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Multi-drug resistant pathogens

Multi-drug resistant pathogens. Helmut Albrecht, MD Division of Infectious Diseases. Disclosures. Grant/Research Support–MSD, J&J, VIIF, Gilead (no payment to me) Consultant–France Foundation (non profit project with Duke), VIIF, Gilead (no honoraria) Speaker’s Bureau–(no honoraria). Agenda.

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Multi-drug resistant pathogens

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  1. Multi-drug resistant pathogens Helmut Albrecht, MD Division of Infectious Diseases

  2. Disclosures • Grant/Research Support–MSD, J&J, VIIF, Gilead (no payment to me) • Consultant–France Foundation (non profit project with Duke), VIIF, Gilead (no honoraria) • Speaker’s Bureau–(no honoraria)

  3. Agenda • State of the union • The players (Resistant pathogens) • What to do about them

  4. Antibiotics • “Deaths in the US declined by 220 per 100,000 with the introduction of sulfonamides and penicillin. This far outweighs any other medical advance in the past century.” • Armstrong et al. JAMA 1999;6:61ff • From 1983 to 2010, FDA approval of new antibiotics has continuously declined, from 4 per year in the early 1980s to less than 1 antibiotic per year now • The last class of drugs with a novel mechanism of action against GN bacteria goes back 40 years. A review of drugs currently in trials revealed no such new drugs. • For the US, antibiotic resistance is responsible for nearly 100,000 deaths caused by hospital-acquired infections per year at an estimated annual cost of $23 billion. • Roberts et al CID 2009;49:1175ff

  5. Why do we see more resistance? • Sicker inpatient population • Patients chronically ill • Larger immunocompromised population • More instrumentation/new procedures • Presence of devices • Increasing resistance in community • Emerging pathogens • Complacency regarding antibiotics • Increased use of (empiric) broad-spectrum antibiotics • Ineffective infection control and compliance • Crowding of patients in confined areas • Decreasing nurse/patient ratio

  6. Why do we see more resistance? • Sicker inpatient population • Patients chronically ill • Larger immunocompromised population • More instrumentation/new procedures • Presence of devices • Increasing resistance in community • Emerging pathogens (Superbugs!) • Complacency regarding antibiotics • Increased use of (empiric) broad-spectrum antibiotics • Ineffective infection control and compliance • Crowding of patients in confined areas • Decreasing nurse/patient ratio

  7. My patient is really ill… • What is the price of prescribing a little more than needed if I do not want to think that hard? • Healthcare dollars (irrelevant, if title true) • C. difficile (potentially deadly) • Side effects (potentially deadly) • Resistance (relevant?)

  8. Getting It RightBloodstream Infections % Mortality

  9. Getting It RightVentilator-associated Pneumonia % Mortality It is a lot more difficult to get it right if the bacteria are multi-drug resistant

  10. Scope of the problem • Nosocomial infections > 8 million excess hospital days • Approximately 80,000 deaths • >75% resistant to at least one drug class • > 50% of inpatients receive antibiotics • 30-50% of these receive them inappropriately • Cost of res. pathogens 100 million - 30 billion US$/year • Phelps Med Care 1989

  11. NEW SUPERBUGS

  12. The Gram Negative Cell Wall Efflux system Porin channels B-lactamases PBPs Adapted from Livermore and Woodford, Trends in Microbiol, 2006.

  13. Bush classification of β-lactamases in GN bacteria

  14. Substrate Profile • Penicillinase • Cephalosporinase • Broad spectrum • Extended broad spectrum • Carbapenemase

  15. Substrate Profile • Penicillinase • Cephalosporinase • Broad spectrum • Extended broad spectrum • Carbapenemase

  16. 19 Months ESBL Klebsiella pneumoniae Outbreak New York Hospital Medical Center of Queens • 432 ceftazidime-resistant Klebsiella pneumoniae • 155 patients colonized (61%) or infected (39%) • 53% crude mortality rate • Not detected for 12 months! Meyer et al. Ann. Int. Med. 119: 353-358 1993

  17. Substrate Profile • Penicillinase • Cephalosporinase • Broad spectrum • Extended broad spectrum • Carbapenemase

  18. Is Klebsiella bad? It depends! Most Klebsiella infections are easy to deal with, but some are worse than others Because the host is bad?! Because the bug is bad?! Because the drugs are bad?!

  19. Susceptibility Profile of KPC-Producing K. pneumoniae

  20. Drugs with Most Reliable Activity Against ESBL-producing Enterobacteriaceae • Carbapenems • (Cephamycins) • (Fluoroquinolones)

  21. Carbapenem Resistance: Mechanisms

  22. Carbapenemases

  23. Carbapenemases in the U.S.

  24. Klebsiella Pneumoniae Carbapenemase • KPC is a class A b-lactamase • Confers resistance to all b-lactams including extended-spectrum cephalosporins and carbapenems • Occurs in Enterobacteriaceae • Most commonly in Klebsiella pneumoniae • Also reported in: K. oxytoca, Citrobacter freundii, Enterobacter spp., Escherichia coli, Salmonella spp., Serratia spp., • Also reported in Pseudomonas aeruginosa (Columbia, thankfully we are talking the country, not us!)

  25. Susceptibility Profile of KPC-Producing K. pneumoniae

  26. KPC Enzymes • Located on plasmids; conjugative and nonconjugative • blaKPC is usually flanked by transposon sequences • blaKPC reported on plasmids with: • Normal spectrum b-lactamases • Extended spectrum b-lactamases • Aminoglycoside resistance

  27. Geographical Distribution of KPC-Producers Frequent Occurrence Sporadic Isolate(s)

  28. KPC Outside of United States • France (Nass et al. 2005. AAC 49:4423-4424) • Singapore (report from survey) • Puerto Rico (ICAAC 2007) • Columbia (Villegas et al. 2006. AAC 50:2880-2882 & ICAAC 07) • Brazil (ICAAC 2007) • Israel (Navon-Venezia et al. 2006. AAC 50:3098-3101) • China (Wei Z, et al. 2007. AAC 51: 763-765)

  29. Inter-Institutional & Inter-State Spread of KPC-Producing K. pneumoniae

  30. Carbapenemase – Producing Enteric GNR; U.K. < 10% susceptible to usual Rx >40% resistant to tigecycline, >90% susceptible to colistin

  31. NDM1 Carbapenemase • First described from India 2008 • Novel resistance mechanism • Gene compatible with multiple types of plasmids- greatly enhances global spread • Already in California, Illinois and Mass. • Some strains sensitive to only polymyxins (highly neuro and nephro-toxic) or Tigecycline • No new drugs close to release

  32. Phenotypic Tests for Carbapenemase Activity • Modified Hodge Test • 100% sensitivity in detecting KPC; also positive when other carbapenemases are present • 100% specificity Procedure described by Lee et al. CMI, 7, 88-102. 2001.

  33. New transmission mechanisms • NDM-1: 77 cases in 13 European countries • 60% from England • Travel to India (including medical tourism) • ESBLs • Travellers diarrhea • Foodborne outbreak • Adoption

  34. 25% of E. coli ESBL (3% Europe, 79 % India, 50% Egypt, 22% Thailand) • Antibiotic use not predictive except for ciprofloxacin • 5/21 persistently colonized

  35. 156 pts affected • 35% of kitchen surfaces colonized • 6 of 44 (14%) of food workers fecal carriers • 2 y.o. from China • Adopted • Secondary transmission in family

  36. Modified Hodge Test Lawn of E. coli ATCC 25922 1:10 dilution of a 0.5 McFarland suspension Test isolates Imipenem disk Described by Lee et al. CMI, 7, 88-102. 2001.

  37. Which is more dangerous?

  38. Resistance in gram-positive organisms • 1990 1997 2000 • PRSP 4% 30-50% 48% • VTSP < 0.2% 3.6-5.1% • MRSA 20-25% 25-50% • GISA 0 <0.1 <0.1 • VRE <0.1 15 21

  39. Community acquired (ca-) MRSA strains generally CANNOT be distinguished from hospital acquired strains by the presence of: • MEC-A gene • SCC pattern • Panton-Valentine leukocidin Evolution of E. faecium resistance • MIC90 of E. faecium • 1968 1969-88 1989-90 • Penicillin 8 64 512 • Ampicillin 2 32 128 • % VRE 0 0 61% Grayson et al, AAC

  40. Why is this different? • Outbreaks in new populations • Different disease spectrum (boils, CAP) • Spider bite history • Specific clones • SCCmec type IV • Panton-Valentine Leukocidin (PVL) • Susceptible to many antibiotics

  41. Children Inmates Military recruits Native populations MSM HIV+ patients Religious communities Football teams Wrestlers Gymnasts Fencing teams IDU Homeless Populations with ca-MRSA

  42. Clinically Relevant CA-MRSA Disease(GA/MD/MN n=1,674, 78%) Fridkin et al. NEJM, 2005

  43. MRSA skin infection: differential diagnosis • Common misdiagnosis: “spider bite”, complete with history of having been bitten!

  44. Range of the brown recluse

  45. déjà vu

  46. déjà vu II • Phage type 80/81: PCN-R clone of SA • Neonatal outbreaks in Australia in 50’s • Became pandemic in adults/children • in hospitals/communities • Highly transmissible and virulent • Carried leukocidin • Robinson et al • Phage type 80/81 carried PVL • MLST 30 • Current SWP clone of CA-MRSA • descendant – acquired SCC IV

  47. Okuma et al. J Clin Micro 2002

  48. Distribution of Virulence and Resistance DeterminantsCA-MRSA (France, Switzerland, USA, Oceania) Vandenesch et al. EID Aug 2003

  49. PVL associated with severe disease • Necrotizing pneumonias • Septic syndrome • Empyema • Most CA-MRSA strains PVL + • Causal role in severe disease presentations is not proven

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