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Small bugs, big data; clinical microbiology in a digitising world (Inaugural lecture 2017)

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Small Bugs, Big Data
Clinical Microbiology in a Digitising World
inaugural speech by pro f .d r . h e i m a n f.l. w e r t h e i m
inaugural speech
prof. dr. heiman wertheim
Heiman Wertheim is a
professor in clinical
microbiology and heads
the clinical microbiology
department at Radboud
university medical center.
Until 2015, Heiman was
director of the Oxford
University Clinical Research
Unit in Hanoi, Vietnam.
He coordinated laboratory
capacity strengthening and conducted research
in Southeast Asia. One of his main interests
is antibiotic resistance in both resource rich
and resource constrained settings and does
this through a multidisciplinary approach:
health systems, policy development, behavior,
surveillance, prevention, genomics, and clinical
Heiman is currently part of a WHO expert panel
to develop a priority pathogens list (PPL) of
antimicrobial resistant bacteria. In the region of
Nijmegen he is active in the Gelderland Antibiotica
Resistentie en Infectiepreventie Netwerk (GAIN).
Heiman is board member for the Nederlandse
Vereniging voor Medische Microbiologie and member
of the Raad voor Wetenschap en Innovatie at the
Federatie Medisch Specialisten.
small bugs, big data
clinical microbiology in a digitising world
Small Bugs, Big Data
Clinical Microbiology in a Digitising World
Inaugural speech delivered at the acceptance of the post of Professor of Medical Microbiology
at Radboud University/Radboud university medical center on Friday 27 January 2017
by Heiman F.L. Wertheim
Graphic design and print: Radboud University, Facilities & Services
Photography cover: Andreas Terlaak
The inaugural lecture can be viewed on YouTube:
© Prof. dr. Heiman F.L.Wertheim, Nijmegen, 2017
No part of this publication may be reproduced and/or published in print, photocopy, microfilm,
audio tape or in any other manner without prior permission of the coyright holder.
5small bugs, big data
Mijnheer de rector magnificus,
leden van het college van bestuur van de Radboud Universiteit,
leden van de raad van bestuur Radboudumc,
collega’s, familie, vrienden en andere aanwezigen,
collaegues, collaborators and friends abroad watching by live stream,
It is a great honour to stand here and give my inaugural lecture for the Chair of Clinical
Microbiology at Radboud University.
It is also an honour to do this in the presence of the invisible 14 quadrillion
microorganisms that you all collectively have brought into this room today; weighing
about 700 kilograms in total. Each one of you has more microbial cells than you have
human cells. And the genes of these microbes contribute more to the proper functioning
of your body than your own genes.
Unravelling the human microbiota is one of the many scientific advances we are
experiencing today. The exponential speed of innovations and subsequent changes will
have a major impact on healthcare. We need to build a vision of how the newly-acquired
knowledge and skills can be utilised in everyone’s best interest – from healthcare
workers to patients. During this lecture, I will provide a snapshot of what I think these
advances in our digitising world mean for clinical microbiology and of my own interest
in the global problem of antimicrobial resistance. These advances have one thing in
common: they produce and analyse lots of data on many small bugs.
Preparing for this lecture was a valuable experience as it encouraged me to reflect on my
professional life. The experience of working and living with my family for nine years in
Vietnam and transitioning to Radboudumc just over a year ago made me more conscious
of the extreme differences we encounter in our world. From a country with a population
of 95 million people, to the Netherlands, a country of 17 million people, where the
number of clinical microbiologists in the province of Gelderland alone exceeds the
total number of clinical microbiologists in Vietnam, a country with a higher infectious
disease burden, widespread antimicrobial resistance, and a greater need for clinical
Back in the Netherlands, I was struck by the high concentration of and access to
expertise and skills and the multidisciplinary approach to health. This is unique and
precious: it explains the success we have as a country in providing high-quality
healthcare, in controlling infectious diseases and drug resistance, and in our world-
class scientific pursuits. The Netherlands has a lot to offer in the struggle to control
infectious diseases, starting from the early pioneers Antoni van Leeuwenhoek, who
6heiman f.l. wertheim
discovered bacteria, and Martinus Beijerink (1851-1931), who discovered viruses, to the
cutting edge research conducted today at our and other institutions.
The Dutch love to explore; I experienced this myself as a child when my parents decided
to move to Panama for several years. In retrospect, it has become clear to me that my
family’s move to Panama shaped me in such a profound way that clinical microbiology
was destined to become my career choice.
panama and infectious diseases
In Panama, the Bridge of the Americas spans the Panama Canal, connecting North
America with South America. It was built over a hundred years ago. My teenage years in
Panama were my first encounter with the tropics and the dangers of mysterious tropical
diseases. Before our move to Panama, we had to consult a travel clinic, where we
received our vaccinations against hepatitis and yellow fever, and were given maps
showing the locations of infectious diseases like malaria. I found this very mysterious
and exciting: a whole invisible natural world was out there with its own rules and with
the potential to cause serious harm to humans. My curiosity was further fed by my
mother, who was reading the historical book The Path Between the Seas about the
creation of the Panama Canal (Figure 1).
She told me fascinating stories from that
period. For instance, because so many canal
workers became sick or died from yellow fever
or malaria, completing the canal was considered
almost impossible. The role of mosquitoes in
transmitting these infections was being debated
at the time. The scientists who suggested that
mosquitoes where responsible and that large-
scale vector control programmes were needed
for disease control were initially ridiculed. One
small detail I remember clearly from her stories
was about ants in a Canal Zone hospital.
Thousands of ants were crawling all over the
helpless patients in their beds. They decided
pragmatically to put the bed legs into pans of
water to prevent the ants from getting into the
beds. As you can imagine, these pans with water
were hardly ever refreshed, and the stagnant
water became a breeding ground for mosquitoes.
If you came to the hospital with a broken leg, you were likely to get a mosquito-borne
disease on top of it.
Figure 1. The path between the seas.
7small bugs, big data
In the end, the good news was that the mosquito hypothesis was finally accepted, vector
control programmes were started and the canal was completed. This interplay between
human behaviour and the microbial environment intrigued me. When I learned about
the work of clinical microbiologists after my medical degree, I knew instantly that this
was going to be my clinical speciality. It provided boundless potential to combine
infectious disease diagnostics with clinical consultation, infection prevention, research,
public health, policy development and a multidisciplinary approach, all within a global
atlas of human infectious diseases
During my residency in clinical microbiology in Rotterdam, I enjoyed studying
infectious disease maps, wondering how these were made, why diseases are where they
are, and where the map-makers got their data. The idea behind the Infectious Disease
Atlas project was to create a single resource illustrating the distribution of infectious
diseases across the globe (Figure 2).
To create the Atlas of Human Infectious
Diseases, we gathered data on
communicable diseases from either
existing datasets, or, if unavailable, we
created our own databases by reviewing
the literature and other sources. We
included drivers of infectious diseases in
our mapping exercises, explaining the
distribution of infections, such as global
connectivity and sanitation. We also
combined disease maps with relevant
climatic variables like rainfall, similar to
the approach taken for Lassa fever and
This was a very rewarding project with
support from over 120 experts around the
world, connected through the world-wide
web, like a crowdsourcing project. Our
talented Vietnamese mapping team
provided excellent capacity to process this massive and valuable data. Through this
work, I realised how important it is to have access to high-quality data and the value of
professionals who can process this data robustly. A few years after completing the Atlas,
we realised how drastically the world of infectious diseases had changed. Many of the
Figure 2. Atlas of Human Infectious Diseases
(Wiley-Blackwell 2011).
8heiman f.l. wertheim
disease maps we made just a few years ago already required a thorough update. Clearly,
we need a better understanding of the many infectious diseases out there and the
conditions of transmission, to make better predictions about where diseases occur or
may occur in the future. To diagnose an outbreak and to predict its progression requires
good diagnostic data.
Enter: clinical microbiology.
clinical microbiology
Good clinical microbiology facilitates direct patient care, feeds surveillance databases
for public health purposes and is critical for investigating outbreaks.
Reliably detecting or excluding the microbiological cause of an infectious disease is
central to clinical microbiology. For this purpose, several direct and indirect methods
have been developed. Microscopy is a direct method used to visualise fungi, parasites
like malaria, or bacteria. We have other techniques, such as culturing organisms in
combination with mass spectrometry or det ecting the pathogen’s specific genes through
polymerase chain reaction (better known as PCR) or detection using a sequencing
approach. There are also indirect methods that can identify a specific host antibody
response to the pathogen using serological techniques.
Figure 3. Alexander Fleming at work in his microbiology laboratory (
9small bugs, big data
Because the epidemiology of infectious diseases are dynamic and outbreaks can occur
suddenly, a clinical microbiologist needs to be flexible and must implement new
diagnostic strategies if the circumstances demand so. Unfortunately, devastating
epidemic diseases like Ebola and outbreaks of drug-resistant infections often originate
in resource-limited settings with weak health systems, where laboratory diagnostics are
scarce. This creates the perfect circumstances for infectious diseases to multiply and
spread. In our highly-connected world, no country is an island – disease can potentially
reach any country, rich or poor, nearby or far away. Controlling infectious diseases in
low-resource settings directly contributes to controlling these diseases in high-income
countries like the Netherlands.
Digitisation provides the means to scale up the transfer of knowledge and technologies
used to diagnose and manage infectious diseases in these higher-risk, low-capacity
settings. This is already happening with molecular and sequencing techniques, and also
with the older microscopy and culturing techniques. The possibilities created by billions
of people connected with access to strong computer processing power and to instant
knowledge and skills are countless.
Smartphones are combined with microscopes to read and analyse blood slides for
malaria without the need of a trained laboratory technician and can report the results
to the attending healthcare worker. These self-reading microscopes are currently being
evaluated in field trials. This is a beautiful example of how a 350-year old technique is
being digitised and contribute to diagnosing malaria, tuberculosis, and other infectious
diseases worldwide. The microscope was invented in the seventeenth century by Antoni
van Leeuwenhoek, who lived in an age of important scientific discoveries.
I would like to briefly touch upon this piece of history as there is an important message
in there, relevant to current times.
antoni van leeuwenhoek
When Antoni van Leeuwenhoek’s first wife died, he started making microscopes. He
was 38 years old at the time. He could experiment without financial worries as he
remarried a woman from a wealthy family. He became very successful in making
microscopes, which could magnify up to 260‐fold. With his microscopes, he examined
everything from pond water, wood, hair, and even the eyes of insects. Around 1676, in
an effort to determine why peppers are so spicy, he started to experiment with ‘pepper
10 heiman f.l. wertheim
In Figure 4 you can find the sketch he made from observing a sample from a bottle
containing pepper water that turned cloudy. This drawing is believed to contain the
first sketch of bacteria. The birth of microbiology...
This revolutionary discovery cannot solely be ascribed to Van Leeuwenhoek’s
achievements, driven by his tireless work ethic, his exceptional lens making skills and
his observational skills. He was also the right man at the right time in the right countr y.
He was living at the start of t he Enlightenment, a time of paradigm shifts and important
scientific discoveries that shaped the world by people like Newton, Spinoza, Descartes
and others. Like Antoni van Leeuwenhoek, we now also live in an age of transformative
scientific achievements. And we have a new lens, the genome sequencer, which allows
us to observe and study natural life like never before, such as the human microbiota.
the human microbiota
The human body is colonised by a vast number of microbes. Collectively referred to as
the human microbiota, it has a mutualistic relationship with the human host. The
human microbiota has been jokingly called the organ system for infectious disease
specialists or clinical microbiologists, just like the neurologist has the nervous system
and the ophthalmologist the eye. In addition to their role in digesting food, these
microbes can shape your immune system, keep potential pathogens at bay, play a role
in how you feel and many other things.
The human microbiota is dynamic and changes with age, disease states, diet and other
factors. And we are continuously sharing these microbes when we interact with each
other, for example through a simple handshake. Inside of us, these microbes also
interact with each other: communicating and sharing genes.
Figure 4. The first sketch (Fig. IV) of a bacterium by Antoni van
Leeuwenhoek (Delft University of Technology).
11small bugs, big data
Dysbiosis of the human microbiota has been linked to many health issues, ranging
from asthma to intestinal disorders like irritable bowel syndrome – not the usual areas
of work for clinical microbiologists. Well-known pathogens are also among our
microbiota, which do not usually cause us harm as the peer pressure of the other
bacteria requires them to behave. However, a change in the microbiota can result in
these opportunistic pathogens causing diseases. Clostridium difficile, which leads to
severe diarrhoea, is a well-known example of this.
We do not yet understand how microbiome data can be used to improve patient
management or to prevent disease; however, several studies have shown that, for
instance, faecal transplantation with a diverse microbiome can improve health. Most
clinical microbiologists are not used to analysing communities of microbes like the
microbiota, an area in which environmental microbiologist feel more at home. This is
a pivotal moment as medical microbiology and environmental microbiology are getting
ever closer to each other. I advise residents in clinical microbiology and others to seize
this opportunity and to follow the pioneering spirit of Antoni van Leeuwenhoek.
Instead of using an optical lens, you will wield the powerful sequencing lens to study
microbial life in relation to disease.
the power of digitisation
To process the ever-increasing volume of information, including big sequence data sets
combined with patient characteristics from electronic patient files, we need more and
more computer power, which will soon reach the capacity of the human brain and
eventually the combined power of all human brains on this world and more. The speed
of current breakthroughs is unprecedented and evolves at an exponential pace. A
milestone was reached last year when artificial intelligence (AI) beat a master in the
very complex Asian game ‘Go’. AI allows computers to learn and improve by analysing
lots of examples instead of being programmed. We can incorporate artificial intelligence
into our daily work to give us more time to do what we are good at as humans: being
creative, understanding context and making human connections.
AI is already disrupting the medical specialties of radiology and pathology, which both
are supporting specialties like clinical microbiology. Artificial intelligence is capable of
interpreting scans better than humans, as it tirelessly learns from millions of scans,
remains objective and can see information invisible to the human eye. It also keeps
working and learning 24/7. The possibilities to improve the quality of our work and
patient outcomes and simultaneously reduce costs are numerous, and I believe this
potential should be embraced more. Clinical microbiology needs to plan strategically
for a future in which artificial intelligence is part of the daily routine and helps to make
us better at what we do. With the Radboud REshape Center and Philips we have started
exploring these possibilities together.
12 heiman f.l. wertheim
Let me take you through the different steps of clinical microbiology to highlight where
digitisation can make a difference.
Clinical microbiology is known for taking its time. To get results, we often have to wait
for pathogens to grow enough for identification and drug-susceptibility testing. The
faster we can secure test results, the higher the clinical impact. In order to see where we
can improve and speed up our work, we need to untangle the diagnostic process: from
deciding whether or not to test, to collecting and sending the right sample, to analysing
it and finally to reporting it. Laboratory tests are ordered on a daily basis, even when the
pre-test probability of the patient with the disease is very low and a laboratory test
would not have any added value and may even cause harm. As most hospitals today
have electronic patient files, we have the potential to reduce unnecessary testing and
increase required testing by matching clinical characteristics with test ordering. After
ordering a test and collecting the sample, we need to ensure that it arrives in a timely
fashion at the correct laboratory.
Diagnostic errors account for up to 10 percent of patient deaths [1]. The majority of
errors, around 60 percent, happen in the pre-analytic phase, which include the
incorrect ordering of tests, the mislabelling of specimens or specimens getting lost [2].
In case of mislabelling, a patient may get the wrong diagnosis or the wrong treatment,
with a prolonged disease, disability or even death as an outcome. By mid-2017,
Radboudumc will have a central specimen receiving area: a unique collaboration
between the different Radboudumc laboratories. Nurses and transport staff only need
to go to one desk rather than seven different places throughout the hospital, thereby
reducing confusion and errors.
We are also considering the option of using radio frequency identification in specimen
labels to allow us to track specimens throughout the hospital. I can track my Amazon
book order at any time, but not a precious specimen needed for an accurate diagnosis?
In addition to specimens, anything critically important can be labelled with
radiofrequency tags (from healthcare workers to patients to hospital beds), which will
enhance both diagnostics and infection control efforts.
Now that the sample has arrived in the clinical microbiology laboratory, the actual
testing can be done; here, too, the techniques are changing.
Before 2000, we had limited methods, such as cultures and serology, to detect a limited
number of pathogens. This was also very labour-intensive and time-consuming. Over
the past fifteen years, we have automated more and integrated molecular diagnostics
into routine clinical microbiology, increasing the speed and also the number of
13small bugs, big data
pathogens that can be simultaneously identified. The drawback of molecular-based
tests like PCR is that you can only find what you are specifically looking for. Furthermore,
some pathogens may not have the target used in the test or may even ‘lose’ the target,
like we have seen with malaria rapid tests [3]. Pathogens lacking or losing the target
have a survival advantage because once a pathogen is detected, both the doctor and the
patient prefer to destroy it. As a result, a pathogen without a target may become
dominant once a test is scaled up– this is microbial evolution driven by diagnostic testing!
It is the role of clinical microbiologists to monitor whether diagnostic tests remain
sufficiently sensitive and accurate.
Considering our aging population and rising healthcare costs, we need to develop and
evaluate diagnostic strategies that improve health and also reduce healthcare costs.
Fast and flexible point-of-care systems close to the patient have a lot of potential in any
setting. In addition, sequencing technology is expected to one day replace most culture-
based techniques, but many years will pass before we reach the required standards.
Another development is testing the host response with point-of-care biomarker tests,
which can guide the attending doctor to the best empiric treatment and the most useful
Table 1. Evolution in clinical microbiology techniques over the years.
Whole genome sequencing of single pathogens, which is different from the sequencing
approach of the microbiota I mentioned earlier, has already become part of the routine
diagnostic arsenal of an academic clinical microbiology laboratory, made possible by
affordable sequencing technologies. It is used for outbreak management, but also has
the potential to support treatment decisions. In 2016, we strengthened our molecular
team with bioinformatics expertise to set up a whole genome sequencing pipeline in
collaboration with the genetics department and the Centre for Molecular and
Biomolecular Informatics (CMBI). For Mycobacterium tuberculosis we will develop a
14 heiman f.l. wertheim
separate WGS pipeline to genotype TB and detect drug resistance, which is normally a
lengthy process. This will help to give the right treatment to these very sick patients
much sooner.
WGS costs will decrease further once implemented on a larger diagnostic scale,
meaning less-skilled staff will suffice over time. Placing bench-top sequencers in
microbiology laboratories, including those in low-resource settings, combined with a
fully-automated workflow and analysis may completely change the landscape of
controlling infectious diseases like TB worldwide [4].
Now I would like to discuss the issue of antibiotic resistance.
the tide of antibiotic resistance
Despite all of our digital advances, hospitals worldwide have different computer
systems for direct patient care and laboratory management. The majority of the
available information is underutilised, despite the fact that we need to provide more
data driven care. Are patients, for instance, getting antibiotics that do not match what
we test in the lab?
In close collaboration with the Information Management team, the Radboudumc
Antibiotic Stewardship-team built algorithms to monitor antimicrobial treatment in
our hospital, to determine whether it is appropriate and to provide advice if needed. It
is also cost-effective, as we can switch patients from intravenous to oral medication
sooner. More IT advancements can be made by sharing and analysing infectious disease
data on a regional level, particularly to control the spread of antibiotic resistance. This
year, the Dutch Ministry of Health will start financially supporting ten health networks
(Dutch: zorgnetwerken) to better coordinate the response to the threat of antibiotic
In the province of Gelderland, key stakeholders formed the Gelders Antibiotic resistance
and Infection prevention Network (GAIN). Considering the changing healthcare
landscape, with more care being provided outside the hospitals, these networks are
critical in monitoring healthcare-related infections and drug resistance and improving
infection control and antibiotic stewardship in a non-hospital setting. We also
contribute to other initiatives regionally, nationally and globally, such as our cross-
border initiatives with Germany. These types of regional collaborations are important
tools for controlling antibiotic resistance.
The Netherlands is exceptionally good at that.
15small bugs, big data
The Netherlands has the lowest rate of methicillin-resistant Staphylococcus aureus in
the world, but also relatively low resistance rates to many other pathogens (Figure 5).
We achieved this great success with a bundle of measures rolled out nationally. The low
resistance rates we experience are being jeopardised by the rising antimicrobial
resistance rates around us, reaching the country through travel and trade. One-third of
healthy people who are negative for drug resistance before travel acquire resistant
bacteria during international travel, with the highest number of acquisitions among
those visiting Asia [5].
As you are all aware, the Netherlands is below sea level and to protect us from the sea
we invested in the Delta Works. Now we are facing the tide of drug resistance. The
national policies we have and the recently implemented health networks can be viewed
as the Delta Works for antimicrobial resistance. Besides building stronger dykes, we
also need to slow the rise of drug resistance or preferably lower it. We can achieve this
by taking our expertise and research activities to the areas where drug resistance is
abundant, like Asia. That is where I want to contribute.
In September 2016, the UN Assembly agreed to act on antimicrobial resistance. For the
first time, heads of state committed to taking a broad, coordinated approach to address
the root causes of antimicrobial resistance across multiple sectors, especially human
Figure 5. MRSA in Europe (source: European Center for Disease Control, ECDC).
16 heiman f.l. wertheim
health, animal health and agriculture. This is just the fourth time a health issue has
been taken up by the UN General Assembly (the others were HIV, non-communicable
diseases and Ebola).
The deadly consequence of antimicrobial resistance and the global nature of this threat
are illustrated by the recent death of an American woman due to a resistant infection
acquired in India. No antibiotic available in the US was able to save her.
hotspot asia: experiences from vietnam
I had a comparable experience with a patient who was admitted to the ICU of a
Vietnamese hospital. The young woman was recovering from her illness but developed
ventilator associated pneumonia due to a multi-drug resistant bacterium, only sensitive
to an antibiotic known as polymixin or better known as colistin, an antibiotic
abandoned many years ago for systemic treatment due to its toxicity. The drug was not
available for human use in Vietnam and the patient died. Five hundred meters away
from the hospital was a veterinary pharmacy with buckets of this drug, which is usually
mixed with animal feed, illustrating the One Health and complex nature of this
problem. Systemic colistin is increasingly used worldwide despite its toxicities due to
the rising number of drug resistant infections. Colistin is now part of the empiric
treatment provided by many intensive care units in Vietnam, treating patients suspected
of having a hospital-acquired infection, of which most are now carbapenem (last resort
antibiotic) resistant.
Figure 6. Colistin as feed additive for animals is used extensively in Asia.
17small bugs, big data
Multi-drug resistance is rampant in Asian hospitals, especially in intensive care units
where there is inadequate infection control.
Where to start and improve the situation?
The issue of drug resistance reflects a health system failure, or more precisely, a ONE
HEALTH system’s failure. LMIC countries thus far have relied on antibiotics to control
infectious diseases rather than prevent them with proper infection control. With
current high resistance levels, they need to ramp up their prevention efforts.
Surveillance of drug resistance is a basic measure to make informed decisions about the
next steps. We are involved in several initiatives to implement effective surveillance
strategies. As antibiotics are the drivers of resistance, we need to ensure that those who
need it, get it and those who do not need it, do not get it.
Figure 7. Over-the-counter antibiotics in Vietnam. In the picture you can find the different kinds of
antibiotics you can get a a small rural pharmacy in Vietnam.
18 heiman f.l. wertheim
Ninety percent of antibiotics in Vietnam are dispensed without a prescription, even
though the law requires one (Figure 7). To find potential control strategies we need a
better grasp on our understanding of how antibiotics are used in the community
setting. We recently launched a study with Oxford and the INDEPTH Network the
ABACUS study aimed at identifying the determinants of appropriate antibiotic use in
low and middle income countries to identify potential interventions to address
antibiotic misuse ( However, we
also need to act now and evaluate promising existing interventions. In the community
setting, most antibiotic overuse is by patients with acute respiratory tract infections,
which are often self limiting and do not require antibiotic treatment.
A major reason for uncontrolled antibiotic use for respiratory infections is diagnostic
uncertainty. In low-income settings, physicians worry about their patients’ inability to
access healthcare if their condition deteriorates. These factors motivate overuse of
antibiotics. We found that C-Reactive Protein or CRP point-of-care testing for
respiratory infections can safely bring down antibiotic overuse in Vietnam [6]. CRP is
an inflammatory protein in the blood. A low test result means that no serious infection
is present and no antibiotics are needed.
In Vietnam, CRP testing has the potential to avert the prescription of at least 1.3 million
courses of antibiotics every year in primary care patients, and this is a conservative
estimate. The success of this trial prompted us to evaluate it in other low-income
countries. CRP can be made for less than a dollar per test and can be combined with
rapid tests for malaria or dengue fever – a huge potential for reducing AB use globally. I
look forward to working on these scale-up studies and improving the correct use of
In addition to improving antibiotic use, we need to understand the reservoir of
resistance and hotspots for transmission. If Dutch travellers can easily pick up drug-
resistant bacteria in Asia, what about locals?
Asia is a hotspot for drug resistance to commonly-used antibiotics critical for healthcare,
and recently even to the last-resort antibiotic colistin. Besides the overuse of antibiotics,
poor access to clean water and sanitation contribute to the spread of resistance.
In a household cohort in northern Vietnam, we regularly sampled the stool of
household members, their animals, the water t hey use and the food they eat. Preliminary
findings show high rates of resistance to common antibiotics and also to colistin in
healthy humans and dogs.
19small bugs, big data
As already mentioned, in Asia, colistin is commonly used as prophylaxis in agriculture.
The resistance gene for colistin, called MCR-1, is positioned on a plasmid and can easily
be shared between bacteria. This plasmid with MCR-1 emerged recently and can spread
very easily. It was present in 80% of the dogs and humans we tested. Bacteria excel at
sharing useful genes including resistance genes: the sharing economy was already invented
by nature. The colistin resistance that originated in Asia is a potential threat to Dutch
intensive care patients who receive colistin as part of prophylaxis. Antibiotic prophylaxis
in general is critical for protecting patients from acquiring an infection during a
medical intervention. Antibiotic resistance is increasingly causing trouble here,
requiring targeted solutions, both abroad and also at Radboudumc.
With the Radboudumc urology department we will evaluate whether culture-guided
antibiotic prophylaxis for prostate biopsies reduces the number of post-biopsy
infections. We increasingly observe breakthrough infections with ciprofloxacin-
resistant bacteria after a prostate biopsy, and ciprofloxacin is the drug we use for
prophylaxis. The strategy is to test patients before biopsy for the presence of resistant
bacteria in the rectum and, in case of ciprofloxacin resistance, an alternative antibiotic
will be used as prophylaxis. We look forward to conducting this diagnostic clinical trial,
which will have an impact on guidelines for this widely-used intervention and
potentially also on other surgical interventions where culture-guided prophylaxis may
be beneficial.
We are experiencing breath-taking advances in computation, artificial intelligence and
physical and biological sciences, also known as the Fourth Industrial Revolution. It is
predicted that the USA within will see a $9 trillion reduction in employment costs due
to AI over the next decade, including knowledge work in healthcare. The McKinsey
Global Institute states that AI contributes to a transformation of society ‘happening at
roughly 3,000 times the impact’ of the Industrial Revolution. Impressive!
20 heiman f.l. wertheim
Is clinical microbiology sufficiently prepared and able to adapt to this reality and seize
the opportunity to improve prevention, diagnosis and treatment of infectious diseases
around the world? I think that we have made a cautious start but we can be bolder. Like
Antoni van Leeuwenhoek before, this is our carpe diem moment.
Along with great promise, our digitising world also brings challenges.
Billions of people are connected and communicating through smartphones. This has
created a society where people reside in their own digital echo chambers. Opinions –
not facts – spread easily: like the effectiveness of vaccination. This is a reality that we
need to consider carefully. As academics, we bear the collective responsibility to bring
forward facts and to guide the greater public debate.
We still have a lot of work to do!
Figure 8. How digitisation transforms industries (McKinsey 2014).
21small bugs, big data
closing remarks and acknowledgements
Radboud University successfully focuses on infectious diseases; however, we are still too
fragmented and want to unite our efforts more effectively in the coming months as
part of the Radboud Center for Infectious Diseases (RCI). And we will undertake this
effort with many partners, both close and far away. Radboud University provides a
unique opportunity to address the global issue of antimicrobial resistance with a
multidisciplinary approach, involving social sciences, pharmacology, computer
sciences, medicine, international law and environmental microbiology. With full
optimism we are building the necessary bridges to deal with small bugs and their big
I have now come to the end of my lecture and switch to the Dutch language for the
Tot slot een woord van dank. Ik ben waar ik ben door een aantal bruggen over te steken.
Ik begin met de meest recente, de Waalbrug in Nijmegen (Figuur 9).
Bij deze dank ik het college van bestuur van de Radboud Universiteit, de decaan en de
raad van bestuur van het Radboudumc voor het in mij gestelde vertrouwen om deze
eervolle positie in te vullen. U heeft net slechts een klein deel van de plannen gehoord,
er moet gelukkig een hoop gebeuren. Ik heb er zin in!
Figure 9. De Waalbrug in aanbouw (Foto Hustinx. Uitgeverij Vantilt/FragmaPublishing).
22 heiman f.l. wertheim
De afdeling medische microbiologie: staf, analisten, deskundigen infectiepreventie,
team-managers, arts-assistenten, administratie, secretariaat, onderzoekers, kwaliteit,
externe relaties, arbo, … ik hoop dat ik het allemaal heb. Dank voor jullie welkom en
steun sinds mijn komst ruim een jaar geleden. Veranderingen zullen altijd blijven ko-
men, dat is in ieder geval wel constant. Ik ga graag met jullie de uitdagingen aan die
zullen komen.
En dat doen wij niet alleen, maar met vele partners binnen het Radboudumc en daar
buiten. Daarin wil ik in het bijzonder de sectie infectieziekten en de apotheek noemen
waar wij dagelijks mee optrekken en steeds meer gezamenlijk projecten aanpakken, zo-
als het Antibiotic stewardship team, waar ook IQ healthcare bij is betrokken.
De andere laboratoria van het Radboudumc waar wij steeds meer mee gaan delen en zo
kwaliteit verhogen en doelmatiger werken. Ik wil hier in het bijzonder Fred Sweep
noemen. Fred dank voor je inzet voor MMB en je goede overdracht van het
Collega’s van het Canisius Wilhemina Ziekenhuis en Rijnstate. Los van de opleiding
willen we meer samen doen. Het mycologisch centrum met CWZ en ook GAIN met de
GGD zijn daar gezonde voorbeelden van. Graag denken wij met jullie na over hoe de
Gelderse medisch microbiogie in de nabije toeksomst in te richten.
De volgende brug is in Hanoi, Long Bien Bridge.
Here I would like to thank Menno de Jong, Jeremy Farrar and Peter Horby for bringing
me to Vietnam and for the opportunity to do wonderful research. Warm feelings and
thanks to our Vietnamese partners who made it all possible. I cannot mention you all
here, but would like to extend my gratitude to Dr Nguyen van Kinh, director of the
NHTD. We had offices next to each other for many, many years and you called me your
younger brother, an honour that I cherish. Thanks to the entire OUCRU team in Hanoi
and HCMC. To Professor and director Guy Thwaites: we look forward to your lecture
later this year in Nijmegen. And to Dr Rogier van Doorn, who is now heading the unit
in Hanoi: great to see you here. My nine years in Hanoi were an unforgettable
experienceand I look forward to continuing to co-supervise PhD students (soon one in
Nijmegen in collaboration with Maastricht University).
23small bugs, big data
Nu mijn Rotterdamse jaren, de Erasmusbrug.
Henri Verbrugh, je was mijn opleider, promotor en mentor. Mijn Rotterdamse tijd en
het stafylokokken werk gaf mij de juiste basis voor wat ik later ging doen. Je maakte mij
na mijn opleiding staflid terwijl ik aangaf uit te willen vliegen naar verre oorden. ‘Dat
doet-ie toch niet’ zei je na mijn promotieplechtigheid tegen Greet Vos, mijn copromotor.
‘Dat doet-ie wel’ zei toen Greet en Greet kreeg gelijk. Beste Greet ik vond het geweldig
om met met jou over stafylokokken in neuzen te sparren en relevant onderzoek te doen.
Recent sparden we weer even over wat te doen met de opgeheven Werkgroep
Infectiepreventie (WIP). Dierbaar om weer meer met elkaar in contact te zijn.
Over de brug in Panama heeft u mij al eerder gehoord. De brug aan de Kortenhoefsedijk
hoort tot mijn jeugdjaren. En zo kom ik bij mijn ouders. Lieve papa en mama – jullie
levenslust is een bron van inspiratie. Papa niet nu denken dat mama mij alleen heeft
gevormd door dat Panamakanaal-boek.
Mijn zussen Mirjam en Anneke, heel lief hoe jullie je over mij bekommerde in mijn
jonge jaren – eigenlijk had ik drie moeders. Anneke – we missen je en wat zou je hebben
genoten van dit academische spektakel. Je wordt hier goed vertegenwoordigd door je
twee heerlijke kinderen Esther en David.
En dan Sigrid, Lara en Peer, mijn mede-boshutbewoners bovenop de wal in Nijmegen-
Oost. Lara en Peer – iets minder digitalisering in huis mag best, ook al heb ik er daarnet
best wat positiefs over gezegd .
Sigrid, het leven met jou en de kinderen is vurrukkulluk.
Na mijn oratie gaan we de boshut aanpakken, echt!
Ik heb gezegd.
24 heiman f.l. wertheim
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ResearchGate has not been able to resolve any citations for this publication.
Full-text available
Background Rapid diagnostic tests (RDTs) for histidine rich protein 2 (HRP2) are often used to determine whether persons with fever should be treated with anti-malarials. However, Plasmodium falciparum parasites with a deletion of the hrp2 gene yield false-negative RDTs and there are concerns the sensitivity of HRP2-based RDTs may fall when the intensity of transmission decreases. Methods This observational study enrolled 9226 patients at three health centres in Rwanda from April 2014 to April 2015. It then compared the sensitivity of RDTs based on HRP2 and the Plasmodium lactate dehydrogenase (pLDH) to microscopy (thick smears) for the diagnosis of malaria. PCR was used to determine whether deletions of the histidine-rich central repeat region of the hrp2 gene (exon 2) were associated with false-negative HRP2-based RDTs. ResultsIn comparison to microscopy, the sensitivity and specificity of HRP2- and pLDH-based RDTs were 89.5 and 86.2% and 80.2 and 94.3%, respectively. When the results for both RDTs were combined, sensitivity rose to 91.8% and specificity was 85.7%. Additionally, when smear positivity fell from 46 to 3%, the sensitivity of the HRP2-based RDT fell from 88 to 67%. Of 370 samples with false-negative HRP2 RDT results for which PCR was performed, 140 (38%) were identified as P. falciparum by PCR. Of the isolates identified as P. falciparum by PCR, 32 (23%) were negative for the hrp2 gene based on PCR. Of the 32 P. falciparum isolates negative for hrp2 by PCR, 17 (53%) were positive based on the pLDH RDT. Conclusion This prospective study of RDT performance coincided with a decline in the intensity of malaria transmission in Kibirizi (fall in slide positivity from 46 to 3%). This decline was associated with a decrease in HRP2 RDT sensitivity (from 88 to 67%). While P. falciparum isolates without the hrp2 gene were an important cause of false-negative HRP2-based RDTs, most were identified by the pLDH-based RDT. Although WHO does not recommend the use of combined HRP2/pLDH testing in sub-Saharan Africa, these results suggest that combination HRP2/pLDH-based RDTs could reduce the impact of false-negative HRP2-based RDTs for detection of symptomatic P. falciparum malaria.
Full-text available
Routine full characterization of Mycobacterium tuberculosis (TB) is culture-based, taking many weeks. Whole-genome sequencing (WGS) can generate antibiotic susceptibility profiles to inform treatment, augmented with strain information for global surveillance; such data could be transformative if provided at or near point of care. We demonstrate a low-cost DNA extraction method for TB WGS direct from patient samples. We initially evaluated the method using the Illumina MiSeq sequencer (40 smear-positive respiratory samples, obtained after routine clinical testing, and 27 matched liquid cultures). M. tuberculosis was identified in all 39 samples from which DNA was successfully extracted. Sufficient data for antibiotic susceptibility prediction was obtained from 24 (62%) samples; all results were concordant with reference laboratory phenotypes. Phylogenetic placement was concordant between direct and cultured samples. Using an Illumina MiSeq/MiniSeq the workflow from patient sample to results can be completed in 44/16 hours at a reagent cost of £96/£198 per sample. We then employed a non-specific PCR-based library preparation method for sequencing on an Oxford Nanopore Technologies MinION sequencer. We applied this to cultured Mycobacterium bovis BCG strain (BCG), and to combined culture-negative sputum DNA and BCG DNA. For flowcell version R9.4, the estimated turnaround time from patient to identification of BCG, detection of pyrazinamide resistance, and phylogenetic placement was 7.5 hours, with full susceptibility results 5 hours later. Antibiotic susceptibility predictions were fully concordant. A critical advantage of the MinION is the ability to continue sequencing until sufficient coverage is obtained, providing a potential solution to the problem of variable amounts of M. tuberculosis in direct samples.
Full-text available
Background: Inappropriate antibiotic use for acute respiratory tract infections is common in primary health care, but distinguishing serious from self-limiting infections is difficult, particularly in low-resource settings. We assessed whether C-reactive protein point-of-care testing can safely reduce antibiotic use in patients with non-severe acute respiratory tract infections in Vietnam. Method: We did a multicentre open-label randomised controlled trial in ten primary health-care centres in northern Vietnam. Patients aged 1–65 years with at least one focal and one systemic symptom of acute respiratory tract infection were assigned 1:1 to receive either C-reactive protein point-of-care testing or routine care, following which antibiotic prescribing decisions were made. Patients with severe acute respiratory tract infection were excluded. Enrolled patients were reassessed on day 3, 4, or 5, and on day 14 a structured telephone interview was done blind to the intervention. Randomised assignments were concealed from prescribers and patients but not masked as the test result was used to assist treatment decisions. The primary outcome was antibiotic use within 14 days of follow-up. All analyses were prespecified in the protocol and the statistical analysis plan. All analyses were done on the intention-to-treat population and the analysis of the primary endpoint was repeated in the per-protocol population. This trial is registered under number NCT01918579. Findings: Between March 17, 2014, and July 3, 2015, 2037 patients (1028 children and 1009 adults) were enrolled and randomised. One adult patient withdrew immediately after randomisation. 1017 patients were assigned to receive C-reactive protein point-of-care testing, and 1019 patients were assigned to receive routine care. 115 patients in the C-reactive protein point-of-care group and 72 patients in the routine care group were excluded in the intention-to-treat analysis due to missing primary endpoint. The number of patients who used antibiotics within 14 days was 581 (64%) of 902 patients in the C-reactive protein group versus 738 (78%) of 947 patients in the control group (odds ratio [OR] 0·49, 95% CI 0·40–0·61; p
Full-text available
In view of increasing attention focused on patient safety and the need to reduce laboratory errors, it is important that clinical laboratories collect statistics on error occurrence rates over the whole testing cycle, including pre-, intra-, and postanalytical phases. The present study was conducted in 2006 according to the design we previously used in 1996 to monitor the error rates for laboratory testing in 4 different departments (internal medicine, nephrology, surgery, and intensive care). For 3 months, physicians and nurses were asked to pay careful attention to all test results. Any suspected laboratory error was recorded with associated pertinent clinical information. Every day, a laboratory physician visited the 4 departments and a critical appraisal was made of any suspect results. Among a total of 51 746 analyses, clinicians notified us of 393 questionable findings, 160 of which were confirmed as laboratory errors. The overall frequency of errors, 3092 ppm, was significantly lower (P <0.05) than in 1996 (4700 ppm). Of the 160 confirmed errors, 61.9% were preanalytical errors, 15% were analytical, and 23.1% were postanalytical. During the last decade the error rates in our stat laboratory have been reduced significantly. As demonstrated by the distribution pattern, the pre- and postanalytical steps still have the highest error prevalences, but changes have occurred in the types and frequencies of errors in these phases of testing.
Background: International travel contributes to the dissemination of antimicrobial resistance. We investigated the acquisition of extended-spectrum β-lactamase-producing Enterobacteriaceae (ESBL-E) during international travel, with a focus on predictive factors for acquisition, duration of colonisation, and probability of onward transmission. Methods: Within the prospective, multicentre COMBAT study, 2001 Dutch travellers and 215 non-travelling household members were enrolled. Faecal samples and questionnaires on demographics, illnesses, and behaviour were collected before travel and immediately and 1, 3, 6, and 12 months after return. Samples were screened for the presence of ESBL-E. In post-travel samples, ESBL genes were sequenced and PCR with specific primers for plasmid-encoded β-lactamase enzymes TEM, SHV, and CTX-M group 1, 2, 8, 9, and 25 was used to confirm the presence of ESBL genes in follow-up samples. Multivariable regression analyses and mathematical modelling were used to identify predictors for acquisition and sustained carriage, and to determine household transmission rates. This study is registered with, number NCT01676974. Findings: 633 (34·3%) of 1847 travellers who were ESBL negative before travel and had available samples after return had acquired ESBL-E during international travel (95% CI 32·1-36·5), with the highest number of acquisitions being among those who travelled to southern Asia in 136 of 181 (75·1%, 95% CI 68·4-80·9). Important predictors for acquisition of ESBL-E were antibiotic use during travel (adjusted odds ratio 2·69, 95% CI 1·79-4·05), traveller's diarrhoea that persisted after return (2·31, 1·42-3·76), and pre-existing chronic bowel disease (2·10, 1·13-3·90). The median duration of colonisation after travel was 30 days (95% CI 29-33). 65 (11·3%) of 577 remained colonised at 12 months. CTX-M enzyme group 9 ESBLs were associated with a significantly increased risk of sustained carriage (median duration 75 days, 95% CI 48-102, p=0·0001). Onward transmission was found in 13 (7·7%) of 168 household members. The probability of transmitting ESBL-E to another household member was 12% (95% CI 5-18). Interpretation: Acquisition and spread of ESBL-E during and after international travel was substantial and worrisome. Travellers to areas with a high risk of ESBL-E acquisition should be viewed as potential carriers of ESBL-E for up to 12 months after return. Funding: Netherlands Organisation for Health Research and Development (ZonMw).