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 The sense of triumph has increasingly been replaced by alarm over whether the bad old days of untreatable infections might be around the corner.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.”

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