Transcript Multi-drug resistant pathogens

Multi-drug resistant pathogens
Helmut Albrecht, MD
Division of Infectious Diseases
Disclosures
• Grant/Research Support–MSD, J&J, VIIF,
Gilead (no payment to me)
• Consultant–France Foundation (non profit
project with Duke), VIIF, Gilead (no
honoraria)
• Speaker’s Bureau–(no honoraria)
Agenda
• State of the union
• The players (Resistant pathogens)
• What to do about them
Antibiotics
• “Deaths in the US declined by 220 per 100,000 with the
introduction of sulfonamides and penicillin. This far
outweighs any other medical advance in the past century.”
Armstrong et al. JAMA 1999;6:61ff
• From 1983 to 2010, FDA approval of new antibiotics has
continuously declined, from 4 per year in the early 1980s
to less than 1 antibiotic per year now
• The last class of drugs with a novel mechanism of action
against GN bacteria goes back 40 years. A review of drugs
currently in trials revealed no such new drugs.
• For the US, antibiotic resistance is responsible for nearly
100,000 deaths caused by hospital-acquired infections per
year at an estimated annual cost of $23 billion.
Roberts et al CID 2009;49:1175ff
Why do we see more resistance?
•
•
•
•
•
•
•
•
•
•
•
•
Sicker inpatient population
Patients chronically ill
Larger immunocompromised population
More instrumentation/new procedures
Presence of devices
Increasing resistance in community
Emerging pathogens
Complacency regarding antibiotics
Increased use of (empiric) broad-spectrum antibiotics
Ineffective infection control and compliance
Crowding of patients in confined areas
Decreasing nurse/patient ratio
Why do we see more resistance?
•
•
•
•
•
•
•
•
•
•
•
•
Sicker inpatient population
Patients chronically ill
Larger immunocompromised population
More instrumentation/new procedures
Presence of devices
Increasing resistance in community
Emerging pathogens (Superbugs!)
Complacency regarding antibiotics
Increased use of (empiric) broad-spectrum antibiotics
Ineffective infection control and compliance
Crowding of patients in confined areas
Decreasing nurse/patient ratio
My patient is really ill…
What is the price of prescribing a little more than
needed if I do not want to think that hard?
•
•
•
•
Healthcare dollars (irrelevant, if title true)
C. difficile (potentially deadly)
Side effects (potentially deadly)
Resistance (relevant?)
Getting It Right
Bloodstream Infections
45
% Mortality
40
Appropriate Therapy
Inappropriate Therapy
35
38.4
34.4
30
30.7
25
27.4
20
20.2
15
17.8
10
5
0
Kang et al
Micek et al
Leibovici et al
Getting It Right
Ventilator-associated Pneumonia
100
90
80
% Mortality
91.2
Appropriate Therapy
70
Inappropriate Therapy
60
50
40
44.2
30
37.1
37.5
20
10
15.6
14.8
0
Clec'h et al
Luna et al
Rello et al
It is a lot more difficult to get it right if the bacteria are multi-drug resistant
Scope of the problem
• Nosocomial infections > 8 million excess hospital days
• Approximately 80,000 deaths
• >75% resistant to at least one drug class
• > 50% of inpatients receive antibiotics
• 30-50% of these receive them inappropriately
• Cost of res. pathogens 100 million - 30 billion US$/year
Phelps Med Care 1989
NEW SUPERBUGS
The Gram Negative Cell Wall
Efflux system
Porin
channels
B-lactamases
PBPs
Adapted from Livermore and Woodford, Trends in Microbiol, 2006.
Bush classification of
β-lactamases in GN bacteria
Functional
Group
1
2
2
3
4
Major
Subgroups
Attributes
Known
types in 2000
All
Chromosal >>> plasmid, SPICE-A bacteria,
all β-lactams except carbapenem, not
inhibited by beta-lactamase inhibitors
51
2-b
Plasmid >>> chromosomal, broad-spectrum
β-lactamases (TEM, SHV), usually
inhibited by β-lactamase inhibitors
16
2-be
Plasmid >>> chromosomal, ESBLs,
variably inhibited by β-lactamase inhibitors
119
3-a,b,c
All
Metallo β-lactamases, ESBLs including
carbapenems (not monobactams)
not inhibited by β-lactamase inhibitors
Mixed group (incl. B. fragilis)
Inhibited by β-lactamase inhibitors
24
9
Substrate Profile
• Penicillinase
• Cephalosporinase
• Broad spectrum
• Extended broad spectrum
• Carbapenemase
Substrate Profile
• Penicillinase
• Cephalosporinase
• Broad spectrum
• Extended broad spectrum
• Carbapenemase
19 Months ESBL Klebsiella pneumoniae Outbreak
New York Hospital Medical Center of Queens
•
432 ceftazidime-resistant Klebsiella pneumoniae
•
155 patients colonized (61%) or infected (39%)
•
53% crude mortality rate
•
Not detected for 12 months!
Meyer et al. Ann. Int. Med. 119: 353-358 1993
Substrate Profile
• Penicillinase
• Cephalosporinase
• Broad spectrum
• Extended broad spectrum
• Carbapenemase
Is Klebsiella bad?
It depends!
Most Klebsiella infections are easy to deal
with, but some are worse than others
Because the host is bad?!
Because the bug is bad?!
Because the drugs are bad?!
Susceptibility Profile of KPCProducing K. pneumoniae
Antimicrobial
Interpretation
Antimicrobial
Interpretation
Amikacin
I
Chloramphenicol R
Amox/clav
R
Ciprofloxacin
R
Ampicillin
R
Ertapenem
R
Aztreonam
R
Gentamicin
R
Cefazolin
R
Imipenem
R
Cefpodoxime
R
Meropenem
R
Cefotaxime
R
Pipercillin/Tazo
R
Cetotetan
R
Tobramycin
R
Cefoxitin
R
Trimeth/Sulfa
R
Ceftazidime
R
Polymyxin B
MIC >4mg/ml
Ceftriaxone
R
Colistin
MIC >4mg/ml
Cefepime
R
Tigecycline
S
Drugs with Most Reliable Activity Against
ESBL-producing Enterobacteriaceae
• Carbapenems
• (Cephamycins)
• (Fluoroquinolones)
Carbapenem Resistance:
Mechanisms
Enterobacteriaceae
Cephalosporinase + porin loss
Carbapenemase
P. aeruginosa
Porin loss
Up-regulated efflux
Carbapenemase
Acinetobacter spp.
Cephalosporinase + porin loss
Carbapenemase
Carbapenemases
Classification
Enzyme
Most Common Bacteria
Class A
KPC, SME,
IMI, NMC,
GES
Enterobacteriaceae
(rare reports in P. aeruginosa)
Class B
IMP, VIM,
(metallo-b-lactamse) GIM, SPM
NDM
P. aeruginosa
Enterobacteriacea
Acinetobacter spp.
Class D
Acinetobacter spp.
OXA
Carbapenemases in the U.S.
Enzyme
Bacteria
KPC, NDM
Enterobacteriaceae
Metallo-b-lactamase
P. aeruginosa
OXA
Acinetobacter spp.
SME
Serratia marcesens
Klebsiella Pneumoniae Carbapenemase

KPC is a class A b-lactamase


Occurs in Enterobacteriaceae



Confers resistance to all b-lactams including extendedspectrum cephalosporins and carbapenems
Most commonly in Klebsiella pneumoniae
Also reported in: K. oxytoca, Citrobacter freundii,
Enterobacter spp., Escherichia coli, Salmonella spp.,
Serratia spp.,
Also reported in Pseudomonas aeruginosa (Columbia,
thankfully we are talking the country, not us!)
Susceptibility Profile of KPCProducing K. pneumoniae
Antimicrobial
Interpretation
Antimicrobial
Interpretation
Amikacin
I
Chloramphenicol R
Amox/clav
R
Ciprofloxacin
R
Ampicillin
R
Ertapenem
R
Aztreonam
R
Gentamicin
R
Cefazolin
R
Imipenem
R
Cefpodoxime
R
Meropenem
R
Cefotaxime
R
Pipercillin/Tazo
R
Cetotetan
R
Tobramycin
R
Cefoxitin
R
Trimeth/Sulfa
R
Ceftazidime
R
Polymyxin B
MIC >4mg/ml
Ceftriaxone
R
Colistin
MIC >4mg/ml
Cefepime
R
Tigecycline
S
KPC Enzymes

Located on plasmids; conjugative and
nonconjugative

blaKPC is usually flanked by transposon
sequences

blaKPC reported on plasmids with:
Normal spectrum b-lactamases
 Extended spectrum b-lactamases
 Aminoglycoside resistance

Geographical Distribution of
KPC-Producers
Frequent Occurrence
Sporadic Isolate(s)
KPC Outside of United States

France (Nass et al. 2005. AAC 49:4423-4424)

Singapore (report from survey)

Puerto Rico (ICAAC 2007)

Columbia (Villegas et al. 2006. AAC 50:2880-2882 & ICAAC 07)

Brazil (ICAAC 2007)

Israel (Navon-Venezia et al. 2006. AAC 50:3098-3101)

China (Wei Z, et al. 2007. AAC 51: 763-765)
Inter-Institutional & Inter-State Spread of
KPC-Producing K. pneumoniae
Carbapenemase – Producing
Enteric GNR; U.K.
< 10% susceptible to usual Rx
>40% resistant to tigecycline, >90% susceptible to colistin
NDM1 Carbapenemase

First described from India 2008

Novel resistance mechanism

Gene compatible with multiple types of
plasmids- greatly enhances global spread

Already in California, Illinois and Mass.

Some strains sensitive to only polymyxins
(highly neuro and nephro-toxic) or Tigecycline

No new drugs close to release
Phenotypic Tests for
Carbapenemase Activity

Modified Hodge Test

100% sensitivity in detecting KPC; also positive
when other carbapenemases are present

100% specificity
Procedure described by Lee et al. CMI, 7, 88-102. 2001.
New transmission mechanisms

NDM-1: 77 cases in 13 European countries
60% from England
 Travel to India (including medical tourism)


ESBLs
Travellers diarrhea
 Foodborne outbreak
 Adoption




25% of E. coli ESBL (3%
Europe, 79 % India, 50%
Egypt, 22% Thailand)
Antibiotic use not predictive
except for ciprofloxacin
5/21 persistently colonized

156 pts affected

35% of kitchen
surfaces colonized

6 of 44 (14%) of
food workers fecal
carriers

2 y.o. from China

Adopted

Secondary
transmission in
family
Modified Hodge Test
Lawn of E. coli ATCC 25922
1:10 dilution of a
0.5 McFarland suspension
Test isolates
Imipenem disk
Described by Lee et al. CMI, 7, 88-102. 2001.
Which is more dangerous?
Resistance in gram-positive organisms
1990
1997
2000
PRSP
4%
30-50%
48%
VTSP
< 0.2%
3.6-5.1%
MRSA
20-25%
25-50%
GISA
0
<0.1
<0.1
VRE
<0.1
15
21
1.MEC-A gene
2.SCC pattern
3.Panton-Valentine leukocidin
Evolution of E. faecium
resistance
MIC90 of E. faecium
1968
1969-88
1989-90
Penicillin
8
64
512
Ampicillin
2
32
128
% VRE
0
0
61%
Grayson et al, AAC
Why is this different?
Outbreaks in new populations
Different disease spectrum (boils, CAP)
Spider bite history
Specific clones
SCCmec type IV
Panton-Valentine Leukocidin (PVL)
Susceptible to many antibiotics
Populations with ca-MRSA
• Children
• Football teams
• Inmates
• Wrestlers
• Military recruits
• Gymnasts
• Native populations
• Fencing teams
• MSM
• IDU
• HIV+ patients
• Homeless
• Religious communities
Clinically Relevant CA-MRSA Disease
(GA/MD/MN n=1,674, 78%)
Disease Syndrome
Skin/soft tissue (non-Trauma)
Abscess
Cellulitis
Folliculitis
Other/Unknown
Wound (Traumatic)
Urinary Tract Infection
Sinusitis
Bacteremia
Pneumonia
Osteomyelitis
Septic arthritis
Bursitis
No. (%)
1, 266 (77%)
751 (59%)
528 (42%)
88 ( 7%)
212 (17%)
157 (10%)
64 ( 4%)
61 ( 4%)
43 ( 3%)
31 ( 2%)
21 ( 2%)
15 ( 1%)
19 ( 1%)
Fridkin et al. NEJM, 2005
MRSA skin infection: differential
diagnosis
Common misdiagnosis:
“spider bite”, complete
with history of having
been bitten!
Range of the brown recluse
déjà vu
Prevalence of PCN resistant Staph aureus
100
80
Hospital
Community
60
40
20
0
1940
1950
1960
1970
1980
déjà vu II
Phage type 80/81: PCN-R clone of SA
Neonatal outbreaks in Australia in 50’s
Became pandemic in adults/children
in hospitals/communities
Highly transmissible and virulent
Carried leukocidin
Robinson et al
Phage type 80/81 carried PVL
MLST 30
Current SWP clone of CA-MRSA
descendant – acquired SCC IV
Okuma et al. J Clin Micro 2002
Distribution of Virulence and Resistance Determinants
CA-MRSA
(France, Switzerland, USA, Oceania)
Gene/Gene Product
SCCmec IV
PVL
lukE-lukD (leukocidin)
γ-hemolysin
γ -hemolysin variant
enterotoxin a
enterotoxin b
enterotoxin c
enterotoxin h
enterotoxin k
Total n=117 (%)
117 (100%)
117 (100%)
116 (99%)
13 (11%)
100 (85%)
23 (20)
9 (8%)
20 (17%)
29 (25%)
24 (21%)
Vandenesch et al. EID Aug 2003
PVL associated with severe
disease
Necrotizing pneumonias
Septic syndrome
Empyema
Most CA-MRSA strains PVL +
Causal role in severe disease presentations is not
proven
Centers for Disease Control Campaign
12 steps to prevent antimicrobial resistance
Prevent Infection
• Vaccinate
• Remove catheters
Diagnose and Treat Effectively
• Target the pathogen
• Access the experts
Use Antimicrobials Wisely
•
•
•
•
•
Practice antimicrobial control
Use local data
Treat infection, not colonization
Know when to say no to vancomycin
Stop treatment when infection is cured or unlikely
Prevent transmission
• Isolate the pathogen
• Brake the chain of contagion
How To Prevent Resistance

Adequate infection control

Appropriate use of antibiotics
Strategies for Managing Outbreaks of Resistance
Lack of association
of resistance with a
plasmid mechanism
Favors clonal or
oligoclonal epidemiology
Amenable to strict
infection control procedures
Plasmid-mediated
mechanism
Polyclonal
epidemiology
Necessitates antibiotic
restriction before
significant reduction in
resistance occurs
Ahmad M et al. Clin Infect Dis 1999;29:352-355
Optimal Use of Antimicrobial:
It’s Role in Preventing Resistance
Will optimal use, including control of antibiotic
use, prevent or slow the emergence of resistance?
“It is unlikely that the resistance problem will rapidly
wane, simply by being more prudent in our use of
antimicrobial agents; on the other hand, it is certain
that if we do not cut back on the use of these agents, the
resistance problem will worsen.”
Williams Science 1998;279:1153
What to do to slow antibiotic resistance
Aggressively attack misuse
• Animal feeds and “treatment” of inanimate objects
• Upper respiratory tract infection
• Colds
• Sinusitis
• Pharyngitis
• Bronchitis - acute
• Fever without evidence of bacterial infections
• ICUs
• Children
• Chronic care facilities
Appropriate Use of Antibiotics
The appropriate empiric treatment for the patient with
Sneezococcus congestii
Coughobacillus snifficile
is Tylenol, decongestants and antitussives not antibiotics
If the patient is really sick and may have pneumonia with
Tyrannococcus rex or other superbugs
you may want to consider Bumfacillin or Gorillamycin
SHEA and IDSA
Recommendation for Hospitals
• Implementation of a system for periodic monitoring of antimicrobial
resistance in community and nosocomial isolates
• Implementation of a system for periodic monitoring of antibiotic use
according to hospital location and/or prescribing service
• Monitoring of relationship between antibiotic use and resistance,
assignment of responsibility through practice guidelines or other
institutional policies
• Application of contact isolation precautions in patients known or
suspected to be colonized or infected with epidemiologically
important microorganisms
Can we win the global battle?
• Keep on developing new antibiotics
• Surprise your opponent (combination, rotation)
• Use the optimal dose of the right antibiotic
for the appropriate duration of therapy
• Know as much about antibiotics as your ID folks
alternatively call them to help you
Double coverage?
• Reasonable data for some gram-positives
• No good data for gram-negatives
• May still be reasonable to cover 2 organisms
and in specific situations
• Double coverage across the board will result in
increased financial burden, resistance, drugassociated morbidity, and potentially antagonism
Synergy vs. antagonism
1 + 1 = 3 vs. 1 + 1 = 0
=
=
Can we win the global battle?
• Keep on developing new antibiotics
• Surprise your opponent (combination, rotation)
• Use the optimal dose of the right antibiotic
for the appropriate duration of therapy
• Know as much about antibiotics as your ID
folks, alternatively call them to help you
Know Antibiotic Principles!
Drug levels and activity
• Volume of distribution (Obesity, third spacing)
• Compartments
• Protein binding
Time vs. concentration-dependant killing
• >MIC > 50% DI vs. Cmax/MIC >8-10
• Aminoglycosides and quinolones
Combining drugs
• Synergy vs. antagonism
You have homefield advantage – use it
Empiric Therapy
Empiric therapy is not an educated guess but a
sophisticated decision based on intimate knowledge of
• The bug
• The host
• The local environment
• All available options
• Antimicrobials
• Principles of antimicrobial therapy
• Supportive and critical care
Take home
• Empiric therapy is overrated
• Diagnostic effort is underrated
• Consider going narrow (may be diagnostic)
• Your empiric therapy will save some, not
save some (if you do not get it right), or in
some cases kill someone