PROTEIN SYNTHESIS INHIBITORS DR FATAI OLUYADI USMLEINCLINED.COM 1

CLASSES  AMINOGLYCOSIDES  TETRACYCLINES  TIGECYCLINE  OXAZOLIDINONES(LINEZOLID)  STREPTOGRAMINS  MACROLIDES  CHLORAMPHENICOL  CLINDAMYCIN USMLEINCLINED.COM 2

BACTERIAL PROTEIN SYNTHESIS USMLEINCLINED.COM 3

OVERVIEW These drugs target bacterial ribosomal subunits, interfering with ribosomal protein synthesis Generally bacteriostatic (except Aminoglycosides is bactericidal) USMLEINCLINED.COM 4

AMINOGLYCISIDES  GENTAMICIN  NEOMYCIN (TOPICAL USE)  AMIKACIN  TOBRAMYCIN  STREPTOMYCIN  KANAMYCIN USMLEINCLINED.COM 5

AMINOGLYCOSIDES MECHANISM OF ACTION Irreversible inhibition of initiation complex through binding of the 30S subunit. Can cause misreading of mRNA. Also block translocation. Require Oxygen for uptake, therefore it is ineffective against anaerobes They are bactericidal (Only protein synthesis inhibitor that is bactericidal) USMLEINCLINED.COM 6

AMINOGLYCOSIDES Clinical Use: Gram –ve Rod infections. Facultative Anerobic bacilli Synergistic with Beta-lactam antibiotics. Ampicillin + gentamycin for E.faecalis, Vancomycin + gentamicin for E.faecalis, Ampicillin + aminoglycosides for Listeria Oral Neomycin is used prophylactically for bowel surgery Streptomycin is used in the treatment of Tuberculosis and Bubonic Plague(Yersinia Pestis) USMLEINCLINED.COM 7

AMINOGLYCOSIDES Pharmacokinetics: Water soluble, available IV, no CNS entry. Once daily dosing decreases toxicity  Concentration dependent killing: one dose a day allows for a higher dose to be used  Time-dependent toxicity: one dose a day allows a peak concentration, not a steady presence of drug. Requires Therapeutic drug monitoring. Decrease dose in renal dysfunction due to renal excretion USMLEINCLINED.COM 8

AMINOGLYCOSIDES ADVERSE EFFECTS Nephrotoxicity Neuromuscular blockade (Like Curare and can cause respiratory paralysis) Ototoxicity(especially when used with loop diuretics Dermatitis with neomycin Teratogen MECHANISM OF RESISTANCE: Bacterial transferase enzymes inactivate drug by acetylation, phosphorylation, or adenylation USMLEINCLINED.COM 9

TETRACYLINES  TETRACYCLINE  DOXYCYCLINE  MINOCYCLINE  DEMECLOCYCLINE MECHANISM OF ACTION Binds to 30s subunit and prevent the attachment of aminoacylt-tRNA. USMLEINCLINED.COM 10

TETRACYCLINES Clinical Use Broad spectrum – Gram +ve, Gram –ve, Anaerobes, Atypicals, protozoa Doxycycline is more lipid soluble and better distributed which makes it a drug of choice in: Vibrio sp., Spirochetes-Rickettsia, borrelia(lyme disease) mycoplasma chlamydiae, brucella Ability to accumulate intracellularly make them very effective against chlamydia and rickettsia. Also used to treat Acne USMLEINCLINED.COM 11

TETRACYCLINES Pharmacokinetics Absorption is impaired by food (less for doxycycline) Absorption is prevented by chelation of divalent cations (Ca 2+, Mg 2+, Fe 2+ ) and by Al 3+ So avoid dairy products, antacids, mineral supplements. Minocycline is very water soluble: High concentration in saliva and tears. Used to eradicate meningococcal carrier state. Doxycycline is lipid soluble and not renally eliminated (No dosage adjustment on renal failure) USMLEINCLINED.COM 12

TETRACYCLINE ADVERSE EFFECTS GI distress, discoloration of teeth, inhibition of bone growth in children, photosensitivity. Contraindicated in Pregnancy Can cause Pill Esophagitis. Also causes Fanconi Syndrome. Demeclocycline is an ADH receptor antagonist hence will cause Nephrogenic diabetes insipidus and used to treat SIADH Mechanism of resistance: Decrease uptake of drug Increased efflux pump activity that pumps drug out of bacterial cells (Plasmid encoded) USMLEINCLINED.COM 13

TIGECYCLINE Similar to Tetracyclines in structure and mechanism of action Has an FDA black box warning for Increase Mortality risk Administered IV, and cleared by the Liver CLINICAL USES Staphylococci including MRSA, VISA and VRSA Penicillin or Vancomycin resistant enterococci (VRE) Other resistant Microorganisms Not Effective against Pseudomonas or Proteus USMLEINCLINED.COM 14

OXAZOLIDINONES  LINEZOLID Mechanism Inhibits protein synthesis by binding to the P-site of 50S subunit and preventing the formation of the initiation complex. Clinical use Gram +ve species including MRSA and VRE USMLEINCLINED.COM 15

LINEZOLID Adverse effects Bone marrow suppression (especially thrombocytopenia), Peripheal Neuropathy, Serotonin syndrome Mechanism of resistance Point mutation of ribosomal RNA USMLEINCLINED.COM 16

STREPTOGRAMINS QUINUPRISTIN/DALFOPRISTIN Mechanism: Blocks the A-site of the 50S subunit of bacterial ribosomes and prevents the elongation of peptide chains. Used In combination for synergy. Dalfopristin binds first and causes a change in shape in the A site and then increases affinity for Quinupristin by a hundred fold. Clinical Use Vancomycin-resistant Enterococcus.Faecium(VRE), MRSA Not effective against E.faecalis Skin infections with S.aureus and S.pyogenes USMLEINCLINED.COM 17

STREPTOGRAMINS ADVERSE EFFECTS Quinupristin and Dalfopristin are inhibitors of Cytochrome P-450 hence, drug interactions Adverse effects are Infusion related Pain at injection site Flu-like symptoms USMLEINCLINED.COM 18

MACROLIDES  ERYTHROMYCIN  CLARITHROMYCIN  AZITHROMYCIN MECHANISM OF ACTION Binds to the 23s RNA of the 50S ribosomal sUbunit, blocking translocation of peptidyl-tRNA. USMLEINCLINED.COM 19

MACROLIDES CLINICAL USE Atypical pneumon – Mycoplasma, Chlamydia, Legionella Sexually transmitted Infections (Chlamydia) Gram +ve cocci – Streptococcal infections in patients allergic to Penicillins Bordetella Pertusis Mycobacterium prophylaxis and treatment (Mycobacterium avium complex) Gram –ve – Including Neiserria, Campylobacter, H.pylori(Clarithromycin) Diabetic Gastroparesis – due to effect on Motilin receptor USMLEINCLINED.COM 20

MACROLIDES ADVERSE EFFECTS Gastrointestinal Mottility issues – Increase Motilin receptor activity Diarrhea Arrythmia – Prolongs QT interval (Ventricular tachycardia) Acute cholestatic hepatitis Rash Eosinophillia Increase Serum concentration of theophyllines and oral anticoagulants Clarithromycin and erythromycin inhibits the Cytochrome P-450 enzymes USMLEINCLINED.COM 21

MACROLIDES MECHANISM OF RESISTANCE Methylation of 23S rRNA-binding site prevents binding of drug. USMLEINCLINED.COM 22

CHLORAMPHENICOL MECHANISM: Blocks peptidyl transferase at 50S ribosomal subunit. CLINICAL USE Meningitis – Hemophilus Influenza, Neisseria meningitides, Streptococcus pneumoniae Rocky mountain spotted fever (Rickettsia ricketsii) Limited use due to toxicities. USMLEINCLINED.COM 23

CHLORAMPHENICOL ADVERSE EFFECTS Anemia (Dose dependent) Aplastic anemia (dose dependent) Gray baby syndrome (in premature infants due to lack of UDP-glucoronyl transferase) Inhibits the Cytochrome P-450 MECHANISM OF RESISTANCE Plasmid encoded acetyltransferase inactivates the drug. USMLEINCLINED.COM 24

CLINDAMYCIN Mechanism of action: Blocks tanslocation of peptidyl tRNA at 50S ribosomal subunit USMLEINCLINED.COM 25

CLINDAMYCIN CLINICAL USE Anerobic infections – Bacteroides spp., Clostridium perfringes Anerobes in Aspiration Pneumonia Anerobes in Lung abcesses Anerobes in Oral infections Anerobes above the diaphragm – Clindamycin, Anerobes below the diaphragm - Metronidazole Invasive group A streptococcal infection Adverse effects: Pseudomembranous Colitis, fever, diarrhea USMLEINCLINED.COM 26