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Antimicrobial Agents and Antimicrobial Resistance.pptx

  1. By Dr. Rakesh Prasad Sah, Associate Professor, Microbiology
  2.  Antimicrobials/anti-infectives: These are umbrella terms for drugs with activity against microorganisms. They include antibacterials, antivirals, antifungals, and antiparasitic agents. Antibiotic: Chemical Substance  m.os./chemical synthesis kill or inhibit growth of m.os. low concn Chloramphenicol  Streptomyces venezuelae chemical methods.
  3. Classification of Antibiotics
  4.  Broad spectrum: For example: tetracyclines are active against many gram- negative rods, chlamydiae, mycoplasmas, and rickettsiae.  Narrow spectrum: For example: vancomycin is active against certain gram- positive cocci, namely, Staphylococci and Streptococci. Classification of Antibiotics
  5.  Antibiotics have one of two effects on the growth and viability of microorganisms:  Bacteriostatic - slows growth or prevents multiplication; not the cure; cure results from combined action of drug and host's defense mechanisms, like phagocytosis.  Bacteriocidal - usually effective only for growing microbes; ineffective dormant cells. Classification of Antibiotics
  6. Penicillins produced by mold Penicillium Cephalosporins produced by mold Cephalosporium Bacitracin produced by Bacillus licheniformis Polymyxins produced by Bacillus polymyxa Aminoglycosides produced by Streptomyces griseus Tetracyclines produced by Streptomyces Chloramphenicol produced by Streptomyces venezuelae Macrolides - (Erythromycin) produced by Streptomyces erythreus Rifamycins produced by Streptomyces mediterrani
  7. 1. Selective toxicity: against target pathogen but not against host.  LD50 vs. MIC  Therapeutic index: (the lowest dose toxic to the patient divided by the dose typically used for therapy).  High therapeutic index  less toxic 2. Bactericidal vs. Bacteriostatic. (Static rely on normal host defences to kill or eliminate the patogen after its growth has been inhibited. (UTIs) CIDAL given when host defenses cannot be relied on to remove or destroy pathogen.)
  8. 1. Favorable pharmacokinetics: reach target site in body with effective concentration. 2. Spectrum of activity: broad vs. narrow. 3. Little resistance development. 4. Lack of “side effects” allergic, toxic side effects, suppress normal flora. 5. There is no perfect drug
  9.  Can be classified as:- 1) Cell wall synthesis inhibition 2) Acting on Cytoplasmic Membrane 3) Protein synthesis inhibition 4) Nucleic acid synthesis inhibition 5) Antimetabolites
  10. DRUGS MECHANISM OF ACTION CellWall Synthesis Inhibition β-lactam antibiotics (Penicillin, cephalosporins) Bind to receptors (penicillin binding proteins present on the inner layer of cytoplasmic membrane) and leads to interference with the synthesis of peptidoglycan of cell wall. Cell membrane vulnerable to damage by solutes of the plasma. Acting on Cytoplasmic Membrane Binds to plasma membrane & disrupts its structure and permeability properties.
  11. DRUGS MECHANISM OF ACTION Protein Synthesis Inhibition A. Inhibitors of Transcription (Rifampicin) Inactivates DNA-dependent RNA polymerase thus inhibiting transcription. B. Inhibitors of Translation Inhibit 30S ribosome Inhibit 50S ribosome Combine with 30S and 50S components of ribosomes and lead to malfunctioning of ribosomes. Affects initiation, elongation or termination of peptide chain leading to inhibition of protein synthesis and cell dies. (Streptomycin, kanamycin, amikacin, tobramycin, tetracycline, doxycycline) (Erythromycin, Azithromycin, Chloramphenicol and lincomycin.)
  12. DRUGS MECHANISM OF ACTION Nucelic Acid Synthesis Inhibition (Quinolones & Fluroquinolones) Norfloxacin, Ciprofloxacin, Ofloxacin Etc Inhibit DNA gyrase and thus blocking DNA synthesis. Antimetabolites Sulfonamides Trimethoprim Dapson Inhibit folic acid synthesis by competing with p-aminobenzoic acid (PABA). Blocks folic acid synthesis by inhibiting the enzyme tetrahydrofolate reductase . Thought to interfere with folic acid synthesis.
  13. Mechanisms of action of antibiotics Interference of cell wall synthesis Inhibition of cytoplasmic membrane function Inhibition of protein synthesis Inhibition of DNA function Metabolic antagonists Penicillins Polymyxin Streptomycin Nalidixic acid Sulphonamide Cephalosporins Nystatin Kanamycin Norfloxacin Dapsone Bacitracin Amphotericin B Amikacin Ciprofloxacin PAS Vancomycin Neomycin Novobiocin Isoniazid Cycloserine Tobramycin Metrozidazole Trimethoprim Doxycycline Minocycline Erythromycin Chloramphenicol
  14.  Penicillins:  Bacteriocidal and inhibits synthesis of cell wall.  Toxicity to humans - has least of any antimicrobial drug for host cells, most serious side-effect is allergic reactions.  Both natural and semi-synthetic forms. Common β-lactam ring nucleus for all penicillins; side groups vary.
  15. Naturals are very narrow spectrum and susceptible to penicillinases, which cleave the β-lactam ring rendering the drug inactive. PenicillinV is preferred for oral administration as it is resistant to acid hydrolysis.
  16. Semi-synthetic penicillin’s are designed to: * increase range of action to include effectiveness against Gram- negative bacteria (e.g. Ampicillin); or * resistance to Penicillinases (e.g. Methicillin).
  17.  Related to penicillins.  Bacteriocidal and their MOA is similar to penicillins  Broad spectrum (active against both Gram positive and Gram negative).  E.g.
  18. Cephalosporins Antibacterial spectrum First generation Cephalexin, Cephaloridine, Cefadroxil, Cepharadine, Cephalothin, Cephazolin Staph. aureus, Streptococci (other than enterococci), E. coli, Klebsiella, Proteus mirabilis and H. influenzae Sencond generation Cefamandole, Cefoxitin, Cefuroxime, Cefonicid, Ceforanide, Cefaclor, Cefprozil, Cefmetazole, Cefotetan etc. First generation spectrum and Proteus, Enterobacter, Citrobacter, Serratia and Gram negative anaerobes. Third generation Cefotaxime, cefoperazone, ceftizome, ceftazidime, Ceftriaxone, Cefixime, Ceftibuten, Cefpodoxime etc. Second generation spectrum and N. gorrhoeae including beta lactamase producing strains, Ps. aeruginosa. Fourth generation Cefepime, Cefpriome, Ceftaroline, Ceftobiprole etc Third generation spectrum including enhanced activity against Enterobacter and Citrobacter spp. that are resistant to third generation cephalosporins.
  19. Polymyxin :  Act as cationic detergents; integrate within & disrupt outer membrane.  Causes loss of osmotic function & selective membrane permeability.  Unique in being Bacteriocidal in absence of cell growth.  More effective against gram negatives than gram positives (due to more LPS in gram negatives)  Toxicity - damages kidneys
  20. Aminoglycosides Macrolides
  21.  Inhibit Transcription  Toxicity - occasional rashes, platelet decrease & some decline in liver function may occur.  Imparts an orange color to urine and sweat.  Example: Rifampicin
  22.  MAO is by inhibiting protein synthesis of bacteria.  Broad-spectrum; Bactericidal.  Side effects: nephron- and oto-toxicity  Example:  Streptomycin  Gentamycin  Amikacin  Kanamycin
  23.  MAO is by inhibiting protein synthesis of bacteria.  Broad-spectrum; inhibits only rapidly multiplying bacteria (Bacteriostatic).  Highly effective against rickettsial and chlamydial infections.  Problems with tetracyclines are: 1. inhibition of normal flora leads to "superinfection“ 2. weakening of bone structure (esp. true in growing children); 3. photosensitivity in some hosts.  Example: Tetracycline, Doxycycline, Minocycline
  24.  MAO is by inhibiting protein synthesis of bacteria.  Primarily Bacteriostatic  Less effective than penicillins, yet good alternative in cases of penicillin allergy.  Problem - numbers of resistant mutants arise with use.  Example: Erythromycin, Azithromycin
  25. Quinolones:  Binds and inhibits activity of DNA gyrase.  Bacteriostatic & Bacteriocidal.  Example:  Nalidixic acid  Norfloxacin  Ciprofloxacin  Ofloxacin  Levofloxacin.
  26. Sulfonamides:  p-aminobenzoic acid (PABA) is the substrate in the essential synthesis of folic acid in most bacteria.  Sulfonamides are structural analogs of PABA; act as competitive inhibitors.  No effect on human cells; we cannot synthesize folic acid, but rather obtain folic acid in diet.  Bacteriostatic  Example: Sulphamethoxazole Trimethoprim:  Inhibits conversion of dihydrofolic acid to tetrahydrofolic acid.  Bacteriocidal
  27.  Refers to development of resistance to an antimicrobial agent by a microorganism.  Two types  Acquired  Intrinsic
  28.  Emergence of resistance in bacteria  ordinarily susceptible to antimicrobial agents  by acquiring the genes coding for resistance.  Most of AMR  shown by bacteria  belongs to this group.  Infection caused by resistant microorganisms often fail to respond to the standard treatment, resulting in  Prolonged illness  Higher healthcare expenditures  Greater risk of death
  29.  Overuse and misuse of antimicrobial agents  single most important cause of development of acquired resistance. (natural phenomenon )  Resistant bacterial populations flourish in areas of high antimicrobial use  where they enjoy a selective advantage over susceptible populations.  Resistant strains then spread in the environment and transfer the genes coding for resistance to other unrelated bacteria.
  30.  Other factors favouring AMR  Poor infection control practices in hospitals ▪ e.g. Poor hand hygiene practices  facilitate transmission of resistant strains.  Inadequate sanitary conditions  Inappropriate food-handling  Irrational use of antibiotics by doctors not following AST report.  Uncontrolled sale of antibiotics over the counters without prescription.
  31.  Refers to the innate ability of a bacterium to resist a class of antimicrobial agents due to its inherent structural or functional characteristics, (e.g. Gram negative bacteria  resistant to Vancomycin).  Is non-transferable.  In +ce of selective antibiotic pressure, bacteria acquire new genes by two methods:-  Mutational Resistance  Transferrable drug Resistance
  32.  Resistance developed due to mutation of the resident genes.  E.g. Mycobacterium tuberculosis – ATT  Usually, Low level resistance, developed to one drug at a time-overcome by using combination of different classes of drugs.
  33.  is plasmid coded - transferred by  conjugation or rarely transduction, transformation.  Resistance coded plasmid (called R plasmid) –  carry multiple genes,  each coding for resistance to one class of antibiotic.  Results in high degree of resistance to multiple drugs, which cannot be overcome by using combination of drugs.
  34.  S.No. Mutational drug resistance Transferable drug resistance 1 Resistance to one drug at a time Multiple drug resistance at the same time 2 Low-degree resistance High-degree resistance 3 Resistance can be overcome by combination of drugs Cannot be overcome by drug combinations 4 Virulence of resistance mutants may be lowered Virulence not decreased 5 Resistance is not transferable to other organisms but spread to off- springs by vertical spread only Resistance is transferable to other organisms. Spread by: Horizontal spread (conjugation, or rarely by transduction/transformation)
  35. Decreased Permeability across the Cell Wall :  Bacteria modify their cell membrane porin channels - either in frequency, size, or selectivity Preventing the antimicrobials from entering into the cell.  Seen in Pseudomonas, Enterobacter and Klebsiella species against drugs, such as imipenem, aminoglycosides and quinolones.
  36. Efflux Pumps:  Mediate expulsion of the drugs from the cell - thereby preventing the intracellular accumulation of drugs.  Escherichia coli and other Enterobacteriaceae  against tetracyclines, chloramphenicol  Staphylococci  against macrolides and streptogramins  Staph aureus and Strept pneumoniae  against fluoroquinolones.
  37. By Enzymatic Inactivation :  β lactamase enzyme production - It breaks down the β lactam rings  inactivating the β lactam antibiotics.  Aminoglycoside modifying enzymes - destroy the structure of aminoglycosides  Chloramphenicol acetyl transferase - destroys the structure of chloramphenicol.
  38. By Modifying target sites:  MRSA -Target site of penicillin i.e. penicillin binding protein (PBP) gets altered to PBP-2a.  Streptomycin resistance in Mycobacterium tuberculosis- due to modification of ribosomal proteins or 16S rRNA.  Rifampicin resistance in Mycobacterium tuberculosis- due to mutations in RNA polymerase.