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What A New Microbe Can Man Can’t?

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Our world is indeed so fascinating, where mankind is in possession of a predictable lethal power to annihilate fellow citizens of any country or countries – just in minutes or hours or days, as it would decide. Whereas, any sudden attack of an unpredictable crippling power of unknown microbes, can make the same mankind feel helpless – grappling to save lives of the citizens – along with its socioeconomic fabric.

Because of the sudden nature of such crippling attacks, mankind is put to fight against time to build a new arsenal of medicines and vaccines – while defending itself under an umbrella of preventive measures. It’s not that such a situation was never envisaged. On the contrary, as we shall see below, the warning from the same came from several credible sources. Even Bill Gates during a TED Talk five years ago had warned: “If anything kills over 10 million people in the next few decades, it’s most likely to be a highly infectious virus rather than a war – not missiles, but microbes.”

A few years later, the 2018 publication of the World Health Organization (WHO) – ‘Managing epidemics,’ articulated a similar cautionary note, which I am quoting in verbatim: “We are continuously learning about the unpredictable powers of nature. This is nowhere more true than in the continuous evolution of new infectious threats to human health that emerge – often without warning – from the natural environment.” Elaborating the point, it further cautioned: “Given the effects of globalization, the intense mobility of human populations, and the relentless urbanization, it is likely that the next emerging virus will also spread fast and far. It is impossible to predict the nature of this virus or its source, or where it will start spreading.”

Ironically, in about a year’s time, by end 2019, a new Coronavirus broke out in Wuhan of China. From January to March 22, 2020, 13,569 people, reportedly, died globally due to Coronavirus (Covid 19) infection. In India, as I write as I write during 14 hours long public curfew, 341 confirmed cases and 6 deaths have been reported. This outbreak has now shaken, almost the entire world – more than even before. The reverberation of the life-shattering impact of the disease, is now being felt and heard across all the facets of human life, including social, economic and political. Thus, the broad point to ponder in this article: Why the mankind can’t do what a new microbe can?

Various elements to it:

There are various elements of the above broad issue. A comprehensive response to which would involve, at least, two critical sub-questions:

  • Was it avoidable? If so, to what extent?
  • Or, at least, could its overall impact have been blunted?

Moving in that direction, let me try to explore some important facts that may help taking an unknown microbe bull by the horn, if such calamity strikes again – unannounced, in future.

None of these facts were unknown:

As we have seen above, the possibility of emergence and a sudden crippling strike of a new microbe was not unknown, including the warning of a global crisis from the W.H.O.  Besides, ‘nearly 50,000 men, women and children are dying every day from infectious diseases; many of these diseases could be prevented or cured for as little as a single dollar per head.’

Another interesting report: ‘Global rise in human infectious disease outbreaks,’ published in the Journal of the Royal Society interface on December 06, 2014, presents more facts. It says: Since 1980, over the last 30 years till 2014, outbreaks of infectious disease mostly caused by bacteria and viruses are steadily increasing with different health impact in different countries.

Several reasons for the high death rate related to infectious disease:

Several reasons could be attributed to high death rates for infectious disease, despite the availability of a large number of powerful antibiotics in the world, which include the following:

  • Developing nations with lesser access to drugs.
  • Fast development of Antimicrobial Resistance (AMR) owing to misuse and abuse of antibiotics.
  • Emergence of new bacteria and viruses, such as, Covid19 catching the population off-guard, as is being warned by top experts, from time to time.

Several times in the past, I wrote on the subjects of access to medicine, Antimicrobial Resistance (AMR), as well as the recent Coronavirus outbreak. Nevertheless, for this specific discussion, I shall focus only on the second and the third points, in the reverse order, with a different perspective.

Fresh threats of new infections are ongoing:

As the 2018 paper of ‘Managing epidemics’, published by the World Health Organization (WHO) had articulated – besides new microbial pandemics, the history of previous viral outbreaks can also possibly repeat themselves. That means: ‘A new HIV, a new Ebola, a new plague, a new influenza pandemic are not mere probabilities. Whether transmitted by mosquitoes, other insects, contact with animals or person-to-person, the only major uncertainty is when they, or something equally lethal, will arrive.’

As these being ‘newer’ types – just as Covid19 is so different from commonly occurring Flu - in all probability would be unique viruses with unique characteristics. For example, as the W.H.O describes, while Seasonal Flu cannot be stopped, countries still have the chance to limit cases of Covid19, through stringent implementation of scientific protocols. More, importantly, Covid-19 seems to lead to much more severe disease than Seasonal Flu strains.

Effective solution of both – the new and the new forms of known viruses, would require successfully navigating through tough challenges, involving multiple areas, such as, medical, technological, social, economic and political. No doubt, the world has progressed a lot in this area. But, effective ‘capacity building’ to combat the sudden onslaught of any deadly microbial pandemic, still remains an unfinished agenda.

The world has moved a lot, but still needs to accelerate capacity building:

Just in 2018, the world remembered the devastating Great Flu pandemic of 1918 on its 100th anniversary. Although, it lasted only a few months, claimed 50 million to 100 million lives worldwide. The book - ‘Influenza: The Hundred Year Hunt to Cure the Deadliest Disease in History,’ provided a glimpse of that scenario. Interestingly, Flu still kills about 1 percent of those infected by this virus. Whereas, about 3.4 percent of Covid-19 cases have been fatal, as on date, according to the W.H.O.

A comparison of these two pandemics will include both the similarities and the differences. The most striking similarity being – in both the global pandemics, most people are just not afraid, but are also getting panicked.

Whereas, the key differences between the two episodes are – the quality health care infrastructure in today’s globalized world, speed of diagnosis and the versatility of available drugs – even for ‘repurposing’, as being done in the present situation. Now, many people understand the need of putting the exposed persons in isolation – or under quarantine, besides co-operating with various infection control measures, as prescribed by the health authorities. In the midst of this crisis, an ongoing and very related critical issue remains virtually ignored - fast developing AMR, as I mentioned above.

Fast developing AMR continues taking many lives:

In this article, instead of dwelling on the cause of AMR and how to address it, I would rather focus on the current threats that AMR poses and will pose in the future, if not addressed on a war footing, collectively.

The latest details in this area are available from the paper – ‘The Antimicrobial Resistance Benchmark 2020’, published by the Access to Medicine Foundation. It emphasized that infectious diseases are still the cause of “more than 500,000 deaths each year, including more than 200,000 infant deaths. In India, for example, resistance exceeds 70 percent for many widespread bacteria.” As I mentioned in one of my previous articles that the 2017 Review Article, titled ‘Antimicrobial resistance: the next BIG pandemic,’ has termed India as ‘the AMR capital of the world.’ Even a 2020 news report says: Two million deaths are projected to occur in India due to AMR by the year 2050.

The current status:

The following two reports of WHO, published in January 2020, unfolded some interesting facts:

The analysis demonstrated, although, many drug companies are making enough investments to discover and develop innovative medicines, anti-infective therapy area does not feature there for most companies. As the reports unraveled:

  • Not just a declining trend of investment, even the current clinical pipeline remains insufficient to tackle the challenge of AMR.
  • With large drug companies continuing to exit the field, primarily due to commercial considerations, small and medium-sized enterprises (SMEs) are entering this space, but not with as much resources and other wherewithal.
  • All the eight new antibacterial agents, approved since July 01, 2017, offer limited clinical benefits.
  • One new anti-TB agent, pretomanid, developed by a not-for-profit organization, has been approved for use within a set drug-combination treatment for MDR TB.
  • The current clinical pipeline contains 50 antibiotics and combinations and 10 biologicals. Six of these agents fulfil at least one of the innovation criteria; only two of these are active against the critical MDR Gram-negative bacteria, with a major gap in activity against metallo-β- lactamase (MBL) producers.

As the AMR situation is getting worse, globally, unlike any possible repetition of a new microbial attack in the future, AMR isn’t a future problem. It needs to be addressed here and now. Fixing the problem does not require a scientific miracle. It demands a very human solution, spearheaded by the R&D based drug companies, the academia and the Governments, collectively. The reasons of why it is not happening - is known to many, but how to chart an effective pathway for its meaningful resolution – possibly isn’t. The signal today is loud and clear that infectious diseases are reemerging and threatening human lives – be it due to AMR or a sudden attack by a new microbe such as Covid19.

Conclusion:

It is loud and clear that infectious diseases will continue to reemerge in various shapes, forms and virulence – having the incredible power of shaking the world, including the most powerful and developed nations, as we all are experiencing today. As and when Covid19 pandemic gets over, and it will, learning from the past situation and picking up the global best practices to combat and decisively win over any such future crisis, will be critical. But, this is easier said than done – going by the past.

All concerned can feel it today, without any shade of doubt. There is no room for complacency in this regard, for anyone, regardless of having the best of health care infrastructure, diagnosing facilities, state of the art treatments of all types, including vaccines, for a wide range of number of life-threatening conditions.

As the W.H.O said, ‘The microbes didn’t go away. They just went out of sight. Instead, the focus turned to chronic, noncommunicable diseases, which came to receive much more attention. But nature was by no means in retreat. In fact, it seemed to return and took many health institutions and decision makers by surprise.’

It’s, therefore, high time for all to read the writing on the wall. A time to accept and realize that, when it comes to an unpredictable, crippling power of bringing the entire world to virtually a grinding halt – making even the most powerful nations feel helpless and highly vulnerable – what a new lethal microbe can do in one go, even the most developed and the powerful nation can’t. An all-time preparedness against biological threats, therefore, has emerged as a new normal.

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.

Is India in The Eye of The AMR Storm?

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‘With 700,000 people losing battle to antimicrobial resistance (AMR) per year and another 10 million projected to die from it by 2050, AMR alone is killing more people than cancer and road traffic accidents combined together.’ This was highlighted in the Review Article, ‘Antimicrobial resistance in the environment: The Indian scenario,’ published in the Indian Journal of Medical Research (IJMR), on June 03, 2019.

The article further noted, ‘AMR engendered from the environment has largely remained neglected so far,’ which has a snowballing effect. Illustrating the enormity of its impact, the researchers recorded: ‘Economic projections suggest that by 2050, AMR would decrease gross domestic product (GDP) by 2-3.5 percent with a fall in livestock by 3-8 percent, costing USD100 trillion to the world.’

Besides International media, fearsome consequences of AMR are also being highlighted by the Indian media from time to time. For example, on November 21, 2018, a leading national business daily carried an apt headline: ‘India in the firing line of antimicrobial resistance.’ More intensive coverage of such nature for this public menace, would hopefully appeal to the conscience of all those who can meaningfully address this situation, especially the government.

Against this backdrop, I shall explore in this article, whether India is really in the eye of this AMR storm, which is posing an unprecedented threat to many lives, perhaps more in India. 

India is being called the AMR capital of the world: 

Analyzing the emerging research data in this area, India was referred to as ‘the AMR capital of the world,’ in the 2017 Review Article, title ‘Antimicrobial resistance: the next BIG pandemic.’ Curiously, besides umpteen number of published papers documenting this scary development, very few enlightened individuals would dare to push an argument to the contrary. Whereas, besides framing a policy document on AMR,nothing much is changing in India on this score. This is happening, even when it is evidenced that a gamut of the most powerful antibiotics, are not working against many deadly bacteria. Added to it, India still doesn’t have a public database that provides death due to AMR.

Are adequate resources being deployed to fight the menace:

Today one would witness with pride that India’s ‘Chandrayaan 2’ lunar mission is moving towards the Moon’s south polar region, where no country has ever gone before. At the same time, despite AMR threat, India’s budgetary allocation for health in 2018-2019, reportedly, shows a 2.1 percent decrease of the total Union Budget from the 2.4 percent in 2017-2018.

It is interesting to note that India: ‘Despite being the world’s sixth largest economy, public health spending has languished at under 1.5 percent of GDP, one of the lowest rates in the world. For comparison, the United Kingdom shelled out 9.6 percent of its GDP in 2017 on health. The United States’ health expenditure is 18 percent of GDP.’

‘Ayushman Bharat’ and health care infrastructure:

Recently lunched public health program - Ayushman Bharat, although is not a Universal Health Care (UHC) program, it has targeted to cover ‘less than half the population and excluding 700 million people’. While giving a thumbs-up to this initiative, if one looks at the overall health infrastructure in India to make it possible as intended, it may not encourage many.

To illustrate this point, let me quote only the salient points, as captured in a 2018 study, published in the British Medical Journal, as follows:

  • The total size of health workforce estimated from the National Sample Survey (NSS) data was 3.8 million as of January 2016, which is about 1.2 million less than the total number of health professionals registered with different councils and associations.
  • The density of doctors and nurses and midwives per 10,000 population is 20.6 according to the NSS and 26.7 based on the registry data.
  • Health workforce density in rural India and states in eastern India is lower than the WHO minimum threshold of 22.8 per 10,000 population.
  • More than 80 percent of doctors and 70 percent of nurses and midwives are employed in the private sector.
  • Approximately 25 percent of the current working health professionals do not have the required qualifications as laid down by professional councils, while 20 percent of adequately qualified doctors are not in the current workforce.

The intent to deliver health care as announced by various governments from time to time is good. But, the available health infrastructure to deliver these meaningfully are grossly inadequate, creating a huge apprehension among many. This is not just because of the grossly inadequate number of hospitals, doctors, nurses and paramedics, but also their even uneven spread in the country. The cumulative impact of these, fueled by corruption, ‘missing doctors, ill-equipped health professionals, and paucity of required funds’ continue creating a humongous problem for the public, at large, to get affordable health care.

At the same time, there is ‘a serious lack of new antibiotics under development to combat the growing threat of antimicrobial resistance.’ Imagine, a situation when India gets caught in the eye of the AMR storm and imagine the consequences of that, as you deem appropriate.

Lack of new antibiotics under development to combat AMR:

The World Health Organization (WHO) report - ‘Antibacterial agents in clinical development – an analysis of the antibacterial clinical development pipeline, including tuberculosis’, launched on September 20, 2017 shows ‘a serious lack of new antibiotics under development to combat the growing threat of antimicrobial resistance.’

It further reported: ‘Most of the drugs currently in the clinical pipeline are modifications of existing classes of antibiotics and are only short-term solutions.’ The report also found, very few potential treatment options for those antibiotic-resistant infections identified by WHO as posing the greatest threat to health, including drug-resistant tuberculosis which kills around 250 000 people each year.

Thus, the point to ponder simultaneously is, whether there is any decline in global investments for antibiotic research, both by the drug industry and the public funders.

Declining investment on new antibiotic R&D: 

As stated in the May 2016 paper, titled ‘Tackling Drug-Resistant Infections Globally. As the report indicates: ‘The UK Prime Minister commissioned the Review on Antimicrobial Resistance to address the growing global problem of drug-resistant infections. It is chaired by Jim O’Neill and supported by the Wellcome Trust and UK Government, but operates and speaks with full independence from both.’

The report acknowledges that new antibiotic research and development has been suffering from decades of under-investment by companies and governments. The reason being, antibiotic discovery and development are no longer an attractive proposition for commercial drug developers, for a key fundamental reason:

And this is, lack of a dependable, commercially-attractive market for antibiotics that meet large unmet medical needs. As a result, the volume of sales of a such new antibiotics will be low, and restricted only to multi-drug resistant bacteria. Otherwise, older and cheaper antibiotics will still work against most other infections. In that scenario, patented new antibiotics will have to compete with generics, keeping the price low. This combination of price pressure and low volumes makes antibiotics unattractive as a commercial proposition for many drug developers.

Which is why, as the report says: ‘Less than 5 percent of venture capital investment in pharmaceutical R&D between 2003 and 2013 was for antimicrobial development.’ Against total venture capital investment of USD 38 billion in pharmaceutical R&D, antimicrobial venture capital investment was mere USD 1.8 billion, during the same period. Coming back to India specific concerns, let’s have a look at the sociocultural issues in the country, associated with AMR.

Sociocultural issues are fueling the fire:

Understandably, the AMR problem remains intricately intertwined with a number of sociocultural issues of India. It has been established in several studies that social level, socioeconomic and socio-cultural status can play a significant role in the health status of people. Most research done on this subject indicates that higher level of socioeconomic classes reflects at a higher level of health and longevity. Much of this comes from the fact that there is a higher level of education and health care that is available for ‘this class level’.

Sociocultural issues in India also includes, poor hygienic practices, inadequate clean water and good sanitation facilities across the country, besides improper implementation and lack of good governance of health policies, rules and regulations. These factors are also aggravating the AMR problems in the country, as stated in the article, titled ‘‘Public Health Challenges in India,’ published in the Indian Journal of Community Medicine, in its April-June 2016 issue. Which is why, just addressing the indiscriminate use of antibiotics and restricting its wide consumption, aren’t not enough, any longer.

Is India in the eye of the AMR storm?

‘Antimicrobial resistance (AMR) has emerged as a major threat to public health estimated to cause 10 million deaths annually by 2050. India carries one of the largest burdens of drug-resistant pathogens worldwide.’ This was highlighted in the research paper, titled ‘Antimicrobial resistance: Progress in the decade since the emergence of New Delhi metallo-β-lactamase in India’, published in the Indian Journal of Community Medicine, on March 12, 2019.

The article noted, ‘AMR has been identified as a global health threat with serious health, political, and economic implications.’ The paper concluded with a serious note, which is worth taking note of. It found, the full throttle efforts to tackle the AMR challenge in India still requires significant efforts from all stakeholders. It underscored, ‘Despite the adoption of a national policy and significant activities already underway, progress is limited by a lack of clear implementation strategy and research gaps.’ 

Suggested areas of focus in India:

As ‘the Sword of Damocles’, in the form of AMR, hangs over the head of Indian population, there are certain important measures that the country can definitely take to contain AMR, whereas some other critical ones will be challenging to roll out, immediately.

It is unlikely, during this period India will have the requisite wherewithal to focus on discovery and development of new antibiotics to tackle AMR. Similarly, only framing rules and regulations for doctors, patients, dispensing chemists or hospitals to prevent antibiotic misuse, which are not persuasively yet strongly implemented, won’t also yield desired results. Nevertheless, efforts must continue for their effective compliance.

That said, what the country can seriously focus on, sans much constraints, is on taking collective measures in resolving some of the crucial but intimately associated sociocultural issues, with all sincerity and precision. A few of these important areas include, intense public awareness campaigns on the growing threat to life due to AMR, clubbing the benefits of availing good sanitation facilities, hygienic lifestyle and everyday practices.

Moreover, misuse of antibiotics in poultry, animal farming and agriculture should be curbed. Alongside, mass vaccination program for prevention of bacterial and viral infections, should be made available all over the country. Monitoring of the incidence of death due to AMR, on an ongoing basis, is another practice should also feature in the must-do list, providing access to this database to public. Responding meaningfully to International coalition for country-specific action, is also very important. To attain this goal a healthy socioeconomic environment needs to be encouraged, with corruption free efficient governance.

Conclusion:

That India is in the eye of the AMR storm, can’t be wished away any longer. Thus, the fight against AMR will need to be a well-orchestrated one, engaging all stakeholders as partners. The private sector should also actively participate in the AMR awareness programs under public–private partnership (PPP) or through Corporate Social Responsibility (CSR) initiatives.

The whole process should be backed by a creative strategy, having buying-in from all concerned, but spearheaded by the government. That’s the minimum that, I reckon, should happen when the country is in the eye of the impending AMR storm.

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.

 

Antimicrobial Resistance: A Recent Perspective

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On January 23, 2018, at the World Economic Forum in Davos, Switzerland – the first independent analysis of pharmaceutical industry efforts to tackle antibiotic drug resistance, was published by the Netherlands based Access to Medicine Foundation.

The issue of Antimicrobial Resistance (AMR) was brought under focus by the World Economic Forum (WEF) not for the first time at Davos in 2018. Its 2013 Annual Report on global risks, also underscored the gargantuan health hazard that AMR poses to mankind. It said, we live in a bacterial world where we will never be able to stay ahead of the mutation curve. A test of our resilience is how far the curve, we allow ourselves to fall behind. It’s indeed a profound statement!

In that sense, the AMF analysis is important. More so, when the global population is virtually at the threshold of facing a situation very similar to pre-antibiotic era, where even a common infection used to pose threat to a life. And now, a fast-developing AMR to many effective antibiotics or even super-antibiotics, are making them almost redundant in many serious conditions. Consequently, around 700,000 people die every year only due to antimicrobial resistance, the world over.

The World Health Organization (WHO) also reiterated its grave concern in this area by a news release on September 20, 2017. It cautioned, “Antimicrobial resistance is a global health emergency that will seriously jeopardize progress in modern medicine.” Against that backdrop, in this article, I shall dwell on some latest developments in this area, both globally and also in India.

Dire need for newer antibiotics – but dry R&D pipeline:

At the very outset, let me flag another critical area that is intimately related to this concern. An article titled, “Where Are the Antibiotics?”, published by the AARP Foundation adds more to this growing concern. It writes, in an era when many breakthrough innovative drugs are curing some of our most deadly afflictions, the quest for meeting the unmet medical needs, seems to have shifted away from development of critically needed breakthrough antibiotics to effectively address AMR, for various reasons.

The author further highlighted that between the time penicillin was discovered in 1928, and the 1970s – 270 antibiotics were approved – a robust arsenal of powerful drugs that kept almost all bacterial infections at bay. However, since then, research into new antibiotics has declined dramatically. Today, just five of the top 50 big drug companies are reportedly developing innovative antibiotics – the article reiterates.  Nevertheless, some recent developments in this area can’t be ignored, either, which I shall touch upon in this discussion.

Global initiatives for a multi-pronged concerted action:

It is understandable that there are no magic bullets to address the fast-growing menace of AMR. It calls for a multi-pronged strategy with well-orchestrated concerted efforts for its effective implementation with military precision. Following are the three primary constituents who should lead from the front in the battle against AMR, as I reckon:

  • The world leaders
  • Each country, individually
  • Pharmaceutical industry, both global and local

The medical profession, including hospitals, nursing homes, the retail chemists and individual patients, also play a significant role to alleviate this problem, especially in India and other developing countries. But, I shall keep that as a subject for a separate discussion, altogether. Let me now touch-upon the first three constituents, one by one, as follows:

1. The world leaders’ initiative:

Realizing that failure to act on AMR will result in a global health and financial crisis, the world leaders met to address this growing menace. Accordingly, on September 21, 2016, the United Nations General Assembly (UNGA) passed a declaration aimed at slowing the spread of antibiotic-resistant superbugs. At this meeting in New York City, the top UN leaders successfully urged all governments to sign a political declaration to tackle the problem of AMR, both globally and in their respective countries. The joint declaration requires each country to develop a 2-year plan to protect the potency of antibiotics for both livestock and humans. The progress of the initiative for each country at the end of those 2 years will be evaluated. However, in this article, I shall focus only on the agreed human-specific actions, which include the following:

  • Antibiotics should be prescribed only when they are absolutely necessary
  • A massive education campaign about antibiotic resistance.
  • Greater monitoring of superbugs to understand the scope and magnitude of the problem.
  • Safeguarding current antibiotic stockpile.

The leaders suggested that people should be encouraged to help prevent the crisis from turning into a death sentence for millions, with the steps, such as:

  • Get available vaccines to prevent illness
  • Stop asking doctors for antibiotics when they have the cold or flu, as antibiotics treat neither
  • To urge their political leaders to commit to action in combating antibiotic resistance.

2. Country-specific initiatives:

In September 2016, just a year after the UNGA high-level meeting on AMR, an update by the United Nations Foundation reported that 151 countries out of 195 WHO member states have responded. The overall response includes the following, among others:

  • 85 percent of countries are developing or have developed National Action Plans (NAC).
  • 52 percent of countries have a fully developed plan with ‘One Health’ approach that seeks to unify human and veterinary medicine, agriculture, and food providers against the progression of AMR by reducing agricultural antimicrobial use.
  • 52 percent of Low and Middle-Income Countries (LMICs) have national-level measures in place on ‘Infection Prevention and Control (IPC)’ measures in human healthcare.

3. Pharmaceutical industry initiatives: 

I shall cite only the latest commendable developments in this area, as I see it. On Jan. 21, 2016 a document titled the ‘Declaration on Combating Antimicrobial Resistance’, was launched, again, as part of the World Economic Forum at Davos, Switzerland.

For the first time, 85 pharmaceutical, biotechnology, generic-drug, and diagnostic companies agreed on a common set of principles for global action to support antibiotic conservation and the development of new drugs, diagnostics, and vaccines. The document, outlining several critical measures the government and industry must take to increase antibiotic effectiveness worldwide, was also drafted and signed by nine industry associations spanning 18 countries.

Global progress assessment of AMR initiatives in 2018:

This brings me back to where I started from, while analyzing what happened in this regard a year after the above declaration was signed. On January 23, 2018, at the World Economic Forum in Davos, Switzerland – the first independent analysis of pharmaceutical industry efforts to tackle drug resistance, was revealed by the AMF. It found companies are developing new drugs, as well as dismantling the incentives that encourage sales staff to oversell antibiotics, setting limits on the concentration of antibiotics in factory wastewater released into the environment, and tracking the spread of superbugs.

In the AMR Benchmark, GSK and Johnson & Johnson lead among the largest research-based pharmaceutical companies. A separate ranking of manufacturers of generic antibiotics features Mylan, Cipla, and Fresenius Kabi Global, in the leading positions. While Mylan leads the generic medicine manufacturers, Entasis, reportedly, leads the biotechnology group. 

Twenty-eight antibiotics are in late stages of development:

The other key findings of the 2018 study include mention of 28 antibiotics that are in later stages of development, targeting pathogens deemed critical AMR priorities by the WHO, and/or US Centers for Disease Control and Prevention. However, only two of these 28 candidates are supported by plans to ensure they can be both made accessible and used wisely if they reach the market. Be that as it may, the benchmark finds room for all companies to improve in this space, the report indicated.

Some major initiatives in India:

The good news is, ‘The National Policy for Containment of Antibacterial Resistance’, with similar objectives, was put in place in India by the Directorate General of Health Services, Ministry of Health & Family Welfare, way back in 2011. Further, on March 20, 2015, to strengthen the surveillance of antimicrobial resistance (AMR) in the country, Indian Council of Medical Research (ICMR) had set up a National Antimicrobial Resistance Research and Surveillance Network (AMRRSN) to enable compilation of national data of AMR at different levels of health care.

Again, in February 2017, the Indian Council of Medical Research (ICMR)  has put a new ‘Treatment Guidelines for Antimicrobial Use in Common Syndromes’, to achieve the same objectives. Despite this, as many medical experts opine, a large number of General Practitioners (GP), including hospitals, nursing homes continued over-prescribing antibiotics. Alarmingly, considered as the last line of defense antibiotics by many doctors – Colistin and Carbapenem resistant infections have also been reported from several Indian hospitals. All this adds further fuel to the AMR fire.

Another matter of huge worry in India:

The February 04, 2018 article titled, ‘Threats to global antimicrobial resistance control Centrally approved and unapproved antibiotic formulations sold in India,’ published in the British Journal of Clinical Pharmacology, highlight serious hurdles for controlling antimicrobial resistance in India, which has had parliamentary investigations into the failures of the country’s drug regulatory system. The study was conducted by researchers from Queen Mary University in London, Newcastle University and Lakshya Society for Public Health Education and Research in Pune. Some of the key findings of the study are as follows:

  • Extensive use unapproved of fixed dose combination (FDC) antibiotics is contributing to the rising rate of AMR in India, which is already one of the highest in the world.
  • Out of the 118 of FDC antibiotics being sold in India, only 43 (36 percent) were approved by the CDSCO. These 118 antibiotic formulations are being sold in 3307 brand names and manufactured by 476 entities. Of these, 464 were Indian manufactures, and 12 were MNCs.

The authors recommend work on understanding why unapproved formulations are being prescribed by medical professionals.

Conclusion:

As the above AARP Foundation article highlights, like all living beings, bacteria constantly evolve to survive. While encountering a new antibiotic, they quickly find ways to evade it, and continue to live or exist. Some have even developed cell wall like virtually impregnable shields, as it were, keeping antibiotics out. Others pump antibiotics out when they get in. Several deadly bacteria have even devised ways to deactivate antibiotics.

The comments made in the article titled, ‘The Future of Antibiotics and Resistance,’ published by The New England Journal of Medicine (NEJM) on January 24, 2013, is also worth noting. It says, the converging crises of increasing resistance and collapse of antibiotic research and development are the predictable results of policies and processes we have used to deal with infections for 75 years. If we want a long-term solution, the answer is not incremental tweaking of these policies and processes. Novel approaches, based on a reconceptualization of the nature of resistance, disease, and prevention, are needed.

The bottom line still remains, AMR is a humongous threat to the global population, not just in India. While its awareness is gradually increasing, much more painstaking work remains to be done by all, both individually and collectively, to contain this global health menace. It’s our responsibility to protect the well-being of our future generations.

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.

Dry New Antibiotic Pipeline: Increasing Incidence Of Deadly Antibiotic Resistance

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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.

Escalating Antibiotic Resistance, And Thwarting Ban Of Irrational FDCs

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September 2016 ‘Fact Sheet’ of the World Health Organization (W.H.O) raised a red flag on fast increasing incidence of Antimicrobial Resistance (AMR). It poses a serious threat to global public health, more than ever before. Consequently, effective prevention and treatment of an ever-increasing and complex range of infections caused by bacteria, parasites, viruses and fungi are becoming more and more challenging.

In this situation, various medical procedures, such as, organ transplantation, cancer chemotherapy, diabetes management and major surgery like, caesarean sections or hip replacements, invite much avoidable a very high element of risk.

Further, a July 2014 paper titled ‘Antibiotic resistance needs global solutions’, published in ‘The Lancet’ reports increase of incidences of drug-resistant bacteria at an alarming rate. In fact, antibiotic resistance is one of the most serious threats in the history of medicine, and new antibiotics and alternative strategies should be sought as soon as possible to tackle this complex problem.

Another more recent paper titled ‘Fixed-dose combination antibiotics in India: global perspectives’, published in ‘The Lancet’ on August, 2016 finds that nowhere in the world this problem is as stark as in India. It emphasizes that the crude infectious disease mortality rate in India today is 416.75 per 100,000 persons, which is twice the rate prevailing in the United States. Misuse, or rather abuse, of Antibiotics is a major driver of resistance. In 2010, India was the world’s largest consumer of antibiotics for human health, the paper says.

Thus, this critical issue calls for urgent action across all government sectors and the society, in general, as W.H.O cautions.

The Devil is also in irrational antimicrobial FDCs:

The reasons for the fast spread of antimicrobial resistance are many, and each one is well documented. One such factor is the use of irrational antimicrobial FDCs. Some of these have already been banned by the Union Government of India, though continue to be manufactured, promoted, prescribed, sold and consumed by the innocent patients unknowingly.

In this article, I shall focus on the banned FDCs of such kind, highlighting how the consequential serious threat to public health and safety is repeatedly getting lost in the cacophony of protracted court room arguments against these bans.

Irrational FDCs and antimicrobial resistance:

That ‘irrational’ FDCs of antibiotics very often hasten the spread of antimicrobial resistance, is now a well-documented fact.

The ‘National Policy for Containment of Antimicrobial Resistance in India 2011’ clearly recognizes that: “Antimicrobial resistance in pathogens causing important communicable diseases has become a matter of great public health concern globally including our country. Resistance has emerged even to newer, more potent antimicrobial agents like carbapenems.” The Policy also recommends removal of irrational antibiotic FDCs from the hospital drug list.

‘The Lancet’ article of August, 2016, as mentioned above, also reiterates, while citing examples, that “Studies of several antibiotic combinations, such as meropenem and sulbactam, have reported no additional advantage over their individual constituents, and have been reported to cause toxic reactions and promote resistance. Despite repeated investigations into the shortcomings of some FDCs, such drugs are still being manufactured and promoted on the Indian drug market.”

Why does it matter so much?

Corrective regulatory measures to contain the spread of antibiotic resistance are absolutely necessary in India, for the sake of the patients. According to a paper titled ‘Antibiotic Resistance in India: Drivers and Opportunities for Action’, published in the PLOS Medicine on March 2, 2016: “Out of around 118 antibiotic FDCs available in the Indian market, 80 (68 percent) are not registered with the Central Drugs Standard Control Organization (CDSCO). Moreover, 63 (19 percent) of around 330 banned FDCs are antibiotics.”

The global relevance:

Such regulatory bans of antimicrobials FDCs in India are important from a global perspective too, as ‘The Lancet’ article of August 2016 observes.

The article recapitulates that the ‘New Delhi metallo-β-lactamase’ – an enzyme that causes bacteria to be resistant to antibiotics, was first reported in India in 2008 and is now found worldwide. The growth of worldwide trade and travel has allowed resistant microorganisms to spread rapidly to distant countries and continents. In addition, some of these banned FDCs in India are reported to be exported to African and Asian countries too.

That said, each country will also need to play a significant role to curtail the abuse or misuse of antibiotics, locally. I find a glimpse of that in England, besides a few other countries.

A research paper of Antibiotic Research UK and EXASOL dated November 12, 2015, concluded that overall antibiotic prescriptions are coming down across England. However, the same paper also articulated that in the deprived areas of the country, such as Clacton-on-Sea, antibiotic prescribing rates are almost twice the national average.

Some big MNCs are no different:

In the Government’s ban list of irrational FDCs even some top brands of pharma MNCs feature, including antibiotic FDC of antibiotics. For example, on Mar 14, 2016, Reuters reported that one of the largest pharma MNCs operating in India – Abbott Laboratories, was selling a FDC of two powerful antibiotics Cefixime and Azithromycin, without approval of the DCGI. This could possibly be a legacy factor, arising out of its acquisition of a good number of branded generic drugs, together with their management, from a domestic pharma company. Abbott, otherwise is well regarded by many as a distinguished global institution, practicing high standards of business ethics and values, across the world.

Be that as it may, this powerful antibiotic cocktail that poses huge health risk to patients has reportedly not received marketing approval in the major global pharma markets, such as, the United States, the United Kingdom, Germany, France or Japan.

The Reuters report also elaborates that the drug ‘had been promoted and administered as a treatment for a broad array of illnesses, including colds, fevers, urinary tract infections, drug-resistant typhoid and sexually transmitted diseases.’ It also found chemists who were selling the drug to prevent post-operative infection and for respiratory problems. After the ban, the company has reportedly stopped manufacturing and sales of this antibiotic FDC.

Irrational FDC ban – a significant corrective measure:

Keeping all this in perspective, the regulatory ban on irrational FDCs of antibiotics on March 10, 2016, along with products falling in several different therapy areas, was a significant regulatory measure, among many others, to contain the menace of AMR in India.

Unfortunately, quite a lot of these formulations are still in the market, actively promoted by their manufacturers and widely prescribed by the doctors, till date. This is mainly because, to protect the revenue and profit generated from these brands, concerned pharma companies have obtained an injunction from various high courts against the ban, which was notified by the Government, earlier.

Thwarting FDC ban – a key issue:

Looking back, 294 FDCs were banned by the DCGI in 2007. At that time also, the same important issue of patients’ health, safety and economic interest got caught in an intriguing legal quagmire. As a result, implementation of the Government’s decision to ban of these irrational FDCs got delayed, indefinitely.

Added to this, irrational antimicrobial FDCs featuring in the ban list of March 10, 2016, got trapped in exactly the same legal battle, yet again. Thus, repeated stalling of Government ban on irrational FDCs, including antibiotics, continue to remain a key health and safety issue in India.

The latest development:

In September 2016, the Union Government has reportedly moved the Supreme Court of India in defense of its March 2016 ban on irrational FDCs.

In its petition, the Union Government has reportedly urged that all cases against the orders related to ban of ‘irrational’ FDCs, now being heard in various High Courts across the country, be transferred to the apex court and heard as a single case. The move is expected to cut any ambiguity that could arise from differing verdicts between high courts.

In case of a verdict favoring the ban of all the notified irrational FDCs, scores of patients will be benefited by not just falling victims to possible health menace arising out of such unjustifiable drugs, as the Government argues, but also due to expected containment of rapid spread of deadly antimicrobial resistance in the country.

Conclusion:

With the ban of irrational FDCs, the Union Ministry of Health has taken one of the much-needed steps to restrict antibiotic resistance in India, besides addressing other health and financial menace caused by such drugs.

The support of the Apex court of India to urgently resolve this legal jig-saw-puzzle, would also help control, though not in a holistic way, the scary antibiotic resistance challenge in India. In that process India would possibly be able to contribute its little bit towards the antibiotic resistance challenge, across the world, if we consider the ‘New Delhi metallo-β-lactamase’ case as a glaring example in this area.

It is, therefore, widely expected that for the greater public interest, the honorable Supreme Court may view this important health and safety issue accordingly, while pronouncing its final verdict. If and when it happens, hopefully soon, the prevailing industry practice in the country to make profits with dubious drug cocktails sans any robust medical rationale, basically at the cost of patients, can’t possibly be thwarted any longer, and will be effectively implemented on the ground.

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.