Dry New Antibiotic Pipeline: Increasing Incidence Of Deadly Antibiotic Resistance

On January 13, 2017, ‘The Telegraph’ quoting the ‘Centers for Disease Control and Prevention (CDC)’ reported that a woman in Nevada was killed by a superbug that proved resistant to every antibiotic available in the United States (US). She was in her 70s, and had recently returned to the US after an extended visit to India. The CDC found her blood containing ‘New Delhi metallo-beta-lactamase (NDM)’ – an enzyme that was first detected in India, makes bacteria resistant to many antibiotics. Nevertheless, this is just not a solitary example. It’s fast giving rise to a snowballing effect.

The magnitude of this problem has now assumed a global dimension. A May 2016 review of ‘Antimicrobial Resistance (AMR)’ estimates: ‘By 2050, 10 million lives a year and a cumulative 100 trillion USD of economic output is at risk due to the rise of drug – resistant infections, if we do not find proactive solutions now to slow down the rise of drug resistance. Even today, 700,000 people die of resistant infections every year.

According to the World Health Organization (W.H.O), AMR is the ability of a microorganism (like bacteria, viruses, and some parasites) to stop an antimicrobial (such as antibiotics, antivirals and antimalarials) from working against it. Consequently, standard treatments become ineffective, infections persist and may spread to others.

As antibiotics are a special category of antimicrobial drugs that underpin modern medicine as we know it: if they lose their effectiveness, key medical procedures (such as gut surgery, caesarean sections, joint replacements, and treatments that depress the immune system, such as chemotherapy for cancer) could become too dangerous to perform. Most of the direct and much of the indirect impact of AMR will fall on low and middle-income countries – the above review reiterates.

The first global report on AMR:

Not so long ago, In 2014, the first global report on AMR, published by the W.H.O reiterated that this scary scenario is no longer a prediction for the future. It is happening right now, and is not a country specific issue, but a global concern that is jeopardizing global health security.

“Hundreds of thousands of antibiotic-resistant infections and tens of thousands of related deaths go uncounted each year. But even if they were closely tracked, the lack of new drugs to meet the rising tide of resistance means the toll will only mount,” Reported Reuters in another article titled “Stronger superbugs and no new drugs to fight them”, on December 15, 2016.

Thus, there isn’t even an iota of doubt now that in the battle against bacterial infections, drug-resistant superbugs are fast emerging as one of the deadliest issues in the health care space, across the world, including India.

Interestingly, no one knows who will fall victim of this scary scenario and when. Neither can one eliminate this risk completely, even in the developed world. Only painstaking medical research, sans sole focus on creamy bottom-line, and with the application of cutting edge technology, can help overcome this fast-growing health menace to mankind.

“It’s all about the bottom line”:

Quoting a biochemistry professor at Indiana University, Bloomington, the above article reported, in 1980, 36 large American and European pharmaceutical companies were involved in research into new antibiotics. This number currently reduces to just four: Novartis AG, Merck & Co, GlaxoSmithKline Plc and Sanofi SA.

The May 2016 Data Table of ‘The Pew Charitable Trust’ indicates, as of March 2016, an estimated 37 new antibiotics with the potential to treat serious bacterial infections are in clinical development for the U.S. market. It is worth noting, the success rate of clinical drug development is low. Historical data show that, generally, only 1 in 5 infectious disease products that enter human testing (phase 1 clinical trial) will be approved for patients.

Moreover, most of these new antibiotics are based on existing drugs. Although, this approach is cheaper and easier to develop a new antibiotic, as compared to new classes of drugs, bacteria may rather quickly succeed in developing resistance to them.

It keeps happening, primarily because the return on investment for antibiotics, which are typically prescribed for a short period of 7 to 14 days, is much lower than the new drugs used for virtually a life treatment of chronic conditions, such as hypertension, hyperlipidemia, or diabetes.

Consequently, most of the constituents of Big Pharma have virtually fled the antibiotic business, as the new drug development ball game today “is all about the bottom line”, the article quoted.

Antibiotic resistance in India:

As W.H.O articulates in its above report, AMR poses a greater challenge in the developing nations, such as India, where the burden of infectious disease is high and health care spending is too low. The problem assumes a more critical dimension in India, that records among the highest bacterial disease burden in the world, with antibiotics playing a critical role in limiting morbidity and mortality.

The 2015 multi-country survey of the W.H.O unveiled a widespread public misunderstanding about antibiotic usage and resistance in India. Some of the major highlights are as follows:

  • Three quarters (75 percent) of respondents think, incorrectly, that colds and flu can be treated with antibiotics, and only 58 percent know that they should stop taking antibiotics only when they finish the course as directed.
  • More than three quarters (76 percent) of respondents report having taken antibiotics within the past 6 months; 90 percent say they were prescribed or provided by a doctor or nurse.
  • While 75 percent agree that antibiotic resistance is one of the biggest problems in the world, 72 percent of respondents believe experts will solve the problem before it becomes too serious.

Nowhere AMR is as stark as in India:

Another article published in the ‘PLOS Medicine’ on March 2, 2016, is quite in tune with the above W.H.O report. It also reiterates that antibiotic resistance is a global public health threat, but nowhere is it as stark as in India. The crude infectious disease mortality rate in India today is 416.75 per 100,000 persons and is twice the rate prevailing in the United States when antibiotics were introduced (roughly 200 per 100,000 persons).

It also captures the following burning issues in this area:

  • Antibiotic use is a major driver of resistance. In 2010, India was the world’s largest consumer for human health.
  • Access to antibiotics is rising, which portends well for the large proportion of India’s population that thus far had poor access to these life-saving drugs.
  • The convergence of factors such as poor public health infrastructure, rising incomes, a high burden of disease, and cheap, unregulated sales of antibiotics have created ideal conditions for a rapid rise in resistant infections in India.
  • Over-the-counter, nonprescription sales of carbapenems in India are among the highest in the world, and contribute to growing carbapenem resistance among gram-negative organisms.
  • Improving regulations of drug production and sales, better managing physician compensation, and encouraging behavior change among doctors and patients, are of immediate priority.

More serious than local perception:

The new report released by the Center for Disease Dynamics, Economics & Policy (CDDEP) in September 2015, has flagged an alarming trend of bacterial resistance to last-resort antibiotics that can lead to life-threatening infections across the world.

While the developed countries still use far more antibiotics per capita, high AMR rates in the developing nations, such as India, Kenya and Vietnam send a strong warning signal to the world.

For example, in India, 57 per cent of the infections caused by Klebsiella pneumoniae, a deadly superbug found in hospitals, were found to be resistant to one type of last-resort drug in 2014 – an increase from 29 per cent in 2008. It is worth noting that these drugs, known as carbapenems, are still effective against Klebsiellainfections in 90 per cent of cases in the U.S, and over 95 per cent in Europe.

A new class of antibiotics discovered with iChip technology:

The good news is, as reported in the June 18, 2015 issue of the Journal of Antimicrobial Chemotherapy, scientists could produce a new class of antibiotic, named Teixobactin, from a hitherto undescribed soil microorganism (provisionally named Eleftheria terrae). It was isolated with a new tool – the iChip, that allowed the environmental bacterium to grow and for the antibiotic it produced to be isolated and subsequently identified.

Working together with collaborators at the University of Central Florida and the Hong Kong Polytechnic University, a research team of Hong Kong University (HKU) has successfully synthesized this ‘game-changing’ antibiotic that can kill a wide range of bacteria seemingly without developing resistance.

Teixobactin has activity against Gram-positive (but not Gram-negative) organisms and mycobacteria and a novel mode of action inhibiting peptidoglycan biosynthesis. Teixobactin, a still-experimental drug that may herald a new era of antibiotic discovery. However, there are no guarantees that it will be able to reach the market post regulatory acid tests, though the use of the iChip will hopefully result in the discovery of further potential new antibiotics.

Country specific frugal innovation is also necessary:

Alongside, various academic initiatives in search of new, path breaking antibiotics, frugal innovation in various countries to address the local issues in this area, could also play a very significant role to contain this menace.

In this context, I shall quote from the example of a small country, such as Singapore, which is contributing significantly to medical research and development in this area.

An article published in a new daily of Singapore – ‘Today’, on December 29, 2016, highlighted that drug-resistant superbugs have become one of the most pressing problems in the healthcare space of even one of the cleanest cities of the world.

Driven by the need to find a more suitable alternative, researchers at the Institute of Bioengineering and Nanotechnology (IBN) of Singapore, have developed a new material that can kill E coli bacteria within seconds. E coli is a type of bacteria found in the intestines of humans and animals, and some strains can cause severe diarrhea, abdominal pain and fever.

The article, reported that the novel synthetic material, known as imidazolium oligomers, can kill 99.7 percent of the bacteria within 30 seconds, more rapidly than any existing antimicrobial product on the market, such as hand wash or surface sprays. Existing products take minutes to hours to kill the bacteria. It was also tested and found to be effective against other common strains of antibiotic-resistant bacteria and fungi, such as Staphylococcus aureus, Pseudomonas aeruginosa and Candida albicans. It has been licensed by a multinational firm for commercial development in October.

If Singapore can take its own initiatives in this crucial health care space, why can’t India?

Conclusion:

Strict enforcement of the existing regulations of the medical sector, particularly in the prescription of medicines, is of crucial importance. Lack of knowledge among medical practitioners, as well as public on rational use of antibiotics, aggravates the issue.

Notwithstanding fast drying-up of global research pipeline for new antibiotics due to several reasons, India needs to address this fast escalating life-threatening problem through various other practical means. One such could be, putting in place a comprehensive National Action Plan for AMR, quite in line with the Global one, which the W.H.O has already recommended.

This critical issue gets further compounded, as a very significant part of an out-of-pocket expenditure on health care is on medicines, and longer treatment with ineffective drugs and/or second line expensive antibiotics, are pushing the treatment costs higher. On the other side, higher priced drug regimens are less likely to be adhered to, which again contributes to the AMR.

“This situation needs to be interrupted and reversed, not only for safeguarding people’s health, but also for providing protection against health care costs and people going into poverty,” advises the premier World Health body.

Finally, it is important for all to bear in mind, no one knows who will fall victim of this scary scenario and when. So, a decisive action from all concerned can’t wait any longer.

By: Tapan J. Ray

Disclaimer: The views/opinions expressed in this article are entirely my own, written in my individual and personal capacity. I do not represent any other person or organization for this opinion.

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