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