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Antibacterial Drugs

Antibacterial Drugs. — General considerations —. Part 1. Overview. Chemotherapy ( 化学治疗 ) Chemotherapeutic agents ( 化学治疗药，化疗药 ) Antimicrobial drugs Antibacterial drugs Antifungal drugs Antiviral drugs Antiparasitic durgs Antineoplastic (anticancer) drugs.

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Antibacterial Drugs

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  1. Antibacterial Drugs — General considerations —

  2. Part 1.Overview • Chemotherapy (化学治疗) • Chemotherapeutic agents (化学治疗药，化疗药) • Antimicrobial drugs Antibacterial drugs Antifungal drugs Antiviral drugs • Antiparasitic durgs • Antineoplastic (anticancer) drugs

  3. Antimicrobial drugs Interactions between microbials, host, and antimicrobial drugs Adverse effects Resistance Pharmacokinetics Therapeutic Effects Host patient’s age, gender, constitution, hepatic/renal function pathogenicity Immunological responses Microbials

  4. A. Terminology • Antibacterial drugs（抗菌药） • killing bacteria or arresting their growth • antibiotics(抗生素） • synthetic antimicrobial drugs（合成抗菌药），such as sulfonamides(磺胺类); quinolones(喹诺酮类); metronidazole(甲硝唑); fluconazol（氟康唑）

  5. A. Terminology 2. Antibiotics（抗生素） • produced by various species of microorganisms (bacteria, fungi, actinomycetes) • suppress the growth of other microorganisms. • Natural and semi-synthetic

  6. A. Terminology 3. Antibacterial spectrum（抗菌谱） • Narrow • Broad 4. Chemotherapetic index (CI, 化疗指数) • CI = LD50/ED50 • Safety margin = LD5/ED95

  7. ED95 LD5

  8. A. Terminology • 5. Bacteriostatic drugs（抑菌药） • inhibiting the growth of microorganisms • e.g. tetracycline, sulfonamides • 6. Bactericidal drugs （杀菌药） • killing microorganisms • e.g. penicillin, aminoglycosides

  9. Bactericidal vs Bacterostatic

  10. A. Terminology 7. Minimum inhibitory concentration (MIC) 8. Minimum bactericidal concentration (MBC) 9. Post antibiotic effect (PAE)

  11. B. Mechanism of Action 1. Inhibiting synthesis of bacterial cell walls（抑制细菌细胞壁合成） 2. Affecting permeability of cell membrane and leading to leakage of intracellular contents（影响胞浆膜通透性，导致胞浆外漏） 3. Inhibiting protein synthesis（抑制蛋白质合成） 4. Affecting nucleic acid metabolism（影响核酸代谢） 5. Blocking essential enzymes of folate metabolism（抑制叶酸代谢的关键酶）

  12. Inhibiting synthesis of bacterial cell walls 肽聚糖 肽聚糖

  13. Intracellular membrane Extracellular

  14. 2. Affecting permeability of membrane • Ionic- sorbent （离子吸附） e.g. aminoglycosides • Interfering ergosterol （干扰麦角固醇） e.g. amphotericin B, nystatin, imidazoles • Cationic detergent （阳离子去污剂样作用） e.g. polymyxins

  15. Lipopoly -saccharide Outer membrane Peptidoglycan Cytoplasmic membrane polymyxins

  16. 3. Inhibiting protein synthesis Ribosomal structure • Bacteria 30S + 50S 70S • 30S subunit • binds mRNA in initiation complex • holds growing peptide chain • 50S subunit • accepts / translocates charged tRNAs • "A" site: Aminoacyl-tRNA (acceptor) site • "P" site: Peptidyl-tRNA (donor) site • Mammals 40S + 60S 80S

  17. aminoglycosides macrolides A P tetracyclines aminoglycosides chloramphenicol, clindamycin (1) (2) (3)

  18. quinolones 4. Affecting nucleic acid metabolism (+) Break back segment (-) (-)

  19. 5. Blocking essential enzymes of folate metabolism 二氢蝶酸合成酶 TMP，甲氧苄啶 二氢叶酸还原酶

  20. C. Bacterial resistance 1. Types of resistance • Intrinsic resistance（固有耐药） – Inherent features, usually expressed by chromosomal genes • Acquired resistance （获得耐药） – emerge from previously sensitive bacterial populations – caused by mutations in chromosomal genes – or by acquisition of plasmids or transposons

  21. 2. Resistance mechanisms • Enzymatic inactivation • Modification of target sites • Reduced permeability • Active efflux system

  22. (1) Enzymatic inactivation • Examples: -lactamase; aminoglycoside-modifying enzymes

  23. (2) Modification of target sites • Mutation of the natural target (quinolone resistance) • Substitution with a resistant alternative to the native, susceptible target (methicillin resistance) • Target modification(ribosomal protection type of resistance to macrolides and tetracyclines) • Increase of the targets

  24. (3) Reduced permeability • Absence, mutation or loss of the appropriate transporteror porins(膜孔蛋白） (4) Active efflux system(主动外排系统) • Tripartite efflux system (三联外排系统):efflux transporter; accessory protein; outer membrane channel— Gram-negative

  25. 3. The transfer of resistance genes • Mutations 突变 • Transduction 转导 • Transformation 转化 • Conjugation 接合

  26. Rational uses of antimicrobial drugs

  27. Basic principles 1. Formulating a pathogenic diagnosis early, which depends on clinical diagnosis, microbiologic diagnosis and testing results in vitro. 2. Choiceness of antimicrobial agents depends on the properties of the drugs. 3. Choiceness of antimicrobial agents depends on patient factors. 4. The uses of antimicrobial agents is strictly controlled in some situations.

  28. 1. Formulating a pathogenic diagnosis early • Empiric Therapy • Vast majority of all antimicrobial therapy • Should be approached rationally • Syndrome • Likely pathogens • Known resistance patterns • Host factors

  29. Identification of infecting organisms • 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

  30. in broth

  31. 2. Choiceness of antimicrobial agents depends on the properties of the drugs A. Kinetics of absorption, distribution, and elimination B. Bacteriostatic vs bactericidal activity: concentration-dependent killing (eg. aminoglycosides and quinolones) and time-dependent killing (eg. b-lactams and vancomycin) C. The potential toxicity of an agent D. Pharmacodynamic, pharmacokinetic or pharmaceutical interaction with other drugs.

  32. 3. Choiceness of antimicrobial agents depends on patient factors • Site of infection • The age and pregnancy status • Hepatic or renal function • The functional state of host defense mechanism • Individual variation

  33. Patientfactors • 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

  34. Excretion • Urine • Aminoglycosides, fluoroquinolones • Bile • Ceftriaxone • Penetration into various sites • Central nervous system • Lung • Bone • Foreign bodies

  35. 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 • Sensitive to ototoxicity

  36. Genetic and metabolic abnormalities • Isoniazid acetylation varies greatly • G-6-PD deficiency and risk of hemolysis • Sulfonamides, nitrofurantoin, primaquine • Pregnancy • Teratogenicity and other toxicity to the fetus • Other toxic reactions (lactic acidosis, pancreatitis) • Excretion in breast milk • Immunocompromise

  37. 4. The uses of antimicrobial agents is strictly controlled in some situations The uses of antimicrobial agents is strictly controlled in: • Viral infections • Fever caused by unidentified reasons • Topical applications • Antimicrobial prophylaxis • Combined uses of antimicrobial drugs

  38. Prophylaxis use of antimicrobials • Non-surgical prophylaxis (1) Rheumatic fever (风湿热) (2) Meningococcal infection (3) Tuberculosis (4) Newborn ophthalmia (新生儿眼炎) (5) Urinary tract infections

  39. Surgical prophylaxis National research council Expected infection wound classification criteria rate Clean ≤2% Clean contaminated ≤10% Contaminated about 20% Dirty about 40%

  40. Surgical prophylaxis (1) Cardiac operation (2) Oral, head, neck, thoracic operation (3) Vascular (abdominal and lower extremity) operation (4) Arthritic or bone fracture operation (5) Gastroduodenal or biliary operation (6) Colorectal operation, appendectomy（阑尾切除术） (7) Penetrating trauma, complex trauma (8) Uterectomy (子宫切除术), uterine-incision delivery (剖宫产) (9) Severe burn wound (10) Orthopedic (整形) operation (with hardware insertion)

  41. Therapeutic use of antimicrobials (1) Diagnosis for choice of effective drugs (2) Severity of infections (3) Optimal doses, routes and duration (4) Sensitivity of bacteria to drugs (5) Consideration of host situations

  42. Combined use of antimicrobials According to their actions, antimicrobial agents can be classified: (1) bactericidal agents for growing bacteria (eg. –lactams) (2) bactericidal agents for resting bacteria (eg. aminoglycosides, quinolones) (3) fast bacteriostatic agents (eg. macrolides, tetracycline, chloramphenicol) (4) slow bacteriostatic agents (eg. sulfonamides) (1) + (2): synergism (1) + (3): antagonism (1) + (4): addition or indifference (3) + (4): addition

  43. 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

  44. Combined use of antimicrobials • Indications – when ineffective with single drug (1) Pathogens unknown (2) Mixed polymicrobial infections (3) Severe infections (4) Prevent emergence of resistance(long-term) Combination therapy Mycobacterium tuberculosis HIV Pseudomonas aeruginosa Invasive aspergillosis(曲霉病)

  45. Use of antimicrobial drugs in patients with hepatic impairment No suitable markers are available for hepatic function. So, drug use in patients with liver disease must take into account 3 general principles: (1) Pharmacokinetics are modified. (2) Drugs may modify the functional status of the liver. (3) Pharmacodynamics may be modified.

  46. 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 Use of antimicrobial drugs in hepatic insufficiency

  47. 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 Use of antimicrobial drugs in renal insufficiency

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