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Carbapenems
See also Beta-lactam antibiotics
General information
Carbapenems differ from penicillins and cephalosporins by a methylene substitution for sulfur in the five-membered beta-ring structure. Imipenem and meropenem belong to this class of compounds.
Although there are various natural carbapenems [ ], their potential is limited by chemical instability. Imipenem (N-formimidoylthienamycin), the first carbapenem in use, is therefore a stabilized synthetic compound. To overcome a second difficulty, namely inactivation by a kidney dehydropeptidase, imipenem has to be combined with cilastatin, a competitive inhibitor of that enzyme. Meropenem has better stability in the presence of renal dehydropeptidase I [ ]. The antibacterial spectrum of carbapenems is among the broadest of all beta-, and they have good stability against many beta-lactamases.
General adverse effects and adverse reactions
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 [ , ]. 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.
Organs and systems
Nervous system
Seizures associated with imipenem + cilastatin have repeatedly been reported [ ]. As with other beta-lactam antibiotics, it is difficult to assess clearly the cause of a seizure in patients with a cluster of other predisposing factors for neurotoxicity [ ] and hence to reach clear estimates of frequency. In a review of 1754 patients there was a similar incidence of seizures with imipenem + cilastatin as with other antibiotic regimens usually containing another beta-lactam [ ]. In rabbits imipenem + cilastatin and another carbapenems were more neurotoxic than benzylpenicillin [ ]. In mice, ataxia and seizures were seen, with much lower blood concentrations of imipenem than cefotaxime or benzylpenicillin (1900 μg/ml versus 3400 μg/ml and 5800 μg/ml) [ ]. In mice imipenem also lowered the convulsive threshold of pentetrazol (pentylenetetrazole) more than cefazolin or two other carbapenems [ ]. Cilastatin alone was not proconvulsant, but it increased the effects of co-administered imipenem.
Imipenem is a more common cause of seizures than other beta-lactam antibiotics, particularly when high doses are given [ ]. In one study, seven of 21 children developed seizure activity while receiving imipenem + cilastatin for bacterial meningitis, a recognized risk factor [ ]. However, computer-assisted monitoring of imipenem + cilastatin dosages in relation to renal function resulted in a reduced incidence of seizures [ ].
In animals, meropenem [ ] and other carbapenems [ , ] were less epileptogenic than imipenem. In 403 children there was no meropenem-associated neurotoxicity [ ] and meropenem was well tolerated in children with bacterial meningitis [ ]. 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 [ , ].
Sensory systems
Taste alterations were seen in some early patients who were treated with carbapenems [ ]; these observations have not subsequently been confirmed.
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