Is fosfomycin (generic name) appropriate for a patient with carbapenemase-producing organisms (CPO) and non-lactose fermenting gram-negative rods in their urine?

Fosfomycin for Carbapenemase-Producing Organisms in Urine

Fosfomycin is appropriate for treating urinary tract infections caused by carbapenemase-producing organisms (CPO) when susceptibility testing confirms the isolate is susceptible to fosfomycin, but it should be used as part of combination therapy rather than monotherapy for these highly resistant pathogens. 1

Key Clinical Decision Points

Mandatory Pre-Treatment Requirements

• Susceptibility testing is absolutely required before initiating fosfomycin therapy for CPO infections, as susceptibility rates in carbapenem-resistant Klebsiella pneumoniae (CRKP) are highly variable, ranging from 39% to 99% 1, 2, 3
• Antimicrobial synergy testing should be performed when possible to confirm that fosfomycin-containing combinations demonstrate synergistic effects against the specific CPO isolate 1, 2
• Note that fosfomycin susceptibility testing is not routinely performed in many clinical laboratories, so you may need to specifically request it 2

Treatment Approach Based on Infection Type

For uncomplicated cystitis caused by CPO:

• Oral fosfomycin 3 grams single dose may be appropriate if the isolate is susceptible 4, 5
• Fosfomycin retains excellent activity against ESBL-producing and carbapenemase-producing Enterobacteriaceae in urinary tract infections, with 98.9% susceptibility in carbapenem-resistant E. coli and 94% in carbapenem-resistant Klebsiella species 5
• The single dose provides therapeutic urinary concentrations for 24-48 hours, which is sufficient for uncomplicated lower UTI 4

For complicated UTI or pyelonephritis caused by CPO:

• Intravenous fosfomycin-containing combination therapy is strongly recommended rather than oral monotherapy 1
• Appropriate combination partners include tigecycline, polymyxin, carbapenems (at high doses), or aminoglycosides 1
• Observational studies show fosfomycin-containing combinations resulted in 114 fewer deaths per 1000 patients (RR=0.55) compared to other combinations, though evidence quality is very low 1, 2

Non-Lactose Fermenting Gram-Negative Rods Consideration

• For Pseudomonas aeruginosa (a common non-lactose fermenter), fosfomycin susceptibility is more variable and heavily dependent on local antibiograms, with rates around 64.5% in some studies 2
• Fosfomycin should never be used as monotherapy for Pseudomonas due to high risk of resistance development during treatment 2
• Combination therapy is mandatory if treating non-lactose fermenters like Pseudomonas with fosfomycin 2

Critical Contraindications and Safety Monitoring

Absolute contraindications for IV fosfomycin: 1, 4, 2

• Hypernatremia (due to high sodium content of IV formulation)
• Cardiac insufficiency
• Renal insufficiency (elimination half-life increases from 5.7 hours to 40-50 hours in anuric patients)

Required monitoring during treatment: 4

• Electrolytes should be monitored during and after treatment, particularly potassium, calcium, and magnesium
• Reversible severe hypokalemia was reported in 3 of 48 ICU patients receiving fosfomycin-containing combinations 1

Evidence Quality and Clinical Reality

• The evidence supporting fosfomycin for CPO infections is predominantly observational with very low certainty, meaning future studies may change current recommendations 1, 2
• Despite low evidence quality, fosfomycin-containing combinations showed treatment efficacy of 54.2% and bacterial eradication rate of 56.3% in ICU patients with carbapenem-resistant infections 1
• The clinical benefits likely outweigh potential harms when treating CPO infections with limited alternatives, particularly given fosfomycin's minimal collateral damage to intestinal flora 1, 3

Practical Algorithm

1. Confirm CPO in urine culture with susceptibility testing specifically including fosfomycin
2. Assess infection complexity: uncomplicated cystitis vs. complicated UTI/pyelonephritis
3. Check for contraindications: hypernatremia, cardiac/renal insufficiency
4. For uncomplicated cystitis with susceptible CPO: Consider oral fosfomycin 3g single dose
5. For complicated UTI or any systemic involvement: Use IV fosfomycin-containing combination therapy (not monotherapy)
6. Monitor electrolytes during treatment, especially potassium
7. If symptoms persist beyond 2-3 days: Reassess and consider alternative agents based on repeat susceptibility testing 4