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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  • 1945The “golden age of antibiotics” begins with the introduction of cephalosporins, chloramphenicol, tetracyclines, erythromycin, vancomycin, gentamicin and many variations on the penicillin (b-lactam) nucleus
  • 1908 – Paul Ehrlich – salvarsan – arsenic compound –effective treatment of syphilis First systematic approach to find compounds to treat infections
  • Discovery of antibiotics – 1928 – Alexander Fleming– growth of Staphylococcus aureuson an agar plate inhibited by growth of a common blue-green mould (fungus) – Penicilliumnotatum
  • Pencillin:1943.resistance in 1947 within 4 yearsMethicillin :1959,resistance in 1961Vancomycin :1958VRE:1987VRSA:2002
  • 4–8 fold more active than linezolid in linezolid-susceptible and resistant strains of staphylococci and enterococci and upto 4-fold higher against anaerobes
  • Telavancin is a new intravenous lipoglycopeptide antibiotic with activity against staphylococci (including methicillin-resistant strains), streptococci, and vancomycin-susceptible enterococci. It is dosed once daily and does not require serum-level monitoring.Indication:Telavancin is FDA approved for the treatment of complicated skin and skin-structure infections (cSSTIs) in adults. It was found to be noninferior to vancomycin for this purpose in a pooled analysis of two randomized controlled trials. The FDA recently denied approval of telavancin for nosocomial pneumonia, requesting additional datThis class of drugs inhibit the synthesis of cell walls in susceptible microbes by inhibiting peptidoglycan synthesis. They bind to the amino acids within the cell wall preventing the addition of new units to the peptidoglycan. In particular they bind to acyl-D-alanyl-D-alanine in peptidoglycan
  • Replacement of the terminal D-alanine residuein the cell wall peptidoglycan substrate for the cross-linking transpeptidase enzyme by D-serine orD-lactate confers moderate and full resistance to vancomycin, respectively
  • Vancomycin is unable to bind to D-Ala-D-Lac precursor substrate compared to D-Ala-D-Ala. The VanA-type is characterized by high-level inducibleresistance to both vancomycin and teicoplanin and is mediated by transposon Tn1546 orclosely related elements [4]. VanB-type strains have variable levels of inducible resistanceto vancomycin only Glycopeptide resistance is due to the presence of an alternative pathway forpeptidoglycan synthesis which allows (i) synthesis of low-affinity precursors in which theC-terminal D-Ala residue is replaced by a D-lactate (D-Lac) in VanA, VanB, and VanDphenotypes and by a D-serine (D-Ser) in the VanC, VanE, and VanG types and (ii)elimination of precursors normally produced by the host. Replacement of the D-AlaC-terminal residue by a D-Lac eliminates a hydrogen bond critical for antibiotic bindingand considerably reduces the affinity for glycopeptides whereas substitution by a D-Serdoes not alter the hydrogen bonds but is responsible for conformational changes whichreduce slightly the affinity for vancomycin
  • withdrawn its approval of telithromycin in December 2006 for acute exacerbation of chronic bronchitis (AECB) and acute sinusitis
  • Active against wide variety of mDr pathogenic nosocomials
  • he Food and Drug Administration (FDA) has approved four carbapenems: imipenem (a primary component of Primaxin IM, Merck)meropenem (Merrem IV, Astra-Zeneca)ertapenem (Invanz, Merck)Doripenemhe Food and Drug Administration (FDA) has approved four carbapenems: imipenem (a primary component of Primaxin IM, Merck)meropenem (Merrem IV, Astra-Zeneca)ertapenem (Invanz, Merck)doripenemhe Food and Drug Administration (FDA) has approved four carbapenems: imipenem (a primary component of Primaxin IM, Merck)meropenem (Merrem IV, Astra-Zeneca)ertapenem (Invanz, Merck)doripenemhe Food and Drug Administration (FDA) has approved four carbapenems: imipenem (a primary component of Primaxin IM, Merck)meropenem (Merrem IV, Astra-Zeneca)ertapenem (Invanz, Merck)doripenemremain the drugs of choice for extended-spectrum, beta-lactamase–producing organisms, resistance may emerge via other beta-lactamases, such as metallo–beta-lactamases, alteration of porin channels, or up-regulation of efflux pumps. Therefore, carbapenems should be used judiciously, and the appropriate use of these agents must be considered carefully.
  • recommended duration of therapy is 5 – 14 days for complicated intra-abdominal infection 10 days for complicated UTI
  • Ceftobiprole was approved earlier this year in Canada, and most recently it was approved in SwitzerlandSeveral novel agents to treat MRSA infections have been approved within the last decade, including quinapristin/dalfopristin (Synercid, King), approved in 1999; linezolid (Zyvox, Phamacia, Upjohn), approved in 2000l; daptomycin (Cubicin, Cubist), approved in 2003; and tigecylcine (Tygacil, Wyeth), approved in 2005
  • Target 1 eg:Platensimycin, class of antibiotics which act by blocking enzymes involved in the condensation steps in fatty acid biosynthesis,[3] which Gram-positive bacteria need to biosynthesise cell membranes (β-ketoacyl-(acyl-carrier-protein (ACP)) synthase I/II (FabF/B))Platensimycin is an experimental new drug in preclinical trials in an effort to combat MRSA
  • . Phages are common in bacterial populations and control the growth of bacteria in many environments, including in the intestine, the ocean, and the soil.Natural phenomenon of Inactivation of antibacterial drugs by enzymatic hydrolysis or formation of inactive derivatives causes widespread drug resistance : A combination of β-lactamase enzyme and a β-lactam antibacterial drug can significantly reduce emergence of resistant microbes
  • . A study in 2004 showed that only 6 out of 506 drugs in development by 15 largepharmaceutical companies and 7 major biotechnology companies were antibiotics
  • OK, we are back to our definitionRemember infection control and its importance
  • Do not include outpatient recommendationsFinancially self-supporting Improve patient careShould be evidence based
  • 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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