antibiotics, antibiotic resistance and the human microbiome...buelow, bello gonzalez et al., in...
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Willem van Schaik
Dept. of Medical Microbiology, University Medical Center Utrecht, Utrecht, The Netherlands
[email protected]/WvSchaik
Antibiotics, antibiotic resistance
and the human microbiome
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Earth forms
First life
O2 in atmosphere
First multi-cellular organisms
First fungi
Plants, insectsDinosaurs
Humans
1
billion
years
5 x 1030 bacteria on EarthWhitman et al., 1998. PNAS 95:6578
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Earth forms
First life
O2 in atmosphere
First multi-cellular organisms
First fungi
Plants, insects
Dinosaurs
Humans
1
billion
years
Hug et al., 2016. Nature Microbiol. 1:16048
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The natural role of antibiotics
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Ernst Duchesne: 1874-1912
Fungi kill bacteria in vitro
Fungi + Salmonella enterica Typhi: mice survive
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Discovery of antibiotics
Sir Alexander Fleming (1881 – 1955)
Penicillium
Staphylococcus aureus
Not successful in purifying active substance
6
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Discovery of antibiotics
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http://www.hhmi.org/biointeractive/penicillin-acting-bacteria
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Collateral damage of antibiotic use?
Prof. Martin J. Blaser
New York Medical Center
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Collateral damage of antibiotic use?
Schulfer & Blaser, 2015. PLOS Pathog 11:e1004903
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Collateral damage of antibiotic use?
Trasande et al., 2013. Intl J Obesity 37:16-23
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Antibiotic resistance
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“The more you use it, the faster you lose it.”Dr. Robert Weinstein
Antibiotic resistance
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Centers for Disease Control and Prevention
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2050?
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cephalosporin-
resistant Escherichia
coli
vancomycin-
resistant
Enterococcus
faecium
methicillin-resistant
Staphylococcus
aureus
2003 2014%resistant in
bloodstream isolates.
Data: EARS-NET
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0-3-30-300-3000-300-30-3-00 3 30 300 3000 300 30 3 0
Trimethoprim, Escherichia coliBaym et al., 2016. Science 353:1147.
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Trimethoprim, Escherichia coli. Time-lapse movie taken over 12 daysBaym et al., 2016. Science 353:1147
Resistance caused by accumulation of mutations
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Rapid transfer
of antibiotic
resistance
Acquisition of antibiotic resistance genes
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pNDM-HK
E. coli srain from Hong
Kong
Resistance genes
β-lactams(blaTEM-1, blaNDM-1, ΔblaDHA-1)
aminoglycosides (aacC2, armA)
sulphonamides(sul1)
macrolides (mel, mph2)
Ho et al. 2010. PLoS ONE
6(3): e17989
Antibiotic resistancethe problem with plasmids
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http://en.wikipedia.org/wiki/Intensive_care_unit
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abx
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http://en.wikipedia.org/wiki/Intensive_care_unit
>50% of ICU patients has a hospital-
acquired infectionVincent et al., 2009. JAMA 302:2323-2329
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Selective digestive tract decontamination
Decontamination of oropharynx and intestinal tract
Mix of colistin, tobramycin, amphotericin. Intravenous cefotaximefor first 4 days at ICU
Widely used in Dutch ICUs
Lowers patient morbidity & mortalityBut effect on resistance?
van der Waaij et al., 1972. J Hyg (Lond) 70:605De Smet et al., 2009. N Engl J Med 360:20Daneman et al., 2013. Lancet Infect. Dis. 13:328Oostdijk et al., 2014. JAMA 312:1429
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10 healthy volunteers, two samples (1 year apart)
10 ICU-patients, stay ≥10 days
Pilot study
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throat swab, sputum
rectal swab
urine
bloodstream, wound
faecal sample
intracerebral hemorrhage
post-operative complications after coronary artery bypass grafting
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-1.0 1.5
-0.8
1.0
105A
105B
105C
108A
108C
108E
120A
120B120C
120D
120E
120F
120G
157A
157B
157C
157D
157E
163A
163B
163C163D
164A
164B
164C
165A
165C
169A
169B
169C
169D
180A
180B
43A
43B H25-0
H25-1 H40-0
H40-1
H41-0
H41-1
H47-0
H47-1
H48-0
H48-1
H56-0
H56-1
H57-0
H57-1
H59-0
H59-1
H65-0
H65-1
H7-0
H7-1
PC1: 39%
PC
2:
15
.5%
A Microbiome of ICU patients
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Microbiome of ICU patients
Diversity of the microbiome decreases in ICU patients
Stable in healthy subjects
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Resistome of ICU patients
Primers for 81 resistance genes
16S rRNA: for relative quantification
Most common resistance genes in gut microbiotaForslund et al., 2013. Genome Res. 23:1163; Hu et al., 2014. Nat. Commun 4:2151
Clinically relevant resistance genesESBLs, carbapenemases, mecA, vancomycin resistance genes
Buelow, Bello Gonzalez et al., in preparation
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Many different
antibiotic resistance
genes
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Some enriched in
ICU patients, but no
‘high-risk’ genes
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Good
Important reduction of E. coli
No selection for high-risk
antibiotic resistance genes
Bad
Microbiota is highly
perturbed
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Finding the right balance
Therapeutic benefitsEmergence of resistance
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Restoring the balance?
Microbiome interventions in critically ill patients are risky
Lancet 2008; 371: 651–59
Lactic acid bacteria
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Van Nood et al., 2013. New Engl. J. Med. 368:407
Infections with Clostridium difficile
After antibiotic treatment
Can cause life-threatening
inflammation of the colon
Fecal transplants?
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Fecal transplants?
“90% cure rate”
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Conclusions
Antibiotics are essential for modern medicine
Antibiotic use may harm human health through
effects on the microbiome
Antibiotic use selects for resistance
Use antibiotics only when benefits outweigh risks
Monitoring of resistance
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Elena Buelow
Marc Bonten
Rob Willems
Evelien Oostdijk
Maaike van Mourik
Iris Braat
Els Oosterink
Wouter de Steenhuijsen Piters
Jumamurat Bayjanov
Eline Majoor
& undergraduate students
Collaborators
FundingEvoTAR: Evolution and
Transfer of Antibiotic
Resistance
Priority Medicines AMR
Vidi
Teresita Bello Gonzalez
Susana Fuentes
Leo Lahti
Dennis Versluis
Mark van Passel
Hauke Smidt
Brian Jones
Lesley Ogilvie
Marco Maria D’Andrea
Heike Schmitt