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PROTEIN SYNTHESIS INHIBITORS
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INTRODUCTION
• These antibiotics exert their actions by targeting the bacterial ribosomal subunit at various steps in the synthesis of bacterial protein.
• Bacterial ribosome is smaller 70 s as compared to the mammalian cytoplasmic ribosome - 80 s
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CLASSES OF DRUGS
• AMINOGLYCOSIDES• TETRACYCLINES• GLYCYLCYCLINE• CHLORAMPHENICOL• MACROLIDES• CLINDAMYCIN• LINEZOLID• DALFOQUISTIN/ QUINOPRISTIN
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Very broad spectrum.
Aerobic gm -ve
SE: Toxicity
Nephro-
Oto-toxic
Very broad spectrum.
Many gm +, some gm –
Pen allergic pt
SE: GI distress
Gm+/- bacteria
Spirochetes, Rickettsiae
Resistant organisms
SE: GI distress
Photosensitivity
Impair teeth & bone growth
Chloramphenicol: many Gm -/+ bacteria Serious infxn. SE: Bone marrow aplasia
Clindamycin: Most Gm +, some Gm – Alternative use. SE: colitis - PMC (C. difficile)
Ethionamide: TB
SE: GI distress
Azithromycin (Zithromax)
p. 554
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Aminoglycosides
• THEY ARE BACTERICIDAL.• Susceptible organisms allow aminoglycosides
to diffuse through their porin channels in their outer membranes.
• These organisms have oxygen dependant system that transports the drug across cell membrane.
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Aminoglycosides
• Streptomycin• Gentamicin• Tobramycin• Amikacin • Neomycin
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• MOA: They bind to the 30s ribosomal subunit distorting its structure, thus interfering with the assembly of functional ribosomal apparatus(initiation).
• They also allow for misreading resulting in mutation or premature chain termination
• Synergism: They synergize with beta lactAM ANTIBIOTICS BECAUSE OF THE LATTERS ACTION ON CELL WALL SYNTHESIS, WHICH ENHANCES DIFFUSION OF THE AMINOGLYCOSIDES INTO THE BACTERIUM.
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Actions
•THAY ARE EFFECTIVE AGAINST AEROBIC GRAM -VE BACILLI and RODS AS ANEROBES LACK THE OXYGEN REQUIRING TRANSPORT SYSTEM.
•Synergistic action occur for infections caused by enterococci and pseudomonas
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Organisms susceptible to aminoglycosides• Klebsiella• Francisella tularensis• Yersinia pestis• Brucella• pseudomonas
• STREPTOMYCIN IS USED TO TREAT TB, PLAGUE & TULAREMIA.
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Resistance
• Decreased uptake of drug due to absence of Porin channels and oxygen dependent uptake system
• Altered 30 s subunit• Plasmid associated synthesis of conjugating
enzymes such as acetyl transferase that eliminates the drug faster.
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Aminoglycosides
Route : parenteral• Exception : neomycin –topical and sometimes
oral for hepatic coma.• The bacteriocidal effect is conc and time
dependent i.e., the greater the conc of drug, the greater the bacteria killing.
• Post antibiotic effect: Toxicity is dependent on drug concentration and thus once daily dosing is recommended which results in fewer toxicities.
• Distribution : low conc. in CSF,• Crosses placenta
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• Excretion : Glomerular filtration• HIGH CONCENTRATIONS ACCUMULATE IN
THE RENAL CORTEX, ENDOLYMPH AND PERILYMPH OF INNER EAR
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Aminoglycosides - SE• OTO TOXICITY
• DEAFNESS (irreversible), VERTIGO (reversible) may be enhanced by loop diuretics
• NEPHRO – TOXICITY: includes acute tubular necrosis which is usually reversible but enhanced by vancomycin, ampho-B, cisplatin
• NEURO MUSCULAR PARALYSIS- ↓ release of Ach• RX – mostly calcium gluconate or neostigmine can
reverse the situation• CONTACT DERMATITIS –neomycin
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Tetracyclines
• Doxycycline• Minocycline• demeclocycline
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TETRACYCLINES
• Consist of 4 fused rings with a system of conjugated double bonds.
• Broad spectrum antibiotics• Are bacteriostatic• MOA: THEY BIND TO THE 30S SUBUNIT OF THE
BACTERIAL RIBOSOME AND BLOCK ACCESS OF THE AMINO ACYL-TRNA TO THE MRNA-RIBOSOME COMPLEX AT THE ACCEPTOR SITE. THUS THEY INHIBIT BACTERIAL PROTEIN SYNTHESIS.
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Actions
• Effective against gram +ve & -ve organisms.• Good activity against: chlamydial and
mycoplasmal species, H-pylori, Rickettsia, Borrelia burgdoferi, Brucella and Vibrio
• Backup to penicillin G in syphilis• Demeclocycline can be used to treat SIADH• Minocycline: meningococcal carrier state
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TETRA CYCLINES• ROUTE : ORAL ,DECREASED BY
• MILK• ANTACIDS• IRON SUPPLEMENTS
• DISTRIBUTION :CROSSES BBB but not sufficient for therapeutic efficacy except Minocycline.
• All tetracyclines readily crosses placenta.• High levels in calcium tissues- bones, teeth, some
tumors• Excretion :renal , exception – doxycycline ( In bile )
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Resistance
• Production of an efflux pump by bacteria which causes elimination of the drug resulting in decreased conc of drug intracellularly.
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TETRA CYCLINES - SE
• MC : GIT- epigastric discomfort, • CALCIUM DEPOSITION : GROWTH –STUNTED,
TEETH – SMALL, DISCOLORED• PHOTO TOXICITY• HEPATO TOXICITY in pregnant women(high doses)• VERTIGO – MINOCYCLINE• SUPERINFECTION: overgrowth of candida and
C.dificile causing pseudomemranous colitis• CI : WOMEN – preg, lactating, children(<8yrs)
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GLYCYLCYCLINES
• TIGECYCLINE: structurally similar to the tetracyclines
• Has a broad-spectrum of activity against:• Gram –ve organisms• Anaerobic organisms• Its bacteriostatic• MOA: Binds to 30s ribosomal subunit preventing the
binding of aminoacyl t-RNA to the A-site.• SE: SIMILAR TO TETRACYCLINE 24
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Macrolides
• Erythromycin• Telithromycin• Azithromycin• Clarithromycin
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Macrolides
• Are bacteriostatic• Macrolides bind to 50 s subunit of the bacterial
ribosome thus inhibiting the translocation step of protein synthesis.
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• Erythromycin• Indication –effective against :• gram +ve cocci (not MRSA)• Legionella pneumophilia,• Campylobacter jejuni• Atypical organism: chlamydia, mycoplasma
and ureaplasma species • used in pt. with allergy to penicillins
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ACTIONS
Clarithromycin• Spectrum : - Haemophilus INFLUENZA, urethritis
caused by chlamydia trachromatis
Azithromycin• Spectrum: Moraxella & H-influenza related
respiratory pneumonias and M. Avium in AIDs pts• Telithromycin: DOC for macrolide resistant strep.
Pneumonia
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Macrolides• Route : • Erythromycin is given orally but are destroyed by
acid and so the enteric coated or esterified form is usually given.
• Clari and azithromycin: orally and stable to acid• IV – for azithromycin also• Distribution : CSF – poor.• Prostate – good• Excretion : in bile by erythromycin and
clarithromycin• Exception – Azithromycin – renal
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• Erythromycin and clarithromycin: are not safe in pregnancy and inhibit cyt P450
• Azithromycin: safe in pregnancy and does not inhibit cyt P450
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Resistance
• Ability of the bacteria to methylate a base in the 23s subunit of rRNA.
• Presence of a plasmid associated erythromycin esterase which inactivates the drug.
• Presence of an efflux pump which limits the conc of drug intracellularly
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Macrolides - SE
• MC : GIT DISTRESS• OTO TOXICITY: which is reversible• CHOLESTATIC JAUNDICE• CI : LIVER FAILURE
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chloramphenicol
• MOA: BINDS TO THE 50 S RIBOSOMAL SUBUNIT THEREBY INHIBITING THE PEPTIDYL TRANSFERASE REACTION.
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Actions
• Broad spectrum antibiotic• Active against rickettsiae• Salmonella typhi• Bacteriodes Fragilis
• Can be bactericidal (more commonly) or bacteriostatic depending on the organism.
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Resistance
• RESISTANCE IS BECAUSE OF R FACTOR WHICH CODES FOR ACETYL CO-A transferase that inactivates the drug
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CHLORAMPHENICOL• ROUTE : ORAL / IV• DISTRIBUTION : CROSSES BBB• Metabolized by hepatic conjugation to metabolite
called glucuronide• EXCRETION : of glucuronide renally • SE: GRAY- BABY SYNDROME- due to poor
conjugating capacity and under developed renal function. Accumulation leads to interference with function of mitochondrial ribosomes.
• HEMOLYTIC ANEMIA : G 6 PD DEFICIENCY
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Clindamycin• MOA and Resistance: same as macrolides• INDICATION: infections caused by anerobes such as
BACTERIODES FRAGILIS, osteomyelitis due to gram +ve cocci
• ROUTE : ORAL• EXCRETION : RENAL & HEPATIC• SE : MC is PSEUDOMEMBRANOUS COLITIS• Treatment of pseudomembranous colitis: first choice-
metronidazole and then vancomycin
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QUINOPRISTIN/DALFOPRISTIN• Quinipristin/dalfopristin• Mixture of two streptogramins in a ratio of 30
to 70.• MOA: Each component of this combination
binds to a separate site on 50 s bacterial ribosome interfering with the binding of amino acyl tRNA with acceptor site.
• Active against VRSA & VRE
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LINEZOLID
• Effective against gram +ve organism such VRSA & VRE
• MOA: binds to the 50s subunit Inhibits formation of 70 s initiation complex and thus inhibits protein synthesis.
• It is bacteriostatic• Inhibits MAO, so caution must be exercised by
pts taking tyramine containing foods