Health

Antibiotic resistance: When a saviour turns a killer

What if a saviour turns into a killer? After 80 years of use, overuse and abuse of antibiotics—termed magic bullets—microbes have become resistant to them. Antibiotic resistant diseases are undoing the great strides in modern treatment. Vibha Varshney exposes a growing public health crisis

 
By Vibha Varshney,
Last Updated: Monday 27 January 2020
Antibiotic resistance - The magic bullet’s toll

With reportage by Agatha Ngotho in Kenya, Engela Duvenage in South Africa, Prosper k Kuorsoh in Ghana, Vincent Yusuf in nigeria, Violet Nakamba in Zambia, Jenipher Asiimwe in Uganda and Alok Gupta in china.

In rural and urban markets of Nigeria, antibiotics are sold openly and without any prescription by hundreds of vendors such as Sadiq Abdullahi in Kpana Market in Utako district of Abuja. Abdullahi sells antibiotics like amoxicillin, ciprofloxacin, metronidazole, penicillin and clindamycin. It’s an open, hot and filthy outlet. People crowd his shop as he sells these antibiotics at prices much lower than those of the registered pharmacy. 

Vendors like Sadiq Abdullahi do not ask customers for prescriptions and sell any amount of antibiotics, disregarding treatment guidelines. Abdullahi sources his drugs from sellers based on the outskirts of Abuja. But these medicines do not even have the mandatory codes for verification of the country’s National Agency for Food and Drug Administration.

Despite his lack of medical qualification, Abdullahi is willing to sell antibiotics to Jumai Abdullahi, a young woman who believes — without medical diagnosis — that she is suffering from typhoid. She represents what is emerging as one of the major reasons for abuse of antibiotics — self-medication. But self-medication is only one of the many ways antibiotics are being misused and this is leading to resistance in microbes.

More than 70,000 people are dying across the world each year due to infectious diseases that have become resistant to antibiotics — the only line of treatment that could have saved their lives. By 2050, the death count will increase to 10 million each year, as much as those killed in the Rwandan genocide — one of the bloodiest in history.

Since the development of antibiotics in the 1940s, these drugs have been used extensively. But over the years, the world is using them indiscriminately and inappropriately. Even low- and middle-income countries matched or surpassed consumption in high-income countries between 2000 and 2015.

Attempts to combat this resistance only end up throwing new problems. It impacts our overall development agenda now, like the United Nations’ Sustainable Development Goals (SDG), which the world needs to meet by 2030. For example, SDG 1 relates to ending poverty, but this is unlikely as antibiotic resistance (ABR) or antimicrobial resistance (AMR) is striking the poor the most and they have to bear the high cost of treating resistant bacterial infections. Similarly, at stake is the SDG 2 to end hunger.

Untreatable infections in food-animals are threatening food security. To achieve the SDG targets, the world has decided to focus on the poorest countries in Africa and Asia.

A shop in Nigeria's Kpana Market selling antibiotics without any prescription (Photograph: Vincent Yusuf)
Unfortunately, it is in these continents that antibiotic misuse is rampant.

People in Ghana too abuse the magic bullets. Ibrahim Ahmed, a resident of Wa Municipality in the Upper West Region, grinds tablets of penicillin and mixes it with honey. He feeds this mixture to his three children during the peak of the harmattan, a season that occurs between November and March, when children suffer from cough due to the dry and dusty wind. There is also a practice where people break open a capsule and sprinkle its content over a wound to avoid infections instead of taking it orally.

In Zambia’s capital Lusaka, when Friday Malimakau gets a cold, he goes to the pharmacy where the pharmacist recommends antibiotics, antihistamines and antacids. Malimakau has been doing this for as long as he can remember. Similarly, Melody Malawo, also a resident of Lusaka, gets antibiotics whenever she feels feverish. “When I go to a hospital, they too give me antibiotics. So now I just go to the nearest pharmacy to save time,” says Malawo.

Bad as the situation might be in Africa, India too fares poorly. A Drug Resistance Index (DRI) developed by researchers from Center for Disease Dynamics, Economics and Policy (CDDEP), Washington and Rollins School of Public Health, Emory University, Georgia was used to track global trends in effectiveness of antibiotic therapy in 41 countries in 2018. The result showed that high-income countries had the lowest DRIs and low-income and middle income countries had high DRIs. Among the 41 countries, India was the worst performer. 

Consumption is rising

A paper published in The Lancet Global Health in November 2017 says that between 2007 and 2012, total sales rose annually in India. What’s worrying is that this increase was driven by fixed-dose combinations (FDCs) most of which are not approved for sale. Of the 118 different antibiotic FDC formulations available in the market, only 43 were approved by India’s drug regulator, the Central Drugs Standard Control Organization.

“Unapproved formulations figured prominently in sales figures — 270 million units of the FDC antibiotics sold in 2011-12 contained unapproved formulations. The Indian government banned some unapproved FDCs, including antibiotic formulations, most recently in 2016. But the bans have been challenged by the industry and it appears the FDCs remain on sale,” write Patricia McGettigan, a clinical pharmacologist at Queen Mary University of London and Allyson Pollock, a professor of public health, New Castle University, the UK, in The Conversation, a news website.

There is also lack of awareness about antibiotics and their correct use, as researchers from Pune-based CSIR-National Chemical Laboratory found when they assessed a cohort of 504 urban Indians for their knowledge, awareness and practice of antibiotic use and antimicrobial resistance.

According to their findings, published in May 2018 in Current Science, 47 per cent were unaware of the differences between over-the-counter drugs and antibiotics. One in four were unaware that dose-skipping could lead to ABR. One in 10 bought medicines without a prescription. 

Other than misuse by humans, antibiotics are used in rearing animals and to protect plants from diseases. Pressures for a profitable yield with a quick turnover have led to a record increase in global antibiotic consumption — 131,109 tonnes in 2013, whch is likely to increase by 52 per cent in 2030, according to research by CDDEP. This is far more than antibiotics used in humans.

Antibiotic resistance is making treatment of infectious diseases like leprosy almost impossible (Photograph: Vikas Choudhary)
South Africa, along with its BRIC partners (Brazil, Russia, India and China), has shown the largest percentage increase in antibiotic consumption this decade. Import data for antimicrobials between 2014 and 2015 estimates procurement for animal health at 23 to 36 per cent and for human use between 74 and 77 per cent. These figures were published in South Africa’s first national Surveillance for Antimicrobial Resistance and Consumption of Antibiotics Surveillance Report in November 2018. 

In China, as much as 70 per cent of antibiotics produced are used in animals. China consumed 162,000 tonnes of antibiotics in 2013, more than half of the global total. About 52 per cent was used on livestock, which is more than that used by humans. While China is at present culling pigs to control the African Swine Fever outbreak, there is a fear that antibiotic use will rise as the country is planning a policy to promote big animal farms.

In India, similar misuse is visible in the case of poultry where farmers put one-day old chicks on antibiotics to prevent them from getting sick and also for growth promotion.

Antibiotics are being misused in other ways too. Victor Yamo of the World Animal Protection in Kenya explains how in dairy farming, antibiotics are being misused to treat mastitis — inflammation of the mammary gland — instead of following animal husbandry practices. Instead of cleaning the cowsheds, farmers use large amounts of antibiotics to prevent diseases.

Reportedly, dairy farmers also use antibiotics to increase the shelf life of milk. Abubakar Bala Mohammed, who has spent 25 years in veterinary practice in Abuja, says that farmers use antibiotics without consulting professionals, and in many cases, they mix three to five antibiotics in the water and give it to animals.

Dooshima Kwange of the Department of Veterinary and Pest Control Services, Federal Ministry of Agriculture and Rural Development, predicts another scarcity scenario. Nigeria’s population will reach 400 million by 2050. Kwange says there will be more pressure on livestock production to ensure food is available to everyone.

Though not much is known about the use of antibiotics in cultivation of crops in India, many are used for this purpose. India’s Directorate of Plant Protection, Quarantine & Storage has approved the use of two antibiotics — streptomycin and tetracyline — in plants. However, instead of being used only to treat bacterial diseases, they are often mixed with pesticides and used liberally on even healthy plants.

In 2019, Delhi-based non-profit Centre for Science and Environment (CSE) reached out to the farmers to understand existing practices of antibiotic use in crops and found that antibiotics are purchased routinely along with other agrochemicals. Jaswant Singh, a rice farmer from Fazilka in Punjab, used streptocycline on his crop despite absence of any infection.

Interaction with farmers pointed towards a weaker extension machinery of state agriculture departments in the absence of which, the antibiotic use is guided by agrochemical dealers. 

Source: *Global increase and geographic convergence in antibiotic consumption between 2000 and 2015, PNAS, April 10, 2018, **Tackling drug-resistant infections globally: final report and recommendations, 2016, Wellcome Trust, HM Government, the UKThe consequence of this indiscriminate use is that the environment is accumulating antibiotic residues. In China, antibiotics are finding their way into the foodchain through waste products.

More than 50,000 tonnes of antibiotics ended up being absorbed in the water and soil, found the Guangzhou Institute of Geochemistry of the Chinese Academy of Sciences.

The average concentration of antibiotics in Chinese rivers was about 303 nanograms per litre, compared with nine nanograms in Italy, 120 nanograms in the US, and 20 nanograms in Germany.

These levels are much higher than AMR industry alliance’s safe standards — 20-32,000 nanogramme per litre, depending on the antibiotic.

Data from surveillance systems shows an interesting picture of antibiotic use in China. The level of antibiotics in the waterways of the populous eastern region was six times higher than concentrations in the central and western regions.

Southern regions consumed much more antimicrobials than those in North China. Reason: Warmer temperatures in the South led to more outbreaks of diseases compared to north China's colder climate.

An assessment of antibiotic pollution in rivers across the world shows similar scenarios. Researchers from University of York tested samples from 711 sites in rivers of 72 countries across six continents for the presence of 14 antibiotics. Antibiotics were found in 65 per cent of the samples.

In Bangladesh, the antibiotic metronidazole was found to be 300 times the safe level. Trimethoprim, an antibiotic used to treat urinary tract infections, was found at 307 of the 711 sites tested.

Ciproflaxacin frequently exceeded safe levels, surpassing the safety threshold at 51 places. The team found that safe limits were most frequently exceeded in Asia and Africa — primarily in Bangladesh, Kenya, Ghana, Pakistan and Nigeria.

“Our data shows that antibiotic contamination of rivers could be an important contributor to AMR,” says Alistair Boxall of the York Environmental Sustainability Institute. 

Bacteria in the Ganga in Varanasi too are resistant to commonly used antibiotics, says a study released in March 2019. Varanasi region receives over 309.8 million liters of treated and untreated domestic waste daily, which has high levels of antibiotics.

Similarly, samples collected from two lakes in Bengaluru showed the presence of antibiotics and microbes resistant to 10 commonly used antibiotics. The results showed that Bellandur lake also has high number of antibiotic resistant bacteria. This water is used for irrigation and while most residential associations test it for contamination, they don’t get samples tested for the presence of antibiotics. 

Revenge of the bug

Constant presence of antibiotics in the environment leads to resistance. The revenge of the bug on human health is already visible in Nigeria, where epidemics of meningitis and inflammation of brain tissue are quite common.

While meningitis can be caused by viral and fungal patho gens, three predominant bacteria — Neisseria meningitidis, Haemophilus influenzae b and Streptococcus pneumoniae — are responsible for more than 70 per cent of bacterial meningitis cases. Even after mass vaccination campaigns using a conjugate vaccine, MenAfriVac, the National Centre for Disease Control's (NCDC) report in December 2019 shows about 2,770 suspected cases.

Garba Iliyasu, an infection disease expert at the Aminu Kano Teaching Hospital and a Lecturer at the Department of Medicine, College of Health Sciences, Bayero University Kano says that the major challenge with meningitis is the increasing resistance to penicillin. 

Accordign to Antimicrobial Use and Resistance in Nigeria: Situation Analysis, published in 2017, 30.8 per cent of all N meningitidis isolates, 66.7 per cent of H influenzae isolates and 45.2 per cent of S pneumoniae isolates were resistant to penicillin.

Iliyasu says that this resistance is making it difficult for the poor to access the treatment. In Nigeria, resistance is not limited to meningitis. Adefolarin Opawoye, an infection diseases expert at the Aminu Kano Teaching Hospital in Kano, North-western Nigeria, says cases of resistant to antibiotics are growing in hospitals and some patients are resistant to all the available antibiotics in the country.

In patients who get infected by organisms that produce Extended Spectrum Beta Lactamases (ESBL), drugs like ciprofloxacin and augmentin no longer works. “Then you have to move on to much more powerful substitutes like piperacillin-tazobactam and meropenem. The cost of drug treatment alone rises to 100,000-150,000 Naira ($260-$420),” he says. 

Cases of antibiotic-resistant Urinary Tract Infections (UTIs) caused by bacteria which produce ESBL is one of the leading causes of clinic visits by women in Nigeria. According to the 2017 AMR country report, 63 studies on UTIs conducted in 26 states and Abuja showed that the pathogens were resistant to all drugs commonly prescribed for UTI in the country.

Resistance rates were highest for ampicillin and cotrimoxazole where most organisms show 100 per cent resistance. 

In Zambia too, Jereme Kanika, a pharmacist says most of the antibiotics especially the first line drugs like penicillin are now failing to work on the patients because of being abused the most.

“When penicillin fails to work on a patient, we introduce them to a more strong and expensive antibiotic,” he said. Other than the cost of newer antibiotics, the extended periods of treatment too takes its toll on the patients.

In Uganda, Joy (name changed) who lives is Wobulenzi, Luwero District in Central Uganda contracted an UTI from a dirty toilet. “The infection was itchy and painful and I bought some tablets from the pharmacist, but they didn’t work on me and I changed medication. This time, I was given an ointment that I had to insert and some tablets. I got well but it took seven months,” she says.

In Uganda there are reports which show that antibiotics are becoming useless. A study Antimicrobial-Resistant Infections among Postpartum Women at a Ugandan Referral Hospital published in 2017 shows that at the Mbarara Regional Referral Hospital, of the 25 UTIs studied, nine of 11 (82 per cent) caused by Enterobacteriaceae tested positive for ESBL production (and therefore multi drug resistant) and 17 out of 22 (77 per cent) were resistant to ciprofloxacin, one of the most sought-after antibiotic to treat bacterial and fungal infections.

Unrestricted use of antibiotics by poultry, fish and pig farmers and food producers is a serious problem in China (Photograph: EPA)
Alex Owusu-Ofori, head of the Clinical Microbiology Unit of the Komfo Anokye Teaching Hospital in Kumasi in the Ashanti Region of Ghana, says that about 70 per cent of the most common bacteria that cause urinary tract infections are resistant to the commonly-used antibiotics in some hospital.

Patients with resistant infections remain sick for longer periods, stay longer in hospitals, pay more for their treatment and are more likely to get complications and die. Multi-drug resistant cases of tuberculosis are common and a cause for concern, says Angela Ama Ackon, deputy director, Ghana's Ministry of Health. 

Post-antibiotic

South Africa, like many other countries, has entered a post-antibiotic era, according to Marc Mendelson, chair of South Africa’s Ministerial Advisory Committee on AMR. Mendelson sees doctors struggling to treat pneumonia and infections of the urinary tract, bloodstream, skin and soft tissue, all caused by bacteria.

Things are worse in Kenya as a study published in PLoS in February 2019 reveals. Researchers analysed 624 samples collected from Kenyatta National Hospital, situated in Nairobi, and found AMR rates higher than local and international reports. Eveylne Wesangula, a member of the Pharmaceutical Society of Kenya, says there is not much data available on AMR and no action can be taken without data.

Wesangula says the Ministry of Health has rolled out a surveillance strategy that will recruit 28 hospitals as sentinel surveillance sites by 2022. This will help the process of collecting and analysing data at the national level. 

Before this, a study published in BMC Infectious Diseases in 2017 had shown that prevalence of antibiotic resistance in Africa was comparable with the rest of the world, but information is not available for 42.6 per cent of the countries in the continent.

Drug resistant diseases are on the rise in India too. Recently, the Indian Council of Medical Research (ICMR) published the annual report of the Antimicrobial Resistance Surveillance Network for January-December 2018. In the study, ICMR tested samples from 20 top medical institutes from across the country.

From these centres, ICMR collected 60,497 isolates in 2018 to check susceptibility of several antibiotics to different bacteria groups like Enterobacteriaceae, typhoidal Salmonella, non-fermenting gram negative bacteria, diarrheal pathogens, Staphylococci and Enterococci and fungal pathogens. 

The findings were again shocking. Take the case of Enterobacteriaceae. Only half (52 per cent) of the isolates were susceptible to piperacillin-tazobactam. As per the findings, maximum susceptibility was shown against colistin (92 per cent) followed by amikacin (68 per cent) and carbapenems (60-65 per cent).

Antibiotic resistance is making treatment of infectious diseases like leprosy almost impossible in India. This, when India had pledged to eradicate leprosy by 2019. Since 2014, India is a part of a growing list of countries, including Brazil and China, where leprosy can no longer be treated by the conventional multidrug treatment (MDT).

What’s worrying is that new patients are now showing resistance to MDT, whereas drug resistance was earlier experienced mostly by those who discontinued treatment. More than 13 per cent of the new cases and 44 per cent of the relapsed cases are showing resistance to rifampicin, one of the three drugs of MDT, say researchers with Stanley Browne Laboratory in Delhi, a WHO centre for surveillance of drug resistance in leprosy. The study was published in Clinical Microbiology and Infection in November 2015.

“Rising cases of drug resistance since 2014, particularly among new patients, shows that resistant strains are actively circulating in India,” says Mallika Lavania, a researcher with Stanley Browne Laboratory. So how are countries trying to combat resistance that seems to be a disruptive development for public health? 

This was first published in Down To Earth's print edition (dated 16-31 January, 2020)

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