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Microbes, Antibodies, and Immunomodulation
Date: 02-11-1997 :: Pg: 31 :: Col: b
The longer one stays in hospital the greater the chances of one getting
an infection. Well, the dictum seems ironocal in that the patient ends
up paying, literally and figuratively, to get infected. DR. S.
SRINIVASAN analyses the problem.
Even half a century or so after Alexander Fleming's historic discovery
of penicillin, the term ``hospital acquired infections'' may sound odd,
even unbelievable. But it exists and it speaks volumes of what exactly
is the position in even the best hospitals in the most advanced
countries. Ironically, the more sophisticated the gadgetry in intensive
care, the greater the threat of catching a new infection. And, the
longer one stays in hospital with one's bills rising like taxi meter,
the more the chances of one getting infected. You virtually end up
paying to get infected, and then pay more to get treated for it as well.
More on this curious vicious cycle later.
With the advent of powerful, modern antibiotics, a whole new era of what
are called `nosocomial infections' has arrived. This term may sound
rather strange and seems to indicate an infection of the nose tissue,
but is in fact derived from the Greek word ``nosokomeian'', which means
a hospital.
To understand ``nosocomial infections'', one needs to understand how
medical intervention can cause a problem, in addition to treating it. A
parallel expression, ``iatrogenic disease'' is relevant here. ``Iatros''
stands for doctor and ``genic'' indicate cause - ``iatrogenic'' thus
stands for anything caused by a doctor. In other words, an iatrogenic
disease is a ``doctor- caused'' disease. There are many example. If a
doctor prescribes a class of drugs called ``corticosteroids'' for
asthama or arthritis, he can create an ``iatrogenic'' peptic ulcer
problem in the stomach as a side-effect. If a mental patient is
prescribed antipsychotic drugs, one can end up with ``iatrogenic
Parkinsonism'' (a disorder of limb movements), again as a side- effect.
Similarly, the nosocomial infections can also be classified as
iatrogenic diseases.
If doctors are aggressively treating infections all the time, then how
can they be also creating new infections? Let us take a fairly
straightforward case of, say, severe and extensive burns in a victim
caused by an accident in the kitchen. Intensive treatment is started
immediately, which means cleaning and dressing the burns, administering
intravenous fluids, replacing blood, inserting a catheter in the urinary
bladder to drain out urine and providing other supportive measures to
sustain vital functions till full recovers. At times, if the patient's
condition deteriorates considerably, she may have to be put on a
respirator with oxygen too.
All these measures provide an easy path for microbes to invade the body,
through the intravenous line, catheter, respirator and so on, especially
at a time when the body defences are down due to the stress of burns,
blood loss, immobilisation, improper nutrition and other factors. Burns
take very, long time to heal, so the hospital stay can extend for
several weeks, if not months. To control infection in the burnt area,
doctors start a course of antibiotics which kill infecting bacteria
alright but soon give way to other types of bacteria resistant to them.
So, the patient ends up catching a different type of infection. This
goes on and on as long as the burn remains unhealed and thus susceptible
to attack by bacteria. In the bargain, the patient becomes a breeding
place for difficult-to-treat bacteria which are ``multi- resistant'' to
a wide range of antibiotics.
ICU - the ideal place for infections.
Dreaded infections in a hospital find their roots in intensive care
units. The reason for this paradoxical phenomenon is easy to understand.
To begin with a patient in the ICU is always in a serious condition -
he/she is severely injured, has undergone a major operation or has a
malfunctioning vital organ. The patient is often unconscious and needs
to be sustained on intravenous fluids, has to breathe with the help of a
respirator and has tubes and gadgets into him her. He/she can develop
bed sores. Coughing out an obstruction in the air-passages, is difficult
and getting pneumonia is a certainty. The urinary catheter is a
continuous source of infection for the urinary system which can soon
affect other parts of the body. There is a depletion of vitamins and
minerals essential for the body's defence mechanisms as there are low
levels of antibodies. He/she is often treated with corticosteroids which
lower the body's defences. The patient is thus ``immuno-compromised'',
which means body immunity is below par.
With all this in mind, doctors bombard ICU patients with the best
antibiotics. These latest generation antibiotics are known as
cephalosporins, fluoro-quinolones, aminoglycosides, and other specific
chemical groups and are often administered in combinations to achieve
the best results. If the body's defences are satisfactory the bacterium
can be tackled using one or more of such drugs. If treatment does not
have to be prolonged, the chances of recovery infections are good. If,
vice-versa, the patient is in for real trouble.
To understand how bacteria can play tricks on doctors, we can draw a
parallel with the cockroach in the kitchen. Even with the best pest
control measures, no one can kill all the cockroaches. Some are bound to
escape, either because they were inherently resistant to the pesticide
or because they did not get sprayed enough. These soon multiply to form
a new population resistant to the spray. To tackle this problem, pest
control experts are constantly formulating newer pesticides and or using
them in combination.
Resistant bacteria are ``selected'' in a similar manner whenever an
antibiotic is given. While many die off, some remain and multiply to
yield a whole new colony of resistant bugs. Of course, the probability
of such a thing happening can be predicted reasonably by what is called
``in vitro'' (literal meaning, in glass, that is laboratory test tube
sensitivity testing, in which a culture of the bacterium isolated from
the body is exposed to the antibiotic to be given, in the laboratory
under controlled conditions. If the bacterium is inhibited or killed, it
is called ``sensitive'' to the antibiotic, and if not, it is deemed
``resistant''. But even if ``in vitro'' testing shows sensitivity, there
is no guarantee that all bacteria will die. So, the danger of some
inherently resistant ones multiplying to yield resistant bugs is always
there.
When it comes to cunning, bacteria can even outsmart the best defences.
For instance, not only do they learn to develop resistance to a strong
antibiotic even as treatment is on, but they can also quickly transmit
the resistance to other bacteria in the process, with devastating
consequences. Research is intense so that counteractive measures can be
taken on a war footing. But somehow, the bugs manage to stay a step
ahead.
Resistance to antibiotics is acquired by bacteria through changes in
genetic make-up, which results in changes in bio-chemistry, which in
turn evades the killing action of the antibiotic. For instance, a
bacterium can learn to prevent the entry of the antibiotic inside itself
or can learn to chemically destroy the antibiotic after it acts.
Powerful enzymes are brought to operation in order to achieve this.
One such enzyme is ``beta-lactamase'' which can destroy even modern
antibiotics of the ``beta lactam group'' known as ``cephalosporins''.
Researchers try to overcome this by discovering newer generations of
``cephalosporins'' which can be stable to attack by ``beta-lactamses''.
The bacteria, in turn, try to overcome this by designing newer and newer
types of ``beta-lactamases'' and bringing them into operation. And so
the ding-dong battle continues.
Transmissible resistance is one in which the resistance is offered by
loosely occurring genetic material called ``plasmids'' which can be
passed on from one bacterium to another. The passing on is done through
``conjugation'' which is a sort of marriage between the bacteria which
then separate and transmit the resistance to others through a chain of
conjugations.
To find out how bacteria behave under ICU conditions in major hospitals,
a study was undertaken in Europe a few years ago. On April 29, 1992,
10,038 patients from ICUs of 17 countries in Western Europe were
surveyed for possible infection. Popularly known as the EPIIC study
(European Prevalence of Infection in Intensive Care) this study came up
with some very interesting results.
Of those surveyed, 45 per cent had some infection on that very day. Of
these, nearly half the number of infections originated in the ICU. It
was noted that those who were at special risk were those with
in-dwelling urinary catheters meant for draining out their urinary
bladder, those with central venous catheters meant for intravenous fluid
administration and measuring central venous pressure, those who were put
on assisted ventilation with a respirator and those who had stayed in
the ICU for 14 days or more for whatever reason. Pneumonia was the
commonest type of infection followed by bronchitis, urinary tract
infection, wide- spread infection all over the body (``septicemia'') and
infection of surgical wounds.
Not only are infections more common in absolute terms in ICU patients,
but it also turns out that the types of bacterial causing these
infections are changing over the years, thanks to the widespread use of
advanced, broad spectrum antibiotics. Decades ago, when catheters and
other invasive devices were not common, bacteria of the ``Gram negative
bacilli'' category were predominant in hospitals. These rod-shaped
bacteria, that look pink after staining, originate in the intestines of
the patient. Today, ``Gram positive cocci'', which originate from
invasive devices, tend to cause a number of infections. Then there are
old organisms which have learnt new tricks. Examples of these are
Pseudomonas, Enterococci, Enterobacter, Citrobacter and Serratia. Once
again, to tackle Gram positive as well as Gram negative infections in
difficult ICU settings, doctors have to resort to therapy with
combinations of ultramodern antibiotics like fourth generation
cephalosporins and glycopeptides.
All this war - like imagens may remind one of missile technology. It is
anybody's guess where this will all end, if it ends at all. Already,
scientists have started looking at totally different modes of infection
control in which the emphasis will be not on killing the invading
bacterium but on boosting the body's defences through
``immunomodulation''. This approach, also known as ``biological response
modification'' reminds one of our changing strategy towards mosquito
control, in which we have started relying equally, if not more, on
mosquito repellants rather than on killing the mosquitoes.
If microbes are going to be forever hoodwinking modern drugs, then it is
perhaps not a wise idea to go after newer and newer antibiotics, but
instead look for more ingenious ways of dealing with them.
Dr. S. SRINIVASAN
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