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on #medsafety #InfectiousDiseases
Came across an allergic reaction to meropenem described as "seizure".
Turns out patient was on valproic acid (VPA) for seizure Rx. Started meropenem for suspected infection.
"Allergy" was drug-drug interaction b/w VPA & carbapenem.
1/n
on #medsafety #InfectiousDiseasesCame across an allergic reaction to meropenem described as "seizure".
Turns out patient was on valproic acid (VPA) for seizure Rx. Started meropenem for suspected infection.
"Allergy" was drug-drug interaction b/w VPA & carbapenem.1/n
Carbapenems are known for lowering seizure threshold. Imipenem is better recognized for the risk, likely b/c it was the 1st carbapenem. Risk factors: preexisting seizure disorder, renal insufficiency+unadjusted dosing, concurrent epileptogenic drugs.
2/n https://accpjournals.onlinelibrary.wiley.com/doi/abs/10.1592/phco.31.4.408
2/n https://accpjournals.onlinelibrary.wiley.com/doi/abs/10.1592/phco.31.4.408
Proposed mechanism of carbapenems seizures: 1) beta-lactam ring and 2) side chains.
1. Antagonism of GABA(A) receptor by beta-lactam ring
seizure potential. Applies to penicillin & derivatives. (Ref: Miller et al. in prev tweet 
)
Carbapenems:
https://aac.asm.org/content/aac/55/11/4943.full.pdf
3/n
1. Antagonism of GABA(A) receptor by beta-lactam ring
seizure potential. Applies to penicillin & derivatives. (Ref: Miller et al. in prev tweet )Carbapenems:
https://aac.asm.org/content/aac/55/11/4943.full.pdf
3/n
2. Side chains
C2 side chain is basic (in pH sense!). Extent of basicity may affect seizure potential. Ertapenem & meropenem have less basic C2 side chains than imipenem, which *in theory* could explain the higher prevalence of seizures (up to 33% in review by Miller et al.)
4/n
C2 side chain is basic (in pH sense!). Extent of basicity may affect seizure potential. Ertapenem & meropenem have less basic C2 side chains than imipenem, which *in theory* could explain the higher prevalence of seizures (up to 33% in review by Miller et al.)
4/n
Let's come back to valproic acid (VPA) interacting w/ meropenem. What's the mechanism?
VPA level
in presence of carbapenems b/c aspects of pharmacokinetics are affected: absorption, distribution & metabolism.
5/n https://journals.sagepub.com/doi/10.1345/aph.1M296
VPA level
in presence of carbapenems b/c aspects of pharmacokinetics are affected: absorption, distribution & metabolism.5/n https://journals.sagepub.com/doi/10.1345/aph.1M296
Absorption:
1. carbapenems inhibit transporter proteins of VPA in GI tract systemic absorption.
2. enterohepatic recycling b/c of anti-bacterial property of carbapenems!
Distribution: carbapenems shift distribution from plasma to erythrocytes. effective VPA level.
6/n
1. carbapenems inhibit transporter proteins of VPA in GI tract
systemic absorption.2. enterohepatic recycling
b/c of anti-bacterial property of carbapenems!Distribution: carbapenems shift distribution from plasma to erythrocytes.
effective VPA level.6/n
Metabolism:
Carbapenems glucuronidation of VPA, i.e. the form of VPA that is excreted.
So, VPA levels
!
This MA/SR on interactions b/w antiepiletics & antibiotics found carbapenem-VPA interaction asso'd w/ by ~43 microgram/mL in VPA level.
https://link.springer.com/article/10.1007%2Fs40262-018-0720-z
7/n
Carbapenems
glucuronidation of VPA, i.e. the form of VPA that is excreted. So, VPA levels
!This MA/SR on interactions b/w antiepiletics & antibiotics found carbapenem-VPA interaction asso'd w/
by ~43 microgram/mL in VPA level.https://link.springer.com/article/10.1007%2Fs40262-018-0720-z
7/n
Bottom line:
1. #Antibiotics are NOT benign.
2. Never hesitate to ask for assistance checking for drug-drug interactions. #Pharmacists are here to help - it's our expertise! #medsafety #patientsafety
/fin
1. #Antibiotics are NOT benign.
2. Never hesitate to ask for assistance checking for drug-drug interactions. #Pharmacists are here to help - it's our expertise! #medsafety #patientsafety
/fin
