- Richard H Drew, PharmD, MS, FCCP
Richard H Drew, PharmD, MS, FCCP
- Professor, Campbell University College of Pharmacy and Health Sciences
- Associate Professor and Clinical Pharmacist, Infectious Diseases
- Duke University Medical Center
The aminoglycoside class of antibiotics consists of many different agents. Gentamicin, tobramycin, amikacin, streptomycin, neomycin, and paromomycin are approved by the US Food and Drug Administration (FDA) and available for clinical use in the United States. Of these, gentamicin, tobramycin, and amikacin are the most frequently prescribed for systemic administration. Plazomicin is an aminoglycoside currently under development in the United States for the treatment of multidrug-resistant organisms.
The most common clinical application (either alone or as part of combination therapy) of the aminoglycosides is in the treatment of serious infections caused by aerobic gram-negative bacilli [1,2]. While less common, aminoglycosides (in combination with other agents) have also been used for the treatment of select gram-positive infections. In addition, certain aminoglycosides have demonstrated clinically relevant activity against protozoa (paromomycin), Neisseria gonorrhoeae (spectinomycin, not available in the United States), and mycobacterial infections (tobramycin, streptomycin, and [most commonly] amikacin).
This topic will review basic issues related to the clinical use of systemic aminoglycosides, including mechanism of action, spectrum of activity, and adverse effects. Dosing and monitoring of aminoglycosides and administration in certain patients populations are discussed elsewhere. (See "Dosing and administration of parenteral aminoglycosides" and "Cystic fibrosis: Antibiotic therapy for lung disease", section on 'Aminoglycosides'.)
The multiple clinical settings in which the aminoglycosides may be used are also discussed separately in the appropriate topic reviews. (See "Gram-negative bacillary bacteremia in adults", section on 'Indications and rationale for combination therapy' and "Principles of antimicrobial therapy of Pseudomonas aeruginosa infections", section on 'Intravenous antibiotics' and "Antimicrobial therapy of native valve endocarditis", section on 'Viridans streptococci and Streptococcus bovis'.)
MECHANISM OF ACTION
The aminoglycosides primarily act by binding to the aminoacyl site of 16S ribosomal RNA within the 30S ribosomal subunit, leading to misreading of the genetic code and inhibition of translocation [3,4]. The initial steps required for peptide synthesis, such as binding of mRNA and the association of the 50S ribosomal subunit, are uninterrupted, but elongation fails to occur due to disruption of the mechanisms for ensuring translational accuracy . The ensuing antimicrobial activity is usually bactericidal against susceptible aerobic gram-negative bacilli.
- Kumana CR, Yuen KY. Parenteral aminoglycoside therapy. Selection, administration and monitoring. Drugs 1994; 47:902.
- Gilbert DN. Aminoglycosides. In: Principles and Practice of Infectious Diseases, 6th Ed, Mandell GL, Bennett JE, Dolin R (Eds), Churchill Livingstone, New York 2005. p.328.
- Fourmy D, Recht MI, Blanchard SC, Puglisi JD. Structure of the A site of Escherichia coli 16S ribosomal RNA complexed with an aminoglycoside antibiotic. Science 1996; 274:1367.
- Mingeot-Leclercq MP, Glupczynski Y, Tulkens PM. Aminoglycosides: activity and resistance. Antimicrob Agents Chemother 1999; 43:727.
- Nanavaty J, Mortensen JE, Shryock TR. The effects of environmental conditions on the in vitro activity of selected antimicrobial agents against Escherichia coli. Curr Microbiol 1998; 36:212.
- Moellering RC Jr. In vitro antibacterial activity of the aminoglycoside antibiotics. Rev Infect Dis 1983; 5:S212.
- Turner PJ. Meropenem activity against European isolates: report on the MYSTIC (Meropenem Yearly Susceptibility Test Information Collection) 2006 results. Diagn Microbiol Infect Dis 2008; 60:185.
- Griffith DE, Aksamit T, Brown-Elliott BA, et al. An official ATS/IDSA statement: diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases. Am J Respir Crit Care Med 2007; 175:367.
- Nahid P, Dorman SE, Alipanah N, et al. Official American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America Clinical Practice Guidelines: Treatment of Drug-Susceptible Tuberculosis. Clin Infect Dis 2016.
- Haidar G, Alkroud A, Cheng S, et al. Association between presence of aminoglycoside modifying enzymes and in vitro activity of gentamicin, tobramycin, amikacin and plazomicin against KPC and ESBL-producing Enterobacter spp. Antimicrob Agents Chemother 2016.
- Davies J, Wright GD. Bacterial resistance to aminoglycoside antibiotics. Trends Microbiol 1997; 5:234.
- Hon WC, McKay GA, Thompson PR, et al. Structure of an enzyme required for aminoglycoside antibiotic resistance reveals homology to eukaryotic protein kinases. Cell 1997; 89:887.
- Daigle DM, McKay GA, Wright GD. Inhibition of aminoglycoside antibiotic resistance enzymes by protein kinase inhibitors. J Biol Chem 1997; 272:24755.
- Doi Y, Arakawa Y. 16S ribosomal RNA methylation: emerging resistance mechanism against aminoglycosides. Clin Infect Dis 2007; 45:88.
- Yokoyama K, Doi Y, Yamane K, et al. Acquisition of 16S rRNA methylase gene in Pseudomonas aeruginosa. Lancet 2003; 362:1888.
- Poole K. Aminoglycoside resistance in Pseudomonas aeruginosa. Antimicrob Agents Chemother 2005; 49:479.
- Westbrock-Wadman S, Sherman DR, Hickey MJ, et al. Characterization of a Pseudomonas aeruginosa efflux pump contributing to aminoglycoside impermeability. Antimicrob Agents Chemother 1999; 43:2975.
- Gerding DN, Larson TA, Hughes RA, et al. Aminoglycoside resistance and aminoglycoside usage: ten years of experience in one hospital. Antimicrob Agents Chemother 1991; 35:1284.
- King JW, White MC, Todd JR, Conrad SA. Alterations in the microbial flora and in the incidence of bacteremia at a university hospital after adoption of amikacin as the sole formulary aminoglycoside. Clin Infect Dis 1992; 14:908.
- Costa Y, Galimand M, Leclercq R, et al. Characterization of the chromosomal aac(6')-Ii gene specific for Enterococcus faecium. Antimicrob Agents Chemother 1993; 37:1896.
- Bratzler DW, Dellinger EP, Olsen KM, et al. Clinical practice guidelines for antimicrobial prophylaxis in surgery. Am J Health Syst Pharm 2013; 70:195.
- Bratu S, Tolaney P, Karumudi U, et al. Carbapenemase-producing Klebsiella pneumoniae in Brooklyn, NY: molecular epidemiology and in vitro activity of polymyxin B and other agents. J Antimicrob Chemother 2005; 56:128.
- Novelli A, Mazzei T, Fallani S, et al. In vitro postantibiotic effect and postantibiotic leukocyte enhancement of tobramycin. J Chemother 1995; 7:355.
- Fantin B, Ebert S, Leggett J, et al. Factors affecting duration of in-vivo postantibiotic effect for aminoglycosides against gram-negative bacilli. J Antimicrob Chemother 1991; 27:829.
- McLean AJ, IoannidesDemos LL, Li SC, et al. Bactericidal effect of gentamicin peak concentration provides a rationale for administration of bolus doses. J Antimicrob Chemother 1993; 32:301.
- Freeman CD, Nicolau DP, Belliveau PP, Nightingale CH. Once-daily dosing of aminoglycosides: review and recommendations for clinical practice. J Antimicrob Chemother 1997; 39:677.
- Allan JD, Moellering RC Jr. Management of infections caused by gram-negative bacilli: the role of antimicrobial combinations. Rev Infect Dis 1985; 7 Suppl 4:S559.
- MECHANISM OF ACTION
- SPECTRUM OF ACTIVITY
- Gram-negative organisms
- Gram-positive organisms
- Gram-negative organisms
- CLINICAL USE
- Combination antibacterial therapy
- Antimycobacterial therapy
- Other aminoglycoside formulations
- PHARMACODYNAMICS AND KINETICS
- Post antibiotic effect
- Concentration-dependent killing
- Synergistic effect
- Absorption and time to peak levels
- Neuromuscular blockade
- DRUG INTERACTIONS