Aminoglycosides

Structure of gentamicin

Structure of streptomycin

Aminoglycosides are bactericidal antibiotics, mainly used in hospitals.

Mechanism of action

They inhibit protein synthesis by irreversible binding to the 30S subunit of the ribosome.

Antimicrobial spectrum

Aminoglycosides are mainly effective against infections caused by Gram-negatives (Escherichia, Klebsiella, Enterobacter, Serratia, Citrobacter, Pseudomonas, Acinetobacter, Salmonella, Shigella) and Gram-positives (Staphylococcus aureus, including β-lactamase-producing strains, Staphylococcus epidermidis). Less sensitive to resistant are streptococci and enterococci. Anaerobes are naturally resistant.

Pharmacokinetics

Aminoglycosides are not absorbed per os and act locally in the GIT. They are used parenterally (mostly i.v.). They are also well absorbed after i.m. administration. They penetrate poorly into body fluids and tissues. They are not metabolised and are excreted by glomerular filtration. Elimination is markedly reduced in renal impairment (in patients with renal insufficiency and failure; in children in the first week of life, especially premature infants due to renal immaturity; in old age when glomerular filtration decreases due to reduced renal blood flow). In these cases, aminoglycosides may accumulate and cause toxic damage. In the renal tubules, they enter cells by active transport and penetrate into lysosomes, where they cause intracellular shedding of autolytic lysosomal enzymes and subsequent cell autolysis and necrosis.

Pharmacodynamics

The effect of aminoglycosides is dependent on plasma concentration. They are hydrophilic, so they do not penetrate biological membranes easily. They are subject to active O2-dependent transport across the inner part of the membrane (therefore they do not act on anaerobes). They induce a rapid killing phase (6 h), followed by a bacteriostasis phase (even when antibiotic concentrations are low), when bacterial regrowth does not occur. This phase is also called the "post-antibiotic effect" (PAE). Its magnitude is determined by the size of the cmax, and the type of bacteria. It is amplified by the presence of leukocytes. Combination with β-lactams facilitates penetration by passive diffusion.

Side effects and toxicity

Aminoglycosides are potentially ototoxic. Ototoxicity may be acute (after high dose) from reversible blockade of calcium current in hair cells, which can be corrected by calcium administration because of the competitive antagonism between the antibiotic and calcium. Chronic ototoxicity is attributed to the time of exposure (AUC) and is up to 50% irreversible, unpredictable, sudden and intense after 5-7 days of treatment. Adverse effects include neurotoxicity. Aminoglycosides are also nephrotoxic due to their effect on the renal tubules. The damage tends to be reversible. It is important to note that they are one of the few antibiotics whose effect and toxicity correlate closely with plasma concentrations (better than dose). Yet the difference between the concentrations underlying antibiotic and toxic effects is small (they have a narrow therapeutic window). Therapeutic drug monitoring (TDM) is performed.

Benefits of aminoglycosides

• Bactericidal
• postantibiotic effect
• low price

Indications

Treatment with aminoglycoside antibiotics is indicated for more serious infections: septic conditions, CNS infections, respiratory tract infections (pneumonia), intra-abdominal and hepatobiliary infections, endocarditis, complicated urinary tract infections with sensitive agents included in the antibiotic spectrum. In monotherapy they are used only in urinary tract infections, otherwise in combination mostly with β-lactams. In enterococcal endocarditis in combination with ampicillin.

Representatives of antibiotics

• basic aminoglycosides of older type (with defined indication): streptomycin, neomycin, kanamycin
• highly effective newer ones with lower toxicity: gentamicin, tobramycin, amikacin, netilmicin

Streptomycin
It is the drug of choice for brucellosis, tularemia, nodular fever, used as an antituberculosis. In combination with penicillin, it is used to treat endocarditis caused by viridal streptococci or enterococci.

Gentamicin

The basic broad-spectrum antibiotic of this group. It should not be given to pregnant women, newborns and premature infants. Adverse effects include nephrotoxicity (albuminuria, proteinuria), ototoxicity (dizziness, vertigo), curareform effects (neostigmine is an antagonist), skin manifestations, increased liver tests, changes in blood pressure and others.

Amikacin

It is used to treat infections that are caused by gentamicin-resistant microbes.

Links

Related articles

• Antibiotics

Sources

• MARTÍNKOVÁ, J., S. MIČUDA a J. CERMANOVÁ. Antibiotika [online]. [cit. 2010-07-25]. <https://www.lfhk.cuni.cz/farmakol/predn/bak/kapitoly/atb-bak.doc/>.

• LINCOVÁ, Dagmar a Hassan FARGHALI, et al. Základní a aplikovaná farmakologie. 2. vydání. Praha : Galén, 2007. ISBN 978-80-7262-373-0.

Antibiotics and chemoterapeutics

baktericidal	aminoglycosides	amikacin, gentamycin, isepamycin, neomycin, netilmicin, spectinomycin, streptomycin, tobramycin
	antituberkulotics	izoniazid, cykloserin, ethambutol, ethionamid, kapreomycin, pyrazinamid, viomycin
	beta-lactam	cephalosporins	I.generation	cafazolin, cefadroxil, cefalexin, cefalotin, cefapirin
			II.generation	cefuroxim, cefamandol, cefpodoxim, proxetil, cefprozil monohydrate, cefuroxim-axetil
			III.generation	cefotaxim, cefetamet pivoxil, cefixim, cefoperazon, cefsulodin, ceftazidim, ceftibuten, ceftriaxon, co-cefoperazon
			IV.generation	cefepim, cefpirom
			V.generation	ceftarolin
		carbapenems	imipenem, doripenem, ertapenem, merapenem
		monobaktams	aztreonam
		penicillins	narrow-spectrum penicillins	penicillin G, penicillin V, cloxacilin, dicloxacilin, oxacilin, flucloxacilin
			broad-spectrum penicillins	amoxicilin, ampicilin, ticarcilin, piperacilin
			beta-lactam inhibitors	co-amoxicilin, co-ticarcilin, sulbaktam, tazobaktam
	glycopeptides	teikoplanin, vankomycin
	quinolones	I.generation	nalidixic acid, oxolinic acid
		II.generation	ciprofloxacin, norfloxacin, pipemicid acid, rosoxacin
		III.generation	sparfloxacin, enoxacin, floroxacin, lomefloxacin, ofloxacin, pefloxacin
		IV.generation	moxifloxacin
	nitroimidazoles	metronidazol, ornidazol
	nitrofurans	furazolidon, nifuratel, nifuroxazid, nitrofurantoin,
	polypeptide antibiotics	bacitracin, colistin, gramicidin, polymyxin B
	rifamycins	rifampicin, rifabutin, rifaximin, rifamycin
bakteriostatic	amphenicol	azidamfenikol, chloramfenikol, florfenikol, thiamfenikol
	glycylcyclines	tigecyclin
	lincosamides	klindamycin, linkomycin
	macrolides	I.generation	erytromycin, josamycin, oleandomycin, spiramycin
		II.generation	azithromycin, clarithromycin, roxithromycin
	oxazolidinones	linezolid
	pyrimidines	co-trimoxazol, pyrimetamin, trimetoprim
	streptogramins	streptogramin A, B
	sulphonamides	sulfamothoxazol, sulfasalazin, sulfathiazol, sulfisoxazol
	sulfones	dapson
	tetracyclines	doxycyklin