Antibiotic Apocalypse

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July 08, 2016 7:30 AM

A spectre of untreated infectious diseases is looming large over humanity with the growing incidence of antibiotic resistance By Raelene Kambli

A spectre of untreated infectious diseases is looming large over humanity with the growing incidence of antibiotic resistance By Raelene Kambli

Rising burden of antimicrobial resistance (AMR) also called antibiotic drug resistance has terrorised the world with fear of   entering into a ‘post-antibiotic’ era. India, too is losing several lives to antibiotic resistance and the burden of which will soon impact, the nation if not tackled. Let’s understand how?

Twenty-year-old Swati (named changed), a medical student from Mumbai was diagnosed with neurotuberculosis one and a half years ago and was put on to first line anti TB drugs. During the course of her treatment, it was found that she showed no improvement and her health deteriorated further. A battery of medical investigations were conducted which revealed that she had developed Multidrug-Resistant Neurotuberculosis after which she was put onto second line TB drugs consisting of some combination drugs of Rifampin, Cycloserine, isoniazid and few others to treat the MDR TB.

A month back, while attending her college lectures Swati felt dizzy and fainted. She was immediately rushed to a hospital and was detected with diabetes ketoacidosis (a serious complication of diabetes that occurs when your body produces high levels of blood acids called ketones).

Currently, Swati is seeking treatment for diabetes from Dr Pradeep Gadge, Consultant Diabetologist, Gadge’s Diabetes Centre and is still on her second line MDR neuro-TB drugs. Dr Gadge is of the opinion that Swati’s medical condition seems to be very delicate at this point of time and her diabetes is adding to her misery. He notifies saying,   “Diabetes is a multi factorial disease where genetics, sedentary lifestyle and certain drugs are responsible for its manifestation. In Swati’s case we are contemplating that her genetics, coupled with the enormous mental stress faced by her deteriorating medical condition and the use of steroids which were a must in her treatment for neuro-TB all could have precipitated into developing diabetes at an early age.”

While speaking to Swati, she informed that in this entire process her family has spent around Rs 8-9 lakhs on hospitals bill, medical tests and medicines. Her father, who is a school teacher is finding it hard to raise the kind of money required for his daughter’s growing medical expenses. Swati on the other hand, aspires to be a doctor, but her dwindling health seems to make this ambition a tall task.  As per experts, treatment for TB usually takes around one year or so, but  Swati had developed  Multidrug-Resistant Neurotuberculosis and so her treatment time will be prolonged.

After speaking to Swati, what lingered in my mind for days together is not the mental stress that this girl is currently going through but rather fear of  a financial crisis her father is soon going to face.

Such is the state of people suffering from antibiotic drug resistance world over.

201607ehm12

Cure becoming the catalyst

Globally, around 700,000 people die each year from antibiotic drug-resistant infections. A review commissioned  headed by the UK Prime Minister David Cameron and chaired by economist, Jim O’Neill in 2015 warned that if the world fails to get to grips with the problem, an extra 10 million people a year will die by 2050. The review also notes that E. coli, malaria and tuberculosis are the biggest drivers of the study’s results, with malaria resistance accounting for the most fatalities and E. coli accounting for the greatest economic cost. Moreover, it appears that the genes responsible for spawning these so-called ‘super bugs’ are also spreading, and turning otherwise mild conditions such as throat infections into deadly killers.

Likewise, researchers at the Center for Disease Dynamics, Economics & Policy (CDDEP)  in September 2015 released data documenting alarming rates of bacteria resistant to last-resort antibiotics that can lead to life-threatening infections across the world. The report states, “Though wealthy countries still use far more antibiotics per capita, high rates in the low- and middle-income countries where surveillance data is now available—such as India, Kenya, and Vietnam—sound a warning to the world. For example, in India, 57 per cent of the infections caused by Klebsiella pneumoniae, a dangerous superbug found in hospitals, were found to be resistant to one type of last-resort drug in 2014, up from 29 per cent in 2008. For comparison, these drugs, known as carbapenems, are still effective against Klebsiella infections in 90 per cent of cases in the US and over 95 per cent of cases in most of Europe.”

201607ehm13Explaining how infectious bacteria develop resistance to certain drugs, Dr Dhruv Mamtora, Consultant Microbiology and Infection Control Officer, SL Raheja Fortis Hospital, Mahim states, “Spontaneous natural development of antimicrobial resistance in microorganisms present in the nature is a slow process. However, the frequent and inappropriate use of a newly discovered antimicrobial drug leads to the development of altered mechanisms of the concerned microbes as a survival strategy. Such antibiotic selection pressure kills the susceptible microbes and helps in selective replication of drug resistant bacteria. These resistant bacteria already existed in the population along with the susceptible ones or susceptible bacteria acquired resistance during antimicrobial treatment. Ultimately, such resistant bacteria multiply abundantly and entirely replace the susceptible bacterial population. This results in treatment failure or ineffective management of such infected patients. Antimicrobial resistance has been observed and reported with practically all the newly discovered antimicrobial molecules till date. Antimicrobial resistance makes the treatment of patients difficult, costly and sometimes impossible.”

Dr Mamtora also provides us global data on certain antibiotic-resistant bacteria of highest concern. The data is as follows:

  • Methicillin-resistant Staphylococcus aureus (MRSA) has declined in incidence in Europe, the US and Canada over the past eight years, to 18 per cent, 44 per cent and 16 per cent, respectively (EARS-Net 2014; CDDEP2015b; Public Health Agency of Canada 2015). It also has begun to decline in South Africa (to 28 per cent), where antibiotic stewardship is taking hold (Kariuki and Dougan 2014; CDDEP 2015b). In sub-Saharan Africa,India, Latin America, and Australia, it is still rising (AGAR 2013; CDDEP 2015b), recorded at 47 per cent in India in 2014, and 90 per cent in Latin American hospitals in 2013 (PAHO,forthcoming).
  • Escherichia coli (E. coli) and related bacteria have become resistant to newer third-generation cephalosporins, indicating that they are difficult-to-treat extended-spectrum betalactamase (ESBL) producers. In 2013, in 17 of 22 European countries, 85 to 100 per cent of E. coli isolates were ESBL positive (EARS-Net 2014). In 2009 and 2010, 28 per cent of all Enterobacteriaceae (the E. coli family) from urinary tract infections in 11 countries in Asia were ESBL producers, and resistance to third- and fourth-generation cephalosporins ranged from 26 to 50 per cent (Lu et al. 2012). In Latin America in 2014 resistance in Klebsiella pneumoniae ranged from 19 per cent in Peru to 87 per cent in Bolivia (PAHO, forthcoming). In sub-Saharan Africa, median prevalence of resistance to third-generation cephalo sporins ranged up to 47 per cent (Leopold et al. 2014).
  • Carbapenem-resistant Enterobacteriaceae (CRE) are resistant even to last-resort carbapenems. In Europe, five countries reported increases in 2013, starting from low levels of less than 10 per cent (EARS-Net 2014). In US hospitals, 11 per cent of K. pneumoniae and two per cent of E. coli were resistant to carbapenems in 2012 (CDC 2013). In Latin America in 2013, resistance of K. pneumonia to carbapenems ranged from full susceptibility in the Dominican Republic to 28 per cent resistant in Guatemala (PAHO, forthcoming). In India, 13 per cent of E. coli were resistant to carbapenems in 2013. For K. pneumoniae, 57 per cent were resistant in 2014 (CDDEP 2015b).
  • Clostridium difficile infections are related to antibiotic use: bacteria are not affected by most antibiotics and therefore proliferate in the human intestine after most other bacteria are killed by antibiotics. C. difficile causes an estimated 14,000 deaths per year in the US (CDC 2013).

Warning signs on the global front

201607ehm14Alexander Fleming

Reports likes these and many other documented facts have revealed the growing economic burden of antibiotic resistance. Experts around the world have been constantly warning for years of an ‘antibiotic apocalypse’.  Alexander Fleming, the British microbiologist who discovered penicillin in 1929 had also warned the world that misuse of the drug could result in selection for resistant bacteria. In an 1945 interview with the The New York Times he said, “The time may come when penicillin can be bought by anyone in the shops. 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.”

Fleming’s prophecy is legitimate. Within 10 years of the discovery of penicillin, the drug also developed resistance in some people. Nevertheless, the problem did not seem to be of such great magnitude then. It is only in the last few decades that the alarming rise in deaths caused by infections, which are a result of antibiotic resistance and discoveries of new resistant bacterias, have turned the spotlight on this frightening issue. Indeed, experts fear that this apocalypse would send medicine back to the dark ages. With this in mind, World Health Organization Director-General Margaret Chan in a public statement has pointed out that once antibiotics stop working, hip replacements, organ transplants, cancer chemotherapy and care of preterm infants will be far more difficult or even too dangerous to undertake. In fact, Sir Malcolm Grant, Chairman, NHS- UK,  who had recently visited Mumbai on a trade mission spoke to Express Healthcare on the urgent need to address the issue of growing antimicrobial resistance. During this meeting, he mentioned about the Longitude Prize which is a challenge with a £10 million prize fund to help solve the problem of global antibiotic resistance.  He went on to say that the challenge is to create a cost-effective, accurate, rapid and easy-to-use test for bacterial infections that will allow health professionals worldwide to administer the right antibiotics at the right time. However, he pointed out that inspite of these efforts, a break through in this regard is currently far beyond sight. (Read his detailed interview on Pg 44 of this issue)

This is a stark reality, that antibiotics which were once called the saviour from many deadly infections have become one of the biggest threats to the world, especially emerging countries such as India. So what’s the scenario in India? Is India braced to battle this apocalypse?

Indian scenario

Several studies conducted by global research organisations point out that countries such as India are an epicentre to such antibiotic resistance. Indian researchers and infection control specialists also continue to raise alarm over rising burden of such resistance within the country. “We are facing an extremely grave situation in India, especially as the health sector is one of the neglected sectors in our country and we still have infectious diseases as the major chunk of the illness.  On one hand we have a high load of drug resistant cases but at the same time the mediation for the same are extremely expensive and most of the patient require long hospital stay, especially in ICUs. In our country, the number of ICU beds is grossly inadequate. This also increases the burden in the hospital and increases the risk of further spread of drug resistant bugs,” discloses, Dr Anita Mathew, Consultant Physician & Infectious Disease Specialist, Fortis Hospital, Mumbai.

Dr KK Aggarwal, Honorary Secretary General, Indian Medical Association and President, Heart Care Foundation of India provide statistics that puts India on a high risk zone. He pointed out that in 2010, India was the largest consumer of antibiotics for human health globally followed by China and the US. Between 2000 and 2010, consumption of antibiotic drugs globally increased by 36 per cent. BRICS countries, i.e., Brazil, Russia, India, China, and South Africa accounted for 76 per cent of overall increase. Referring to the WHO’s global report on antimicrobial resistance released in 2014, he informed that there were an estimated 450 000 new MDR-TB cases in 2012, about half of which were reported from India, China and the Russian Federation.  Moreover, a recent report published by WHO predicts that antibiotic resistance may cause rise in death of Indians to 20 lakhs per year by 2050.

Dr Ramakanta Panda, Vice Chairman & Managing Director, Asian Heart Institute, Mumbai adds saying, “Meta analyses of the drug susceptibility results of various laboratories in India reveal an increasing trend of development of resistance to commonly used antimicrobials in pathogens like Salmonella, Shigella, Vibrio cholerae, Staphylococcus aureus, Neisseria gonorrhoeae, N. meningitidis, Klebsiella, e.coli, Pseudomonas , Mycobacterium tuberculosis, HIV, plasmodium and others.”

Moreover, an article published in the Open Magazine last October, reported on how India’s excessive antibiotic usage was now leading to a powerful never-before-seen mutation within bacteria. The article pointed out that NDM-1 (New Delhi Metallo -beta-lactamase – 1) a bacteria gene discovered first in India and later in countries such as the US, the UK, Canada, Japan and China had taken away several lives.

Agreeing that countries such as India could be breeding grounds for such resistant bacterias, so, what are the determining factors for this problem?

The root cause

According to a study published in 2015 by Professor Ramanan Laxminarayan, Vice-President for Research and Policy, Public Health Foundation of India and late Professor Ranjit Roy Chaudhury, Ex-chairman of the National Committee for formulating the policy and guidelines in drugs and clinical trials in India, the concurrence of factors such as poor public health infrastructure, rising incomes, a high burden of disease, and cheap, unregulated sales of antibiotics has created ideal conditions for a rapid rise in resistant infections in India.

Dr Soumya Swaminathan, Director General, Indian Council of Medical Research, Government of India, pointed out two major related factors that have contributed to the rise of antibiotic resistance within the country. One is the inappropriate use of antibiotics which are freely available over-the-counter and secondly, the fact that doctors prescribe these antibiotics without understanding the implications of each of these drugs. Therefore there is a lot of overuse and misuse of antibiotics in India.

201607ehm17

Dr Panda expounds further, “In India, very effective antibiotics have also been failing to give desired results as bacteria have become resistant to them. As doctors prescribe antibiotics for regular infections that would heal themselves anyway cause bacteria to mutate and develop resistance. The result is a potentially nightmarish proliferation of antibiotic resistant super bugs. The issue of getting infections in hospitals is not new. However, the spread of these infections from the ‘hospital environment’ to the patient is very high. Also, increasing is the severity of these infections. Doctors have observed that the bacteria are becoming more resistant, making it harder to treat these infections.  Hospitals in India have a high burden of infections in their ICUs and wards, many of which are resistant to antibiotic treatment says a recent report by the Global Antibiotic Resistance Partnership (GARP)-India Working Group and the Center for Disease Dynamics, Economics & Policy (CDDEP).  It won’t be an exaggeration to say that in the next few years, deadlier hospital acquired infections will kill more people than diseases itself.  Other problems such as self-medication by patients, unrestricted over-the-counter (OTC) sale of antibiotics and unauthorised use of antibiotics by quacks etc., are all contributing to antimicrobial resistance.”

Dr Panda is meticulous in identifying the root cause of this problem. All the same, Anurag Roy, Business Unit Director, Asia Pacific, Middle East and Africa, DSM Sinochem Pharmaceuticals brings in a new perspective to this issue.  Time and again we have referred to the inappropriate use of antibiotics and lack of infection controls within hospitals that lead to growing resistant bacteria, but we have missed out an important aspect – good manufacturing practices among pharma companies and  the responsible management of the entire supply chain.


Good manufacturing practices for pharma industry

  • Introduce new production techniques and implement strict quality controls along the production and supply chain
  • Treat wastewater from the antibiotic production in dedicated Waste Water Treatment Plants (WWTPs) before it leaves the production site to municipal plants
  • Limit discharges and emissions of active pharmaceutical ingredients (APIs) into the rivers, local lakes and drainage systems
  • Renew efforts to develop medicines to fight emerging antibiotic – resistant bacteria, joining hands with the government to make the effort worth the investment

Roy says, “Producing antibiotics creates loads of waste in the form of water, air and solids. If these waste streams are not managed and disposed responsibly, the pollutants they contain end up in our environment. These create an increasingly growing breeding ground for bacteria to develop resistance. Thousands of tonnes of antibiotics are produced every year in India and China, and there are numerous factories that do not use proper waste management and treatment systems. They dump untreated effluents into water streams, lakes and rivers in and around their factories and plants. They have either no dedicated waste treatment systems or don’t want to invest in these as these are cost-intensive. Some of the manufacturers have it but don’t want to use it as it involves additional resources. The result is that sometimes a single water source gets a huge load of harmful effluents from multiple manufacturing plants posing a grave danger to the environment and disturb the entire eco-system of the habitat.”

Furthermore, Dr Swaminathan raises another concern. She mentions, “ Antibiotics are been mixed with animal and poultry feeds. This is potentially dangerous as these antibiotics find their way through water and soil and lead to drug resistance within the environmental bacteria, in the bargain transferring drug resistance to humans”.

Well, it’s time we take some responsible actions. India has quite a few efforts taken by both government and private  healthcare players in this direction so far such as, research conducted by some pharma companies on new drugs to fight resistance, research on infection control mechanisms by healthcare institutes like AIIMS, formulations of AMR policy by government bodies etc. However, are these efforts effective to bring about a change? Or the road map to achieve success in this sphere still looks gloomy?

Efforts to tide over

During our investigation, experts have conveyed that there is a serious lack of data integration when it comes to AMR in India. This is quite detrimental to the progress of any initiative taken in this regard.

Dr Swaminathan agrees that there is no serious compilation of data on this subject. Moreover, she said that the ICMR is now taking proactive steps to address this health concern in India. She said,
“Four hospitals in India currently have the surveillance programme conducted- AIIMS, PGI Chandigarh, JIPMER- Pondicherry  and CMC Vellore which will help to understand the resistance pattern of these bacteria. This will soon be increased to 10 major hospitals in India which will give us an idea on the system and protocols that will curtail resistance. One of the lessons we  have learnt so far is that we really need to act on framing and implementing strict infection control policies within every hospital in India. We  are also coming up with an antibiotic stewardship programme that will consist of SOPs and manual for infection control within hospitals and the terms on which antibiotics can be used within hospitals.”

201607ehm15Percentage of carbapenem-resistant Klebsiella pneumoniae, by country (most recent year, 2011–2014) Source: CDDEP 2015

One more potential area of concern is the availability of many irrational combination drugs. She further stated, “Although the government has banned around 350 odd combination drugs, some of these irrational combination drugs had the tendency to develop resistant bacteria which is why these drugs had to be banned. More so, I suggest that pharma companies should market their combination drugs more responsibly, especially when they are marketing these drugs to the doctors. It is very important to explain the causes and effects of each of the drug’s components to the practitioners so that they make an informed decision while prescribing these drugs to their patients .”

201607ehm16Spread of New Delhi metallo -beta-lactamase – 1: first detection Source: CDDEP 2015

On this suggestion, Roy recommends some good manufacturing practices to his colleagues from the pharma industry. They are as follows:

  • Introduce new production techniques and implement strict quality controls along the production and supply chain
  • Treat wastewater from the antibiotic production in dedicated Waste Water Treatment Plants (WWTPs) before it leaves the production site to municipal plants
  • Limit discharges and emissions of active pharmaceutical ingredients (APIs) into the rivers, local lakes and drainage systems
  • Renew efforts to develop medicines to fight emerging antibiotic-resistant bacteria, joining hands with the government to make the effort worth the investment

Having said that, we cannot deny efforts taken by the government lately. Ban on certain irrational combination of drugs, stricter marketing codes for pharma companies, setting up of surveillance units within hospitals will set a clear road map ahead. But all these efforts will make no change without public initiative. This calls for a need to create public awareness on this issue. In this regard, an impressive effort taken by the government recently is the ‘Medicines with the Red Line’-to spread awareness about irrational use of antibiotics. According to this campaign, packs of certain medicines will soon carry a ‘red line’ differentiating them from other drugs. The move is aimed at discouraging unnecessary prescription and over-the-counter sale of antibiotics causing drug resistance for several critical diseases including TB, malaria, urinary tract infection and even HIV.

Lastly…

We will have to move ahead with the never say die attitude and come up with more effective measures. Here are five ways by which India can leap frog in our efforts to fight the antibiotic apocalypse.

Data integration: Appropriate  data is a valuable asset in solving any healthcare concern. Stakeholders involved in large healthcare initiatives usually face problems when trying to incorporate data from multiple sources in order to craft a usable set of action plans. Effective tools and strategies for data integration will solve this issue and in turn help in coming with a clear road map. The government’s existing e-governance platform can be utilised to fulfill this purpose.

Create an AMR innovation fund: In an era where India is projected to be as an innovation hub, an concerted efforts can be made to create an innovation fund to tackle AMR, where the government and the private sector can both chip in. This fund can be utilised for research activities and to create awareness campaigns. The other way is to create this fund  by using Corporate Social Responsibility (CSR) as an financing option. Many corporates do invest in R&D as part of their CSR activity, a fund can be created by leveraging such opportunities.

Investing in more drug development: Pharma companies should consciously re-examine their existing antibiotics portfolios. They need to test whether changing their existing doses or combination of drugs with other  antimicrobials could slow down the spread of drug resistance and treat ‘resistant infections’ more effectively.

Use various diagnostics tools: Stressing on right diagnostics will lead to more patients receiving the right antibiotic to treat their infection, and fewer antibiotics would be prescribed unnecessarily.

Invest in human resource:  It is crucial to train the next generation of medical practitioners, scientists, microbiologists, pharmacologists, medicinal chemists and biochemists, as well as economists, social scientists  among others. These professionals will need to find novel approaches and therapies for microbial diseases, whilst maintaining a connected and global outlook.

raelene.kambli@expressindia.com

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