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
• NIH and VA for supporting
• Research grants from Case Western Reserve
University, LSCDVAMC Foundation for
Medical Research,
• Pfizer, Steris Corporation, Rib-X, and CheckPoints
• 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. baumannii
bla
AMEs
QRDR
RND
Efflux pumps
OMPs
Tet
ADC
aacC1
gyrA
AdeABC
HMP-AB
tetA
OXA
aacC2
parC
AdeM
OmpA
tetB
IMP
aacC3
AdeIJK
33-36 kDa
tetM
VIM, GIM
SIM, SPM,
NDM
aacA4
AdeS
CraS
AdeDE
25/29 kDa
CarO
tetX
PER
aphA1
Res Is??
OprD
(43kDA)
PBPs
TEM*
aphA6
AbaR 1-24
OmpW
SHV
aadA1
Col R
44, 47kDa, 22
integrons
pmrAB
CTX-M
rmt*
OMVs
“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
• 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
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
Major concerns…real ?
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.
Tigecycline?
Patients
25
18
17
29
75
34
45
% Improvement
84
50
82.4
30
70
68
78-90%
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
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