What is the use, spectrum, and toxicity of fosfomycin (antibiotic) in pediatric patients post-bone marrow transplant (BMT)?

Fosfomycin Use in Pediatric Patients Post-Bone Marrow Transplant

Fosfomycin is recommended as part of combination therapy for carbapenem-resistant bacterial infections in immunocompromised pediatric patients post-BMT, with efficacy against multidrug-resistant organisms and a generally favorable safety profile, though hypokalemia requires monitoring. 1

Spectrum of Activity

• Fosfomycin has a broad spectrum of activity against both gram-positive and gram-negative aerobic microorganisms, making it valuable for immunocompromised patients post-BMT 2
• Particularly effective against:
  • Carbapenem-resistant Enterobacteriaceae (CRE) when the isolate is susceptible to fosfomycin 1
  • Extended-spectrum beta-lactamase (ESBL)-producing enterobacteria 2
  • Methicillin-resistant Staphylococcus aureus (MRSA) 2
  • Vancomycin-resistant Enterococcus (VRE) 2
• Fosfomycin demonstrates synergistic in-vitro activity against carbapenem-resistant Klebsiella pneumoniae (CRKP) when used in combination therapy 1
• Susceptibility rates in CRKP can vary widely (39-99%), making susceptibility testing mandatory before initiating therapy 1, 3

Administration in Pediatric Patients

• Intravenous fosfomycin is preferred for serious systemic infections in immunocompromised patients post-BMT 4
• Oral fosfomycin (as fosfomycin tromethamine) is primarily indicated for uncomplicated lower urinary tract infections 5
• For systemic infections, fosfomycin should be used in combination with other antibiotics (such as tigecycline, polymyxin, or carbapenems) rather than as monotherapy 1, 6
• Antimicrobial susceptibility testing or synergy testing should be performed before initiating treatment 1, 3

Pharmacokinetics and Excretion

• Fosfomycin is excreted unchanged in both urine and feces 7
• Following oral administration, approximately 38% of a dose is recovered from urine and 18% from feces 7
• Mean urinary concentration peaks at 706 μg/mL within 2-4 hours after a single oral 3-gram dose under fasting conditions 7
• Fosfomycin has excellent tissue penetration, including bone, central nervous system, and soft tissues, making it suitable for deep-seated infections 2, 4
• In patients with renal impairment, the half-life increases significantly (from 11 hours to 50 hours in severe cases), and dosage adjustment may be necessary 7

Efficacy in Pediatric Patients Post-BMT

• Fosfomycin-containing combination therapy has shown promising results in treating serious infections in immunocompromised patients 4
• In patients with carbapenem-resistant infections, fosfomycin combination therapy was associated with 114 fewer deaths per 1000 patients compared to other antimicrobial combinations (RR = 0.55,95% CI 0.28-1.10) 1
• A study of pediatric patients with complicated infections showed successful eradication of disease with fosfomycin combination therapy, particularly for deep-seated infections caused by multi-drug resistant pathogens 4

Toxicity and Adverse Effects

• Intravenous fosfomycin is generally safe with mild adverse reactions in pediatric patients 4
• The most significant adverse reaction is reversible severe hypokalemia, reported in approximately 6% of ICU patients receiving fosfomycin-containing combination therapy 1
• Other potential adverse effects include:
  • Mild, self-limited diarrhea (reported in approximately 3% of patients) 5
  • Gastrointestinal disturbances 4
• Patients with hypernatremia, cardiac insufficiency, or renal insufficiency should avoid fosfomycin use 1

Monitoring Recommendations

• Therapeutic drug monitoring (TDM) should be performed when possible in patients receiving fosfomycin for treatment of carbapenem-resistant gram-negative bacilli infections 1
• Regular monitoring of serum potassium levels is essential due to the risk of hypokalemia 1
• Renal function should be monitored, especially in patients with pre-existing renal impairment, as fosfomycin clearance is significantly affected 7

Clinical Considerations for Post-BMT Patients

• Fosfomycin should be considered as part of combination therapy for multidrug-resistant infections in post-BMT patients 2
• Susceptibility testing is mandatory before initiating therapy due to variable resistance patterns 1, 3
• For bacteremia or sepsis in post-BMT patients, fosfomycin should be used in combination with other appropriate antibiotics 2
• The duration of therapy should be individualized based on the site and severity of infection, with longer courses typically needed for deep-seated infections 4

Common Pitfalls to Avoid

• Avoid fosfomycin monotherapy for serious systemic infections, as this may lead to treatment failure and resistance development 6
• Do not use fosfomycin in patients with hypernatremia, cardiac insufficiency, or renal insufficiency 1
• Failure to perform susceptibility testing before initiating therapy can lead to ineffective treatment 1, 3
• Inadequate monitoring of electrolytes, particularly potassium, may result in undetected hypokalemia 1