What are the recommended oral and intravenous (IV) doses of fosfomycin for a patient with a urinary tract infection (UTI) and fever, caused by Klebsiella that is sensitive only to fosfomycin?

Fosfomycin Dosing for Febrile UTI Caused by Pan-Resistant Klebsiella

For a febrile UTI caused by Klebsiella sensitive only to fosfomycin, use intravenous fosfomycin in combination therapy rather than oral monotherapy, as oral fosfomycin is inadequate for Klebsiella and fever indicates complicated infection requiring parenteral treatment. 1, 2

Critical Dosing Distinctions

Oral Fosfomycin

• The oral formulation (3 grams single dose) is NOT recommended for Klebsiella UTI, even when susceptibility is confirmed, due to poor clinical efficacy and high failure rates 1, 3, 4
• Oral fosfomycin achieves only 37% bioavailability and is FDA-approved exclusively for uncomplicated cystitis caused by E. coli and Enterococcus faecalis—not Klebsiella 4
• The presence of fever indicates pyelonephritis or complicated UTI, which is an absolute contraindication to single-dose oral therapy 1

Intravenous Fosfomycin

• IV fosfomycin must be used in combination therapy for carbapenem-resistant Klebsiella pneumoniae (CRKP) when susceptibility is confirmed 1, 2
• The ESCMID guidelines recommend IV fosfomycin for complicated UTI without septic shock based on the ZEUS trial 5, 2
• Typical IV dosing ranges from 12-24 grams daily in divided doses (though specific dosing protocols vary by institution and severity) 2

Combination Therapy Requirements

Fosfomycin should never be used as monotherapy for Klebsiella infections, even with confirmed susceptibility 1, 2

• Combination partners include:
  • Tigecycline 1
  • Polymyxins (colistin) 1
  • Carbapenems (if any residual activity demonstrated on synergy testing) 1
  • Cephalosporins (such as cefuroxime, without adverse interactions) 6

Mandatory Precautions Before Initiating Therapy

Contraindications to Screen For

• Hypernatremia - fosfomycin contains high sodium content 1, 6
• Cardiac insufficiency - sodium load poses significant risk 1, 6
• Renal insufficiency - fosfomycin elimination is prolonged (half-life increases from 11 to 50 hours with declining renal function) 3, 4

Required Monitoring

• Serum potassium levels must be monitored closely, as hypokalemia occurs in approximately 6% of ICU patients receiving IV fosfomycin 2, 6
• Confirm susceptibility testing, as resistance genes are increasingly prevalent in carbapenem-resistant strains 2

Clinical Pitfalls to Avoid

• Do not use the oral single-dose formulation for any Klebsiella infection - this is the most common error, as oral fosfomycin has poor efficacy against Klebsiella despite in vitro susceptibility 1, 7
• Klebsiella susceptibility to fosfomycin is highly variable (39-99% depending on local epidemiology), making susceptibility testing mandatory 2
• The cumulative fraction of response for Klebsiella with oral fosfomycin is only 55% even under optimal acidic urine conditions (pH 6.0), compared to 99% for E. coli 7
• One case series reported success with 7-day oral fosfomycin for KPC-producing Klebsiella lower UTI, but this represents anecdotal evidence insufficient to guide practice for febrile UTI 8

Practical Algorithm for This Clinical Scenario

1. Confirm the patient has fever - this indicates complicated UTI/pyelonephritis requiring IV therapy 1
2. Verify fosfomycin susceptibility and screen for contraindications (hypernatremia, cardiac/renal insufficiency) 1, 2, 6
3. Initiate IV fosfomycin in combination with tigecycline, polymyxin, or another active agent based on synergy testing 1, 2
4. Monitor serum potassium throughout treatment course 2, 6
5. Consider alternative agents if available - ceftazidime-avibactam, meropenem-vaborbactam, or plazomicin are preferred first-line options for CRKP when susceptible 1