1 PROTEIN SYNTHESIS INHIBITORS

2 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 5

6 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. 7

Aminoglycosides Streptomycin Gentamicin Tobramycin Amikacin Neomycin 8

9 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.

10 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. 11

12 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.

13 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 14

15 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 16

17 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.

18 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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21 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. 22

23 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 25

Macrolides Are bacteriostatic Macrolides bind to 50 s subunit of the bacterial ribosome thus inhibiting the translocation step of protein synthesis. 26

27 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 28

29 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 30

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 31

32 Macrolides - SE MC : GIT DISTRESS OTO TOXICITY: which is reversible CHOLESTATIC JAUNDICE CI : LIVER FAILURE

33 chloramphenicol MOA: BINDS TO THE 50 S RIBOSOMAL SUBUNIT THEREBY INHIBITING THE PEPTIDYL TRANSFERASE REACTION.

34 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 35

36 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 37

38 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

39 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