou ML, Dronne N. Trometamol-fosfomycin (Monuril). Bioavailability and food-drug interactions. Eur Urol 1987; 13 (suppl): 6468.
  • 9
    Muller-Serieys C, Bergogne-Berezin E, Joly-Guillou ML. La fosfomycin-trometamol(Monuril): pharmacocinetique et interaction aliment-medicament. Pathol Biol 1987; 35: 753767.
  • 10
    Naber KG, Thyroff-Friesinger U. Fosfomycin-trometamol versus ofloxacin/co-trimoxazole as single dose therapy of acute uncomplicated urinary tract infection in females: a multicentre study. Infection 1990; 18 (suppl): S70S76.
  • 11
    Kahan FM, Kahan JS, Cassidy PJ, Kropp H. The mechanism of action of fosfomycin (phosphonomycin). Ann N Y Acad Sci 1974; 235: 364386.
  • 12
    Kanimoto Y, Greenwood D. Comparison of the response of Escherichia coli to fosfomycin and fosmidomycin. Eur J Clin Microbiol 1987; 6: 386391.
  • 13
    Greenwood D, Jones A, Eley A. Factors influencing the activity of the trometamol salt of fosfomycin. Eur J Clin Microbiol 1986; 5: 2934.
  • 14
    Shrestha NK, Tomford JW. Fosfomycin: a review. Infect Dis Clin Pract 2001; 10: 255260.
  • 15
    Kashanian J, Hakimian P, Blute M Jr et al. Nitrofurantoin: the return of an old friend in the wake of growing resistance. BJU Int 2008; 102: 16341637.
  • 16
    Mazzulli T, Skulnick M, Small G et al. Susceptibility of community Gram-negative urinary tract isolates to mecillinam and other oral agents. Can J Infect Dis 2001; 12: 289292.
  • 17
    Williams GJ, Wei L, Lee A, Craig JC. Long-term antibiotics for preventing recurrent urinary tract infection in children. Cochrane Database Syst Rev 2006; 3: CD001534.
  • 18
    Oteo J, Bautista V, Lara N et al. Parallel increase in community use of fosfomycin and resistance to fosfomycin in extended-spectrum beta-lactamase (ESBL) -producing Escherichia coli. J Antimicrob Chemother 2010; 65: 24592463.
  • 19
    Naber GK, Schaeffer AJ, Heyns CF et al. Urogenital infections. Ed. 2010. European Association of Urology. – International Consultation on Urological Diseases.
  • 20
    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: 18621877.
  • 21
    de Cueto M, Hernandez JR, Lopez-Cerero L et al. Activity of fosfomycin against extended-spectrum beta-lactamase producing Escherichia coli and Klebsiella pneumoniae. Enferm Infecc Microbiol Clin 2006; 24: 613616.
  • 22
    Wagenlehner FM, Schmiemann G, Hoyme U et al. National S3 guideline on uncomplicated urinary tract infection: recommendations for treatment and management of uncomplicated community-acquired bacterial urinary tract infections in adult patients. Urologe A 2011; 50: 153169.
  • 23
    UpToDate: Fosfomycin Drug Information. 2011. Available at: http://www.uptodate.com.contents.fosfomycin-drug-information (last accessed 12 June 2011).