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ANTIBIOTICS

ANTIBIOTICS. Lector prof. Posokhova K.A. The problem. drug companies have little interest in financing the testing of their newly discovered antibiotics, because they are more focused on drugs that people require daily for the rest of their lives.

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ANTIBIOTICS

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  1. ANTIBIOTICS Lector prof. Posokhova K.A.

  2. The problem drug companies have little interest in financing the testing of their newly discovered antibiotics, because they are more focused on drugs that people require daily for the rest of their lives

  3. superbugs microorganisms with multiply resistance • MRSA - methicillin/oxacillin-resistant Staphylococcus aureus • VISA- vancomycin intermediate resistant Staphylococcі • VRE - vancomycin-resistant enterococci • ESBLs - extended-spectrum beta-lactamases(microorganisms – resistant to cephalosporins and monobactams) • PRSP - penicillin-resistant Streptococcus pneumoniae 1952 – 100 % Staphylococcusinfections were cured by penicillin 1982 – only 10 % infections At nowadays ?........ MRSA causes 19 000 deathsannually in USA (more than VIL)

  4. Principles of rational antibiotic therapy • Presence of substantiated indications for prescription of an antibiotic • Choosing of the most effective and the least toxic drug, intime administration • Introduction of optimal doses with optimal frequency, taking into consideration complexity of the disease • Choosing of the optimal way of introduction • Estimation of duration of treatment • Control after treatment • Monitoring and prophylaxis of negative side effects • Decision on expediency of combined antibiotic therapy

  5. ANTIBIOTICS • Beta-lactam antibiotics: • А. Penicillins • Б. Inhibitors of beta-lactamases and combined drugs, • В. Cephalosporins • Г. Monobactams • Д. Tienamycin (carbapenems). • Macrolides, azalides, streptogramins, prystinamycines. • Linkozamides. • Tetracyclines. • Aminoglycosides. • Chloramphenicols. • Glycopeptides. • Cyclic polipeptides (polimixins). • Other antibiotics

  6. ANTIBIOTICS

  7. PENICILLINS Natural (biosynthetic) penicillins: • benzylpenicillin (penicillin G), phenoxymethylpenicillin (penicillin V), novocain salt of benzylpenicillin (benzylpenicillin procain), bicillin-1 (benzatyn benzylpenicillin), bicillin-3, bicillin-5. Semisynthetic penicillins: • 1antistaphylococci penicillinase resistant penicillins – izoxazolil-penicillins (oxacillin, dicloxacillin, methicillin); • 2of a spread spectrum – aminopenicillins (ampicillin, amoxicillin); • 3antipseudomonade – carboxypenicillins (carbenicillin, ticarcillin); ureidopenicillins (azlocillin, piperacillin, sulbenicillin); • 4 combined with inhibitors of beta-lactamases - “protected” penicillins (amoxicillin/clavulanate, ampicillin/sulbactam, ticarcillin/clavulanate, piperacillin/tazobactam).

  8. S H2N CH3 CH3 T L O N C O OH Nucleus of penicillin molecule L – beta-lactame ring, T – thiazoline ring

  9. Mechanism of penicillins action They form complexes with enzymes - trans- and carboxypeptidases (PCP), which control synthesis of peptidoglycan – component of cell-wall of microorganisms

  10. Spectrum of action of biosynthetic penicllins

  11. schemes on introduction of biosynthetic penicillins

  12. Complications of biosynthetic penicillins • Allergic reactions (10%) • Endotoxic shock • Disorders of electrolyte balance • Neurotoxic reactions (in using of big doses) – encephalopathy (hyperreflexia, seizures, hallucinations, coma) • Daily dose of BPduring intratecal introductionshould not overcome 10000 U (5000 U – for children) • Interstitial nephritis

  13. Oxacillin Antistaphylococci penicillinase-resistant semisynthetic penicillin, acid stable Administration: intramuscular, intravenously, oraly 3-6-8 g/24 hours (4-6 times of injections)

  14. Spectrum of action of aminopecillins (ampicillin, amoxicillin) wide spectrum, destroyed by beta-lactamases Influence on: streptococci, Haemophilus influenzae, causative agent of wooping cough, gonococci, meningococci, proteus, Escherichia coli, salmonella, shigella .

  15. Ampicillin

  16. Amoxicillin

  17. Differences between ampicillin and amoxicillin

  18. Indications for administration of amoxicillin

  19. Side effects of semisynthetic penicillins • Irritation of mucous membrane of digestive tract(diarrhea) • Disbacteriosis • Superinfection (colonizing of gut with Candida fungi, enterococci, Pseudomonas aeruginosa, clostridia) • Pain in injection area, aseptical inflammation, phlebitis • Allergic reactions • Granulocytopenia (oxacillin) • Reduction of platelets agregation (ampicillin) • Disorders of liver function • Encephalopathy (in introduction of high doses)

  20. Inhibitors of beta-lactamases Clavulanic acid Sulbactam Tazobactam

  21. Unasyn (ampicillin/sulbactam)

  22. Inhibitor-protected (“screened”, “protected”) penicillins Amoxicillin/clavulanate (amoxyclav, augmentin) Ampicillin/sulbactam (sultamycillin, unasin) Ticarcillin/clavulanate (timentin) Piperacillin/tazobactam

  23. S H2N L D N CH2 O CO CH3 O O C OH Structure of cephalosporins L – beta-lactame ring, D – dihydrothiazine ring

  24. Classification of cephalosporins

  25. Cefazolin-sodium (C I)

  26. Cezolin (Cefazolin, C I)

  27. Cefalexin ( C I)

  28. Zinnat (Cefuroxime, C II)

  29. Cefotaxime (C III)

  30. Claphoran (cefotaxime, C III)

  31. Cefobid (Cefoperazone, C III)

  32. Antimicrobial spectrum of cephalosporins

  33. Complications, caused by cephalosporins • Irritation of mucous membrane of digestive tract, infiltrates after intromuscular introduction , phlebitis after inrtavenous introduction • Disbacteriosis, superinfection • Allergic reactions, including cross allergy with penicillins • Granulocytopenia (in case of treatment during more than 2 weeks) • Hemorrhages (inhibition of synthesis of factors of blood coagulation in liver) – cephalosporins ІІІ • Nephrotoxicity (accumulation in epithilial cells of kidney canalicules) • Encephalopathy (hyperreflexia, seizures, coma) 

  34. Cephalosporines Not recommended to combine with other nephrotoxic drugs (aminoglycosides) Contraindicated to combine with loop diuretics (furosemid, etacrinic acid)

  35. Monobactams Aztreonam Action spectrum - Gram (-) bacteria, including Escherichia coli, Clebsiellas, Proteus, Haemophilus influenzae (activity is equal to the activity of cephaloporins of third generation) Ways of introduction: oral (20% are being absorbed), intramuscular, intravenous Clinical uses: sepsis, infection of urinary tract, soft tissues, meningitis and others (often combined with aminoglycosides , clindamycin, metronidazole, vankomycin).

  36. Carbapenems (tienamytsin) Tienam (imipenem + cylastatin) Meropenem The widest spectrum of antibacterial action most of aerobe and anaerobe Gram(+) and Gram (-) bacteria, including those which produce beta-lactamase

  37. Classificaion ofmacrolides І. Natural substances: erythromycin, oleandomycin,spiramycin, jozamycin, midecamycin. ІІ. Semi-synthetic substances: roxythromycin, clarithromycin, flurythromycin, dyrythromycin, miokamycin, rokitamycin. III. Azalides (neutrogen atom is introduced in lacton ring): azithromycin.

  38. Erythromycin

  39. Macropen (midecamycin)

  40. Sumamed (azithromycin)

  41. spectrum of action of maclrolides and azalides • staphylo-, strepto-, hono-, anaerobe cocci, enterobacteria • H.influenzae (clarythromycin, azithromycin) • intracellular situated microorganisms (strains of Helicobacter, Chlamydia, Legionellа, M. pneumoniae, U. urealyticum etc.)

  42. Pharmacokinetics of macrolides Quiclkly and fully distributed through the tissues (do not pass through HEB) Correlation concentration tissues/blood: • Erythromycin – (5-10) : 1 • Azithromycin – (100-500) : 1 • Their concentration in phagocyting cells prevails concentration in blood pasma in 12-20 times, they get accumulated in source of inflammation - macrolides paradoxis

  43. Indications for usage of macrolides and azalides LOR- infections, infections of upper respiratory tracts, gynecological infections, skin and soft tissues infections; ulcer disease; dyphteria; whooping-cough; honorrhea; syphilis; typhoid fever (azithromycin). Drugs of choice for: mycoplasma, chlamidia, legionella pneumonia

  44. Side affects of macrolides • Dispeptic disorders, disbacteriosis, superinfection • Cholestasis, cholestatic jaundice (erythromycin) • Depression of liver microsome enzyme activity (erythromycin, oleandomycin can not be combined with theophylline, ergot alkaloids, carbamazepine) • Development of resistance in process of treatment

  45. Linkosamides Linkomycin Clindamycin • Action spectrum: Gram positive aerobe cocci, grampositive and gramnegatvie anaerobes • Penetrate all the tissues (don’t pass through HEB) including intracellurally • Usage: usually in heavy infections, caused by anaerobe microorganisms • A lot of side effects

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