Understanding the factors that influence the distribution of antibiotic resistance. PHDL Seminar November 12th 2018 Derek MacFadden MD FRCPC *No Relevant Disclosures/Conflicts of Interest
Objectives 1. Review factors related to distribution of antibiotic resistance. 2. Review the evidence supporting the role of climate on the population level distribution of antibiotic resistance. 3. Review estimates of burden of antibiotic resistance and how this is (and might be) measured.
Emergence of Antibiotic Resistance Marston et al. Antimicrobial Resistance. JAMA. 316(11):1193-1204.
Projected Burden of Resistance O’Neill. UK-AMR Review. https://amr-review.org/
Antibiotic Resistance is OneHealth http://www.cdc.gov/drugresistance/threat-report-2013
Antibiotic Resistance is Heterogeneous by Region CPE Endemicity 2010-2015 Albiger et al. Eurosurveillance 2015.
Antibiotic Resistance is Driven By Antimicrobial Use (Selection) 2010 Outpatient All ages All drugs #RX per 1000 Hicks et al. NEJM 2013.
Epidemiology of Antibiotic Resistance 1. Surveillance - generate a database of geographically distributed measures of antibiotic resistance 2. Evaluate factors associated with the population distribution of antibiotic resistance www.resistanceopen.com
Epidemiology of Antibiotic Resistance 1. Surveillance - generate a database of geographically distributed measures of antibiotic resistance 2. Evaluate factors associated with the population distribution of antibiotic resistance www.resistanceopen.com
http://www.resistanceopen.org
Digital Surveillance http://www.resistanceopen.org
MacFadden et al. J Infect Dis 2016.
Surveillance Metrics Current Status: In Progress: • 50 Countries • Metagenomic Data • >1700 Indices • High Resolution States/ • >10.6 million Isolates Countries • 2012-2017 • ProMED Collaboration
Epidemiology of Antibiotic Resistance 1. Surveillance - generate a database of geographically distributed measures of antibiotic resistance 2. Evaluate factors associated with the population distribution of antibiotic resistance
Epidemiology of Antibiotic Resistance 1. Surveillance - generate a database of geographically distributed measures of antibiotic resistance 2. Evaluate factors associated with the population distribution of antibiotic resistance
What Factors Impact on Distribution of Antibiotic Resistance? 1. Antibiotic Use 2. Geography? 3. Population Factors? 4. Care setting? 5. Environmental/Climate Factors? We have a poor understanding of population level determinants of antibiotic resistance. Goossens et al. Outpatient antibiotic use in Europe. Lancet. 2005.
What Factors Impact on Distribution of Antibiotic Resistance? 1. Antibiotic Use 2. Geography? 3. Population Factors? 4. Care setting? 5. Environmental/Climate Factors? We have a poor understanding of population level determinants of antibiotic resistance. Goossens et al. Outpatient antibiotic use in Europe. Lancet. 2005.
What About Climate? 1. Temperature is one of the major drivers of bacterial growth. 2. Seasonality in infection with Gram-negative and Gram-positive infections = Carriage? 3. Horizontal gene transfer is typically temperature dependent. 4. Suggestion of latitude gradients, typically attributed to antibiotic use.
What Factors Impact on Distribution of Antibiotic Resistance? • Evaluated prevalence of resistance to routinely tested antibiotics in E. coli, K. pneumoniae, S. aureus across the continental United States. • ResistanceOpen, US Census, NOAA Climate, CDC prescribing.
What Factors Impact on Distribution of Antibiotic Resistance? • Evaluated prevalence of resistance to routinely tested antibiotics in E. coli, K. pneumoniae, S. aureus across the continental United States. • ResistanceOpen, US Census, NOAA Climate, CDC prescribing.
What Factors Impact on Distribution of Antibiotic Resistance? Predictors • Historical Minimum Temperature - parallels use in vector-borne diseases - ecologic suitability • Population Density • Antibiotic Prescribing Rates • Reported Laboratory Standard • Outpatient/Inpatient Sources
What Factors Impact on Distribution of Antibiotic Resistance? Dataset • 1.6 million human bacterial pathogens • 41 States, 223 facilities • 2013-2015
What Factors Impact on Distribution of Antibiotic Resistance? Analysis • Population level comparison • Univariate associations with resistance prevalence • Multivariable weighted regression models
Antibiotic Resistance in E. coli Amoxicillin MacFadden et al. Antibiotic Resistance Increases with Local Temperature. Nature Climate Change. 2018.
Antibiotic Resistance in E. coli All tested antibiotics Resistance Min. Temperature
Antibiotic Resistance in K. pneumoniae Septra
Antibiotic Resistance in K. pneumoniae All tested antibiotics Resistance Min. Temperature
Antibiotic Resistance in S. aureus Cloxacillin
Antibiotic Resistance in S. aureus All tested antibiotics Resistance Min. Temperature
Significant Predictors of Resistance
Significant Predictors of Resistance Cloxacillin: Adjusted Min Temp effect estimate -> 0.58 (p<0.0001)
Change Over Time
Summary • Antibiotic prescribing, population density, and temperature are associated with increased antibiotic resistance for common pathogens. • The relationship between temperature and antibiotic resistance may be increasing over time?
Limitations • Capturing relevant time periods/measures for antibiotic prescribing • Population level data • Confounding
Follow Up • How do we validate these findings? • Different region • Longitudinal data • Best possible AMR and AM consumption data
What Factors Impact on Distribution of Antibiotic Resistance? • Evaluated prevalence of resistance to routinely tested antibiotics in E. coli, K. pneumoniae, S. aureus across Europe . • EARS-NET (ECDC), ESAC-NET (ECDC), MERRA-2.
What Factors Impact on Distribution of Antibiotic Resistance? Dataset • 4.5 million human bacterial pathogens • 28 Countries across Europe • Spanning 2000-2016
What Factors Impact on Distribution of Antibiotic Resistance? Analysis • Temperature Association (previous study) • Longitudinal Model (country specific intercepts) • Evaluate rates of change as explanation for geographic distribution
What Factors Impact on Distribution of Antibiotic Resistance? Predictors • Annual Minimum Temperature • Population Density • Antibiotic Consumption Rates • Country Specific Intercepts • Time
McGough et al. BioRxiv 2018.
Escherichia coli
Escherichia coli
Klebsiella pneumoniae
Klebsiella pneumoniae
Staphylococcus aureus
Staphylococcus aureus
Summary • Antibiotic resistance is generally increasing over time in European countries. • Antibiotic prescribing and population density are associated with antibiotic resistance. • Antibiotic resistance is increasing more rapidly in warmer countries.
WHY? http://www.cdc.gov/drugresistance/threat-report-2013
WHY? • Season/temperature associated with carriage of resistant Gram-negatives. Kaiser et al. Infect Cont Hosp Epi. 2010.
WHY? McBride et al. Applied and Env Micro 1977.
WHY? • Temperature associated with rate of horizontal gene transfer (NDM-1 in Delhi). Walsh et al. Lancet ID. 2011.
WHY? • Temperature potent driver of growth (environment). Ratkowsky et al. J Bacteriology. 1982.
Additional Evidence 103 countries, 6 major areas (abx usage, governance, • health expenditure, GDP, education, infrastructure, climate) Strong significant positive univariate correlation between • temperature and resistance ( E.coli and E.coli/Kleb/Staph ). Collignon et al. Lancet Planetary Health 2018.
Additional Evidence Significant factors in multivariable model: • Governance index • GDP/capita • Infrastructure index • Pitfalls: • Indexes were means of standardized variables • Variables that were averaged didn’t necessarily move in • parallel directions (e.g. temperature and precipitation) Why wasn’t usage significant? (positive control) • Collignon et al. Lancet Planetary Health 2018.
Additional Evidence • Longitudinal state-level resistance prevalence data across the United States. • NHSN (CAUTI) and IMS Quintiles state-level antibiotic consumption. • Mixed effects multivariable model. • Significant positive temperature associations for common antibiotics for E.coli and Klebsiella spp . Goldstein et al. In submission.
A warming planet with increasing population density may be further driving increases in AMR. nasa.gov
Estimating the Burden of AMR O’Neill. UK-AMR Review. https://amr-review.org/
Estimating the Burden of AMR • Antimicrobial resistance is not antibiotic resistance. • AMR - Viruses, Protozoa, Mycobacteria, Bacteria
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