AMINOGLYCOSIDES The different members of this group share many properties in common. The different members of this group share many properties in common.

AMINOGLYCOSIDES Streptomycin Streptomycin Gentamicin Gentamicin Tobramycin Tobramycin Amikacin Amikacin Netilmicin Netilmicin Kanamycin Kanamycin Neomycin Neomycin

AMINOGLYCOSIDES Amino sugars linked through glycosidic bonds. Amino sugars linked through glycosidic bonds. Polycations: This is in part responsible for many of their shared pharmacokinetic properties Polycations: This is in part responsible for many of their shared pharmacokinetic properties

ANTIBACTERIAL ACTIVITY Primarily active against aerobic gram negative bacteria. Primarily active against aerobic gram negative bacteria. Active against many staphylococci and certain Mycobacteria. Active against many staphylococci and certain Mycobacteria. Anaerobic bacteria are not susceptible. Anaerobic bacteria are not susceptible.

SENSITIVITY AND RESISTANCE

AMINOGLYCOSIDE TRANSPORT Transport across the cell membrane is by active transport. Transport across the cell membrane is by active transport. Antimicrobial activity is reduced in an anaerobic environment and at low pH. Antimicrobial activity is reduced in an anaerobic environment and at low pH.

RESISTANCE Cross-resistance occurs to varying degrees with the different aminoglycosides. Cross-resistance occurs to varying degrees with the different aminoglycosides. Amikaciin Amikaciin

ABSORPTION AND DISTRIBUTION Oral bioavailability is low. Oral bioavailability is low. Once daily dosing (postantibiotic effect). Once daily dosing (postantibiotic effect). Distribution into most body tissues including the CNS is low. Distribution into most body tissues including the CNS is low.

EXCRETION Rapidly and almost entirely excreted by glomerular filtration (proportional to creatinine clearance). Rapidly and almost entirely excreted by glomerular filtration (proportional to creatinine clearance). Accumulation occurs with impaired renal function. Accumulation occurs with impaired renal function.

PHARMACOKINETICS Monitor the serum concn’s of the drugs (T.I. is close to 1). Monitor the serum concn’s of the drugs (T.I. is close to 1).

THERAPEUTIC USES Severe, complicated infections. Severe, complicated infections. Often combined with β-lactams. Often combined with β-lactams.

STREPTOMYCIN Bacterial endocarditis (combined with a penicillin or vancomycin). Bacterial endocarditis (combined with a penicillin or vancomycin). Tuberculosis. Tuberculosis.

Gentamicin, Tobramycin, Netilmicin and Amikacin Similar in clinical indications and range of activity. Similar in clinical indications and range of activity. Gentamicin is often preferred but resistance may limit its use. Gentamicin is often preferred but resistance may limit its use.

THERAPEUTIC USES Serious gram negative infections especially those due to Pseudomonas, Enterobacter, Klebsiella, Serratia etc. Serious gram negative infections especially those due to Pseudomonas, Enterobacter, Klebsiella, Serratia etc. UTI’s, bacteremia, meningitis, infected burns, pneumonia, osteomyelitis, ear infections etc. UTI’s, bacteremia, meningitis, infected burns, pneumonia, osteomyelitis, ear infections etc.

THERAPEUTIC USES Severe Pseudomonas infections are best treated with one of these 4 AG’s plus an antipseudomonal penicillin or cephalosporin. Severe Pseudomonas infections are best treated with one of these 4 AG’s plus an antipseudomonal penicillin or cephalosporin. Gentamicin combined with a penicillin is often used to treat bacterial endocarditis. Gentamicin combined with a penicillin is often used to treat bacterial endocarditis.

THERAPEUTIC USES Tobramycin is often used in pseudomonal infections. Tobramycin is often used in pseudomonal infections. Amikacin is used as the preferred agent in hospitals. Amikacin is used as the preferred agent in hospitals. Netilmicin- may be useful in resistant infections. Netilmicin- may be useful in resistant infections.

DRUG INTERACTIONS Antipseudomonal penicillins inactivate aminoglycosides. Antipseudomonal penicillins inactivate aminoglycosides. Ethacrynic acid and other loop diuretics. Ethacrynic acid and other loop diuretics. Nephrotoxic agents. Nephrotoxic agents. Neuromuscular blocking agents. Neuromuscular blocking agents.

Inhibit protein synthesis by binding to the 30S ribosomal subunit Pharmacokinetics-Poorly absorbed from the GI tract, Don’t get into the CNS very well, Rapidly excreted by kidney Toxicity-Ototoxicity, Nephrotoxicity, Neuromuscular blockade SHARED PROPERTIES OF THE AMINOGLYCOSIDES

Streptomycin T.B., Endocarditis Gentamicin Endocarditis, gram negative infections, Pseudomonas Tobramycin Gram negative infections, Pseudomonas Amikacin Reserve drug for gram negative- infections THERAPEUTIC USES OF THE AMINOGLYCOSIDES

Wheel of Bugs Gram-negative Gram-positive Anaerobic P. aeruginosa H. influenzaeNeissseria spp E. Coli (coliforms) S. aureus Streptococcus spp Bacteroides spp Clostridium spp Enterococcus spp

MECHANISM OF ACTION Bactericidal. Bactericidal. They inhibit protein synthesis by binding irreversibly to the 30S ribosomal subunit. They inhibit protein synthesis by binding irreversibly to the 30S ribosomal subunit.

aa A 50S 30S mRNA template Transferase site P Nascent polypeptide chain Mechanism of action of Aminoglycosides AG’s

50S 5’ 3’ 5’ 3’ AUG 5’3’ AUG 30S 3’ AUG X Blocks initiation Premature termination Wrong amino acid is incorporated + aminoglycoside mRNA translation Effects of Aminoglycosides Mature protein Growing polypeptide

30S Aminoglycosides on Protein Synthesis 50S 5’3’ Blocks initiation 3’ 5’ Prematuretermination 5’ 3’ AUG mRNA translation + Amino Glycoside 3’ 5’ Incorporation of wrong amino acid X Mature Protein Growing Polypeptide

MECHANISM OF ACTION Exact mechanism of cell death is unknown. Exact mechanism of cell death is unknown. Postantibiotic effect. Postantibiotic effect.

RESISTANCE Alterations in ribosomal proteins. Alterations in ribosomal proteins. Decreased permeability to the antibiotic. Decreased permeability to the antibiotic. Induction of bacterial enzymes that inactivate these drugs. Induction of bacterial enzymes that inactivate these drugs.

RESISTANCE Alterations in ribosomal proteins. Alterations in ribosomal proteins. Decreased permeability to the antibiotic. Decreased permeability to the antibiotic.

TOXICITY Ototoxicity (Vestibular and Auditory). Ototoxicity (Vestibular and Auditory). Nephrotoxicity. Nephrotoxicity. Neuromuscular Blockade. Neuromuscular Blockade.

OTOTOXICITY The most serious toxic effect (uncommon, irreversible and cumulative). The most serious toxic effect (uncommon, irreversible and cumulative). Caused by all the aminoglycosides Caused by all the aminoglycosides

OTOTOXICITY Both auditory and vestibular dysfunction can occur. Both auditory and vestibular dysfunction can occur. Results from destruction of sensory hair cells. Results from destruction of sensory hair cells.

OTOTOXICITY Several factors increase the risk. Several factors increase the risk. Careful monitoring is important. Careful monitoring is important.

NEPHROTOXICITY Aminoglycosides accumulate in the renal cortex (mainly proximal tubules). Aminoglycosides accumulate in the renal cortex (mainly proximal tubules). Several factors may increase the risk. Several factors may increase the risk. Reversible and usually mild. Reversible and usually mild. Reduced excretion can lead to ototoxicity. Reduced excretion can lead to ototoxicity.

NEPHROTOXICITY Several factors may increase the risk. Several factors may increase the risk. Reversible and usually mild. Reversible and usually mild. Reduced excretion can lead to ototoxicity. Reduced excretion can lead to ototoxicity.

NEUROMUSCULAR BLOCKADE Rare but potentially serious. Rare but potentially serious. Occurs at high concentrations of aminoglycosides or in patients with an underlying risk factor. Occurs at high concentrations of aminoglycosides or in patients with an underlying risk factor. Acute neuromuscular blockade, respiratory paralysis and death can occur. Acute neuromuscular blockade, respiratory paralysis and death can occur.

Amino Glycosides

NEUROMUSCULAR BLOCKADE Results from decreased ACH release and decreased postsynaptic sensitivity. Results from decreased ACH release and decreased postsynaptic sensitivity. Treated with supportive measures and calcium (or neostigmine). Treated with supportive measures and calcium (or neostigmine).