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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

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

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

• 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

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 )

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)

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

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

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

• 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.

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

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