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 VA for 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 ATB R 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. baumannii are 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. Survey of “Resistance genes” in A. baumannii blaAMEsQRDRRND Efflux pumps OMPsTet ADCaacC1gyrAAdeABCHMP-ABtetA OXAaacC2parCAdeMOmpAtetB IMPaacC3AdeIJK33-36 kDatetM VIM, GIM SIM, SPM, NDM aacA4AdeS CraS AdeDE 25/29 kDa CarO tetX PERaphA1 Res Is?? OprD (43kDA) PBPs TEM*aphA6AbaR 1-24OmpW SHVaadA1 Col R pmrAB 44, 47kDa, 22 integrons CTX-Mrmt*OMVs

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

10. 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

11. Part II MDR P. aerugoinosa The resistance challenge of the ages

12. Pa facts Colonization rates by Pa are high in the hospital (50%); immunity and burn Seriously ill patients in 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,

13. Mechanisms of resistance in Pa

14. Pa and ATB R ß-lactamases-all classes represented –Cephalosporinases, –class A ESBLs (PER), –OXA ESBLs (OXA-10, -14), –Carbapenemases (KPC and GES), M  Ls Loss of permeability (porins and efflux)

15. Back to school: mechanism of action

16. Mechanisms of resistance

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

18. Colistin is King???

19. CID 2010

20. The colistin “bottom line” “Efficacy rate” of 57-76% in IV form; “microbiological eradication” of 67-90.9%Renal tox 0-37% Nebulized colistin (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/IVe colistin (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

21. Tigecycline? 1.Rapid resistance can emerge; 2.Cases of breakthrough bacteremia reported; 3. Adequacy of blood levels?? 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. Patients% Improvement 2584 1850 1782.4 2930 7570 3468 4578-90% Major concerns…real ? 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

23. Colistin and vanco??

24. Combination therapy for PSDA?

25. The worst case scenario?

26. 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