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1. Antituberculous Drugs. Antituberculous Drugs First-line agents : First-line agents :IsoniazidRifampinPyrazinamideEthambutolStreptomycin Second-line.

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Presentation on theme: "1. Antituberculous Drugs. Antituberculous Drugs First-line agents : First-line agents :IsoniazidRifampinPyrazinamideEthambutolStreptomycin Second-line."— Presentation transcript:

1 1. Antituberculous Drugs

2 Antituberculous Drugs First-line agents : First-line agents :IsoniazidRifampinPyrazinamideEthambutolStreptomycin Second-line agents : Second-line agents :Para-aminosalicylicEthionamideAmikacinCapreomycinFluoroquinolones

3 DrugTypical Adult Dosage 1 First-line agents (in approximate order of preference) Isoniazid300 mg/d Rifampin600 mg/d Pyrazinamide25 mg/kg/d Ethambutol15-25 mg/kg/d Streptomycin15 mg/kg/d Second-line agents Amikacin15 mg/kg/d Aminosalicylic acid8-12 g/d Capreomycin15 mg/kg/d Ciprofloxacin1500 mg/d, divided Clofazimine200 mg/d Cycloserine mg/d, divided Ethionamide mg/d Levofloxacin500 mg/d Rifabutin300 mg/d 2 Rifapentine600 mg once or twice weekly 1 Assuming normal renal function mg/d if used concurrently with a protease inhibitor.

4 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. Isoniazid

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

6 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. Isoniazid

7

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

11 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. Rifampicin

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

13 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. Ethambutol 1 . Antimycobacterial actvity 1 . Antimycobacterial actvity 3 . Adverse reactions 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.Treatment should be initiated with antituberculous drugs early. Be initiated with combination of antituberculous drugs.Be initiated with combination of antituberculous drugs. be continued for a long time (6-9 months).be continued for a long time (6-9 months). e.g. 2HRZ/4HR and 2SHRZ/4HRE e.g. 2HRZ/4HR and 2SHRZ/4HRE

17 2. Antifungal agents

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

19 Oral infection with Candida (Thrush) internal_medicine.htmhttp://vasculitis.med.jhu.edu/treatments/cytoxan.html

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

21 Broad-spectrumBroad-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;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 ulcerslocal administration: mycotic corneal ulcers Amphotercin B Polyenes

22 Mechanism of action Amphotercin B

23 Adverse reactions: (1) fever, chill, hyperpnea, myalgiaand hypotension, etc. (~75%) (1) fever, chill, hyperpnea, myalgia and hypotension, etc. (~75%) (2) nephrotoxicity: renal tubular acidosis and renal wasting K + and Mg 2+ (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 a norrow-spectrum antifungal drug.a norrow-spectrum antifungal drug. drug resistance occurs rapidly when flucytosine is used alone.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.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.).depressing the function of bone marrow (leading to leukopenia and thrombocytopenia, etc.). Plasma levels of hepatic enzymes are elevated (reversible).Plasma levels of hepatic enzymes are elevated (reversible). rash, nausea, vomiting, diarrhea.rash, nausea, vomiting, diarrhea. Flucytosine (5-FC)

26 Mechanism of action

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

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

29 Ketoconazle : Ketoconazle : the first oral azoles introduced into clinical use (systemically or topically).the first oral azoles introduced into clinical use (systemically or topically). less selective for fungal P450less selective for fungal P450 clinical use has been limited by endocrine side effects, liver toxicity and the drug interactions.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 or fluconazole has replaced ketoconazle for patients who can afford the more expensive, newer product. Itraconazole: Itraconazole: antifungal spectrum: broader than kotoconazoleantifungal spectrum: broader than kotoconazole side effects (interact with hepatic microsomal enzymes): less than kotoconazole.side effects (interact with hepatic microsomal enzymes): less than kotoconazole. Azoles antifungal agents

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

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

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 1.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 Four types of antiviral agents

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-  : 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 A.Formulate a clinical diagnosis of microbial infection. B.Obtain specimens for laboratory examination, empirical therapy begins. C.Formulate a microbiologic diagnosis. D.Determine the necessity for empirical therapy. E.Institute treatment. Therapeutic applications of Anti- infectives

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

49 A.kinetics of absorption, distribution, and elimination; B.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. Pharmacological factors:

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

51 MRI Study of the Brain Showing a Heterogeneous Mass in the Right Frontal Lobe That Compresses the Right Lateral Ventricle. PANEL A: A T 2 -weighted image without contrast shows a mass (arrow) with high signal intensity centrally, a heterogeneous peripheral ring of signal intensity similar to that of the brain parenchyma, and a surrounding area of bright signal in the white-matter tracts. PANEL B:On the contrast-enhanced T 1 -weighted image (Panel B), the mass has low signal intensity in the central region, suggesting the presence of fluid, and is surrounded by a ring of enhancement. Beyond the ring of enhancement, a less well-defined area of abnormal low signal extends along the white-matter tracts Friedlander et al. NEJM 348 (21): 2125, May 22, 2003 Example of anatomic location of infection affecting antimicrobial agent selection: Brain abscess

52 A.Age B.Hepatic or renal function C.Pregnancy status D.The functional state of host defense mechanism E.Individual variation Host factors:

53 Age –Gastric acidity low in young children and elderly –Renal, hepatic function vary with age Dose adjustment for creatinine clearance and hepatic dysfunction is critical to avoid toxicities –Developing bone and teeth Tetracyclines stain teeth Quinolones may impair bone and cartilage growth

54 normal dosage decreasing dose decreasing dose using prohibited at necessary time Penicillin G Cefazolin Cefazidime Vancomycin Aminoglycosides Polymixins ethambutol Erythromycin Flucytosine Piperacillin Mezocillin Cefalotin Ceftriaxone Lincomycin Clindamycin Fleroxacin Sulfonamides Tetracyclines Chloramphenicol Isoniazid Rifampicin Amphotercin B Ketoconazole Miconazole Antimicrobial agents dosing in hepatic insufficiencyAntimicrobial agents dosing in hepatic insufficiency

55 Antimicrobial agents dosing in renal insufficiency normal dosage decreasing dose decreasing dose using prohibited at necessary time Macrolides Chloramphenicol Isoniazid Rifampicin Doxycycline Penicillin G Carbenicillin Cefalotin Cefazolin Cefamandole cefuroxime Cefazidime ofloxacin Vancomycin Aminoglycosides Polymixins Flucytosine Sulfonamides Tetracyclines nitrofurantoin

56 Pregnancy –Teratogenicity and other toxicity to the fetus –Other toxic reactions Excretion in breast milk Immune system and host defense Allergy history Genetic and metabolic abnormalities –Isoniazid acetylation varies greatly –G-6-PD deficiency and risk of hemolysis Sulfonamides, nitrofurantoin

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

58 Nonsurgical prophylaxis , e.g., 1) Tuberculosis 2) Malaria 3) HIV infection 4) Meningococcal infection 5) Rheumatic fever 6) Urinary tract infections (UTI) Prophylaxis use of Anti-infectives

59 Surgical prophylaxis National research council expected infection wound classification criteria rate Clean ≤2% Clean contaminated ≤10% Contaminated about 20% Dirty about 40% Prophylaxis use of Anti-infectives

60 Surgical prophylaxis , e.g., 1) Cardiac operation 2) Noncardiac, thoracic operation 3) Vascular (abdominal and lower extremity) operation 4) Head and neck operation 5) Gastroduodenal or biliary operation 6) Orthopedic operation (with hardware insertion) 7) Penetrating trauma 8) Burn wound 9) Colorectal operation 10) Appendectomy Prophylaxis use of Anti-infectives

61 Usage of Antimicrobial Agents Route of administration - orally or parenterally Duration of therapy days days for serious infection Dose

62 Two is better than one? –Empiric therapy –Polymicrobial infection –Increase efficacy--synergism –Prevent emergence of resistance Combination therapy –Mycobacterium tuberculosis –HIV –Pseudomonas aeruginosa –? Invasive aspergillosis Antimicrobial agents combinations

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64 Mechanism of synergistic action: 1)Blockade of sequential steps in a metabolic sequence 2)Inhibition of enzymatic inactivation 3)Enhancement of antimicrobial agent uptake 4)Inhibition of different resistant strain respectively


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