Aminoglycosides are among the oldest antibiotics available to treat serious infections caused by primarily, Gram-negative bacteria. The most commonly utilized parenteral agents in this class include gentamicin, tobramycin and amikacin. Aminoglycosides are concentration-dependent, bactericidal agents that undergo active transport into the cell where they inhibit protein synthesis on the 30S subunit of the bacterial ribosome. As the use of aminoglycosides became more widespread, the toxic effects of these agents, most notably ototoxicity and nephrotoxicity, became more apparent. When other, safer, antimicrobial agents became available, the use of aminoglycosides sharply declined. The development of multi-drug resistance among bacteria has now lead clinicians to reexamine the role of the aminoglycosides in the treatment of serious infections. This review will revisit the mechanism and risk factors for the development of aminoglycoside-induced nephrotoxicity, as well as strategies to prevent patients from developing nephrotoxicity.
Bakker-WoudenbergIARoosendaalR. Impact of dosage schedule of antibiotics on the treatment of serious infections. Intensive Care Med. 1990;16
(suppl 3):S229–S234.
5.
DrusanoGL. Role of pharmacokinetics in the outcome of infections. Antimicrob Agents Chemother. 1988;32
(3):289–297.
6.
MandellGLBennettJEDolinR. Mandell, Douglas, and Bennett’s Principles and Practice of Infectious Diseases. 7th ed. Philadelphia, PA: Churchill Livingstone/Elsevier; 2010.
7.
BeckerBCooperMA. Aminoglycoside antibiotics in the 21st century. ACS Chem Biol. 2013;8
(1):105–115.
8.
PatersonDLRobsonJMBWagenerMM. Risk factors for toxicity in elderly patients given aminoglycosides once daily. J Gen Internal Med. 1998;13
(11):735–739.
9.
EdsonRSTerrellCL. The aminoglycosides. Mayo Clin Proc. 1999;74
(5):519–528.
BurtonMEShawLMSchentagJJ, eds. Applied Pharmacokinetics and Pharmacodynamics, 4th ed. Philadelphia, PA: Lippincott, Williams & Wilkins; 2006.
12.
TurnidgeJ. Pharmacodynamics and dosing of aminoglycosides. Infect Dis Clin North Am. 2003;17
(3):503–28.
13.
Lopez-NovoaJMQuirosYVicenteL. New insights into the mechanism of aminoglycoside nephrotoxicity: an integrative point of view. Kidney Int. 2011;79
(1):33–45.
14.
MooreRDSmithCRLipskyJJ. Risk factors for nephrotoxicity in patients treated with aminoglycosides. Ann Intern Med. 1984;100
(3):352–357.
15.
PrinsJMWeverlingGJde BlokK. Validation and nephrotoxicity of a simplified once-daily aminoglycoside dosing schedule and guidelines for monitoring therapy. Antimicrob Agents Chemother. 1996;40
(11):2494–2499.
16.
VerpootenGAGiulianoRAVerbistL. Once-daily dosing decreases renal accumulation of gentamicin and netilmicin. Clin Pharmacol Ther. 1989;45
(1):22–27.
17.
De BroeMEVerbistLVerpootenGA. Influence of dosage schedule on renal cortical accumulation of amikacin and tobramycin in man. J Antimicrob Chemother. 1991;27
(suppl C):41–47.
18.
HawserSPBouchillonSKHobanDJ. In vitro susceptibilities of aerobic and facultative anaerobic Gram-negative bacilli from patients with intra-abdominal infections worldwide from 2005–2007: results from the SMART study. Int J Antimicrob Agents. 2009;34(6):585–588.
19.
KaysSECrowellWAJohnsonMA. Iron supplementation increases gentamicin nephrotoxicity in rats. J Nutr. 1992;121
(11):1869–1872.
20.
TrollforsBAlestigKKrantzI. Quantitative nephrotoxicity of gentamicin in nontoxic doses. J Infect Dis. 1980;141
(3):306–309.
21.
KlasterskyJHensgensCHenriA. Comparative clinical study of tobramycin and gentamicin. Antimicrob Agents Chemother. 1974;5
(2):133–138.
ParsonsPPGarlandHOHarpurES. Acute gentamicin-induced hypercalciuria and hypermagnesiuria in the rat: dose–response relationship and role of renal tubular injury. Br J Pharmacol. 1997;122
(3):570–576.
24.
BandayAAFarooqNPriyamvadaS. Time dependent effects of gentamicin on the enzymes of carbohydrate metabolism, brush border membrane and oxidative stress in rat kidney tissues. Life Sci. 2008;82
(9-10):450–459.
25.
BarclayMLBeggEJHicklingKG. What is the evidence for once-daily aminoglycoside therapy?Clin Pharmacokinet. 1994;27
(1):32–48.
26.
BarzaMIoannidisJPCappelleriJC. Single or multiple daily doses of aminoglycosides: a meta-analysis. BMJ. 1996;312
(7027):338–345.
27.
FreemanCDStrayerAH. Mega-analysis of meta-analysis: an examination of meta-analysis with an emphasis on once-daily aminoglycoside comparative trials. Pharmacotherapy. 1996;16
(6):1093–1102.
28.
HatalaRDinhTCookDJ. Once-daily aminoglycoside dosing in immunocompetent adults: a meta-analysis. Ann Intern Med. 1996;124
(8):717–725.
29.
MunckhofWJGraysonMLTurnidgeJD. A meta-analysis of studies on the safety and efficacy of aminoglycosides given either once daily or as divided doses. J Antimicrob Chemother. 1996;37
(4):645–663.
30.
PrinsJMBullerHRKuijperEJ. Once versus thrice daily gentamicin in patients with serious infections. Lancet. 1993;341
(8841):335–339.
31.
RybakMJAbateBJKangSL. Prospective evaluation of the effect of an aminoglycoside dosing regimen on rates of observed nephrotoxicity and ototoxicity. Antimicrob Agents Chemother. 1999;43
(7):1549–1555.
32.
PrinsJMBullerHRKuijperEJ. Once-daily gentamicin versus once-daily netilmicin in patients with serious infections—a randomized clinical trial. J Antimicrob Chemother. 1994;33
(4):823–835.
33.
MurryKRMcKinnonPSMitrzykB. Pharmacodynamic characterization of nephrotoxicity associated with once-daily aminoglycoside. Pharmacotherapy. 1999;19
(11):1252–1260.
34.
FreemanCDNicolauDPBelliveuPP. Once-daily dosing of aminoglycosides: review and recommendations for clinical practice. J Antimicrob Chemother. 1997;39
(6):677–686.
35.
DavisBD. Mechanism of the bactericidal action of the aminoglycosides. Microbiol Rev. 1987;51
(3):341–350.
AndersonETYoungLSHewittWL. Simultaneous antibiotic levels in “breakthrough” gram-negative rod bacteremia. Am J Med. 1976;61
(4):493–497.
38.
MooreRDSmithCRLietmanPS. Association of aminoglycoside plasma levels with therapeutic outcome in gram-negative pneumonia. Am J Med. 1984;77
(4):657–662.
39.
MooreRDLietmanPSSmithCR. Clinical response to aminoglycoside therapy: importance of the ratio of peak concentration to minimal inhibitory concentration. J Infect Dis. 1987;155
(1):93–99.
40.
ZhanelGGCraigWA. Pharmacokinetic contributions to postantibiotic effects, focus on aminoglycosides. Clin Pharmacokinet. 1994;27
(5):377–392.
41.
ZhanelGGHobanDJHardingGKM. The postantibiotic effect: a review of in vitro and in vivo data. DICP. 1991;25
(2):153–163.
42.
DaikosGLLo1ansVTJacksonGG. First-exposure adaptive resistance to aminog1ycoside antibiotics in vivo with meaning for optimal clinical use. Antimicrob Agents Chemother. 1991;35
(1):117–123.
43.
VerpootenGAGiulianoRAVerbistL. Once daily dosing decreases renal accumulation of gentamicin and netilmicin. Clin Pharmacol Ther. 1989;45
(1):22–27.
44.
VandewalleAFarmanNMorinJP. Gentamicin incorporation along the nephron: autoradiographic study on isolated tubules. Kidney Int. 1981;19
(4):529–539.
45.
BaileyTCLittleJRLittenbergB. A meta-analysis of extended-interval dosing versus multiple daily dosing of aminoglycosides. Clin Infec Dis. 1997;24
(5):786–795.
46.
ZaskeDESawchukRJGerdingDN. Increased dosage requirements of gentamicin in bum patients. Trauma. 1976;16
(10):824–828.
47.
WatlingSMDastaIF. Aminoglycoside dosing considerations in intensive care unit patients. Ann Pharmacother. 1993;27
(3):351–357.
48.
MarikPEHavlikIMonteagudoSE. The pharmacokinetics of amikacin in critically ill adult and pediatric patients: comparison of once- vs. twice-daily dosing regimens. Antimicrob Chemother. 1991;27
(suppl C):81–89.
49.
GillMAKernJW. Altered gentamicin distribution in ascitic patients. Am Hosp Pharm. 1979;36
(12):1704–1706.
50.
HessenMTPitsakisPGLevisonME. Absence of a postantibiotic effect in experimental pseudomonas endocarditis treated with imipenem, with or without gentamicin. Infect Dis. 1988;158
(3):542–548.
51.
PotelGCaillon 1FantinB. Impact of dosage schedule on the efficacy of gentamicin, tobramycin, or amikacin in an experimental model of Serratia marcescens endocarditis: in vitro–in vivo correlation. Antimicrob Agents Chemother. 1991;35
(1):111–116.
52.
StreetmanDSNafzigerANDestacheCJ. Individualized pharmacokinetic monitoring results in less aminoglycoside-associated nephrotoxicity and fewer associated costs. Pharmacotherapy. 2001;21(4):443–451.
