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RECENT ADVANCES IN                   ANTIBACTERIALS<br /> Dr.Harmanjit Singh<br />Department of Pharmacology<br />GMC, Pat...
INTRODUCTION<br /><ul><li> History
Antimicrobial resistance
 Recently introduced Antibacterial drugs
 Drugs in pipeline
 Targets for the next generation
 New strategies for drug discovery</li></li></ul><li>Antimicrobials<br />DEFINITION OF ANTIMICROBIAL AGENT ( AMA )<br />  ...
History<br />PAUL EHRLICH<br />Coined the term ‘ CHEMOTHERAPY<br /> Discovered Salvarsan (for Syphilis )<br /> FATHER OF C...
…….History<br />Fleming and Penicillin<br />
<ul><li> Domagk discovered  Sulphonamides
 Selman Waksman discovered</li></ul>Streptomycin<br /> In 1947, Chloramphenicol was first used clinically to treat Typhus<...
 1960 onwards second generation anttibiotics like Methicillin were discovered<br /> Following this, semi synthetic derivat...
Antimicrobials Targets<br />z<br />
Between 1962 and 2000, no major classes of antibiotics were introduced <br />Methicillin<br />Fischbach MA and Walsh CT Sc...
Timeline of antibiotic resistance<br />Vancomycin<br />Methicillin<br />Penicillin<br />MRSA<br />VRE<br />VRSA<br />Penic...
COMMON MODES OF ANTIMICROBIAL RESISTANCE <br />e.g.  aminoglycosides & tetracyclines<br />e.g. aminoglycosides , chloramph...
Why do we need newer antimicrobials<br />Bacterial resistance to antimicrobials-health and economic problem<br />Chronic r...
NEWER<br />ANTIBACTERIALS<br />
Oxazolidinones<br />Considered to be the first truly new class of antibacterial drugs introduced in the past 3 decades<br ...
Recently approved for  pediatric use in 2005 </li></li></ul><li>Newer Oxazolidinones<br />DRUGS IN PIPELINE:<br /><ul><li>...
Improved potency
Aqueous solubility
Reduced toxicity</li></li></ul><li>Mechanism of Resistance to older oxazolidinones<br /><ul><li>Occurs due to mutations in...
Telavancin:Approved in 2009 for complicated skin and skin structure infections(MRSA)
DRUGS IN PIPELINE
Oritavancin: Phase III  trial
Dalbavancin: Phase III trial</li></li></ul><li>…….Newer glycopeptides<br /><ul><li>MOA:</li></ul>     Inhibits peptidoglyc...
  Increases cell permeability causing rapid bactericidal activity</li></li></ul><li>……..Newer glycopeptides<br />Advantage...
Renal and hepatic excretion
No known nephrotoxicity or dose adjustments
Less frequent dosing
Longer t 1/2 life</li></li></ul><li>Mechanisms of resistance to  older glycopeptide<br />Synthesis of low-affinity precurs...
Developed for the treatment of vancomycin-resistant enterococcal infections
Daptomycin-Only drug in this class
 Approved in 2003
 Rapidly bactericidal
 No cross resistance
Indication:
  Treatment of complicated skin and skin structure infections </li></li></ul><li>…….Lipopeptides<br />MOA: <br />     Bind...
Ketolides<br />Drug resistance in community acquired respiratory tract infections           discovery and development of k...
 Newer Ketolides<br /><ul><li>APPROVED DRUG
Telithromycin-Approved in 2004
DRUGS IN PIPELINE
Cethromycin-Phase III trials
Solithromycin- Phase III trials</li></li></ul><li>MECHANISM OF ACTION  OF KETOLIDES<br />Vs<br />DOMAIN II<br />DOMAIN V<b...
……..Newer ketolides<br /><ul><li>Telithromycin-
First ketolide antibiotic to enter clinical use
Approved by the FDA in 2004
 For community acquired pneumonia- still in use
 Chronic bronchitis </li></ul>                                            Withdrawn in December 2006 <br /><ul><li> Acute ...
 For the treatment of community acquired pneumonia
For the prevention of post-exposure inhalational anthrax
Given an "orphan drug" status for this indication
Solithromycin: Under research
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Recent advances in Antibacterials by Dr.Harmanjit Singh, GMC, Patiala

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Recent advances in Antibacterials by Dr.Harmanjit Singh, GMC, Patiala

  1. 1. RECENT ADVANCES IN ANTIBACTERIALS<br /> Dr.Harmanjit Singh<br />Department of Pharmacology<br />GMC, Patiala <br />
  2. 2. INTRODUCTION<br /><ul><li> History
  3. 3. Antimicrobial resistance
  4. 4. Recently introduced Antibacterial drugs
  5. 5. Drugs in pipeline
  6. 6. Targets for the next generation
  7. 7. New strategies for drug discovery</li></li></ul><li>Antimicrobials<br />DEFINITION OF ANTIMICROBIAL AGENT ( AMA )<br /> Substance that kills or inhibits the growth of microorganisms such as bacteria, fungi, or protozoans.<br />Anantibacterial agent kills or inhibits the growth of bacteria .<br />
  8. 8. History<br />PAUL EHRLICH<br />Coined the term ‘ CHEMOTHERAPY<br /> Discovered Salvarsan (for Syphilis )<br /> FATHER OF CHEMOTHERAPY<br />He used the term ‘MAGIC BULLETS’<br />
  9. 9. …….History<br />Fleming and Penicillin<br />
  10. 10. <ul><li> Domagk discovered Sulphonamides
  11. 11. Selman Waksman discovered</li></ul>Streptomycin<br /> In 1947, Chloramphenicol was first used clinically to treat Typhus<br /> G.Brotzu discovered Cephalosporins<br /> Benjamin M. Duggar isolated Chlortetracyclinefrom a mud sample obtained from a river in Missouri.<br />
  12. 12. 1960 onwards second generation anttibiotics like Methicillin were discovered<br /> Following this, semi synthetic derivatives of older antibiotics with more desirable properties & different spectrum of activity were produced e.g. Fluoroquinolones, Oxazolidinones etc.<br />
  13. 13. Antimicrobials Targets<br />z<br />
  14. 14. Between 1962 and 2000, no major classes of antibiotics were introduced <br />Methicillin<br />Fischbach MA and Walsh CT Science 2009 <br />
  15. 15. Timeline of antibiotic resistance<br />Vancomycin<br />Methicillin<br />Penicillin<br />MRSA<br />VRE<br />VRSA<br />Penicillin resistant S.aureus<br />
  16. 16. COMMON MODES OF ANTIMICROBIAL RESISTANCE <br />e.g. aminoglycosides & tetracyclines<br />e.g. aminoglycosides , chloramphenicol & penicillins<br />e.g. Penicillins<br />e.g.tetracyclines<br />
  17. 17. Why do we need newer antimicrobials<br />Bacterial resistance to antimicrobials-health and economic problem<br />Chronic resistant infections contribute to increasing health care cost<br />Increase morbidity & mortality<br /> with resistant microorganisms <br />
  18. 18. NEWER<br />ANTIBACTERIALS<br />
  19. 19. Oxazolidinones<br />Considered to be the first truly new class of antibacterial drugs introduced in the past 3 decades<br />Linezolid-<br /><ul><li>Approved for adults use in 2000
  20. 20. Recently approved for pediatric use in 2005 </li></li></ul><li>Newer Oxazolidinones<br />DRUGS IN PIPELINE:<br /><ul><li>MOA: </li></ul> Bind to the 23S portion of the 50S subunit preventing translation initiation<br /><ul><li>ADVANTAGE OVER LINEZOLID:
  21. 21. Improved potency
  22. 22. Aqueous solubility
  23. 23. Reduced toxicity</li></li></ul><li>Mechanism of Resistance to older oxazolidinones<br /><ul><li>Occurs due to mutations in ribosomal RNA (rRNA)</li></ul> Resistance overcome by:<br /><ul><li>Newer oxazolidinones by additional hydrogen bond interactions with 23S rRNA</li></li></ul><li>Newer glycopeptides<br />Vancomycin & Teicoplanin are already in use<br /><ul><li> Recently APPROVED DRUG
  24. 24. Telavancin:Approved in 2009 for complicated skin and skin structure infections(MRSA)
  25. 25. DRUGS IN PIPELINE
  26. 26. Oritavancin: Phase III trial
  27. 27. Dalbavancin: Phase III trial</li></li></ul><li>…….Newer glycopeptides<br /><ul><li>MOA:</li></ul> Inhibits peptidoglycan biosynthesis by <br /> inhibiting transglycosylation + transpeptidation<br /><ul><li>Blocks utilization of D-Ala-D-Ala or D-Ala-D-Lac containing PG precursors </li></li></ul><li>……..Newer glycopeptides<br />Additional mode of action shown by Telavancin-<br /><ul><li>Causes disruption of membrane potential
  28. 28. Increases cell permeability causing rapid bactericidal activity</li></li></ul><li>……..Newer glycopeptides<br />Advantage over Vancomycin<br /><ul><li>Additional mechanisms of action
  29. 29. Renal and hepatic excretion
  30. 30. No known nephrotoxicity or dose adjustments
  31. 31. Less frequent dosing
  32. 32. Longer t 1/2 life</li></li></ul><li>Mechanisms of resistance to older glycopeptide<br />Synthesis of low-affinity precursors in which C-terminal D-Ala residue is replaced by: <br /><ul><li>D-lactate (D-Lac)or by D-serine (D-Ser)</li></ul>Resistance overcome by:<br /><ul><li>High binding affinity for both substrates(D-Ala-D-Lac precursor substrate OR D-Ala-D-Ala) due to presence of hydrophobic side chain </li></li></ul><li>Lipopeptides<br /><ul><li>New class of antibiotic
  33. 33. Developed for the treatment of vancomycin-resistant enterococcal infections
  34. 34. Daptomycin-Only drug in this class
  35. 35. Approved in 2003
  36. 36. Rapidly bactericidal
  37. 37. No cross resistance
  38. 38. Indication:
  39. 39. Treatment of complicated skin and skin structure infections </li></li></ul><li>…….Lipopeptides<br />MOA: <br /> Binds to bacterial membranes and causes a rapid depolarization <br /> Inhibition of protein, DNA, and RNA synthesis <br />Equal in efficacy to vancomycin, oxacillin, or nafcillin, in the treatment of complicated skin and skin structure infections<br />Warning issued by FDA in July 2010------can cause life-threatening eosinophilic pneumonia.<br />
  40. 40. Ketolides<br />Drug resistance in community acquired respiratory tract infections discovery and development of ketolides<br />Semisynthetic 14 membered ring macrolides<br />Carbonyl group at the C3 position,responsible for sensitivity to macrolide resistant strains<br />
  41. 41. Newer Ketolides<br /><ul><li>APPROVED DRUG
  42. 42. Telithromycin-Approved in 2004
  43. 43. DRUGS IN PIPELINE
  44. 44. Cethromycin-Phase III trials
  45. 45. Solithromycin- Phase III trials</li></li></ul><li>MECHANISM OF ACTION OF KETOLIDES<br />Vs<br />DOMAIN II<br />DOMAIN V<br />
  46. 46. ……..Newer ketolides<br /><ul><li>Telithromycin-
  47. 47. First ketolide antibiotic to enter clinical use
  48. 48. Approved by the FDA in 2004
  49. 49. For community acquired pneumonia- still in use
  50. 50. Chronic bronchitis </li></ul> Withdrawn in December 2006 <br /><ul><li> Acute sinusitis </li></li></ul><li>……..Newer ketolides<br /><ul><li>Cethromycin:undergoing research
  51. 51. For the treatment of community acquired pneumonia
  52. 52. For the prevention of post-exposure inhalational anthrax
  53. 53. Given an "orphan drug" status for this indication
  54. 54. Solithromycin: Under research
  55. 55. For the treatment of community acquired pneumonia</li></li></ul><li>Glycylcyclines<br /><ul><li>New class of antibiotics derived from tetracycline
  56. 56. Designed to overcome two common mechanisms of tetracycline resistance
  57. 57. resistance mediated by acquired efflux pumps
  58. 58. ribosomal protection
  59. 59. Only one glycylcycline antibiotic for clinical use: TIGECYCLINE</li></li></ul><li>……..Glycylcyclines<br />Tigecycline:<br /><ul><li>Approved in 2005
  60. 60. Indication:
  61. 61. Complicated skin and skin structure infections &
  62. 62. Intra-abdominal infections
  63. 63. New Delhi metallo-β-LactamaseproducingEnterobacteriaceae has also shown susceptibility to tigecycline
  64. 64. Also active against MRSA </li></li></ul><li>……..Glycylcyclines<br /><ul><li>MOA:
  65. 65. Bind to 30 S subunit of bacterial ribosome
  66. 66. 20-fold more efficient than tetracycline
  67. 67. DOSE: Only I/V formulation available
  68. 68. Slow I/V infusion of 100 mg
  69. 69. followed by maintenance dose(50 mg)
  70. 70. No dose adjustment in renal failure (in comparison to tetracycline)</li></ul>DRUG IN PIPELINE:<br />PTK0796<br /><ul><li>Oral formulation
  71. 71. In a phase II trial</li></li></ul><li>Newer carbapenems<br /><ul><li>Beta-lactam antibiotics with a broad spectrum of antibacterial activity
  72. 72. NEWER CARBAPENEM:
  73. 73. Ertapenem: Approved in 2001
  74. 74. Doripenem:Approved in 2007
  75. 75. DRUG IN PIPELINE:
  76. 76. Razupenem:Phase II clinical trial</li></li></ul><li>…….Newer carbapenems<br />Doripenem :<br /> Suitable alternative to currently available antipseudomonalcarbapenems (i.e, imipenem, meropenem)<br /><ul><li>Indication:
  77. 77. Complicated urinary tract infections
  78. 78. Intra-abdominal infections
  79. 79. MOA:
  80. 80. Bind to penicillin binding proteins (PBPs) and inhibit cross-linking of the peptidoglycan structure</li></li></ul><li>……Newer carbapenems<br /><ul><li>Advantage :</li></ul> 1.Spectrum of activity <br /><ul><li> similar to that of meropenem against gram-ve &
  81. 81. similar to imipenem against gram+ve bacteria</li></ul>2. Slightly better in vitro activity against P. aeruginosa<br />3. Not degraded by renal dehydropeptidase<br /><ul><li>Dose:
  82. 82. Available as I/V formulation only
  83. 83. 500mg by I/V infusion every 8 hours</li></li></ul><li>……Newer carbapenems<br /><ul><li>Ertapenem
  84. 84. Long half life carbapenem
  85. 85. Once daily dosing
  86. 86. High protein binding
  87. 87. Not for P. aeruginosa
  88. 88. Low toxicity</li></li></ul><li>Newer cephalosporins<br /><ul><li>Approved cephalosporins
  89. 89. Ceftaroline: Approved in 2010
  90. 90. For the treatment of
  91. 91. community - acquired pneumonia &
  92. 92. complicated skin and soft - tissue infections
  93. 93. Drugs in pipeline
  94. 94. Ceftobiprole: Awaiting FDA approval</li></li></ul><li>…….Newer cephalosporins<br /><ul><li>MOA:
  95. 95. Bind strongly to PBP2a of methicillin resistant Staphylococci
  96. 96. Novel cephalosporin have
  97. 97. Broad spectrum activity against MRSA and multi-drug resistant S. pneumoniae
  98. 98. DOSE: 600 mg IV every 12 hours </li></li></ul><li>Carbacephem antibiotics <br />Loracarbef <br />A  carbacephem  synthetically made ​​based on the structure of cephalosporin .<br />The carbacephems are similar but with a carbon replaced by sulfur .<br /> <br /> cell wall synthesis inhibitor <br /> Not in much use because of its adverse effects like diarrhea & seizures <br />
  99. 99. Novel Dihydrofolatereductase inhibitors<br />Iclaprim<br /><ul><li>Diaminopyrimidine that inhibit DNA/RNA synthesis
  100. 100. Awaiting FDA approval
  101. 101. Indication:
  102. 102. For the treatment of complicated skin and soft tissue infections caused by antibiotic-resistant bacteria
  103. 103. Designed to overcome trimethoprim resistance
  104. 104. Active against MRSA, penicillin resistant S. pneumoniae ( PRSP)</li></li></ul><li>Pleuromutilins<br /><ul><li>Newer class of antibiotic
  105. 105. MOA:
  106. 106. Bind to 50S subunit of ribosomes inhibiting protein synthesis
  107. 107. Approved Drug:
  108. 108. Retapamulin:
  109. 109. Approved in 2007
  110. 110. Topical antibiotic
  111. 111. Treatment of skin infections such as impetigo S. aureus (methicillin-susceptible only) or S. pyogenes
  112. 112. Drug in pipeline
  113. 113. Azamulin</li></li></ul><li>Macrocyclic antibiotic drugs.<br />Fidaxomicin<br /><ul><li>Narrow spectrum bactericidal agent
  114. 114. Demonstrated selective eradication of pathogenic Clostridium difficile
  115. 115. MOA:
  116. 116. Inhibit bacterial enzyme RNA polymerase</li></ul>Awaiting FDA approval<br />
  117. 117. RIFAMYCINS<br />Rifampin, Rifabutin & Rifapentine are already approved dugs<br />Rifaximin : Newer non systemic rifamycin<br /><ul><li>Approved for  traveler's diarrhea, hepatic encephalopathy
  118. 118.  Irritable bowel syndrome, small intestinal bacterial overgrowth & Clostridium difficile infection </li></li></ul><li>New Targets for the Next Generation of Antimicrobial drugs<br /><ul><li>Targeting virulence factors
  119. 119. Targeting bactericidal functions of bacterial proteins
  120. 120. Modulating host response pathways
  121. 121. Peptides derived from vertebrates, invertebrates and microorganisms</li></li></ul><li>…….Future targets<br />1.Targeting virulence factors e.g.<br />- Inhibition of bacterial adhesion<br /> - inhibition of toxin production<br /> - inhibition of toxin delivery<br /> - inhibition of virulence regulators <br />
  122. 122. …….Future targets<br />2. Targeting bactericidal functions of bacterial proteins<br />E.g. Targeting enzymes like<br /> β-ketoacyl-acyl-carrier-protein synthase I/II<br /> Required for fatty acid biosynthesis in bacteria<br />DRUG IN PIPELINE:<br /><ul><li>Platensimycin - preclinical trials in an effort to combat MRSA in a mouse model</li></li></ul><li>…….Future targets<br />3. Modulating host response pathways<br />innate immune response<br /> Activation of TLR (Toll-like receptor) family of proteins<br /> Produce antimicrobial peptides<br />TLR activators and modulators could potentially have an antimicrobial role<br />
  123. 123. …….Future targets<br />4. Antimicrobial peptides derived from vertebrates, invertebrates and microorganisms- Novel potential therapeutic target<br />MOA:Depolarisescytoplasmic membrane of bacteria<br />Examples:<br /><ul><li>Dermaseptin ------ frog skin
  124. 124. Defensin & Crustin -----crustacean
  125. 125. DRUGS In pipeline:
  126. 126. Omiganan Clinical trials
  127. 127. Pexiganan</li></li></ul><li>New Strategies for Antibacterial Drug Discovery<br /><ul><li>Therapeutic use of bacteriophages to treat pathogenic bacterial infections
  128. 128. Common resistance mechanisms can be bypassed by producing -antibacterial drug as </li></ul>Prodrug highly potent drug within a microbe<br />
  129. 129. New Strategies for Antibacterial Drug Discovery<br /><ul><li>Production of hybrid antibacterial drugs- for high potency against two targets.
  130. 130. E.g. Mutilin-quinolone hybrid AM-3005 is a Type II topoisomerase inhibitor and also a protein synthesis inhibitor
  131. 131. Rifamycin-quinolone hybrid which is a RNA polymerase inhibitor and also a DNA gyrase inhibitor
  132. 132. Improved formulations of alternative drug delivery methods
  133. 133. e.ginhaled Amikacinnanoscale liposome formulation</li></li></ul><li>Limitations of antimicrobial research & development pipeline<br /><ul><li>Drug research and development is quite expensive and time-consuming
  134. 134. Average cost per each new drug is estimated to be US$ 800 million to 1.7 billion
  135. 135. Increasing number of pharmaceutical companies are withdrawing from the market of antibiotic development
  136. 136. Few antibacterial agents in the pipeline</li></li></ul><li>: Antimicrobial Stewardship<br />Antimicrobial stewardship refers to a program or series of interventions to monitor and direct antimicrobial use at a health care institution, thus providing a standard,<br /> evidence-based approach to judicious antimicrobial use<br /> It includes :-<br /><ul><li> Infection control plus antimicrobial management</li></ul>Appropriate antimicrobial selection, dosing, route, and duration<br />System selection of antimicrobials that cause the least collateral damage<br />MRSA<br />ESBLs<br />Clostridium difficille<br />Metallo-beta-lactamases and other carbapenemases<br />VRE<br />
  137. 137. Goals of Antimicrobial Stewardship<br />Primary goal<br />Optimize clinical outcome/minimize unintended consequences of antimicrobial use<br />Unintended consequences:<br />Toxicity <br />Selection of pathogenic organisms<br />Emergence of resistant pathogens<br />Secondary goal<br />Reduce healthcare costs without adversely impacting quality of care<br />
  138. 138. TO SUMMARISE <br /> There is a great need of newer antibiotics because of increasing microbial resistance<br /> Because of increase cost of development and increasing resistant, only few drugs are in pipeline<br /> Some of the newer agents are effective against resistant strains<br /> programs like Antibiotic stewardship can be helpful to combat the resistance <br /> Rational use of antibiotics remains the most important measure <br />
  139. 139. THANK YOU<br />

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