1. Protein Synthesis Inhibitors

2. TETRACYCLINES MACROLIDES CLINDAMYCIN CHLORAMPHENICOL STREPTOGRAMINS OXAZOLIDINONES

4. Antimicrobial Activity – broad-spectrum bacteriostatic antibiotics – active against many gram-positive and gram-negative bacteria (aerobic, anaerobes) including rickettsiae, chlamydiae, mycoplasmas, and L forms; and against some protozoa (eg, amebas) TETRACYCLINES

6. Mechanism of action Tetracyclines enter microorganisms by – In part passive diffusion – in part by an energy-dependent process of active transport – bind reversibly to the 30S subunit of the bacterial ribosome, – blocking the binding of aminoacyl-tRNA to the acceptor site on the mRNA-ribosome complex – prevents addition of amino acids to the growing peptide

7. TETRACYCLINES

8. Resistance impaired influx or increased efflux by an active transport protein pump ribosome protection due to production of proteins that interfere with tetracycline binding to the ribosome enzymatic inactivation The most important of these are production of an efflux pump and ribosomal protection

9. Pharmacokinetics Absorption is impaired divalent cations (Ca 2+, Mg 2+, Fe 2+ ) or Al 3+ ; by dairy products and antacids, which contain multivalent cations; and by alkaline pH – except doxycycline and minocycline Diffuse readily into body fluids – Minocycline reaches very high concentrations in tears and saliva

10. Pharmacokinetics Carbamazepine, phenytoin, barbiturates, and chronic alcohol – may shorten the half-life of doxycycline 50% by induction of hepatic enzymes Tetracyclines are classified as: – short-acting (chlortetracycline, tetracycline, oxytetracycline), – intermediate-acting (demeclocycline and methacycline), – long-acting (doxycycline and minocycline)

11. Clinical Uses Mycoplasma pneumoniae, Chlamydiae Rickettsiae Spirochetes Helicobacter pylori Cholera tularemia, and brucellosis – (combination with aminoglycosides)

12. Minocycline – eradicate the meningococcal carrier state Demeclocycline – inhibits the action of antidiuretic hormone in the renal Tigecycline – Staphylococcus aureus, MRSA, VRSA – enterococci, including vancomycin-resistant strains – Proteus and P aeruginosa, however, are intrinsically resistant

13. Adverse Reactions GASTROINTESTINAL ADVERSE EFFECTS – Nausea, vomiting, and diarrhea Nausea, anorexia, and diarrhea can usually be controlled by administering with food BONY STRUCTURES AND TEETH – bound to calcium deposited in newly formed bone or teeth in young children (under 8 years of age) – fluorescence, discoloration, and enamel dysplasia (fetal teeth)

15. Adverse Reactions KIDNEY TOXICITY – Renal tubular acidosis (fanconi syndrome) LOCAL TISSUE TOXICITY – venous thrombosis PHOTOSENSITIZATION – sensitivity to sunlight or ultraviolet light Demeclocycline VESTIBULAR REACTIONS – Dizziness, vertigo, nausea, and vomiting

16. MACROLIDES Macrocyclic lactone ring

17. Mechanism of action binding to the 50S ribosomal RNA, which blocks the aminoacyl translocation reaction and formation of initiation complexes Bacteriostatic Bacteriocide (higher doses) Activity is enhanced at alkaline pH

19. Resistance reduced permeability of the cell membrane or active efflux production of esterases (by Enterobacteriaceae) that hydrolyze macrolides modification of the ribosomal binding site (so-called ribosomal protection) by chromosomal mutation or by a macrolide-inducible or constitutive methylase

20. MACROLIDES Erythromycin – Antimicrobial Activity pneumococci, streptococci, staphylococci, and corynebacteria, Mycoplasma, legionella, Chlamydia trachomatis, C pneumoniae, helicobacter, listeria The antibacterial action of erythromycin may be inhibitory or bactericidal, particularly at higher concentrations, for susceptible organisms

21. Clinical Uses Drug of choice in corynebacterial infections, chlamydial infections and in community acquired pneumonia Useful as a penicillin substitute in penicillin allergic individuals with infections caused by staphylococci, streptococci, or pneumococci.

22. Adverse Reactions GASTROINTESTINAL EFFECTS – Anorexia, nausea, vomiting, and diarrhea LIVER TOXICITY – acute cholestatic hepatitis (fever, jaundice, impaired liver function) – allergic reactions include fever, eosinophilia, and rashes

23. DRUG INTERACTIONS inhibit cytochrome P450 enzymes – theophylline, oral anticoagulants, cyclosporine, methylprednisolone, oral digoxin

24. CLARITHROMYCIN Clarithromycin has improved acid stability and oral absorption compared with erythromycin Mycobacterium avium M leprae Toxoplasma gondii

25. AZITHROMYCIN penetrates into most tissues (except cerebrospinal fluid) and phagocytic cells The drug is slowly released from tissues (tissue half-life of 2–4 days) elimination half-life is 3 days administered 1 hour before or 2 hours after meals azithromycin does not inactivate cytochrome P450 enzymes

26. AZITHROMYCIN M avium T gondii, staphylococci, streptococci (less than erythromycin) H influenzae Chlamydia

27. KETOLIDES Telithromycin – poor substrates for efflux pump-mediated resistance – bind to ribosomes of some bacterial species with higher affinity than macrolides – community-acquired bacterial pneumonia – acute exacerbations of chronic bronchitis – sinusitis – streptococcal pharyngitis

28. CLINDAMYCIN Mechanism of action – The binding site for clindamycin on the 50S subunit – inhibits protein synthesis interfer with the formation of initiation complexes and with aminoacyl translocation reactions. Antibacterial Activity – Streptococci, staphylococci, and pneumococci – Bacteroides species and other anaerobes – Community-acquired strains of MRSA

29. Resistance mutation of the ribosomal receptor site modification of the receptor by a constitutively expressed methylase enzymatic inactivation of clindamycin Gram-negative aerobic species are intrinsically resistant because of poor permeability of the outer membrane

30. Pharmacokinetics penetrates well into most tissues brain and cerebrospinal fluid being important exceptions It penetrates well into abscesses and is actively taken up and concentrated by phagocytic cells

31. Clinical Uses skin and soft-tissue infections anaerobic infection caused by bacteroides infections originating in the female genital tract, eg, septic abortion and pelvic abscesses Prophylaxis of endocarditis (valvular heart disease) AIDS related – Toxoplasma of the brain – Pneumocystis jiroveci

32. Adverse Effects diarrhea, nausea Superinfection (colitis due to Clostridium difficile)

33. CHLORAMPHENICOL Antimicrobial Activity – binds reversibly to the 50S subunit of the bacterial ribosome – inhibit the peptidyl transferase step of protein synthesis – Chloramphenicol is a bacteriostatic broad-spectrum antibiotic aerobic and anaerobic gram-positive and gram-negative organisms.

35. Resistance selection of mutants that are less permeable to the drug production of chloramphenicol acetyltransferase, a plasmid-encoded enzyme that inactivates the drug

36. Pharmacokinetics completely absorbed (oral) widely distributed to virtually all tissues and body fluids (CNS & CSF) Inactivated by conjugation with glucuronic acid

37. Clinical Uses serious rickettsial infections – typhus and Rocky Mountain spotted fever – alternative to a -lactam antibiotic for treatment of meningococcal meningitis and pneumococci

38. Adverse Reactions GASTROINTESTINAL DISTURBANCES – nausea, vomiting, and diarrhea BONE MARROW DISTURBANCES – dose-related reversible suppression of red cell production – Aplastic anemia (idiosyncratic reaction) TOXICITY FOR NEWBORN INFANTS – gray baby syndrome vomiting, flaccidity, hypothermia, gray color, shock, and collapse

39. INTERACTION WITH OTHER DRUGS inhibits hepatic microsomal enzymes – phenytoin, tolbutamide, chlorpropamide, and warfarin bactericidal drugs such as penicillins or aminoglycosides

40. STREPTOGRAMINS Quinupristin-dalfopristin quinupristin, a streptogramin B dalfopristin, a streptogramin A— 30:70 ratio bactericidal for most organisms except Enterococcus faecium

41. ANTIBACTERIAL ACTIVITY gram-positive cocci – multidrug-resistant strains of streptococci penicillin-resistant strains of S pneumoniae, methicillin-susceptible and resistant strains of staphylococci, and E faecium (but not E faecalis ).

42. Mechanism of action bind to the 50S ribosomal subunit Quinupristin inhibits polypeptide elongation Dalfopristin binds at an adjacent site, changing the conformation of the 50S ribosome – synergistically enhances the binding of quinupristin

43. Resistance Resistance is due to modification of the quinupristin binding site (MLS-B type), enzymatic inactivation of dalfopristin, or efflux

44. Adverse Reactions pain at the infusion site, and an arthralgia-myalgia syndrome Quinupristin and dalfopristin significantly inhibit CYP3A4 – Drug interactions warfarin, diazepam, astemizole, terfenadine, cisapride, nonnucleoside reverse transcriptase inhibitors, and cyclosporine

45. OXAZOLIDINONES Linezolid – Linezolid is 100% bioavailable after oral administration – prevention formation of the ribosome complex that initiates protein synthesis – bind to 50S subunit – Resistance is caused by mutation of the linezolid binding site on 23S ribosomal RNA

46. ANTIBACTERIAL ACTIVITY vancomycin-resistant E faecium infections nosocomial pneumonia community-acquired pneumonia skin infections, complicated or uncomplicated Off-lable use – Nocardia – Multidrug resistant tuberculosis

47. Adverse Reaction Thrombocytopenia Anemia and neutropenia peripheral neuropathy lactic acidosis have been reported with prolonged courses of linezolid

48. MUPIROCIN active against many gram-positive and selected gram-negative bacteria. It has good activity against S. pyogenes and methicillin-susceptible and methicillin resistant strains of S. aureus

49. Mechanism of Action Mupirocin inhibits bacterial protein synthesis by reversible inhibition of ILe tRNA synthase There is no cross-resistance with other antibiotic classes Resistance – mutations of the gene encoding ILe tRNA synthase or an extra chromosomal copy of a gene encoding a modified ILe tRNA synthase

50. Dosage Form Mupirocin is available as a 2% cream or ointment for dermatologic use and as a 2% ointment for intranasal use