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.
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
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
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
136.
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
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