1. Antituberculous Drugs

1. 1. Antituberculous Drugs

2. Antituberculous Drugs • First-line agents： Isoniazid Rifampin Pyrazinamide Ethambutol Streptomycin • Second-line agents： Para-aminosalicylic Ethionamide Amikacin Capreomycin Fluoroquinolones

4. Isoniazid 1．Antituberculous activity • Bacteriostatic & bactericidal for tubercle bacilli • Remarkably selective for mycobacteria • Resistance mutants occurs easily when given as the sole drug. • Be active against both extracelluar and intracellular tubercle bacilli. • Penetrating into phagocytes, Diffusing readily into all body fluid and tissues, including caseous material.

5. 2．Mechanism of action • Inhibiting synthesis of mycolic acids – the essential components of mycobacterial cell walls. • The Bacterial Cell Wall Gram Positive Gram Negative Mycobacteria Peptidoglycan Mycolate Porin Cytoplasmic membrane Acyl lipids LAM Outer membrane proteins

6. Isoniazid 3．ADME • Absorbed from the gastrointestinal tract readily. • Distributed widely in all body fluids and tissues. • Metabolism, especially acetylation by liver N-acetyltransferase, is genetically determined (slow acetylators，rapid acetylators, and middle acetylators). • Excreted mainly in the urine.

8. Isoniazid 4．Clinical Uses • Combination with rifampicin or second-line agents, used for severe infections with M tuberculosis. • As a single agent, indicated for prevent and treatment of active tuberculosis of early stage. • Allergic reactions: rashes, systemic lupus erythematosus, etc. • Hepatotoxicity • Peripheral neuritis (slow acetylators, the structure of isoniazid is similar to that of pyridoxine, Vit B6) • CNS toxic effects • GI effects 5．Adverse reactions

9. Rifampicin 1. Antibacterial activity • Broad-spectrum • Resistance mutants occurs easily, if used alone. • Bactericidal for mycobacteria. • Penetrates most tissues and into phagocytes.

10. DNA template DNA template 2．Mechanism of action • Binding strongly to the b subunit of bacterial DNA-dependent RNA ploymerase • Inhibiting RNA synthesis. 3．Mechanism of resistance • Resistance results from one of several possible points in the gene for b subunit ofRNA polymerase. These mutation prevent binding of rifampicin to RNA polymerase.

11. Rifampicin 4．ADME • Absorbed well after oral administration. The absorption is attenuated by food and para-aminosalicylic (PAS). • Distributed widely, even in CSF when meninges is infectious. • Metabolized in liver by deactylation, and rifampicin is a enzyme inducer. • Excreted mainly through the liver into bile, then undergoes enterohepatic recirculation.

12. Rifampicin 5. Clinical Uses • mycobacterial infections • other indications 6. Adverse reactions • GI effects • Cholestatic jaundice or hepatitis • Hypersensitive reaction • Causing a harmless orange color in urine, sweat, tear, and contact lenses.

13. Ethambutol 1．Antimycobacterial actvity • Nearly all strain of M. tuberculosis are sensitive. • Be bactericidal to intercellular and extrecellular M. tuberculosis. • Ethambutol inhibits mycobacterial arabinosyl transferases, which are involved in the polymerization reaction of arabinoglycan, an essential component of the mycobacterial cell wall. • Resistance to ethambutol is due to mutations resulting in overexpression of mycobacterial arabinosyl transferases. 2．Clinical Uses • Treatment for tuberculosis of various forms when given concurrently with isoniazid. 3．Adverse reactions • Retrobulbar neuritis. • Hypersensitive reactions. • GI upset, rash, fever, headache, etc.

14. Pyrazinamide • Bactericidal (in vitro a slightly acidic pH). • Well absorbed (p.o.), widely distributed. • Resistance for Pyrazinamide develops fairly readily, but there is no cross-resistance with other antituberculous drugs. • Adverse reactions hepatotoxicity, GI reactions, drug fever, and hyperuricemia (acute gouty arthritis).

15. Streptomycin • The first effective drug to treat tuberculosis. • in treatment of life-threatening forms of tuberculosis, eg, meningitis and disseminated disease, and in treatment of infections resistant to other drugs. • Resistance to Streptomycin developed easily when it is used alone. • Given simultaneously to prevent emergence of resistance and toxic reaction.

16. The principle for using antituberculous drugs • Treatment should be initiated with antituberculous drugs early. • Be initiated with combination of antituberculous drugs . • be continued for a long time (6-9 months). e.g. 2HRZ/4HR and 2SHRZ/4HRE

17. 2. Antifungal agents

18. Antifungal agents Fungal infections traditionally have been divided to two distinct classes: systemic and superficial. So, the major antifungal agents are described with “systemic” and “topical”. Onychomycosis

19. Oral infection with Candida (Thrush) http://vasculitis.med.jhu.edu/treatments/cytoxan.html www.thachers.org/ internal_medicine.htm

20. Classification of antifungal agents • Polyenes: Amphotercin B • Azoles: Ketoconazole, Fluconazol • Pyrimidine analogues: Flucytosine • Echinocandins:Caspofungin, micafungin, anidulafungin • Allylamine: Terbinafine

21. Polyenes Amphotercin B • Broad-spectrum • Amphotericin B remains the drug of choice for all life-threatening mycotic infections (It is often as the initial regimen). e.g. Cryptococcal meningitis; • local administration: mycotic corneal ulcers

22. Amphotercin B Mechanism of action

23. Adverse reactions: (1) fever, chill, hyperpnea, myalgiaand hypotension, etc. (~75%) (2) nephrotoxicity: renal tubular acidosis and renal wasting K+ and Mg2+ (3) hematological Toxicity: hypochromic, normocytic anemia, etc. (4) hepatotoxicity, (5) cardiac toxicity, (6) CNS side effects (7) hypersensitive reaction Prevention of adverse reaction: (1) Pretreatment with oral acetaminophen or use of intravenous hydrocortisone hemisuccinate. (2) Supplemental K+ is required. (3) Do physical examination termly. (4) drug interactions

24. New formulations of Amphotercin B :

25. Flucytosine (5-FC) • a norrow-spectrum antifungal drug. • drug resistance occurs rapidly when flucytosine is used alone. • used predominantly in combination with amphotericin B for therapy of crypotococcal meningitis in AIDS patient, or with itraconazole for chromoblastomycosis. Adverse reactions: • depressing the function of bone marrow (leading to leukopenia and thrombocytopenia, etc.). • Plasma levels of hepatic enzymes are elevated (reversible). • rash, nausea, vomiting, diarrhea.

26. Mechanism of action

27. Azoles antifungal agents Imidazoles • ketoconazle • miconazole • clotrimazole Triazoles • fluconazole • Itraconazole • voriconazole

28. Azoles antifungal agents Mechanism of action: • reduce ergosterol synthesis by inhibition of fungal cytochrome P450 enzyme Antifungal activity : • Systemically (ketoconazle, fluconazole, itraconazole, voriconazole) or topically (miconazole, clotrimazole).

29. Azoles antifungal agents Ketoconazle : • the first oral azoles introduced into clinical use (systemically or topically). • less selective for fungal P450 • clinical use has been limited by endocrine side effects, liver toxicity and the drug interactions. • itraconazole or fluconazole has replaced ketoconazle for patients who can afford the more expensive, newer product. Itraconazole: • antifungal spectrum: broader than kotoconazole • side effects (interact with hepatic microsomal enzymes): less than kotoconazole.

30. Azoles antifungal agents Fluconazole • good water solubility and good CSF penetration (high bioavailability). • drug interactions and side effects are also less because of its least effect on hepatic enzyme of all the azoles. • Be used in: (1) Candidiasis, (2) Cryptococcosis. Voriconazole • The newest triazole to be licensed • less mammalian P450 inhibition • Visual disturbance are common (30%) • Be used in: (1) candidiasis (2) aspergillosis

31. Topical antifungal agents Polyenes : Nystatin: (topically used) Griseofulvin (systemic treatment) - Nucleoside analogue Allylamines: Terbinafine: oral formulation - squalene epoxidase inhibitor

32. 3. Antiviral Drugs

33. Antiviral Drugs 1. Characters of Virus Viruses are obligate intracellular parasites their replication depends primarily on synthetic processes of the host cell. Consequently, to be effective, antiviral agents must either block viralentry into or exit from the cell or be active inside the host cell. As a corollary, nonselective inhibitors of virus replication may interfere with host cell function and produce toxicity. 2.Classification of virus DNA virus RNA virus

34. The major sites of antiviral drug action

35. Four types of antiviral agents • Agents to Treat Herpes Simplex Virus (HSV) • & Varicella Zoster Virus (VZV) Infections • (1) Acyclovir • HSV (renal function), HSV meningitis • (2) Ganciclovir • HSV • CMV (bone marrow suppression) • (3) Idoxuridine • HSV (topical use) • (4) Vidarabine (Ara-A) • HSV

36. 2. Antiretroviral agents Zidovudine（AZT）： (1) First drug for HIV infection approved by FDA. (2) Different stage of HIV infection, to improve the symptom of patients and save the lives. (3) AZT+3TC+proteinase inhibitor efficacy，resistance, toxicity (4) Side effects: GI CNS Bone marrow suppression

37. Lamivudine（3TC）： (1) Uncleosides as antiviral agents (2) Effective on AZT-resistant HIV (3) Lower toxicity than AZT 3. HIV proteinase inhibitor saquinavir： (1) Selective inhibition of HIV proteinase (2) Single use or alone (3) Sensitive to AZT-resistant HIV

38. 4. Other antiviral agents (1).ribavirin（virazole）： Board antiviral spectrum Effective to DNA or RNA virus Type A, B Influ., HSV, adnoviral pneumonia. (2) Amaantadine ： specifical inhibition of influ. Prevention for Type 1 influ. (3) Interferon-g： Board antiviral spectrum Influ., HSV, viral hepatitis and cancer. fever and bone marrow suppression

39. Clinical Uses of Antimicrobial Agents

40. Identification of Infecting Organism • Staining of clinical specimens • Gram stain, Acid-fast stain, silver stains… • Antigen detection (e.g. ELISA, latex agglutination) • Nucleic acid detection (e.g. PCR) • Culture methods • Obtain culture material prior to antimicrobial therapy, if possible

41. Antimicrobial Susceptibility Testing • Minimum inhibitory concentration (MIC) • Minimum bactericidal concentration (MBC) 99.9% decrease in growth over 24 hours • Multiple techniques • Disk: semi-quantitative • Broth Dilution: quantitative

42. Empiric Therapy • Vast majority of all antimicrobial therapy • Should be approached rationally • Syndrome • Likely pathogens • Known resistance patterns • Host factors

43. Empiric Therapy for Peritoneal Dialysate Infection Collect specimens for laboratory testing

44. Gram Positive cultured

45. Gram Negative cultured

46. Identification of Infecting Organism Antimicrobial Susceptibility Testing Further modify the empiric therapy

47. Therapeutic applications of Anti-infectives • Formulate a clinical diagnosis of microbial infection. • Obtain specimens for laboratory examination, empirical therapy begins. • Formulate a microbiologic diagnosis. • Determine the necessity for empirical therapy. • Institute treatment.

48. Choice of antimicrobial agent 1. Choiceness of antimicrobial agents depends on pharmacological factors and host factors. 2. The uses of antimicrobial agents is strictly controlled in some situations. • Viral infections • Fever caused by unidentified reasons • Topical applications • Antimicrobial prophylaxis • Antimicrobial agents combinations

49. Pharmacological factors: • kinetics of absorption, distribution, and elimination; • Bacteriostatic vs bactericidal activity; concentration-dependent killing & time-dependent killing; C. the potential toxicity of an agent; D. pharmacodynamic or pharmacokinetic interaction with other drugs.

50. Site of infection • Adequate concentrations of antimicrobials must be delivered to the site of infection • Local concentrations greater than MIC • Subinhibitory concentrations may still alter bacterial adherence, morphology, aid in phagocytosis and killing • Serum concentration easy to determine, tissue concentrations more difficult to assess • Protein binding of drugs • Excretion • Urine: Aminoglycosides, fluoroquinolones (Urinary tract infections ) • Bile: Ceftriaxone • Penetration into various sites • Central nervous system • Lung • Bone • Foreign bodies