Carbapenems, seizures

The most common adverse effects of carbapenems—which tend to be more common with imipenem—are nausea, vomiting, diarrhea, skin rashes, and reactions at the infusion sites. Excessive levels of imipenem in patients with renal failure may lead to seizures. Meropenem, doripenem, and ertapenem are much less likely to cause seizures than imipenem. Patients allergic to penicillins may be allergic to carbapenems as well. 

The safety profile of the carbapenems is comparable to that of other beta-lactam antibiotics, in particular with regard to laboratory abnormalities, the most common ones being those related to liver function (3,4). In patients with pre-existing nervous system disease or who take dosages above the recommended limits (for example in renal impairment) seizures appear to be more common with imipenem + cilastatin. 

Seizures associated with imipenem + cilastatin have repeatedly been reported (5-7). As with other beta-lac-tam antibiotics, it is difficult to assess clearly the cause of a seizure in patients with a cluster of other predisposing factors for neurotoxicity (8) and hence to reach clear estimates of frequency. In a review of 1754 patients there was a similar incidence of seizures with imipenem -I- cilastatin as with other antibiotic regimens usually containing another beta-lactam (9). In rabbits imipenem -I- cilastatin and another carbapenems were more neurotoxic than benzylpenicillin (10). In mice, ataxia and seizures were seen, with much lower blood concentrations of imipenem than cefotaxime or benzylpenicillin (1900 pg/ml versus 3400 qg/ml and 5800 qg/ml) (11). In mice imipenem also lowered the convulsive threshold of pentetrazol (pentylenetetrazole) more than cefazolin or two other carbapenems (12). Cilastatin alone was not proconvulsant, but it increased the effects of co-adminis-tered imipenem. 

In animals, meropenem (17) and other carbapenems (18,19) were less epileptogenic than imipenem. In 403 children there was no meropenem-associated neurotoxicity (20) and meropenem was well tolerated in children with bacterial meningitis (21). In summary, a larger dose range of meropenem than imipenem appears to be tolerated, but when strictly observing known risk factors for seizure propensity the difference between the two compounds is very small (22,23). 

Carbapenems (imipenem more than meropenem) are believed to increase central nervons system excitation by inhibition of GABA binding to receptors. Combinations with other GABA inhibiting drngs snch as theophylline or qninolones have been reported to provoke seizures (45,46). 

Two carbapenems, meropenem and panipe-nem + betamipron, reduced serum valproic acid concentrations, and increased the risk of seizures (47,48). The mechanism of the interaction was unclear. Accelerated... 

Most common side effects include diarrhea, nausea, vomiting, headache, rash, and infusion-related reactions. Frequency and potential risk of seizures with imipenem appear to be greater in comparison with the other carbapenems and beta-lactam antibiotics. Seizures have occurred most commonly in patients with CNS disorders or bacterial meningitis and/or compromised renal function. May be prevented by dose adjusting for renal insufficency. Pseudomembranous colitis. 

Antibiotic carbapenem active against many aerobic and anaerobic bacteria, including penicillinase-producing organisms a bactericidal inhibitor of cell wall synthesis. Used with cilastatin (which inhibits metabolism by renal dehydropeptidases). Tox allergy (partial cross-reactivity with penicillins), seizures (overdose). Meropenem is similar but does not require cilastatin. 

Although there is only an isolated report of an interaction between valproate and imipenem, there are now several reports of the interaction between valproate and meropenem or panipenem. Seizures or increased seizure frequeney have been reported. It would therefore seem prudent to monitor the valproate levels in any patient also given carbapenems, being alert for the need to increase the valproate dosage, or to use another antibacterial, or an alternative to valproate. Carbamazepine and phenytoin did not interact in the above reports. The manufacturers of ertapenem have no reports of an interaction on their files, but prudently warn about a possible interaction with valproate because of the interactions seen with other carbapenems. 

Nervous system The carbapenems can cause seizures [SEDA-33, 491]. A 69-year-old man with diabetes and hypertension developed a glioblastoma, which was removed [4 j. About 1 month later, he developed skin and respiratory infections and was given imipenem. During the next 2 days his consciousness became impaired... 

Carbapenems An old Chinese man with epilepsy had seizures when meropenem was added to treatment with valproate [407 ]. In a retrospective study of six critically ill patients taking valproate who concurrently received meropenem (n = 4), imipenem (n = 1), or ertapenem (n = 1) mean plasma valproate trough concentrations fell by 58% and estimated mean valproate clearance increased by 191% compared with values obtained while they were not receiving a carbapenem five patients had generalized seizures during concurrent valproate -b carbapenem treatment, including two with no prior history of seizures [408 ]. Meropenem is an enzyme inducer. Because of this pharmacokinetic interaction, concurrent use of these medications should be avoided. 

Like other beta-lactam antibiotics, the carbapenems can cause seizures, which have been reported in association with imipenem + cilastatin 2, 3", 4, 5", 6, ], dori-penem /8, P 7, ertapenem [10, ll ], and panipenem [12 ]. 

Susceptibility fiictois The proconvulsant activity of the carbapenems, particularly imipenem, has limited their usefulness in patients at high risk of seizures, such as patients with nervous system infections, especially meningitis, chronic or acute nervous system damage, and more generally in patients with compromised rerud function and a reduced threshold for seizure activity. The risk of seizures due to carbapenems is increased by renal insufficiency... 

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