title: 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%, 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 indicates a safer pattern of moderate doses with more frequent administration of amikacin at the tubular injury level. Higher doses of amikacin could be safely administered to achieve PK/PD goal of Cmax>40 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.
authors.affiliation: Department of Clinical Pharmacy, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran. farhad.najm@gmail.com.
authors.forename: Farhad
authors.initials: F
authors.lastname: Najmeddin
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, Sina Hospital, Tehran University of Medical Sciences, Tehran, Iran. aarezoo24@gmail.com.
authors.forename: Arezoo
authors.initials: A
authors.lastname: Ahmadi
authors.affiliation: Department of Clinical Pharmacy, Faculty of Pharmacy, Shiraz University of Medical Sciences, Fars, Iran. Mahmoudi_l@sums.ac.ir.
authors.forename: Laleh
authors.initials: L
authors.lastname: Mahmoudi
authors.affiliation: Department of Clinical Pharmacy, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran. kourosh.sadeghi@gmail.com.
authors.forename: Kourosh
authors.initials: K
authors.lastname: Sadeghi
authors.affiliation: Department of Clinical Pharmacy, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran. khalilih@sina.tums.ac.ir.
authors.forename: Hossein
authors.initials: H
authors.lastname: Khalili
authors.affiliation: Research Center for Rational Use of Drugs, Tehran University of Medical Sciences, Tehran, Iran. atabaknajafi@hotmail.com.
authors.forename: Alireza
authors.initials: A
authors.lastname: Ahmadvand
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, Sina Hospital, Tehran University of Medical Sciences, Tehran, Iran. atabaknajafi@hotmail.com.
authors.forename: Atabak
authors.initials: A
authors.lastname: Najafi
authors.affiliation: Department of Clinical Pharmacy, Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran, Iran. mojtahed@sina.tums.ac.ir.
authors.forename: Mojtaba
authors.initials: M
authors.lastname: Mojtahedzadeh
mesh_terms: D000328:Adult; D000583:Amikacin / Q000008:administration & dosage* / Q000627:therapeutic use; D000900:Anti-Bacterial Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D016638:Critical Illness; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D018805:Sepsis / Q000188:drug therapy*; D016037:Single-Blind Method
chemical_list: D000900:Anti-Bacterial Agents; D000583:Amikacin