基础医学各论III课件：25_general consideration

1、Warning! Dont abuse the antibiotics,Chemotherapeutic Drugs - General Considerations -,Overview,Chemotherapy Chemotherapeutic agents Antimicrobial drugs / Anti-infective Agents Antibacterial drugs Antifungal drugs Antiviral drugs Antiparasitic durgs Antineoplastic / anticancer drugs,Pharmacokinetics,

2、Adverse effects,pathogenicity,Immunological responses,Therapeutic Effects,Resistance,Host Factors： patients age, gender, constitution, hepatic, renal function,ideal antimicrobial drugs,High sensitivity Nontoxic or low-toxic (safety) Nonresistance Satisfied pharmacokinetic properties Good price,1. An

3、tibacterial drugs 2. Antibiotics 3. Bacteriostatic drugs 4. Bactericidal drugs 5. Antibacterial spectrum board spectrum, narrow spectrum 6. Chemotherapetic index (CI) LD50/ED50, LD5/ED95 penicillin 7. Minimum inhibitory concentration (MIC) 8. Minimum bactericidal concentration (MBC) 9. Resistance 10

4、. Post antibiotic effect (PAE) 11. First expose effect,Terminology,Antibacterial drugs kill bacteria and arresting its growth antibiotics and synthetic antimicrobial agents such as sulfonamides and quinolones.,Terminology,2. Antibiotics nature products : produced by various species of microorganisms

5、 (bacteria, fungi , actinomycetes) suppress the growth of other microorganisms. partially synthesized (semi-synthesized) antibiotics Penicillin V,Terminology,3. Bacteriostatic drugs inhibit the growth of microorganisms e.g. Sulfonamides, Tetracycline 4. Bactericidal drugs kill microorganisms e.g. Pe

6、nicillin, Aminoglycosides,Terminology,5. Antibacterial spectrum Narrow INH (isoniazid) Broad penicillin 6. Chemotherapeutic index (CI) CI= LD50 / ED50 CI= LD5 / ED95,Terminology,Antimicrobial Susceptibility Testing,7. Minimum inhibitory concentration (MIC) 8. Minimum bactericidal concentration (MBC)

7、: 99.9% decrease in growth over 24 hours,9. Resistance: after long-term exposure to the chemotherapeutic agents, the microorgnism, parasites and cancer cells are resistant to the chemotherapeutic agent treatment. e.g. penicillin-resistant streptococcus pneumoniae 10. Post antibiotic affect (PAE) : P

8、ersistence of suppression of bacterial growth after limited exposure to an antimicrobial agent. e.g. aminoglycosides 11. First expose effect: after first exposure to the antibiotics, the antibiotics are not as sensitive as before to the bacteria within a certain peroids.,1. inhibit synthesis of bact

9、erial cell walls (penicillin, cephalosporins) 2. affecting permeability of cell membrane and leading to leakage of intracellular compounds (antifungal agents, nystatin) 3. inhibit protein synthesis (Aminoglycosides) 4. affect bacterial nucleic acid metabolism (quinolones, norfloxacin) 5. block essen

10、tial enzymes of folate metabolism (sulfonamides),Mechanism of Action,Antibacterial Targets,Bacterial Resistance,Resistance: mechanisms, pathways,1. Enzymatic inactivation e.g. b-lactamase,Enzymatic modification e.g. Aminoglycoside modification,3. Active efflux e.g. Tetracycline resistance,4. Decreas

11、ed permeability e.g. Porin mutations - cephalosporin,5. Target alteration Streptomycin resistance penicillin binding proteins,Intrinsic resistance Inherent features ，usually expressed by chromosomal genes Acquired resistance emerge from previously sensitive bacterial populations Caused by mutations

12、in chromosomal genes Or by acquisition of plasmids or transposons,Bacterial Resistance,Mutations Transduction Transformation Conjugation,The transfer of Resistance genes,Mutations,May occur in the gene encoding i) The target protein ii) A protein involved in drug transport iii) A protein important f

13、or drug activation iv) A regulatory gene or promoter affecting expression of the target, a transport protein, or an inactivating enzyme. Gyrase (quinolones), RNA polymerase (rifampin),Transduction,Transformation,Conjugation,Multi-drug resistance MDR (略),Methicillin-resistant coagulase negative staph

14、ylococci, MRCNS Lactamase, PBP-2a Penicillin-resistant streptococcus pneumoniae, PRSP PBP-1a, PBP-2a, PBP-2x, PBP-2b (penicillin) Active efflux system (macrolides) Vancomycin-resistant Enterococcus, VRE PBP avidity van-A, van-B, van C-1, van C-2, van D, van E,4. The 3rd generation-cephalosporins -re

15、sistant Extended spectrum-lactamases, ESBL Class I chromosone mediated -lactamases G- -bacilli Carbapenem resistant (pseudomonsa aeruginosa) OprD porin 6. Quinolone-resistant escherichia coli, AREC Active efflux system,Multi-drug resistance MDR (略),According to bio-activity Anti G+ antibiotic Anti G

16、- antibiotic Broad-spectrum antibiotic Anti mycobacterium antibiotic Anti anaerobe antibiotic - lactamase inhibitor,Antimicrobial drugs classification,According to the chemical structure： -lactams: Penicillins; Cephalosporins; Aminoglycosides; Macrolides; Lincosamides ;Vancomycins Tetracyclines; Chl

17、oramphenicol 5. Quinolones 6. Sulphonamides 7. Nitrofurans 8. Antimycobacterial agents 9. others: Oxazolidinones; Streptogramins,Clinical Uses of Antimicrobial Agents,Identification of Infecting Organism,Staining of clinical specimens Gram stain, Acid-fast stain, silver stains Antigen detection (e.g

18、. 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 ho

19、urs 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 specimen

20、s for laboratory testing,Gram Positive cultured,Gram Negative cultured,Identification of Infecting Organism,Antimicrobial Susceptibility Testing,Further modify the empiric therapy,Formulate a clinical diagnosis of microbial infection. Obtain specimens for laboratory examination, empirical therapy be

21、gins. Formulate a microbiologic diagnosis. Determine the necessity for empirical therapy. Institute treatment.,Therapeutic applications of Anti-infectives,1. Choiceness of antimicrobial agents depends on pharmacological factors and host factors. 2. The uses of antimicrobial agents is strictly contro

22、lled in some situations. Viral infections Fever caused by unidentified reasons Topical applications Antimicrobial prophylaxis Antimicrobial agents combinations,Choice of antimicrobial agent,kinetics of absorption, distribution, and elimination; Bacteriostatic vs bactericidal activity; concentration-

23、dependent killing D. pharmacodynamic or pharmacokinetic interaction with other drugs.,Pharmacological factors:,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 bac

24、terial 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

25、 Central nervous system Lung Bone Foreign bodies,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 periphe

26、ral 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 su

27、rrounded 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,Example of anatomic location of infection affecting antimicrobial agent selection: Brain absce

28、ss,Age Hepatic or renal function Pregnancy status The functional state of host defense mechanism Individual variation,Host factors:,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

29、 to avoid toxicities Developing bone and teeth Tetracyclines stain teeth Quinolones may impair bone and cartilage growth,Antimicrobial agents dosing in hepatic insufficiency,Antimicrobial agents dosing in renal insufficiency,Pregnancy Teratogenicity and other toxicity to the fetus Other toxic reacti

30、ons 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,1. Choiceness of antimicrobial agents depends on pharmacological factors and host

31、factors. 2. The uses of antimicrobial agents is strictly controlled in some situations. Viral infections Fever caused by unidentified reasons Topical applications Antimicrobial prophylaxis Antimicrobial agents combinations,Choice of antimicrobial agent,Nonsurgical prophylaxis，e.g. , 1) Tuberculosis

32、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 expected infection wound classification criteria rate Clean 2% Clean contaminated 10% Contaminated about 20% Dirty about 40%,Prophylaxis use of Anti-infectives,Surgical prophylaxis， e.g., 1) Cardiac operation 2) Noncardiac, thoracic operatio