Epidemiology of antimicrobial resistance and the effect of interventions in food-producing animals

234 Pages·2016·7.78 MB·English

by  Alejandro Dorado García

Epidemiology of antimicrobial resistance and the
effect of interventions in food-producing animals
Alejandro Dorado García
2016
Epidemiology of antimicrobial resistance and the effect of interventions in
food-producing animals
PhD Thesis, Utrecht University, the Netherlands
ISBN: 978-90-393-6581-6
Cover: Alejandro Dorado García & Bram Hendrawan
Lay out: Alejandro Dorado García & Joost Hordijk
Printing: Gildeprint
Epidemiology of antimicrobial resistance and the
effect of interventions in food-producing animals
Epidemiologie van antimicrobiële resistentie en het effect van interventies in
voedselproducerende dieren
(met een samenvatting in het Nederlands)
Proefschrift
Ter verkrijging van de graad van doctor aan de Universiteit Utrecht op
gezag van de rector magnificus, prof. dr. G.J. van der Zwaan, ingevolge
het besluit van het college voor promoties in het openbaar te verdedigen
op dinsdag 28 juni 2016 des middags te 4.15 uur
door
Alejandro Dorado García
geboren op 17 februari 1984
te Madrid, Spanje
Promotoren
Prof. dr. ir. Dick J.J. Heederik
Prof. dr. Jaap A. Wagenaar
This thesis was accomplished with financial support from four different sources:
The POM project, funded by The Netherlands Organization for Health Research and
Development (ZonMw) (grant number 125020009), the former Product Boards for Livestock
Meat and Eggs and the Dutch Ministry of Agriculture Nature and Food Quality.
The Bactopath project, supported by Senter Novem (contract no. FND07003), the former
Product Boards for Livestock Meat and Eggs (contract no. 13.31.001) and The Netherlands
Organization for Health Research and Development ZonMw (contract no. 50-51700-98-053).
The Netherlands Veterinary Medicines Authority (SDa).
The 1Health4Food (1H4F) research program, ESBL-attribution project (TKI-AF-12067).

Beoordelingscommissie
Prof. dr. J.A. Stegeman
Prof. dr. R.A. Coutinho
Prof. dr. M.J.M. Bonten
Prof. dr. A.W. Friedrich
Prof. dr. B. González Zorn
Paranimfen
Dr. E. Ugarte Berzal
Dr. L. Hidalgo del Río
CONTENTS
1. General introduction 9
Part I - Livestock-associated methicillin-resistant Staphylococcus aureus (MRSA) in veal
calf farming
2. Risk factors for persistence of livestock-associated MRSA and 25
environmental exposure in veal calf farmers and their family members:
an observational longitudinal study
3. Effects of reducing antimicrobial use and applying a cleaning and 45
disinfection program in veal calf farms: experiences from an intervention
study to control livestock-associated MRSA
Part II - Livestock-associated MRSA and extended-spectrum β-lactamase (ESBL)-
producing Escherichia coli in pig farming
4. Dose-response relationship between antimicrobial drugs and livestock- 73
associated MRSA in pig farming
5. Farm management practices associated with ESBL-producing 111
Escherichia coli in pigs: a longitudinal study in the context of reduced
use of antimicrobials
Part III - Commensal indicator Escherichia coli in animal production sectors
6. Quantitative assessment of antimicrobial resistance in livestock during 131
the course of a nationwide antimicrobial use reduction in the Netherlands
Part IV - Extended-spectrum β-lactamase (ESBL)-producing Escherichia coli in humans,
animals and their environment
7. The epidemiology of ESBL/AmpC genes and plasmids in human, animal 165
and environmental reservoirs: a meta-analysis
Part V - Concluding remarks
8. General discussion 201
Summary (in English, Dutch and Spanish) 217
Acknowledgements 227
About the author 231

Chapter 1
General introduction
“The time may come when penicillin can be bought by
anyone in the shops. Then there is the danger that the
ignorant man may easily underdose himself and by
exposing his microbes to non-lethal quantities of the drug
make them resistant”
Alexander Fleming,
December 11, 1945
Chapter 1 | General introduction
The antibiotic era and the emergence of bacterial resistance
Until the 20th century infectious diseases had been the leading cause of human morbidity
and mortality but the greatest developments in the known history of medicine were about
to happen. It was in 1899 when Emmerich and Löw realized that prepared extracts from
Pseudomonas aeruginosa had antibacterial activity against other pathogenic bacteria. Their
preparations were used in hospitals with inconsistent results and high toxicity, whereupon the
treatment was abandoned. Later, in 1945 further investigations would confirm the production
of quinolones by this bacterial species1,2. Paul Ehrlich set the next milestone in 1904 initiating
a systematic screening of chemical compounds in search of a drug against syphilis. He
was the first to formulate the hypothesis of a “magic bullet” that would just target disease-
causing microbes without harming the human body2. This large-scale systematic search of
compounds led Fritz Mietzsch and Josef Klarer to synthesize the first ‘sulfa’ antimicrobial
in the early 1930s. This approach is nowadays the cornerstone of drug discovery used by
the pharmaceutical industry2. Alexander Fleming made in 1929 his first observations on the
antimicrobial properties of Penicillium fungi. He persistently tried to encourage the scientific
community to purify the active substance until 1945, when penicillin started to be marketed
and widely distributed2,3. Between 1950s and 1970s most of the antimicrobials we use now,
were discovered and practically no new classes have been found since then2.
Antimicrobials have several mechanism of action including interference with synthesis
of cell walls (e.g. β-lactams such as penicillin, cephalosporins and carbapenems), inhibition
of protein synthesis (e.g. tetracyclines and macrolides), interference with DNA synthesis
(e.g. quinolones and fluoroquinolones), inhibition of metabolic pathways (e.g. trimethoprim-
sulfamethoxazole), and bacterial membrane disruption (e.g. polymyxins). Bacteria resistant
to these attacks will survive and proliferate when they are exposed to these agents.
Microorganisms have adaptive responses to changing environments and selective pressures
have been observed in the lab even before the extensive use of penicillins4. Overexploitation
and misuse of antimicrobials over the last decades has intensified this process. As a result,
effectiveness of available antimicrobials has been diminished and new mechanisms of
bacterial resistance have arisen or become more visible. However, antimicrobial substances
already existed in nature long before their discovery. Phylogenetic reconstruction studies
have shown that resistance genes to several antimicrobial classes were already present
before the large scale use of antimicrobials,6. Recent microbiome research found functional
resistance genes, conferring resistance to even synthetic antimicrobials, in the microbiome of
human populations without apparent exposure to modern medicine practices7.
Antimicrobial resistance can be intrinsic or can be developed de novo via mutations or
gene transfer. The resistances based on mutations are mostly vertically propagated during
bacterial replication. Development of resistance can also happen through acquisition of
resistant genes from other bacteria. In that case, genetic material is horizontally transferred
from resistant strains to antimicrobial susceptible bacteria through conjugation, transformation
10