Administration of higher doses of amikacin in early stages of sepsis in critically ill patients.
AbstractHigh-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.
Dellinger RP, Levy MM, Carlet JM, et al. Surviving Sepsis Campaign: international guidelines for the management of severe sepsis and septic shock: 2008. Intensive Care Med 2008;34(1):17-60.
Kumar A, Zarychanski R, Light B, et al. Early combination antibiotic therapy yields improved survival compared with monotherapy in septic shock: a propensitymatched analysis. Crit Care Med 2010;38(9):1773-85.
Leekha S, Standiford HC. Empiric antimicrobial therapy for Gram-negative sepsis: Back to the future. Crit Care Med 2011;39(8):1995-6.
Lee K, Kim MN, Kim JS, et al. Further increases in carbapenem-, amikacin-, and fluoroquinolone-resistant isolates of Acinetobacter spp. and P. aeruginosa in Korea: KONSAR study 2009. Yonsei Med J 2011;52(5):793-802.
Tambyah PA, Hara GL, Daikos GL, et al. Treatment of extensively drug-resistant Gram-negative infections in= critically ill patients: Outcome of a consensus meeting at the 13th Asia-Pacific Congress of Clinical Microbiology and Infection, October 2012. J Glob Antimicrob Resist 2013;1(3):117-22.
Mojtahedzadeh M, Mahmoudi L. Aminoglycoside resistance in ICUs: are we running out of drugs, for bad bugs. Iranian J Pharm Res 2011;10(3):391-2.
European Committee on Antimicrobial Susceptibility Testing. Breakpoint tables for interpretation of MICs and zone diameters. ECAST. (Accessed in 2014, 14, at http://www.eucast.org/fileadmin/src/media/PDFs/EUCAS T_files/Breakpoint_tables/Breakpoint_table_v_3.1.pdf).
Mavros MN, Polyzos KA, Rafailidis PI, et al. Once versus multiple daily dosing of aminoglycosides for patients with febrile neutropenia: a systematic review and meta-analysis. J Antimicrob Chemother 2011;66(2):251-9.
Avent M, Rogers B, Cheng A, et al. Current use of aminoglycosides: indications, pharmacokinetics and monitoring for toxicity. Intern Med J 2011;41(6):441-9.
Cooper TW, Pass SE, Brouse SD, et al. Can pharmacokinetic and pharmacodynamic principles be applied to the treatment of multidrug-resistant Acinetobacter? Ann Pharmacother 2011;45(2):229-40.
Uhart M, Leroy B, Maire P, et al. Guidelines for aminoglycoside use and applicability to geriatric patients. Med Mal Infect 2013;43(3):118-22.
Zazo H, Martín-Suárez A, Lanao JM. Evaluating amikacin dosage regimens in intensive care unit patients: A pharmacokinetic/pharmacodynamic analysis using Monte Carlo simulation. Int J Antimicrob Agents 2013;42(2):155-60.
Tam VH, Ledesma KR, Vo G, et al. Pharmacodynamic modeling of aminoglycosides against Pseudomonas aeruginosa and Acinetobacter baumannii: identifying dosing regimens to suppress resistance development. Antimicrob Agents Chemother 2008;52(11):3987-93.
Haase M, Bellomo R, Devarajan P, et al. Accuracy of neutrophil gelatinase-associated lipocalin (NGAL) in diagnosis and prognosis in acute kidney injury: a systematic review and meta-analysis. Am J Kidney Dis 2009;54(6):1012-24.
Moore E, Bellomo R, Nichol A. Biomarkers of acute kidney injury in anesthesia, intensive care and major surgery: from the bench to clinical research to clinical practice. Minerva Anestesiol 2010;76(6):425-40.
Eriksson U, Seifert B, Schaffner A. Comparison of effects of amphotericin B deoxycholate infused over 4 or 24 hours: randomised controlled trial. BMJ 2001;322(7286):579-82.
Smyth AR, Bhatt J. Once-daily versus multiple-daily dosing with intravenous aminoglycosides for cystic fibrosis. Cochrane Database Syst Rev 2010;2(1):CD002009.
Prescott WA, Nagel JL. Extended-interval once-daily dosing of aminoglycosides in adult and pediatric patients with cystic fibrosis. Pharmacotherapy 2010;30(1):95-108.
Tam VH, Nikolaou M. A novel approach to pharmacodynamic assessment of antimicrobial agents: new insights to dosing regimen design. PLoS Comput Biol 2011;7(1):e1001043.
Mahmoudi L, Mohammadpour A, Ahmadi A, et al. Influence of sepsis on higher daily dose of amikacin pharmacokinetics in critically ill patients. Eurn Rev Med Pharmacol Sci 2013;17(3):285-91.