Single- and multiple-dose pharmacokinetics of ethambutol and rifampicin in a tuberculosis patient with acute respiratory distress syndrome undergoing extended daily dialysis and ECMO treatment

Abstract

The dosing of drugs in critically ill patients undergoing renal replacement therapy is based on limited data. We report for the first time single- and multiple-dose pharmacokinetics of ethambutol (EMB), which is cleared renally to 80%, and rifampicin (RIF), which is cleared renally to <30%, in a patient requiring both extracorporeal membrane oxygenation (ECMO) and renal replacement therapy. Extended dialysis removed a considerable amount of both EMB and RIF, with a dialyser plasma clearance ranging between 37 and 95 ml/min for EMB and between 39 and 53 ml/min for RIF. The EMB peak level (3h after a 2-h infusion) using a dose of 1000 mg/day on the first day of treatment was 2.3mg/l, which is in the low therapeutic range (2-5mg/l). Doubling the dose to 2000 mg/day resulted in peak levels slightly to markedly above the recommended range. There was no detectable effect of the ECMO membrane on the removal of both drugs. After an initial dose as for patients without renal impairment (15 mg/kg/day), therapeutic drug monitoring should be used to guide EMB dosing in patients undergoing extended daily dialysis.

Pharmacokinetic changes of antibiotic, antiviral, antituberculosis and antifungal agents during extracorporeal membrane oxygenation in critically ill adult patients

“…The available studies have shown significant variability, suggesting the importance of therapeutic drug monitoring (TDM). One case report showed that extended dialysis in an ECMO patient effectively eliminates ethambutol, and rifampicin could also be found in the spent dialysate, despite previous reports indicating that it is not dialysable . In a matched cohort study with 5 patients receiving RRT and ECMO and 6 patients receiving ECMO only, variation in meropenem clearance was correlated with presence of RRT .…”

“…Because these drugs are cleared by extended dialysis, the impact of ECMO is difficult to assess. However, the removal of ethambutol and rifampicin by the ECMO membrane was not detected when pre‐ and post‐ECMO filter levels were measured . In another case report, the plasma concentration of rifampicin was below the therapeutic level, despite the use of a higher dose (750 mg) than is recommended (600 mg) .…”

“…There were 2 case reports regarding antituberculosis agents in adult ECMO patients ( ter levels were measured. 29 In another case report, the plasma concentration of rifampicin was below the therapeutic level, despite the use of a higher dose (750 mg) than is recommended (600 mg). 60 This indicated that rifampicin PK were influenced by ECMO or exhibit variation among patients.…”

“…One case report showed that extended dialysis in an ECMO patient effectively eliminates ethambutol, and rifampicin could also be found in the spent dialysate, despite previous reports indicating that it is not dialysable. 29 In a matched cohort study with 5 patients receiving RRT and ECMO and 6 patients receiving ECMO only, variation in meropenem clearance was correlated with presence of RRT. 30 In an observational study, oseltamivir PK was compared among ECMO patients with preserved renal function, patients on both ECMO and continuous venovenous haemodiafiltration (CVVHDF) and healthy volunteers.…”

Medication Complications in Extracorporeal Membrane Oxygenation

“…Ethambutol doses between 1000-2000 mg/day are suggested for patients on renal replacement therapy to achieve target peak levels. 100 These conflicting data supports the use of therapeutic drug monitoring in ECMO patients to ensure target concentrations.…”