1. Antibacterial Drugs — General considerations —

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

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

4. 1.Antibacterial drugs （抗菌药） killing bacteria or arresting their growthkilling bacteria or arresting their growth antibiotics ( 抗生素）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）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） A. Terminology

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

6. 3. Antibacterial spectrum （抗菌谱） Narrow Narrow Broad Broad 4. Chemotherapetic index (CI, 化疗指数 ) CI = LD 50 /ED 50 CI = LD 50 /ED 50 Safety margin = LD 5 /ED 95 Safety margin = LD 5 /ED 95 A. Terminology

7. ED 95 LD 5

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

9. Bactericidal vs Bacterostatic

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

12. 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） B. Mechanism of Action

14. 1.Inhibiting synthesis of bacterial cell walls 肽聚糖 肽聚糖

15. Intracellular membrane Extracellular

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

17. Lipopoly -saccharide Outer membrane Peptidoglycan Cytoplasmic membrane polymyxins

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

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

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

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

22. 1. Types of resistance Intrinsic resistance （固有耐药） Intrinsic resistance （固有耐药） – Inherent features, usually expressed by chromosomal genes Acquired resistance （获得耐药） 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 C. Bacterial resistance

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

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

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

26. Absence, mutation or loss of the appropriate transporter or porins ( 膜孔蛋白）Absence, mutation or loss of the appropriate transporter or porins ( 膜孔蛋白） (3) Reduced permeability (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

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

28. Rational uses of antimicrobial drugs

29. 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. Basic principles

30. 1. Formulating a pathogenic diagnosis early Empiric TherapyEmpiric Therapy Vast majority of all antimicrobial therapyVast majority of all antimicrobial therapy Should be approached rationallyShould be approached rationally –Syndrome –Likely pathogens –Known resistance patterns –Host factors

31. Identification of infecting organisms Staining of clinical specimensStaining of clinical specimens –Gram stain, acid-fast stain, silver stains… Antigen detection (e.g. ELISA, latex agglutination)Antigen detection (e.g. ELISA, latex agglutination) Nucleic acid detection (e.g. PCR)Nucleic acid detection (e.g. PCR) Culture methodsCulture methods –Obtain culture material prior to antimicrobial therapy, if possible

32. in broth

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

34. A.Site of infection B.The age and pregnancy status C.Hepatic or renal function D.The functional state of host defense mechanism E.Individual variation 3. Choiceness of antimicrobial agents depends on patient factors

35. Patient factors Site of infectionSite 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

36. ExcretionExcretion –Urine Aminoglycosides, fluoroquinolones –Bile Ceftriaxone Penetration into various sitesPenetration into various sites –Central nervous system –Lung –Bone –Foreign bodies

37. AgeAge –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

38. 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

39. 4. The uses of antimicrobial agents is strictly controlled in some situations 4. The uses of antimicrobial agents is strictly controlled in some situations The uses of antimicrobial agents is strictly controlled in: A.Viral infections B.Fever caused by unidentified reasons C.Topical applications D.Antimicrobial prophylaxis E.Combined uses of antimicrobial drugs

40. Non-surgical prophylaxis 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 Prophylaxis use of antimicrobials

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

42. 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 （阑尾切除术） (6) Colorectal operation, appendectomy （阑尾切除术） (7) Penetrating trauma, complex trauma ( 子宫切除术 )( 剖宫产 ) (8) Uterectomy ( 子宫切除术 ), uterine-incision delivery ( 剖宫产 ) (9) Severe burn wound ( 整形 ) (10) Orthopedic ( 整形 ) operation (with hardware insertion)

43. (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 Therapeutic use of antimicrobials

44. 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) + (2): synergism (1) + (3): antagonism (1) + (3): antagonism (1) + (4): addition or indifference (1) + (4): addition or indifference (3) + (4): addition (3) + (4): addition Combined use of antimicrobials

46. Mechanism of synergistic action 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

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

48. 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: 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.

49. normal dosage decreasing dose decreasing dose using prohibited at necessary time Penicillin G CefazolinCefazidimeVancomycinAminoglycosidesPolymixinsEthambutol Erythromycin Flucytosine Piperacillin Mezocillin Cefalotin Ceftriaxone Lincomycin Clindamycin FleroxacinSulfonamidesTetracyclinesChloramphenicolIsoniazidRifampicin Amphotercin B KetoconazoleMiconazole Use of antimicrobial drugs in hepatic insufficiency

50. Use of antimicrobial drugs in renal insufficiency normal dosage decreasing dose decreasing dose using prohibited at necessary time MacrolidesChloramphenicolIsoniazidRifampicinDoxycycline Penicillin G Carbenicillin Cefalotin Cefazolin Cefamandole cefuroxime Cefazidime ofloxacin Vancomycin Aminoglycosides Polymixins FlucytosineSulfonamidesTetracyclinesNitrofurantoin