DESCRIPTION
Aminoglycosides are a group of antibiotics that inhibit bacterial protein synthesis and are particularly active against Gram-negative bacteria. This group of antibiotics includes several drugs, sharing the same basic chemical structure:
1. amikacin
2. arbekacin
3. gentamicin
4. kanamycin
5. neomycin
6. netilmicin
7. paromomycin
8. streptomycin
9. tobramycin
CHEMICAL STRUCTURE
The aminoglycosides consist of two or more amino sugars joined in glycosidic linkage to an hexose nucleus. Different aminoglycosides are distinguished by the amino sugars attached to the aminocyclitol. Streptomycin differs from the other aminoglycoside antibiotics in that it contains streptidine rather than 2-deoxystreptamine, and the aminocyclitol is not in a central position.
SPECTRUM AND INDICATIONS
The antibacterial activity of most aminoglycosides is directed primarily against aerobic gram-negative bacilli. They should not be used as single agents for infections caused by gram-positive bacteria but, if combined with a cell wall-active agent, such as a penicillin or vancomycin, aminoglycosides produce synergistic bactericidal effects against enterococci, streptococci, and stafilococci. On the contrary, aminoglycosides have little activity against anaerobic microorganisms or facultative bacteria under anaerobic conditions.
Empirical therapy
The primary indication for aminoglycosides is as short-term empirical therapy pending the outcome of investigations. Their value as empirical drugs relates to their rapid bactericidal activity and the comparatively low levels of resistance in many community and health care–associated Gram-negative pathogens. When used empirically, no further doses should be given beyond 48 hours.
Directed therapy
Aminoglycosides are indicated for directed therapy in only a few circumstances. These include, but are not restricted to:
1. infections when resistance to other safer antimicrobials has been shown (second line therapy)
2. combination therapy for serious Pseudomonas aeruginosa infections and brucellosis
3. low doses as synergistic treatment for streptococcal and enterococcal endocarditis.
In accordance with the theoric model, they are often emplyed in combination with beta lactam antibiotic in the treatment of sepsis but recent clinical studies have shown that the combination has neither clinical benefits nor protective effect against antimicrobial resistance.
Beta lactam antibiotic monotherapy versus beta lactam-aminoglycoside antibiotic combination therapy for sepsis, 2009
Effect of Aminoglycoside and β-Lactam Combination Therapy versus β-Lactam Monotherapy on the Emergence of Antimicrobial Resistance: A Meta-analysis of Randomized, Controlled Trials. 2005.
PHARMACOKINETICS
ABSORPTION:
The aminoglycosides are highly polar and, thus, poorly absorbed from the gastrointestinal (GI) tract. Some new formulations could improve intestinal transport thus making possible oral somministration.
A novel emulsifier, labrasol, enhances gastrointestinal absorption of gentamicin 2001
Toxic levels also may result from sustained topical application to large wounds, burns, or cutaneous ulcers, particularly with renal insufficiency. Long-term oral or rectal administration of aminoglycosides may result in accumulation to toxic concentrations in patients with renal impairment. Aminoglycosides are absorbed rapidly after intramuscular injection. In critically ill patients, especially those in shock, drug absorption from intramuscular sites may be reduced by poor perfusion.
DISTRIBUTION
These polar drugs do not penetrate into most cells, central nervous system (CNS), and the eye. Except for streptomycin, there is negligible binding of aminoglycosides to plasma proteins. The volume of distribution of these drugs approximates the volume of extracellular fluid. Concentrations of aminoglycosides in secretions and tissues are low. High concentrations are found only in the renal cortex and the inner ear, likely contributing to the aminoglycosides’ nephrotoxicity and ototoxicity. Aminoglycoside concentrations in CSF following parenteral administration are <10% of those in plasma (~25% with meningitis). Thus, CSF levels are usually subtherapeutic unless delivered intrathecally.
Administration of aminoglycosides to pregnant women may result in drug accumulation in fetal plasma and amniotic fluid. Streptomycin and tobramycin can cause hearing loss in children born to women who receive the drug during pregnancy. Gentamicin is more likely to cause kidney damage.
Immediate and long-term renal effects of fetal exposure to gentamicin. 1990
Aminoglycosides should be used with caution during pregnancy and only in the absence of suitable alternatives.
ELIMINATION
The aminoglycosides are excreted almost entirely by glomerular filtration. The plasma half-lives of the aminoglycosides vary between 2 and 3 hours in patients with normal renal function. Since aminoglycoside elimination depends almost entirely on the kidney, a linear relationship exists between the serum creatinine and the t1/2 of all aminoglycosides in patients with moderately compromised renal function.
Because the incidence of nephrotoxicity and ototoxicity is related to the concentration to which an aminoglycoside accumulates, it is critical to reduce the maintenance dosage of these drugs in patients with impaired renal function. The size of the individual dose, the interval between doses, or both can be altered.
Aminoglycoside use in renal failure 2010
Determination of drug concentration in plasma is essential for the proper administration of aminoglycosides.
Aminoglycosides can be removed from the body by either hemodialysis or peritoneal dialysis. Approximately 50% of the administered dose is removed in 12 hours by hemodialysis. The amount of aminoglycoside removed can be replaced by administering ~15–30% of the maximum daily dose each day. Frequent monitoring of plasma drug concentrations is crucial.
Influence of hemodialysis on gentamicin pharmacokinetics, removal during hemodialysis, and recommended dosing. 2008
Peritoneal dialysis is less effective than hemodialysis in removing aminoglycosides. Clearance rates are ~5–10 mL/min but highly variable. If a patient who requires dialysis has bacterial peritonitis, the antibiotic can be added to the dialysate to achieve concentrations equal to those desired in plasma. This is particularly useful in peritonitis which are the most important complication of peritoneal dialysis.
Use of bolus intraperitoneal aminoglycosides for treating peritonitis in end-stage renal disease patients receiving continuous ambulatory peritoneal dialysis and continuous cycling peritoneal dialysis. 2000
Aminoglycosides can be inactivated by various penicillins in vitro and in patients with endstage renal failure, further complicating dosage recommendations. Amikacin is least affected by this interaction.
Effect of concomitant administration of piperacillin on the dispositions of netilmicin and tobramycin in patients with end-stage renal disease.1990
MOLECULAR MECHANISM
The aminoglycoside antibiotics are rapidly bactericidal. Bacterial killing is concentration-dependent, but residual bactericidal activity persists even after the serum concentration has fallen below the minimum inhibitory concentration. These properties account for the efficacy of once-daily dosing regimens.
Driven by the membrane electrical potential (interior negative), aminoglycosides diffuse through aqueous channels formed by porin proteins in the outer membrane of gram-negative bacteria and enter the periplasmic space.
Bacterial uptake of aminoglycoside antibiotics. 1987.
Outer membrane channels and active transporters for the uptake of antibiotics. 2001
This rate-limiting process (and thus the antimicrobial efficacy of aminoglycosides) can be blocked or inhibited by a reduction in pH or anaerobic conditions, as in an abscess.
Failure of aminoglycoside antibiotics to kill anaerobic, low-pH, and resistant cultures. 1988
Once inside the cell, aminoglycosides bind to polysomes and interfere with protein synthesis by causing misreading and premature termination of mRNA translation.
The primary site of action of the aminoglycosides is the 30S ribosomal subunit; some aminoglycosides also bind to several sites on the 50S ribosomal subunit. Aminoglycosides disrupt the normal cycle of ribosomal function by interfering with the initiation of protein synthesis, leading to the accumulation of abnormal initiation complexes. Aminoglycosides also cause misreading of the mRNA template and incorporation of incorrect amino acids into the growing polypeptide chains. Aminoglycosides vary in their capacity to cause misreading, presumably owing to differences in their affinities for specific ribosomal proteins; bactericidal activity and the ability to induce misreading are strongly correlated. Moreover, the aminoglycosides are specific for prokaryotic ribosomes.
Antibiotics and the ribosome. 2006
Stereospecificity of aminoglycoside-ribosomal interactions. 2002.
Defining the basis for the specificity of aminoglycoside-rRNA recognition: a comparative study of drug binding to the A sites of Escherichia coli and human rRNA. 2005.
The resulting aberrant proteins may be inserted into the cell membrane, altering permeability and further stimulating aminoglycoside transport. Moreover, incorporation of mistranslated, misfolded proteins into the cell membrane stimulates the formation of lethal hydroxyl radicals by activating the bacterial envelope stress response system and interfering with the electron transport chain.
How antibiotics kill bacteria: from targets to networks. 2010
SIDE EFFECTS
NEUROMUSCULAR BLOCKADE
Acute neuromuscular blockade and apnea have been attributed to the aminoglycosides.
Neuromuscular blockade due to gentamicin sulfate 1988
Patients with myasthenia gravis are particularly susceptible.
Investigation on the mechanism of exacerbation of myasthenia gravis by aminoglycoside antibiotics in mouse model. 2005
In humans, neuromuscular blockade generally has occurred after intrapleural or intraperitoneal instillation of large doses of an aminoglycoside, but the reaction can follow intravenous, intramuscular, and even oral administration.
Neuromuscular blockade may be reversed with calcium gluconate infusion.
OTHER EFFECTS ON THE NERVOUS SYSTEM
The administration of streptomycin may produce dysfunction of the optic nerve, including scotomas, presenting as enlargement of the blind spot, and (rarely) peripheral neuritis. Paresthesia occasionally follows streptomycin use, usually within 30–60 minutes, and can persist for several hours.
OTHER ADVERSE EFFECTS
In general, aminoglycosides have little allergenic potential; anaphylaxis and rash are unusual.
Parenterally administered aminoglycosides are not associated with pseudomembranous colitis.
TOXICITY
All aminoglycosides can produce reversible and irreversible vestibular, cochlear, and renal toxicity.
OTOTOXICITY
Vestibular and auditory dysfunction can follow the administration of any of the aminoglycosides. Aminoglycosides progressively accumulate in the inner ear, and toxicity is more likely to occur in patients with persistently elevated plasma drug concentrations.
There have been proposed some mechanisms of action.
Polimorphisms in mitocondrial DNA seems to be implicated, because of different affinity to the drug.
Mitochondrial 12S rRNA mutations associated with aminoglycoside ototoxicity 2010
Drug store in inner ear is also improved by inflammation itself.
Infection-Mediated Vasoactive Peptides Modulate Cochlear Uptake of Fluorescent Gentamicin 2010
Ototoxicity is largely irreversible and results from progressive destruction of vestibular or cochlear sensory cells, which are highly sensitive to damage by aminoglycosides. The degree of permanent dysfunction correlates with the number of damaged sensory hair cells. Repeated courses of aminoglycosides, each probably resulting in the loss of more cells, are more likely to cause deafness. Since the initial symptoms may be reversible, patients receiving high doses and/or prolonged courses of aminoglycosides should be monitored carefully, but deafness may occur even after therapy is discontinued.
Loop diuretics such as ethacrynic acid and furosemide may potentiate the ototoxic effects of the aminoglycosides and should be avoided when possible.
Comparative analysis of combination kanamycin-furosemide versus kanamycin alone in the mouse cochlea 2010
Hearing loss following exposure to aminoglycosides is more likely to develop in patients with preexisting auditory impairment.
Clinical Symptoms of Cochlear Toxicity
A high-pitched tinnitus often is the first symptom of toxicity and can persist for days to weeks. It is followed in a few days by auditory impairment. Since high-frequency hearing is lost first, the patient may be unaware of the difficulty unless audiometric examination is performed.
Clinical Symptoms of Vestibular Toxicity
Headache may precede the onset of labyrinthine dysfunction, followed immediately by nausea, vomiting, and difficulty with balance, which develop acutely and persist for 1–2 weeks. The acute stage is followed by manifestations of chronic labyrinthitis, in which the patient has difficulty when attempting to walk or make sudden movements; ataxia is prominent. The chronic phase persists for ~2 months. Recovery may require 12–18 months; most patients have some permanent residual damage. Although there is no specific treatment for the vestibular deficiency, early drug discontinuation may permit recovery before irreversible damage of the hair cells.
NEPHROTOXICITY
Approximately 8–26% of patients who receive an aminoglycoside for more than several days will develop mild renal impairment that almost always is reversible. The most nephrotoxic aminoglycosides are neomycin, gentamicin, and tobramycin.
The toxicity results from accumulation and retention of aminoglycoside in the proximal tubular cells.
Megalin seems to be implicated in the transport of aminoglycosides into proximal tubular cells.
Molecular mechanisms underlying renal accumulation of aminoglycoside antibiotics and mechanism-based approach for developing nonnephrotoxic aminoglycoside therapy. 2006
Megalin's tissue distribution could explain also its accumulation in cells of the inner ear and the possible fetal damage.
Another hypothesis involves transient receptor potential receptors that are, typically, weakly-selective calcium-permeant cation channels that transduce environmental stimuli.
This mechanism in not dependent on endocytosis pathway like the previous one.
TRPV1 regulators mediate gentamicin penetration of cultured kidney cells. 2005
The initial manifestation is excretion of enzymes of the renal tubular brush border, followed by a defect in renal concentrating ability, mild proteinuria, and the appearance of hyaline and granular casts. The glomerular filtration rate is reduced after several additional days. The nonoliguric phase of renal insufficiency is thought to be due to the effects of aminoglycosides on the distal portion of the nephron that reduce sensitivity to endogenous vasopressin. While severe acute tubular necrosis may occur rarely, the most common finding is a mild rise in plasma creatinine.
In this pathway PPAR seems to be one of the keypoints. PPARs promote mitochondrial proton gradient uncoupling, reduce ROS, increase heat generation and they also suppress inflammation. They are inibithed by the drug class of the thiazolidinediones so we ask ourselves if diabetic patients treated with oral hypoglycemic drugs could be protected.
The nephroprotective effects of pioglitazone and glibenclamide against gentamicin-induced nephrotoxicity in rats: a comparative study. 2010
The impairment in renal function is almost always reversible because the proximal tubular cells can regenerate. Toxicity correlates with the total amount of drug administered and is more likely to be encountered with longer courses of therapy. Constantly elevated concentration of drug in plasma above a critical level correlates with toxicity. The most important result of this toxicity may be reduced excretion of the drug, which, in turn, predisposes to ototoxicity.
Other drugs, such as amphotericin B, vancomycin, angiotensin-converting enzyme inhibitors, cisplatin, and cyclosporine, may potentiate aminoglycoside-induced nephrotoxicity. Volume depletion and hypokalemia also have been implicated.
RESISTANCE
Bacteria may be resistant to aminoglycosides because of failure of the antibiotic to penetrate intracellularly, low affinity of the drug for the bacterial ribosome (by alterating the 30S ribosomal subunity or methylation of the aminoglycoside binding site), or—most commonly—drug inactivation by moditying enzymes acquired by conjugative transfer of resistance plasmids. These enzymes phosphorylate, adenylate, or acetylate specific hydroxyl or amino groups, preventing binding to ribosomes.
Aminoglycosides versus bacteria--a description of the action, resistance mechanism, and nosocomial battleground. 2007.
Curiosity: amikacin is modified by only a few of these inactivating enzymes; thus, strains that are resistant to other aminoglycosides may remain susceptible to amikacin.
DOSING
Current practice is to administer the total daily dose as a single injection, which is associated with less toxicity and equal efficacy as multiple-dose regimens either in adult or in children.
Single or multiple daily doses of aminoglycosides: a meta-analysis. 1996.
Extended-interval aminoglycoside administration for children: a meta-analysis. 2004.
Aminoglycoside extended interval dosing in neonates is safe and effective: a meta-analysis. 2005.
This diminished toxicity is probably due to a threshold effect from accumulation of drug in the inner ear or in the kidney. Despite the higher peak concentration, a once-daily dosing regimen provides a longer period when concentrations fall below the threshold for toxicity than does a multiple-dose regimen, accounting for its lower toxicity. Aminoglycoside bactericidal activity, on the other hand, is related directly to the peak concentration achieved because of concentration-dependent killing and a concentration-dependent postantibiotic effect.
So, once-daily regimens are safer with equal efficacy, cost less, and are administered more easily.
Exceptions include use in pregnancy, and low-dose combination therapy of bacterial endocarditis. Once-daily dosing also should be avoided in patients with creatinine learances of <20–25 mL/min, where dosing every 48 hours is more appropriate.
Whether once-daily or multiple-daily dosing is used, the dose must be adjusted for patients with
creatinine clearances of <80–100 mL/min, and plasma concentrations must be monitored. Nomograms may be helpful in selecting initial doses, but variability in aminoglycoside clearance among patients is too large for these to be relied on for more than a few days. If a patient likely will be treated with an aminoglycoside for more than 3–4 days, then plasma concentrations should be monitored.
BIBLIOGRAFIA ESSENZIALE
AIFA. Guida all'uso dei farmaci, 5a edizione.
Cochrane Reviews
Goodman & Gilman's The Pharmacological Basis of Therapeutics, 11th edition.
Katzung. Basic and Clinical Pharmacology, 11th edition.
PubMed
Therapeutic guideline
Wikipedia
Lavoro svolto da Vittoria Basile e Daniele Ferrero
