Superbug

1. www.drsarma.in Superbug Dr. Sarma. R.V.S.N. M.D., M.Sc.(Canada), FIMSA, Senior Consultant Physician & Cardio-Metabolic Specialist

2. Antimicrobial Resistance

4. Lancet Infect Dis 2010; 10: 597–602 Published Online - August 11, 2010

5. Worldwide Prevalence of MRSA Grundmann H et al. Lancet 2006;368:874.

6. Antibiotic Prescriptions

7. No Major New Discoveries

8. A Changing Landscape for Approved Antibacterials 18 16 14 12 10 Number of agents approved 8 6 4 0 2 0 Resistance 1983-87 1988-92 1993-97 1998-02 2003-05 2008 Bars represent number of new antimicrobial agents approved by the FDA during that period • Infectious Diseases Society of America. Bad Bugs, No Drugs. July 2004; Spellberg B et al. Clin Infect Dis. 2004;38:1279-1286; • New antimicrobial agents. Antimicrob Agents Chemother. 2006;50:1912

9. Penicillin Cleavage by Penicillinase b – Lactam Ring b - Lactamase Active Inactive

10. Bacterium Resistant to Penicillin Penicillinase Plasmid Gene for b - Lactamase This organism can freely grow in the presence of Penicillin

11. The Busy Genome: Elements of Horizontal Exchange Genomic islands e.g. Escherichia Coli Common: 4.1 Mb K12 Islands: 0.53 Mb 0157:H7 Islands: 1.34 Mb Prophages Conjugative Transposons (gram +ve) Minimal species Genomic backbone Super Integrons (Mainly  Protobacteria) Insertion Sequences Integrons Transposons

12. Acquisition of Hospital Infections

13. Inappropriate Antibiotic Therapy Inappropriate empiric antibiotic therapy can lead to increases in: • mortality • morbidity • length of hospital stay • cost burden • resistance selection A number of studies have demonstrated the benefits of early use of appropriate empiric antibiotic therapy for patients with nosocomial infections

14. Inappropriate Antibiotic Therapy Inappropriate antibiotic therapy can be defined as one or more of the following: • ineffective empiric treatment of bacterial infection at the time of its identification • the wrong choice, dose or duration of Rx. • use of an antibiotic to which the pathogen is resistant

15. Mechanism of Antibiotic Resistance Antibiotic resistance either arises as a result of innate consequences or is acquired from other sources Bacteria acquire resistance by: • Mutation: spontaneous single or multiple changes in bacterial DNA • Addition of new DNA: usually via plasmids, which can transfer genes from one bacterium to another • Transposons: short, specialised sequences of DNA that can insert into plasmids or bacterial chromosomes

16. Mechanism of Antibiotic Resistance Structurally modified antibiotic target site, resulting in: • Reduced antibiotic binding • Formation of a new metabolic pathway preventing metabolism of the antibiotic

17. Structurally Modified Antibiotic Target Site Antibiotics normally bind to specific binding proteins on the bacterial cell surface Antibiotic Binding Target site Cell wall Interior of organism

18. Structurally Modified Antibiotic Target Site Antibiotics are no longer able to bind to modified binding proteins on the bacterial cell surface Antibiotic Modified target site Cell wall Changed site: blocked binding Interior of organism

19. Altered Uptake Of Antibiotics: Decreased Permeability Altered uptake of antibiotics, resulting in: • Decreased permeability • Increased efflux

20. Altered Uptake Of Antibiotics: Decreased Permeability Antibiotics normally enter bacterial cells via porin channels in the cell wall Antibiotic Porin channel into organism Cell wall Interior of organism

21. Altered Uptake Of Antibiotics: Decreased Permeability New porin channels in the bacterial cell wall do not allow antibiotics to enter the cells New porin channel into organism Antibiotic Cell wall Interior of organism

22. Altered Uptake of Antibiotics: Increased Efflux Antibiotics enter bacterial cells via porin channels in the cell wall Porin channel through cell wall Antibiotic Entering Entering Cell wall Interior of organism

23. Altered Uptake of Antibiotics: Increased Efflux Once antibiotics enter bacterial cells, they are immediately excluded from the cellsvia active pumps Antibiotic Porin channel through cell wall Entering Exiting Cell wall Interior of organism Active pump

24. Antibiotics Inactivation (Cleavage) Antibiotic inactivation • Bacteria acquire genes encoding enzymes that inactivate antibiotics Examples include: • -Lactamases • Aminoglycoside-modifying enzymes • Chloramphenicol acetyl transferase

25. Antibiotics Inactivation (Cleavage) Inactivating enzymes target antibiotics Antibiotic Enzyme Binding Target site Cell wall Interior of organism

26. Antibiotics Inactivation (Cleavage) Enzymesbindtoantibioticmolecules Enzymebinding Antibiotic Binding Target site Enzyme Cell wall Interior of organism

27. Antibiotics Inactivation (Cleavage) Enzymes destroy antibiotics or prevent binding to target sites Antibiotic altered, binding prevented Antibioticdestroyed Antibiotic Target site Enzyme Cell wall Interior of organism

28. Multiple Mechanisms Of Antibacterial Resistance Modified target Altered uptake Drug inactivation -lactam + + ++ Glycopeptide + Aminoglycoside – + ++ Tetracycline – + Chloramphenicol – + Macrolide ++ Sulphonamide ++ – Trimethoprim ++ – Quinolones – +

29. Three mechanisms of -lactam antibiotic resistance are recognised: Reduced permeability Inactivation with -lactamase enzymes Altered penicillin-binding proteins (PBPs) -Lactam Antibiotic Resistance Mechanisms

30. -Lactam Antibiotic Resistance Mechanisms

31. AmpC and Extended-Spectrum -lactamase (ESBL) production are the most important mechanisms of -lactam resistance in nosocomial infections The antimicrobial and clinical features of these resistance mechanisms are highlighted in the following slides -Lactam Antibiotic Resistance

32. Worldwide problem: Incidence increased from 17% to 23% between 1991 and 2001 in UK Very common in Gram-negative bacilli AmpC gene is usually sited on chromosomes, but can be present on plasmids Enzyme production is either constitutive (occurring all the time) or inducible (only occurring in the presence of the antibiotic) -Lactam Resistance: AmpC Production Pfaller et al. Int J Antimicrob Agents 2002;19:383–388; Sader et al. Braz J Infect Dis 1999;3:97–110; Livermore et al. Int J Antimicrob Agents 2003;22:14−27

33. An increasing global problem Found in a small, expanding group ofGram-negative bacilli, most commonly the Entero-bacteriaceae spp. Usually associated with large plasmids Enzymes are commonly mutants of TEM- and SHV-type -lactamases -Lactam Resistance: ESBL Production Jones et al. Int J Antimicrob Agents 2002;20:426–431; Sader et al. DiagnMicrobiol Infect Dis 2002;44:273–280

34. Inhibited by -lactamase inhibitors Usually confer resistance to: 1, 2 and 3rd generation Cephalosporins eg. Ceftazidime Monobactams eg. Aztreonam Carboxypenicillins eg. Carbenicillin Varied susceptibility to Piperacillin / Tazobactam Typically susceptible to Carbapenemsand Cephamycins Often non-susceptible to fourth generation Cephalosporins Antimicrobial Features of ESBLs

35. Introduction of methicillin in 1959 was followed rapidly by reports of MRSA isolates Recognizedhospital pathogen since the 1960s Major cause of nosocomial infections worldwide Contributes to 50% of infectious morbidity in ICUs Surveillance studies suggest prevalence has increased worldwide, reaching 25–50% in 1997 Features of methicillin-resistant Staphylococcus aureus (MRSA) Jones. Chest 2001;119:397S–404S

36. MRSA in hospitals leads to an associated rise in incidence in the community Community-acquired MRSA strains may be distinct from those in hospitals In a hospital-based study, >40% of MRSA infections were acquired prior to admission Risk factors for community acquisition included: Recent hospitalization; Previous antibiotic therapy Residence in a long-term care facility; Intravenous drug use Emergence of MRSA in the community • Hiramatsu et al. Curr Opin Infect Dis 2002;15:407–413 • Layton et al. Infect Control Hosp Epidemiol 1995;16:12–17; Naimi et al. 2003;290:2976−2984

37. Mechanism involves altered target site new penicillin-binding protein — PBP 2' (PBP 2a) encoded by chromosomally located mecA gene Confers resistance to all -lactams Gene carried on a mobile genetic element — staphylococcal cassette chromosome mec (SCCmec) Laboratory detection requires care Not all mecA-positive clones are resistant to methicillin Antimicrobial features of MRSA (1) • Hiramatsu et al. Trends Microbiol 2001;9:486–493 • Berger-Bachi & Rohrer. Arch Microbiol 2002;178:165–171

38. Cross-resistance common with many other antibiotics Ciprofloxacin resistance is a worldwide problem in MRSA: involves ≥2 resistance mutations usually involves parC and gyrA genes renders organism highly resistant to ciprofloxacin, with cross-resistance to other quinolones Intermediate resistance to glycopeptides first reported in 1997 Antimicrobial features of MRSA (2) • Hiramatsu et al. J Antimicrob Chemother 1997;40:135–136 • Hooper. Lancet Infect Dis 2002;2:530–538

39. Vancomycin-resistant enterococci (VRE) Vancomycin-resistant S. aureus (VRSA) Glycopeptide resistance: focus on vancomycin resistance

40. Resistance most common in organisms associated with nosocomial infections Pseudomonas aeruginosa Acinetobacter spp. also increasing among ESBL-producing strains Meropenem Yearly Susceptibility Test Information Collection (MYSTIC) surveillance programme (1997―2000) 13.4% of Gram-negative strains resistant to ciprofloxacin P. aeruginosa and Acinetobacter baumannii are the most prevalent resistant strains increasing prevalence of resistance during surveillance period Features of quinoloneresistance: Gram-negative organisms • Masterton. J Antimicrob Chemother 2002;49:218–220 Thomson. J Antimicrob Chemother 1999;43(Suppl. A):31–40

41. MRSA S. aureus occurred in 22.9% of pneumonias in hospitalised patients in USA and Canada (1997 SENTRY data) Enterococcus spp. resistance has developed rapidly, especially among VRE Streptococcus pneumoniae resistance emerging in many countries, including community-acquired resistance Hong Kong (12.1%), Spain (5.3%) and USA (<1%) marked cross-resistance with other frequently used antibiotics Features of quinoloneresistance: Gram-positive organisms • Hooper. Lancet Infect Dis 2002;2:530–538

42. Antibiotic resistance in the hospital setting is increasing at an alarming rateand is likely to have an important impact on infection management Steps must be taken now to control the increase in antibiotic resistance Summary • Cosgrove et al. Arch Intern Med 2002;162:185–190

43. The Academy for Infection Management supports the concept of using appropriate antibiotics early in nosocomial infections and proposes: selecting the most appropriate antibiotic based on the patient, risk factors, suspected infection and resistance administering antibiotics at the right dose for the appropriate duration changing antibiotic dosage or therapy based on resistance and pathogen information recognising that prior antimicrobial administration is a risk factor for the presence of resistant pathogens knowing the unit’s antimicrobial resistance profile and choosing antibiotics accordingly Summary

44. Hand washing plays an important role in nosocomial pneumonias Wash hands before and after suctioning, touching ventilator equipment, and/or coming into contact with respiratory secretions. Use a continuous subglottic suction ET tube for intubations expected to be > 24 hours Keep the HOB elevated to at least 30 degrees unless medically contraindicated

45. Outline of the talk • Various Antibiotic Classes • Mechanisms of action of Anti Bacterials • Mechanisms of Bacterial Resistance • Animation on Drug Resistance •  Lactamases – Drug Resistance • NDM1 – Superbug – Concerns • Other Superbugs – Global Issues • How to prevent Drug Resistance • Where we are heading in future

46. Various Antibiotic Classes • Mechanisms of action of Anti Bacterials • Mechanisms of Bacterial Resistance • Animation on Drug Resistance •  Lactamases – Drug Resistance • NDM1 – Superbug – Concerns • Other Superbugs – Global Issues • How to prevent Drug Resistance • Where we are heading in future

47. Bad Bugs, No Drugs1 The Antimicrobial Availability Task Force of the IDSA1 identified as particularly problematic pathogens A. baumannii and P. aeruginosa ESBL-producing Enterobacteriaceae MRSA Vancomycin-resistant enterococcus Declining research investments in antimicrobial development2 • 1. Infectious Diseases Society of America. Bad Bugs, No Drugs: As Antibiotic Discovery Stagnates, A Public Health Crisis Brews. http://www.idsociety.org/pa/IDSA_Paper4_final_web.pdf. July, 2004. Accessed March 17, 2007. 2. Talbot GH, et al. Clin Infect Dis. 2006;42:657-68.

49. Enterobacteriaceae The rapid and disturbing spread of: extended-spectrum ß-lactamases AmpC enzymes carbapenem resistance metallo-β-lactamases KPC and OXA-48 β-lactamases quinolone resistance

50. β-lactamases capable of conferring bacterial resistance to the penicillins first-, second-, and third-generation cephalosporins aztreonam (but not the cephamycins or carbapenems) These enzymes are derived from group 2b β-lactamases (TEM-1, TEM-2, and SHV-1) differ from their progenitors by as few as one AA Extended-Spectrum β-Lactamases