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Gram Negatives : Clinical Management of the Multi-drug Resistant infections

Gram Negatives : Clinical Management of the Multi-drug Resistant infections. Karl Weiss, MD, MSc, FRCPC Hôpital Maisonneuve-Rosemont Faculté de Médecine University of Montreal. Disclosure. Research grants Abbott Bayer Bristol Myers Squibb Genzyme corp. Glaxo-SmithKline

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Gram Negatives : Clinical Management of the Multi-drug Resistant infections

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  1. Gram Negatives : Clinical Management of the Multi-drug Resistant infections Karl Weiss, MD, MSc, FRCPC Hôpital Maisonneuve-Rosemont Faculté de Médecine University of Montreal

  2. Disclosure Research grants • Abbott • Bayer • Bristol Myers Squibb • Genzyme corp. • Glaxo-SmithKline • Government of Canada • Merck-Frosst • Optimer Pharma • Pfizer • Roche • Sanofi-Aventis • Theravance • Valorisation Recherche Quebec

  3. Objectives • 1. review the current knowledge of clinical management of ESBL infections. • 2. Understand the impact of carbapenemases producing organisms in terms of therapeutic options. • 3. revisit the old new classes of antibiotics • 4. briefly discuss the infection control issues for ESBL, KPC…. • 5. Get the list of my favourite restaurants in Montreal !

  4. Gram Negative Organisms • Gram-negative organisms • ESBL • Carbapenemases producing organisms • AmpC

  5. Weiss K el al. Conseil du médicament du Québec.

  6. A new threat for canadians ? Simner PJ et al. Diag Microbiol Infect Dis 2011:69:326-334.

  7. Gram Negatives organisms • Heterogenous group of bacteria compared to VRE or MRSA • Single organism vs multiple • Historically viewed as less threatening • Mostly hospital-acquired organims (ie : MRSA) • Increasing community-acquired UTIs

  8. ESBL • ESBLs hydrolyse penicillins, cephalosporins (except cephamycins) and aztreonam. • Variation among the degree of hydrolytic activity. • TEM and SHV have greater activity against ceftazidime than cefotaxime, in contrast to CTX-M. • Bonnet R. AAC 2004;48:1-14

  9. Questions • Four Statements • 1. All cephalosporins are useless against ESBL-producing bacteria • 2. All carbapenems are equal against ESBL-producing bacteria • 3. Fluoroquinolones have a role against ESBL-producing bacteria • 4. Piperacillin-tazobactam is a good therapeutic alternative

  10. ESBL • Clinical consequences • Increased morbidity ? • Increased mortality ? • What type of infections • Urinary tract infections • Bacteremia (UTI or biliary tract origin) • Intra-abdominal

  11. The ESBL confusion ! • If you are confused… • It is just starting ….

  12. ESBL • Heterogenous not only in terms of species (E.coli and Klebsiella sp) but also in terms of enzymes (TEM, SHV, CTX-M…). • More studies with K. pneumoniae than E. coli • Falagas ME et al. J of Hospital Infection 2009;73:345-354.

  13. Impact on mortality • Non comparative studies • 2 studies • Paterson et al. JCM 2001; 39:2206-12 • Wong-Beringer et al. CID 2002;34:135-46. • Small number of patients (10-36) • Variable rates of failure, heterogeous groups • Comparative studies finding no effect of ESBL on outcomes • 6 studies • Comparative studies finding important effects of ESBL on outcomes • 3 studies Ramphal R et al CID 2006;46: suppl 4 : S164-172.

  14. Clinical impact of ESBL infections

  15. ESBL : clinical impact 10 / 53 18.8 % 14 / 115 12.1 %

  16. An example of what is available Chinese study, retrospective, 85 patients, one center. ESBL : 27 % of all isolates Du B et al. Intensive Care Med 2002:28:1718-1723.

  17. Impact of antibiotic treatment

  18. ESBL : even more confusing • 36 episodes of bacteremia (E. coli + Klebsiella, 5 types of ESBL : 3 TEM/2 SHV) • Avoid ceftazidime, ceftazidime < ceftriaxone or cefotaxime Wong-Beringer A et al. CID 2002;34:135-46.

  19. ESBL • Issues with studies • Small number of patients • Rarely prospective • Heterogenous (bacteria + type of ESBL) • Underlying medical conditions (bacteremia) • Increasing carriage in the community but still rare … why ? Biased perspective ? • Rodriguez-Bano J et al. JAC 2008;62:1142-1149.

  20. CJIDMM 2009

  21. Will Tigecycline save the day ? Morosini MI et al. AAC 2006;50:2695-2699.

  22. Tigecycline activity against ESBLs

  23. Tigecycline and Carbapenems-resistant ESBLs • Ertapenem resistance among ESBL K.pneumoniae isolates • Multicenter israeli study : 25/663 (2.3%) • Some were resistant to Imipenem-meropenem, others S. • Leavitt A et al. JCM 2009;47:969-74. • Ertapenem-resistant ESBL producing Klebsiella pneumoniae treated with tigecycline. • Chen PL et al. Diag Microbiol Infect Dis 2010:68:312-314. • Skurnik D et al. Case-report, mediastinitis. J of Medical Microbiology 2010;59:115-119.

  24. Treatment : cephalosporins. • Cefepime • Better in vitro activity against ESBL-producing bacteria. • Limited clinical data • Nosocomial pneumonia in the ICU (failure : 4/13 vs 0/10 for imipenem). • Zanetti G et al. AAC 2003;47(11):3442-7. • Cephamycins • Flomoxef (available in Taiwan)- 27 patients. • Equivalent to carbapenems • Lee CH et al/ JAC 2006:58:1074-1077. • Ceftaroline

  25. Treatment • Beta-lactams/B-lactamase inhibitor combinations

  26. Fosfomycin • Introduced in 1988, 40 countries, over 20 million scripts. • Available in Canada as a sachet (contains 3 g of fosfomycin) – Monurol. • Mandarin or orange flavor • Dose : 1 sachet as a single dose for uncomplicated UTIs in adults. • 93 % efficacy is a spanish study (community-acquired ESBL infections). • Intravenous formulation (Japan) Falagas ME et al. www.thelancet.com/infection vol 10, January 2010.

  27. Treatment Paterson DL. CMI,2000;6:460-63. Pitout J. Drugs, 2010;70:313-333.

  28. ESBL decolonisation • Prospective, controlled cohort study, 100 patients. • Chlorhexidine 0.2 % mouth rinse 3X daily • Paromomycin : 1 g daily X 4 • Oral antibiotics for UTI colonisation • Success : 15/18 • Very limited data, but some potential. • Buehlmann M et al. J Hosp Infect 2011,77(2):113-7.

  29. ESBL : infection control in Canada Ofner-Agostini M et al. AJIC 2007;Nov;35(9):563-8.

  30. The real issue : travelling around the world. • ESBL • Sweden – 100 healthy travelers • 24 % post travel : ESBL-producing E. coli. • India : 7/8 • 10/31 : other Asian countries • 4/14 : Middle East • Tham J et al. Scand J Infect Dis 2010;42:275-80 • Laupland KB et al. J Infect 2008;57:441-8

  31. Carbapenemases • Klebsiella pneumoniae Carbapenemases (KPC) • MBLs : hydrolyze all Beta-lactams (except aztreonam) • New Dehli metallo-beta-lactamases (NDM-1)

  32. Carbapenemases • 1998 : KPC in the USA. • Yigit H et al, 2001 AAC 45:1151-1161. ICARE project • Plasmid-mediated • Several variants : KPC 1-7 • KPCs alone reduce susceptibility to carbapenems / need to have impaired outer-membrane permeability for full resistance. • MBL • Pseudomonas spp • Enterobacteriaceae (K. pneumoniae, Citrobacter freundii, E. coli….) • NDM-1 : emerging problem worldwide • Yong D et al. AAC, 2009:53:5046-5054

  33. Ambler Classification of B-lactamases

  34. Carbapenemases • First canadian cases • Goldfarb D et al. JCM 2009,47(6):1920-1922.

  35. Carbapenemases • European consensus • Grundmann H et al. Euro Surveill 2010 Nov 18;15(46).pii: 19711. • K. Pneumoniae ST258 is a major concern (KPC) • NDM-1 is a major epidemiological challenge and a threat to hospital patients. • Transfer of carbapenem-resistant plasmid from K. pneumoniae to E.coli • Goren MG et al. Emerg Infect Dis 2010;Jun 16(6):1014-7.

  36. Carbapenemases • Review of 15 publications involving 55 patients • Tigecycline and aminoglycosides were associated with postive outcomes in the majority of cases. • Monotherapy with polymyxins : low clinical success rate • Combination therapy : better outcome • Limited clinical data • Hirsh EB et al. JAC 2010 Jun:65(6):1119-25.

  37. Carbapenemases • How about combination therapy ? • Tigecycline alone vs tigecycline + either meropenem or rifampin in a pulmonary model. • 5 KPC strains • Rifampin : no benefit • Meropenem (if MIC < 16 ug ml) possible benefit • Wiskirchen DE et al AAC 2011, Jan 31.

  38. The old new drugs : the polymyxins • 5 chemically different compounds (polymyxins A-E) • Discovered in 1947 • Only polymyxins B and E (Colistin) have been used in clinical practise. • From Bacillus polymyxa • Introduced in the 1950s

  39. Polymyxins • Two forms : • Colistin sulfate and colistimethate sodium (less potent and less toxic, IV, IM, nebulization). • Binds to LPS and leads to permeability changes • No oral absorption • Renal excretion (60% excreted unchanged) Falagas M et al. CID 2005:40:1333-41

  40. Polymyxins

  41. In vitro susceptibility testing • NCCLS guidelines in 1970, modified in 1981, and withdrawn in 2000. • Disk diffusion (10 ug colistin sulfate disk, Oxoid) • Considered susceptible if zone > or = 11 mm • Agar and broth microdilution acceptable • S < or = 4 mg / ml • R > 8 mg / ml • Gales AC et al. JCM 2001;39:183-90 • Hogardt M et al. JCM 2004;54:1057-61

  42. Polymyxins • USA : 2.5-5 mg / kg per day in 2-4 doses • UK : 4-6 mg / kg per day in 3 doses • Studies : up to 720 mg per day • Markou N et al. Crit Care 2003;7:R78-83. • sometimes given in IU/kg • Intrathecal administration possible but not approved • 3.2-10 mg per day IT, up to 20 mg per day • Benifla M et al. JAC 2004:54:290-2

  43. Polymyxins • Issues • 1. side effects : nephrotoxicity, neurotoxicity • Less than initially described and dose-dependent • 2. Synergistic activity • CF patients : combination with an antipseudomonal agent • Colistin, rifampin and amikacin • Conway SP, Thorax 1997:52:987-93 • Tascini C et al, J Chemother 2004;16:282-7. • Giamarellos-Bourboulis EJ et al Diag Micro and Inf Dis 2002;44:259-63.

  44. Conclusion • Emerging, heterogenous problem • Antibiotic stewardship • Infection control • Old drugs are coming back • Fosfomycin, Polymyxins • Pivmecillinam • Nicolle LE. Scand J Infec Dis 2007;39(8):748-9. • Temocillin • Livermore D et al. JAC 2009;63:243-45. • Vaccines ?

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