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Aminoglycosides

Aminoglycosides

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Published by: dhainey on Jan 26, 2009
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06/15/2013

 
AMINOGLYCOSIDES, MACROLIDES,METRONIDAZOLE,CLINDAMYCIN, VANCOMYCIN
Erythromycin, amikacin, vancomycin,clindamycinAMINOGLYCOSIDES
Streptomycin 1943; Strept.griseus
 Neomycin 1949; Strept.fradiae
Paromomycin (Humagel) 1956;Strept. rimosus
Kanamycin 1957; Strept.kanamyceticus
Tobramycin (Nebcin) 1967; Strept.tenebrarius
Gentamicin (Garamycin) 1963;Micromonospora purpurea
Sisomicin Micromonosporainyoensis
 Netilmicin (Netromycin) derivativeof Sisomicin
Amikacin (Amikin) derivative of Kanamycin
NOMENCLATURE AND PROPERTIES
Nomenclature
“-mycin” Streptomyces
-micinMicromonospora
Physical and Chemical Properties
Compounds with 2 or more aminosugarslinked by glycosidic bonds to an aminocyclitolgroup (hexose ring): streptidine (streptomycin)or 2-deoxystreptamine.
Water-soluble, stable in solution, more activeat alkaline pH.
POST-ANTIBIOTIC EFFECT
-its antibacterial activity persists beyond the time duringwhich measurable drug is present
CONCENTRATION-DEPENDENT KILLING-
increasing concentrations kill an increasing proportionof bacteria and at a more rapid rate
ADMINISTRATION, DISTRIBUTION, ANDEXCRETION
Administration
Must be given parenterally to achieveadequate serum levels except Neomycin,Kanamycin, and Paromomycin.
Distribution
Penetrate most body fluids well except CSFwhere penetration is poor.
High concentration found in renal cortex andin the endolymph and perilymph of the inner ear.
Cross the placental barrier 
fetal plasma andamniotic fluid.
Excretion
Through the urine by glomerular filtration.
PHARMACOKINETIC PROFILE
DRUG ROA ABSORPTION t ½ (hrs.) PPB
Gentamicin IV/IMPoor 2 <10StreptomycinIMPoor 2 2.5 35KanamycinIV/IM Poor 2 2.5 <10TobramycinIV/IM Poor 2 <10AmikacinIV/IM Poor 2 2.5 <10 NetilmicinIV/ IM Poor 2 <10
MECHANISM OF ACTION
Inhibition of protein synthesis by:1. Being actively transported through the cellwall.2. Binding to ribosomal sites
A. Interference with the initiation complex of  peptide formation.B. Misreading of the genetic code of the mRNAtemplate
incorporation of incorrect AA intothe growing polypeptide chains
non-functional or toxic protein.C. Breaking up of polysomes into non-functional monosomes.30S Streptomycin30S and 50S Other aminoglycosides
MECHANISMS OF RESISTANCE
Impaired intracellular transport
Absent oxygen-dependent transport system for aminoglycoside.
Altered ribosomal binding site
Lowered affinity of 30S ribosomal subunit binding site to aminoglycoside as a result of mutation.
Inactivation of the drug my microbial enzymes
Production of enzymes that inactivate the drug by adenylylation, acetylation, or  phosphorylation.
ANTIMICROBIAL ACTIVITY & ADVERSEREACTIONS
Antimicrobial Activity:Bactericidal
Adverse Reactions1. OtotoxicityVestibular damage:Vertigo, ataxia, loss of  balance.Cochlear damage:Tinnitus, high-frequency hearing loss.2. Nephrotoxicity: Proteinuria, cylindruria, andinability to concentrate the urine.Risk factors: Advanced age, preexisting renaldisease, concurrent use of Vancomycin,Amphotericin B, Cephalothin, Cisplatin,Cyclosporine.3. Neuromuscular paralysis4. Allergic reaction: Contact dermatitis
CLINICAL USES
For the treatment of infections caused by aerobicor facultative gm (-) bacilli: Gentamicin,Tobramycin, Amikacin, Netilmicin
For Ps. aeroginosa infection: In comb. with PCN,Ceftazidime, Imipenem,Aztreonam.
Drug of choice for tularemia, plague, and brucellosis (with PCN): Streptomycin
Drug of choice for enterococcal endocarditis:Streptomycin or Gentamicin with PCN G
 
MACROLIDES
Erythromycin:Stearate, ethyl succinate, estolate,gluceptate,lactobionate(1952; Streptomyces erythreus)
Clarithromycin
Azithromycin
Roxithromycin
DirithromycinChemistry:
Macrocyclic lactone ring with 1 or more deoxysugars: Desosamine or cladinose.
Poorly absorbed in water; readily dissolved inorganic solvents.
Stable at 4oC; loses activity at 20oC and at acid pH.
MECHANISM OF ACTION
Inhibits protein synthesis by binding to 23S rRNAcomponent of the 50S subunit
blockade of ribosomaltranslocation and formation of initiation complexesMECHANISMS OF RESISTANCE
Reduced permeability of the cell membrane.
Production (by enterobacteriaceae) of esterasesthat hydrolyze the macrolides.
Modification of the ribosomal binding site(ribosomal protection) by chromosomal mutationor by a macrolide-inducible or constitutivemethylase.
PHARMACOKINETIC PROFILE &ANTIMICROBIAL ACTIVITY
Drug ROAAbsorptiont ½ (hrs)Erythromycin PO, IVGood 1.5Clarithromycin POGood4 6Azithromycin POGood10 50Roxithromycin PO Good12Telithromycin POGoodAntibacterial Activity: Bacteriostatic
CLARITHROMYCIN
Derived from erythromycin by addition of amethyl group.
Metabolized in the liver into 14-hydroxyclarithromycin.
Low incidence of GI intolerance.
Less frequent dosing
AZITHROMYCIN
Derived from erythromycin by addition of amethylated nitrogen into the 15-atom lactone ring.
Long half-life (2-4 days).
Does not inactivate cytochrome P450 enzymes.
A D R & DRUG INTERACTIONS
Adverse Reactions
GI: Anorexia, NAV, diarrhea.
Liver toxicity: Acute cholestatic hepatitis(estolate).
Allergic reactions: Fever, eosinophilia, rashes.Drug Interactions
Inhibits cytochrome P450 enzyme system
increased serum concentration of theophylline,oral anticoagulants, cyclosporine,methylprednisolone, astemizole.
Increases bioavailability of oral Digoxin
increased serum conc.
CLINICAL USES
Drug of choice for Mycoplasma pneumonia,Legionella pneumonia, pertussis, diphtheria,chancroid, Campylobacter enteritis, chronic prostatitis due to Chlamydia, and Chlamydiatrachomatis infections during pregnancy andchildhood.
For prophylaxis against endocarditis during dental procedures in patients with valvular heart disease.METRONIDAZOLE
Chemistry
 Nitroimidazole compound with a molecular wt. of 170.
Mechanism of Action
Bactericidal activity through 3 steps:1. Penetration into the bacterial cell.2. Reductive activation.3. Toxic effect of the reduced intermediate products.
Mechanism of Resistance
Resistant strains are less able to reduce thedrug into active intermediate compounds
noaccumulation of drug within cell.MECHANISM OF ACTION
PHARMACOKINETICS, ANTIMICROBIALACTIVITY, & ADR 
Pharmacokinetics
85% absorbed after oral administration; <20%PPB.
May be given orally, IV or by rectal suppository.
Widely distributed in tissues and fluids.
Metabolized in liver; excreted in urine.
t1/2:7.5 hours.Antimicrobial Activity: BactericidalAdverse Reactions:
 NAV, anorexia, unpleasant metallic taste.
 Neurotoxicity manifested by sensory neuropathy,ataxia, encephalopathy, and seizures.
Stomatitis, pancreatitis, dark or reddish-brownurine.
DRUG INTERACTIONS & CLINICAL USES
Drug Interactions
+ Alcohol
Disulfiram-like effects.
+ Coumarin
potentiation of anticoagulanteffect.
+ Phenytoin and Phenobarbital
eliminationof metronidazole is accelerated.
 
+ Cimetidine
decreased metronidazole plasmal clearance.
+ Lithium
accelerated lithium toxicity.
Clinical Uses
Drug of choice for amoebiasis, giardiasis, andurogenital trichomoniasis.
Drug of choice for non-specific vaginitis.
Alternative drug to Vancomycin for C.difficile colitis.CLINDAMYCIN
Chemistry: 7-chloro-7-deoxy derivative oLincomycin.
Mechanism of Action:Inhibits protein synthesis by binding to the 50Sribosomal subunit of the bacteria
interferes withformation of initiation complexes and aminoacyltranslocation reactions.
Mechanisms of Resistance1.Mutation of the ribosomal receptor site.2. Modification of the receptor by aconstitutively expressed methylase.3. Enzymatic inactivation of Clindamycin.
ANTIMICROBIAL ACTIVITY,PHARMACOKINETICS, & ADR 
Antimicrobial Activity:BacteriostaticPharmacokinetics:
Well absorbed PO; 60-90% PPB.
Widely distributed in tissues and body fluids.
Metabolized in liver; excreted through bile &urine; t1/2: 2.5 h.Adverse Reactions
GI:NAV, diarrhea, epigastric pain.
Allergic reactions:Rashes, fever.
Reversible elevations of SGOT and SGPT.
Pseudomembranous colitis secondary toovergrowth of Clostridium difficile.
CLINICAL USES
For the treatment of anaerobic intrabdominal and pelvic infections especially those involving B.fragilis (with aminoglycoside or aztreonam).
For the treatment of actinomycosis in PCN-allergic patients.
For the treatment of infections due to Staph.aureus or Strep, like osteomyelitis and septicarthritis as alternative drug to b-lactamantibiotics.
Prophylaxis of endocarditis in patients withvalvular heart disease undergoing dental procedure.VANCOMYCINSource: Streptococcus orientalisChemistry: Glycopeptide with a mol. wt. of 1449.Mechanism of action:Inhibits cell wall synthesis by binding to D-Ala-D-Ala terminus of the peptidoglycan pentapeptide
inhibits transglycosylase
prevents further elongation of  peptidoglycan
weakening of peptidoglycan
cellsusceptible to lysis.MECHANISM OF ACTION
MECHANISM OF RESISTANCE,ANTIMICROBIAL ACTIVITY, &PHARMACOKINETICS
Mechanism of Resistance:- Modification of D-Ala-D-Ala binding site of the peptidoglycan in which D-Ala is replaced by D-lactate
loss of hydrogen bond that facilitates high-affinity binding of Vancomycin to its target
loss of activity.Antimicrobial Activity: BactericidalPharmacokinetics:
Poorly absorbed PO --> given parenterally by IV.
Widely distributed to tissues; 55% PPB.
Excretion by glomerular filtration.
t1/2: 7-8 hours.
ADVERSE DRUG REACTIONS
 
Phlebitis at site of injection.
Fever and chills.
“Red man” or “red neck” syndrome:Tingling,erythema, flushing of the face, neck, and thoraxsecondary to the release of histamine.
Ototoxicity and nephrotoxicity especially in theelderly, those with impaired renal function, andthose receiving aminoglycosides concomitantly.
CLINICAL USES
Drug of choice in:
Infections caused by methicillin-resistant strains of Staph. aureus, Staph. epidermidis, and other coagulase-negative staphylococci.
Sepsis and endocarditis caused by Staph species or Streptococci in patients allergic to PCN andcephalosporins.
Enterococcal infections in PCN-allergic patients.
Diphtheroid infections.
Seriously ill patients with Clostridium difficilecolitis.

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