Aminoglycosides: An introduction, classification, mechanism, structure, uses, with its effects.

Aminoglycoside

structure-of-aminoglycosides
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Aminoglycoside is mainly distributed into the extracellular fluid and penetrates into the CSF. These are not metabolized in the body. They are excreted unchanged in the urine.

These have bactericidal action against gram-negative aerobes and are more active at alkaline pH. These cause ototoxicity and nephrotoxicity. These exhibit partial cross-resistance among them. Transport of aminoglycosides into the bacterial cell requires oxygen, hence anaerobes are resistant to the aminoglycoside.

History-

The aminoglycoside antibiotics are contained one or more amino sugars linked to an aminocytitol ring by glycosidic bonds in the composition. Aminoglycosides are broad-spectrum antibiotics, and in general, they have greater activity against gram-negative than gram-positive bacteria.  Streptomycin, is the first antibiotic of this group, was a well-planned work of Waksman (1944) and his associates, who isolated it from a strain of Streptomyces griseus. The aminoglycoside can produce severe adverse effects, which include nephrotoxicity, ototoxicity, and neuro effects. These properties have limited the use of aminoglycoside chemotherapy to serious systemic indications. Some of the aminoglycosides are can be administered for ophthalmic and topical purposes.

NameSource
StreptomycinStreptomyces griseus
NeomycinS. fradiae
KanamycinS. kanamyeleticus
GentamicinMicromonospora purpura
NetilmicinMicromonospora species
Tobramycin (Nebramycin)S. tenebrarius
Framycetin (Soframycin)S. decaris
ParomomycinS. rimosus and S. paramomycinus
AmikacinIt is a 1-L-(-) 4-amino-2-hydroxy butyryl kanamycin

Classification of aminoglycoside-

Systemic aminoglycosideTopical aminoglycoside-
StreptomycinNeomycin
AmikacinFramycetin
Gentamicin
Sisomicin
Kanamycin
Netilmicin
Tobramycin
Paromomycin

Mechanism of action-

Aminoglycosides diffuse through porin channels in the outer membrane of susceptible organisms. These susceptible organisms also have an oxygen-dependent system that used to transports the drug across the cytoplasmic membrane. Inside the cell, they bind the 30S ribosomal subunit, where they interfere with assembly of the functional ribosomal apparatus and/or cause the 30S subunit of the completed ribosome to misread the genetic code.

machinism-of-aminoglycosides-in-a-chart

Aminoglycosides have concentration-dependent bactericidal activity; that is, their efficacy is dependent on the maximum concentration (Cmax) of drug above the minimum inhibitory concentration (MIC) of the organism. For aminoglycosides, the target Cmax is eight to ten times the MIC. They also exhibit a post-antibiotic effect (PAE), which is continued bacterial suppression after drug concentrations fall below the MIC. The larger the dose, the longer the PAE. Because of these properties, high-dose extended-interval dosing is commonly utilized. This dosing strategy also reduces the risk of nephrotoxicity and increases convenience.

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Antibacterial spectrum-

The aminoglycosides are effective for the majority of aerobic gram-negative bacilli, including those that may be multidrug-resistant, such as Pseudomonas aeruginosa, Klebsiella pneumoniae, and Enterobacter sp.  Additionally, aminoglycosides are often combined with a beta-lactam antibiotic to employ a synergistic effect, particularly in the treatment of Enterococcus faecalis and Enterococcus faecium infective endocarditis.

Some therapeutic applications of four commonly used aminoglycosides—amikacin, gentamicin, tobramycin, and streptomycin.

Resistance-

Resistance to aminoglycosides occurs via 1) efflux pumps, 2) decreased uptake, and/or 3) modification and inactivation by the plasmid-associated synthesis of enzymes. Each of these enzymes has its own aminoglycoside specificity, and therefore, the cross-resistance cannot be presumed.

Note: Amikacin is less vulnerable to these enzymes than other antibiotics in this group.

Pharmacokinetics-

Absorption

Due to the highly polar, the polycationic structure of the aminoglycosides prevents adequate absorption after the oral administration, and so, all the aminoglycosides (except neomycin) must be given parenterally to achieve their adequate serum concentrations. (Note: Neomycin is not given parenterally due to severe nephrotoxicity.)

It is administered topically for skin infections or orally to decontaminate the gastrointestinal tract prior to colorectal surgery.

Distribution

Because of their hydrophilicity, aminoglycoside tissue concentrations may be subtherapeutic, and penetration into most body fluids is variable.  Concentrations achieved in CSF are inadequate, even in the presence of inflamed meninges. For central nervous system infections, the intrathecal or intraventricular routes may be utilized.  All aminoglycosides cross the placental barrier and may accumulate in fetal plasma and amniotic fluid.

Elimination

On average there are more than 90% of the parenteral aminoglycosides are excreted unchanged from the urine. Accumulation occurs in patients with renal dysfunction; thus, dose adjustments are required. Neomycin is primarily excreted unchanged in the feces.

Chemistry of aminoglycoside-

Structure-

structure-of-aminoglycosides
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SAR of aminoglycoside-

SAR-of-aminoglycosides-amino-sugar-portion

-The aminoglycoside antibiotic contains two important structural features. They are amino sugar portion and centrally placed hexose ring, which is either 2-deoxystreptamine or streptamine.

-Two or more amino sugars joined in glycoside linkage in aminoglycosides and a centrally placed substituted 1,3 diamioncyclo hexane (aminocyclitol) ring.

-The ring is a 2-deoxy streptamine in all aminoglycosides except streptomycin, where it is streptidine. In streptidine, two amino sugars are attached to strepidine.

-In the families of kanamycin and gentamycin, two amino sugars are attached to 2-deoxy streptamine.

-In the neomycin family, there are amino sugars attached to 2-deoxy streptamine.

-The bacterial inactivating enzymes targets C-6 and C-2 position and the substitution with a methyl group at C-6 increase the enzyme resistance.

-The cleavage of 3-hydroxyl or both groups do not affect the activity.

-The activity (e.g. amikacin) and ethylation (e.g. 1-N-ethylsisoomycin) through does not increase the activity helps to retain the antibacterial potency.

-Substitution on position 2 i.e. 2-hydration and substitution on position 5 i.e. 5-deoxygenation increased inhibition of bacterial inactivating enzyme systems. (Sisomicin derivatives).

Systemic aminoglycoside-

Streptomycin

Streptomycin is the oldest aminoglycoside antibiotic which is obtained from Streptomyces griseus. It was used extensively in the past but is now practically restricted to the treatment of tuberculosis. It is less potent than many other aminoglycosides. The antimicrobial spectrum of streptomycin is relatively narrow and primarily covers aerobic gram-negative bacilli. Sensitive organisms are—H. ducreyi, Brucella, Yersinia pestis, Francisella tularensis, Nocardia, Calym. granulomatis, M. tuberculosis.

 Only a few strains of E. coli, H. influenzae, V. cholerae, Shigella, Klebsiella, enterococci; and some other gram-positive cocci are now inhibited, at too higher concentrations. All other organisms including Pseudomonas are unaffected.

Dosage forms: Streptomycin injection B.P.

Molecular formula- C21H39N7O12

Molecular weight- 581.6 g/mol

IUPAC Name- 2-[(1R,2R,3S,4R,5R,6S)-3-(diaminomethylideneamino)-4-[(2R,3R,4R,5S)-3-[(2S,3S,4S,5R,6S)-4,5-dihydroxy-6-(hydroxymethyl)-3-(methylamino)oxan-2-yl]oxy-4-formyl-4-hydroxy-5-methyloxolan-2-yl]oxy-2,5,6-trihydroxycyclohexyl]guanidine 

Structure of streptomycin-

structure-of-streptomycin

Properties and uses- Streptomycin is a white hygroscopic powder.

It is very soluble in water and practically insoluble in ethanol.

The development of resistant strains of bacteria and chronic toxicity constitutes major drawbacks of this category.

It is used as an antitubercular drug.

In most other situations, e.g. urinary tract infection, peritonitis, septicemias, etc.

It is assayed by the microbiological method.

Amikacin

Amikacin is a semisynthetic derivative of kanamycin to which it resembles in pharmacokinetics, dose, and toxicity. In amikacin, the outstanding feature is its resistance to bacterial aminoglycoside inactivating enzymes. Hereby, amikacin has the widest spectrum of activity, which including in many organisms resistant to other aminoglycosides.

However, the relatively higher dose of amikacin is needed for Pseudomonas, Proteus, and Staph. Infections. The range of conditions in which amikacin can be used is the same as for gentamicin.

Dose15 mg/kg/day in 1–3 doses.

Molecular formula-C22H43N5O13

Molecular weight- 586.6 g/mol

IUPAC Name- (2S)-4-amino-N-[(1R,2S,3S,4R,5S)-5-amino-2-[(2S,3R,4S,5S,6R)-4-amino-3,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-4-[(2R,3R,4S,5S,6R)-6-(aminomethyl)-3,4,5-trihydroxyoxan-2-yl]oxy-3-hydroxycyclohexyl]-2-hydroxybutanamide  

Structure of Amikacin-

structure-of-amikacin

Properties and uses- It is recommended as a reserve drug for empirical treatment of hospital-acquired gram-negative bacillary infections where gentamicin/tobramycin resistance is high.

It is effective in tuberculosis but used only for multidrug-resistant infection.

More hearing loss than vestibular disturbance occurs in toxicity.

Amikacin is a semisynthetic drug derived from kanamycin A.

it is very effective and less ototoxic than other aminoglycosides.

Gentamicin

Gentamicin was the third systemically administered aminoglycoside antibiotic that to be introduced for clinical use, and it was obtained from Micromonospora purpurea in 1964. It quickly surpassed streptomycin and other aminoglycosides because of higher potency and the broader spectrum of activity. Currently, it is the most commonly used aminoglycoside for acute infections and may be considered the prototype of the class.

Gentamicin is mainly active against aerobic gram-negative bacilli, including E. coli, Klebsiella pneumoniae, Enterobacter, H. influenzae, Proteus, Serratia, and Pseudomonas aeruginosa. Many strains of Brucella, Campylobacter, Citrobacter, Fransisella, and Yersinia are also sensitive. The limited number of gram-positive bacteria are susceptible, especially Staph. aureus, Strep. faecalis and some Listeria, but Strep. pyogenes, Strep. pneumoniae and enterococci are usually insensitive. Gentamicin is ineffective against Mycobacterium tuberculosis and other mycobacteria.

Molecular formula-C21H43N5O7

Molecular weight- 477.6 g/mol

IUPAC Name- 2-[4,6-diamino-3-[3-amino-6-[1-(methylamino) ethyl] oxan-2-yl] oxy-2-hydroxycyclohexyl] oxy-5-methyl-4-(methylamino) oxane-3,5-diol 

Structure of gentamicin-

structure-of-gentamicin

Properties and uses Gentamycin exist as white hygroscopic powder.

It is soluble in water, and practically insoluble in alcohol, although it is a broad-spectrum antibiotic.

It is used in the treatment of infections caused by gram-negative bacteria of particular interest. Because it has a high degree of activity against P. aeruginosa, where the important causative factor is burned skin.

It is used topically in the treatment of infected bed-sores, pyodermata, burns, and eye infection.

It is assayed by the microbiological method.

Sisomicin

Sisomicin is introduced in the 1980s, it is a natural aminoglycoside from Micromonospora inyoensis that is chemically and pharmacokinetically similar to gentamicin.  But somewhere, it is more potent on Pseudomonas, a few other gram-negative bacilli, and beta-hemolytic Streptococci. It is moderately active on faecal Streptococci—can be combined with penicillin for SABE.

However, it is susceptible to aminoglycoside inactivating enzymes and offers no advantage in terms of ototoxicity and nephrotoxicity.  It can be used interchangeably with gentamicin for the same purposes in the same doses.

Molecular formula-C19H37N5O7

Molecular weight- 447.5 g/mol

IUPAC Name- (2R,3R,4R,5R)-2-[(1S,2S,3R,4S,6R)-4,6-diamino-3-[[(2S,3R)-3-amino-6-(aminomethyl)-3,4-dihydro-2H-pyran-2-yl]oxy]-2-hydroxycyclohexyl]oxy-5-methyl-4-(methylamino)oxane-3,5-diol  

Structure of sisomicin-

structure-of-sisomicin

Kanamycin

Kanamycin was obtained from S. kanamyceticus in the year 1957, and it was the second systemically used aminoglycoside to be developed after streptomycin. Kanamycin is similar to streptomycin in all respects including efficacy against M. tuberculosis and lack of activity on Pseudomonas. However, it is more toxic, both to the cochlea and to the kidney. Hearing loss, which is irreversible, is more common than vestibular disturbance.

Because of toxicity and a narrow spectrum of activity, it has been largely replaced by other aminoglycosides for the treatment of gram-negative bacillary infections.  It may be used only if mandated by a sensitivity report of the infecting strain. Kanamycin is generally used as a second-line drug in resistant tuberculosis.

Dose– 0.5 g i.m. BD (15 mg/kg/day).

Molecular formula- C18H36N4O11

Molecular weight- 484.5 g/mol

IUPAC Name- (2R,3S,4S,5R,6R)-2-(aminomethyl)-6-[(1R,2R,3S,4R,6S)-4,6-diamino-3-[(2S,3R,4S,5S,6R)-4-amino-3,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-2-hydroxycyclohexyl]oxyoxane-3,4,5-triol  

Structure of kanamycin-

structure-of-kanamycin

Properties and uses- Kanamycin is a white crystalline powder, soluble in water, practically insoluble in acetone and in alcohol.

The mixture consists of three related structures, that is, Kanamycin A, B, and C.

The kanamycin does not possess a D-ribose molecule that is present in neomycin and paromomycin.

 The use of kanamycins is restricted to infections of the intestinal tract and to systemic infections.

It is assayed by the microbiological method.

Netilmicin

The Netilmicin is a semisynthetic derivative of gentamicin that has a broader spectrum of activity than gentamicin. It is relatively resistant to many aminoglycosides inactivating enzymes and thus effective against some gentamicin-resistant strains. Netilmicin is more active against Klebsiella, Enterobacter, and Staphylococci, but less active against Ps. aeruginosa.

The netilmicin has similar pharmacokinetic characteristics and dosage to gentamicin. Experimental studies have shown it to be less ototoxic than gentamicin and tobramycin, but clinical evidence is inconclusive, and hearing loss occurs, though fewer cases of vestibular damage have been reported. A marginal improvement in the antibacterial spectrum, clinical efficacy, and possibly reduced toxicity indicates that netilmicin could be a useful alternative to gentamicin.

Dose– 4–6 mg/kg/day in 1–3 doses

Molecular formula-C21H41N5O7

Molecular weight- 475.6 g/mol

IUPAC Name- (2R,3R,4R,5R)-2-[(1S,2S,3R,4S,6R)-4-amino-3-[[(2S,3R)-3-amino-6-(aminomethyl)-3,4-dihydro-2H-pyran-2-yl]oxy]-6-(ethylamino)-2-hydroxycyclohexyl]oxy-5-methyl-4-(methylamino)oxane-3,5-diol  

Structure of netilmicin-

structure-of-netilmicin

Properties and uses- Netilmicin is a white or yellowish-white hygroscopic powder.

It is very soluble in water and practically insoluble in acetone and alcohol.

It is similar to gentamycin and tobramycin.

The majority of the aminoglycoside inactivating enzymes do not metabolize it.

It is useful for the treatment of serious infections due to susceptible enterobacteria and other aerobic gram-negative bacilli.

It is assayed by the microbiological method.

Tobramycin

Tobramycin was obtained from S. tenebrarius in the 1970s. The antibacterial, pharmacokinetic properties, as well as dosage, of tobramycin, are almost identical to gentamicin. But it is 2–4 times more active against Pseudomonas and Proteus, including some resistant to gentamicin, but the majority are cross-resistant.

 However, it is not useful for combining with penicillin in the treatment of enterococcal endocarditis. It should be used only as an alternative to gentamicin. Its major indication of serious infections is caused by Pseudomonas and Proteus. Ototoxicity and nephrotoxicity are probably less than gentamicin.

Dose-: 3–5 mg/kg day in 1–3 doses.

Molecular formula-C18H37N5O9

Molecular weight-467.5 g/mol

IUPAC Name- (2S,3R,4S,5S,6R)-4-amino-2-[(1S,2S,3R,4S,6R)-4,6-diamino-3-[(2R,3R,5S,6R)-3-amino-6-(aminomethyl)-5-hydroxyoxan-2-yl]oxy-2-hydroxycyclohexyl]oxy-6-(hydroxymethyl)oxane-3,5-diol  

Structure of tobramycin-

structure-of-tobramycin

Properties and uses- Its activity are similar to gentamycin.

The superior activity of tobramycin against P. aeruginosa may make it useful in the treatment of bacterial osteomyelitis, and pneumonia caused by P. species.

Paromomycin

Paromomycin is a chemically related to neomycin. This aminoglycoside antibiotic has pronounced activity against many protozoan parasites, including E. histolytica, Giardia lamblia, Trichomonas vaginalis, Cryptosporidium and Leishmania, in addition to many bacteria sensitive to neomycin. Like other aminoglycosides, it is not absorbed from the gut.

 An oral formulation is used for the treatment of intestinal amoebiasis and giardiasis but was soon discontinued when metronidazole gained popularity. For its antibacterial activity in the gut, it can be used as an alternative to neomycin for hepatic encephalopathy. Parenterally, it is being used for visceral leishmaniasis.

Dose- Oral 500 mg TDS (25–30 mg/kg/day).

Molecular formula- C23H45N5O14

Molecular weight- 615.6 g/mol

IUPAC Name- (2S,3S,4R,5R,6R)-5-amino-2-(aminomethyl)-6-[(2R,3S,4R,5S)-5-[(1R,2R,3S,5R,6S)-3,5-diamino-2-[(2S,3R,4R,5S,6R)-3-amino-4,5-dihydroxy-6 (hydroxymethyl)oxan-2-yl]oxy-6-hydroxycyclohexyl]oxy-4-hydroxy-2 (hydroxymethyl)oxolan-3-yl]oxyoxane-3,4-diol

Structure of paromomycin-

structure-of-paromomycin

Tropical aminoglycoside-

Neomycin

Neomycin is obtained from S. fradiae, and it is a wide-spectrum aminoglycoside. It is active against most gram-negative bacilli and some gram-positive cocci. However, Pseudomonas and Strep. pyogenes is not sensitive. Neomycin is highly toxic to the internal ear (mainly auditory) and to the kidney. It is not used systemically.

Absorption from the gastrointestinal tract is minimal. It is not administered orally and topically because it may cause systemic toxicity. Neomycin is a mixture of closely related epimers, neomycin B, and C.

Neomycin B differs from neomycin C by the nature of the sugar attached terminally to D-ribose, this sugar called neosamine. B1 differs from neosamine C in its stereochemistry.  In neomycin B1, the neobiosamine moiety contains. β-L-iodopyranosyl, whereas in neomycin C the configuration is inverted and it is 2-D-glucopyranosyl.

Molecular formula- C23H46N6O13

Molecular weight- 614.6 g/mol

IUPAC Name- 2R,3S,4R,5R,6R)-5-amino-2-(aminomethyl)-6-[(1R,2R,3S,4R,6S)-4,6-diamino-2-[(2S,3R,4S,5R)-4-[(2R,3R,4R,5S,6S)-3-amino-6-(aminomethyl)-4,5-dihydroxyoxan-2-yl]oxy-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-3-hydroxycyclohexyl]oxyoxane-3,4-diol

Structure of neomycin-

structure-of-neomycin

Properties and uses- Neomycin is a white or yellowish-white hygroscopic powder.

It is very soluble in water, very slightly soluble in alcohol, and practically insoluble in acetone.

Neomycin is a mixture of closely related epimers, neomycin B, and C.

It is photosensitive and its main use is in the treatment of the ear, eye, and skin infections, and these include burns, wounds, ulcers, and infected dermatoses.

It is assayed by the microbiological method.

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Framycetin-

Framycetin is obtained from S. lavendulae, and it is very similar to neomycin. It is too many toxins for systemic administration and it is used topically on skin, eye, ear in the same manner as neomycin.

Dose– SOFRAMYCIN, FRAMYGEN 1% skin cream, 0.5% eye drops, or ointment.

Structure of framycetin-

structure-of-framycetin

Adverse effect of aminoglycosides-

-Ototoxicity

-Nephrotoxicity

-Neuromuscular paralysis

-Allergic reactions

-Paralysis

-Skin rash

Common properties of aminoglycosides-

-All are used as sulfate salts, which are highly water-soluble, and the solutions are stable for months.

-They ionize in solution; are not absorbed orally; distribute only extracellularly; do not penetrate the brain or CSF.

-All these are excreted unchanged in the urine by glomerular filtration.

-All these are bactericidal and act more active at alkaline pH.

-They act by interfering with bacterial protein synthesis.

-All they are primarily active against aerobic gram-negative bacilli and they do not inhibit anaerobes.

-There is only partial cross-resistance among them.

-They have a relatively narrow margin of safety.

-All exhibit ototoxicity and nephrotoxicity.


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