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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networks and reporting) ED patients entered into Sepsis pathway at Westmead Hospital Sydney (Shetty and Iredell – unpublished data) Amith Shetty Harvey Lander Kelly Thompson Simon Finfer ED Treated Sepsis N= 896 IHM 76/896 (8.5%) Unknown qSOFA N= 3 qSOFA ≥2 N= 239 (26.8%) IHM 49/239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