Does fosfomycin provide coverage against Klebsiella pneumoniae?

Does Fosfomycin Cover Klebsiella?

Yes, fosfomycin provides coverage against Klebsiella pneumoniae and Klebsiella oxytoca, with susceptibility rates ranging from 65% to 100% depending on resistance patterns, but you must always confirm susceptibility testing before use and consider combination therapy for serious infections. 1, 2

Spectrum of Activity

• Oral fosfomycin has in vitro activity against Klebsiella pneumoniae and Klebsiella oxytoca as documented in FDA labeling, with MICs of 64 mcg/mL or less against most strains 2
• For multidrug-resistant K. pneumoniae strains, fosfomycin susceptibility is 92.2%, making it the most active antimicrobial agent among tested antibiotics 3
• Carbapenem-resistant K. pneumoniae (CRKP) shows variable susceptibility rates of 39% to 99% depending on local epidemiology and resistance mechanisms 1

Critical Resistance Patterns You Must Know

Carbapenemase-Producing Strains

• 93% of KPC-producing K. pneumoniae remain susceptible to fosfomycin (MIC50/90 of 16/64 mcg/mL), including 87% of tigecycline- and/or colistin-nonsusceptible strains 4
• Notably, 5 out of 6 extremely drug-resistant strains (resistant to both tigecycline and colistin) remained fosfomycin-susceptible 4
• However, carbapenemase-producing strains show higher resistance rates (40-45%) compared to carbapenemase-negative strains (20-25%) 5

Major Resistance Mechanism

• FosA3 enzyme production is the primary resistance mechanism, with fosA3 gene detected in all fosfomycin-resistant K. pneumoniae isolates 6
• High-level resistance (MIC >256 mg/L) occurs when FosA3 overexpression combines with mutations in glpT and/or uhpT transporter genes 6
• Importantly, fosA3 can remain silent in susceptible isolates but confer resistance when activated 6

Route-Specific Recommendations

For Uncomplicated UTI

• Single 3-gram oral dose achieves therapeutic urinary concentrations for 24-48 hours and is appropriate for uncomplicated cystitis 7, 2
• Approximately 38% of oral dose is recovered in urine with mean concentrations of 706 mcg/mL within 2-4 hours 2

For Serious Infections

• The IDSA recommends fosfomycin-containing combination therapy for serious K. pneumoniae infections when susceptibility is confirmed 1
• Intravenous fosfomycin (2-4 g every 6 hours) combined with other antibiotics showed 100% bacteriological and clinical success in critically ill ICU patients with carbapenem-resistant K. pneumoniae infections 8
• The ESCMID recommends IV fosfomycin for complicated UTI without septic shock based on clinical trial data 1

Critical Pitfalls to Avoid

Always Confirm Susceptibility

• Never assume susceptibility—always perform susceptibility testing as resistance genes are increasingly prevalent in carbapenem-resistant strains 1
• Use agar dilution or E-test methods, as these show 100% categorical agreement with reference methods, while automated systems (Phoenix) show only 86% agreement 5

Never Use as Monotherapy for Serious Infections

• Monotherapy should be avoided due to high risk of resistance development during treatment 7
• Combination with amikacin shows synergism in only 16.2% of isolates and may be insufficient for carbapenemase-producing strains 6

Monitor for Adverse Effects

• Check serum potassium levels regularly—hypokalemia occurs in approximately 6% of ICU patients receiving IV fosfomycin 1
• Avoid in patients with hypernatremia, cardiac insufficiency, or renal insufficiency due to high sodium content of IV formulation 1, 9

Renal Dosing Considerations

• In renal impairment, elimination half-life increases from 11 hours to 50 hours, and urinary recovery decreases from 32% to 11% 2
• In anuric patients on hemodialysis, half-life extends to 40 hours 2