Download Can Man win the war on Microbes?

Battle of the Titans: Can Man win the war on Microbes?
Protocol
The AgVice-Chancellor, Professor Rahman Ade-Bello,
The Deputy Vice Chancellors,
The Registrar and other Principal Officers of the University
Distinguished Members of Council,
The Provost College of Medicine and Deans here present,
Distinguished Scholars and Professors here present,
My Lords Spiritual and Temporal,
My professional and Academic colleagues,
Our Students,
Gentlemen of the fourth estate,
Distinguished Ladies and Gentlemen
Preamble
Two roads diverged in a wood, and I took the one less travelled by, and that has made the
difference - Robert Frost 1920
I feel highly honoured to stand before you today to deliver my inaugural lecture. When I was
made a Professor with effect from 2008, I knew I owed the University a debt to give this
inaugural lecture in the quickest time possible and today as I stand before you I look back on my
journey in the field of Medical Microbiology which started in 1989, 23 years ago.
The topic I have chosen is a reflection of my understanding of the world we live, in co-existence
with microbes and it is a testament to the giant strides we have made as a race in our battle
against infectious diseases. It is a story of possible reversals of our achievements as the microbes
fight back. It is also a reflection of my personal journey from a shaky beginning as a Clinical
Microbiologist to this time, this place this hour standing before this August assembly of Mentors,
Colleagues, family, friends, mentees and students sharing with you my viewpoint on where the
field is or should be going. Intertwined with this story will be my contributions to this field of
medicine.
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Between 1987 and 1989 three events occurred that impacted me greatly and influenced
the choice of my Sub-specialty.
The first was the advent of the Human immunodeficiency virus which was just being
recognized. I met an American Microbiologist who was very involved with this epidemic
and as she recounted her experiences, Clinical Microbiology began to sound very
interesting considering that it was a subject I just tolerated as a medical student. She also
gave me a book to read “And the Band Played On: Politics, People, and the AIDS
Epidemic” by Randy Shilts which chronicled the discovery and spread of Human
Immunodeficiency Virus (HIV) and Acquired Immune Deficiency Syndrome (AIDS). He
described in detail the struggles of researchers, patients and activists in discovering AIDS
and HIV and showed how Government indifference and political infighting allowed the
continued spread of the AIDS and set the stage for the pandemic we have today. This
book ignited a fire in me. Up to this point I had no interest whatsoever in Microbiology
despite the valiant efforts of my brother-in-law, friend and mentor, Professor Olubunmi
Rotimi to entice me into Microbiology. He tried everything and had failed. I was
determined to be a Pediatrician!
The second event was the case of a young lady of about 21yrs of age who came to our
clinic with non-specific symptoms who had been given a diagnosis of typhoid fever
based on a single widal result from a private laboratory. No cultures were done. She had
been started on chloramphenicol somewhere else and when she did not get better had
been prescribed Cefuroxime (Zinnat), flagyl and a host of other antibiotics in a bid to heal
her. She went from bad to worse ending up with a distended abdomen and bloody mucoid
stool. She was referred to a general hospital for surgery. At surgery nothing could be done
because when she was opened up, they saw a gangrenous colon. They closed her up and
she died a few days later. She died from pseudomembranous colitis caused by the
organism Clostridium difficile that thrives in an environment where the normal flora has
been decimated with antibiotics.
Event three was that of a healthy young man driving down from Northern Nigeria to
Lagos. At Lokoja he felt a sharp pain in his chest and pulled up by the side of the road.
Feeling breathless he went into the town and was diagnosed as typhoid fever because the
widal was 1:160 (despite the absence of any symptoms suggestive of typhoid). He was
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immediately started on chloramphenicol. He did not get better and was moved from clinic
to clinic where repeats of the widal tests were done (with results of fluctuating titres). He
was told in clinic after clinic that the typhoid was still there and had many repeats of
treatment for typhoid. By the time we saw him two months later he had had various
courses of chloramphenicol, ampicillin, gentamicin, cefuroxime, erythromycin etc and
was now in a wheel chair, very ill and still very breathless. No one had done a Chest
Xray! They were all focused on the widal test and neglected the patient history and
obvious symptom. We went back to his history and a chest x-ray showed a
pneumothorax. He had had a spontaneous pneumothorax while driving and insertion of a
test tube would have reinflated the lungs and solved the problem! Unfortunately that was
no longer the worst of his problems! He now had aplastic anaemia (bone marrow can no
longer produce red and white blood cell) an uncommon but recognised side effect of
chloramphenicol and died a week later from overwhelming sepsis.
It reinforced the value of proper patient evaluation, selection of the right diagnostic tests,
importance of understanding the results in the context of patients’ symptoms and finally
to respect antibiotics and recognize that they are chemicals and must be used responsibly
and with caution.
As a young doctor, I therefore made the decision, that was to radically change the direction of
my life, to veer away from the more traditional specialties of Medicine, Surgery, Paediatrics and
Obstetrics and Gynaecology into the relatively uncharted waters of Clinical Microbiology, a field
of medicine that was sparsely populated and certainly little understood in terms of patient care in
Nigeria, I did not realize the struggle I would have in getting professional and personal
validation.
Clinical Microbiology is an extremely academic field especially because the organisms we study
being highly adaptive, change their characteristics rather frequently so as to continue to survive
such that new information rapidly becomes stale.
It is a field of medicine that is still little understood by the public and even our clinical
colleagues. There is a tendency to assume that we are meant to be confined to the laboratory
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only! But the solution to the problem of infectious diseases is not to be found at only one
location as microbes are not limited by manmade boundaries therefore the Clinical
Microbiologist cannot be put in a box that has ‘laboratory only’ written on it, we have to stay on
the frontlines wherever the microbes go and so we have gone into the critical care units, clinics,
wards, surgical units and into the community, in essence we follow where the microbial
footprints lead us.
The Beginning of The Battle
In the beginning God created the world and on the 6th day after He made man in His likeness, He
said:
“Be fruitful and multiply and replenish the earth and subdue it,
and have dominion on the fish of the sea, fowl of the air and over
every living thing that moveth upon the earth” (Gen. 1:28 King James Version) –
What we did not realize was that the microbes were eves dropping, that they also heard the
injunction and in a very efficient way set about populating the world and setting the stage for a
long drawn out battle for survival such that today, one of the greatest threat to mankind is
infectious disease and every year new infections are emerging and old infections that we thought
we had eliminated are re-emerging in new forms. The list is long: Human Immunodeficiency
virus, Avian influenza virus, Severe Adult Respiratory distress Syndrome (SARS), Hanta virus,
Nimpah virus, Marburg fever, Ebola fever virus, Lassa fever, Dengue fever, LUJO virus, malaria,
pneumonia, cholera, diphtheria, Pertusis (whooping cough), tuberculosis and a host of multidrug
resistant bacteria that have given rise to a long list of acronyms; MRSA, MRSE, VRE, ViSA,
VRSA, ESBL, KPC, ESKAPE, MDR, XDR. The situation is so dire now that Antimicrobial
resistance was the theme of the WHO world health day 2011 and we are now hearing talk of the
post-antibiotic era or The Apolcalypse.1
This lecture will be focusing mainly on bacteria, antimicrobial resistance and infection control. It
will start at the beginning when man and microbes met and how we, using, antibiotics dabbled
into the genetic pool of microbes and started a train of events the consequences of which we did
not initially anticipate. It will highlight how we by our complacency and misuse are destroying
the efficacy of one of the greatest weapons we have against microbes. I will attempt to show how
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Nigerians at every level continue to underestimate the enemy. By the end of the lecture you will
be able to determine if you believe we are winning the war or what we need to do to win it.
Who is the adversary? What are these microbes?
Microbes generally refer to Bacteria and Viruses. They are probably the most abundant life form
in the world inhabiting every known ecological niche. This lecture will be focusing mainly on
bacteria but it is important to differentiate them from viruses and they differ in many respects.
Bacteria are unicellular single celled organisms containing both DNA and RNA. Most of them
are independent life forms and live freely in the environment. Viruses on the other hand are just
pieces of genetic material (either DNA or RNA) surrounded by a protein coat. One fundamental
difference is that while bacteria are inhibited or killed by antibiotics, viruses are totally
unaffected by antibiotics. However, most viral infections are self limited and are taken care of by
the body defense system
Bacteria have lived on Earth for 3.5 billion years far longer than man.2 The Earliest fossil
evidence show the presence of man was 2.5million years ago but it was not till about 200,000
years ago that man as we know him today appeared on this planet so it is to be expected that
bacteria are far better adjusted to the environment than we are.3
There are over 1030 bacteria on earth4 divided among a thousand million species with as much as
100 trillion beneath the surface of the earth.5 It has been estimated that if all the microbes were
brought to the surface of the earth they would form a layer 5ft thick over all the surface of the
earth6. Microbes so outnumber animals that the mass of all microbes on earth is 25 times more
than the mass of all animals put together. 6
Microbes are everywhere, air, soil, in the sea, on every surface including the human body. We
are covered completely on the inside (on mucous membranes) and on the outside (on skin) by
microbial life with more microbes on our body than there are humans on Earth. There are more
than 600,000 bacteria living per square inch of skin with an average person carrying about a
quarter of a pound of bacteria at any given time. Microbial cells outnumber all the cells in our
body by a factor of 10 to one.6 Some of these are permanent residents and we call them the
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normal flora.7 The normal flora is extremely important in maintaining health, they help to prime
the immune system, prevent pathogens (disease causing bacteria) from being able to attach and
produce chemicals which inhibit or kill other bacteria.8,9,10
Of the one thousand million microbes that exist only 538 bacteria, 317 fungi, 287 worms, 208
viruses and 57 parasitic worms have been shown to cause infections!11 These organisms that
cause infections are called Pathogens and bacteria have been the villains of infectious diseases.
So how do these tiny creatures cause so much havoc and what has been our response?
Emergence of Infectious diseases.
After the great injunction, man went out and multiplied and populated the earth but so did the
microbes. However it appears that the microbes that infected man were well adapted to man and
appeared to live in relative symbiosis till about two million years ago, when man learnt to make
fire and tools and eventually began to hunt for food.12 Animal proteins were introduced into our
diet and we became stronger and bigger and as we hunted we came more often into contact with
animals and meat products as well as microbes associated with animals. The first evidence of
disease appeared to have been zoonotic probably trichinosis and encephalitis.13 However large
scale disease did not begin till the introduction of agriculture about 10,000 BC, when man began
to settle into communities and farm. Irrigation of the land led to areas of stagnant water in which
microbes and insects bred leading to disease such as Cholera (Contaminated water) and Malaria
(by mosquito). We were also living in closer proximity to one another facilitating easier disease
transmission.13 This early urbanization set the stage for future epidemics such as Small pox,
Measles, Typhoid and Scarlet fever that would plague the world for many years.12
Between 9,000 and 3,000BC, the domestication of animals in Eurasia and the Americas resulted
in an ongoing contact between Man and Animals with a lot of germs crossing the species barrier
and adapting to humans. Some of these included Small pox (believed to have come from
domestication of Camels in Asia Minor), Leprosy (Buffalo in India) as well as Tuberculosis from
the domestication of Cattle.14
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These diseases became more acute as urbanization continued and cities grew in population and
trade routes opened up passages for the transfer of microbes between communities leading to
spread of epidemic diseases,15 that were characterized by transmission of disease between family
members, communities and their domestic animals and were often attributed to punishment from
God or from demonical fumes (miasmas) arising from stagnant water, marshes, other
environmental sources as well as haunted places.16
This was the era of the great epidemics and pandemics with the indiscriminate spread and
symptoms of bubonic plague, small pox, typhus, cholera and influenza which were to continue
into 1950’s and claim millions of lives. For example the black death caused by the organism
Yersinia pestis now called Pastuerella pestis between 1347 and 1351 killed over 75million
people in Western Europe, Russia, China and North Africa and returned every generation till the
1700s. This period of epidemics continued into the 18th century where a third pandemic of plague
that started in China and killed over 2m people was still ongoing as recently as 1959 though
casualties had reduced to only about 200/year.14,17
This era, the pre-antibiotic era characterized by large casualties from infectious diseases was
terrifying to people as they had no understanding of where the plagues came from all they could
do was to appease the gods. During this era began the theories as to the causes of epidemic and
pandemic transmission of infection heralding in the beginning of the study of infectious disease.
Thus in the 16th century, a Veronese scholar and physician, Girolamo Fracastaro proposed in
1530 the theory that ‘seeds of disease’ (seminaria) were responsible for the spread of infections
during the epidemics which he later, in 1546, expanded into a proposal that there were three (3)
modes of disease transmission: direct contact with infected person, direct contact with infected
clothing or other contaminated materials and through the air18
This theory of the “seeds of disease” was largely ignored till 1673, when Anthony Van
Leuwenhoek, a humble draper with a love for grinding magnifying lenses, gave credibility to the
“seed theory” of disease. Using his magnifying glass, he examined everything, rain water, pepper
infusions, gingivial scrapings, faeces and discovered a new world of living creatures that were
invisible to the eye, He discovered bacteria and called them animalcules (little animals).19 This
discovery of the microscope opened the way for many discoveries that would give man a leg up
in the battle against infectious diseases.
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Subsequently evidence for the microbial aetiology of contagious diseases were confirmed when
Robert Koch established the aetiology of Anthrax (Bacillus anthracis) in 1876, Tuberculosis
(Mycobacterium tuberculosis) in 1882 and Cholera (Vibrio cholera) in 1883. He then went on to
give us a set of criteria required to establish microbial aetiology of disease which are called
Koch’s Postulates16 which we still use till today. The entrenchment of the germ theory of disease
meant that man had discovered his foe. We now knew what we were up against and so began
another race to identify the weapons to destroy it.
Mans response to Microbes
With knowledge of the foe we began looking for weapons to destroy it. We went in two
directions those looking at ways to enhance our ability to resist infection and those looking for
chemicals that would destroy it. I will today be focusing on antibiotics because they have been
the most significant weapons against bacterial infections, though we must acknowledge the
contributions that vaccines have made to the amelioration and prevention of diseases such as
tuberculosis, whooping cough, Diphtheria, Tetanus, measles and certainly to the eradication of
smallpox.
Our earliest forays in searching for antimicrobials focused on dyes which were championed by
Ehrlich who in 1891 experimented with the dye methylene blue as an antidote to malaria and
soon rolled out Trypan red for Trypanosomiasis, trypan blue and afridol violet for cattle
trypanosomiasis. Other chemicals such as the arsenicals and its derivatives like atoxyl and
Arsphenamine (salversan) were also used with limited success and were fraught with side
effects.16
In 1913, Ehrlich was to give us a name for antibiotics which we still have in our psyche in our
approach to antibiotics. While describing the ideal drug, he coined the word “bewitched balls”
which later became popularly known as “magic bullets” for compounds which would fly in
search of the enemy and strike parasites with intensity while been entirely harmless to the human
host16. He never found this magic bullet but he has been credited by some scholars as being
responsible for the age of chemotherapy- which I call the ‘The era of Man’s supremacy”
In 1929 the antimicrobial Prontosil (a precursor of the sulfonamides) was discovered and
introduced as a cure for puerperal sepsis20 but it was not until 1939 with the discovery of
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penicillin that we truly discovered the magic bullets and opened the way for the discovery of
various antibiotics. These were truly exciting times as the discovery of new antibiotics followed
one after the other. By 1945, Penicillin was available commercially and between 1945 and 1962
we discovered -lactams, chloramphenicol, macrolides, tetracyclines aminoglycosides,
glycopeptides, quinolones and streptogramins - 9 different classes of antibiotics- all attacking
these organisms through essentially four mechanisms: Cell wall inhibition, Inhibition of protein
synthesis, Nucleic acid inhibition and cell membrane inhibition. (Figure 1)
Diseases that would have caused epidemics were conquered and mortality rates fell dramatically.
We had turned infectious diseases from a major public health issue into a technical problem that
could be treated with antibiotics. .
\
Figure 1: Antimicrobial target sites of antibiotics
(http://www.wiley.com/college/pratt/0471393878/student/activities/bacterial_drug_resistance/index.html)
We appeared to have conquered the microbes; we had vaccines and we had antibiotics. We had a
pill for every bacterial infection, there was a spectacular improvement in public health that we
were so confident that we had conquered infectious diseases. This mood of complacency was
well captured by Sir MacFarlane Burnett, the Australian Nobel Laureate who in 1962 said in the
Preface to his book Natural History of Infectious Diseases, "At times one feels that to write about
infectious disease is almost to write of something that has passed into history."21 and by Sir
Walter H. Stuart the American Surgeon General who in 1968 said before the American congress
that ‘It was time to close the books on infectious diseases”22
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We reduced our investment on public health; we relied solely on antibiotics. We believed the
magic bullet and bought into its myth. We believed that being magic they could work on
anything, on viruses on parasites. We used them on everything from the common cold (caused by
viruses) to gastrointestinal disturbances that were usually self limited. We had turned infectious
disease into a short term problem and most prescriptions for antibiotics were for 5 days. In many
parts of the world infectious diseases was no longer the problem we had cleaned up our act: there
was safe water, good housing, good sanitation, safe waste disposal and people were living longer
so the pharmaceutical industry also reduced their investment in research into new antimicrobial
agents. Between 1962 and 2000 no new antibiotic class was introduced 23
Figure 2: Timeline of New antibiotics
Fischbach MA and Walsh CT Science 2009
Microbes Fight back
Bacteria represent micro-engineering at its finest. They are between 2-4m in diameter or
length.24 They have two basic shapes circular (cocci) or rods (baccilli). The circular forms may
be in different configurations diplococcic (two cocci), tetrads (4 cocci), in chains (streptococci)
or in bunches like grapes (staphylococci). The bacilli may be curved (vibrio) spiral (spirillae or
spirochaetes). They contain a DNA that is over 1mm long that fits into this tiny cavity only
because it is supercoiled.24 They have all they need to reproduce, respire and survive. Most of
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them are independent living and are extremely adaptive to their environment. This ability to
adapt is aided by and is also a function of their rapid rate of reproduction.
Most bacteria of medical importance double their population every 20-30mins.24 Bacteria
multiply by binary fission with one mother cell giving rise to two daughter cells and two cells to
four cells and in 7 hours one bacterium would have given rise to over 4m bacteria and the
population would have doubled 20 times!! What I call the pyramid of growth. Compare this to
the human race that doubles its population every 10-20 yrs. (figure 3).
What does this mean? Why should we care if they double their population every 20 minutes?
Mr. Vice-Chancellor sir, this rate of division comes with error so we find that the bacterial
genome is error prone, there is spontaneous mutations in the DNA of the bacterium in every
growth cycle. What this means is that within 8hrs one mistake in the genome of one bacterium
would be replicated so many times and would be present in 4m bacteria and by 9hrs would be
found in 32m bacteria!!
Therefore within any colony of organisms there will be many variants and these variants will
have different characteristics from the mother cell. These characteristics could be in the form of
changes in receptors to antibiotics, in a nutritional requirement, morphological characteristic or a
biochemical pathway or even in virulence that could have significant impact on humans. The
survival of this variant will depend on the environment in which it finds itself. For example if the
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variation results in a change to a receptor to which an antibiotic binds, then this variant (strain)
will be at an advantage and survive in the presence of the antibiotic while sensitive strains will
die; what we call antibiotic selection pressure. With a sustained antibiotic selection pressure and
absence of the sensitive strains this antibiotic resistant variant rapidly becomes the dominant
strain.
Therefore, no sooner did we introduce a new antibiotic than there were reports of bacteria that
were resistant to it. Penicillins were introduced commercially in 1943 by Florey and Chain and
by 1946 there were reports of strains of Staphylococcus aureus that could not be treated by
penicillin.25 (Table 1) Looking at figure 4, the average rate at which organisms develop
resistance has increased dramatically. Before the 1970s the average rate of resistance developing
was 9.9yrs and for some antibiotics such as Erythromycin, and vancomycin it took over 30yrs for
resistance to develop. By the 1970s however, the party was over, the rate of resistance
developing had dropped to only 1.3yrs such that no sooner was an antimicrobial introduced than
resistant organisms began to appear so for many of our modern day drugs such as ciprofloxacin,
imipenem, ceftriaxone resistance developed within one year on the average.
12
Table 1: Dates Antibiotic resistance are Reported
Walsh C. 2003.
13
Figure 4: Time to resistance developing
Adapted from Walsh 2003
This increased rate of antibiotic resistance has been linked to overuse of antibiotics and to the
fact that most “new antibiotics “ since 1962 are modifications of existing ones.23,25 Bacteria
therefore already have a mechanism of resistance in place to the class of the “new drug” which
they only need to modify slightly. This overuse of antibiotics is a global problem in the United
States of America alone over 50m unnecessary prescriptions are written every year for infections
that are caused mainly by viruses or that will resolve without antibiotics.26 (figure 5)
14
Durnham E. NPR Adapted from Center for Disease Control
This link between antibiotic consumption and antibiotic resistance is better appreciated in figure
6 with the direct correlation observed between increasing rates of ciprofloxacin-resistant
Streptococcus pneumoniae isolates recovered from invasive patient infections with increasing
consumption of the quinolone, ciprofloxacin27. Unfortunately we do not have these kinds of
national statistics in Nigeria though numerous small studies suggest that we have similar trends.
Pallares et al., 2003
Fig 6: Increasing rates of ciprofloxacin resistant Streptococcus pneumoniae with increasing
consumption of quinolones.
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Across the country between 33%-100% of patients will take antibiotics without prescription28-30
and the situation is not better in the hospitals where high rates of antibiotic prescriptions are
given. Doctors prescribe at least one antibiotic in 50%-83% of patient encounters .28,31-33
Indications for antibiotics have been largely inappropriate with 25% of antibiotics prescribed for
malaria, 22% for respiratory tract infections and 6.1% for typhoid 31,32 even for menstrual pain.30
The most common drugs prescribed are Cephalosporins, Penicillins, Quinolones and
macrolides.28,31-33 This high rate of antibiotic consumption combined with the ease with which
antibiotics can be purchased without prescription is compounded by the use of antibiotics in
animal husbandry.
In Nigeria, combinations of antibiotics like erythromycin, tetracycline and neomycin as well as
veterinary equivalents of the quinolones and aminoglycosides are used often in in subtherapeutic doses as growth promoters in the poultry industry.34 This was borne out by our
findings of high rates of antibiotic resistance in Salmonella species obtained in chickens from
major poultry companies in Ibadan.35 All the Chicken isolates were highly resistant to
ciprofloxacin one of the drugs used for severe gram negative infections in patients, (Table 2)
Adapted from Fashae, et al 201035
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The nature of antibiotic resistance is to grow because it is a survival strategy for microbes.
When antibiotics are used against any organism it will kill off all sensitive atrains leaving behind
all the variants that are resistant to it. Once the sensitive strains have been killed off the resistant
starins rapidly multiply and become the predominant strains, It becomes obvious therefore that
this error prone genome is not a mistake it is an evolutionary masterstroke that allows for
genomic plasticity ensures an efficient adaptation to their environment and in this case an
environment made hostile by antibiotics.36,37 The earliest reports on antibiotic resistance in
Nigeria came in the 1970s and by the 1980s and 1990s there were reports from all over the
country of antimicrobial resistant strains.38,39 At least 30% of all the common pathogens
Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae and pseudomonas aeruginoasa
were already resistant to the common antibiotics such as penicillin, cotrimoxazole, cloxacillin,
and gentamicin38,40-43. (Figure 7) Resistance to other organisms like Enterococci44, Salmonella
spp45, Neisseria gonorrhoeae46 were also emerging. We also reported the first cases of multidrug
resistant Acinetobacter infections in Nigeria47,. Of 58 isolates, >30% were already resistant to
Ceftriaxone, ceftazidime, ticarcillin/Clavulanate and ciprofloxacin,
Between 1994 and 2007, the percentage of Multidrug resistant Pseudomonas aeruginosa an
opportunistic gram negative bacterium responsible for bloodstream infections, urinary tract and
wound infections rose from below 10% in 1994 to over 60% in 2007 at the Lagos University
Teaching Hospital (LUTH).48, 49(Fig 8) What this means is that our ability to treat infections
caused by this organism is dimi nished and may require more expensive and often more toxic
second or third line antibiotics.
17
Figure 7: antimicrobial resistance in Lagos 1980’s and 1990’s
Adapted from Oduyebo, Ogunsola Odugbemi 1997, Aibinu et al 2007
Figure 8: Trends in rates of Multidrug resistant Pseudomonas aeruginosa in LUTH 1994- 2007
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Microbes resist antibiotics in a number of ways; by preventing entry into the cell, by producing
chemicals (enzymes) that destroy the antibiotic, by acquiring intracellular pumps which pump out the
antibiotic as soon as it enters the cell (efflux system) and by changing the configuration of receptors to
which the antibiotics attach to the bacterium to effect their action24,. (Figure 9)
Figure 9: Mechanisms of Antibiotic Resistance.
These changes are expressions of changes that have occurred at the genetic level and may occur due to
errors during division of the bacterial genome itself (chromosomal) or by the acquisition of foreign genes
which may be from the environment (Transformation), or through infecting viruses (bacteriophages) that
transfer genes from bacterium to bacterium or by direct transfer from one bacterium to another through a
sex tube or pilus; a process known as conjugation24. These kinds of exchange occur particularly in the
colon (the large intestine) where there are about 108 (100,000,000) organisms per gram of faeces.10 The
kind of foreign genes that can be acquired differ but what is consistent is that they are all mobile elements
which include, plasmids, transposons, insertional sequences.24 Plasmids which are (circular, extrachromosomal, double- stranded DNA capable of autonomous reproduction have been the most studied.
They carry genes which may code for various factors including drug resistance and are responsible for
horizontal transfer of resistance may also possess certain genetic elements ( which may also be found on
chromosomes) called integrons that have the ability to trap numerous genes and disseminate them at one
go thus conferring multiple antibiotic resistance in one transfer50. We now suspect that their activity is at
the root of the rapid dissemination of antibiotic resistance seen amongst gram negative bacteria in the last
6 decades.51 Integrons play a crucial role in bacterial evolution and they have adapted to the high selective
pressure of unbridled antibiotic use in human medicine and animal husbandry to ensure the survival of
their kind.
19
They therefore represent one more weapon in the arsenal of our bacterial foes and we found them in
Salmonella isolates recovered from chickens in Ibadan. In a study of five (5) commercial chicken farms in
Ibadan, we found Class 1 integrons in isolates of non-typhoidal Salmonella species that cause foodborne
infections. These integrons conferred resistance to gentamicin52 while in Lagos we also found
simultaneous occurrence of class 1 and 2 integrons in two isolates of Providentia spp from
chickens 53 What this means is that there is an increased potential for the transfer of these resistance
genes from chicken into the genetic pool of microbes in our gut. We are what we eat.
Dissemination of Resistance genes
The transfer of resistance genes requires microbial transfer from a person, food, water, contaminated
environment, or equipment to another person.54 For this transfer to occur there must be a reservoir of the
microbe, a means of transmission and a susceptible host. The successful outcome of this interaction is
premised on the ability of the microbe to survive during transfer, which means the closer the reservoir is
to the new host the better. The kinds of environment that favour high transmission rates are hospitals and
places where people live in close proximity such as prisons and slums.
Hospitals are particularly unique because not only is there a high rate of antibiotic use that creates the
kind of selection pressure that breeds resistance but it is the only place where you have a large
congregation of the ill and infectious in close proximity. The potential for spread of infection and
antibiotic resistant organisms is therefore high as healthcare workers walking from patient to patient
transfer microbes via unwashed hands.55,56 Infections that occur in the hospital which was not incubating
when the patient was admitted or manifests after discharge is called a healthcare associated infection
examples of which include post surgical site infections, catheter associated blood stream infections,
Catheter associated urinary tract infections, One of the main characteristics of this kind of infection is that
it tends to be due to multiply drug resistant microbes. In the very ill, mortality rates can be very high but
the danger is not only to patients but healthcare workers. Multidrug resistant tuberculosis HIV, Hepatitis
B and C as well as epidemic prone diseases such as Lassa fever, Ebola fever, SARS, have been
responsible for healthcare worker deaths. In the Lassa fever outbreak in Imo state in 1989, all the cases
and deaths were hospital associated and of the 34 infections, 22 patients died and these included 2
surgeons, I physician and 4 nurses The cause of the high transmission rates was due to reuse of syringes
as well poor sterilisation practices57.
More recently there was a report of a new multidrug resistant Klebsiella pneumonia containing a
gene called the NDM-1 gene (New Delhi metallo betalactamase enzyme) first detected in
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Swedish patient of Indian origin in 2008.58 It was later detected in bacteria in India, Pakistan, the
United Kingdom (in a patient that had gone to India for dialysis), United States, Canada, Japan
and Brazil.59 It has now spread to other bacterial species. Bacteria carrying this gene are
dangerous because they are resistant to all known antibiotics including the last line antibiotics
used against gram negative bacteria called the carbapenems – meropenem and Imipenem. The
only options left are a new antibiotic, tygecycline and a very old and toxic one called colistin and
a successful outcome of treatment with either of these antibiotics is not assured. We have not yet
detected this gene in isolates of bacteria here but with the increasing trips to India and Pakistan
for medical care, it is just a matter of time before one of these bugs hitches a ride back in one of
our patients.
Microbiologists on the front line of the human response
“What is the role of a Clinical Microbiologist in tilting the outcome of the war with microbes in
favour of mankind? The Clinical Microbiologist must understand pathogenesis, correlate
microbial characteristics with symptoms and signs and most importantly have strategies to break
the chain of diseases transmission. We need to understand how these microbes impact people in
their habitat within the hospital and in the communities and use this understanding to defeat
them. We must search for the sources of resistant genes because they totally undermine the
human response. In this battle therefore, we must recognize the enemy by its name not just its
biological name we need to identify the individual strain or variant so we know its peculiar
characteristics, a process called typing.
Typing allows us to identify the variants that occur as a result of bacterial mutagenesis or gene
transfer. It is subspecies characterization. And it is important for tracking the epidemiology of
antibiotic resistance and focusing our response. In responding we also target the organism at
different stages of the disease process either by diagnosing the infection and treating the host or
breaking the chain of transmission (Infection prevention and Control) or protecting a susceptible
host from acquiring the disease,
Our strategy has therefore been premised on the following
1. Know thy enemy – (Diagnosis, Typing, identifying new strains, characterisation)
21
2. Track the enemy (surveillance of antimicrobial resistant organisms, and diseases)
3. Fortify your defenses (Prophylaxis, vaccines, Infection control and other public health
strategies)
4. Prepare the weapons (Protect the present antibiotics, discovery of antibiotics drugs, new
modes of drug delivery)
Knowing the enemy
Clostridium difficile is another organism that has been causing deaths in the last two decades, a
very interesting microorganism. It is the quintessential hospital-acquired pathogen. It is more
commonly found in the hospital environment than in the community and is associated with
antibiotic use. It causes antibiotic-associated diarrhoea, antibiotic- associated colitis and
Pseudomembranous colitis.60-62 and was first described in 1935 as a part of the normal intestinal
flora of newborn infants63. They called it Bacillus difficilis. It was not till 1978 that it was
recognized as the aetiology of the disease pseudomembranous colitis. It requires that the normal
flora is destroyed by antibiotics, surgery or other drugs before it can multiply.64,65 It produces
two toxins, Toxin A and Toxin B 66,67 and only toxin producing strains cause disease68.
Up to 1992 many typing methods had been attempted to allow microbiologists recognize the
various strains. The most categorical was the serotyping method of Delmee which recognized 10
major groups A-D, F-K, and X.69 Serogroup A could be further subdivided into 12 subtypes (A1 A12) by SDS-PAGE analysis of the whole cell proteins70 but the bands were difficult to analyse.
Unfortunately the serotype method was not universally applicable because the antisera were
difficult to produce due to many cross reactions between strains requiring extensive crossabsorption. It was clear that a more universally applicable system was required. Various methods
had been tried but they were laborious, complex or difficult to interprete.71-73
We hypothesized that since serotyping was based on cell surface structures then a process that
analysed surface proteins was likely to be more closely related to the serotypes without the
problems associated with cross reactions. Our hypothesis was correct. Using 61 strains obtained
from patients, animals and National Culture collection Type cultures we showed that the
serotypes could be divided based on the arrangements of the surface proteins.
22
Only 2-3 major bands were obtained by SDS-PAGE of extracted surface proteins and they had
molecular weights of 30-67 KD. Numerous faint bands (minor) were also visible but it was
found that good discrimination could be achieved on the basis of the major bands alone. The
serogroup type strains showed distinct differences in band patterns and The SP group of all
strains was easily distinguished visually74 (figures 10,11).
Figure 10
23
Figure 11
F.T. Ogunsola et al., 1995
This result gave us the basis for the next step in developing a more discriminatory method based
on variations at the genetic level. This was important because methods that are based on
phenotypic characteristics can be disadvantaged by unstable expression, can be less reproducible
and discriminatory. We were able to develop a new typing method which is now the gold
standard for typing C. difficile globally. We modified the PCR ribotyping method of Gurtler.75
It exploits the variations that occur in the intergenic space between the 16S and 23S ribosomal
genes (which are both highly conserved in bacterial species) in the genome of the organism. It is
a very discriminatory and reproducible method but its complexity and use of toxic organic
solvents and radioactive substances precluded its widespread application.
What we did was to simplify the method and develop a primer that amplified closer to the ends
of each gene so that the PCR product was shorter. (figure 12)
24
Figure 12
We shortened the process from a 6 step procedure to a 3 step procedure and shortened the time
taken to process each sample. The original typing scheme had a DNA extraction process that took 23hrs involving toxic organic solvents and modified it to one that took 30mins and only involved boiling
the organism in a 5% solution of a resin called chelex 100.76
Figure 13
25
We also simplified the analysis of the PCR products and were able to discriminate between all the
serotypes. This method is now the reference method for identifying C. difficile strains the world over76.
As I said earlier C. difficile disease is associated with antibiotic use and because the largest
concentration of antibiotic use is in hospitals it tends to be a hospital acquired infection. In the
last decade C. difficile associated diseases have become more prevalent especially in the western
world, and more severe. In addition the profile of patients affected has changed from elderly
people above 65years to young healthy people in the prime of life. This change is due to the
emergence of a hypervirulent and more antibiotic-resistant strain ribotype 027 which produces
16 times more toxin A and 23 times more toxin B than other C. difficile strains77 Toxin
production by an emerging strain of Clostridium difficile associated with outbreaks of severe
disease in North America and Europe. This has led in some parts of the world to a 5-fold increase
in mortality from 10/1 000 000 person-years in 1999–2000 to 48/1 000 000 person-years in
2006–2007.78
Globally, 5.9 to 11% of healthy adults will carry C .difficile in their colon.79 We hypothesized that
in Nigeria because of the indiscriminate use of antibiotics in the community that the carriage
rates of C .difficile-associated diarrhoea will be high amongst healthy Nigerians within the
community and would not be significantly different to rates obtained in the hospital. We
therefore randomly selected 4 local governments in Lagos state and over a four year period
looked for Clostridium difficile spores and free toxin in the stool of people with and without
diarrhoea and compared with that of in- patients at the Lagos University Teaching hospital.80
We found no significant difference in carriage rates between the 4 local governments (figure. 14)
and about one in five (20%) Lagosians carry Clostridium difficile strains in their faeces. We also
proved our hypothesis and that there would be no difference between community and hospital
carriage rates because of the pervasive antibiotic use in the community. (Table 2) People using
multiple antibiotics were also more likely to harbor C. difficile. We surmised that this high
carriage rate is an indirect measure of the amount of antibiotics consumed in the community
which further confirms what we already suspected.
26
Figure 14. Geographical distribution of C. difficile in four Local Government in Lagos state
Table 2 Correlation of antibiotic use with C. difficile carriage in the hospital and community
27
Ag Vice Chancellor sir, why do we care? We are in the middle of another epidemic a global
pandemic of Antibiotic resistant microorganisms and we are not fringe players. The WHO has
shown that in every type of microorganism today, antimicrobial resistance is a growing problem;
Artesunate resistance is increasing amongst malaria parasites, We are the country with the fourth
largest number of tuberculosis patients in the world and multidrug resistant tuberculosis is
already being identified, Multidrug resistant Staphylococcus aureus, Multidrug resistant gram
negative bacteria producing all manner of enzymes that hydrolyse antibiotics (Extended
spectrum beta lactamases (ESBLs) and carbapenamases as well as fluoroquinolone-resistant
Escherichia coli (most common cause of urinary tract infections and gram negative blood
infections) and Fusobacterium spp causing periodontitis. 81-84
Table 3
Top 10 countries with TB patients
India
China
Indonesia
Nigeria
South Africa
Bangladesh
Ethiopia
Pakistan
Philippines
Democratic Republic of the Congo
http://www.who.int/tb/publications/2009/airborne/b
ackground/info/en/index.html
In Nigeria, study after study shows the presence of high antibiotic resistance rates but we have
no coherent national data! We are not carrying out National surveillance studies that will give us
the true picture of things and provide the kind of data that is useful for policy decisions. Such
studies are driven by governments. Antibiotic misuse and overuse by the both the medical
profession and patients, misuse and overuse in animal husbandry as well as substandard
28
concentrations of antibiotics in fake antibiotics nave been identified as major drivers of this
epidemic in developing countries.
It is clear that we recognize our enemy and we can call it by name. We also now know where he
is and he is everywhere. We now know that not all the microbes are enemies that some are good
and that damage to these good bacteria (normal flora) can lead to disease. I hope you are
convinced that once you are infected with a microbe, close proximity to others helps to facilitate
its transfer and spread.. In the pre-antibiotic days, urbanization as a result of agriculture was one
of the most significant contributory factors to the aetiology of the widespread and recurring
epidemics of plague, cholera and small pox.!
Ag Vice Chancellor Sir, This story will therefore not be complete without talking about the slums
which are a direct result of rapid urbanization and have been described by UN Habitat as “a
heavily populated urban area characterised by substandard housing and squalor”85 In 1820 when
the word first appeared it was used to “ identify the poorest quality housing, and the most
unsanitary conditions; a refuge for marginal activities including crime, ‘vice’ and drug abuse; a
likely source for many epidemics that ravaged urban areas; a place apart from all that was decent
and wholesome.”
Between 2003 and 2007, as part of a project of the Harvard School of Public Health ‘s Aids
Prevention Initiative in Nigeria (APIN) project, funded by the Bill and Melinda Gates
Foundation, we started working in one such slum Kuramo village, in Victoria island. We found a
community of about 10-15000 people mostly Nigerians of Yoruba extraction, living in 8
settlements Kuramo, Igbosere, Apese,Inupa, Olukotun, Magbon, Itirin and Onijegi along the
beach front. Seven of them were what was left of traditional fishing villages that predated
Victoria Island. Kuramo was the newest and most disorganised and was originally settled by
people fleeing from the clearing of Maroko by the military. These settlements were characterized
by Inadequate access to safe water; Inadequate access to sanitation and other infrastructure; Poor
access to health care, Poor structural quality of housing; Overcrowding and insecure residential
status. Our plan was to carry out a study to determine the prevalence and incidence of HIV and
other sexually transmitted diseases amongst commercial sex workers (CSWs) in Kuramo village
and environs. Our objectives were to determine the level of awareness and attitudes to HIV and
29
the existing preventive methods, To identify the prevalent HIV subtypes and follow disease
progression in those affected. (This was before HIV drugs were universally available)
However because of the poor living conditions we found it unethical not to provide some
primary health care so we built a clinic and collaborated with the Local government in
Iru/Victoria Island LGDA who seconded staff to provide antenatal care, immunizations while we
provided HIV and STI diagnosis and treatment. We also organized them into a community health
association and trained peer educators to advocate HIV counseling and testing in the community.
We conducted a census of three of the communities and numbered all the buildings and did a
door to door survey of all consenting women assess their knowledge attitude and practice to HIV
and risk factors for acquisition and dissemination of the virus. Of the 1136 women interviewed
over 60% were aged 15-25yrs. Many had multiple sex partners an the mean age at first sexual
intercourse was 17yrs. Women had on average two sexual partners in the preceding month.
Although 89.6% of the women were aware of condoms, over 60% had not used condoms at the
last sexual intercourse and 20.7% admitted to having exchanged sex for money. Knowledge of
STI and HIV was widespread though misinformation was common. Despite the prevalent high
risk behavior, 75% felt they were at little or no risk of acquiring HIV virus. Our findings showed
the HIV and syphilis prevalence rates were 22% and 10.8% respectively. HIV rates were four
times and syphilis infection rates about 50 times the national average of 5% and 0.2%.86 This
confirms the high rates of transmission of microbes in slums. During the period of study, HIV
drugs became available through another grant the Presidential Emergency Plan for AIDS relief
and we started treatment. In 2006 Kuramo was destroyed by the Government and people ran out
into the general community. A tragedy! As people ran out we lost many from the treatment
program but more importantly we also helped to disseminate syphilis HIV. Ibelieve we must find
an alternate way of dealing with slums.
30
Kuramo Clinic
Table 4
31
Table 5
Table 6
32
Other Pictures from Kuramo and the Laboratory
33
34
Ag Vice chancellor sir, Africa in general and Nigeria in particular is still in the grip of infectious
diseases. The two greatest killers are respiratory tract infections and diarrhea but also include
Ebola, Lassa, Malaria, HIV, Tuberculosis, Cholera, typhoid, respiratory tract infections, post
partum infections. Our ability to combat infectious diseases is being rapidly eroded by this silent
epidemic of antibiotic resistant organisms. The high rates of transmission that are more prevalent
where humans live in close proximity will further exacerbate the epidemic. African communities
are growing rapidly and it has been predicted that by 2050, the population in Africa will hit 2
billion and 60% of these will be living in the cities, mostly in slums. We can see the trend
already. Lagos, if the rural urban migration continues unabated, will double its population by
2024 (in 12 yrs) which means more slums. I have counted at least 20 large slums in Lagos there
are many more small slum communities. We must find a sustainable solution to the problem of
slums.
A great biologist Hans Zinsser in his book Rats Lice and history (1935) wrote
“ Bacteria, Protozoa, viruses, infected fleas, ticks, mosquitoes and bedbugs
will always lurk in shadows ready to pounce where neglect, poverty, famine
or war lets down the defenses. And even in normal times they prey on
the weak, the very young and the very old “
We continue to work in slums because we cannot solve the problem of infectious diseases and
antibiotic resistance without solving the problem of poverty and deprivation because slums are a
breeding ground from where the microbes spread to all parts of the country and even into our
homes. Slums and hospitals are therefore the last stand battle fields against infectious diseases
and antimicrobial resistance.
Solutions
The question is: Are we winning the war on microbes? I think not, but neither have we lost it
yet. Microbes are certainly reversing the gains we have made on infectious diseases but
we still have options:
35
Antibiotic Stewardship
We must conserve this life saving resource by using antibiotics responsibly. We must reduce
unnecessary prescriptions. It has been shown that the three most common for which a doctor will
prescribe an antibiotic are Fever, sore throat and diarrhoea. In all three situations in viruses
account for a large proportion o cases and antibiotics do not act on viruses. There must therefore
be strict indicators for antibiotic use. The general public should no tbe allowed to have access to
antibiotics without a prescription and I am aware that many pharmacists today will not sell
antibiotics without a prescription
Hospitals must develop antibiotic policies and regulate the use of antibiotics, we need to audit
prescriptions and request that indications are clear for their use. This needs a well functioning
laboratory. Our antibiotic prescriptions are often empiric i.e. without any laboratory support.
Laboratories need to be strengthened to produce accurate results in the shortest possible time; we
must invest in new technologies. Laboratories are very capital intensive and if we are to realise
the benefits we must invest in infrastructure, human capacity building
We need to actively begin a national surveillance network so we can track resistance. This will
require continuous funding that might be obtained through public private partnerships with
pharmaceutical industries or with international donor agencies or through research funds in the
University. We lack country wide data.
Government must see this as a an emergency and ensure that legislation is enforced that
prevents the easy sale of antibiotics in the street, market place and by patent medicine sellers. We
also require National or state policies that empower us to protect antibiotics and preventtheir
continued abuse. Since the public We therefore need education of the public and healthcare
workers on the rational use of antibiotics and the dangers of antibiotic resistance
Infection Control and prevention
Antibiotic resistance is bred and disseminated most frequently in the hospital because of
selection pressure. Infection prevention and control guidelines promote activities that promote
the spread of these microbes from patient to patient. The most important is hand hygiene because
the hands are the most important means by which microbes including drug resistant microbes are
spread in the health facility.
Infection control is a quality standard, it is evidence-based and competency driven. Research
must continue into new strategies and procedures to break the chain of transmission of microbes
in the hospital. We must continue operational research that tests our processes. There is still a lot
of work that needs to be done in the area of Infection control of airborne diseases such as
tuberculosis. This will be a focus of my lab in the coming years.
36
There is a dearth of infection of infection control practitioners and we need to focus on research
and surveillance of antibiotic resistance. Since 2009, I have been working with the World health
Organisation as an Infection Control expert and a member of the Global Infection prevention
and control network which assist the WHO in drawing up guidelines for infection control and the
Chairman of the working group developing a generic curriculum that can be adapted by countries
to train infection control practitioners. I am also a member of the rapid response team of experts
for outbreaks in Africa and have been deployed twice now on missions to Uganda as an infection
control expert to assist with the Ebola outbreaks to strengthen IPC structures and train
healthcare workers in the field. Infection Control is still a major problem in Africa and Nigeria.
Most countries have no Policy or guideline. What has been substituted has been what we call
infection control in silos or vertical programmes so we have HIV infection control, TB infection
control and so on run by programme managers and various NGOs. Once the program is over the
infection control program is also gone. What we advocate is that for sustainability these
programs should strengthen existing systems by training personnel already in the field of IPC.
Research into new antimicrobials
Research and development of new antibiotics is very expensive and globally there is a drive to
promote more commitment to the development of new classes of antibiotics. It takes on the
average 10 or more years and millions of dollars from laboratory research to production of a new
antimicrobial. What is called the drug pipeline (Figure 15)
Figure 15: The Product Pipeline in 2006
37
Between 2004 and 2007 I was Principal investigator of a randomised phase III double blind
placebo controlled study to test the effectiveness of a microbicide an investigational product 6%
Cellulose sulphate vaginal gel for the prevention of HIV and Sexually transmitted disease.87 Our
objective was to show effectiveness of the product and confirm the safety profile. It was a multi
country study and within Nigeria it was conducted at two sites at College of Medicine,
University of Lagos and Port Harcourt. It was funded by USAID, monitored by Family Health
International in North Carolina from where the Project manger also came from. had a staff of
over 40 people and we were working out of two clinics, in Ikeja and Apapa and running a
Laboratory in the College of Medicine. We were to recruit 3000 women at high risk for HIV. In
2007 the study was discontinued due to safety concerns from one of the sites outside Nigeria.
This was not before $2,000,000 (N300, 000,000) had been spent. Drug research is expensive and
companies need to know there will be a return on their investments and antimicrobial resistance
is further eroding this confidence.
However we in the Universities must continue to carry out studies into new antimicrobials. . We
have a rich heritage of traditional herbs that can be researched, in the last few years we have
been working on the antimicrobial properties of Garcinia Kola., and have confirmed its activity
against Streptococcus mutans (dental caries)88 Fusobacterium nucleatum (periodontitis)89,
Clostridium difficile, 90 Candida species as well as multidrug resistant gram negative bacteria and
Staphylococcus aureus, These are early days yet but we will be moving this area of research
forward.
For us to Combat antimicrobial resistance, the effort must be coordinated Nationally Government
must take this problem seriously we cannot let the complacency that got us here to continue.
The WHO in 2011 came out with a policy statement to help member states adequately conmbat
antimicrobial resistance and it has 6 components
1. Commit to a comprehensive, financed national plan with accountability and civil society
engagement
2. Strengthen surveillance and laboratory capacity
3. Ensure uninterrupted access to essential medicines of assured quality
4. Regulate and promote rational use of medicines,including in animal husbandry, and
ensure proper patient care
5. Enhance infection prevention and control (IPC)
6. Foster innovations and research & development for new tools
Finally I will leave us with the words of Dr Stuart Levy a leading figure in the antimicrobial
wars
38
“Last year an event doctors had been fearing finally occurred. In three geographically separate
patients, an often deadly bacterium, Staphylococcus aureus, responded poorly to a once reliable
antidote--the antibiotic vancomycin… The looming threat of incurable S. aureus is just the latest
twist in an international public health nightmare: increasing bacterial resistance to many
antibiotics that once cured bacterial diseases readily ……Strains of at least three bacterial
species capable of causing life-threatening illnesses (Enterococcus faecalis, Mycobacterium
tuberculosis and Pseudomonas aeruginosa) already evade every antibiotic in the clinician's
armamentarium, a stockpile of more than 100 drugs ……
(The Challenge Of Antibiotic Resistance , By: Levy, Stuart B., Scientific American, 00368733,
Mar 98, Vol. 278, Issue 3 )
The time to act is Now.
39
ACKNOWLEDGEMENTS
First I will like to thank the Lord for where I am today for he ordered my footsteps.
To my parents Prof. Akin Mabogunje and Justice Titilola Mabogunje, I thank the Lord for your
life and for who I am today. Discipline, Love and lots of argument characterized our home. You
encouraged us to speak the truth and do the right thing even when it was not popular or easy.
A special thank you must go to Prof. Vincent Olubunmi Rotimi. I did not become a
microbiologist by accident. He prepared the ground that made me receptive to late events that got
me here. He still mentors me and mentors my mentees. I can never repay the dept. I can only say
yes! I do not regret taking the road less travelled.
I am grateful to my teachers at the University of Ife, Ile-Ife who laid the foundation for my
growth. It was a strong foundation. I will mention in particular Prof Gani Ladipo, Prof Bankole,
Prof T. Adesanya Ige Grillo, Prof. Bamgboye, Prof Odesanmi, and Dr Caxton-Martins.
I want to thank all those who have mentored me and impacted on my academic and professional
career. I thank most sincerely Prof. Tolu Odugbemi who took an interest in my progress and
challenged me to work hard.
Special thanks go to Prof. Brian Duerden my PhD supervisor at the University of Wales, College
of Cardiff, Prof Yinka Ogundipe, Prof. Akinkugbe, Prof Lekan Abudu, Dr Jon Brazier, and Dr
John Magee who helped to hone my critical thinking skills.
I have also had the advantage of having strong women in my life who have impacted me and
given me their friendship, Prof. Ronke Akinsete, Prof. Yetunde Olumide, Prof Oyin Olurin, Prof.
Bisi Sowunmi, Dr. Kofo Rotimi, Mrs. Bonike Adesanya, and Dr Carmen Lucia Pessoa of WHO
Geneva.
To the members of the Department of Medical Microbiology, it has been a journey and I have
learnt something from you all. Prof. Sunday Omilabu, Dr Wellington Oyibo, Dr Oyin Oduyebo,
Dr Adenusi, Dr Oladele, Prof Coker, Mrs M.T. Niemogha, Ag. Kola Oyedeji, Alfred Azenibor,
Mrs Tayo Adenipekun and the Non academic staff. Thank you all for your contributions to my
growth.
In the last 8 years I acquired another family, a network bound by research interests, the APIN and
MEPIN families. I must acknowledge specially the contributions of Professor Phyllis Kanki of
the Harvard school of Public health for her contributions to my academic life as well as the
development of infrastructure at the College of Medicine and LUTH. I thank you for your
unwavering support. I thank Professor Rob Murphy for his contributions. I also thank other
members of the family from around the country and in particular Dr Prosper Okonkwo and Dr
Wole Odutolu.
40
I thank my many friends and people I work with at both Idiaraba and Akoka. I dare not attempt
mention you by name but I appreciate you all.
I must acknowledge all my academic children in particular my two PhD students DR Kayode
Fashae and Dr Tenny Egwuatu I have learned a lot from you both and I thank you for your
contributions to my growth and in the preparation of this lecture. I cannot but mention my other
children Dr Bolanle Balogun, Dr Sonachi Ezeiru, Dr Jumoke Olufemi, My Kuramo girls. Their
commitment to the provision of healthcare to the people of Kuramo made the project possible.
My residents, past and present I thank you
Many People have Impacted my life and contributed to today that I cannot mention by name I
appreciate you all, I thank the Old Girls of Queen’ of the college set of 1970-74/76, The Christ
Morning Star society and other members of the Anglican Church of the Ascension Opebi,
Members of the Department of Anatomic and Molecular Pathology which has been my second
home for many years, The Girls, Ag. Otusanya and the CS study team, members of the APIN
Lab, My many PA’s, Mr. Sunny Aigbefo and the Karale team who actualize my dream of taking
health care to the poor. I thank you.
I will at this point want to thank My Provost Professor Wole Atoyebi and My CMD, Professor
Akin Osibogun, for their leadership and their support of my many ideas, The CMAC, Prof
Gbenga Ogunlewe for her support. I will at this stage also want to thank the members of College
administration and Finance department whom I have come to know so well as we navigated and
grew from one grant to the other. Thank you.
I want to thank my siblings for their constant support. In particular, Seun and Toki Mabogunje,
Bimpe and Femi Oye, Sola and Simi Mabogunje, Gboyega and Nirvana Mabogunje.
My wonderful in-laws, The Ogunsolas you have always been there for me. Prof. and Mrs. Niyi
Ogunsola, Mr. and Mrs. Ayo Ogunsola, Mr. Bambo Adesanya, Chief and Mrs. Akinbiyi, Chief
and Mrs. Ajibola Ogunsola, Chief and Mrs. Sola Ogunsola, Chief Yinka Ogunsola and the large
family.
Ag. Vice Chancellor Sir, It only remains for me to thank my immediate family,
My children Seun and Busola Denton, Akin Ogunsola, Olumayowa Ogunsola and my beautiful
granddaughter Eniabitobi Denton
Last but not the least I will like to thank my husband Ag. Olusegun Ogunsola who in the last 29
years of our marriage has patiently supported me as I went from one exam or report to the other.
I thank you with all my heart for your support, strength, reliability and encouragement. You
allowed me to achieve my dreams.
41
Ag. Vice Chancellor sir,
Distinguished Ladies and Gentlemen
I thank you all for honoring me with your presence today.
42
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