Why are acinetobacter and pseudomonas so antibiotic resistant
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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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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

Professor, Case Western Reserve University School of Medicine


Appreciation and disclosures

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


Objectives

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


Part i

Part I

MDR and PDR Ab


Why are acinetobacter and pseudomonas so antibiotic resistant

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


Why are acinetobacter and pseudomonas so antibiotic resistant

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


The clinical challenge of a baumannii

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 ?


Why are acinetobacter and pseudomonas so antibiotic resistant

“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.


Major threat carbapenem r

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


Part ii mdr p aerugoinosa

Part IIMDR P. aerugoinosa

The resistance challenge of the ages


Pa facts

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,


Mechanisms of resistance in pa

Mechanisms of resistance in Pa


Pa and atb r

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)


Why are acinetobacter and pseudomonas so antibiotic resistant

Back to school: mechanism of action


Why are acinetobacter and pseudomonas so antibiotic resistant

Mechanisms of resistance


Therapy for mdr ab et al

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?


Why are acinetobacter and pseudomonas so antibiotic resistant

Colistin is King???


Why are acinetobacter and pseudomonas so antibiotic resistant

CID 2010


The colistin bottom line

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


Tigecycline

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


Why are acinetobacter and pseudomonas so antibiotic resistant

Colistin and vanco??


Combination therapy for psda

Combination therapy for PSDA?


Why are acinetobacter and pseudomonas so antibiotic resistant

The worst case scenario?


Summary

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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