What antibiotic can be prescribed for a patient with a urinary tract infection (UTI) who is allergic to levofloxacin, Macrobid (nitrofurantoin), and penicillin?

Antibiotic Options for UTI with Multiple Allergies

For a patient allergic to levofloxacin, Macrobid (nitrofurantoin), and penicillin, the best first-line option is fosfomycin trometamol 3 grams as a single dose, with trimethoprim-sulfamethoxazole 160/800 mg twice daily for 3 days as an alternative if fosfomycin is unavailable. 1

Primary Recommendation: Fosfomycin

Fosfomycin trometamol 3 grams as a single oral dose is the optimal choice for this patient. 1

• Fosfomycin is listed as first-line treatment for uncomplicated cystitis in women by the European Association of Urology 2024 guidelines 1
• This agent demonstrates 95.9-96.1% susceptibility rates against both non-ESBL and ESBL-producing E. coli, the most common uropathogen 2
• The single-dose regimen maximizes adherence and minimizes resistance development 2
• Fosfomycin maintains high activity (38.1-36.5% susceptibility) even against K. pneumoniae, though less robust than for E. coli 2
• Importantly, fosfomycin is structurally unrelated to fluoroquinolones, nitrofurantoin, or beta-lactams, making cross-reactivity with the patient's known allergies extremely unlikely 3

Alternative Option: Trimethoprim-Sulfamethoxazole

If fosfomycin is unavailable, trimethoprim-sulfamethoxazole (TMP-SMX) 160/800 mg twice daily for 3 days is the next best alternative. 1, 4, 5

• TMP-SMX is listed as an alternative treatment in the EAU 2024 guidelines for uncomplicated cystitis 1
• FDA-approved for treatment of UTIs caused by susceptible E. coli, Klebsiella, Enterobacter, Morganella, and Proteus species 4, 5
• This combination is structurally distinct from the patient's known allergens 4, 5

Important Caveat About TMP-SMX Resistance

• Local resistance patterns must be considered, as some communities report up to 29% resistance rates for E. coli 6
• TMP-SMX should only be used empirically if local E. coli resistance is <20% 1
• If the patient was recently exposed to TMP-SMX or is at risk for ESBL-producing organisms, this option becomes less favorable 3

Third-Line Option: Cephalosporins

Cephalosporins such as cefadroxil 500 mg twice daily for 3 days can be considered if both fosfomycin and TMP-SMX are contraindicated or unavailable. 1

• Listed as an alternative in EAU 2024 guidelines when local E. coli resistance is <20% 1
• Critical allergy consideration: While the patient is allergic to penicillin, the cross-reactivity rate between penicillins and cephalosporins is approximately 1-3% for first-generation cephalosporins 1
• The nature and severity of the penicillin allergy must be clarified before prescribing a cephalosporin—if the patient had anaphylaxis or severe IgE-mediated reaction to penicillin, cephalosporins should be avoided 1
• If the penicillin "allergy" was a non-IgE-mediated reaction (e.g., GI upset, rash without urticaria), cephalosporins may be safely used with appropriate counseling 1

Clinical Decision Algorithm

1. First choice: Prescribe fosfomycin 3 grams single dose 1, 2

2. If fosfomycin unavailable: Check local antibiogram for E. coli resistance to TMP-SMX 1

   • If resistance <20%: Use TMP-SMX 160/800 mg twice daily for 3 days 1, 4, 5
   • If resistance ≥20%: Proceed to step 3

3. If both unavailable or contraindicated: Clarify penicillin allergy history 1

   • If non-severe reaction: Consider cefadroxil 500 mg twice daily for 3 days 1
   • If severe IgE-mediated reaction: Obtain urine culture and susceptibility testing before empiric treatment 1

Critical Pitfalls to Avoid

• Do not use fluoroquinolones (including ciprofloxacin) as the patient is allergic to levofloxacin, and cross-reactivity within the fluoroquinolone class is high 7, 8, 9
• Avoid nitrofurantoin in all formulations (macrocrystals, monohydrate, prolonged-release) due to documented allergy 1
• Do not use pivmecillinam as it is a beta-lactam with potential cross-reactivity to penicillin allergy 1
• Obtain urine culture if symptoms do not resolve within 4 weeks or recur within 2 weeks, as this suggests resistant organisms requiring targeted therapy 1
• Pregnancy considerations: TMP-SMX is contraindicated in the first and third trimesters 1

When Culture-Guided Therapy is Essential

If the patient has complicated UTI, pyelonephritis, or failed initial empiric therapy, obtain urine culture and susceptibility testing before selecting antibiotics. 1

• Culture results allow for targeted therapy and avoid unnecessary broad-spectrum antibiotic use 1
• For patients with recurrent UTIs or recent antibiotic exposure, empiric therapy is less reliable and culture-guided treatment is preferred 1, 3