“Antibiotics part I”

1. “Antibiotics part I” assistant Gordiychuk D. Kharkiv National Medical University Department of Pharmacology and Medical Prescription

2. Plan of lecture: • Principles of antibiotictherapy. • Pharmacology of Penicillins, Cephalosporines, Carbapenems and Monobactams.

3. Antibiotics Antibiotics and vaccines are among the biggest medical advances since 1000. (Culver Pictures)

4. Antibiotics ("Anti" – against, "bios" - life) • Antibiotics - a substance produced by microorganisms, or produced from vegetable and animal tissues, and their semi-synthetic and synthetic analogs selectively inhibit the viability of microorganisms sensitive to them. Importance of Antibiotics: • The elimination of the global crisis of infectious diseases (cholera, plague, dysentery). • Effective at the dangerous diseases (sepsis, meningitis, peritonitis, pneumonia). • ≈ 20 million people die each year from infectious diseases. • 1/3 of all hospital patients are treated with antibiotics. • Over the past 20 years there were 20 new infectious diseases (Legionnaires' disease, hairycell leukemia, hemorrhagic fever and others). • Unconventional use of antibiotics: peptic ulcer, asthma, myocardial infarction, atherosclerosis. • In breadth of application group of antibiotics ranked the first place in the world. • Today, there is no person at least who did not use antibiotics. • There is no country that doesn’t threat of epidemics and pandemics.

5. Antibiotics could be • narrow-spectrum and effective only against a limited variety of pathogens or broad-spectrum, affecting many different types of pathogens • bactericidal if they kill the susceptible bacteria or bacteriostatic if they inhibit the growth of bacteria

6. Classification of antibiotics.

7. A brief history of antibiotics • 1928 - Scottish microbiologist A.Fleming discovered penicillin - P.notatum. • 1940 - British W. Florey and Chain received penicillin E. • In 1945, Fleming, Florey, Chain received the Nobel Prize for the discovery of penicillin. • 1942 - Z. Yermolyeva - Penicillin crustosum. • 1944 - American Z. Waxman – streptomycin. • 1960-1980 - cyclosporine, rifampicin, semisyntheticpenicillins, tetracyclines, macrolides, azalides. • Today ≈ 6 thousand antibiotics. But, 2-3% of them are use (300 INN ≈ 2000 oficinal names). • ~ recent year: modifying old drugs, finding new discipline in antibacterial combats.

8. Requirements for Antibiotic • high selectivity • lack of toxicity • long-term providing of therapeutic concentrations • lack of rapid resistance development • availability of suitable dosage forms

9. Classification according SPECTRUM OF ACTION. • Narrow spectrum (mainly Gr + and Gr-): • Natural, antistaph. penicillins • Cephalosporins I generation, monobactams • Polimyxins, gramicidin C • Fuzidin • Antifungal • Broad-spectrum: • Semi-syntheticpenicillins and cephalosporins II -IV • Carbapenems, Tetracyclines, Macrolides, Aminoglycosides • Chloramphenicol

10. Antimicrobial drugs have also been classified broadly into: 1.bacteriostatic, i.e. those that act primarily by arresting bacterial multiplication, such as tetracyclines, chloramphenicol, macrolides, lincosamides. 2.bacteriocidal, i.e. those which act primarily by killing bacteria, such as penicillins, cephalosporins, aminoglycosides, isoniazid, rifampicin, quinolones etc.

12. Classification according MECHANISM OF ACTION

13. Cytoplasmic membrane Cell wall Nuclearapparatus Ribosomes Bacterial cell Violation of protein synthesis at the level of ribosomes. Violation of cytoplasmic membranes permeability. Violation of RNA synthesis Violation of the cell wall synthesis. Tetracyclines Chloramphenicols Lincosamides Macrolides Azalides Aminoglycosides Fuzidinum B-lactams Glycopeptide Polymyxins Gramicidin Antifungal Rifampicin

14. Negative effects of Antibiotics: 1.The emergence of sustainability: •   production of beta-lactamase; •   changes in the permeability of the cytoplasmic membrane; •   changes in the structure of certain portions of ribosomes proteins or enzymes 2.  Superinfection; 3. Dysbiosis; 4. Allergic reactions; 5. Systemic toxicity, nephrotoxicity, hepatotoxicity. • Penicillins are the least toxic!!!

15. Antimicrobial therapy and pregnancy • Azithromycine • Erythromycine • Penicillins • The most of • cefalosporines

16. Conditions for rational use of antibiotics • Antibiotics should be given according to antibiogram. • Choose the most active and least toxic antibiotic. • To determine the optimal antibiotic dose and route of administration based on the its pharmacokinetic and the concomitant disease. The concentration of antibiotic in the blood should be 3-4 times bigger in comparison with minimum inhibitory concentration for the selected pathogen. • Apply the first striking dose, followed by supporting. • To determine the tolerance of antibiotics in patients according to the basis of medical history. • To take in account an adverse effects of antibiotics, especially in the liver and/or kidney failure. • Early antibiotic treatment till consolidation of therapeutic effect. • Consideration of cross sensitivity. • Use a combination of antibiotics in order to expand and strengthen the action of the antibacterial effect. • Use of antifungal drugs to prevent dysbiosis.

17. BETA-LACTAM ANTIBIOTICS (inhibitors of cell wall synthesis) • Their structure contains a beta-lactam ring. • The major subdivisions are: • penicillins whose official names • usually include or end in “cillin” • (b) cephalosporins which are • recognized by the inclusion • of “cef” or “ceph” in their • official names. • (c) carbapenems (e.g. meropenem, • imipenem) • (d) monobactams (e.g. aztreonam) • (e) beta-lactamase inhibitors (e.g. • clavulanic acid, sulbactam).

18. β-lactams Mechanism of Action • Action target: cell wall • on penicillin binding proteins (PBPs) • Transpeptidases (form cross-links in peptidoglycan) • Beta-lactam ring attached to 5-membered thiazolidine ring • Accessibility of PBPs differ in gram+ and gram- bacteria. • Amino acyl side chain groups determine spectrum, adsorption, susceptibility to lactamase. • Bactericidal inhibitors.

20. Penicillin

21. Classification of penicillins • 1.Natural penicillins: • a) Short acting: • Penicillin-G • Penicillin-sodium • Penicillin-potassium • Penicillin V • b) Long acting: • Penicillin G. procaine • Benzathine penicillin (Bicillin-I) • Bicillin-3,-5

22. Classification of penicillins • 2. Semisynthetic penicillins: • I. Penicillinase resistant • Oxacillin • Dicloxacillin • Cloxacillin • Methicillin • II. Broad spectrum penicillins • Aminopenicillins • Ampicillin • Amoxicillin • Pivampicillin • Talampicillin

23. Classification of penicillins • III. Carboxypenicillins • Carbenicillin • Ticarcillin • IV. Ureidopenicillins • Azlocillin • Piperacillin • V. Combined penicillins • Unazin • Ampiox (Ampicillin+Oxacillin) • Augmentin (Amoxycillin+Clavulanic acid) • Magnapen (Ampicillin+Flucloxacillin)

24. Spectrum of natural penicillins • Gr+ microorganisms include: • staphylococci, • streptococci (pneumoniae, pyogenes and viridans group), • bacillus anthracis, • clostridium perfringens, • corynebacteria diphtheriae and listeria monocytogenes

25. Spectrum of natural penicillins (cont.) • Sensitive Gr- microorganisms include: • Neisseria gonorrhoeae, • Neisseria meningitis, • Leptotrichia buccalis, • Treponema pallidum, • Treponema partenue.

26. Pharmacokinetics of natural penicillins • 1. Acidic instability (exception Penicillin V) • 2. Extracellular distribution mainly • 3. Poor penetration through BBB • 4. Crossing the placenta • 5. Protein binding 60% • 6. Small amount metabolizing • 7. Excretion mainly by tubular secretion. It may be suppressed by probenecid (uricosuric)

27. Clinical uses of natural penicillins • Endocarditis • Pericarditis • Meningitis • Pneumonia • Septicemia caused by streptococcus pyogenes • Gonorrhea • Syphillis (congenital and neurosyphillis).

28. Clinical uses of natural penicillins(cont.) • Anthrax, • Actinomycosis (abdominal, cervicofacial or thoracic disease), • Botulism, • Gas gangrene, • Tetanus, • Diphtheria (prevention of carrier state), • Empyema, • Rheumatic fever, • Listeriosis.

29. Side effects of natural penicillins • Penicillin G (benzyl penicillin) is one of the least toxic antibiotics. It does not cause any direct toxicity. Only in very high doses, especially injected IV, it can cause neurotoxic effect and bleeding. • The hypersensitivity reactions are the major problem, incidence up to 10%.

30. Semisynthetic penicillins I. Penicillinase resistant: • Oxacillin, Dicloxacillin, Cloxacillin, Methicillin • The advantages of penicillinase resistant semisynthetic penicillins over natural ones are in efficacy against penicillinase producing staphylococci and stability of some of them (Oxacillin) in acidic medium. • They are used in treatment of infection caused by staphylococci resistant to penicillins.

31. Semisynthetic penicillins • II. BROAD SPECTRUM PENICILLINS • a) Aminopenicillins • The aminopenicillins have identical spectrum and • activity, but amoxicillin is better absorbed orally • (70–90%). • They are effective against: • streptococci, enterococci • Gram-negative organisms (including H. pylori) • but have variable activity against staphylococci • ineffective against P. aeruginosa. Amoxycillin and Ampicillin

33. b) Antipseudomonal penicillins These drugs retain activity against streptococci and possess additional effects against Gr- organisms, including various Enterobacteriaceae and Pseudomonas. • Carboxypenicillins • Carbenicillin • Ticarcillin • Ureidopenicillins • Azlocillin • Mezlocillin • Piperacillin

34. There is cross-allergy between all the various forms of penicillin, probably due in part to their common structure, and in part to the degradation products common to them all. Partial cross-allergyexists between penicillins and cephalosporins (a maximum of 10%) which is of particular concern when the reaction to either group of antimicrobials has been angioedema or anaphylactic shock. Carbapenems and the monobactams apparently have a much lower risk of cross-reactivity.

35. Adverse effects • Thrombophlebitis • Allergic reactions • Superinfections (diarrhea) • Seizures (rare)

36. Stevens – Johnson syndrome Lyell syndrome

37. Resistance • Failure to bind to PBPs • Cannot penetrate porins (gram-) • Production of lactamase (penicillinase) • Lack autolytic enzyme • B-lactamase Types: • Different substrate specificity • Penicillinases • Cephalosporinases Location: • Gram+: extracellularly • Gram-: periplasmic space

39. Policy to deal drug resistance • Ideally, bacteriological management of clinical infection should involve: • Identification of causative organism • Sensitivity test • Follow-up the drug effect • Monitor antibiotic level to avoid toxicity. • In reality, most patients requiring antimicrobial therapy are treated empirically. In serious infections immediate chemotherapy may be life-saving.

41. CEPHALOSPORINS • Cephalosporins have 7-aminocephalosporanic acid nucleus. • Cephalosporins are produced semisynthetically from cephalosporin- C obtained from a fungus Cephalosporium. • Spectrum – broad • Mechanism - inhibition of synthesis of bacterial cell wall. • Effect - bactericidal

42. 5 generations of CEPHALOSPORINS • 1.FIRST GENERATION • Cephalosporins of the first generation are highly active against Gram+ but weaker against Gram- microorganisms. I.Cefazolin II.Cefalexin • 2. SECOND GENERATION • The drugs were developed subsequently to the first generation; they are more active against Gram-negative microorganisms. III.Cefuroxim IV.Cefaklor

43. 5 generations of CEPHALOSPORINS (cont.) • 3. THIRD GENERATION • They have enhanced activity against gram-negative bacilli, including most enteric organisms and Serratia marcescens. Ceftriaxone and cefatoxime have become agents of choice in the treatment of meningitis. • Ceftazidime has activity against Pseudomonas aeruginosa. • V.Ceftriaxone • VI.Cefixime • VII.Cefoperazone • VIII.Ceftazidime • IX.Cefatoxime

44. 5 generations of CEPHALOSPORINS (cont.) • 4. 4-th generation • These drugs are in many ways similar to cephalosporins of 3rd generation • X. Cefepim • XI.Cefpirom • 5. 5-th generation • XII.Ceftobiprole • XIII. Ceftaroline • Antimicrobial activity: Ceftobiprole has powerful antipseudomonal effect and is less susceptible to development of resistance. Ceftaroline does not have an anti-pseudomonal activity.

45. CEPHALOSPORINS • Type of action: bactericidal = penicillins • Spectrum: WIDE • INDICATIONS • infectious diseases of the respiratory, urinary and biliary tract, abdominal cavity, skin, bones, joints, heart, • Gonorrhea, burns, surgical prophylaxis, • Meningitis and Pseudomonas infection - III -IV generation. • Side effects: hemorrhage, hemato-, nephro-, neuro-, hepatotoxicity. • Contraindications: porphyria, epilepsy, severe liver and kidney diseases, pregnancy, lactation.

46. Sulperazon- "protected" (Cefoperazone + Sulbactam) • Spectrum: wide G+, Gr-, anaerobes • Resistant to β-lactamases of extended spectrum (sulperazon and carbapenems) • Application: for severe community-acquired and hospital-acquiredinfective processes: primary and secondary peritonitis, infected pancreatic necrosis, sepsis, diabetic foot, phlegmons, nosocomial pneumonia.

47. Comparison activity of CEPHALOSPORINS.

48. Pharmacological "face" of CEFALOSPORINES • Similar to penicillin in structure and action. • Wide spectrum. • Powerful bactericidal effect. • Low toxicity. • Good compatibility with other antibacterial agents. • Most resistant to staphylococcal β-lactamase. • Cross allergic to penicillin. • It penetrates into the tissue fluid, joints, bones. • Good compatibility with other antibacterials.

49. CARBAPENEMS and MONOBACTAMS  - resistant to  -lactamases, * - resistant to renal dehydropeptidase

50. Pharmacological «face» of CARBAPENEMS and MONOBACTAMS