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Kourosh Sadeghi,1 Hadi Hamishehkar,2 Farhad Najmeddin,1 Arezoo Ahmadi,3 Ebrahim Hazrati,4 Hooshyar Honarmand,1 Mojtaba Mojtahedzadeh1,5 1Department of Clinical Pharmacy, School of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran; 2Department of Clinical Pharmacy, Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; 3Department of Anesthesia and Intensive Care, Sina Hospital, Tehran University of Medical Science, Tehran, Iran; 4Department of Anesthesia and Intensive Care, Imam Reza Hospital, Army University of Medical Sciences, Tehran, Iran; 5Pharmaceutical Sciences Research Center, School of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran Introduction: To achieve target concentrations, the application of higher-than-standard doses of amikacin is proposed for the treatment of sepsis due to an increase in volume of distribution and clearance, but little data are available on aminoglycoside administration in critically ill elderly patients. Patients and methods: Forty critically ill elderly patients (aged over 65 years) who required amikacin therapy due to severe documented, or suspected gram-negative infections, were randomly assigned to two treatment groups. Group A (20 patients) received 15 mg/kg amikacin and Group B (20 patients) received 25 mg/kg amikacin per day as a single daily dose. All the patients were monitored for renal damage by the daily monitoring of serum creatinine. The amikacin peak (Cmax) and trough (Cmin) serum concentrations were measured on Days 3 and 7 postadministration. Results: Data from 18 patients in Group A and 15 patients in Group B were finally analyzed. On Day 3, the amikacin mean Cmax levels in the standard and high-dose treatment groups were 30.4±11 and 52.3±16.1 µg/mL (P<0.001), and the Cmin levels were 3.2±2.1 and 5.2±2.8 µg/mL, respectively (P=0.035). On Day 7, the Cmax levels in the standard and high-dose

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%, P<0.05). No difference was observed between groups for the values of eGFR change and the SrCr percent change from the baseline (P=0.359 and P=0.114, respectively). Frequency of acute kidney injury also did not differ between groups (P=0.342). Serum NGAL level values' change from the baseline was more in the HDED regimen in comparison with the MDNLD regimen at third day and fifth day of the treatment (P=0.001 and P =0.002, respectively). This in