Ethambutol Is Cleared by a Contemporary High-Flux Hemodialyzer, and Drug Monitoring Ensures Safety and Therapeutic Effect

Abstract

It is uncertain, given the lack of recent data and the inconclusive nature of previous data, whether ethambutol is cleared by hemodialysis using contemporary dialyzers. We measured serum ethambutol concentrations before, during, and 1 h after hemodialysis in a 75-year-old Caucasian man receiving ethambutol for disseminated Bacille Calmette-Guérin infection. There was a mean 41% decrease in serum ethambutol concentration during dialysis, confirming the hemodialyzability of ethambutol and the utility of drug monitoring in ensuring safety.KEYWORDS drug monitoring, ethambutol, hemodialysis E thambutol, a dextro-2,2=-(ethylenediimino)-di-1-butanol dihydrochloride with a molecular weight of 277.23, is highly active against Mycobacterium tuberculosis, Mycobacterium bovis, and certain nontuberculous mycobacteria but not against Mycobacterium simiae, Mycobacterium ulcerans, or Mycobacterium haemophilum (1). The hydrochloride salt has two apparent dissociation constants of 6.35 and 9.35 pKa, and the monohydrochloride predominates in solution at neutrality (2). The logarithm of its partition coefficient (log P) is Ϫ0.14 (2).The MIC of ethambutol for wild-type M. tuberculosis is 0.5 to 2 mg/liter (3), while the MIC for Bacille Calmette-Guérin (BCG) strains of M. bovis is 2 to 4 mg/liter (4, 5). Ethambutol is used as part of the primary treatment regimens for tuberculosis and systemic BCG infection but has significant potential side effects. The most serious adverse effect of ethambutol is optic neuritis, which is dose related (3, 6). A study by Griffith et al. (7) found that the incidence of optic neuritis when ethambutol was taken for Ͼ2 months at a dose of 25 mg/kg daily was 5% to 6%, whereas with a dose of 15 mg/kg daily, it was 1%.Eighty percent of absorbed ethambutol is excreted unchanged by the kidney, with the remainder excreted as inactive metabolites, also in the urine (8). Given its high degree of renal clearance, the risk of ocular toxicity is increased with impaired renal function (9), especially as the half-life of 4 h may be more than doubled in end-stage renal disease (10). This poses a serious problem in patients on hemodialysis who require treatment with ethambutol, particularly because there is an increased risk of tuberculosis in this population (11). While the risk of toxicity with ethambutol is dose dependent, the doses at which adverse events occur vary with individual patients and the rates at which they clear the drug. Therefore, the exact dose adjustment to be made should be guided by therapeutic drug monitoring to suit the individual pharmacokinetics of ethambutol for a particular patient with end-stage renal disease.

Difficulties in Diagnosing and Treating Disseminated Bacillus Calmette-Guérin (BCG) Infection After Intravesical BCG Therapy in a Patient with Liver Cirrhosis: A Case Report

“…Interestingly, according to Park et al, this incidence increases to 17% when a liver disease coexists, irrespective of the presence or absence of cirrhosis [ 48 ]. In contrast, ethambutol is not associated with clinically important hepatotoxic effects [ 25 , 49 ].…”

Ethambutol and isoniazid induced severe neurotoxicity in a patient undergoing continuous ambulatory peritoneal dialysis

“…Nearly 80% of EMB is eliminated unchanged by the kidney,10 but in patients with compromised renal function, the clearance of EMB significantly decreases and its half-life is prolonged following the usual dosage of 15 mg/kg 11. One recent study reported a 41% decrease in serum ethambutol concentration during dialysis in a patient using contemporary High-Flux Hemodialyzer 12. A pharmacokinetic study of one CAPD patient found that 35.3% of EMB is eliminated by peritoneal dialysis 13…”

“…This agent is metabolised into a less active compound by n-acetyltransferase in the liver and then eliminated by the kidneys. Pharmacokinetic studies on haemodialysis patients have found that only 9.2% of INH is recovered in dialysate, which suggests that hepatic metabolism is the primary mechanism for the clearance of INH 12. Peritoneal dialysis is responsible for 1.3% of all INH clearance; the concentration of INH in the peritoneal fluid after 6 hour of dwell time reaches 53.3% of its simultaneous serum concentration 27…”

Therapeutic drug monitoring in patients with tuberculosis and concurrent medical problems

“…Given the risk for ocular toxicity, consideration may be given to substituting moxifloxacin for ethambutol in patients with renal dysfunction. TDM has been suggested for guiding therapy in patients receiving dialysis [180,181].…”