Does phenytoin interact with any antibiotics?

Phenytoin-Antibiotic Interactions

Yes, phenytoin interacts with several antibiotics through multiple mechanisms that can lead to either phenytoin toxicity or reduced efficacy, requiring careful monitoring and dose adjustments.

Critical Interactions Leading to Phenytoin Toxicity

Isoniazid (Anti-Tuberculosis)

• Isoniazid significantly increases phenytoin levels by inhibiting CYP2C19 and CYP2C9 enzymes, preventing phenytoin metabolism and leading to potentially catastrophic toxicity 1, 2.
• The interaction can cause progressive neurological deterioration including loss of balance, psychosis, nystagmus, hyperreflexia, and stupor, with serum levels exceeding 40 mg/L 2.
• Monitor phenytoin levels closely and consider switching to an alternative anticonvulsant (e.g., levetiracetam) when initiating isoniazid therapy 2.
• This risk is particularly elevated in slow acetylator populations 2.

Trimethoprim-Sulfamethoxazole (TMP-SMX)

• TMP-SMX increases the risk of phenytoin toxicity through enzyme inhibition 1.
• The sulfonamide component can both inhibit phenytoin metabolism and displace it from protein binding sites 3, 4.
• Close monitoring of phenytoin levels is essential when initiating TMP-SMX 1.

Macrolide Antibiotics (Excluding Azithromycin)

• Erythromycin, clarithromycin, and roxithromycin significantly increase phenytoin plasma concentrations by inhibiting hepatic cytochrome P-450 enzymes 5.
• These macrolides increase the area under the curve, maximum plasma concentration, and elimination half-life of phenytoin 5.
• Azithromycin does not interact with phenytoin and is the preferred macrolide when concurrent use is necessary 1.

Other Antibiotics Causing Protein Displacement

• Ceftriaxone, nafcillin, and sulfamethoxazole displace phenytoin from serum protein carriers, increasing free phenytoin concentrations both in vitro and in vivo 6.
• This displacement can lead to underestimation of free phenytoin when using standard prediction equations 6.
• Free phenytoin concentrations decrease toward predicted values after antibiotic discontinuation 6.

Interactions Reducing Phenytoin Efficacy

Rifampin (Anti-Tuberculosis)

• Rifampin is a potent inducer of CYP450 enzymes and dramatically reduces phenytoin levels, requiring substantial dose increases to maintain therapeutic concentrations 1.
• Patients already on warfarin required a 50% increase in maintenance dose after carbamazepine initiation, suggesting similar magnitude effects may occur with phenytoin 1.
• When rifampin is discontinued, phenytoin doses must be reduced within 2 weeks to prevent toxicity as the inductive effect resolves 1.

Penicillin G

• Penicillin G may reduce phenytoin absorption when administered with bile acid sequestrants, though this interaction is less clinically significant 1.

Biphasic Interaction Pattern

Phenytoin exhibits a unique biphasic interaction with rifampin: Initially, rifampin may transiently increase phenytoin effects through protein displacement, but ultimately induces CYP450 enzymes requiring higher phenytoin doses 1.

Clinical Management Algorithm

When Initiating Antibiotics in Phenytoin-Treated Patients:

1. Identify the antibiotic class:

   • Isoniazid, TMP-SMX, or macrolides (except azithromycin) → High risk of toxicity
   • Rifampin → Risk of subtherapeutic levels
   • Ceftriaxone, nafcillin → Protein displacement risk

2. For toxicity-risk antibiotics:

   • Obtain baseline phenytoin level before starting antibiotic 3
   • Monitor for early signs of toxicity: ataxia, nystagmus, confusion, psychosis 2
   • Recheck phenytoin levels at 2,4, and 8 weeks 1
   • Consider prophylactic phenytoin dose reduction of 20-30% 7
   • Strongly consider switching to alternative anticonvulsant (levetiracetam) or alternative antibiotic (azithromycin for macrolides) 2, 1

3. For enzyme-inducing antibiotics (rifampin):

   • Anticipate need for phenytoin dose increases of 50% or more 1
   • Monitor levels weekly during rifampin initiation 1
   • Remember to reduce phenytoin dose within 2 weeks of rifampin discontinuation 1

4. For protein displacement interactions:

   • Monitor free phenytoin concentrations rather than total levels 6
   • Standard prediction equations will underestimate free phenytoin 6

Critical Pitfalls to Avoid

• Never assume the interaction is unidirectional: Phenytoin's non-linear clearance means small changes in absorption or metabolism cause disproportionately large changes in plasma concentration 4.
• Do not overlook the need for dose adjustment after antibiotic discontinuation: Failure to reduce phenytoin after stopping enzyme inhibitors or increase after stopping inducers can lead to toxicity or seizures 1.
• Avoid administering phenytoin within 1 hour before or 4-6 hours after bile acid sequestrants if patient is on both 1.
• The FDA label specifically warns that phenytoin levels may be increased by chloramphenicol, isoniazid, phenothiazines, salicylates, and sulfonamides 3.

Additional Considerations

• Ciprofloxacin does not significantly interact with phenytoin but does interact with theophylline and warfarin 1.
• Tetracycline absorption may be reduced when given with bile acid sequestrants, but this does not directly affect phenytoin 1.
• The interaction between isoniazid and phenytoin is bidirectional, with both drugs' serum concentrations potentially increasing 1.