Drug Interactions Between Doxycycline/Cefazolin and Divalproex/Levetiracetam
Neither doxycycline nor cefazolin have clinically significant interactions with divalproex or levetiracetam, and both antibiotics can be safely used for bilateral foot cellulitis in patients taking these antiepileptic drugs.
Levetiracetam: No Interactions with Either Antibiotic
Levetiracetam has no pharmacokinetic interactions with other medications because it does not undergo hepatic metabolism via cytochrome P450 enzymes and is not protein-bound to a clinically significant degree 1, 2.
Levetiracetam is eliminated primarily by renal excretion (66% unchanged) and a minor hydrolysis pathway that is not affected by other drugs 1.
No dose adjustment is required when levetiracetam is combined with doxycycline or cefazolin 2.
Divalproex (Valproic Acid): Critical Distinction Between Antibiotics
Safe Antibiotics: Doxycycline and Cefazolin
Doxycycline and cefazolin do not interact with valproic acid and can be used safely without dose adjustments 3, 2.
Valproic acid interactions occur primarily with enzyme-inducing antiepileptics (carbamazepine, phenytoin, phenobarbital) and carbapenem antibiotics specifically 4, 3, 2.
Dangerous Antibiotic Class: Carbapenems (NOT Your Antibiotics)
Carbapenem antibiotics (meropenem, ertapenem, imipenem, doripenem) cause a severe drug interaction with valproic acid that decreases valproate serum concentrations by 60-90% within 24-48 hours, leading to breakthrough seizures 4, 5.
This carbapenem-valproate interaction occurs through inhibition of valproate hydrolysis and enhanced renal clearance, with valproate levels dropping from therapeutic (70-130 mcg/mL) to subtherapeutic (10-70 mcg/mL) within days 5.
Carbapenems should be avoided entirely in patients taking valproic acid; if absolutely necessary, add a second antiepileptic agent and monitor valproate levels every 1-2 days 4.
Clinical Application for Cellulitis Treatment
For bilateral foot cellulitis in a patient on divalproex or levetiracetam, use cefazolin 1-2 g IV every 8 hours or doxycycline 100 mg twice daily without concern for antiepileptic drug interactions 6, 7.
Cefazolin is recommended as first-line therapy for methicillin-sensitive Staphylococcus aureus skin infections and does not affect valproate or levetiracetam levels 6, 7.
Doxycycline can be combined with beta-lactams for MRSA coverage if needed, with no interaction concerns 8.
Critical Pitfall to Avoid
The only antibiotic class that interacts dangerously with valproic acid is carbapenems (meropenem, ertapenem, imipenem, doripenem) - not cephalosporins like cefazolin or tetracyclines like doxycycline 4, 5.
Do not confuse cefazolin (a cephalosporin) with carbapenems; they are structurally different beta-lactam classes with completely different interaction profiles 4.