Why are Acinetobacter and Pseudomonas so antibiotic

resistant?

Robert A. Bonomo, MDChief, Medical Service

Director VISN 10 GRECCLouis Stokes Cleveland VAMC

Vice Chairman, Department of MedicineUniversity Hospitals Case Medical Center

Professor, Case Western Reserve University School of Medicine

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

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

MDR and PDR Ab

Multi-Drug Resistant (MDR) A. baumannii are among the most “problematic

pathogens” encountered by clinicians

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

• 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 ?

Survey of “Resistance genes” in A. baumanniibla AMEs QRDR RND

Efflux pumpsOMPs Tet

ADC aacC1 gyrA AdeABC HMP-AB tetA

OXA aacC2 parC AdeM OmpA tetB

IMP aacC3 AdeIJK 33-36 kDa tetM

VIM, GIMSIM, SPM,

NDM

aacA4 AdeSCraS

AdeDE

25/29 kDa CarO

tetX

PER aphA1 Res Is?? OprD(43kDA)

PBPs

TEM* aphA6 AbaR 1-24 OmpW

SHV aadA1 Col R

pmrAB44, 47kDa, 22 integrons

CTX-M rmt* OMVs

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!

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 IIMDR P. aerugoinosa

The resistance challenge of the ages

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,

Mechanisms of resistance in Pa

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)

Back to school: mechanism of action

Mechanisms of resistance

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?

Colistin is King???

CID 2010

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

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

25 84

18 50

17 82.4

29 30

75 70

34 68

45 78-90%

Major concerns…real ?

bacteremic patients treated with tige failed to clear their bacteremia 10-fold more commonly

than patients treated with comparator drugsGordon JAC 2009, Gardiner CID

Colistin and vanco??

Combination therapy for PSDA?

The worst case scenario?

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