Antibacterial resistance: Microbial rebellion

Rampant use of antibiotics is changing the character of bacteria and making them resistant. Curing diseases is becoming difficult leading to higher mortality

By Kundan Pandey
Published: Thursday 11 June 2020

Kaushalya Devi, a 78-year-old woman from Rani Bagh in Delhi, was admitted in the geriatric medicine ward at the All India Institute of Medical Sciences (AIIMS), New Delhi, in June 2019 for an urinary tract infection. She was suffering from high fever, pain in lower abdomen and increased urination. Treatment began on expected lines: administration of antibiotics. But Kaushalya did not respond to the treatment.

Exasperated doctors sent her urine sample to the microbiology department to check whether she is resistant to any antibiotics. The results showed that E coli, the culprit behind her infection, was resistant to nine of the 10 antibiotics that were checked. Fortunately, the bacterium was susceptible to the antibiotic, Mitrofurantoin, which the doctors ultimately administered to her. 

But not everyone is this lucky. Raghuvar Das, in his late 70s, was admitted to the same department in early September 2019. A resident of Meerut, he was suffering from pneumonia and the bacteria causing his pneumonia was resistant to all of the available antibiotics. “About 32-45 per cent of my patients are suffering from multidrug resistance,” says Vijay Kumar, an assistant professor at AIIMS. Das succumbed to the disease on September 19, 2019. Antibiotic resistance (ABR) is specifically used to describe the resistance displayed by bacteria. Bacteria, not humans, become antibiotic resistant and then infect humans and are harder to treat than non-resistant bacteria. Antimicrobial resistance (AMR) is a broad term to describe the resistance of microbes such as parasites, viruses and fungi. 

Such is the menace of antibiotic resistance that the department has changed its protocol. Instead of starting treatment and then testing for drug sensitivity if the treatment does not work, they now test for drug sensitivity before starting treatment. 

This is not a problem endemic to AIIMS or to New Delhi. Antibiotic resistance is emerging as a disruptive public health problem across the country. There is no estimate of the number of people suffering from the drug resistance in India. While infants and elderly are believed to be the worst affected, it does not mean that the other age groups are safe. 

Take the case of Amit Kumar, a 19-year-old student of medicine at R G Kar Medical College in Kolkata, West Bengal. On May 22, 2019, a small red lesion appeared on his leg which started bleeding the next day. It seemed that a small abrasion he had was the entry point for Staphylococcus aureus, a common hospital-acquired infection. The doctor prescribed two common antibiotics, amoxicillin and clavulanic acid, for seven days. 

But these antibiotics were not effective and the wound started discharging pus after three days. He gave his pus sample for culture on June 10. The results showed the bacteria causing the problem were resistant to four antibiotics, including clavulanic acid that he had taken earlier. The bacterial infection was due to Methicillin Resistance Staphylococcus aureus (MRSA), which was found sensitive to four antibiotics, out of which he was prescribed linezolid and mupirocin for five days. Though this lesion began healing, Kumar found another lesion on his face on July 28, which too tested positive for MRSA. He decided to take another course of linezolid and mupirocin and the wound started healing after a week.

Two out of every three
healthy persons have
antibiotic resistant
organisms in their
digestive tracts

Widespread and spreading

Antibiotic resistance is equally rampant in rural areas too. Ayush, a seven-year-old boy from Surajwasa village of Ujjain district in Madhya Pradesh, lost both his parents to HIV and TB in 2013. In November 2018, Ayush, who now stays with his grandparent, too contracted TB and was taken to the district hospital. After completing the six-month course of medicine, he was termed fit in May. However, his grandparents noticed blood in his cough and rushed him back to the hospital. Doctors said that now the treatment would take longer as the pathogen is resistant and the patient must not miss even a single dose, says Rati Lal, his grandfather. “It’s tough for us. We have already lost two family members to this disease and we are frightened that the boy might also meet the same fate,” says Lal. 

Similarly, Semalia Gaund, a 60-year-old resident of Panna district, Madhya Pradesh, has been suffering from TB-like symptoms since 2004. His August, 2019 prescription shows he is suffering from drug resistant TB. But he doesn’t know that. He says he is getting treatment for last 15 years, first at the Nowgong Government Hospital in Chhatarpur district of Madhya Pradesh and then at Satna District Hospital. Now, because he cannot travel too long, he is getting treatment at the Panna District Hospital. 

A paper published in PLoS Medicine in 2016 says that annually, more than 58,000 newborns are estimated to die from sepsis due to pathogens resistant to first-line antibiotics. In 2011, Down To Earth (DTE) magazine reported the case of Naseem Haider, a taxi driver in Uttar Pradesh’s Bijnor. The reporter found Haider in the hospital, watching his 25-day-old son twitch inside the incubator. Born premature, this palm-sized infant, weighing no more than a kg had a feeding tube piercing through one nostril and an oxygen tube through the other. His vital organs were constantly being monitored via wires attached to his body. The baby was born in a private hospital and was given ampicillin, the first antibiotic administered to any premature child to prevent infection. But due to complications (high heart rate), he was shifted to the bigger and specialised Mangla Hospital where he was hooked on to a ventilator that pumped oxygen into his underdeveloped lungs. Three days later he was prescribed cefotaxime, an antibiotic that costs R30 per 250 mg, but showed no improvement. Instead, he developed low blood pressure. Investigations showed he had sepsis, a bacterial infection of the blood. Doctors again changed the antibiotic—this time, to meropenem that costs R300 per dose. 

The baby then contracted pneumonia caused by Klebsiella bacteria, which is resistant to all antibiotics except two. “We included polymyxin B and colistin in the infant’s regime even though their adverse effects are massive,” said his doctor Vipin Vashishtha. “The infant has a slim chance of survival,” said Vashishtha, who rues that all the infections were acquired in the hospital itself. “Howsoever well the equipment are sterilised, the chances of infection are high in critical cases,” he said. The risk is higher for premature babies because of their weak immune system. Vashishtha had reported 14 similar cases of antibiotic resistance in his hospital between April 2009 and February 2011. So children are extremely vulnerable to the impacts of antibiotic resistance. 

Antibiotic resistance is making treatment of infectious diseases like leprosy almost impossible. India has pledged to eradicate leprosy by 2019. Shahla is a 24-year-old who lives in a slum near Delhi’s Vijay Nagar area along with her family of eight. In 2007, when she developed skin lesions, she ignored them. The disease remained undiagnosed for two years till she developed numbness in the affected area. Doctors diagnosed leprosy and treated her with multi-drug therapy (MDT)—a specific combination of three pills which takes from six months to a year to kill the leprosy-causing germ Mycobacterium leprae. MDT has helped countries significantly reduce the disease burden since its introduction in 1982. 

Doctors declared her cured by early 2014, but within six months she developed erythema nodosum leprosum (ENL) lesions, a complication of leprosy that can result in deformity. Subsequent blood tests showed that Shahla is resistant to MDT. Doctors at The Leprosy Mission (TLM), an international charitable organisation, are now giving her the second-line of treatment. They say Shahla will take another two years to be cured. 

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 MDT. What’s worrying is that new patients are now showing resistance to MDT, whereas drug resistance is usually experienced by those who discontinue the 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. So the options are closing up for patients. 

The researchers arrived at this conclusion after diagnosing 215 new and 16 relapsed cases at TLM Hospital between 2009 and 2014. 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. 

DR-TB is one of the major emerging public health challenges in India. There are 26,966 multi drug resistant (MDR)-TB patients in India—the highest in the world. While there are 2,130 extensively drug resistant (XDR) TB patients in the country, as per the India TB Report 2019, around 10 per cent of patients in India are drug resistant, says Aparna Srikantam, a doctor who is associated with Lepra Society, a Telangana-based non-profit working with TB patients. Srikantam says that generally patients do not understand the difference between TB and drug resistant TB and the importance of adhering to the treatment protocol. 

Drug resistant TB (DR-TB) is now prevalent among children. A paper published in Pediatric Infectious Disease Journal in December 2018 says prevalence of DR-TB has increased to 9.6 per cent among children affected from TB in Mumbai. It was just 5.6 per cent in 2010, conclude the researchers from Seth G S Medical College and K E M Hospital and BJ Wadia Hospital in Mumbai, Maharashtra.

Without regulatory
scrutiny, it is hard to
decipher whether
the medicine will do
good or harm

Patient overflow

Overall, drug resistant diseases are on the rise. A study published in Infection Control & Hospital Epidemiology on October 18, 2019, looked at colistin-resistant Klebsiella pneumonia patients admitted to AIIMS between January 2016 and October 2017. Of the 846 isolates, 34 (4 per cent) were resistant to colistin. In total, 22 case-patients were identified. These patients were also resistant to other antibiotics like carbepenems, extended spectrum cephalosporins, and penicillin/B- lactamase. About 45 per cent of these patients died within 14 days. 

Recently, the Indian Council of Medical Research (ICMR) published the annual report Antimicrobial Resistance Surveillance Network for January 2018-December 2018. This report is the part of ICMR’s efforts initiated in 2013 to enable compilation of data on six pathogenic groups on antimicrobial resistance from the country. This effort aimed to understand the extent and pattern of Antibiotic Resistance (ABR) and also to use this evidence to guide strategies to control the spread of ABR. In the study, ICMR tested samples from 20 top medical institutes from across the country, including AIIMS, New Delhi, Christian Medical College, Vellore and Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh. 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). 

Drug resistant microbes have been found in healthy people too. A study by ICMR found that two out of every three healthy persons have antibiotic resistant organisms in their digestive tracts. The research, which was published in Indian Journal of Medical Research in 2019, shows the scale of rapidly spreading antibiotic resistance in the Indian population. The study was conducted on people living near Chandigarh. It was based on analysis of stool samples of 207 individuals who had not consumed any antibiotics in last one month and also not suffered from any chronic illness. Lead author of the study, Pallab Ray, a professor of medicine microbiology at PGIMER, Chandigarh, says isolates taken from 130 of the 207 individuals were found to be resistant to one or more antibiotics. In this study, maximum resistance was noticed against cephalosphorins. Overall, 60 per cent were resistant to it followed by fluoroquinolones (41.5 per cent). Ray says this is a warning sign. The findings show how the healthy human intestinal gut flora has converted into a reservoir of antibiotic-resistant organisms. While these organisms are resistant to low-end antibiotics, but if the misuse persists, it can become resistant to high-end antibiotics as well. 

Things are progressively getting worse as was revealed by a report Antimicrobial Resistance and its Containment in India published by the Union Ministry of Health and Family Welfare and WHO in November 2016. This report reveals that in last decade, there has been a rapid increase in the proportion of isolates of Staphylococcus aureus that are resistant to methicillin. In 2008, about 29 per cent of isolates were of Methicillin-resistant Staphylococcus aureus (MRSA), and by 2014, this had risen to 47 per cent. 

According to data from the Indian Network for Surveillance of Antimicrobial Resistance (INSAR), MRSA prevalence rate is 41 per cent and showed a high rate of resistance to ciprofloxacin, gentamicin, cotrimoxazole, erythromycin and clindamycin. The report also showed that the emergence of resistance is not limited to the older and more frequently-used classes of drugs, but there has also been a rapid increase in resistance to the newer and more expensive drugs, like carbapenems, which is worrisome. Carbapenems are a class of antibiotics widely considered to be the last-resort antibiotics, which are pressed into use when first and second line treatment options have failed, says the report. 

National crisis 

Antibiotic resistance may be a global phenomenon, but India is the epicentre of this catastrophe. The country is afflicted by easy access to the strongest of antibiotics without prescriptions or diagnoses. Even qualified doctors and not just quacks prescribe drugs with little thought; overuse in hospitals has created colonies of these superbugs; excessive usage in the livestock sector has contaminated the environment. All this has created a perfect recipe for these super-resistant microbes to menace our health, says Amandeep Aggarwal, a professor at RD Aggarwal Memorial Healthcare, Sangrur. A report by the Centre for Disease Dynamics, Economics & Policy’s The State of World’s Antibiotic 2015 provides a glimpse on consumption of antibiotics. India was the top antibiotic consumer in 2010 with 13 billion Standard Units (SUs), followed by China with 10 billion SUs. The US was at third position consuming antibiotics with 7 billion SUs. However, in terms of per capita, the US led in 2010 with 22 SU per person, compared with 11 SU in India and 7 SU in China. 

A study published in the Proceedings of the National Academy of Sciences in April, 2018, says that between 2000 and 2015, India’s antibiotics consumption increased by 103 per cent, the highest in low and middle-income countries. The study tracked antibiotic consumption in 76 countries and also projected the total global antibiotic consumption through 2030. The study says that increase in global consumption of antibiotics (65 per cent)—which is the cause of growing antibiotic resistance—was led by consumption surge in low- and middle-income countries (LMICs). For every 1,000 inhabitants in India, the average amount of antibiotics consumed every day increased by 63 per cent between 2000 and 2015, says the report. 

Authors of the study have underlined their concern saying that the use of last-resort compounds such as glycylcyclines, oxazolidinones, carbapenems and polymyxins are rapidly increasing in all countries. The increase is not just due to human consumption, but also because of overuse in the livestock industry. All these factors point to the fact that we will not know which antibiotics will work in the future. We don’t have a medical protocol. There is a fear that our civilisation can go back to the pre-antibiotic era. A growing list of infections—pneumonia, TB, blood poisoning, gonorrhoea and foodborne diseases—are becoming hard to treat because antibiotics have become less effective or ineffective. 

Researchers from Pune-based CSIR-National Chemical Laboratory assessed a cohort of 504 urban Indians for their knowledge, awareness and practice of antibiotic use and antimicrobial resistance. According to the findings, published in May 2018 in Current Science, 47 per cent were unaware of the differences between over-the-counter drugs (OTC) and antibiotics. One in four were unaware that dose-skipping could lead to ABR. One in 10 bought medicines without a prescription or started an antibiotic course without consulting a physician. 

There is chaos in the market which is leading to a medical crisis in the treatment of ABR. Patricia McGettigan, a reader in clinical pharmacology and medical education, Queen Mary University of London and Allyson Pollock, a professor of public health, New Castle University, the UK, have published a paper in The Lancet Global Health in November 2017, where they have highlighted the unprecedented condition of antibiotic sales in the Indian market. Between 2007 and 2012, they found total sales were rising annually and the increase was driven by fixed-dose combinations (FDCs). The most astonishing fact was that they found 118 different antibiotic FDC formulations were available in the market, but only 43 were approved by India’s drug regulator, the Central Drugs Standard Control Organization. The sale of unapproved new medicines is illegal in India, yet 75 formulations that are being used had no approval. Without regulatory scrutiny, it is hard to decipher whether the medicine will do good or harm. 

Unapproved formulations figured prominently in sales figures—270 m 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 McGettigan and Pollock in The Conversation, a news website. 

Costly need 

When Naseem Haider’s newborn baby in Uttar Pradesh’s Bijnor was put on polymyxin B and colistin, the family went into a financial crisis. One dose of polymyxin B costs R1,400. The infant was given one dose every day. For Haider, hospital expenses alone were between R3,000 and R10,000 per day. Medicines cost R2,000 per day. He had spent over R1.5 lakh on his son’s hospital stay, investigations and medicines. He had not paid the hospital bill for six days and had already borrowed money from relatives and neighbours. He was resigned to the fate that he would have to take the sick child home and watch him die. A paper published in Journal of Infection in Developing Countries in 2014 gives a glimpse of the burden of the antibiotic resistance on individuals. The study, conducted on 220 patients, concluded that the cost of treatment of a resistant bacterial infection to be more than a year’s wage of a rural worker. In the study, they found that the median difference between resistant and susceptible groups in overall, antibiotic and pharmacy costs was R41,993, R8,315 and R21,492 respectively. The study says that health consequences such as intensive care admissions, complications, mortality, and length of stay were significantly higher in the resistant group as compared to susceptible group. It is estimated that by 2050, 10 million people will die every year globally due to antibiotic resistance, most of them in India. So how much do we know about antibiotic resistance that is threatening to become a countrywide health crisis? 

(Names of patients have been changed to protect identity) With inputs from Rohan Gupta, Sonal Matharu and Vibha Varshney

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