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Why are Acinetobacter and Pseudomonas so antibiotic resistant?

Why are Acinetobacter and Pseudomonas so antibiotic resistant?. Robert A. Bonomo, MD Chief, Medical Service Director VISN 10 GRECC Louis Stokes Cleveland VAMC Vice Chairman, Department of Medicine University Hospitals Case Medical Center

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Why are Acinetobacter and Pseudomonas so antibiotic resistant?

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  1. Why are Acinetobacter and Pseudomonas so antibiotic resistant? Robert A. Bonomo, MD Chief, Medical Service Director VISN 10 GRECC Louis Stokes Cleveland VAMC Vice Chairman, Department of Medicine University Hospitals Case Medical Center Professor, Case Western Reserve University School of Medicine

  2. Appreciation and Disclosures • NIH and VAfor supporting • Research grants from Case Western Reserve University, LSCDVAMC Foundation for Medical Research, • Pfizer, Steris Corporation, Rib-X, and Check-Points • Collaborators

  3. Objectives • Overview of the problem (and crisis) of ATBR in Gram negative bacteria • MDR A.baumannii and Pseudomonas aeruginosa, • Summarize the rapidly expanding landscape of resistance determinants • Use this knowledge to devise effective treatment strategies

  4. Part I MDR and PDR Ab

  5. Multi-Drug Resistant (MDR) A. baumanniiare among the most “problematic pathogens” encountered by clinicians

  6. Acinetobacter has evolved many molecular strategies to escape ALL ANTIBIOTICS that resemble more the tactics of organized crime than traditional warfare

  7. The clinical challenge of A. baumannii • Many hospital acquired infections • Infection control “nightmare” • Relative mortality increased; in many surveys, seems to be the pathogens associated with increased mortality • Difficult to treat because of antibiotic resistance ? Convergence of resistance and virulence ?

  8. “The Resistance Island” 86 Kb, 88 orfs, 82 orfs from another source and 45 resistance genes AbaR1-24! Fournier et al., PLoS Genet. 2006 Jan;2(1):e7. Epub 2006 Jan 13.

  9. Major Threat : Carbapenem R • OXAs and MBLs • Naturally occurring and acquired • OXAs- Types and Groups • Narrow spectrum • Carbapenem hydrolyzing (CHDLs) • ES type • Carbapenemases (Acinetobacter) • Are not ES; do not have both properties • Imipenem> meropenem Poirel et al AAC 2010

  10. Part IIMDR P. aerugoinosa The resistance challenge of the ages

  11. Pa facts • Colonization rates by Pa are high in the hospital (50%); immunity and burn • Seriously ill patientsin ICUs. • Aggregate NNISS and EU data • 20 to 30% of nosocomial pneumonias • 10 to 20% of urinary tract infections • 3% to 10% of bloodstream infections,

  12. Mechanisms of resistance in Pa

  13. Pa and ATBR • ß-lactamases-all classes represented • Cephalosporinases, • class A ESBLs (PER), • OXA ESBLs (OXA-10, -14), • Carbapenemases(KPC and GES), MbLs • Loss of permeability (porins and efflux)

  14. Back to school: mechanism of action

  15. Mechanisms of resistance

  16. Therapy for MDR Ab et al. Do we have enough patients studied properly? Animal models may have (significant) limitations? Colistin? Tigecycline? Minocycline? Rifampin? Teicoplanin? Vancomycin?

  17. Colistin is King???

  18. CID 2010

  19. The colistin “bottom line” “Efficacy rate” of 57-76% in IV form; “microbiological eradication” of 67-90.9%Renal tox 0-37% Nebulizedcolistin (CF studies + others) effective; FDA warning; impact of shift to more resistant strains ; use with IV!! 32+ cases “microbiological eradication” in the CNS with ITh/IVecolistin (safe e 1) (2.5 mg/kg, 10-20 mg ITh) Colistin was independently associated with higher mortality vs. treatment with sulbactam in patients with A. b infections

  20. Tigecycline? Rapid resistance can emerge; Cases of breakthrough bacteremia reported; Adequacy of blood levels?? Major concerns…real ? Pachon and Vila Curr Opin Investig Drugs. 2009 Feb;10(2):150-6. Giamarellou & Poulakou, Drugs. 2009 Michalopoulos A, Falagas ME. Expert Opin Pharmacother. 2010 Apr;11(5):779-88. bacteremic patients treated with tige failed to clear their bacteremia 10-fold more commonly than patients treated with comparator drugs Gordon JAC 2009, Gardiner CID

  21. Colistin and vanco??

  22. Combination therapy for PSDA?

  23. The worst case scenario?

  24. Summary Extraordinary challenge against cunning pathogens Basic understanding of molecular biology is needed (the complexities of resistance genes will only increase) Research is needed in therapeutics and infection control CALL TO ARMS: Coordinate scientific and clinical trials to answer these important questions

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