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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 師署 立 彰 化 醫 院感 染 科 廖 忠 信 醫 師.

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Presentation on theme: "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 師署 立 彰 化 醫 院感 染 科 廖 忠 信 醫 師."— Presentation transcript:

1 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 1.Identification of infecting organism 2.Determination of anti-microbial susceptibility of infecting organism 3.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 1.in-vitro results 2.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 1.Route of administration 2.Dosing regimen 3.Monitoring response of patient to anti- microbial therapy

6 Molecular mechanisms of antibiotic resistance in bacteria 1.Molecular genetics of antibiotic resistance 2.Mechanisms of antibiotic resistance 3.Control of antibiotic resistance

7 Molecular genetics of antibiotic resistance 1.Plasmids 2.Transposable genetic elements 3.DNA integration elements

8 Mechanisms of antibiotic resistance 1.Enzymatic inhibition 2.Decreased permeability of bacterial membrane 3.Promotion antibiotic efflux 4.Altered target sites 5.Altered of target enzymes 6.Overproduction of target

9 Pharmacokinetics & pharmacokinetics of anti- infective agents 1.Pharmacokinetics (PK) 2.Pharmacokinetics (PD)

10 Pharmacokinetics (PK) 1.Pharmacokinetic modeling 2.Absorption 3.Distribution 4.Metabolism and bio-transformtion 5.Elimination

11 Pharmacokinetics (PD) 1.Antimicrobial activity 2.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 1.Penicillins 2.Cephalosporins 3.Other ß-lactam 4.Fusidic acids 5.Aminoglycosides 6.Tetracyclines & chloramphenicol 7.Rifamycins 8.Metronidazole 9.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) 1.Mechanism of action 2.Bacterial resistance 3.Classification 4.Pharmacologic properties 5.Untoward reactions 6.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 1.Classification 2.Mechanism of action 3.Spectrum of activity 4.Mechanism of resistance 5.Pharmacologic properties 6.Adverse reactions & toxicities 7.Clinical use

16 Classification 1.First generation: cefazolin, cephalothin, cephapirin, cephradine 2.Second generation: cephamycin ; cefamandole, cefonicid, cefuroxime, cefmetazole, cefotetam, cefoxitin 3.Third generation: cefoperazone, cefotaxime, ceftazidime, ceftizoxime, ceftriaxone, moxalactam 4.Fourth generation: cefepime, cefpirome 5.Oral form: first, second, third generation

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

18 Aminoglycosides 1.Mechanism of antimicrobial activity 2.Aminoglycoside resistance: (1) intrinsic (2) acquired: reduction entry / efflux, enzymatic modification 3.Pharmacology: administration, distribution, metabolism, excretion 4.Toxicity: renal, ear (cochlear, vestibular), neuromuscular blockade 5. Clinical use / dose given: MDD / ODD 6. Special indication: cystic fibrosis, IE, peritonitis, gonorrhea

19 Penicillin 1.Nucleus: thiazolidine ring / ß-lactam ring / side chain 2.ß-lactamase from S. aureus to hydrolysis ß-lactam ring 3.Inhibit cell wall / peptidoglycan => Gm(+) vs Gm(-) 50~100 vs 1~2 molecules 4.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: 1.Range from rash to anaphylaxis and act as hapten to combine with protein 2.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 discovery => 1964 cephalothin => >20 available (from cephalosporin C) 2.Broad spectrum, low toxicity, easy used, favored PK profile 3.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 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 Mechanism of resistance

25 Adverse reactions and toxicities 1.Hypersensitivity reactions: most common, but less than penicillin; associated c cutaneous rash, eosinophilia, fever & infrequently c serum sickness, anaphylaxis, angioedema 2.Hematologic reaction: eosinophilia, cytopenia (WBC, pl & RBC) 3.GI tract: diarrhea, obstructive biliary toxicity (ceftriaxone) 4.Others: seizure, local phlebitis, pain IIM), superinfection or overgrowth of Candida spp. / Cl. difficle

26 Aminoglycosides one part of As, belongs to conc- dependent bactericidal activity 2.Active for P. aeruginosa, mycobacteria, protozoan, N. gonorrhea 3.Potential of toxicity: nephro, oto-toxicity & neuro-muscular blockade 4.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 1.Total daily dosage could achieve targeted peak serum conc. for a given level of renal function 2.When renal function impaired, total daily dose may be reduced or dosage interval prolonged

32 Glycopeptides & lipopeptides 1.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 1.Recommendation for a serum target level <40~50μg/mL for ototoxicity (vertigo / tinnitus): rare; but augmentation by AG co-administration 2.Synergisitc nephrotoxic effect by vancomycin & AG: 14~20% 3.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 4.Neutropenia: 1~2% after long-term use (>6.2 months) and suggest monitor WBC 2 weeks later 5.Pregnancy C: safe during 2nd / 3rd trimesters 6.Treatment of C. difficile- related diarrhea by vancomycin => might induce C. difficle colitis also

35 Clinical uses 1.Endocarditis: drug choice for MRSA (4~6 weeks); plus GM or RIF for native valve type 2.Meningitis / ventriculitis: combined c 3 cefa (cefotaxime / ceftriaxone) for pneumococcal meningitis 3.Osteomyelitis: 4~6 weeks plus complete surgical debridement for successful outcome 4.Pseudomembraneous colitis: 7~10D oral vancomycin for C. difficle / S. aureus related colitis 5.Febrile neutropenia: controversial 6.Prophylaxis: for endocarditis while GU / GI procedure on cardiac dz

36 Quinolones nalidixic acid => 1970s oxolinic acid & cinoxacin => 1980s FQ derivative 2.Broad spectrum of activity, good oral absorption, good tolerability 3.Temafloxacin, sparfloxacin, grepfloxacin, trovafloxacin removed from market due to toxicity 4.4. mechanism of action: work on DNA gyrase ( gyrA / B ) & topo-isomerase IV ( parC / E )


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