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Antimicrobial agents

Antimicrobial agents. PharmDr. Ondřej Zendulka, Ph.D. Antimicrobial agents. difference antibiotics-chemotherapeutics classification: chem. structure mechanism of action extent of effect antibacterial spectrum. Antimicrobial agents. Mechanisms of action: selective toxicity

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Antimicrobial agents

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  1. Antimicrobial agents PharmDr. Ondřej Zendulka, Ph.D.

  2. Antimicrobial agents • difference antibiotics-chemotherapeutics • classification: • chem. structure • mechanism of action • extent of effect • antibacterial spectrum

  3. Antimicrobial agents • Mechanisms of action: selective toxicity • interference with the cell wall • block of bact. cell metabolism • nucleic acid synthesis inhibition • proteosynthesis inhibition

  4. Antimicrobial agents Bacterial cell wall

  5. Antimicrobial agents Bacterial cell wall

  6. Antimicrobial agents Bacterial cell wall

  7. Terminology • selective toxicity • antimicrobial spectrum • MIC, MBC, MAC • postantibiotic effect • resistance

  8. Antimicrobial agents Resistance = ability of microbial cells to withstand the effect of ATB • Mechanisms of resistance: • decrease of ATB‘s intracelullar conc. • inactivation of ATB • modification of ATB‘s target site

  9. Antimicrobial agents • absolute • relative • primary • secondary • coupled • cross

  10. Antimicrobial agents • Combinations of ATBs: • spectrum widening • resistance development restriction • decrease in AE incidence • increase in effectivity • effects: synergistic, additive, indifferent, antagonistic

  11. Antimicrobial agents • Which ATB? • empirical x bacterial sensitivity • pharmacokinetics • Antibiotic policy in CR • prophylactic administration of ATBs

  12. Antimicrobial agents • oxazolidinones • lincosamides • aminoglycosides • glycopeptides • miscellaneous ATBs • local ATBs • sulphonamides • quinolones • imidazoles • Antibiotics • β-lactams • amphenicols • tetracyclines • macrolides • azalides • streptogramines • ketolides

  13. β-lactams penicillins cephalosporins cephamycins monobactams carbapenems + inhibitors of β-lactamases

  14. Penicillins MofA: binding to PBP, inhibition of transpeptidases, autolysis => bactericidal

  15. Penicillins • produced by Penicillium mould • resistance : β-lactamases • modification of PBP • cell wall penetration block • low toxicity, AE hypersensitivity

  16. Narrow spectrum penicillines • benzylpenicillin (pen. G) • phenoxymethylpenicillin (pen. V) • oxacillin, cloxacillin…..

  17. Wide spectrum penicillines • ampicillin, amoxicillin • ticarcillin • piperacillin

  18. Inhibitors of β-lactamases • usually without own antimicrobial properties • clavulanic acid, sulbactam, tazobactam • coamoxicillin (clavulanic ac.) • cotikarcillin (clavulanic ac.) • coampicillin (sulbactam) • sultamicillin (sulbactam) • copiperacillin (tazobactam)

  19. Cephalosporins • Spectrum: • differs between generations • Adverse effects: • hypersensitivity • disulfiram reaction • hematotoxicity • Cef-…

  20. Monobactams • bactericidal G- aerobes • β-lactamases resistant • aztreonam, carumonam Carbapenems • wide spectrum • imipenem, meropenem

  21. Glycopeptides • Mof A: inhibition of cell wall synthesis • Spectrum: only G + • slow developing resistance • not absorbed from GIT • nephro-, ototoxicity, release of histamine • vancomycin, teicoplanin

  22. Antibiotics inhibiting proteosynthesis • chloramphenicol • tetracyclines – doxycycline, miniocycline • macrolides - erythromycin, spiramycin, josamycin, roxithromycin, clarithromycin, azithromycin

  23. Antibiotics inhibiting proteosynthesis • lincosamides – clindamycin, lincomycin • aminoglycosides - streptomycin, sisomicin, tobramycin, netilmicin, amikacin, isepamicin

  24. ATBs for local use • Neomycin • aminoglycoside • in combination with bacitracin (Framykoin) • Bacitracin • polypeptide • low resistance and allergy • Mupirocin • inhibition of proteosynthesis • skin infections therapy

  25. Chemotherapeutics • Sulphonamides • Trimethoprim • Quinolones • Metronidazole • Nitrofurantoin

  26. Sulphonamides • one of the oldest • basic structure – sulfanilamide • small therapeutic importance • MofA: competitive inhibition of bacterial cell metabolism on the level of folic acid • bacteriostatic effect • spectrum: streptococcus, haemophillus, nocardia, actinomycets, chlamydia, Toxoplasma gondi, Neisseria meningitidis • today – therapy of urinary tract infections and in the combination with trimethoprim

  27. Sulphonamides • Sulfisoxazole • short acting, fast absorption and elimination • protein binding up to 92% • urinary infections • Sulfathiazole • for topicall administration • Sulfamethoxazole • in combination with trimethoprim - cotrimoxazole • protein binding 70% • Sulfasalazine • poor absorption from GIT = local effect in the intestine, ulcerative colitis

  28. Trimethoprim • blocks dihydrofolate reductase (50 000x more selective to bacterial enzyme) • synergistic effect with sulphonamides • high levels in prostate and vaginal mucus (lower pH) • CYP metabolism • urine (low pH = faster elimination) • combination: trimethoprim a sulfamethoxazole = co-trimoxazole 1:5: Triprim, Biseptol Kotrimoxazol, Sumetrolin • I: respiratory infections, prevention and therapy of pneumonia, urinary infections

  29. Quinolones • MofA: inhibition of DNA gyrase - nucleic acid synthesis inhibition (topoisomerase II) • bactericidal • spectrum: older molecules mainly G-; modern drugs wide spectrum

  30. Quinolones • high F after p.o. administration, good distribution except CNS, excreted into urine • AE: 2-8% nemocných GIT problems, • cephalgia, sleeping disorders • skin symptoms • risk of tendons rupture • I: urinary tract infections • prostatitits • bone and joint infections • skin infections • prophylaxis in neutropenic patients • CI: children, breastfeeding, pregnancy

  31. Quinolones • Quinolones for the therapy of urinary infections • poor tissue distribution, excreted unchanged • oxoline and nalidixic acid • norfloxacine – partial systemic effect, therapy of gonorrhea • high rate of mild adverse effects (GIT)

  32. Quinolones • Quinolones for therapy of systemic infections-Fluoroquinolones • ciprofloxacin, ofloxacin, lomefloxacin, pefloxacin…. • good tissue distribution • therapy of respiratory, skin, GIT and other severe infections • sparfloxacin, trovafloxacin, rufloxacin, grepafloxacin • bile elimination • life-threatening infections caused by multiresistant strains • AE: often, mild, GIT, artralgia, cartilage disruption

  33. Imidazoles • MofA: inhibition of DNA replication • spectrum: anaerobes and protozoa : Bacteroides, Clostrididum, Giardia • Metronidazole • metabolized in liver and excreted into urine • AE: metallic taste • nausea, vommiting, diarrhoea • CNS (cephalgia, sleping disorders, depression) • disulfiram reaction • Ornidazole • Tinidazole – antiparasitic agent

  34. Others • Nitrofurantoin • MofA: interferes with bacterial DNA • spectrum: E.coli, Klebsiella, Enterobacter, enterococci, staphylococci • administered orally • effective levels in urine, alkaline pH decreases the efficacy • AE: often • GIT irritation, polyneuropathy, myelotoxicity, chronic hepatitis, pulmonary disorders • I: therapy and prophylaxy of urinary tract infections Furantoin, Nitrofurantoin

  35. ATBs in dentistry Use • prevention – for risk patients (due to ADA) • artificialheartvalves • a historyofinefectiveendocarditis • a cardiactranspplantwithdevelopedvalveproblem • someofcongenitalheartconditions • - in sometypesofstomatosurgeries • for all dental procedures that involve manipulation of gingival tissue or the periapical region of the teeth, or perforation of the oral mucosa

  36. ATBs in dentistry Drugs • penicillin 1,5-3 mil. IU • amoxicillin/clavulanic acid 1,2g i.v. /1g p. o. • ampicillin/sulbactam 2g i.v./ 750 mg p.o. • beta lactamsallergicpatients • clindamicin 600 mg p.o./i.m./i.v. • vancomycin 500 mg/i.v. • peroraladministrationisrecommendedat least 1 hr beforeprocedure and parenteralamdinistration 15-30 minsbefore. In long lastinginterventionscanbe ATB administeredrepetedlyafter 4-6 hrs

  37. Antivirotics • MofA: • block of viral penetration/uncoating • inhibition of virus specific proteins/enzymes • reverse transcriptase inhibition • DNA polymerase inhibition • inhibition of viral mRNA translation

  38. Antivirotics • against influenza and Varicella-herpes viruses • antiretroviral substances • HIV proteases inhibitors • immune response modulators

  39. Influenza therapy • Amantadine • antiparkinsonic agent, flu type A2 • MofA: interferes with virus uncoating • administered orally, distributed into the CNS • AE: fuzzines, hallucinations, anxiety, sleeplessness, • GIT disturbances • Rimantadine • lower BBB penetration • AE: mainly in GIT • I: prophylaxis and therapy of flu type A (200 mg/day)

  40. Influenza therapy Neuramidase inhibitors • Zanamavir, oseltamivir • therapy and prophylaxis of A and B flu types • acts extracellularly, inhibits propagation of infection • poor F after p.o. = inhalation of powdered drug • AE: bronchoconstriction, pharyngeal irritation

  41. Therapy of herpetic infections • Aciclovir (acycloguanosine) MofA: DNA synthesis inhibition - DNA competitive polymerase inhibition • efficacy: herpes hominis, varicella-zoster, less against cytomegalovirus and Epstain-Baar v. • AE: thromboflebitis after i.v.injections, neurologic symptoms (fuzziness, hallucination, depersonalisation) – more pronounced in renal failure • Acyclovir 800 Stada, Herpesin, Virolex, Zovirax

  42. Therapy of herpetic infections Famciclovir Valaciclovir Trifluridine (trifluorothymidine) Vidarabin (adenin arabinosid) Ribavirine Idoxuridine Foscarnet

  43. ANTIMYCOTICS

  44. MYCOSES incidence: immunodeficiency, DM, radiotherapy, chemotherapy, HIV Classification: pathogen: candodisis aspergillosis cryptococcosis zygomycosis localization: systemic organ mucosal skin

  45. ANTIMYCOTICS Specific Nonspecific • selective toxicity for • mycotic cell • targeted against mycotic cell specific structures • toxic for all organisms • MofA – protein denaturation, • cell membrane disruption etc. • antiseptic and disinfectant • agents

  46. ANTIMYCOTICS • Nonspecific I. • 1) Acids and derivatives: Ac. salicylicum, • Ac.boricum, Ac. undecylenicum, Ac. • benzoicum • 2) Phenols: resorcinol, hexachlorophene • 3) Organic dyes: • crystal gentian - (Methylrosanilinii chloridum) • methylen blue - (Methylthioninii chloridum) • brilliant green - (Viride nitens)

  47. ANTIMYCOTICS NONSPECIFIC II. 4) Aldehydes: formaldehyde, glutaraldehyde 5) Halogens and derivatives: iodine, iodine-povidon, chlorine, iodine-glycerol 6) Oxidizing agents: KMnO4 , H2O2 (1-3%) 7) Tars: Lithanthracis pix, Betulae pix, Fagi pix…

  48. ANTIMYCOTICS - polyenes Systemic - azoles + - allylamines Topicall - antimetabolites - others

  49. ANTIMYCOTICS squalene oxidosqualene lanosterol ergosterol ALLYLAMINES squalenepoxidase Syntesis of cell wall components AZOLES lanosterol-14 -demethylase POLYENES

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