Kharkiv National Medical University Department of Pharmacology and Medical Prescription

1. assistant Gordiychuk D. Kharkiv National Medical UniversityDepartment of Pharmacology and Medical Prescription “Antibiotics Part II. Antimycobacteria agents.”

2. Plan of lecture: • Pharmacology of Tetracyclines, Aminoglycosides, Macrolides and Azalides, Chloramphenicoles, Rifampicine, Lincosamides. • Pharmacology of Antimycobacterial agents.

3. 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.

4. 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

5. 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, monobactams, carbapenems, cephalosporins, aminoglycosides, rifampicin etc.

6. Aminoglycosides (Classification) 2 GENERATION • Gentamycin • Tobramycin • Netilmycin 1 GENERATION • Neomycin • Streptomycin • Kanamycin • Monomycin 3 GENERATION • Amikacin

7. Mechanism of Aminoglycosides action • Aminoglycosides are bactericidal antibiotics. • The antibacterial properties of aminoglycosides is a result of inhibition of bacterial protein synthesis through irreversible binding to the 30S-bacterial ribosome. • However other antibiotics that inhibit the synthesis of proteins (such as tetracycline) are not bactericidal. • Recent experimental studies show that the initial site of action is the outer bacterial membrane. The cationic antibiotic molecules create fissures in the outer cell membrane, resulting in leakage of intracellular contents, enhanced antibiotic uptake and creation of defective bacterial proteins. • This rapid action at the outer membrane is responsible for the bactericidal activity. • Energy is needed for aminoglycoside uptake into the bacterial cell.Anaerobes have less energy available for this uptake, so aminoglycosides are less active against anaerobes.

8. Spectrum of aminoglycosides • Staphylococci, • Streptococci, • Escerichia, • Salmonella, • Shigella, • Vibrio cholerae, • Klebsiella pneumonica • Aerobacter, • Neiseria, • Brucella, • Proteus, • Yersiniapestis, • Serratia, • Pseudomonos aeruginosa.

9. Spectrum of aminoglycosides • Some of the drugs are effective against Mycobacteria tuberculosis (Streptomycin, Kanamycin, and Amikacin). • Aminoglycosides are effective only against aerobic organisms, since anaerobes lack the oxygen-requiring transport system. • Drugs II and III generation potentiate the action of penicillins and cephalosporins.

10. Clinical uses of AMINOGLYCOSIDES • Respiratory infections, • Subacute bacterial endocarditis, • Plague • Tularemia • Meningitis (Gentamycin) • Urinary tract infections • Osteomyelitis • Lung abcesses • Septic processes caused by Pseudomonas aeruginosa • Tuberculosis (Streptomycin, Kanamycin, and Amikacin).

11. Side effects of AMINOGLYCOSIDES • Ototoxicity • Vestibulotoxicity (nausea,vomiting,vertigo, nistagmus) • Nephrotoxicity • Neuromuscular blockade (reduction of Ca2+ and Ach release, especially neomycin and streptomycin) • Allergic reactions • Superinfection • Imunosupression - Contraindicated introduction of aminoglycosides in the same syringe with penicillins, polymyxin B, cephalosporins - possible physical and chemical incompatibility!!!

13. Tetracyclines NaturalSemisynthetic Tetracycline Methacycline Doxacycline (Vibramycine)

14. Tetracyclines are also classified as: • short-acting (chlortetracycline, tetracycline, • oxytetracycline) based on plasma t1/2 of 6–8 h; • (2) intermediate acting (demeclocycline and • methacycline) – t1/212 h; • (3) long-acting (doxycycline and minocycline) • with plasma t1/2 16–18 h. • The almost complete absorption and slow • excretion of DOXYCYCLINE AND MINOCYCLINE • ALLOW FOR ONCE-DAILY DOSING.

15. Mechanism of TETRACYCLINE action • Penetration of antibiotic into susceptible microorganisms is mediated by transport protein; • On penetration the drug is binding to the 30 S subunit of the bacterial ribosome; • It results in inhibition of bacterial protein synthesis.

16. Spectrum of Tetracyclines • Brucella • Pasterella multocida, • F. tularensis • anaerobes; • spirochetes, T. pallidum and Borrelia; • rickettsiae (typhus etc.) • chlamydiae. • Moderately sensitive: • Actinomyces. • Entomoeba histolitica (at high concentrations), • Malarial Plasmodium • Cocci; • Gram-positive bacilli: • Clostridia, • listeria, • corynebacteria, • B. anthracis; • Gram-negative bacilli: • H. ducreyi • Vibrio cholerae, • Yersiniapestis, • Y. enterocolitica, • Campylobacter, • H. pylori

17. Exclusion of spectrum Tetracyclines do not inhibit: • Pseudomonas aeruginosaand Mycobacterium tuberculosis. • Many staphylococci, steptococci, enterococci and enterobacteria are now resistant to these antibiotics!!!

18. Resistance • Because many strains of the following groups of Gr+ microorganisms [Streptococcus pyogenes, Streptococcus pneumoniae, Enterococcus group (Streptococcus faecalis and Streptococcus faecium), Alpha-hemolytic Streptococci (viridans group); other microorganisms Chlamydia psittaci] have been shown to be resistant to Tetracycline, culture and susceptibility testing are recommended. • Up to 44 % of strains of Streptococcus pyogenes and 74 % of Streptococcus faecalis are resistant to Tetracycline drugs. • Therefore, Tetracyclines should not be used for streptococcal disease unless the organisms have been demonstrated to be susceptible. • Because of resistance to Tetracyclines, testing of susceptibility is recommended in infections caused by: Escherichia coli, Klebsiella species, Enterobacter aerogenes, Shigella species.

19. Clinical uses of TETRACYCLINES • Empirical therapy • Chlamydial urethritis and endocervicites • Atypical pneumonia caused by Mycoplasma • Cholera • Brucellosis • Plauge • Relapsing fever • Rickettsial infections

20. Clinical uses of TETRACYCLINES (second choice) • Tetanus • Antrax • Actinomycosis • Tularemia • Syphilis • Amebiasis • Chloroquin resistant malarial P. Falciparum • Acne vulgaris • Legionnaires' disease

21. Side effects of TETRACYCLINES • GIT: anorexia, nausea, epigastric distress, vomiting, diarrhea, glossitis, hypertrophy of tongue papillae (black hairy tongue), dysphagia, enterocolitis, pancreatitis,dysbacteriosis; • Hepatotoxicity, steatosis; • Teeth: disturbances of teeth growth, discoloration of teeth, enamel hypoplasia; • Disturbances of bones growth; • Pseudotumor syndrome (rare): severe headache and vision problems due to dangerous secondary intracranial hypertension; • Vertigo; • Phototoxicity (risk of sunburn); • Catabolic effect.

22. Side effects of tetracyclines (cont.) • Skin: maculopapular and erythematous rashes. • Exfoliative dermatitis has been reported but is uncommon. • Onycholysis and discoloration of the nails have been reported rarely. • They may increase muscle weakness in myasthenia gravis and exacerbate systemic lupus erythematosus. • Other: bulging fontanels in infants; • Blood: hemolytic anemia, thrombocytopenia, thrombocytopenic purpura, neutropenia and eosinophilia have been reported; • Superinfection, candidiasis, vitamin B deficiency, hyperbilirubinemia.

23. Tetracycline teeth Phototoxic Sunburn after Doxycycline intake

24. Contraindications • Pregnancy or lactation, • Children before 8 years old, • Hepatic insufficiency, • Renal insufficiency, • Hypersensitivity to tetracyclines.

25. MACROLIDES and AZALIDES

26. MACROLIDES mechanism of action: Binds with 5OS-subunit of microbial ribosomes and inhibit RNA and protein synthesis in the bacterial cell.

27. MACROLIDES SPECTRUM • WIDE SPECTRUM:GR + and GR- cocci, bacillus, intra-cellular organisms. • Staphylococci, • Streptococci, • Gonococci, • Anaerobic cocci, • Enterobacteriaceae • Strains of Pseudomonas, H. influenzae, Campylobacter, Helicobacter, Chlamydia, Ligionella, Bordetella, M. pneumonia, • P. carinii, T. gondii, M. avium complex. • Resistant to MACROLIDES ARE MOST OF Gr- bacterias!!!

28. Indications for MACROLIDES • Infection of the upper and lower respiratory tract(acute bronchitis, exacerbation of chronic bronchitis, acquired pneumonia). • ENT infections(acute otitis, tonsillitis, tonzilofaringit). • Gynecological infections. • Skin and soft tissue infection(pyoderma, boils). • Toxoplasmosis, mycobacteriosis of HIV infected. • Ophthalmic infections, • Diphtheria, • Leprosy, • Cystic fibrosis. • Syphilis, prostatitis, urethritis, chlamydia, etc.

29. FEATURES of MACROLIDES • Bacteriostatic effect mainly against GR+ bacteria (streptococci, staphylococci). • Activity against intracellular bacteria (chlamydia, mycoplasma, legionella). • One of the least toxic antibiotics. • Well absorbed from the gastrointestinal tract, acidstable,are able to consentrate in the inflammation area. • Bioavailability greater than that of tetracyclines (well penetrate into tissues and cells with creation of high concentration). • Inductors of microsomal liver enzymes.

30. Adverse reactions of MACROLIDES. • Cross-sensitivity, • Dyspeptic disorders, • Cholestasis, • Reversible ototoxicity, • Ventricular tachycardia, • Cross-resistance, • Embryonic and foetotoxic effects (clarithromycin).

31. Lincosamides • Mechanism of action: Inhibition of microbial cell proteins synthesis (similar to macrolides). • Mostly bacteriostatic action type (high conc.- bactericidal). • The narrow spectrum: mostly Gr + cocci. • Able to accumulate in bone and joints!!! • Rapid development of resistance. • No cross-sensitivity with β-lactams.

32. Lincosamides • Indications: • As a reserve antistaphylococcal drugs in tonzillofaringitis, pneumonia, infections of the skin, soft tissues, bones, joints. • Side effects: • Severe pseudomembranous colitis(ulceration, perforation of the intestine, peritonitis). • Treatment of colitis - vancomycin or metronidazole, detoxification therapy!!!!

33. Chloramphenicol (Levomycetin) • Chloramphenicol palmitate • Chloramphenicol succinate • Spectrum is very broad, much resembling that of tetracycline, like the last it is not active against Pseudomonas aeruginosa. • But in contrast to tetracyclines it does not act on Chlamydiae or Enterobacter species. • Chloramphenicol is the most toxic antibiotic!!!

34. Mechanism of CHLORAMPHENICOL action • Chloramphenicol binds to a ribosome on the 50S subunit, which is responsible for catalyzing the formation of bonds between amino acids, preventing the bacteria from linking amino acids together. • Chloramphenicol is able to halt the production of bacterial proteins, which keeps the bacteria from replicating and growing. This brings about bacteriostatic effect.

35. Indications for CHLORAMPHENICOL • Meningitis:!!!Drug is excellent BBB penetrating!!! • Staphylococcal brain abscesses (the first choice). • Typhoid fever, formerly chloramphenicol was the drug of first choice for typhoid, but now it is seldom used because of multiple drug-resistance of Salmonella typhi. • Anaerobic infections (Bact. fragilis). Chloramphenicol may be used as a second choice agent in the treatment : • Cholera (tetracycline-resistant), • Brucellosis, • Rickettsial infections.

36. Indications • Because of its excellentBBB penetration (far superior to any of the cephalosporins), chloramphenicol remains the first choice treatment for staphylococcalbrain abscesses. • It is also useful in the treatment of brain abscesses due to mixed organisms or when the causative organism is not known.

37. Indications. • Chloramphenicol is active against the three main bacterial causes of meningitis: Neisseria meningitidis, Streptococcus pneumoniae and Haemophilus influenzae. In the West, chloramphenicol remains the drug of choice in the treatment of meningitis in patients with severe penicillin or cephalosporin and GPsallergy are recommended to carry intravenous chloramphenicol in their bag. • In low income countries, the WHO recommend that oily chloramphenicol be used first-line to treat meningitis.

38. Chloramphenicol side effects. • Aplastic anaemia is the most serious side effect of chloramphenicol, it is rare and is generally fatal. It usually occurs weeks or months after chloramphenicol treatment has been stopped. • Bone marrow suppression, as a direct toxic effect of Chloramphenicol on human mitochondria. It manifests first as a fall in hemoglobin levels; this anaemia is fully reversible once the drug is stopped and does not predict future development of aplastic anaemia. • Increased risk of childhood leukemia.

39. Chloramphenicol side effects. • Gray baby syndrome in intravenous use of chloramphenicol. • This causes several adverse effects, including hypotension and cyanosis. The condition can be prevented by using the drug at the recommended doses, and monitoring blood levels.

40. CHLORAMPHENICOL side effects. • Newborn infants lack an effective glucuronic acid • conjugation mechanism for the degradation and • detoxification of chloramphenicol. • Consequently, when infants are given dosages above 50 mg/kg/d, the drug may accumulate, resulting in the • gray baby syndrome, with vomiting, flaccidity, hypothermia, gray color, shock, and collapse. • To avoid this toxic effect, chloramphenicol should • be used with caution in infants and the dosage • limited to 50 mg/kg/d or less (during the first week • of life) in full-term infants.

41. Chloramphenicol inhibits hepatic microsomal enzymes that metabolize phenytoin and warfarin.

42. NB! • Chloramphenicol should not be used for infections treatable by other safer antimicrobials!!!!

43. Rifampicin. • Rifamycin • Rifampicin • Rifabutin • Rifaximin Mechanism of action: incorporation into DNA spiral, inhibition of DNA-dependent RNA-polymerase → inhibition of replication and transcription in microorganisms. Spectrum of action:wide, Mycobacterium tuberculosis, leprosy. Bactericidal. Indications: tuberculosis, leprosy, infections caused by multidrug-resistant pathogens. Side effects: allergic reactions of heavy genesis, manifested by liver damage; flu-like syndrome, hemolytic anemia.

44. Antitubercular drugs.

45. TUBERCULOSIS (TB) • It is an infectious disease caused by various strains of mycobacteria, usually Mycobacterium tuberculosis. • Typical localization - the lungs, but disease can also affect other parts of the body. • It is spread through the air when people who have an active TB infection cough, sneeze, or otherwise transmit respiratory fluids through the air.

46. TUBERCULOSIS (TB) The classic symptoms of active TB infection are: • a chronic cough with blood-tinged sputum, • fever, chills, • night sweats, • loss of appetite, weight loss, fatigue. • Diagnosis of active TB relies on radiology (commonly chest X-rays), as well as microscopic examination and microbiological culture of body fluids. • Diagnosis of latent TB relies on the tuberculin skin test (TST) and/or blood tests.

47. Spread of tuberculosis in the world • In 2003 tuberculosis, affected 8.7 million people. Most of these people lived in Asia and Africa, a small proportion were in Europe and in America. • In India near 2 million people develop active form of disease. • About 0,5 million die of TB every year in this country.

48. Spread of tuberculosis in the world

49. Mycobacterium tuberculosis • Mycobacteria are slowly growing microorganism and thus relatively resistant to chemotherapeutic agents. • Some of mycobacterium cells can be dormant and completely resistant to many drugs. • Mycobacterial cell wall is impermeable to many agents. • Mycobacteria may reside inside the macrophages, being inaccessible to the drugs poorly penetrating into macrophages. • Mycobacteria is highly resistant in environment. • Mycobacteria are capable of developing resistance to any single drug. • To delay the development of resistance combination of several drugs are used in the treatment of tuberculosis. • The response of mycobacterial infection to chemotherapy is slow, the treatment is long lasting.

50. Classification of anti-TB drugs (according to antitubercular efficacy) • Ethionamide (ET) • Cycloserine (C) • Capreomycin • Levofloxacin C. (Less Effective) • Paraaminosalicylic Acid ( PAS) • Thiacetazone (T) A. (The most effective) • Isoniazid (INH) • Rifampicin ( R) B. (Effective) • Streptomycin (S) • Pyrazinamide (Z) • Ethambutol (E) • Kanamycin (K)