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Microbiome & Infection Control - NJ Fawcett
- 1. "Your Microbial Armor ?- the role of the human microbiome in infection prevention and control" Dr Nicola Fawcett Registrar in Acute/General Medicine MRC Clinical Research Fellow, University of Oxford
- 2. phylogenomics.blogspot.co.uk Avoiding the pitfalls of giving a microbiome talk….
- 3. phylogenomics.blogspot.co.uk Avoiding the pitfalls of giving a microbiome talk…. “Although numerous studies correlate microbiome composition and function with disease states, […] few clearly demonstrate a clear pathophysiologic mechanism and causality.” - Harris et al, Open Forum Infec Dis 2017
- 4. Is the Microbiome relevant to IPC? • Probiotics /Prebiotics/Synbiotics • Faecal Microbiota Transplant • Selective Digestive Decontamination in ICU
- 5. Is the Microbiome relevant to IPC? • Probiotics /Prebiotics/Synbiotics • Faecal Microbiota Transplant • Selective Digestive Decontamination in ICU “The intact human microbiome is a primary host defense for the prevention of the colonization, dominance, and infection of pathogens” Kamada et al, Nat Immunol 2013
- 6. The Medical Ward Round (internet)
- 7. The Medical Ward Round (reality)
- 8. The Medical Ward Round (reality) Mrs Tiggywinkle 82yr lady from a nursing home acutely confused Productive cough (but chronic) Urine dipstick positive
- 9. The Medical Ward Round (reality) This lady has a history of recurrent ESBL urinary tract infections and is flagged as MRSA positive. We are looking for a side room Mrs Tiggywinkle 82yr lady from a nursing home acutely confused Productive cough (but chronic) Urine dipstick positive
- 10. The Medical Ward Round (reality) This lady has a history of recurrent ESBL urinary tract infections and is flagged as MRSA positive. We are looking for a side room Antibiotics, just in case? Mrs Tiggywinkle 82yr lady from a nursing home acutely confused Productive cough (but chronic) Urine dipstick positive
- 11. • Women attending STD Clinic, recent recurrent UTI • Asymptomatic at enrollment • urine culture with at least 10^5 (CFUs)/mL of uropathogen • No complicated factors (eg diabetes, pregnant) No antibiotics (330) 86.9% Antibiotics given to treat cultured Organism(369) 53.2% Cai et al, CID 2012 & 2015 Recurrence • 13% at 1 yr • 38% at 2yrs • 47% at 1yr • 70% at 2yrs P < .0001 Antibiotic treatment of asymptomatic bacteruria Tripled risk of UTI recurrence And increased risk of resistant infection
- 12. Edlund et al, JAC 2000 Cai et al CID 2012 “…the suppression of the normal microflora may lead to reduced colonisation resistance with subsequent overgrowth of preexisting […]resistant potential pathogens that may spread within the body and cause severe infections
- 13. Kamada et al Nature Immunology 2016
- 14. Kamada et al Nature Immunology 2016 The Gut microbiome The human body contains approximately equal bacterial and human cells 3x1013* *Sender et al PLoS Biology 2016 1011 bacteria/g
- 15. Dethlefsen et al 20113 What do antibiotics do to the gut bacteria? Diversity of the gut bacteria Time Ciprofloxacin given Ciprofloxacin given
- 16. Characterization of the intestinal microbiota during allogeneic hematopoietic stem cell transplantation. Ying Taur et al. Clin Infect Dis. 2012;55:905-914 © The Author 2012. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com. • 94 stem-cell transplant patients • Serial stool samples • 16sRNA pyrosequencing • ‘intestinal dominance = >30% colonisation
- 17. Ying Taur et al. Clin Infect Dis. 2012;55:905-914
- 18. Ying Taur et al. Clin Infect Dis. 2012;55:905-914
- 19. Ying Taur et al. Clin Infect Dis. 2012;55:905-914
- 20. Ying Taur et al. Clin Infect Dis. 2012;55:905-914
- 21. Colonisation resistance? Ying Taur et al. Clin Infect Dis. 2012;55:905-914
- 22. Ubeda et al JCI 2010 Donskey e t al NEJM 2000 Ying Taur et al. Clin Infect Dis. 2012;55:905-914 Antibiotics can trigger VRE BSI in mice Anaerobes protective Stool concentrations up to 109/g VRE > 104/g VRE strongly associated with environmental contamination in hospitals
- 23. Antibiotics may increase risk of colonisation with MDROs #inmice Lewis et al J Infect Dis 2015 LogCFUs Untreated mice (yellow) Vancomycin treated (red) VRE CRE K. pneumo.
- 24. Antibiotic therapy should aim to treat, but also minimise effect on the protective host microbiota The aim is to restore balance, not disrupt
- 25. - Leger et al, Immunity 2017 Man et al Nat Rev Micro 2017 van Rensburg et al Mbio 2015 Not just the gut… Alverdy et al JCritCareMed 2017 Ichinohe et al PNAS 2011
- 26. Is the Microbiome relevant to IPC? • Probiotics /Prebiotics/Synbiotics • Faecal Microbiota Transplant • Selective Digestive Decontamination in ICU
- 27. FMT for recurrent C.diff. 289 patients from 25 articles, overall success rate of 91% “FMT is a safe and effective treatment option for CDI” Frozen encapsulated FMT just as effective - The ‘Crapsule’ -Youngster et al JAMA 2014 Spores only? Ethanol treated stool can also be effective - Khanna et al JID 2016 -Petrof et al Microbiome 2013
- 28. Diagnosis HLH Treated for Pseudomonas Aeruginosa infection -prolonged abx Persistent CPE bacteraemia K. pneumo Septic arthritis Both hips Treated Doripenem, colistin rifampin Plazomicin Eventual resolution Osteomyelitis R femur CPE K. pneumo Treated All stool cultures CPE negative 14yr, Haemophagocytic Lymphohistocysosis - immunosuppressed Freedman A, Eppes S., abstr 1805. Abstr Soc Healthcare Epidemiol IDWeek 2014 Prior to episode 10 months5 weeks Persistent CPE in stool No further infections 1.5 yrs FMT FMT for MDR decolonisation? Review: Manges et al Infec Dis 2016
- 29. • 60yr male Singh 2006 Recurrent transplant pyelonephritis ESBL 2003 2nd renal transplant 2011-2012 8 episodes ESBL pyelonephritis 2012 Transplantectomy Persistent rectal ESBL carriage 2013 FMT Week 1 ESBL carriage Week 2-12 ESBL negative Singh et al. Clin Microbiol Infect 2014 FMT FMT for MDR decolonisation?
- 30. Nancy F. Crum-Cianflone et al. J. Clin. Microbiol. 2015;53:1986-1989 resp drain ulcer resp multi neckwound resp urine resp FMT 66yr ICU, ventilator-dependent, quadriplegia, for sacral debridement 1st 15 weeks: 2 episodes sepsis 4 treated infections 12 MDROs isolated from 24 cultures Recurrent C. diff. 2nd 15 weeks: No episodes of sepsis 1 infection 4 MDROs from 11 cultures 2 years 1 cellulitis/bacteraemia – S. pyogenes 2x bacteraemia – nonMDR E. coli & P. aeruginosa resp Hx Heavily colonised with: A. baumannii, CPE P aeruginosa VRE E. faecalis UTI 2’ K pneumo. FMT for MDR decolonisation?
- 31. Probiotics? Some evidence: Antibiotic-associated diarrhoea Necrotising Enterocolitis VAP -Reviewed: Harris et al, Open Forum Infect Dis. 2017
- 32. 4556 newborns enrolled in rural india double blinded RCT of Synbiotic (lactobacillus plantarum + fructooligosaccharide) 319 recorded cases of sepsis Synbiotic resulted in risk reduction of: 83% for gram+ infections 75% for gram- infections 47% for culture-negative sepsis 34% reduction in LRTI 40% reduction in sepsis or death in 8 weeks NNT 27 “To me, probiotics are still “something promising since 25 years”, without ever having substantiated that promise. […]This new study may change my view completely.” -Prof. Marc Bonten, ReflectionsIPC Blog 2017
- 33. I love the smell of meropenem on the ward. Smells like…victory The role of IPC (c. 2006) Infection Prevention and Control
- 34. Antiiotics and MIcrobiology (c.2015) IPC – 2017 http://www.nature.org/ourinitiatives/regions/northamerica/unitedstates/hawaii/explore/weed-warrior.xml The role of IPC (c. 2017) One of the best defenses against pathogen colonisation and infection is the preservation of the protective host microbiome
- 36. The Medical Ward Round (reality) “We really don’t want to give this lady co-amoxiclav for a chest infection – she’s just had an ESBL UTI and it’ll wipe everything else out – she’ll just be 100% ESBL! She’s not septic - let’s hold fast and get some more information” 82yr nursing home resident Confused Productive chronic cough Urine dip positive Prev ESBL UTIs MRSA colonised
- 37. Microbiome hat Hospital Infection Control hat Lalalala! Save the good microbes ecology, live in balance Dirt is good Circle of life etc etc Kill the bugs! Destroy them all! Disinfect your hands & surfaces & eradicate them from this world ! BWAHAHA!Our Bacterial friends A BIT ‘DUAL PERSONALITIES’ IN MICRO AT THE MOMENT … Acknowledgements MRC UK University of Oxford Modernising Medical Microbiology Derrick Crook, Sarah Walker, Tim Peto Leon Peto Dona Foster Resources @drnjfawcett Livinginamicrobialworld.wordpress.com MicrobiomeDigest @microbiomdigest Jonathan Eisen @phylogenomics Jack Gilbert @gilbertjacka Ed Yong @edyong209
- 39. Extra slides not for initial presentation
- 40. Antiseptics and the microbiome • Chlorhexidine bathing reduced gram- colonisation of patient’s skins and acquired infections in ICU (rev Cassir et al EJClin Micro&ID 2015, Swan et al 2016, ) • Chlorhexidine mouthwash may contribute to hypertension by killing nitrate-reducing oral bacteria (Kapil et al Free RadBio&Med 2013) • The skin microbiome is fairly resistant to most topical skin cleansers (Two et al J InvestDerm 2016)
- 41. Mice not inoculated with resistant bacteria Mice inoculated and given saline injection Mice given iv ampicillin Mice given oral ampicillin Effect of ampicillin po vs iv. on gut carriage of bla-CMY2 E.coli in mouse model Oral iv Oral iv Ampicillin = renally excreted Zhang et al AAC 2013
- 42. My patient in front of me My group of patients Patients I may encounter at some point Other patients and population Front-line Doctors Stewardship Decisions DirectIndirect Group Behaviour effect Immediate Delayed Good evidence Decent evidence Hypothetical Future “I’ve seen it happen in front of me” “It could happen to me/my patient” Consequences Doctors care about* *at point of prescription
- 43. My patient in front of me My group of patients Patients I may encounter at some point Other patients and population Front-line Doctors Stewardship Decisions DirectIndirect Group Behaviour effect Immediate Delayed Good evidence Decent evidence Hypothetical Future “if we all use too many antibiotics… resistance will happen… through complex mechanisms… in the future… ” “I’ve seen it happen in front of me” “It could happen to me/my patient” Consequences Doctors care about* *at point of prescription
- 44. My patient in front of me My group of patients Patients I may encounter at some point Other patients and population Front-line Doctors Stewardship Decisions DirectIndirect Group Behaviour effect Immediate Delayed Good evidence Decent evidence Hypothetical Future “if we all use too many antibiotics… resistance will happen… through complex mechanisms… in the future… ” “I’ve seen it happen in front of me” “It could happen to me/my patient” Consequences Doctors care about* *at point of prescription Antibiotic overuse will do harm to the patient in front of you
- 46. Your gut microbiome is more important than maybe we first realised
- 47. Dr. Meghan Azad from the University of Manitoba, for Institute of Human Development, Child and Youth Health Talks
- 48. Recent or previous microbiology culture results and susceptibility patterns are checked Checking for recent or previous alert organisms i.e. multi-drug resistant bacteria such as Methicillin-Resistant Staphylococcus aureus (MRSA) ,ESBL- producing organisms ,Carbapenemase-Producing Enterobactericeae (CPE) and Glycopeptide-Resistant Enterococci (GRE) once a significant infective organism is identified then therapy should be de- escalated to mono-spectrum targeted agents which are equally if not more effective but also they have much less collateral damaging effect i.e. are less likely to disturb the microbial flora and lead to the emergence of multi- antimicrobial resistant organisms in addition to super-infection such as the occurrence of Clostridium difficile infections Al Wali, BMJ 2016 Gotts et al, BMJ 2016
- 49. Costelloe et al, BMJ 2010 E.coli resistance and prior antibiotic exposure Still a weak association even with antibiotics up to 12 months prior to infection 0-1 month 0-3 months 0-6 months 0-12 months Antibiotic use associated with resistance Antibiotic use associated with susceptibility Previous antibiotic use is associated with resistant infection
- 50. Bryce et al BMJ 2016 Risk of resistant E.coli UTI and prior antibiotic use in children
- 51. Ruppe et al AAC 2012 Quantitative culture of stools (Total enterobacteriaceae and ESBLs in patients presenting with UTI ) 10-100% of total cultured Enterobacteriaceae being ESBL from stool associated with increased risk of ESBL UTI . <0.1% - predicts no ESBL UTI Is low level carriage of ESBLs Clinically Relevant?
- 52. Gut carriage and transmission of resistant Enterobacteriaceae Community Reservoir: • Prevalence of ESBL E.coli in Nursing Home in N. Ireland 40.5% – 51% of carriers had no history of hospital admission Abroad: • Travellers in Sweden-carriage of ESBLs: – Prior to travel 4% – After travel 32% (Travel to India – 82%) – Found in travellers without GI symptoms • Antibiotic use by travellers increases risk of subsequent ESBL carriage • Antibiotic use consistently a risk factor for ESBL carriage in patients (other risk factors: exposure to hospital environment, travel to endemic area) • Gut carriage of ESBLS is a risk factor for ESBL infection Rooney et al, JAmChem 2009, Ostholm Balkhed JAmXChem 2013 , Doi et al Clin Microb Infect 2010,
- 54. Antibiotics: The collateral damage Target: Streptococcus Causing pneumonia Remember: we contain microbes too!
- 55. Antibiotics: The collateral damage Target: Streptococcus Causing pneumonia Target: all microbes on the human body Remember: we contain microbes too!
- 59. How do antibiotics affect the gut bacteria? >Reduced diversity of bacteria >Increase in antibiotic resistance x x x x x CDC Infographic 2014
- 60. Messages for the generalists and the public • People who take antibiotics are more likely to get resistant infections in the future • If you take antibiotics, they are less likely to work for you in the future • Antibiotics disrupt the balance of healthy bacteria in your body, which can make you more susceptible to infections in the future • If in doubt, don’t disrupt!
- 61. The Faecal Sample • 109 CFU Anaerobes (Bacteroides/Parabacteroides) • 105 -107 CFU – Enterococci – Bifidobacterium – Prevotella • 104-6 Enterobacteriaceae
- 62. Enterococcus Domination Streptococcus Domination Proteobacteria Domination Predictor HR (95% CI) P HR (95% CI) P HR (95% CI) P Vancomycin 2.12 (.67–10.21) .222 0.95 (.33–3.77) .938 5.17 (.52–707.15) .192 Metronidazole 3.38 (1.65–6.73) .001 1.94 (.81–4.30) .131 1.73 (.41–6.03) .426 Fluoroquinolones 1.09 (.49–2.24) .832 1.19 (.51–2.60) .677 0.09 (.00–.75) .020 Beta-lactam 1.64 (.74–3.99) .232 1.69 (.62–5.64) .319 1.23 (.27–7.50) .800 VRE Bacteremia Gram-negative Bacteremia Dominating Taxon HR (95% CI) P HR (95% CI) P Enterococcus 9.35 (2.43–45.44) .001 1.35 (.25–5.08) .690 Streptococcus 0.21 (.00–1.75) .184 0.82 (.09–3.65) .823 Proteobacteria 0.75 (.01–6.14) .837 5.46 (1.03–19.91) .047 Antibiotics affecting risk of gut microbiota domination Gut microbiota domination and risk of BSI *regression analysis including age, female, diagnosis, prior abx, regimen, fever Ying Taur et al. Clin Infect Dis. 2012;55:905-914
- 63. Ub Mice given oral VRE challenge with ampicillin, then either faecal transplant or PBS/saline. Protective effect shown due to anaerobes (Barnesiella ) Note size of effect: 10^9 CFU of VRE per gram - at this density decolonisation and infection co Difficult . FMT decreases concentrations more than a BILLION fold Antianaerobic antibiotics result in high level VRE colonisation More than 10^4 /g VRE – 10/12 VRE environmental screens positive Less than 10^4 – 1/9 sets positivie Donskey e t al NEJM 2000 the hypothesis that antibiotics promote the overgrowth of vancomycin-resistant enterococci regimens with potent antianaerobic activity but minimal activity against other components of colonization.