Which agents can be combined with intravenous fosfomycin for a complicated urinary tract infection caused by a carbapenem‑resistant organism in an adult patient?

Combination Partners for IV Fosfomycin in Carbapenem-Resistant Complicated UTI

For complicated UTI caused by carbapenem-resistant organisms, IV fosfomycin should be combined with tigecycline, polymyxins (colistin), carbapenems (at high doses), or aminoglycosides (gentamicin, amikacin), but only after confirming fosfomycin susceptibility or demonstrating synergistic effects through antimicrobial synergy testing. 1

Mandatory Pre-Treatment Requirements

Before initiating any fosfomycin-containing combination therapy, you must:

• Confirm susceptibility through antimicrobial susceptibility testing, as fosfomycin susceptibility in carbapenem-resistant Klebsiella pneumoniae (CRKP) varies dramatically from 39% to 99% 1
• Perform synergy testing when possible to document that the specific combination demonstrates synergistic effects against the patient's isolate 1
• Screen for contraindications: avoid fosfomycin entirely in patients with hypernatremia, cardiac insufficiency, or renal insufficiency due to the high sodium content of IV formulations 1, 2

Evidence-Based Combination Partners

First-Line Combination Options

Tigecycline + IV Fosfomycin:

• Observational studies included tigecycline as a primary combination partner for CRKP infections 1
• Used successfully in ICU patients with treatment efficacy of 54.2% and bacterial eradication rate of 56.3% 1

Polymyxins (Colistin) + IV Fosfomycin:

• Polymyxin combinations were among the most commonly studied regimens in observational data 1
• Therapeutic drug monitoring (TDM) is strongly recommended for polymyxins due to narrow therapeutic index 1

Aminoglycosides + IV Fosfomycin:

• Gentamicin or amikacin can be combined with fosfomycin 1, 3
• Aminoglycoside-containing combinations showed 59 fewer deaths per 1000 patients (RR=0.86) and 417 fewer clinical treatment failures per 1000 patients (RR=0.41) compared to non-aminoglycoside combinations 1
• Limit aminoglycoside duration to ≤7 days to minimize nephrotoxicity risk 1
• TDM is strongly recommended for aminoglycosides due to narrow therapeutic index 1

Carbapenems (High-Dose) + IV Fosfomycin:

• Despite carbapenem resistance, high-dose carbapenems combined with fosfomycin can be effective due to synergistic activity 1, 4
• "Double carbapenem" regimens combined with fosfomycin have been successfully used for NDM-producing Enterobacteriaceae in UTI 5
• TDM is recommended for carbapenems in this setting 1

Alternative Combinations

Ceftazidime-Avibactam + IV Fosfomycin:

• One Italian study showed that ceftazidime-avibactam plus fosfomycin had fewer secondary infections compared to ceftazidime-avibactam plus other agents for KPC-producing K. pneumoniae bloodstream infections 1

Levofloxacin or Rifampin + Carbapenem + Fosfomycin:

• In vitro and dynamic bladder models demonstrated that carbapenem-fosfomycin combinations with levofloxacin or rifampin prevented bacterial regrowth in CRE UTI 4

Dosing and Duration

• IV fosfomycin: 6 grams every 8 hours for 7 days (extend to 14 days if concurrent bacteremia) 6
• Oral fosfomycin: 3 grams every 48-72 hours for 3 doses can be added to IV regimens or used as step-down therapy in select cases 6, 4

Critical Safety Monitoring

Monitor for hypokalemia:

• Reversible severe hypokalemia occurred in 3 of 48 ICU patients (6.3%) receiving fosfomycin-containing combinations 1
• Serum potassium monitoring is essential 7

Monitor for heart failure:

• In the FOREST trial, 8.6% of patients receiving IV fosfomycin developed heart failure compared to 1.4% with meropenem 1
• Exercise particular caution in patients with pre-existing cardiac risk factors 1

Evidence Quality and Clinical Context

The evidence supporting fosfomycin-containing combinations is predominantly observational with very low certainty 1, 3. However, fosfomycin-containing combinations demonstrated 114 fewer deaths per 1000 patients (RR=0.55,95% CI 0.28-1.10) compared to other combinations in pooled observational studies 1. Despite low evidence quality, clinical benefits likely outweigh potential harms when treating carbapenem-resistant UTI with limited alternatives 1, 3.

Common Pitfalls to Avoid

• Never use oral single-dose fosfomycin monotherapy for carbapenem-resistant complicated UTI—this requires IV formulation in combination therapy 2, 3
• Do not assume susceptibility—fosfomycin susceptibility testing is not routinely performed in many laboratories, so specifically request it 3
• Avoid empiric use—fosfomycin combinations should only be used after susceptibility confirmation due to variable resistance patterns 1, 2
• Do not overlook FosA-like resistance genes, which are increasingly prevalent in CRKP and cause fosfomycin resistance 1