Opinion - Op-Ed
The microbes strike back
N. Gopal Raj
Without new antibiotics, the outlook looks grim.
DANGEROUS COME BACK: Bacteria are fighting back.
Are we at the end of the penicillin story?
There was a happy period in the last century when
it appeared that humanity was at long last gaining
the upper hand in its age-old struggle against
disease-causing microbes. So much so that a U.S.
Surgeon General is often credited with saying in
the 1960s, “The time has come to close the book on
infectious diseases.”
But bacteria have fought back, finding ways to
become resistant to various antibiotics. The sense
of triumph has increasingly been replaced by alarm
over whether the bad old days of untreatable
infections might be around the corner.
The problem of antibiotic resistance has been
there from the start. Shortly after penicillin was
discovered and even before it had entered clinical
use, bacteria resistant to it were found.
In his Nobel Lecture in December 1945, Alexander
Fleming, the discoverer of penicillin, was
remarkably prescient. “It is not difficult to make
microbes resistant to penicillin in the laboratory
by exposing them to concentrations not sufficient
to kill them, and the same thing has occasionally
happened in the body.
“The time may come when penicillin can be bought
by anyone in the shops. Then there is the danger
that the ignorant man may easily underdose himself
and by exposing his microbes to non-lethal
quantities of the drug make them resistant.”
Use of an antibiotic creates an evolutionary
pressure that leads to resistant forms
proliferating. Under-dosage can hasten the
process. But for several decades as resistant
bacteria became more prevalent, they were held in
check with newer antibiotics.
In India, as elsewhere in the world, these
antibiotics have had a huge impact on infectious
diseases, remarked Lt. Gen. D. Raghunath
(retired), who was Director General of the Armed
Forces Medical Services and now heads the Sir
Dorabji Tata Centre for Research in Tropical
Diseases in Bangalore.
Prior to the antibiotic era, “you just couldn't
get rid of these organisms at all and hospital
wards used to be filled with people with chronic
infections” of various kinds, he said. Pneumonia
was often deadly even to those in the prime of
life. It was not uncommon for a cut or prick to
lead to sepsis that killed a person in a matter of
days. Surgery has become safer as a result of the
ability to control any subsequent infection.
The steady discovery of novel antibiotics from
1940 to 1980 has not been sustained, he observed
in a paper in the Journal of Biosciences. The
1990s saw only one new class of antibiotics being
approved while all other introductions were
variants of existing classes.
With few new antibiotics under development, the
problem of resistance has become all the more
acute.
But the battle between microbes that produce
antibiotics and those that resist them has been
going on long before humans arrived. Penicillin
was isolated from a mould that Fleming found which
killed bacteria. The biological pathways that
produce antibiotics have evolved over millions of
years. In a similar fashion, other bacteria have
found ways to avoid being wiped out by such
toxins.
Bacteria can take in genetic material from one
another as well as from viruses that infect them.
Through such genetic transfers, they are able to
draw on the existing repertoire of resistance
mechanisms. This is an important route by which
germs become less susceptible to the antibiotics
that humans throw at them.
In addition, mutations, which occur randomly, can
also produce genes that aid resistance. Research
recently published shows that sub-lethal doses of
antibiotics can enhance the mutation rate.
Thus, genes for antibiotic resistance already
exist or can be readily generated. When widespread
use (or misuse) of antibiotics takes place,
bacteria with such genes gain an edge over
susceptible strains and become more prevalent.
Even when synthetic antimicrobials were
introduced, which would not have been encountered
naturally, bacteria were able to evolve resistance
to them in course of time.
Over the years, a number of disease-causing
bacteria have become resistant to several
antibiotics. There is a growing global problem too
of “superbugs” – germs that are resistant to so
many drugs that treating such infections becomes
difficult.
MRSA
One such “bug” is known as methicillin-resistant
Staphylococcus aureus (MRSA). A bacterium often
found on the skin and inside the nose, the
drug-resistant form of it can produce dangerous
infections of the skin, soft tissue, bones, the
bloodstream, heart valves and lungs.
Methicillin resistance was first reported in
England in 1961 and appeared in the U.S. a few
years later. Various strains of MRSA are now found
across the world.
“The evolution of MRSA exemplifies the genetic
adaptation of an organism into a first-class
multidrug-resistant pathogen,” remarked Cesar A.
Arias and Barbara E. Murray in a commentary
published in the New England Journal of Medicine
last year. Worse, it had turned into an important
cause of infections acquired outside hospitals.
Hospitals in the wealthy countries have been
reeling from an explosion of MRSA, noted another
report. It is estimated that in the U.S. alone,
such infections cost billions of dollars to treat
and claim thousands of lives each year.
In India
Published papers show that MRSA is a problem in
Indian hospitals too. Recent work done at the Sir
Dorabji Tata Centre indicates that community
transmission of MRSA is occurring in this country
as well.
Staphylococcus aureus is classified as a Gram
positive bacterium. (This classification is based
on whether the bacteria can be stained with a
particular technique.) The same process of
escalating antibiotic resistance has been
occurring in Gram negative bacteria too.
Various Gram negative bacteria acquired genes for
what are termed “extended spectrum
beta-lactamases”, enzymes that can break up a wide
range of antibiotics.
As a result, strains of bacteria such as
Klebsiella pneumoniae, which can produce a variety
of serious infections in hospitals, and
Escherichia coli, a common cause of urinary tract
infections, became resistant to many antibiotics.
Antibiotics known as carbapenems, which had been
held in reserve, were therefore needed to treat
such infections.
But then bacteria found ways to evade the action
of carbapenems too. One way to do so was by
acquiring genes for enzymes called carbapenemases
that target those antibiotics as well.
Klebsiella pneumoniae carbapenemases were reported
in the U.S. and subsequently worldwide, observed
Patrice Nordmann, head of a unit studying emerging
antibiotic resistance at Hopital de Bicetre in
France, and his colleagues in a paper published
last year. “Their current spread worldwide makes
them a potential threat to currently available
antibiotic based treatments.”
NDM-1
Another carbapenemase that offers a similar sort
of antibiotic resistance is New Delhi
metallo-beta-lactamase 1 (NDM-1), which was the
subject of a recent paper by Karthikeyan K.
Kumarasamy and others in the Lancet Infectious
Diseases.
It was not possible to say whether the gene for
NDM-1 originated in India or was introduced from
somewhere else, Dr. Nordmann said in a telephone
interview. But the main reservoir for
dissemination of this gene worldwide was clearly
Bangladesh, India and Pakistan. His own unit had
10 samples of bacteria with the NDM-1 gene that
had come from people in Australia, France, Kenya
and Oman. The common factor was that these people
had either been hospitalised in the sub-continent
or, as in the case of a French girl, spent time in
the region.
In the case of the Klebsiella pneumoniae
carbapenemases, Greece, Israel and the eastern
U.S., were the three principal reservoirs.
But drug-resistant Klebsiella pneumoniae was a
problem mostly in hospitals, he remarked. “My most
important concern would that it [the NDM-1 gene]
is located to a large extent in E. coli [
Escherichia coli].” E. coli was a source of
community-acquired infections such as those of the
urinary tract. With India's large population and
poor sanitation, such a drug-resistant bacterium
could spread through food and water.
“Treatment of infections caused by pathogens
producing carbapenemases, including NDM-1, poses a
serious challenge as these infections are
resistant to all commonly used antibiotics,”
observed B.V.S. Krishna of the Department of
Clinical Microbiology at the Royal Infirmary of
Edinburgh, U.K., in a letter published recently in
the Indian Journal of Medical Microbiology.
The negatives
The lack of antibiotic policies and guidelines to
help doctors make rational choices about
antibiotic treatment was a major driver of the
emergence and spread of multidrug resistance in
India, he pointed out. This was augmented by the
unethical and irresponsible marketing practices of
the pharmaceutical industry as well as the silence
and apathy of the regulating authorities. Poor
microbiology services in most parts of the country
added to the problem.
V.M. Katoch, Director-General of the Indian
Council of Medical Research, recently announced
that a unit would be established to issue
guidelines on antibiotic use and keep track of
hospital-acquired infections.
But without new antibiotics, the outlook appears
grim. As Dr. Arias and Dr. Murray remarked in
their article, “We have come almost full circle
and arrived at a point as frightening as the
pre-antibiotic era: for patients infected with
multidrug-resistant bacteria, there is no magic
bullet.”
