Fosfomycin

Background

Mechanism of Action

• Inhibits an enzyme-catalyzed reaction in cell wall synthesis
• Bacteridical

Spectrum of Activity

• Active against many Gram-positive bacteria, including MSSA, MRSA, Staphylococcus epidermidis, Streptococcus pneumoniae, Enterococcus faecalis, Enterococcus faecium, and VRE
• Active against many Gram-negative bacteria, including regular Enterobacterales, CRE, and ESBL
  • Includes Salmonella, Shigella, E. coli, Klebsiella, Enterobacter, Serratia, Citrobacter, and Proteus mirabilis
  • Unclear if effective against Pseudomonas
• Limited activity against gut anaerobes, but does cover Peptostreptococcus
• Intrinsic resistance in Pseudomonas (probably), Acinetobacter, Stenotrophomonas maltophilia, Burkholderia cepacia, some coagulase-negative staphylococci (Staphylococcus capitis and Staphylococcus saprophyticus), Morganella morganii, and Mycobacterium tuberculosis

PK/PD

• Efficacy predicted by time above MIC
• Oral bioavailability 34 to 58%; higher if taken on an empty stomach
• Elimination half-life of 5.7 hours, 93 to 99% excreted unchanged in the urine

Breakpoints

• Determined by agar (not broth) dilution
• Enterobacterales: susceptible if MIC ≤32, resistance if MIC >32
• Pseudomonas aeruginosa: no MIC breakpoints; ECV is 128 mg/L
• Acinetobacter: no MIC breakpoints or ECV

Dosing

• Uncomplicated UTI: fosfomycin 3 g PO once
• Complicated UTI: fosfomycin 3 g PO q72h for 2 to 3 doses
• Intravenous: fosfomycin disodium 8 g IV q12h
• CNS or other severe infection: fosfomycin disodium 8 to 12 g IV q12h
• Continuous infusion may result in better PK/PD: 8 g IV load followed by 16-24 g continuous infusion over 24 hours

Renal Dosing

• Oral: no dosage adjustment necessary for oral, though elimination may be prolonged
• Intravenous
  • CrCl >=130 mL/min: maximum indicated dose for indication (up to 24 g/day in 3 to 4 divided doses)
  • CrCl 40-129 mL/min: normal dose, in 2 to 4 divided doses
  • CrCl 30-39: 70-80% of normal daily dose, in 2 to 3 divided doses
  • CrCl 20-29: 50-70% of normal daily dose, in 2 to 3 divided doses
  • CrCl 10-19: 30-50% of normal daily dose, in 2 to 3 divided doses
  • CrCl <10: 20% of normal daily dose, in 1 to 2 divided doses
  • Intermittent hemodialysis: 2 g after each session (up to 4 g for severe or less susceptible infections)

Safety

Monitoring

• Hypokalemia, high sodium content, dose-limiting nausea, vomiting, and diarrhea

Pregnancy

• Safe in pregnancy

Further Reading

• Fosfomycin. Clin Microbiol Rev. 2016 Apr;29(2):321-47. doi: 10.1128/CMR.00068-15. PMID: 26960938; PMCID: PMC4786888.