Diagnostics and antibiotic resistance
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After nearly 40 years of medical service, when Sunit Singhi retires in July, he would step down with some regret. That even doctors in large public hospitals such as the Post Graduate Institute of Medical Education and Research (PGIMER) in Chandigarh, which admits nearly 1,000 children in emergency care and treats 10,000 in outpatient care every month, can’t access good point-of-care diagnostics to help avoid needless medication of newborn babies.
In newborns, infection is pretty non-specific. If the child is not feeding or is sleepy, it could be an early sign of illness. “But the babies are brought to us when diseases have advanced and there’s no choice but to give broad- spectrum antibiotics. You can’t fault anybody for that. For any given patient, life is precious and you can’t take any chance,” says Singhi, head of the department of paediatrics at PGIMER and president of the World Federation of Paediatric Intensive and Critical Care Societies.
India is at the centre of a microbial maelstrom that looks ominous. Hospital-acquired infections are surfacing in the community from where they are passed on to newborn babies, who acquire them from mothers.
In a randomized controlled study of 400 babies at Jawaharlal Institute of Postgraduate Medical and Education Research in Puducherry, neonate experts looked at sepsis cases using Bengaluru-based start-up Xcyton Diagnostics Ltd’s Polymerase Chain Reaction (PCR) platform that helps amplify the genetic material in a sample.
While PCR detected 72% of the cases and the group recorded six deaths in 185 children, blood culture detected 18% of the cases and recorded 33 deaths in 185 babies.
The most common bug in both groups was Klebsiella, a class of bacteria that infect people with illness.
“As we submit our paper to international journals, editors are questioning how one-day-old sepsis can have hospital-acquired bug like Klebsiella. They are asking why Group-B streptococcus bacteria (found in the genital tracts of women which are passed on to the babies) is not present in these samples,” says B.V. Ravikumar, a medical doctor and founder of Xcyton. “We don’t know because no systematic study has been done in India.”
In the last few years, India has been a punching bag for global researchers studying anti-microbial resistance. In 2010, Cardiff University professor Timothy Walsh reported some patients with antibiotic-resistant bacteria in the UK hospitals who had acquired it in Delhi and called the resistant gene NDM-1 (New Delhi Metallo-beta-lactmase-1).
To confirm his hypothesis, he travelled to Delhi a year later and tested water and seepage samples. Sure enough, he found NDM-1 in some samples. The Indian government’s response at that time was knee-jerk, almost dismissive. But soon after, it started a resistance surveillance network at National Centre for Disease Control (NCDC) in Delhi.
A study by Ramanan Lakshminarayan and colleagues at Centre for Disease Dynamics, Economics and Policy in Washington, published in The Lancet, reported a sharp rise in antibiotic consumption in a few emerging economies, India being one where, thanks to its self-medication habits, antibiotic use increased by 62% as opposed to 36% in the rest of the world between 2000 and 2010. In December, British economist Jim O’Neill, using mathematical models designed by KPMG and RAND economists, predicted that anti-microbial resistance could claim the same number of human lives as all major killer diseases combined by 2050. India alone will have 2 million deaths.
“We know the bulk of the problem, what we don’t know is what is being practised in clinics and what its clinical outcome is. Doses given by doctors are not correct; they even prescribe wrong combinations,” says V.M. Katoch, former director general of the Indian Council of Medical Research (ICMR) who retired in February.
After the ‘superbug’ scare, ICMR set up a Drug Resistance Research Network, which links to centres in different regions, even collecting data on patients —what drugs they take, where they take and how they take them. Along with NCDC surveillance data, the ICMR research network will show some actionable data in two to three years.
The previous United Progressive Alliance government intended to put in place an antibiotic policy and an expert group was asked to prepare a reference document. The document prescribed an “ideal situation”, banning over-the-counter sale of antibiotics. “Such ideal practices would lead to millions of deaths, so the policy needed a revision. It wasn’t scrapped,” says Katoch. The policy document is still under revision.
It’s a long, hard battle, believes Katoch. He cites the example of leprosy eradication where the entire country was covered by one regimen over 25 years, after which India became 98% disease-free with no cases of resistance. He believes devising a similar standard of care for widely prevalent microbes will help in containing resistance.
One disease, many bugs
In the midst of this escalating crisis, a vital topic is missing from the drug resistance debate in India: Providing a handy, but powerful, diagnostic tool in the hands of practitioners so that they know the bug they are treating.
In a 2009 landmark paper, Antibiotic Stewardship, M.S. Dryden and his colleagues at Southampton University, UK, showed that 50% of human antibiotic use could be avoided without negative consequences.
A case in point is pneumonia.
Of the nearly 0.8 million newborn deaths in India, pneumonia takes the highest toll. According to the World Health Organization, 34 million, or 23% of global pneumonia episodes, occur in India every year. While Indian doctors dispute this figure, they agree pneumonia is the largest killer of children below two years of age. The estimate, according to an Indian multi-centric study led by Johns Hopkins University, is that 3% of newborns, or 4.5 million babies, get pneumonia.
More than the number, it is how the disease is treated that is worrisome. Nearly every case of pneumonia is treated with antibiotics even though a good number of them are viral. This was long suspected but never proven in India.
In a recent clinical study, done in collaboration with Karolinska Institute in Sweden, Singhi and colleagues studied 1,000 severe cases of pneumonia in two phases. The study, the biggest so far and meant to understand the etiology of pneumonia in India, is ongoing but the early analysis shows a “majority” of pneumonia cases are non-bacterial.
Antibiotics will not help fight these infections. This offers little solace because doctors have only a few anti-virals for just a handful of conditions.
In the pneumonia study, a host of organisms have been identified. It was possible because the researchers used a Syndrome Evaluation System, a sophisticated molecular diagnostics platform made by Xcyton, which can identify multiple organisms from a single sample in a single test in a matter of a few hours. Such diagnostic multiplexes come at a price—ranging from $100 to $500—and in their present form cannot be used in far-flung locations, but they are helping dispel some myths around infectious diseases and their treatment.
The theory of one organism, one disease no longer holds good. What’s worse, a significant number of infections are fungal and remain undiagnosed. For many years now, India has debated which pneumonia vaccine to produce or procure for its national immunisation programme. According to pneumococcal vaccine manufacturers, pneumococcus accounts for 50% cases. The Chandigarh pneumonia study disputes it, showing pneumoccocus causes just about 30% of pneumonia. This has prompted the government to approve a larger nationwide study to identify the rank order of bugs. Not knowing exactly which bug causes pneumonia has added to the disease burden as well as to the therapy dilemma.
But when 80% of the country does not have microbiology or culture facilities, counting on diagnostics for writing the right prescription may sound fanciful. Still, if antimicrobial prescription can be rationalized at the hospitals, says Singhi, it can prevent the resistance from spreading to the community.
Realistically, it may be a challenge to take diagnostics to remote areas but there have been a few successes, says Mark Perkins, chief scientific officer of Foundation for Innovative New Diagnostics (FIND), in Geneva. Millions of people are tested for malaria quite close to where they live.
In India, where HIV/AIDS could be controlled remarkably, diagnostic kits were an integral part of the programme. However, diagnostics need to be made simple, as simple to use as pregnancy tests, says Perkins. The way forward, according to Mrinal Sircar, head of pulmonology and critical care at Fortis Hospital in Noida, Delhi, is not to use a missile where a bullet is sufficient. “We need a technological leap; just as in telephony we skipped wired lines for wireless. If a general practitioner knows in five minutes what is causing cold and fever, he’d stop using antibiotics. The whole paradigm will change.”
Mobile telephony is too simple an example, says Perkins, but in principle if countries, particularly lower-income ones, can skip over the era of microbiology and move to molecular diagnostics, then they can make a difference.
At FIND, he is assisting Bigtec Labs of Bengaluru to help simplify and automate its PCR-based diagnostics, which can be used for disease and resistance detection of TB, malaria, chikungunya, dengue and other diseases.
Apart from the cost, one of the reservations clinicians have in using multiplexes is that because they are sensitive, they pick up more bugs than are actually affecting patients and thus lead to more antibiotics use.
In a small study of 80 patients at Fortis, Sircar found that compared to the control group, the multiplex group was not using more antibiotics. “My sense is that if we do a large prospective study, we’ll see a decrease in use of antibiotics even in ICU settings,” he says.
In the West, doctors prescribe more drugs to avoid litigation. In India, it’s a cultural thing. A lack of diagnosis gives some doctors their importance as many of them, even today, are looked upon as “gods” with a ready solution to every health problem.
Diagnostics is an intervention by itself. Today, they don’t just detect the disease but give information about drug resistance, which is critical as most drugs are showing resistance within one to five years of launch, says Perkins.
In an ideal world, Singhi would want these multiplexes to be available at all hospitals. “But where is the money for millions of such platforms and trained technicians?” he asks. Yet, he’s hopeful of gradually saving more babies.
“Since independence, we have improved from 175 deaths to 41 deaths per 1,000 births. We are now targeting to bring it down to 20. We are working hard on it.”
A version of this article will appear in German daily Der Tagesspiegel.