Neurotoxicity of carbapenem antibiotics: consequences for their use in bacterial meningitis

S. Ragnar Norrby*

Department of Infectious Diseases and Medical Microbiology, University of Lund, Lund University Hospital, SE 22185 Lund, Sweden

As reviewed by Schliamser et al.,1 ß-lactam antibiotics are potentially neurotoxic and may cause seizures if given in high doses relative to renal function and/or bodyweight. This was especially the case for the carbapenems and penems then studied, i.e. imipenem and FCE 22101 (ritipenem), which in a rabbit model were about 10 times more neurotoxic than benzylpenicillin.2 In patients, imipenem–cilastatin has been documented to cause seizures at a relatively high frequency if overdosed.3 The practical consequences of this are of limited importance if the dosage recommendations of the imipenem–cilastatin manufacturer are followed. However, as demonstrated by Wong et al.,4 the neurotoxic potential of imipenem– cilastatin was prohibitive for its use for the treatment of bacterial meningitis: at a dose of 25 mg/kg qds, seven of 25 children developed seizures and the trial had to be prematurely terminated.

It seems clear that the high degree of neurotoxity of imipenem–cilastatin and ritipenem is not a class phenomenon for carbapenems and penems but that, as discussed here, there are carbapenems that have a lower degree of neurotoxicity and therefore can be given at high doses and are useful in the treatment of infections in the central nervous system (CNS).

Pathogenesis of neurotoxicity of carbapenems

Studies by Hikida et al.5 and Sunagawa et al.6 have shown that the most probable mode by which carbapenems are neurotoxic is by interaction with the {gamma}-amino butyric acid receptor A (GABAA) and that this interaction depends primarily on the side chain on the second carbon atom in the carbapenem nucleus. The more basic this side chain is, the better is the binding to the GABAA and the higher the convulsant activity of the compound in animal models. Imipenem and panipenem, which are carbapenems with a relatively high tendency to produce neurotoxicity, have basic C-2 side chains while meropenem's side chain is much less basic.6 Several studies have indicated that the most important factor governing the neurotoxicity of a carbapenem is the concentration achieved in the brain tissue.1 In these animal experiments, meningitis did not increase the risk of seizures, nor was there any correlation between the drug concentration in cerebrospinal fluid (CSF) and epileptogenic activity. The brain tissue concentrations achieved in rabbit experiments with imipenem were similar to those reported in dogs given meropenem.2,7 However, others have postulated a correlation between the neurotoxicity of imipenem and the slow elimination of that antibiotic from CSF.8,9

In all of the animal studies mentioned above there is a consensus that meropenem is less neurotoxic than imipenem and that this is probably due to differences in the C-2 side chain. Since imipenem is always given together with cilastatin, a compound designed to inhibit the renal metabolism of imipenem and to eliminate its nephrotoxic potential, it could be argued that cilastatin increases the risk of neurotoxic reactions. However, several studies have demonstrated clearly that cilastatin is not neurotoxic and that the toxic moiety is the parent carbapenem compound rather than the open ß-lactam metabolite, resulting from degradation in the kidneys or elsewhere, of carbapenem.2,9

The lower incidence of seizures with meropenem is supported by the fact that in the phase I–III studies of that antibiotic, low frequencies of seizures were reported.10

Use of meropenem in meningitis

The high frequency of resistance to cephalosporins in Gram-negative aerobic bacilli and the increasing prevalence of highly penicillin-resistant pneumococci are factors that have increased the interest in alternatives to thirdgeneration cephalosporins as empirical therapy for bacterial meningitis. Meropenem is one such alternative, since it is highly resistant to virtually all clinically important ß-lactamases, including class I cephalosporinases and extended spectrum ß-lactamases (ESBLs).11 The MICs of meropenem against these organisms (excluding Pseudomonas aeruginosa, Stenotrophomonas maltophilia and some strains of Acinetobacter spp.) are normally <1 mg/L. In addition, meropenem has a high degree of activity against pneumococci, which have MIC90s of 0.13 mg/L when penicillin sensitive and 1 mg/L when penicillin resistant. Thus, meropenem is active against the three major pathogens causing bacterial meningitis (Streptococcus pneumoniae, Haemophilus influenzae and Neisseria meningitidis), as well as against Enterobacteriaceae and Listeria monocytogenes (MIC90 0.25 mg/L). This antibacterial spectrum means that meropenem is two- to fourfold more active than imipenem against Gram-negative pathogens but has only about half the activity against Gram-positive bacteria.

Three studies have been published in which meropenem was compared with other antibiotics for treatment of bacterial meningitis. Schmutzhard et al.12 randomized 56 adult patients to meropenem (n = 28), cefotaxime (n = 17) or ceftriaxone (n = 11). The dose of meropenem was 40 mg/kg up to 2 g every 8 h. In the meropenem group, five patients had meningococcal meningitis, six had pneumococcal meningitis and in four patients other pathogens were isolated, one of which was P. aeruginosa. In patients randomized to a cephalosporin, one had H. influenzae, three had meningococci, eight had pneumococci and three had other organisms. All bacterial isolates were eliminated during treatment. At the end of treatment, 23/23 patients on meropenem, nine of 12 on cefotaxime and eight of 10 on ceftriaxone were classified as cured. Reasons for exclusion from evaluation of clinical efficacy were not given for all patients but one patient randomized to meropenem had a post-traumatic brain abscess and another patient in the ceftriaxone group had meningitis caused by a ceftriaxone-resistant P. aeruginosa. The latter patient was treated successfully with meropenem outside the trial protocol. In cured patients, neurological sequelae or hearing impairment was noted in 16 patients on meropenem and 11 on cephalosporin. The high frequencies of hearing impairment, 11/28 in the meropenem group and nine of 28 in the cephalosporin groups might have been due to the fact that five of the patients had a history of pre-existing hearing loss and that audiometry was performed in all patients after treatment. In none of the patients were seizures seen during treatment.

Klugman et al.13 randomized 98 children with bacterial meningitis to meropenem 40 mg/kg every 8 h and 98 children to cefotaxime 75–100 mg/kg every 8 h. In evaluable patients, cure without sequelae was reported in 54/75 patients (72%) on meropenem and 52/64 (81%) randomized to cefotaxime. Of the remaining patients, two (both on cefotaxime) died and 21 patients (28%) on meropenem and 10 on cefotaxime (16%) had neurological and/or audiological sequelae. H. influenzae, N. meningitidis, S. pneumoniae or other organisms were isolated in 34, 29, 12 and 0, respectively, of patients randomized to meropenem and 32, 21, nine and two, respectively, of those given cefotaxime. In two of 63 meropenem patients and one of 58 cefotaxime patients from whom repeat CSF cultures were obtained, Haemophilus spp. could be isolated; the remaining cultures were sterile. Seizures after the start of therapy were seen in five patients randomized to meropenem and three who were given cefotaxime.

In a second paediatric study using the same meropenem dose and a cefotaxime dose of 45 mg/kg every 6 h, 258 patients (129 in each group) were included.14 Of the evaluable patients, 41 (53%) on meropenem and 42 (56%) on cefotaxime were cured without sequelae 5–7 weeks after treatment. Thirty-four (44%) and 29 (39%), respectively, survived with sequelae and three (4%) and four (5%), respectively, died. Microbiological eradication was achieved in 95% of meropenem patients and 96% of those on cefotaxime. Delayed sterilization of CSF was seen in two patients on meropenem and one on cefotaxime. These organisms were all H. influenzae as were two strains that persisted in the cefotaxime group. Seizures during treatment were reported in 15/129 children on meropenem (12%) and 22/129 (17%) on cefotaxime.

These three studies, and particularly the paediatric ones, provide excellent documentation of the clinical efficacy of meropenem in the treatment of meningitis. It seems clear that meropenem is as effective as cefotaxime for this indication. The trials did not include any patients with highly penicillin-resistant pneumococci as the cause of their meningitis. This was despite the fact that the paediatric studies were performed in countries with a high or moderately high incidence of such organisms (South Africa, Israel, Latin America and the USA). However, the mean CSF concentration of meropenem following a single dose of 40 mg/kg in patients with inflamed meninges who had received dexamethasone (which markedly reduces the CSF concentrations of ß-lactam antibiotics)17 has been reported to be 3.28 mg/L 2.5–3.5 h after administration.15 It has also been demonstrated, in hydrocephalic patients, that the elimination of meropenem is considerably slower from CSF (mean half-life 7.4 ± 2.9 h) than from serum (mean half-life 1.7 ± 0.6 h).16 It may be assumed that with repeated doses some CSF accumulation is obtained. These concentrations of meropenem should be compared with its reported activity against penicillin-resistant pneumococci, which are inhibited (MIC90) by 1 mg/L.11 Furthermore, in experimental meningitis in guinea-pigs, meropenem at a dose of 40 mg/kg eliminated penicillin-resistant pneumococci from the CSF in four of five animals and was significantly more acrive than the same dose of ceftriaxone.17 Thus, it seems that meropenem at the dose used in meningitis should be able to at least suppress growth of penicillin-resistant pneumococci although evidence of clinical efficacy needs to be obtained.

Conclusions

Carbapenems are not alike when it comes to the risk of neurotoxic adverse reactions. Meropenem has proven to be less neurotoxic in animal studies and seems also to be associated with fewer risks for seizures in patients. An important consequence is that meropenem, in contrast to imipenem, can be used for the treatment of bacterial meningitis. As such it is of interest in countries where the frequencies of organisms resistant to ampicillin and third-generation cephalosporins is high. There is also a need to evaluate meropenem and other carbapenems for their use in neonatal infections caused by Gram-negative bacilli that produce ESBLs or class I cephalosporinases.

Notes

* Tel: +46-46-171-126; Fax: +46-46-138-175; E-mail: Ragnar.Norrby{at}infek.lu.se Back

References

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