lesson 1 Introduction and General Principle of antimicrobial therapy (1).pptx

principles of antimicrobial therapy

1. Anti m icrobial s Dr . J. Murigi

2. ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● Key Concepts History Definition Chemotherapy , Antimicrobial activity, Bacteriostatic agents, Bactericidal agents, MIC, MBC, Antimicrobi Chemotherapeutic index, Antibiotic resistance Superinfections, PAE Classification & Mechanism of Action. Mechanism of Drug Resistance. Selection of an Antimicrobial Agent. 8

3. Chemotherapy Chemotherapy : is the drug treatment for the diseases caused by bacteria and the other pathologic microorganisms, parasites , fungal and other . It is a therapy with a drug of chemical synthesis . Actually, it is a therapy (made of synthetic or extracted substances ) aimed at destroying harmful living agents e.g ., infectious agents or cancer cells.

4. The objective of chemotherapy is to study and to apply the drugs that have highly selective toxicity to the pathogenic microorganisms in host body and have no or less toxicity to the host, so as to prevent and cure infective diseases caused by pathogens .

5. ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● Antimicrobial agents: chemical substances that can kill or suppress the growth of microorganisms Antimicrobials are drugs that destroy microbes , prevent their multiplication or growth , or prevent their pathogenic action Differ in their physical, chemical, & pharmacological properties Differ in antibacterial spectrum of activity Differ in their mechanism of action 20 What are Antimicrobials???

6. Antibiotics “Antibiotic” is from antibiosis, meaning against life . Substances produced by various species of microorganisms: bacteria, fungi— to kill or suppress the growth of other microorganisms . It soluble substance . They selectively suppress the growth of or kill other microorganisms at very low concentrations Today the term antibiotic extends to include synthetic antibacterial agents : sulfonamides and quinolones.

7. ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● 1928 Penicillin 1945 Nobel Prize 1955 buried in St. Paul's Cathedral, United Kingdom Gitausc, PhD History of Chemotherapy 13

8. History of Antimicrobial Therapy 1928 Penicillin discovered by Alexander Fleming 1940 Florey and Chain mass produce penicillin for war time use, becomes available to the public. 1935 Sulfa drugs discovered 1944 Streptomycin discovered by Waksman from Streptomyces griseus

9. THE HISTORY Antimicrobials have been used for millennia to treat infections. Various moulds and plant extracts were used to treat infections by some of the earliest civilisations – the ancient Egyptians, for example, applied mouldy bread to infected wounds. Nevertheless, until the 20th century, infections that we now consider straightforward to treat – such as pneumonia and diarrhoea – that are caused by bacteria, were the number one cause of human death in the developed world.

10. Alexander Fleming was, it seems, a bit disorderly in his work and accidentally discovered penicillin. Upon returning from a holiday in Suffolk in 1928, he noticed that a fungus, Penicillium notatum , had contaminated a culture plate of Staphylococcus bacteria he had accidentally left uncovered. The fungus had created bacteria-free zones wherever it grew on the plate. Fleming isolated and grew the mould in pure culture. He found that P. notatum proved extremely effective even at very low concentrations, preventing Staphylococcus growth even when diluted 800 times, and was less toxic than the disinfectants used at the time.

11. Classification of antimicrobial agents Based on mechanism of action Based on therapeutic use/organisms affected Based on spectrum of activity Based on type of action Antimycobacterial agents Based on source Based on Chemical structure

12. ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● Classification --- chemically 21

13. ● ● ● ● ● ● ● ● ● ● ● 22 ● ● ● ● ● ● ● ● Classification- - - chemically

14. ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● Classification… MoA 23

15. ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● Classification…Types of organisms 24

16. ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● Classification…Spectrum of activity 25

17. ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● Classification…..Type of action 26

18. ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● Classification…..Sources Gitausc, PhD 27

19. ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● Bacteriostatic drugs Bactericidal drugs Growth Replication Gitausc, PhD 30 Kill Basic Concept

20. Effects of bactericidal and bacteriostatic drugs on the growth of bacteria in vitro.

21. Types of Bacteria Aerobic bacteria needs oxygen to survive Anaerobic bacteria survives in the absence of oxygen

22. Bacteria Shapes Round cocci Rod-like bacilli Spiral-shaped spirochetes

23. SELECTION OF ANTIMICROBIAL AGENTS Selection of the most appropriate antimicrobial agent requires knowing: - the organism’s identity. the organism’s susceptibility to a particular agent. the site of the infection. patient factors e.g. age , weight , pregnancy or breast- feeding , hepatic and renal status , etc. the safety of the agent. the cost of therapy. However, some patients require empiric therapy (umbrella therapy)—that is, immediate administration of drug(s) prior to bacterial identification and susceptibility testing.

24. Effect of the site of infection on therapy: ( The blood-brain barrier ) Adequate levels of an antibiotic must reach the site of infection for the invading microorganisms to be effectively eradicated. Lipid solubility of the drug: lipid-soluble drugs, such as chloramphenicol and metronidazole, have significant penetration into the CNS. Molecular weight of the drug: high molecular weight (for example, vancomycin) penetrate poorly, even in the presence of meningeal inflammation. Protein binding of the drug.

25. ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ※ P ost A ntibiotic E ffect (PAE) – Delayed regrowth of bacteria following exposure to an antibiotic – Varies according to drug- bug combination Basic Concept 32

26. Superinfections 36 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● Refers to the appearance of a new infection as a result of antimicrobial therapy Use of most AMAs causes some alteration in the normal microbial flora of the body Normal flora contributes to host defence by elaborating substances called bacteriocins which inhibit pathogenic organisms Ordinarily, pathogen has to compete with the normal flora for nutrients, etc. to establish itself. Lack of competition allow even a normally non-pathogenic component of the flora, which is not inhibited by the drug (e.g. Candida), to predominate & invade.

27. Superinfections 37 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● Commonly associated with the use of broad/extended -spectrum antibiotics (tetracyclines, chloramphenicol, ampicillin, newer cephalosporins ( esp. when combined ) Tetracyclines are more liable than chloramphenicol Ampicillin is more liable than amoxicillin to cause superinfection diarrhoeas Why ?? Incomplete absorption allow higher amount to reach bowel) Common when host defence is compromised

28. ● Superinfections ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● Superinfection sites include; oropharynx; intestinal, respiratory & genitourinary tracts; occasionally skin…. WHY?? Normally harbour commensals /normal microflora Predisposing factors? 38

29. ● Treating superinfections 39 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● Candida albicans : monilial diarrhoea, thrush, vulvovaginitis; Rx: nystatin or clotrimazole Resistant staphylococci : enteritis: Rx: cloxacillin or vancomycin/linezolid Clostridium difficile : pseudomembranous enterocolitis due to clindamycin, tetracyclines, aminoglycosides, ampicillin : Rx with metronidazole + vancomycin Proteus : UTI , enteritis : Rx: cephalosporin or gentamicin Pseudomonas : UTI, enteritis : Rx with carbenicillin, piperacillin, ceftazidime, cefoperazone or gentamicin

30. ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● Minimizing superinfections 40 Use specific ( narrow- spectrum ) AMA whenever possible Do not use antimicrobials to treat trivial, self- limiting or untreatable (viral) infections Do not unnecessarily prolong antimicrobial therapy

31. ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● Biochemistry / Metabolism Structure / Function Growth / Proliferation Bacteriostatic / Bactericidal ※ 2. Mechanisms of Action 41

32. ● Inhibit cell wall synthesis Penicillins Cephalosporins Carbapenems Monobactams (aztreonam) Vancomycin Inhibit protein synthesis Chloramphenicol Tetracyclines Macrolides Clindamycin Streptogramins (quinupristin/dalfopristin) Oxazolidinones (linezolid) Aminoglycosides Interfered the permeability of the plasma membrane Amphotericin B polymyxins 46 Alter nucleic acid metabolism Rifamycins Quinolones Inhibit folate metabolism Trimethoprim Sulfamethoxazole Classification of Antimicrobials based o ● n M ● o ● A ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●

33. Safety of the agent Many of the antibiotics, such as the penicillins , are among the least toxic of all drugs because they interfere with a site unique to the growth of microorganisms. Other antimicrobial agents (for example, chloramphenicol ) are less microorganism specific and are reserved for life- threatening infections because of the drug’s potential for serious toxicity to the patient.

34. Cost of therapy Often several drugs may show similar efficacy in treating an infection, but vary widely in cost. Standard treatment of Helicobacter pylori includes various combinations of two or three antimicrobial agents along with a proton pump inhibitor. Figure illustrates relative cost of some drugs used for the treatment of peptic ulcers caused by H. pylori. It also demonstrates that a triple therapy regimen including clarithromycin is significantly more expensive than the bismuth subsalicylate based quadruple therapy.

35. Route of Administration The oral route of administration is chosen for infections that are mild and is favourable for treatment on an outpatient basis . In patients requiring a course of i.v therapy initially, the switch to oral agents should occur as soon as possible. However, some antibiotics, such as vancomycin , the aminoglycosides , and amphotericin B , are so poorly absorbed from the GIT that adequate serum levels cannot be obtained by oral administration . Parenteral administration is used for drugs that are poorly absorbed from the GIT and for treatment of patients with serious infections , for whom it is necessary to maintain higher serum concentrations of antimicrobial agents than can be reliably obtained by the oral route.

36. DETERMINANTS OF RATIONAL DOSING Rational dosing of antimicrobial agents is based on their pharmacodynamics (the relationship of drug concentrations to antimicrobial effects) and pharmacokinetic properties (the absorption, distribution, metabolism and elimination of the drug by the body). 1-Concentration-dependent killing : Certain antimicrobial agents, including aminoglycosides , show a significant increase in the rate of bacterial killing as the concentration of antibiotic increases from 4- to 64-fold the MIC of the drug for the infecting organism.

37. 2-Time-dependent (concentration-independent) killing: By contrast, β-lactams , glycol peptides , macrolides , clindamycin , and linezolid do not exhibit this concentration-dependent property; that is, increasing the concentration of antibiotic to higher multiples of the MIC does not significantly increase the rate of kill.

38. ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● If an inhibitory or bactericidal concentration exceeds that which can be achieved safely in vivo , then the microorganism is considered resistant to that drug. ※ Bact e rial Drug Resistance 59

39. ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● Intrinsic resistance: gene passage, never change Acquired resistance: plasmid, disappear Types of Bacterial Drug Resistance 60

40. ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ※ Mechanisms of Bacterial Drug Resistance 61

41. ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● (1) Permeable barrier 62 Porins

42. ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● Efflux pumps 63

43. ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● β- lactamase Aminoglycoside modifying enzyme Other enzymes (3) Drug inactivation 64

44. ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● Mutation of the natural target Target modification Acquisition of a resistant form of the native, susceptible target Increase the expression of target protein (4) Target alteration 65

45. ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● *Personally Reading Mutation Transduction Transformation Conjugation 67 4. Transfer of Resistance genes

46. ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● Empiric Infecting organism(s) not yet identified More “ broad spectrum ” Definitive Organism(s) identified & specific therapy chosen More “ narrow spectrum ” Prophylactic or preventative Prevent an initial infection or its recurrence after infection 68 Antimicrobial therapy

47. Is the Patient Infected ??? What to look out for?

48. ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● CAREFUL history & physical exam( + relevant laboratory data & signs and symptoms Temperature White blood cell count (WBC) WBC in normally sterile fluids (e.g. CSF) Any swelling or erythema at a particular site Purulent drainage from a visible site Patient complaints Predisposing factors – Surgery, procedures, physical limitation etc . 69

49. ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● Confirm the presence of infection History & physical Signs & symptoms Predisposing factors Identification of pathogen Collection of infected material Stains Serologies Culture & sensitivity 70 Selecting an AMA

50. ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● Selection of presumptive therapy Drug factors Host factors Monitor therapeutic response Clinical assessment Lab tests Assessment of therapeutic failure 71 Selecting an AMA

51. ● ● ● ● ● ● ● ● ● ● ● Drug Host (patient) Infectious pathogen Antimicrobial effects resistance The relationship of Host- Dr u G i g t a - u P s c a , P t h h D ogen in chemotherapy 72 Selecting ● ● a n ● A ● M ● A ● ● ●