Aminoglycosides antibiotics 12th December 2013

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Aminoglycoside Antibiotics:

Aminoglycoside Antibiotics Prof. R. K. Dixit Pharmacology and Therapeutics K. G. M. U. Lucknow

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First member Streptomycin discovered by Waksman in 1944 Natural and semi-synthetic antibiotics Produced from Actinomycetes Those obtained from Streptomyces – Have suffix mycin ( eg . Streptomycin) Those obtained from Micromonospora – Have suffix micin ( eg . Gentamicin,)

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Structure characterized by Two aminosugars joined to One aminocyclitol moiety by Glycosidic (-O-) bond In most of members aminoacyclitol moiety is 2- Deoxystreptamine . In streptomycin the aminocyclitol is Streptidine . Aminosugar -O- -O- 2-Deoxystreptamine Aminosugar

General character of Aminoglycosides group :

General character of Aminoglycosides group Formulations are Sulfate or hydrochloric salts Formulations are water soluble and stable Highly polar basic drugs. Ionize during dissolution Distribution inside the cells is minimal Penetration through BBB is minimal Least metabolized by hepatic enzymes Excretion is mainly renal (unchanged form, through glomerular filtration) (Not absorbed from GIT)

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Bactericidal in nature More active in alkaline pH MOA is by interfering with protein synthesis Attach with 30S ribosomal subunit (ATT) Concentration dependent (PAE) Mainly gram negative (plus tuberculosis by streptomycin, Kanamycin, Amikacin) Cross resistance is partial Therapeutic index is narrow

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Have NONE side effects N ephrotoxic O totoxic N euromuscular blockage E tc.(Teratogenicity)

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Nephrotoxicity Streptomycin is least nephrotoxic . Larger the number of NH2 more nephrotoxicity. Nephrotoxicity is caused by Inhibition of an intracellular lysosomal phospholipase-A2 in renal brush border. Leading to lysosomal distension, Rupture and Release of acid hydrolases Release of Free Aminoglycosides into cytosol. This free drug binds to other cellular organelles ( eg . In mitochondria it displaces Ca++ leading to mitochondrial degeneration and necrosis.) Nephrotoxicity is reversible Verapamil and Ca++ can Reduce nephrotoxic potential But Also reduce antibacterial effect

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KAN ( K anamycin, A mikacin, N eomycin) mainly damage cochlea rest vestibular damage All are teratogenic Neomycin and Framycetin have extreme systemic toxicity ( only topically used) Amikacin has widest spectrum Avoid concurrent use of other Ototoxic drugs ( Frusemide , Ethacrinic acid, Minocycline ) Neomycin used orally for Hepatic Encephalopathy)

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Avoid concurrent use of other nephrotoxic drugs (Amphotericin B, Vancomycin, Cephalothin, Cephradrine, Cyclosporin, Cisplatin) Be overcautious while using in extremes of age and renal compromised Be overcautious while using in operated patients (Received Curare)

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Don’t mix with any other drug (Pharmaceutical Drug Interaction) Partially removed by peritoneal and haemodialysis The excretion is proportional to creatinine clearance. Half life increases in renal insufficiency. Dose adjustment is needed in renal insufficiency Most precise method for calculating dose is using creatinine clearance But in Practice most often used formula to calculate dose is Daily dose of Aminoglycoside (in Renal compromised patient) = Normal therapeutic dose Serum Creatinine Value (mg/dl)

Members:

Members A mikacin S treptomycin S isomicin S pectinomycin K anamycin I spepamycin N etilmicin G entamicin T obramycin Ribostamycin Arbekacin Bekanamycin Dibekacin Hygromycin Verdamicin Astromicin Paromomycin ASKING Truth IS Great TASK

MOA:

MOA Bactericidal (Gram Negative, No action on Anaerobes) Initial entry of Aminoglycosides through bacterial cell wall to periplasmic space Through porin channels by passive diffusion (1) Later on further Entry across cytoplasmic membrane is carrier mediated (linked to electron transport chain, energy and oxygen dependent) Active transport (2) Advantage of adding Beta lactams Beta Lactam antibiotics weaken the bacterial cell wall Facilitate passive diffusion of Aminoglycoside.(Synergism)

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Penetration is dependent on Maintenance of polarized membrane Oxygen dependent active process Not active in absence of oxygen Not effective against anaerobes Not effective in presence of big abscess pH alteration. Alkalization favors penetration into cell

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Prevent polysome formation (accumulation of nonfunctional monosomes) Inside the bacterial cell Aminoglycoside bind with 30S ribosome subunit ( or at the interface of 30S and 50S) Inhibit formation of initiation complex Inhibit protein synthesis Misreading of mRNA Codon Entry of wrong amino acid in the chain Formation of wrong peptide chain (Check the growth of bacteria, Bacteriostatic)

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How Cidal action is achieved Ans - Defective proteins incorporated in cell membrane. Due to secondary changes in the integrity of bacterial cell membrane. (Increase permeability for ions, amino acids, proteins- Leading to leaking of these out side) Bonus of incorporation of defective protein in cell membrane More entry of antibiotic occurs in to the cell. Further increasing affectivity Death Of Bacteria

Resistance development (Conjugation and transfer of plasmid) :

Resistance development (Conjugation and transfer of plasmid) Development and synthesis of plasmid mediated bacterial transferase enzyme (Acetyltransferase, Phosphotransferase, Adenylyltransferase), which inactivates Aminoglycosides. Impermeability of porins, Impaired active transport Inactivating enzymes in the cell membrane – Phosphorylate / Adenylate / Acetylate and inactivate Aminoglycosides Phosphorylated / Adenylated / Acetylated conjugates of Aminoglycoside can not bind at target ribosomal subunit and site. Decreased affinity of ribosomal proteins for binding with Aminoglycosides

Side effects and Toxicity:

Side effects and Toxicity Ototoxic - Concentrated in labyrinthine fluid Released from there when plasma concentration decreases. Less seen in routine dose. (High dose, long time high chance) Damage of sensory and hair cells Vestibular- Presents with Vertigo, Ataxia, Nystagmus (Headache, Nausea, Vomiting, Dizziness) Recover slowly ( Least recovery in elderly) Cochlear- Starts from base spreads to apex. High frequency affected first Recovery is very poor. Deafness may be permanent, more in elderly Presents with tinnitus (reversible) followed by hearing loss (irreversible)

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Nephrotoxicity- More damage of cortical nephrons Related to total exposure More in Elderly More in pre-existing renal disease Reversible Tubular damage (Loss of concentrating mechanism) Reduction in GFR (Interference with the prostaglandin production in kidney) Urine contains albumin and casts Nitrogen retention in body Nephrotoxicity- Reduced clearance of Aminoglycosides – High blood levels of Aminoglycosides – High chances of Ototoxicity

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Neuromuscular Blockade More with Neomycin and Streptomycin Reduce Acetylcholine release from Motor Endings Interfere with mobilization of synaptic vesicles By antagonizing calcium Decreased sensitivity of the muscle end plates to Ach. Non significant in otherwise normal cases in routine Dangerous in Myasthenia gravis Direct administration of Aminoglycosides into pleural and peritoneal cavities If patient received curare like muscle relaxant during surgical procedure Partially antagonized by IV calcium

Streptomycin:

Streptomycin Narrow spectrum (Gram negative + M. tuberculosis) Uses Tuberculosis (First drug to show antitubercular activity) (PESRI-25,20,15,10,5 mg/kg) Acts against extracellular bacilli (due to poor penetration in the cell ) Also active against Atypical Mycobacterium (M. kansasii and M. avium intracellulare .) Resistance develops fast (Never use streptomycin alone as antitubercular) SABE Plague – (Streptomycin {Tetracycline} Tularemia- (DOC {Tetracyclines alternate} Brucellosis

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Tularemia  (rabbit fever, deer fly fever, and Ohara's fever ) is caused by the  bacterium   Francisella tularensis a gram-negative ,  nonmotile   coccobacillus . Depending on the site of infection, tularemia has six characteristic clinical symptoms: ulceroglandular , glandular, oropharyngeal, pneumonic, oculoglandular, and typhoidal. Brucellosis, also called Bang's disease, Crimean fever, Gibraltar fever, Malta fever, Mediterranean fever, rock fever, or undulant fever is a highly contagious  zoonosis  caused by ingestion of  unsterilized   milk  or  meat  . Transmission from human to human, through  sexual contact  or from mother to child, is rare but possible. Brucella  are small,  gram-negative , non-motile, non-spore-forming, rod shaped ( coccobacilli ) bacteria. They function as  facultative intracellular parasites . Plague  is a deadly  infectious disease  that is caused by the  enterobacteria   Yersinia pestis . The symptoms of plague depend on the concentrated areas of infection in each person: such as bubonic plague  in lymph nodes,  septicemic plague  in blood vessels,  pneumonic plague  in lungs, and so on. It is treatable if detected early.

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P yrazinamide (25)– Cidal, Intra, Inhibition of Mycolic Acid, Hyperuricemia, Hepatotoxicity E thambutol (20)– Static, Inhibits arabinosyl transferase and inhibit Mycolic acid incorporation, Hyperuricemia, Optic Neuritis S treptomycin (15)- NONE R ifampicin (10)- Red discoloration, Cidal, Both Extra and Intra, Inhibition of DNA dependent RNA polymerase, Inducer, Hepatitis I soniazid (5)- Peripheral neuropathy , Pyridoxine, Inhibition of Mycolic Acid of cell wall, Cidal to multiplying, Both Extra and Intra ATT

Gentamicin (Gentamicin):

Gentamicin (Gentamicin) Most commonly used Aminoglycosides (Jantamycin) Obtained from Micromonospora purpurea Broader spectrum ( But not effective in T.B) Synergism with Beta lactams Activity decreases in presence of pus Uses -Usually in combination with Penicillin, Cephalosporin or Fluoroquinolones, (BA, CA, FA with or without M) SABE Usually in peritoneal dialysate in topical creams for dressing and eye preparations combined with Ticarcillin for Pseudomonas

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Gentamicin-PMMA (Polymethyl methacrylate) A new drug delivery system for Osteomyelitis. Small acrylic beads impregnated with gentamicin. Threaded over surgical wire and implanted in bone cavity Left for 10days. Then removed along with wire.

Amikacin:

Amikacin Semisynthetic derivative of Kanamycin Next to gentamicin regarding use Resistant is less Widest spectrum ( Second line ATT) Reserve drug as alternate to Gentamicin More hearing loss

Kanamycin:

Kanamycin Highly Ototoxic Highly Nephrotoxic) Narrow spectrum Rarely used now ( Second line anti-tubercular drug)

Tobramycin:

Tobramycin More active against Pseudomonas and Proteus Reserve alternative of Gentamicin

Sisomicin (Not Sisomycin):

Sisomicin (Not Sisomycin ) Obtained from Micromonospora Same as gentamicin Greater efficacy against Pseudomonas

Netilmicin (Not Netilmycin):

Netilmicin (Not Netilmycin ) Semisynthetic derivative of Sisomicin Similar to Gentamicin but wider spectrum Effective in Gentamicin resistant cases of Proteus, Pseudomonas, Klebsiella, E.coli

Paromomycin:

Paromomycin To treat intestinal amoebiasis Cryptosporidiosis in immunocompromised (AIDS patients) Spectinomycin Chlamydial treatment along with Doxycycline

Framycetin (Soframycin):

Framycetin ( Soframycin ) Too toxic for systemic use Topically as ointment, cream, eye drops, etc.

Neomycin:

Neomycin Wide spectrum Highly Cochlear Toxic, and Nephrotoxic Most common use is topical, ointment, eye and ear drops ( in combination with Polymyxin, Bacitracin as Nebasulf, Polybiotic cream, etc) Neomycin with Polymyxin-B solution is used as an irrigant in urinary bladder to prevent bacteriuria associated with use of indwelling catheter.

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Oral neomycin has damaging effect on intestinal villi - Malabsorption syndrome. Damages colonic flora- deficiency of vit . K Superinfection Not used systemically ( Except for preparation of bowel for surgery and in Hepatic Coma or Hepatic Encephalopathy )

Hepatic coma (Hepatic Encephalopathy):

Hepatic coma (Hepatic Encephalopathy) Colonic bacteria produce NH3. NH3 can cross BBB NH3 is toxic to nervous system NH3 is converted to Urea by Liver (Urea does not cross BBB) In hepatic failure conversion of NH3 to Urea does not occur Increased level of NH3 produces encephalopathy. Neomycin suppresses colonic flora NH3 production in colon is reduced NH3 level in blood is reduced Other drug used for this purpose is Lactulose

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