Imipenem-cilastatin dosing

Ritchie, D.J. Reichley, R.M. Canaday, K.L. Bailey, T.C. Evaluation and financial impact of imipenem/cilastatin dosing in elderly patients based on renal function and body weight. J. Pharm. Technol. 1993, 9, 160-163. 

Adjust dose of imipenem/cilastatin based on body weight (refer to package insert). 

Imipenem-Cilastatin IV Dosing Schedule for Adults with Normal Renal... 

Imipenem is a more common cause of seizures than other beta-lactam antibiotics, particularly when high doses are given (13-15). In one study, seven of 21 children developed seizure activity while receiving imipenem + cilastatin for bacterial meningitis, a recognized risk factor (13). However, computer-assisted monitoring of imipenem + cilastatin dosages in relation to renal function resulted in a reduced incidence of seizures (16). 

Drusano GL, Standiford HC, Bustamante Cl, Rivera G, Forrest A, Leslie J, Tatem B, Delaportas D, Schimpff SC. Safety and tolerability of multiple doses of imipenem/cilastatin. Clin Pharmacol Ther 1985 37(5) 539 3. 

A 20-year-old man with abdominal trauma received a single dose of piperacillin (1 g) followed by nine doses of imipenem + cilastatin (500 mg tds for 3 days) and 2 weeks later developed jaundice, fatigue, and pruritus (94). A liver biopsy showed centrilobular cholestasis, portal infiltration with eosinophils, and cholangitis. Lymphocyte transformation tests for piperacillin and imipenem/cilastatin were positive, suggesting an immunological mechanism. He made a full clinical and biochemical recovery after 3 months. 

Some resistant strains lack thymidine kinase. Cannot activate drug. Granuiocytopenia, thrombocytopenia. IV. Excreted unchanged in urine, decrease dose with renal dysfunction. Do not coadminister zidovudine (granulocytopenia) or imipenem-cilastatin (seizures). 

It should be noted that focal tremors, myoclonus and convulsions are a known adverse effects of imipenem/cilastatin and are most likely to occur in patients with reduced renal function. However, the patients cited above received imipenem/cilastatin in doses adjusted for their renal function. The manufacturers of imipenem/cilastatin recommend that patients who develop focal tremors, myoclonus and convulsions while receiving the antibacterial should be started on an antiepileptic drug. If symptoms persist the dose should be reduced, or the drug withdrawn. ... 

IV IV infusion over 20 minutes results in peak plasma levels of imipenem antimicrobial activity that range from 14 to 83 mcg/mL, depending on the dose. Plasma levels declined to 1 mcg/mL or less in 4 to 6 hours. Peak plasma levels of cilastatin following a 20-minute IV infusion range from 15 to 88 mcg/mL, depending on the dose. The plasma half-life of each component is approximately 1 hour. Protein binding is 20% for imipenem and 40% for cilastatin. 

Imipenem urine levels remain above 10 mcg/mL for the 12-hour dosing interval following IM administration of 500 or 750 mg doses. Total urinary excretion of imipenem and cilastatin averages 50% and 75%, respectively, following either dose. 

Pharmacokinetic studies have not been performed in horses however, i.v. doses of 0.7-1.Img/kg three times a day have been suggested as being suitable for use in small animals. Imipenem has to be administered i.v. because it is not absorbed following p.o. administration. Imipenem has been shown to penetrate inflamed meninges. It is metabolized extensively by the renal tubules to a potentially toxic compound. Therefore, it is usually combined with cilastatin, a drug that inhibits the renal tubular enzymes. The combined product produces high urine concentrations of active antibiotic and avoids renal toxicity. In the presence of cilastatin, 70% of a dose of imipenem is excreted unchanged in the urine. The half-life of imipenem in the dog is 30-45 nrin. 

Imipenem, a carbapenem antimicrobial, also possesses nephrotoxic potential. In animal models, nephrotoxicity is dose dependent and characterized by tubular necrosis. Interestingly, imipenem nephrotoxicity is markedly attenuated by co-administration of cilastatin, an inhibitor of the cytosolic and brush border enzyme dehydropeptidase I (DHP). Although DHP is responsible for hydrolyzing imipenem to inactive metabolites, the major protective effect of cilastatin appears to be due to inhibition of renal imipenem accumulation rather than DHP inhibition. 

Thienamycin (Fig. 10.5E) is a broad-spectrum p-lactam antibiotic with high P-lactamase resistance. Unfortunately, it is chemically unstable, although the N-formimidoyl derivative, imipenem, overcomes this defect. Imipenem (Fig. 10.5E) is stable to most P-lactamases but is readily hydrolysed by kidney dehydropeptidase and is administered with a dehydropeptidase inhibitor, cilastatin. Meropen-em, marketed more recently, is more stable than imipenem to this enzyme and may thus be administered without cilastatin. Its chemical structure is depicted in Fig. 10.5F. Ertapenem (Fig. 10.5G) has properties similar to those of meropenem but affords the additional advantage of once-daily dosing. 

Both drugs are used IV only. Imipenem is given with cilastatin, which inhibits its rapid metabolism by renal dihydropeptidases both drugs undergo renal elimination— 4- dose in renal dysfunction. 

IM/IV. Administered with cilastatin (inactive), which inhibits renal metabolism of imipenem. Poor oral absorption. Renal failure requires dose reduction. 

---