What is safer for a patient on valproate (valproic acid) with an Extended-Spectrum Beta-Lactamase (ESBL) infection, levofloxacin (Levaquin) or imipenem?

Levofloxacin is Safer than Imipenem for ESBL Infections in Patients on Valproate

For patients on valproate therapy with ESBL infections, levofloxacin is the safer choice compared to imipenem due to the clinically significant drug interaction between carbapenems and valproic acid that can lead to subtherapeutic valproate levels and seizure risk.

Drug Interaction Considerations

• Carbapenems (including imipenem) significantly decrease serum valproate concentrations by an average of 66% within 24 hours of co-administration, potentially leading to loss of seizure control 1, 2
• This interaction has been documented with all carbapenems including imipenem, meropenem, ertapenem, and doripenem, with meropenem showing the most pronounced effect (89.3% decrease versus 51.5% with other carbapenems) 3
• The interaction between valproate and carbapenems is considered probable to definite in clinical assessments and has led to electroclinical deterioration in 55% of patients 2
• Fluoroquinolones like levofloxacin do not have this interaction with valproate and therefore maintain therapeutic antiepileptic levels 1

Antimicrobial Efficacy Considerations

• While carbapenems are traditionally considered first-line agents for ESBL infections, fluoroquinolones remain viable options when susceptibility is confirmed 4, 5
• Levofloxacin can be used for ESBL infections if the organism shows susceptibility on antimicrobial testing 4
• The World Journal of Emergency Surgery guidelines note that fluoroquinolones (including levofloxacin) can be used in patients with beta-lactam allergies for intra-abdominal infections, which would include those caused by ESBL-producing organisms 4
• Carbapenems like imipenem have the broadest spectrum of activity against ESBL-producing organisms but should be avoided when possible to reduce selection pressure for carbapenem-resistant organisms 5, 6

Clinical Decision Algorithm

1. First step: Confirm ESBL production and obtain susceptibility testing results for both levofloxacin and imipenem 5

2. If the ESBL organism is susceptible to levofloxacin:

   • Use levofloxacin as the preferred agent for patients on valproate 4, 1
   • Monitor therapeutic response closely 4

3. If the ESBL organism is resistant to levofloxacin:

   • Consider alternative non-carbapenem options if susceptible (e.g., tigecycline, ceftazidime/avibactam) 4, 5
   • If imipenem must be used due to susceptibility patterns:
     • Add an alternative antiepileptic agent before starting imipenem 1
     • Monitor valproate levels daily 2
     • Expect significant decreases in valproate levels within 24 hours 3, 2
     • Be prepared to increase valproate dosing or switch to alternative anticonvulsants 1

Important Caveats

• Local resistance patterns should guide therapy - in areas with high fluoroquinolone resistance rates (>20% among E. coli), levofloxacin may not be appropriate empirically 5
• Severity of infection matters - for critically ill patients with ESBL infections, carbapenems may still be necessary despite the interaction with valproate, requiring close neurological monitoring and adjustment of antiepileptic therapy 4, 1
• If using levofloxacin, ensure it is combined with metronidazole for intra-abdominal infections to provide anaerobic coverage 4
• The interaction between carbapenems and valproate generally resolves shortly after discontinuation of the carbapenem 1

Alternative Options When Both Agents Are Problematic

• For less severe ESBL infections, consider carbapenem-sparing regimens like ceftolozane/tazobactam with metronidazole 5
• Tigecycline is a viable treatment option for complicated intra-abdominal infections due to ESBL-producing organisms and does not interact with valproate 4, 5
• Newer agents like ceftazidime/avibactam may be effective against ESBL producers without the valproate interaction 7, 5