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Antimicrobial Agents and Resistance.pptx

  1. 1. Antimicrobial Agents and Resistance Dr. Krithikaa Sekar, MD, Assistant Professor, Microbiology, SLMCH
  2. 2. Definitions • Antibiotic – Substance of biological origin like fungi and Actinomycetes which inhibits the growth of other organisms • Antimicrobial agent – Any compound - natural or synthetic or semi synthetic that is active against microorganisms • Chemotherapeutic agent – Synthetic chemical • Bacteriostatic agents (Sulphonamides &Chloramphenicol) - inhibits the growth of microorganisms • Bactericidal agent – Kills microorganisms • Therapeutic index - The ratio of the dose toxic to the host to the effective therapeutic dose.
  3. 3. History of Antimicrobial Therapy • 1909 Paul Ehrlich • Differential staining of tissue, bacteria • Search for magic bullet that would attack bacterial structures, not ours. • Developed salvarsan, used against syphilis.
  4. 4. • 1929 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
  5. 5. Sir Alexander Fleming
  6. 6. Fleming’s Petri Dish
  7. 7. Historical distinctions • Antibiotics: substances produced by organisms that have inhibitory effects on other organisms. • Penicillin, streptomycin • Synthetic drugs: produced in a lab. • Salvarsan, sulfa drugs • Nowadays, most antimicrobials are semi-synthetic • Distinction between “antibiotics” and “synthetic drugs” slowly being abandoned.
  8. 8. Where do antibiotics come from? • Several species of fungi including Penicillium and Cephalosporium • E.g. penicillin, cephalosporin • Species of actinomycetes, Gram positive filamentous bacteria • Many from species of Streptomyces • Also from Bacillus, Gram positive spore formers • A few from myxobacteria, Gram negative bacteria • New sources explored: plants, herps, fish
  9. 9. Mechanism of Action of Antibiotics
  10. 10. VI. Antibacterial Agents A. Inhibitors of cell wall synthesis 1. Penicillins 2. Cephalosporins 3. Other antibacterial agents that act on cell walls B. Disrupters of cell membranes 1. Polymyxins 2. Tyrocidins C. Inhibitors of protein synthesis 1. Aminoglycosides 2. Tetracyclines 3. Chloramphenicol 4. Other antibacterial agents that affect protein synthesis a. Macrolides b. Lincosamides D. Inhibitors of nucleic acid synthesis 1. Rifampin 2. Quinolones E. Antimetabolites and other antibacterial agents 1. Sulfonamides 2. Isoniazid 3. Ethambutol 4. Nitrofurans
  11. 11. Antibiotic Mechanisms of Action Transcription Translation Translation Alteration of Cell Membrane Polymyxins Bacitracin Neomycin
  12. 12. 1-Inhibition of cell wall synthesis • beta-lactam containing antibiotics inhibit transpeptidase; bacteria cannot synthesize reinforced cell wall and they lyse when they try to grow • Vancomycin and cyclo-Ser inhibit specific binding of Ala’s in crossbridges to transpeptidase in many gram+ bacteria • Bacitracin inhibits secretion of NAG and NAM subunits • All of these only kill growing bacteria
  13. 13. Inhibition of cell wall synthesis Betalactum antibiotics • Penicillin • Cephalosporins • Other betalactum antibiotics like Carbapenum (Imipenum, Meropenum) Monobactams-aztreonam Other inhibitors • Isoniazid and Ethionamide– block mycolic acid synthesis • Ethambutol – interferes synthesis of arabinogalactan of cell wall • Cycloserine – inhibits D- alanine synthetase and alanine racemase important for cell wall synthesis
  14. 14. Cell wall synthesis inhibitors
  15. 15. Inhibition of Cytoplasmic Membrane synthesis • Polymyxin B • Polymyxin E1 • Amphotericin B • Imidazoles • Triazoles • Polyenes
  16. 16. Antibacterial Agents
  17. 17. 1. Penicillins • Penicillins contain a b-lactam ring which inhibits the formation of peptidoglycan crosslinks in bacterial cell walls (especially in Gram-possitive organisms) • Penicillins are bactericidal but can act only on dividing cells • They are not toxic to animal cells which have no cell wall
  18. 18. Synthesis of Penicillin  b-Lactams produced by fungi, some ascomycetes, and several actinomycete bacteria  b-Lactams are synthesized from amino acids valine and cysteine
  19. 19. b Lactam Basic Structure
  20. 20. Penicillins Resistance • This is the result of production of b-lactamase enzyme in the bacteria which destroys the b-lactam ring • It occurs in e.g. Staphylococcus aureus, Haemophilus influenzae and Neisseria gonorrhoea
  21. 21. Penicillins Examples • There are now a wide variety of penicillins, which may be acid labile (i.e. broken down by the stomach acid and so inactive when given orally) or acid stable, or may be narrow or broad spectrum in action • Benzylpenicillin (Penicillin G) is acid labile and b-lactamase sensitive and is given only parenterally • It is the most potent penicillin but has a relatively narrow spectrum covering Strepptococcus pyogenes, S. pneumoniae, Neisseria meningitis or N. gonorrhoeae, treponemes, Listeria, Actinomycetes, Clostridia
  22. 22. Penicillins Examples • Phenoxymethylpenicillin (Penicillin V) is acid stable and is given orally for minor infections • it is otherwise similar to benzylpenicillin • Ampicillin is less active than benzylpenicillin against Gram-possitive bacteria but has a wider spectrum including (in addition in those above) Strept. faecalis, Haemophilus influenza, and some E. coli, Klebsiella and Proteus strains • It is acid stable, is given orally or parenterally, but is b-laclamase sensitive
  23. 23. Penicillins Examples • Amoxycillin is similar but better absorbed orally • It is sometimes combined with clavulanic acid, which is a b-lactam with little antibacterial effect but which binds strongly to b-lactamase and blocks the action of b-lactamase in this way • It extends the spectrum of amoxycillin
  24. 24. 2. Cephalosporins • They also owe their activity to b-lactam ring and are bactericidal. • Produced from a fungus Cephalosporium acremonium. • Good alternatives to penicillins when a broad - spectrum drug is required • should not be used as first choice unless the organism is known to be sensitive
  25. 25. Cephalosporins • BACTERICIDAL- modify cell wall synthesis • Interfere at the final step of peptidoglycan synthesis ( Transpeptidation) • CLASSIFICATION- first generation are early compounds • Second generation- resistant to β-lactamases • Third generation- resistant to β-lactamases & increased spectrum of activity • Fourth generation- increased spectrum of activity
  26. 26. Cephalosporins • FIRST GENERATION- eg cefadroxil, cefalexin, Cefadrine - most active vs gram +ve cocci. An alternative to penicillins for staph and strep infections; useful in UTIs • SECOND GENERATION- eg cefaclor and cefuroxime. Active vs enerobacteriaceae eg E. coli, Klebsiella spp,proteus spp. May be active vs H influenzae and N meningtidis • THIRD GENERATION- eg cefixime and other I.V.s cefotaxime,ceftriaxone,ceftazidine. Very broad spectrum of activity inc gram -ve rods, less activity vs gram +ve organisms. • FOURTH GENERATION- cefpirome better vs gram +ve than 3rd generation. Also better vs gram -ve esp enterobacteriaceae & pseudomonas aerugenosa. I.V. route only • FIFTH GENERATION- Ceftaroline, Ceftabiprole- four generation spectrum plus Pseudomonas and MRSA
  27. 27. 3. Aminoglycosides a) Mode of action - Irreversibly bind to the 30S ribosome and freeze the 30S initiation complex, slow down protein synthesis that has already initiated and induce misreading of the mRNA. b) Spectrum of Activity - Many gram-negative and some gram-positive bacteria; Not useful for anaerobic or intracellular bacteria c)Resistance – Common d) Synergy - Synergize with β-lactam antibiotics which inhibit cell wall synthesis and thereby increase the permeability of the aminoglycosides
  28. 28. 4. Tetracycline a) Mode of action - Reversibly bind to the 30S ribosome and inhibit binding of aminoacyl-t-RNA to the acceptor site on the 70S ribosome. b)Spectrum of activity - Broad spectrum; Useful against intracellular bacteria c) Resistance - Common d) Adverse effects - Destruction of normal intestinal flora resulting in increased secondary infections; staining and impairment of the structure of bone and teeth
  29. 29. 5. Other Antibiotics Macrolides (bacteriostatic) 1)Erythromycin a) Mode of action - The macrolides inhibit translocation. b) Spectrum of activity - Gram-positive bacteria, Mycoplasma, Legionella c) Resistance – Common 2)Azithromycin – S.pyogenes and S.pneumoniae 3)Clarithramycin – H.pylori gastritis & M.intracellulare
  30. 30. Other Antibiotics Chloramphenicol, lincomycin, clindamycin (bacteriostatic) a) Mode of action – They bind to the 50S ribosome and inhibit peptidyl transferase activity. b) Spectrum of activity 1) Chloramphenicol - Broad range 2) Lincomycin -and clindamycin - Restricted range c) Resistance - Common d) Adverse effects - Chloramphenicol is toxic (bone marrow suppression) but it is used in the treatment of bacterial meningitis.
  31. 31. Other Antibiotics- Vancomycin • This interferes with bacterial cell wall formation and is not absorbed after oral administration and must be given parenterally. • It is excreted by the kidney. • It is used i.v. to treat serious or resistant Staph. aureus infections and for prophylaxis of endocarditis in penicillin-allergic people.
  32. 32. Other Antibiotics- Quinolones (bactericidal) nalidixic acid, ciprofloxacin, ofloxacin, norfloxacin, levofloxacin, lomefloxacin, sparfloxacin • Mode of action - These antimicrobials bind to the A subunit of DNA gyrase (topoisomerase) and prevent supercoiling of DNA, thereby inhibiting DNA synthesis. • Spectrum of activity - Gram-positive cocci and urinary tract infections • Resistance - Common for nalidixic acid; developing for ciprofloxacin
  33. 33. (cont’d) Mechanism of Action INHIBITION OF DNA/RNA SYNTHESIS
  34. 34. Quinolones Examples and clinical pharmacokinetics • Nalidixic acid, the first quinolone, is used as a urinary antiseptic and for lower urinary tract infections, as it has no systemic antibacterial effect. • Ciprofloxacin is a fluoroquinolone with a broad spectrum against Gram-negative bacilli and Pseudomonas, • It can be given orally or i.v. to treat a wide range of infections, including respiratory and urinary tract infections as well as more serious infections, such Salmonella. • Activity against anaerobic organism is poor and it should not be first choice for respiratory tract infections.
  35. 35. Other Antibiotics- Metronidazole • Metronidazole binds to DNA and blocks replication. • Metronidazole is active against anaerobic organisms (e.g. Bacteroides, Clostridia), which are encountered particularly in abdominal surgery. • It is also used against Trichomonas, Giardia and Entamoeba infections. • Increasingly, it is used as part of treatment of Helicobacter pyloris infestion of the stomach and duodenum associated with peptic ulcer disease. • It is used also to treat a variety of dental infections, particularly dental abscess
  36. 36. Other Antibiotics- Nitrofurantoin • This is used as a urinary antiseptic and to treat Gram-negative infections in the lower urinary tract. It is also used against Trypanosoma infections. • It is taken orally and is well absorbed and is excreted unchanged in the urine.
  37. 37. Other Antibiotics- Sulfonamides and trimethoprim • Sulfonamides are rarely used alone today. • Trimethoprim is not chemically related but is considered here because their modes of action are complementary.
  38. 38. Sulfonamides, Sulfones (bacteriostatic) • Mode of action - These antimicrobials are analogues of para- aminobenzoic acid and competitively inhibit formation of dihydropteroic acid. • Spectrum of activity - Broad range activity against gram-positive and gram-negative bacteria; used primarily in urinary tract and Nocardia infections. • Resistance - Common • Combination therapy - The sulfonamides are used in combination with trimethoprim; this combination blocks two distinct steps in folic acid metabolism and prevents the emergence of resistant strains.
  39. 39. Trimethoprim, Methotrexate, (bacteriostatic) • Mode of action - These antimicrobials binds to dihydrofolate reductase and inhibit formation of tetrahydrofolic acid. • Spectrum of activity - Broad range activity against gram- positive and gram-negative bacteria; used primarily in urinary tract and Nocardia infections. • Resistance - Common • Combination therapy - These antimicrobials are used in combination with the sulfonamides; this combination blocks two distinct steps in folic acid metabolism and prevents the emergence of resistant strains.
  40. 40. p-aminobenzoic acid + Pteridine Dihydropteroic acid Dihydrofolic acid Tetrahydrofolic acid Pteridine synthetase Dihydrofolate synthetase Dihydrofolate reductase Thymidine Purines Methionine Trimethoprim Sulfonamides
  41. 41. Sulfonamides and trimethoprim Mode of action • Folate is metabolized by enzyme dihydrofolate reductase to the active tetrahydrofolic acid. • Trimethoprim inhibits this enzyme in bacteria and to a lesser degree in animal s, as the animal enzyme is far less sensitive than that in bacteria.
  42. 42. Other Antibiotics- Antitubercular Drugs
  43. 43. Antibacterial Resistance
  44. 44. 48 DEFINITION • is the ability of the parasite to survive and/or multiply despite the administration and absorption of a drug given in doses that is equal to or higher than those usually recommended
  45. 45. 49 Mechanism • produces enzymes that destroy the active drug eg.,Staphylococci’s beta lactamases destroying Penicillin • Alteration in permeability eg., Tetracycline accumulates in susceptible bacteria not in resistant bacteria • Developing altered structural target for the drug eg., erythromycin resistant bug having an altered receptor on 50s subunit of the ribosome • Developing an altered metabolic pathway eg.,sulfonamide resistant organism utilizing preformed folic acid • Developing an altered enzyme that are much less affected by the drug
  46. 46. 50 Origin • NON GENETIC ORIGIN: -non multiplying organism resistant to drugs -cell wall deficient strains are resistant to cell wall inhibitors -intracellular organisms resistance to aminoglycosides • GENETIC ORIGIN: -chromosomal by means of mutation -Extra chromosomal by means of plasmids
  47. 47. 52 Cross resistance • Micro organisms resistant to a certain drugs may also be resistant to other drugs that share a mechanism of action eg., tetracyclines
  48. 48. 53 Genetic basis of resistance • CHROMOSOMAL : -spontaneous mutation in locus controlling susceptibility to the drug -presence of drug favour growth of mutant -causes a change in structural receptor of the drug -eg., loss of PBP resulting resistance to beta lactum drugs etc.,
  49. 49. 54 • EXTRA CHROMOSOMAL: -R Plasmid associated - carry genes for one or multiple drug resistance -often forms enzymes capable of destroying drugs- beta lactamase -codes for enzymes that Acetylate, adenylylate, or phosporylate aminoglycosides -enzymes determining active transport of Tetracycline across cell wall
  50. 50. 55 Continues… • R plasmids are transferred by: Transduction Transformation Conjugation Transposition
  51. 51. 56 Tranposons • Movable DNA elements carrying genes • Has ability to ‘hop’ from plasmid to plasmid and between plasmid to chromosomes- JUMPING GENE • May carry single or multiple resistance • Can enter and remain stable in different species, hence spreads R markers throughout the bacterial kingdom
  52. 52. 57 • Generally chromosomal resistance is SINGLE, LOW LEVEL usually NON ENZYMATIC • Plasmid or Transposon resistance are HIGH LEVEL, MULTIPLE and ENZYMATIC
  53. 53. 58 Methicillin Resistant Staphylococcus aureus • MRSA/ORSA • Independent of beta lactamase production • Due to mecA gene presence on the chromosome • Causes lack or inaccessibility of certain PBPs in the organism • Shows resistance to other as well • Mainly colonized groin, axilla, perineum esp., HCW • Susceptible to glycopeptide antibiotics like vancomycin, teicoplanin etc.,
  54. 54. 59 Multi Drug Resistant Tuberculosis • MDR-TB • Primary drug resistance in M.tb occurs in 10% of isolates commonly to H and S • H and R are the primary drugs in most of the regimens • Resistance to H and R is considered as MDR-TB • Resistance to other drugs also seen • Highest rates are seen in Nepal, India, New York etc., • Due to alterations in genes eg., cat gene for H etc., • Poor compliance is responsible • Significant world wide problem
  55. 55. 60 Extended Spectrum ß Lactamase • Kind of ß Lantanas produced by GNB confers resistance to III generation cephalosporins and aztreonam • All sensitive to carbapenam drugs • Either plasmid or chromosomal mediated
  56. 56. Antifungal Agents A. Imidazoles and triazoles B. Polyenes 1. Amphotericin B 2. Nystatin C. Griseofulvin D. Other antifungal agents 1. Flucytosine 2. Tolnaftate 3. Terbinafine Antiviral Agents A. Purine and pyrimidine analogues 1. Idoxuridine and trifluridine 2. Vidarabine 3. Ribavirin 4. Acyclovir 5. Ganciclovir 6. Zidovudine B. Amantadine C. Treatment of AIDS
  57. 57. URL- Lecture Handouts and MCQs • https://drive.google.com/file/d/175pHcNcPkMvQiEVVczDhxgD20V1g aiCT/view?usp=sharing • https://drive.google.com/file/d/1rrztZ- aOOlDmXvQfBngCH9FGinGflZBd/view?usp=sharing