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抗 生 素 之 介 紹

抗 生 素 之 介 紹. 署 立 彰 化 醫 院 感 染 科 廖 忠 信 醫 師. Principles of anti-infective therapy. 1. Choice of proper anti-microbial agent 2. Anti-microbial combinations 3. Dosage and evaluation of efficacy. Choice of proper anti-microbial agent. Identification of infecting organism

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抗 生 素 之 介 紹

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  1. 抗 生 素 之 介 紹 署 立 彰 化 醫 院 感 染 科 廖 忠 信 醫 師

  2. Principles of anti-infective therapy 1. Choice of proper anti-microbial agent 2. Anti-microbial combinations 3. Dosage and evaluation of efficacy

  3. Choice of proper anti-microbial agent • Identification of infecting organism • Determination of anti-microbial susceptibility of infecting organism • Host factors: history of previous adverse reactions to antimicrobial agents, age, genetic or metabolic abnormalities, pregnancy, renal & hepatic function, site of infection

  4. Anti-microbial combinations • in-vitro results • Indications for clinical use: prevention of emergence of resistant organisms, poly-microbial infections, initial therapy, decreased toxicity, synergism 3. Disadvantage of inappropriate use: antagonism, cost, adverse effects

  5. Dosage and evaluation of efficacy • Route of administration • Dosing regimen • Monitoring response of patient to anti-microbial therapy

  6. Molecular mechanisms of antibiotic resistance in bacteria • Molecular genetics of antibiotic resistance • Mechanisms of antibiotic resistance • Control of antibiotic resistance

  7. Molecular genetics of antibiotic resistance • Plasmids • Transposable genetic elements • DNA integration elements

  8. Mechanisms of antibiotic resistance • Enzymatic inhibition • Decreased permeability of bacterial membrane • Promotion antibiotic efflux • Altered target sites • Altered of target enzymes • Overproduction of target

  9. Pharmacokinetics & pharmacokinetics of anti-infective agents • Pharmacokinetics (PK) • Pharmacokinetics (PD)

  10. Pharmacokinetics (PK) • Pharmacokinetic modeling • Absorption • Distribution • Metabolism and bio-transformtion • Elimination

  11. Pharmacokinetics (PD) • Antimicrobial activity • Methodology for study of PD effects of anti-infective agents (1) in-vitro models / animal models / human trials (2) concentration-dependent killing agents (3) time-dependent killing agents (4) post-antibiotic effect

  12. Introduction of antibiotics • Penicillins • Cephalosporins • Other ß-lactam • Fusidic acids • Aminoglycosides • Tetracyclines & chloramphenicol • Rifamycins • Metronidazole • macrolides, clindamycin, ketolides 10. Glycopeptides 11. Polymyxins 12. Oxazoidinones 13. Sulfonamides & trimethoprim 14. Quinolones 15. Antimycobacterail agents 16. Systemic antifungal agents 17. Antiviral drugs

  13. Penicillins (PCN) • Mechanism of action • Bacterial resistance • Classification • Pharmacologic properties • Untoward reactions • Clinical use

  14. Classification 1. Natural penicillins: PCN G, PCN V 2. Isoxazolyl penicillins (penicillinase-resistant penicillins):methacillin, nafcillin 3. Aminopenicillin: ampicillin, amoxicillin 4. Carboxy-penicillins: carbenicillin, ticarcillin 5. Ureidopenicillins: azlocillin, mezlocillin, piperacillin

  15. Cephalosporins • Classification • Mechanism of action • Spectrum of activity • Mechanism of resistance • Pharmacologic properties • Adverse reactions & toxicities • Clinical use

  16. Classification • First generation: cefazolin, cephalothin, cephapirin, cephradine • Second generation: cephamycin; cefamandole, cefonicid, cefuroxime, cefmetazole, cefotetam, cefoxitin • Third generation: cefoperazone, cefotaxime, ceftazidime, ceftizoxime, ceftriaxone, moxalactam • Fourth generation: cefepime, cefpirome • Oral form: first, second, third generation

  17. Other ß-lactam • Carbapenems: thienamycin, imipenem, meropenem, ertapenem • Monobactams: aztreonam • ß-lactamase inhibitors: (1) clavulanate (2) sulbactam (3) tazobactam

  18. Aminoglycosides • Mechanism of antimicrobial activity • Aminoglycoside resistance: (1) intrinsic (2) acquired: reduction entry / efflux, enzymatic modification • Pharmacology: administration, distribution, metabolism, excretion • Toxicity: renal, ear (cochlear, vestibular), neuromuscular blockade 5. Clinical use / dose given: MDD / ODD 6. Special indication: cystic fibrosis, IE, peritonitis, gonorrhea

  19. Penicillin • Nucleus: thiazolidine ring / ß-lactam ring / side chain • ß-lactamase from S. aureus to hydrolysis ß-lactam ring • Inhibit cell wall / peptidoglycan => Gm(+) vs Gm(-) 50~100 vs 1~2 molecules • PBP (penicillin-binding protein): trans-peptidation / carboxy-peptidation & inhibited by ß-lactam antibiotics

  20. Bacterial resistance Mechanism: (1) destruction by ß-lactamase (2) failure to penetrate outer membrane of GNB to reach PBP (3) GNB outer membrane efflux drug (4) binding affinity decreased to PBP

  21. Untoward reactions Hypersensitivity reactions: • Range from rash to anaphylaxis and act as hapten to combine with protein • Penicillin allergy: (1) major determinant: penicilloyl and penicillanic acid derivative (2) minor determinant: benzyl penicillin, Na benzyl penicilloate 3. Mediated by IgE and minor determinant are major cause of anaphylactic reactions

  22. Cephalosporin • 1945 discovery => 1964 cephalothin => >20 available (from cephalosporin C) • Broad spectrum, low toxicity, easy used, favored PK profile • Cephem nucleus: ß-lactam ring fued c 6-member dihyfrothiazine ring (S)

  23. Classification Related to microbiologic & pharmacologic differences: 1st: focus on Gm(+) 2nd: varying on Gm(+) & enhanced on GNB; cephamycin => against anaerobic bacteria, as B. fragilis 3rd: marked increased on GNB, but GPC decreased & ceftazidime for P. aeruginosa 4th: active against GNB (P. aeruginosa) & GPC => 3 / 4 so-called extended spectrum cephalosporins / ESBL or ampC

  24. Mechanism of resistance 1. ß-lactamase destruction (1) staphylococci: reduced by binding affinity to BPB decreased (2) GNB: type / amount vary and antibiotic degraded at periplasmic space 2. Reduce penetration of antibiotic through membrane to PBP: through porin depend on size, shape, charge & hydrophilic 3. Increased efflux from periplasmic space: higher permeability in E. coli than P. aeruginosa (due to AcrAB efflux system) 4. Alteration PBP to reduce binding affinity: S. pneumoniae, MRSA, H. influenzae, N. gonorrhea

  25. Adverse reactions and toxicities • Hypersensitivity reactions: most common, but less than penicillin; associated c cutaneous rash, eosinophilia, fever & infrequently c serum sickness, anaphylaxis, angioedema • Hematologic reaction: eosinophilia, cytopenia (WBC, pl & RBC) • GI tract: diarrhea, obstructive biliary toxicity (ceftriaxone) • Others: seizure, local phlebitis, pain IIM), superinfection or overgrowth of Candida spp. / Cl. difficle

  26. Aminoglycosides • 1940 one part of As, belongs to conc-dependent bactericidal activity • Active for P. aeruginosa, mycobacteria, protozoan, N. gonorrhea • Potential of toxicity: nephro, oto-toxicity & neuro-muscular blockade • Resistant decreased by known mechanism, new dosage strategies, avoid risk factors, shorter course

  27. Mechanism of resistance 1. Intrinsic: (1) enzyme: active electron transport chain => anaerobic bacterail to AG (2) non-enzyme: mutations at 16S rRNA => M. tuberculosis (SM), M. abscessus, M. chelonae (amikacin)

  28. 2. acquired: combined of (1) decreased drug intake (2) efflux pump activity (3) enzyme modification 3. Exposure to AG can select 2 types of drug-resistant subpopulations (1) activattion of Mex XY efflux pump (2) phenomen of adaptive resistance => clinical tx failure

  29. 4. Enzymatic modification: (1) amino group => modified by N-acetyl- transferase (AAC) (2) hydroxyl group => modified by O- nucleotidy-transferase (ANT) or O- phospho-transferase (APH) (3) modofied drug bind poorly to ribosomes => high level of resistance

  30. Toxicity 1. Other than spectinomycin, AG had the potential injury to renal PCT, damage to cochlea / vestibular apparatus & neuro-muscular blockade 2. Untoward effects (rare): hypersensitivity reactions, inflammation, phlebitis, pain while injection (IM), no irritation on cavity injection, hepatoxicity or photosensitivity

  31. Once-daily dosing regimens • Total daily dosage could achieve targeted peak serum conc. for a given level of renal function • When renal function impaired, total daily dose may be reduced or dosage interval prolonged

  32. Glycopeptides & lipopeptides • vancomycin: (1) 1950 soil & tx for PCN-R S .aureus => replace by methicillin / cephalosporin due to toxicity => 1980 steady increased of R strain after large use (2) inhibition of cell wall: block trans-glycosylation by binding to D-ALA-D-ALA terminal of pentapeptide c stable complex => could not processed by glycosyl-transferase & interrupt cooperation of murein monmers into growing peptidoglycans => interrupt of cell wall synthesis

  33. Antimicrobial activity Broad spectrum of activity against of Gm(+): (1) staphylococci: S. aureus, S. epidermidis, S. saprophyticus, S. haemolyticus, S. hominis (2) enterococci: E. faecalis, E. faecium (3) streptococci: S. pneumoniae, GAS, GCS, GGS, S. bovis, viridans group (4) L. monocytogenes (5) Gm(+) anaerobes: Peptostreptococci, Actinomyces, Propionibacterium, Clostridium spp

  34. Adverse effects • Recommendation for a serum target level <40~50μg/mL for ototoxicity (vertigo / tinnitus): rare; but augmentation by AG co-administration • Synergisitc nephrotoxic effect by vancomycin & AG: 14~20% • Infusion-related reactions: most; red-neck or red-man Sx => rash or pruritus over head, face, neck, upper trunk +/- hypotension, angioedema; 3.4~11.2% & histamin release from basophil / mast cell • Neutropenia: 1~2% after long-term use (>6.2 months) and suggest monitor WBC 2 weeks later • Pregnancy C: safe during 2nd / 3rd trimesters • Treatment of C. difficile- relateddiarrhea by vancomycin => might induce C. difficle colitis also

  35. Clinical uses • Endocarditis: drug choice for MRSA (4~6 weeks);plus GM or RIF for native valve type • Meningitis / ventriculitis: combined c 3 cefa (cefotaxime / ceftriaxone) for pneumococcal meningitis • Osteomyelitis: 4~6 weeks plus complete surgical debridement for successful outcome • Pseudomembraneous colitis: 7~10D oral vancomycin for C. difficle / S. aureus related colitis • Febrile neutropenia: controversial • Prophylaxis: for endocarditis while GU / GI procedure on cardiac dz

  36. Quinolones • 1962 nalidixic acid => 1970s oxolinic acid & cinoxacin => 1980s FQ derivative • Broad spectrum of activity, good oral absorption, good tolerability • Temafloxacin, sparfloxacin, grepfloxacin, trovafloxacin removed from market due to toxicity • 4. mechanism of action: work on DNA gyrase (gyrA / B) & topo-isomerase IV (parC / E)

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