Download Public health consequnces of antimicrob

Public health consequences of
antimicrobial resistance
CIDM-PH
Nov 2016
[email protected]
INFECTIOUS
DISEASES
sepsis
resistance
ecology
MICROBIOLOGY
CRITICAL
CARE
CORE RESEARCH THEMES
CORE DISCIPLINES
1. Sepsis
1.1 clinical definitions, epidemiol. & outcomes
1.2 bacterial quantitation: diagnosis/prognosis
1.3 randomised clinical trials (RCTs)
1. Infectious Diseases
(antibiotic stewardship, sepsis management,
clinical trials, risk assessment)
2. Resistance
2.1 high throughput (‘one health’) surveillance
2.2 real-time (point of care) diagnostics
2.3 bacterial genome-wide association studies
2. Critical Care
(sepsis recognition and management,
clinical trials, managing the ecology of infection)
3. Ecology
3.1 effects of antibiotics
3.2 impact of faecal microbial therapy, FMT
3.3 bioremediation: problem bacterial strains
3.4 bioremediation: problem AbR plasmids
3. Microbiology
(genetics/genomics/microbiome analyses,
laboratory diagnostics, AMR epidemiology;
surveillance networks and reporting)
ED patients entered into Sepsis pathway at Westmead Hospital Sydney
(Shetty and Iredell – unpublished data)
Amith Shetty
Harvey Lander
Kelly Thompson
Simon Finfer
ED Treated Sepsis
N= 896
IHM 76/896 (8.5%)
Unknown qSOFA N= 3
qSOFA ≥2
N= 239 (26.8%)
IHM 49/239 (20.5%)
qSOFA <2
N= 654 (73.2%)
IHM 27/654 (4.1%)
Amith Shetty
Harvey Lander
Kelly Thompson
Simon Finfer
ASID clinical research
SMEDSA ED registry
ASSOP&GNSOP networks
1.00
Survival estimates for patients with any bacterial load in the first 6 hours
Blood from an Australian septic shock cohort
NHMRC632622 (in prep.)
0.50
0.75
bacterial DNA detection at >102 cfu/mL is
twice as sensitive in septic shock (positive in
55%; results <4h) as is blood culture (positive
in 28%; results >16-48h).
0.25
In logistic regressions, bacterial DNA load >102
cfu/mL has a greater predictive power (RR
1.27) for mortality than any other risk marker,
including inotropic support (RR 1.16)
0.00
Log-rank p=0.04
0
at risk
No 63
Yes 47bacterial
30
60
90
days
59
DNA
36 load
No
57
predicts
36 survival
Yes
57
36
preliminary survival analysis indicates a strong
relationship between detection of any
bacterial load above threshold in the first 6
hours after ED arrival and death at 90 days
(n=108; HR 3.2, 95% CI 1.1-9.4, p 0.03)
sepsis
• nascent networks for sepsis monitoring and
ED-based trials of early interventions
• new tools for early recognition of increased
mortality risk in sepsis
– Bacterial load and survivorship
• AMR doubles mortality
– NPV >99.5% for AMR targets
NHMRC1046886:
USA, China, UK, Italy,
Singapore, Ghana, Nepal,
Vietnam, Bangladesh
\
LE170100093
Aust Unity ACFs
1127292 and GNSOP
• 1046889
• antibiotic effects
• 1084244
• SuDDICU
• 1127292
• eSuDDICU
antibiotic effects: myths and legends
• (antibiotic cycling)
– homogeneity is not a driver of AMR per se
– mathematical models challenged/overturned
• (drug sparing)
– FEP is more likely to drive APP-B resistance than
APP-B itself; consistent with observed epidemiol.
– co-inheritance of AMR in mobile transmission
systems is often not considered/included
Biodiversity and extinction: more
questions than answers
• “Superbugs”?
–
–
–
–
–
MRSA
S pyogenes
C difficile
E coli ST131 ….ESBLs (CTX-M-15)
K pn ST258 …..CRE (KPC)
– More virulent? More resistant?
– Do these go together?
– Are bugs evolving still? Is biodiversity being lost?
Ferenci and Phan 2015.
How porin heterogeneity
and trade-offs affect the antibiotic
susceptibility of Gram-negative
bacteria. Genes. 6: 1113-1124
Evidence for convergent evolution in K pneumoniae OmpK36
small, simple;
mostly stochastic
large, complex;
addiction and incompatibility
>500 Enterobacteriaceae with blaIMP4 2004-16
Citrobacter
Klebsiella
E. coli
Enterobacter
PBRT
K. pneumoniae
IncL/M
Newcastle68
IncHI2 IncA/C Total
68
E. cloacae
35
11
1
47
*
E. coli
61
1
62
All
164
11
2
177
Ecoli 4469
Entcl 4531
Kpn4569
Still the same plasmid >12 years later
Now endemic in NSW
JIE4469
JIE4531
JIE4569
isolate
hospital
date
Inc
E. coli ST357
E. cloacae
K. pneumo
Auburn
Westmead
Cooma
14/05/2015
19/07/2015
26/08/2015
M
M
M
Reuter et al 2013
Enterobacter genome
50-10,000 SNPs
pEl1573 (GenBank
ref. JX101693)*
2 SNPs (qac, ORF)
Identical*
2 SNPs (IS26)
*pEl1573 E. cloacae (2003)
IncM
pEl1573
*pJIBE401 K. pneumoniae87.73
(2003)
kb plasmid
AAC 2012;56(11):6029-
<2SNPs over 12 years
Agyekum et al. JCM 2016
TEM/CMY-2 in E coli
NHMRC1084672
Plasmid decolonisation in vivo
Population management
+ antibiotic
a
no antibiotic
AT/T
rep
AbR
Ab
b
stable incompatible
no antibiotic
Millan B, Park H, Hotte N, Mathieu O,
Burguiere P, Tompkins TA, Kao D, Madsen
KL. Fecal Microbial Transplants Reduce
Antibiotic-resistant Genes in Patients With
Recurrent Clostridium difficile Infection.
Clin Infect Dis. 2016;62:1479HC
BFT
PFT
FMT
healthy control
before transplant
post failed transplant
faecal microbiota tx
• 1046889
• antibiotic effects
• 1084244
• SuDDICU
• 1127292
• eSuDDICU
NHMRC1107322(2016-2020)
(i) define libraries of lytic phage active against high-risk
clonal E. coli (ST131) and K. pneumoniae (ST258);
(ii) define mechanisms of bacterial resistance to phages;
(iii) test efficacy of phage cocktails in colonised mice and
choose those most effective and least likely to result in
development of phage resistance; and
(iv) pilot optimised phage cocktail for eradication of E. coli
ST131/ K. pneumoniae ST258 from humans.
threat to PH?
• AMR septic shock has a
higher mortality than Ebola
and is much more common
(~800 deaths pa in Aust)
• kills more than breast
cancer prostate cancer and
HIV/AIDS combined (CEC)
threat to PH?
• ‘a catastrophic threat comparable to global
warming’ (Davies SC 2013)
• loss of biodiversity and extinction events
• more pathogenic and AMR microbiome
• reduced colonisation resistance
INFECTIOUS
DISEASES
sepsis
resistance
ecology
MICROBIOLOGY
CRITICAL
CARE