Recent Advances in Antibacterial Drugs
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Recent Advances in Antibacterial Drugs
- 1. RECENT ADVANCES IN ANTIBACTERIALS Dr.Harmanjit Singh Department of Pharmacology GMC, Patiala
- 4. Recently introduced Antibacterial drugs
- 5. Drugs in pipeline
- 6. Targets for the next generation
- 8. History PAUL EHRLICH Coined the term ‘ CHEMOTHERAPY Discovered Salvarsan (for Syphilis ) FATHER OF CHEMOTHERAPY He used the term ‘MAGIC BULLETS’
- 9. …….History Fleming and Penicillin
- 11. Selman Waksman discoveredStreptomycin In 1947, Chloramphenicol was first used clinically to treat Typhus G.Brotzu discovered Cephalosporins Benjamin M. Duggar isolated Chlortetracyclinefrom a mud sample obtained from a river in Missouri.
- 12. 1960 onwards second generation anttibiotics like Methicillin were discovered Following this, semi synthetic derivatives of older antibiotics with more desirable properties & different spectrum of activity were produced e.g. Fluoroquinolones, Oxazolidinones etc.
- 14. Between 1962 and 2000, no major classes of antibiotics were introduced Methicillin Fischbach MA and Walsh CT Science 2009
- 15. Timeline of antibiotic resistance Vancomycin Methicillin Penicillin MRSA VRE VRSA Penicillin resistant S.aureus
- 16. COMMON MODES OF ANTIMICROBIAL RESISTANCE e.g. aminoglycosides & tetracyclines e.g. aminoglycosides , chloramphenicol & penicillins e.g. Penicillins e.g.tetracyclines
- 17. Why do we need newer antimicrobials Bacterial resistance to antimicrobials-health and economic problem Chronic resistant infections contribute to increasing health care cost Increase morbidity & mortality with resistant microorganisms
- 21. Improved potency
- 24. Telavancin:Approved in 2009 for complicated skin and skin structure infections(MRSA)
- 26. Oritavancin: Phase III trial
- 29. Renal and hepatic excretion
- 30. No known nephrotoxicity or dose adjustments
- 33. Developed for the treatment of vancomycin-resistant enterococcal infections
- 34. Daptomycin-Only drug in this class
- 35. Approved in 2003
- 37. No cross resistance
- 38. Indication:
- 40. Ketolides Drug resistance in community acquired respiratory tract infections discovery and development of ketolides Semisynthetic 14 membered ring macrolides Carbonyl group at the C3 position,responsible for sensitivity to macrolide resistant strains
- 47. First ketolide antibiotic to enter clinical use
- 48. Approved by the FDA in 2004
- 49. For community acquired pneumonia- still in use
- 51. For the treatment of community acquired pneumonia
- 52. For the prevention of post-exposure inhalational anthrax
- 53. Given an "orphan drug" status for this indication
- 56. Designed to overcome two common mechanisms of tetracycline resistance
- 57. resistance mediated by acquired efflux pumps
- 58. ribosomal protection
- 60. Indication:
- 61. Complicated skin and skin structure infections &
- 63. New Delhi metallo-β-LactamaseproducingEnterobacteriaceae has also shown susceptibility to tigecycline
- 65. Bind to 30 S subunit of bacterial ribosome
- 66. 20-fold more efficient than tetracycline
- 67. DOSE: Only I/V formulation available
- 68. Slow I/V infusion of 100 mg
- 69. followed by maintenance dose(50 mg)
- 73. Ertapenem: Approved in 2001
- 77. Complicated urinary tract infections
- 79. MOA:
- 82. Available as I/V formulation only
- 84. Long half life carbapenem
- 87. Not for P. aeruginosa
- 89. Ceftaroline: Approved in 2010
- 90. For the treatment of
- 91. community - acquired pneumonia &
- 92. complicated skin and soft - tissue infections
- 95. Bind strongly to PBP2a of methicillin resistant Staphylococci
- 97. Broad spectrum activity against MRSA and multi-drug resistant S. pneumoniae
- 101. Indication:
- 102. For the treatment of complicated skin and soft tissue infections caused by antibiotic-resistant bacteria
- 103. Designed to overcome trimethoprim resistance
- 105. MOA:
- 106. Bind to 50S subunit of ribosomes inhibiting protein synthesis
- 107. Approved Drug:
- 108. Retapamulin:
- 109. Approved in 2007
- 110. Topical antibiotic
- 111. Treatment of skin infections such as impetigo S. aureus (methicillin-susceptible only) or S. pyogenes
- 112. Drug in pipeline
- 114. Demonstrated selective eradication of pathogenic Clostridium difficile
- 115. MOA:
- 116. Inhibit bacterial enzyme RNA polymeraseAwaiting FDA approval
- 119. Targeting bactericidal functions of bacterial proteins
- 120. Modulating host response pathways
- 124. Defensin & Crustin -----crustacean
- 125. DRUGS In pipeline:
- 126. Omiganan Clinical trials
- 128. Common resistance mechanisms can be bypassed by producing -antibacterial drug as Prodrug highly potent drug within a microbe
- 130. E.g. Mutilin-quinolone hybrid AM-3005 is a Type II topoisomerase inhibitor and also a protein synthesis inhibitor
- 131. Rifamycin-quinolone hybrid which is a RNA polymerase inhibitor and also a DNA gyrase inhibitor
- 132. Improved formulations of alternative drug delivery methods
- 134. Average cost per each new drug is estimated to be US$ 800 million to 1.7 billion
- 135. Increasing number of pharmaceutical companies are withdrawing from the market of antibiotic development
- 137. Goals of Antimicrobial Stewardship Primary goal Optimize clinical outcome/minimize unintended consequences of antimicrobial use Unintended consequences: Toxicity Selection of pathogenic organisms Emergence of resistant pathogens Secondary goal Reduce healthcare costs without adversely impacting quality of care
- 138. TO SUMMARISE There is a great need of newer antibiotics because of increasing microbial resistance Because of increase cost of development and increasing resistant, only few drugs are in pipeline Some of the newer agents are effective against resistant strains programs like Antibiotic stewardship can be helpful to combat the resistance Rational use of antibiotics remains the most important measure
- 139. THANK YOU
Editor's Notes
- 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