Administration of Higher Doses of Amikacin in Early Stages of Sepsis in Critically Ill Patients

Abstract

High-dose extended-interval dosage (HDED) regimen of aminoglycosides is now considered as the standard dosage strategy in sepsis. Although safety and efficacy of this dosing regimen is well studied, but new experiments show increased the risk of resistance development associated with %T>MIC less than 60% of the dosing interval following extended interval dosing. Moreover, limited information is available about safety of more frequent administration of high dose aminoglycosides. Authors studied nephrotoxicity following seven days' exposure to more frequent administration of higher doses of amikacin comparing with HDED regimen. In addition to Serum Creatinine (SrCr) and estimated glomerular filtration rate (eGFR), nephrotoxicity was studied with Neutrophil gelatinase-associated lipocalin (NGAL), a direct marker of tubular injury. A total of 40 patients with sepsis were quasi-randomized in two groups. Seven days' course of treatment with a moderate dose of amikacin (12.5 mg/Kg) was administered every 12 hours, known as the moderate-dose non-liberal-interval dosage (MDNLD) regimen compared with the high-dose extended-interval dosage (HDED) regimen (25 mg/Kg every 24 hours). The pharmacokinetic/pharmacodynamic (PK/PD) goal of the MDNLD regimen was the Cmax>40 and the %T>MIC more than 60% during the PK/PD goal for the HDED regimen was the Cmax>60. The eGFR change from the baseline was the primary outcome of the study with a minimum clinical significance of 20 ml/min (estimated SD of 20, Power>90%, P40 and %T>MIC more than 60% of the dosing interval. This dosing regimen would be considered as an alternative to minimize the resistance development associated with the extended-interval dosing in septic patients with multi-drug resistant gram-negative organisms.