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Drug Therapy Indian Pediatrics 2001; 38: 1370-1373 |
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Imipenem |
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Imipenem is a broad spectrum b-lactam antibiotic, belonging to the group carbe-penems. It is derived from a compound called theinamycin, which is produced by Strepto-myces cattleya(1). Mechanism of Action Imipenem binds to penicillin binding proteins, disrupts bacterial cell wall synthesis and causes death of the micro-organisms(1). The excellent activity of imipenem is the result of lack of permeability barrier, high affinity for penicillin binding proteins and great b-lactamase stability(2). Pharmacokinetics Imipenem is not absorbed orally. When given parenterally, it is degraded by a naturally occurring enzyme renal dehydro-peptidase present in the proximal renal tubules; therefore it is used in combination with cilastatin in 1:1 ratio. Cilastatin is inhibitor of the enzyme dehydropeptidase and has no intrinsic antibacterial activity. Half-life of both imipenem and cilastatin is one hour(1). Animal studies have shown that cilastatin eliminates the nephrotoxicity produced by high doses of imipenem. Various authors have reported plasma protein binding of imipenem up to 20% and that of cilastatin as 35%(3,4). When used in combination with cilastatin, about 70% of the administered drug is recovered from the urine as active form(5). Dosage of the imipenem needs to be modified in patients with renal insufficiency. If creatinine clearance is 20-50 ml/minute, dose of imipenem should be decreased to half of the recommended dosage and if clearance is <20 ml/minute, dose needs to be decreased to one fourth(6). Imipenem as well as cilastatin penetrate well into the cerebrospinal fluid in presence of meningeal inflammation(7). Both imipenem and cilastatin are effectively removed during hemodialysis. Bermal et al. have seen that dialysis removed 80-90% of imipenem and 60% of cilastatin from the plasma(2). Spectrum of Activity Imipenem has an excellent activity against aerobic and anaerobic Gram-positive as well as Gram-negative bacteria. It has high in vitro activity against Escherichia coli, Strepto-cocci, Haemophilus influenzae, Staphyloco-ccus aureus, Listeria monocytogenes, Pseudomonas aeruginosa, enterococci and Listeria. Anaerobes including b-fragilis are highly susceptible(1). The only bacteria considered resistant to imipenem are Pseudo-monas cepacia, Pseudomonas maltophilia and Streptococcus faecium(5). Methicillin resistance of staphylococci is medicated by the mec A gene. This gene encodes for penicillin binding protein (PBP 2a), which has low affinity for all b-lactams and is responsible for resistance of staphylococci to all b-lactams including carbapenems(8). Some of the nosocomial isolates of P. aeruginosa are resistant to imipenem. This resistance is often associated with loss of 46-48-K Da outer membrane protein, which has been named as Opr-D. In strains deficient in Opr-D, production of b-lactamases leads to imipenem resistance(9). There is also report of presence of carbapenemases, enzymes able to hydrolyze carbepenems with fast kinetics(10). Reports of nosocomial P. aeruginosa isolates producing acquired carbapenamases from various countries suggest that this fearsome mechanism of resistance could become a global problem(11). Side Effects Most common side effects with imipenem are nausea and vomiting(1). Other side effects reported with this drug are diarrhea, rash, thrombophlebitis, thrombocytosis, neutro-penia, eosinophilia and derangements of liver and renal functions(1,7). Use of imipenem is not recommended for patient with history of anaphylactic reaction with penicillin(12). Like other b-lactams, it also has a neurotoxic potential and it seems to be higher than that of penicillins and cephalo-sporins(13). The studies in animals have shown that interaction of imipenem with gamma-aminobutyric acid receptors of brain cells lowers the seizure threshold(14). The important factor increasing the risk of neurotoxicity with this drug is administration of excessive dosages relative to body weight or renal functions. Calandra et al. have reported that the seizures during therapy with imipenem subsided with a decrease or discontinuation of imipenem and treatment with anti-convulsants like phenytoin and diazepam(15). Colonization with candida or imipenem resistant bacteria has been reported in about 16% and super-infection in about 6% of patients on imipenem therapy. Winston et al have described super infection with resistant organisms in 6 of 17 patients treated for P. aeruginosa infections(16). Imipenem can lead to production of b-lactamases from which it itself is resistant, but other concurrently administered anti-biotics may not be. Therefore, if used extensively in intensive care setting, it has potential to make other penicillins and cephalosporins ineffective(17). Therapeutic Uses Imipenem is potentially useful drug for initial and empirical treatment of nosocomial infections thought to be caused by multiple bacterial species or multi-resistant organisms. Alpert et al. have used imipenem successfully in children of age group 3 months to 13 years having cellulitis, osteomyelitis, septic arthritis, lymphadenitis, renal infections, pneumonia and wound infections(18). Ahonkhai et al. have reported safety and efficacy of imipenem in children of age group 26 days to 11 years(19). Oral et al. have shown that imipenem/cilastatin is a good alternative for Klebseilla pneumonia sepsis in neonates(20). In a study by Wong et al. eradication of bacteria from cerebrospinal fluid was demonstrated within 24 hours of antibiotic therapy in 22 out of 24 patients and rest 2 patients achieved bacteriological cure after 2-3 days of imipenem/cilastatin. Usefulness of imipenem/cilastatin for the treatment of bacterial meningitis may be limited by a possible increased incidence of drug related seizures(21). However, because course of drug related seizures is relatively benign, imipenem still has a significant role in treatment of drug resistant meningitis. Imipenen has a potential to act as mono-therapy for fever and suspected infections in patients with malignancies(22). Bodey et al. have shown 76% response with imipenem in 45 documented infectious in neutropenic patients(23). To conclude, imipenem should be reserved for serious infections caused by resistant organisms to minimize the rapid emergence of resistant bacteria. Dosage The recommended dosage(18,19,24) is depicted in Table I.
+ Most of the authors have mentioned the use of imipenem as IV infusion.
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