Fosfomycin - Department of Microbiology ( Protected ) Antimicrobial Prescribing Guideline

Publication: 10/08/2015  --
Last review: 25/07/2018  
Next review: 25/07/2021  
Clinical Guideline
CURRENT 
ID: 4302 
Supported by: Improving Antimicrobial Prescribing Group
Approved By: Drug and Therapeutics Committee 
Copyright© Leeds Teaching Hospitals NHS Trust 2018  

 

This Clinical Guideline is intended for use by healthcare professionals within Leeds unless otherwise stated.
For healthcare professionals in other trusts, please ensure that you consult relevant local and national guidance.

Department of Microbiology (Protected) Antimicrobial Prescribing Guidelines

Fosfomycin

Drug information

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Introduction

Fosfomycin is a phosphonic acid derivative, with an extremely low molecular weight, and shows almost no binding to proteins. Fosfomycin is a unique antibiotic that is chemically unrelated to any other known antibacterial agent.

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Antimicrobial activity

Fosfomycin exerts a bactericidal effect on proliferating pathogens by preventing the enzymatic synthesis on the bactericidal cell wall. It inhibits the first stage of intracellular bacterial cell wall synthesis by blocking peptidoglycan synthesis. Fosfomycin has a broad spectrum of activity against a wide range of Gram-positive and Gram-negative bacteria.

Commonly susceptible species

Aerobic Gram-positive microorganisms

Staphylococcus aureus

Streptococcus pyogenes

Streptococcus pneumonia

Aerobic Gram-negative microorganisms

Citrobacter spp.

Edwardsiella spp.

Enterobacter cancerogenus

Escherichia coli

Haemophilus influenza

Klebsiella oxytoca

Neisseria spp

Proteus mirabilis

Proteus penneri

Providencia rettgeri

Anaerobic microorganisms

Peptococcus spp.

Peptostreptococcus spp

 

Species in which acquired resistance may be a problem

Gram-positive microorganisms

Enterococcus faecalis

Staphylococcus epidermidis

Gram-negative microorganisms

Enterobacter cloacae

Klebsiella pneumonia

Proteus inconstas

Pseudomonas aeruginosa

Serratia marcescens

Inherently resistant species

Gram-negative microorganisms

Morganella morganii

Anaerobic microorganisms

Bacteroides spp.

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Dose/Routes of administration

Fosfomycin is available in both oral and intravenous (IV) formulation.
Oral Formulation

Indication

Crcl ≥10 mL/min

Crcl <10mL/min

Uncomplicated lower urinary-tract infections

Adult female

3g oral x 1dose

Inadequate concentrations may be reached in the urine.
Do not use.

Adult male

3g oral repeated after 3 days  (Day 0,3)

Complicated Lower urinary-tract infections:

3g oral every 2 days for 4 doses (Day 0,2,4,6)

Catheter associated urinary-tract infection

3g oral repeated after 3 days (Day 0,3)

The contents of ONE sachet should be taken in half a glass of water as a single dose on an empty stomach (at least two -three hours before or after food), preferably before bedtime and after emptying the bladder.

Intravenous Formulation

The daily dose of IV Fosfomycin is determined based on indication, severity, site of infection, susceptibility of the pathogen(s) and the estimated creatinine clearance.
Some doses for more common indications are provided below. These apply to adults and adolescents aged 12 and older and weighing more than 40kg with a creatinine clearance of more than 80mL/min. The specific dose of fosfomycin required may depend on the bacteria causing the infection. Microbiology should be contacted to discuss what dose to give.    

Indication

Daily dose

Acute osteomyelitis

12-24ga in 2-3 divided dose

Complicated urinary tract infection

12-16gb in 2-3 divided dose

Nosocomial lower respiratory tract infection

12-24ga in 2-3 divided dose

Bacterial meningitis

16-24ga in 3-4 divided dose

Individual doses must not exceed 8g

  1. The high-dose regimen in 3 divided doses should be used in severe infections expected or known to be caused by less susceptible bacteria.
  2. There are limited safety data in particular for doses in excess of 16g/day. Special caution is advised when such doses are prescribed.

Dose in cystic fibrosis
Fosfomycin is also used to treat Pseudomonas aeruginosa infection in patients with cystic fibrosis unable to tolerate standard treatment.
The standard dose for adult cystic fibrosis patients is 4g 6 hourly

Indication

Daily dose

Pseudomonas aeruginosa infection in patients with cystic fibrosis

4g 6 hourly

Dose in renal impairment

No dosage adjustments are required when given orally for patients with a creatinine clearance greater than 10ml/min. It is contra-indicated in those with a creatinine clearance <10ml/min.

For those receiving IV fosfomycin, the dose recommendations for patients with renal impairment are based on pharmacokinetic modelling and limited clinical data. It is unclear if dose reductions are necessary for patients with an estimated creatinine clearance between 40-80 mL/min. Caution should be exercised in these cases.

Dose should be titrated base on creatinine clearance values using the Cockcroft and Gault formula.
A loading dose should be given to patients with renal impairment. This dose is an increase by 100% (i.e. double the dose) of the calculated maintenance dose, but must not exceed 8 g.

CLCR patient

Daily dosage recommended a

40 mL/min

70% (in 2- 3 divided doses)

30 mL/min

60% (in 2- 3 divided doses)

20 mL/min

40% (in 2-3 divided doses)

10 mL/min

20% (in 1-2 divided doses)

a The dose is expressed as a proportion of the dose that would have been considered appropriate if the patient's renal function were normal
Worked examples based on a patient requiring a daily dose of 20g:

CLCR patient

Daily dosage recommended a

Actual daily dose

Loading doseb

40 mL/min

70% (in 2- 3 divided doses)

14g given as 7g 12-hourly

8g

30 mL/min

60% (in 2- 3 divided doses)

12g given as 4g 8-hourly

8g

20 mL/min

40% (in 2-3 divided doses)

8g given as 4g 12-hourly

8g

10 mL/min

20% (in 1-2 divided doses)

4g given as 2g 12-hourly

4g

a The dose is expressed as a proportion of the dose that would have been considered appropriate if the patient's renal function were normal
b The loading dose should not exceed 8g

Dose in renal replacement therapy
Patient undergoing chronic intermittent dialysis (every 48 hours) should receive 2 g of IV fosfomycin at the end of each dialysis session.

During continuous veno-venous hemofiltration (post-dilution CVVHF), fosfomycin is effectively eliminated. Patients undergoing post-dilution CVVHF will not require any dose adjustment.

No clinical data exist for intravenous fosfomycin in patients undergoing pre-dilution CVVHF or other forms of renal replacement therapy.

Dose in obesity
No data available.

Dose in liver failure
There are no data indicating that dose adjustment is necessary in patients with hepatic impairment.

Paediatric doses (Intravenous Formulation)
Neonates, infants and children < 12 years of age (<40 kg)
The dosage of IV Fosfomycin in children should be based on age and body weight (BW):

Age/weight

Daily dose

Premature neonates
(age a < 40 weeks)

100 mg/kg BW
in 2 divided doses

Neonates
(age a 40-44 weeks)

200 mg/kg BW
in 3 divided doses

Infants 1-12 months
(up to 10 kg BW)

200-300 b mg/kg BW
in 3 divided doses

Infants and children aged 1-12 years
(10-40 kg BW)

200-400 b mg/kg BW
in 3-4 divided doses

a Sum of gestational and postnatal age.
b The high-dose regimen may be considered for severe infections and or serious infections (such as meningitis), in particular when known or suspected to be caused by organisms with moderate susceptibility.

No dose recommendations can be made for children with renal impairment.

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Therapeutic Drug Monitoring (checking levels)

Clinical experience has identified hypernatraemia can result from fosfomycin treatment when administered intravenously. A 4 g intravenous dose of fosfomycin contains 1.28 g sodium. Laboratory monitoring for hypernatraemia should be considered both during and after treatment.

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Pharmacokinetics

Pharmacokinetics
A single intravenous infusion of 4 g and 8 g of fosfomycin in young healthy males resulted in a maximum serum concentrations (Cmax) of approx. 200 and 400 micrograms/mL, respectively. The serum half-life was approx. 2 hours. In elderly and/or critically ill male and female subjects, single intravenous doses of 8 g of fosfomycin resulted in mean Cmax and half-lives in plasma of approximately 350-380 micrograms/mL and 3.6-3.8 h, respectively.

Distribution
The apparent volume of distribution of fosfomycin is approx. 0.30 L/kg body weight. Fosfomycin is distributed well to tissues. High concentrations are reached in eyes, bones, wound secretions, musculature, cutis, subcutis, lungs and bile. In patients with inflamed meninges, cerebrospinal fluid concentrations reach approx. 20-50% of the corresponding serum levels. Fosfomycin passes the placental barrier. Low quantities were found in human milk (about 8 % of the serum concentrations). The plasma protein binding is negligible.

Metabolism
Fosfomycin is not metabolised by the liver and does not undergo enterohepatic circulation. No accumulation is therefore to be expected in patients with hepatic impairment.

Elimination
80-90% of the quantity of fosfomycin administered to healthy adults is eliminated renally within 10 hours after a single intravenous administration. Fosfomycin is not metabolised, i.e. the biologically active compound is eliminated. In patients with normal or mildly to moderately impaired renal function (creatinine clearance ≥ 40 mL/min), approximately 50-60% of the overall dose is excreted within the first 3-4 hours.

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Allergy advice

If an allergic reaction to fosfomycin occurs, discontinue use and institute appropriate therapy.

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Key interactions (include BNF black dot)

Metoclopramide reduces the bioavailability of oral fosfomycin due to increase gastrointestinal mobility.

Combination with other antibiotics
In vitro tests have shown that combination of fosfomycin with β-lactam antibiotics such as penicillin, ampicillin, cefazolin or the class of carbapenems, usually shows an additive to synergistic effect. The same applies to the combination of fosfomycin with most anti-staphylococcal (linezolid, quinopristin/dalfopristin, moxifloxacin) agents in treatment of staphylococcal infections. The combination of fosfomycin with aminoglycosides has predominantly indifferent to additive effects.

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Side effects and monitoring required

When given intravenously, the most commonly reported adverse reactions during treatment are gastrointestinal disturbances and injection site reactions. Other important adverse reactions include hypokalaemia and/or hypernatraemia

When given orally, the most common adverse reactions involve the gastrointestinal tract, mainly diarrhoea. These events are usually self-limited in duration and resolve spontaneously.

[THIS LIST IS NOT EXHAUSTIVE]

Monitoring: Electrolytes and fluid balance

The use of IV Fosfomycin is associated with a high sodium intake. This may result in hypokalaemia (26%) and heart failure or hypertension (3%). (Michalopoulos AS et al. 2011)
Serum electrolyte levels and water balance must be monitored during therapy with IV fosfomycin.

Drug indications

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Prophylaxis indications in LTHT

Fosfomycin is not routinely recommended for this purpose due to limited data available.

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Treatment indications in LTHT

Oral Fosfomycin

The use of oral fosfomycin is included in the following treatment guidelines:

  • Lower urinary tract infections (in males and non-pregnant females)
  • Catheter associated urinary tract infections

IV Fosfomycin

IV fosfomycin is a fully protected antimicrobial and as such should only be considered after discussion with a consultant medical microbiologist/infectious disease physician.
It is usually reserved for when the first-line treatment is ineffective or inappropriate.

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Prescribing restriction

IV fosfomycin is a fully protected antimicrobial and as such can only be prescribed with approval from a consultant medical microbiologist/infectious disease physician.

Exception in adult cystic fibrosis: where it is prescribed for a patient whose indication is the treatment of pseudomonas infection in cystic fibrosis.

Provenance

Record: 4302
Objective:
Clinical condition:
Target patient group:
Target professional group(s): Pharmacists
Secondary Care Doctors
Adapted from:

Evidence base

References

  1. BNF Link
  2. Falagas ME, Giannopoulou KP, Kokolakis GN et al. Fosfomycin: Use beyond urinary tract and gastrointestinal infections. Clin Infect Dis 2008; 46: 1069-77.
  3. Karageorgopoulos DE, Wang R,Yu X et al. Fosfomycin: evaluation of the published evidence on the emergence of antimicrobial resistance in Gram-negative pathogens. J Antimicrob Chemother 2012; 67: 255-68.
  4. Michalopoulos AS, Livaditis IG and Gougoutas V. The revival of fosfomycin. Int J Infect Dis. 2011; 15: e732-39
  5. Naber, K. G., B. Wullt, et al. Antibiotic treatment of uncomplicated urinary tract infection in premenopausal women. Int J Antimicrob Agents. 2011; 38 (Suppl): 21-35.
  6. Summary of Product Characteristics. Fomicyt 40mg/ml Powder for Solution for Infusion. Date of revision of text 11th December 2017. Nordic Pharma Limited.
  7. Gattringer, R et al., Single-dose pharmacokinetics of fosfomycin during continuous venovenous haemofiltration Journal of Antimicrobial Chemotherapy (2006) 58, 367–371
  8. NICE: Multidrug resistant urinary tract infections: fosfomycin trometamol https://www.nice.org.uk/advice/esuom17/chapter/key-points-from-the-evidence
  9. Summary of Product Characteristics. Monuril 3g granules for oral solution. Date of revision of text 20th January 2016. Profile Pharma Limited.

Approved By

Drug and Therapeutics Committee

Document history

LHP version 1.0

Related information

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