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1. Antituberculous Drugs Antituberculous Drugs • First-line agents： Isoniazid Rifampin Pyrazinamide Ethambutol Streptomycin • Second-line agents： Para-aminosalicylic Ethionamide Amikacin Capreomycin Fluoroquinolones Drug Typical Adult Dosage1 First-line agents (in approximate order of preference) Isoniazid 300 mg/d Rifampin 600 mg/d Pyrazinamide 25 mg/kg/d Ethambutol 15-25 mg/kg/d Streptomycin 15 mg/kg/d Second-line agents Amikacin 15 mg/kg/d Aminosalicylic acid 8-12 g/d Capreomycin 15 mg/kg/d Ciprofloxacin 1500 mg/d, divided Clofazimine 200 mg/d Cycloserine 500-1000 mg/d, divided Ethionamide 500-750 mg/d Levofloxacin 500 mg/d Rifabutin 300 mg/d2 Rifapentine 600 mg once or twice weekly 1Assuming 2150 normal renal function. mg/d if used concurrently with a protease inhibitor. 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. 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 Cytoplasmic membrane Mycolate Porin Outer membrane proteins Acyl lipids LAM Isoniazid 3．ADME • Absorbed from the gastrointestinal tract readily. • Distributed widely in all body fluids and tissues. • Metabolism, especially acetylation by liver Nacetyltransferase, is genetically determined (slow acetylators，rapid acetylators, and middle acetylators). • Excreted mainly in the urine. 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. 5．Adverse reactions • 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 Rifampicin • • • • 1. Antibacterial activity Broad-spectrum Resistance mutants occurs easily, if used alone. Bactericidal for mycobacteria. Penetrates most tissues and into phagocytes. 2．Mechanism of action • Binding strongly to the b subunit of bacterial DNA-dependent RNA ploymerase • Inhibiting RNA synthesis. DNA template DNA template 3．Mechanism of resistance • Resistance results from one of several possible points in the gene for b subunit of RNA polymerase. These mutation prevent binding of rifampicin to RNA polymerase. Rifampicin 4．ADME • Absorbed well after oral administration. The absorption is attenuated by food and paraaminosalicylic (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 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. 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. 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). 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. The principle for using antituberculous drugs • Treatment should be initiated with antituberculous drugs early. • Be initiated with combination antituberculous drugs . of • be continued for a long time (6-9 months). e.g. 2HRZ/4HR and 2SHRZ/4HRE 2. Antifungal agents Antifungal agents Onychomycosis Fungal infections traditionally have been divided to two distinct classes: systemic and superficial. So, the major antifungal agents are described with “systemic” and “topical”. Oral infection with Candida (Thrush) http://vasculitis.med.jhu.edu/treatments/cytoxan.html www.thachers.org/ internal_medicine.htm Classification of antifungal agents • Polyenes: Amphotercin B • Azoles: Ketoconazole, Fluconazol • Pyrimidine analogues: Flucytosine • Echinocandins: Caspofungin, micafungin, anidulafungin • Allylamine: Terbinafine Polyenes Amphotercin B • Broad-spectrum • Amphotericin B remains the drug of choice for all lifethreatening mycotic infections (It is often as the initial regimen). e.g. Cryptococcal meningitis; • local administration: mycotic corneal ulcers Amphotercin B Mechanism of action Adverse reactions: (1) fever, chill, hyperpnea, myalgia and 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 New formulations of Amphotercin B : 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. Mechanism of action Azoles antifungal agents Imidazoles • ketoconazle • miconazole • clotrimazole Triazoles • fluconazole • Itraconazole • voriconazole 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). 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. 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 Topical antifungal agents Polyenes : Nystatin: (topically used) Griseofulvin (systemic treatment) - Nucleoside analogue Allylamines: Terbinafine: oral formulation - squalene epoxidase inhibitor 3. Antiviral Drugs 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 The major sites of antiviral drug action Four types of antiviral agents 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 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 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 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 Clinical Uses of Antimicrobial Agents 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 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 Empiric Therapy • Vast majority of all antimicrobial therapy • Should be approached rationally – Syndrome – Likely pathogens – Known resistance patterns – Host factors Empiric Therapy for Peritoneal Dialysate Infection Collect specimens for laboratory testing Gram Positive cultured Gram Negative cultured Identification of Infecting Organism Antimicrobial Susceptibility Testing Further modify the empiric therapy Therapeutic applications of Antiinfectives 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. 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. A. Viral infections B. Fever caused by unidentified reasons C. Topical applications D. Antimicrobial prophylaxis E. Antimicrobial agents combinations Pharmacological factors: 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. • 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 Example of anatomic location of infection affecting antimicrobial agent selection: Brain abscess MRI Study of the Brain Showing a Heterogeneous Mass in the Right Frontal Lobe That Compresses the Right Lateral Ventricle. PANEL A: A T2-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 T1-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 Host factors: A. B. C. D. Age Hepatic or renal function Pregnancy status The functional state of host defense mechanism E. Individual variation • 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 •Antimicrobial agents dosing in hepatic insufficiency normal dosage decreasing dose at necessary time Penicillin G Erythromycin Cefazolin Flucytosine Cefazidime Vancomycin Aminoglycosides Polymixins ethambutol decreasing dose Piperacillin Mezocillin Cefalotin Ceftriaxone Lincomycin Clindamycin Fleroxacin using prohibited Sulfonamides Tetracyclines Chloramphenicol Isoniazid Rifampicin Amphotercin B Ketoconazole Miconazole • Antimicrobial agents dosing in renal insufficiency normal dosage Macrolides Chloramphenicol Isoniazid Rifampicin Doxycycline decreasing dose at necessary time decreasing dose Penicillin G Carbenicillin Cefalotin Cefazolin Cefamandole cefuroxime Cefazidime ofloxacin Vancomycin Aminoglycosides Polymixins Flucytosine using prohibited Sulfonamides Tetracyclines nitrofurantoin • 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 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. A. Viral infections B. Fever caused by unidentified reasons C. Topical applications D. Antimicrobial prophylaxis E. Antimicrobial agents combinations Prophylaxis use of Anti-infectives • 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 • Surgical prophylaxis National research council wound classification criteria Clean Clean contaminated Contaminated Dirty expected infection rate ≤2% ≤10% about 20% about 40% Prophylaxis use of Anti-infectives • 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 Usage of Antimicrobial Agents • Route of administration - orally or parenterally • Duration of therapy - 3-5 days - 7-10 days for serious infection • Dose Antimicrobial agents combinations • 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 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