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CHEMOTHERAPEUTICS OF INFE CTIOUS DISEASES

CHEMOTHERAPEUTICS OF INFE CTIOUS DISEASES. Anton Kohút. Basic terminol o g y. antiba c teri a l spe c trum MI C re s ist a nc e dysmi c r o bia superinfe ction ba c teric i d al e f fe c t ba c teriostatic e f fe c t. Basic criteria for ATB. maxim al mi c robia l toxicit y

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CHEMOTHERAPEUTICS OF INFE CTIOUS DISEASES

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  1. CHEMOTHERAPEUTICSOF INFECTIOUSDISEASES Anton Kohút

  2. Basic terminology • antibacterial spectrum • MIC • resistance • dysmicrobia • superinfection • bactericidal effect • bacteriostatic effect

  3. Basic criteria for ATB • maximal microbial toxicity • minimal organ toxicity

  4. Mechanism of ATB action a 3 4 b 1 2 a b

  5. Mechanismsof action • interference with cell wall synthesis (-lactams, vancomycin, cycloserin) • influence of cell membrane (polymyxines) • interference with protein synthesis (CMP, TTC, AMG, macrolides) • interference with nucleic acid metabolism (grizeofulvin, rifampicin, quinolones) • interference with intermediary metabolism (sulfonamides)

  6. ResistanceIs antibiotic resistance inevitable?

  7. Mechanisms of resistance • enzymes • change ofcell wall permeability • ↑synthesis of antagonist(folic acid) • change ofpenicilin-binding protein(PBP) • Resistance to antibiotics occurs through four general mechanisms: target modification; efflux; immunity and bypass; and enzyme-catalyzed destruction

  8. In the past two decades we have witnessed: • the rise of so-called extended spectrum β-lactamases (ESBLs), which are mutants of enzymes that previously could only inactivate penicillins but now have gained activity against many cephalosporins; • carbapenemases such as KPC and NDM-1 that inactivate all β-lactam antibiotics; • •

  9. • plasmid-mediated (and thus horizontally disseminated) resistance to fluoroquinolone antibiotics; • the spread of virulent MRSA (methicillin-resistant Staphylococcus aureus) in the community; • the rise of multi-drug resistant Neisseria gonorrhoea; • the emergence and global dissemination of multi-drug resistant Acinetobacter baumannii, Pseudomonas aeruginosa, Klebsiella pneumoniae and Enterobacteriaceae; • the spread of extensively drug resistant Mycobacterium tuberculosis; • resistance to the two newest antibiotics to be approved for clinical use - daptomycin and linezolid.

  10. The discovery of antibiotic classes

  11. Toxic effects of ATB

  12. Toxic effects of ATB myelosuppresion(CMP) hematotoxicity(sulfonamides) hepatotoxicity(macrolides) nephrotoxicity(aminoglycosides) ototoxicity (aminoglycosides) neurotoxicity(anti-TBC)

  13. Other side effects (SE) allergy(-lactams) dysmicrobia(large spectrum ATB) superinfection (large spectrum ATB) Jarisch-Herxheimer (PNC) sy Hoigné(PNC-retard)

  14. Jarisch-Herxheimer

  15. Combinations of ATB

  16. Combinations of ATB Aims: • increase of therapeutic effect • decrease in SE • prophylaxis of resistance Bacteriostatic (with rapid onset) + bactericidal  NEVER !

  17. Principles of ATB therapy

  18. primary focus inf. possible inf. agent sensitivity variability of pacient´s response kinetics  penetration hospitalisation ATB SE effectiveness of elimination organs start therapy in right time regular dosing optimal ther. period don´t repeat therapy price of ATB Principles of ATB therapy

  19. Bacteria by Site of Infection

  20. Inhibitors of cell wall synhesis-lactams

  21. Alexander Fleming, 1928

  22. Penicillins basic PNC anti-staphyloccocal aminoPNC carboxyPNC acylureidoPNC carbapenems monobactams -lactamase inhib.

  23. Penicillium notatum 6-aminopenicillanic acid penem Penicillins(bactericidal)

  24. benzylpenicilline – PNC G procain-benzyl-PNC benzatine-PNC phenoxymethyl-PNC penamecilline Basic PNC

  25. Natural Penicillins(penicillin G, penicillin VK) Gram-positiveGram-negative pen-susc S. aureusNeisseria sp. pen-susc S. pneumoniae Group streptococciAnaerobes viridans streptococci Above the diaphragm EnterococcusClostridium sp. Other Treponema pallidum (syphilis)

  26. Penicillin G

  27. Mechanism of action • Gram + • peptidoglycane • PBP • lipidic bilayer

  28. Mechanism of action • Gram -  LPS  lipids • membrane  porines • peptidoglycane • PBP • membrane

  29. i.v.benzylpenicilline – PNC G i.m.Pc-PNC, benzatine-PNC extracellular distribution renal excretion of active substance (probenecide) acidostabile incomplete absorption (60%) hydrolytic cleavage, activation, prolonged effect (penamecilline) Pharmacokinetics

  30. PNC a poorly lipid soluble and do not cross the blood brain brain barrier Whey are actively excreted unchanged by the kidney (the dose should be reduced in severe renal failure)  Tubular secretion can be blocked by probenecid to potentiate PNC action

  31. gram + cocci(St. pyogenes, St.viridans, St. pneumoniae) staphylococci (-lactamase-negative) gram + bacilly (B.anthracis, C. diphteriae, L. monocytogenes, C.perfringens  tetani) gram – bacilly(Pasteurella) spirochetes (Treponema) borelia, leptospira(B.anthracis, C. diphteriae, L. monocytogenes, C.perfringens  tetani) Antimicrobial spectrum

  32. anaphylaxis Jarisch-Herxheimer sy Hoigné neurotoxicity allergy pregnancy  breast feeding are not contraindicted SE

  33. Penicillinase-Resistant Penicillins(nafcillin, oxacillin, methicillin) Developed to overcome the penicillinase enzyme of S. aureus which inactivated natural penicillins Gram-positive methicillin-susceptible S. aureus Group streptococci viridans streptococci

  34. meticilline(acidolabile) oxacilline cloxacilline dicloxacilline acidostabile absorption subst.- dependent strong alb. binding good diffusion in parenchym. org. weak BB barrier passage Antistaphylococcal PNC(penicillinase-resistant)

  35. Sensitivity: staphylococci (-lactamase-positive) Resistance: enterococci gram - bacteries Antistaphylococcal PNC (penicillinase-resistant)

  36. Aminopenicillins(ampicillin, amoxicillin) Developed to increase activity against gram-negative aerobes Gram-positive Gram-negativepen-susc S. aureus Proteus mirabilis Group streptococci Salmonella, Shigella viridans streptococci some E. coli Enterococcus sp. L- H. influenzae Listeria monocytogenes

  37. ampicilline amoxicilline combination with clavulanic acid acidostabile absorption variable low albumine binding good inflammatory tissue diffusion increased bile concentration mild nephrotoxicity Amino-PNC(penicillinase-non-resistant)

  38. Sensitivity: gram + cocci enterococci gram – cocci(N.meningitis & gonorrhoeae) H. influenzae aerobic gram – bacilly(E.coli, Salmonella,Shigella) Resistance: enterobacteriaceae staphylococci(-lactamase-positive) Pseudomonas B. fragilis Amino-PNC (penicillinase-non-resistant)

  39. clavulanic acid sulbactam tazobactam irreversible inhibition combination with -lactame ATB similar kinetics & tissue penetration with no antibacterial activity -lactamase inhibitors

  40. Penicillin Pearls • Amoxicillin - Largest selling antibiotic Amoxicillin – High dose for otitis media • Augmentin now has several new products • Ampicillin/Sulbactam – Anaerobes!

  41. Carboxypenicillins(carbenicillin, ticarcillin) Developed to further increase activity against resistant gram-negative aerobes Gram-positiveGram-negativemarginalProteus mirabilis Salmonella, Shigella some E. coli L- H. influenzae Enterobacter sp. Pseudomonas aeruginosa

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