1. Antibiotics – mechanism of resistance – related history [MRSA , VRE , VISA, ESBLS] By Dr.Raghu prakash reddy

4. Ignác Semmelweis (1818-1865) – assistant in midwifery of Allgemeines Krankenhaus (Vienna) in 1846 – noted that up to 1/5 women died from "childbed" puerperal fever after physician-assisted delivery – by contrast, mortality was low in deliveries performed by midwives

5. History of infection control • Ignác Semmelweis – discovered that physician handwashing with carbolic acid prior to delivery dramatically reduced mortality – he wrote a bunch of letters to the establishment outlining his discovery – he was declared a lunatic and institutionalized – died from blood poisoning 10 d after receiving a finger cut while forced into a straightjacket

6. History of infection control • Joseph Lister (1827-1912) – English surgeon – knew of Louis Pasteur's "germ theory" – reasoned that if airborne microbes could sour milk and rot meat, they may also infect wounds – in the 1860s, he introduced disinfection of operating theatres using carbolic acid spray "Listerian antisepsis“ – gloves were originally introduced to prevent dermatitis from antiseptics

8. Asepsis • Antisepsis vs. asepsis – aseptic techniques introduced in early 1900s – focused on preventing microbes from getting to the patient rather than fumigating everything – surgeons used gloves, gowns, masks, filtered air, etc. in combination with disinfection – asepsis continued as the primary means of infection control into the 1950s

9. Selman Waksman suggests the word "antibiotic" (coined in 1889 by P. Vuillemin) after Dr. J. E. Flynn, the editor of Biological Abstracts asked him to suggest a term for chemical substances, including compounds and preparations that are produced by microbes and have antimicrobial properties. Although there is no journal citation, Waksman recalled the incident in his book The Antibiotic Era . Because the word was accepted quickly and the meaning became confused, Waksman published a comprehensive definition in 1947: "an antibiotic is a chemical substance produced by microbes that inhibits the growth of and even destroys other microbes (and is active in dilute solutions)" was added later The word antibiotic came from the word antibiosis a term coined in 1889 by Louis Pasteur's pupil Paul Vuillemin which means a process by which life could be used to destroy life

10. Brief History of Antibiotics • 1928- Penicillin discovered by Fleming • 1932- Sulfonamide antimicrobial activity discovered {Erlich}• • 1943- Drug companies begin mass production of penicillin • 1948- Cephalosporins precursor sent to Oxford for synthesis • 1952- Erythromycin derived from Streptomyces erythreus • 1956- Vancomycin introduced for penicillin resistant staphylococcus • 1962- Quinolone antibiotics first discovered • 1970s- Linezolide discovered but not pursued • 1980s- Fluorinated Quinolones introduced, making then clinically useful • 2000- Linezolide introduced into clinical practice

11. Antibiotic natural source first description as anti-infective drug discoverer sulfanilamide (prontosil 1932 1941 G.Domagk penicillin Penicillium notatum A.Fleming, Florey, Chain streptomycin Streptomyces griseus 1944 S.A.Waksman cephalosporin Cephalosporium acremonium 1945 G.Brotzu bacitracin Bacillus subtilis 1945 B.A.Johnson chloramphenicol Streptomyces venezuellae 1947 I.Ehrlich polymyxin Bacillus polymyxa 1947 C.G.Ainsworth chlortetracyclin Streptomyces aureofaciens 1948 B.M.Duggar neomycin Streptomyces fradiae 1949 S.A.Waksman oxytetracyclin Streptomyces rimosus 1950 A.C.Finlay

12. The End of Infectious Disease • In 1967, U.S. Surgeon General William H. Stewart told a White House gathering of health officers that “it was time to close the book on infectious diseases”and shift all national attention (and dollars) to what he termed ‘the New Dimensions’of health: chronic diseases” • In the US, deaths from infectious disease dropped by 8.2% annually from 1938 to 1952, and by 2.3% annually thereafter until 1980. • New antibiotics were being discovered on a yearly basis to replace any that had lost effectiveness

13. The End of Infectious Disease •From 1981 to 1995 deaths from infectious disease increased by 4.8% annually. •In 1998 WHO estimated that over 13 million deaths worldwide were caused by infectious disease, almost a quarter of the total deaths in that period. That percentage was up to 26% in 2001. •In 1995 the annual in-hospital costs associated with resistance of 6 bacterial species to a single antibiotic were estimated to be $1.3 billion. •37 new human pathogens have been identified in the last 30 years. •12% of known human pathogens have been recognized as emerging or reemerging health threats

14. The End of Infectious Disease • Since 1967: – Legionnaire’s disease – Toxic shock syndrome – AIDS – Lymedisease – West Nile encephalitis – SARS – Avian Flu • Chronic diseases associated with pathogens: – Peptic ulcers ( Helicobacter pylori ) – Liver cancer (Hepatitis B and C) – Lymearthritis ( Borreliaburgdorferi )

16. It is not difficult to make microbes resistant to penicillin in the laboratory by exposing them to concentrations not sufficient to kill them, and the same thing has occasionally happened in the body… — Alexander Fleming, 1945

17. The greatest possibility of evil in self-medication is the use of too small doses so that instead of clearing up infection, the microbes are educated to resist penicillin and a host of penicillin-fast organisms is bread out which can be passed to other individuals and from them to other until they reach someone who gets a septicemia or a pneumonia which penicillin cannot save. . Sir Alexander Flemming

18. Howard Florey

22. Basic Classes of Antibiotics • Although a large number of antibiotics exist, they fall into only a few classes with an even more limited number of targets. – β-lactams (penicillins) –cell wall biosynthesis – Glycopeptides (vancomycin) –cell wall biosynthesis – Aminoglycosides (gentamycin) –protein synthesis – Macrolides (erythromycin) –protein synthesis – Quinolones (ciprofloxacin) –nucleic acid synthesis – Sulfonamides (sulfamethoxazole) –folic acid metabolism

25. The four main mechanisms of antibacterial action

26. Lipid Carrier Cycle

28. Historical Aspects • 1941 Albert Alexander first recepient of penicillin • 1942 first resistant isolates of Staph aureus reported • 1960 Methicillin introduced • 1964 first MRSA reported • 1980s MRSA became major nosocomial infection

30. Historical aspects • 1980s –ESBL producing GN bacteria • 1990 Vancomycin resistant Enterococci emerged • 2000 VISA (intermediate level resistance) • 2002-VRSA (high level resistance) • 2002- Linezolid resistant enterococci and Staphylococci reported

31. Evolution of b-Lactamase Plasmid-Mediated TEM and SHV Enzymes Ampicillin Third-Generation Cephalosporins 1963 1965 TEM-1 E coli S paratyphi 1970s TEM-1 Reported in 28 Gram- Negative Species 1980s 1983 ESBL in United States 1987 ESBL in Europe 2000 >120 ESBLs Worldwide

35. What does not destroy me makes me stronger . — Nietzsche, 1899

39. What's MRSA And What Can Be Done About It?

40. Mechanisms of Antibiotic Resistance

41. Horizontal Gene Transfer

42. Resistance to Antibiotics • Bacteria (and viruses) are very resourceful creatures and they have developed resistance mechanisms to essentially every antibiotic that has been developed. • Moreover, increased use of antibiotics results in increased resistance (the paradox of antibiotics). • The basic resistance mechanisms are quite simple: 1.Modify the antibiotic 2.Modify the target of the antibiotic 3.Destroy the antibiotic 4.Make it more difficult for the antibiotic to get into the cell 5.Actively remove the antibiotic from the cell

43. Active efflux of antibiotics

44. Efflux pump is a less potent and less common cause of resistance Efflux pump PmrA Mutation of bacterial genes for binding sites causes resistance gyrA, parC, ( parE, gyrB )

45. Antibiotic Efflux Pumps

46. Alteration of the Drug Target Site Vancomycin

47. Genetic basis Genetic selection underlies all resistance Some single amino acid substitution by mutation (ESBL) are rapid and some need multiple genes to cause resistance (VRE) • Mutations • Plasmids • Transposons • Integrons

48. Beta Lactamases • Classified based on Prim structure – Class A (Serine residue) – Class B (metallo-enzyme) – Class C (Serine residue) – Class D (Serine residue) • Class A&D - plasmid mediated • Class B&C - encoded by chromosomal genes

49. Beta Lactamases • Major defence of GNB against B lactams • Hundreds have co-evolved with newer drugs • Spread from Staphylococci to H Influenzae and N gonorrhoeae • With over-use of new B lactams in last 2 decades “new” Extended spectrum beta lactamases(ESBLs), carbapenemases

50. • TEM type ESBL • SHV type ESBL • CTX type ESBL • OXA type ESBL • Plasmid mediated Amp C enzymes • Carbapenemases New Beta lactamases

51. Epidemiology of the Transmission of Antibiotic-Resistant Bacteria

52. Antibiotics in Agriculture Antibiotics in poultry

53. Antibiotics Subject Antimicrobial (Pounds) Human 3,000,000 Beef* 3,700,000 Swine* 10,300,00 Chicken* 10,500,000 Total in animals 24,500,000

57. The Dramatic Rise in Plasmid-Mediated MBL and Other Carbapenemases • The quiet before the storm • Only 1 publication of a transferable MBL in P aeruginosa in 1993 • 2005 – The presence of transferable MBLs in 28 countries • 2005 ICAAC – 31 abstracts on carbapenemases/MBLs • 2005 ICAAC – major scientific symposium: The Expanding World of Carbapenemases • They have arrived in the United States • Government, industry, and academics working as one seems to be the required path to regain our previous advantage over infesting microbes – promote antimicrobial prescription discipline Walsh TR, et al. Clin Micro Reviews. 2005;18:306-325. Jones RN, et al. Diagn Microbiol Infect Dis. 2005;51:77-84. ICAAC 2005 Symposium 113 (C1), December 16, 2005.

58. The History of Medicine 2000 B.C.—Here, eat this root. 1000 A.D.—That root is heathen. Here, say this prayer. 1850 A.D.—That prayer is superstition. Here, drink this potion. 1920 A.D.—That potion is snake oil. Here, swallow this pill. 1945 A.D.—That pill is ineffective. Here, take this penicillin. 1955 A.D.—Oops…bugs mutated. Here, take this tetracycline. 1960–1999—39 more “oops.”Here, take this more powerful antibiotic. 2000 A.D.—The bugs have won! Here, eat this root. — Anonymous (WHO, 2000)

60. THANK U

61. What Is Antimicrobial Stewardship? • A marriage of infection control and antimicrobial management • Mandatory infection control compliance • Selection of antimicrobials from each class of drugs that does the least collateral damage • Collateral damage issues include – MRSA – ESBLs – C difficile – Stable derepression – MBLs and other carbapenemases – VRE • Appropriate de-escalation when culture results are available Dellit TH, et al. Clin Infect Dis. 2007;44:159-177 .

62. IDSA Guidelines – Definition of Antimicrobial Stewardship • Antimicrobial stewardship is an activity that promotes – The appropriate selection of antimicrobials – The appropriate dosing of antimicrobials – The appropriate route and duration of antimicrobial therapy

63. The Primary Goal of Antimicrobial Stewardship • The primary goal of antimicrobial stewardship is to – Optimize clinical outcomes while minimizing unintended consequences of antimicrobial use • Unintended consequences include the following – Toxicity – The selection of pathogenic organisms, such as C difficile – The emergence of resistant pathogens

64. Antimicrobial Stewardship: Suggested Starting Points • Obtain baseline information – Antimicrobial usage and expenditures – Institutional susceptibilities – Recurrent problems • Strategies – Baseline: create collaborative antibiotic guidelines (participation and buy-in from as many doctors as possible) – Low-hanging fruit: IV to per os switches, dosing, streamlining antimicrobials based on culture results