ANTIMICROBIALS Block 2.4 Digestion & Defense 2019 Prof Asghar Mehdi Ph.D

1. ANTIMICROBIALS Block 2.4 Digestion & Defense 2019 Prof Asghar Mehdi Ph.D Department of Pharmacology

2. Learning from practice • A 35 year old male presented with a 5cm carbuncle on the posterior aspect of Neck. The boy is otherwise healthy. • (ANTIBIOMA} COLLECTION OF ANTIBIOTIC IN PUSS) • A 55 year old hospitalized diabetic on dialysis develops empyema involving the R hemi-thorax.His recent HbA1c 11 Department of Pharmacology

3. Learning from practice • A 25 year old male had an RTA was brought to the ER conscious had open fracture of R femur. The orthopedic surgeon decides to go for emergency surgery. • A 35 year old male university student reported in ER with complaints of severe epigastric pain. On evaluation a provisional diagnosis of perforated duodenal ulcer was made. The surgical team plans for exploratory laparotomy. Department of Pharmacology

4. OUTLINE • Antimicrobials – introduction. • Types of antibiotics. • Factors affecting selection. • Role of culture and sensitivity. • Classification. • Mechanism of action. • When to use more then one? Department of Pharmacology

5. Antimicrobials. OVERVIEW. • The use of antimicrobials has contributed to the dramatic fall in morbidity from communicable and infectious diseases over the last 50 years globally. • One of the first things that has to be determined is whether or not antimicrobial therapy is necessary!! • ‘evidence is overwhelming that antimicrobials are vastly overprescribed on outpatient basis. • (IN MOST OF THE CASES ANTIBACTERIAL ARE MISSUSED) Department of Pharmacology

6. Importance. • Antimicrobials are among the most commonly use of drugs. • 30% or more of all hospitalized patients are treated with one or more courses of antimicrobial therapy. • However they are also among the drugs most commonly misused by physician. Department of Pharmacology

7. Microbial Sources of Antibiotics Antibiotics are produced by various species of microorganisms  (or by pharmaceuticalchemists)  that suppresses the growth of other organisms. Chemotherapy: Suppresses the growth of cells / organisms by synthetic chemicals. Department of Pharmacology

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9. The antimicrobials drugs are effective in the treatment of infections because of their selective toxicity. (the ability to kill an invading microorganism without harming the cell of the host) Department of Pharmacology

10. Selective toxicity Class I: use of glucose, or some alternative carbon source, for the generation of ATP & synthesis of simple carbon compounds. Theseare not promising targets for two reasons. First, bacterial and human cells use similar mechanisms to obtain energy from glucose (tricarboxylic acid cycle). Second, even if glucose oxidation is blocked, many other compounds (amino acids, lactate, etc.) can be utilized by bacteria as an alternative energy source. Class III: assembly of small molecules into macromolecules – proteins, RNA, DNA, polysaccharides and peptidoglycan. The cell wall of bacteria contains peptidoglycan, a substance that does not occur in eukaryotes. In Gram-negative bacteria, this bag consists of a single thickness, but in Gram-positive bacteria there may be as many as 40 layers of peptidoglycan. Class II: use of these precursors in an energy-dependent synthesis of all amino acids, nucleotides, phospholipids, amino sugars, carbohydrates and growth factors required by cell for survival and growth. These reactions are better targets because some pathways exist in pathogens, but not in human cells. The folate pathway is found in bacteria but not in humans. Department of Pharmacology

11. ~ GOAL OF ANTIMICROBIAL THERAPY ~ What is the primary goal of antimicrobial therapy?? • ‘ TO ASSIST THE IMMUNE SYSTEM • RID THE BODY OF INVADING ORGANISMS ....... • TO HELP THE BODY HEAL ITSELF Department of Pharmacology

12. Classification according To therapeutic actions. • Anti bacterial • Anti viral • Antifungal • Antiprotozoal • Anti-helimenthics • Miscellaneous. Department of Pharmacology

13. Classification: According to its activity. • BACTERISTATIC inhibits bacterial multiplication - Sulfonamides, Tetracyclines & Chloramphenicol • BACTERICIDAL those which act primarily on cell wall of the bacteria. Penicillin • This classification is arbitrary as most of the bacteriostatic drugs when given in high doses may result in bactericidal activity. • (BACTERICIDALS ARE MORE EFFECTIVE THEN BACTERISTATIC). • (BACTERISTATIC DRUGS CAN BECOME BACTERICIDALS IF GIVEN IN HIGHER CONCENTRATION). Department of Pharmacology

14. Bactericidal versus bacteriostatic Some drugs can be both static and cidal depending on dose and the bug. Department of Pharmacology

15. Intro to antimicrobial therapy • static and cidal agents about equally effective in immunocompetent hosts • Cidal agents should be used in host with impaired defense mechanisms as in HIV, Pt’s on chemotherapy, Poorly controlled diabetes Department of Pharmacology

16. Culture & sensitivity (CHECK ORGANISM AND SENSITIVITY BEFORE GIVING ANTIBIOTIC) Department of Pharmacology

17. Testing the sensitivity Department of Pharmacology

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19. Relationship b/w tissue & plasma concentration • Minimum Inhibitory Capacity - Is the lowest concentration that inhibit bacterial growth.Organisms are classified as susceptible, resistant & intermediate on the bases of MIC. • In general the peak serum concentration of a drug should be (in multiples) 4-10 times greater than MIC in order for the pathogen to be susceptible. • BECAUSE: tissue concentration of a drug is lower than plasma concentration. Local factors - low pH, high protein concentration, anaerobic conditions may impair drug activity. Department of Pharmacology

20. Relationship b/w Plasma conc & MIC. A: Staph pneumonia B: Staph aureus C: E.coli D: Enterobacter E: Pseudomonas A,B & C are sensitive. D Intermediate E Resistant Department of Pharmacology

21. PAE: Post Antibiotic Effect • PAE After an antibiotic is removed from a bacterial cultures, evidence of persistent effect on bacterial growth may exist. • Most bactericidal drugs exhibit PAE. Penicillin's against gram positive cocci Aminoglycosides against gram negative bacilli. Department of Pharmacology

22. CDKR: Concentration dependent killing rate SomeAminoglycosides -Tobramycin and Fluroquinolones- Ciprofloxacin exhibit CDKR against gram negative bacteria. In contrast Penicillin’s & other ß lactam drugs do not exhibit CDKR. Department of Pharmacology

23. CHEMOTHERAPEUTIC SPECTRA. • Narrow spectrum: chemotherapeutic agents active against a single specie or limited group of microorganism (gram positive bacteria) • Extended spectrum: antibiotics that are affected against gram positive organisms and also against significant number of gram negative bacteria. example ampicillin. • Broad spectrum: drugs that are active against wide variety of microbial species. Its administration can dramatically alter the nature of the normal bacterial flora and can precipitate a super infection. Imipenem Department of Pharmacology

24. ~ FACTORS DETERMINING THE SUCCESS OF CHEMOTHERAPY ~ HOST (Billy) DRUG (penicillin) ** BUG Streptococcus Department of Pharmacology

25. FACTORS DETERMINING THE SUCCESS OF CHEMOTHERAPY • DRUG parameters • Pharmacodynamics (mechanism) • Can’t work if there is no target • Synergism? • Antagonism? • Pharmacokinetics (ADME) • reach effective level or not? • Access the infection site (CSF)? • Dosage adjustment requirements? • Adverse effects ...... compliance • can the patient tolerate?? • How much drug can be given? Department of Pharmacology

26. Urine infections are easy to treat??? • Route of elimination affects both selection & use of antimicrobial drugs. Hence drugs that are eliminated by kidneys are more effective for UTI than are drugs that are largely metabolized or undergo biliary excretion. • Urine concentration of a antimicrobial drug is 10-50 times the peak serum concentrations. Department of Pharmacology

27. ~ FACTORS DETERMINING THE SUCCESS OF CHEMOTHERAPY ~ HOST (Billy) ** DRUG (penicillin) BUG Streptococcus Department of Pharmacology

28. HOST determinants • Immune system status - History of drug reaction (allergy), Immunocompromised / immunocompetent - Type of drug & Duration of treatment • Altered drug distribution - impaired organs of elimination renal / hepatic insufficiency. • Age - genetic factors -pregnancy • Antibiotic access: Abscess, foreign bodies, indwelling catheters • EDUCATION (compliance) ...... yes take ALL the tablets!!! Department of Pharmacology

29. Site of infection • CNS: Penicillin G can penetrate the BBB only when meninges are inflamed but the aminoglycosides do not. Hence aminoglycosides if required need to be given intrathecally. • Bone: antibiotic conc are low in bone hence patients with osteomyelitis are treated with antibiotics for long durations. • Prostrate: Because of its epithelium & low pH hence it favors the entry of weak bases such as Trimethoprim and tends to exclude entry of weak acids such as Penicillin's. Department of Pharmacology

30. ~ FACTORS DETERMINING THE SUCCESS OF CHEMOTHERAPY ~ HOST (Billy) DRUG (penicillin) BUG Streptococcus ** Department of Pharmacology

31. Bacterial determinants • Identification by gram stain, Culture & sensitivity. Take samples before starting antibiotics. • Common pathogens in specific locations / settings. • Hospital / community acquired. • Is it sensitive to antimicrobials? • Consider RESISTANCE if clinical improvement not seen after 48-72 hours / clinical pathology evidence. Department of Pharmacology

32. Classification Department of Pharmacology

33. CLASSIFICATION OF ANTIMICROBIAL AGENTS. METABOLIM. SULPHOAMIDES. TRIMETHOPRIM. CELL WALL SYNTHESIS. β-LACTAMASE. VANCOMYCIN. INHIBITORS OF NUCLEIC ACID FUNCTION / SYNTHESIS. FLUOROQUINOLONES. RIFAMPIN. PROTEIN SYSNTHESIS. TETRACYCLINES. AMINOGLYCOSIDES. MACROLIDES. CLINDAMYCIN. CHLORAMPHENICOL. Department of Pharmacology

34. FOLATE ANTAGONIST. INHIBITORS OF FOLATE SYNTHESIS. INHIBITORS OF FOLATE REDUCTION. INHIBITORRS OF FOLATE SYNTHESIS AND REDUCTION. MAFENIDE. SULFADIAZENE. SULFASALAZINE. PYRIMETHAMINE. TRIMETHOPRIN. CO-TRIMOXAZOLE. Department of Pharmacology

35. Protein synthesis inhibitors: • Agents that bind to 30s OR 50s ribosomal subunits and alter protein synthesis which eventually leads to cell death. Department of Pharmacology

36. INHIBITORS OF CELL WALL SYNTHESIS. • β-LACTAM ANTIBIOTICS. • PENICILLINS. • CEPHALOSPORINS. • CARBAPENEMS. • MONOBACTAMS. Department of Pharmacology

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39. INHIBITORS OF CELL WALL SYNTHESIS. • PENICILLINS. • AMPICILLIN ( PENBRITIN, OMNIPIN,AMPICIL) • AMOXICILLIN (AMOXIL, CIPAMOX, WYMOX) • OXACILLIN. • TICARCILLIN. Department of Pharmacology

40. Inhibitors of cell wall synthesis.CEPHALOSPORINS. 3RD GENERATION. 1ST GENERATION. 2ND GENERATION. CEFACLOR. CEFONICID. CEFOTETAN. CEFOXITIN. CEFAZOLIN. CEPHALEXIN. CEPHAPIRIN. CEFIXIME. CEFOTAXIME. CEFTAZIDIME. 4th Generation: CEFEPIME Department of Pharmacology

41. INHIBITORS OF CELL WALL SYNTHESIS. CARBAPENEMS. • IMIPENEM. • CILASTATIN. • OTHER ANTIBIOTICS. • VANCOMYCIN. • BACITRACIN. Department of Pharmacology

42. β-LACTAMSE INHIBITORS. • CLAVULANIC ACID. • SULBACTAM. • TAZOBACTAM. Department of Pharmacology

43. POINTS TO REMEMBER. • The choice of antibiotics. • Correct dosage mode of administration. schedule of dosage & duration of therapy. • Clear prescription. • Existing prescription& concurrent illness( predisposing factors.) • Significance of laboratory support. • Side effects: safety factors and FDA clearance proven due as most of the unwanted side effects are due to negligence, ignorance nature of doctor and lack of knowledge. • Combination therapy. Department of Pharmacology

44. Considerations IN SELECTION OF AN ANTIMICROBIAL DRUG • Consider toxicities and adverse effects • Consider ‘cidal’ versus ‘static’ as well as broad versus narrow spectrum • Consider COST!!!!! • the cheapest that is effective and tolerated should be used • GOAL: pick a selectively active drug against most likely invading microbe .... with least effect on host! • is a antimicrobial is needed?? • Antibacterials shouldn’t be used for viral infections!! • Don’t use antimicrobials as antipyretics!!... fever is produced by disorders other than infections • Use ‘enough’ of the narrowest antimicrobial long enough to prevent development of resistant forms Department of Pharmacology

45. How is antimicrobial therapy used? • DEFINITIVE • Know the organism and susceptibilities • Use a narrow spectrum agent • EMPIRIC • Organism not yet identified and have sent off cultures • Use a broader spectrum agent • PROPHYLACTIC • Prevent initial or recurrent infection • Spectrum of agent depends on situation Department of Pharmacology

46. EMPIRIC THERAPY • Giving antimicrobials prior to definitive diagnosis (culture results). It should cover all the likely pathogens, because the infecting organism has not been identified. • Advantages: • Infections best treated early • Easier to kill when a small number • Tissue destruction may occur with long infection. • Rapid therapy may be life-saving Department of Pharmacology

47. EMPIRIC THERAPY: Disadvantages • Whenever the clinician is faced with initiating therapy on a presumptive bacteriological diagnosis, cultures of the presumed site of infection and blood should be taken prior to the institution of drug therapy. • Unnecessary toxicity and cost of therapy • Increased resistance in community (unnecessary exposure) Department of Pharmacology

48. EMPIRIC THERAPY • Couple of situations where empiric therapy is highly justified • Neutropenic, febrile cancer patients • Community acquired pneumonia Department of Pharmacology

49. PROPHYLACTIC THERAPY • Prophylaxis to protect healthy folks after exposure to a disease • Prevent endocarditis in pts with valvular heart disease who are undergoing procedures that produce a high incidence of bacteremia (before procedure) • Prevent wound infections that might occur after surgical procedures (bowel surgery) • Anthrax, malaria, cholera, rheumatic fever, plague, others Department of Pharmacology

50. Prophylaxsis • Centers for Disease Control and Prevention (CDC) recommendations: • early involvement of infectious disease experts, • antibiotic selection based on local patterns of susceptibility, • proper antiseptic technique • appropriate use of prophylactic antibiotics in surgical procedures, • infection control procedures to isolate the pathogen, • strict compliance to hand hygiene. • appropriate use of vaccination, • judicious and proper use of indwelling catheters Department of Pharmacology