Two newly released studies from India make the global fight against antibiotic resistance and drug-resistant tuberculosis (TB) feel even more daunting.
India is critical to the control of TB and other antibiotic resistance, as it is both the largest consumer of antibiotics in the world and has the highest burden of TB, affecting 2.2 million of its people each year, a quarter of the world total.
In the first of the studies, both published in The Lancet Infectious Diseases, Imperial College London researchers suspect that TB cases in India number 2-3x higher than previously estimated. Dr. Nimalan Arinaminpathy, lead author, explained “This is because many patients in India use the private medical system as opposed to the state system. However, this vast private system consists of a huge number of providers and is largely unregulated – meaning that most cases of TB seen in the private healthcare system are not reported to public health officials.” They based this on nationwide sales of tuberculosis drugs across the private sector, and then calculations of the numbers of patients likely associated with these drugs. They suspect that patients are sent off without the appropriate education and support and that they likely stop the treatment as soon as they feel better, rather than completing the requisite 6-9 months of therapy. This shortened and inadequate therapy is known to drive antibiotic resistance, as is being seen in Mumbai. This study was funded by the Bill and Melinda Gates Foundation and was a collaborative effort.*
In the second study, funded by the Gates Foundation and Grand Challenges Canada, researchers at McGill University’s Faculty of Medicine and others** sent “standardized” patient actors to pharmacies in three large Indian cities to see how pharmacists treated patients with symptoms of TB.
The good news, such as it is, is that pharmacists did not dispense first-line anti-tuberculosis drugs and, if the patient presented lab confirmation of tuberculosis, 67% were referred to appropriate specialized treatment centers.
The bad news is that if patients just recounted symptoms of TB, only 13% of the 599 patients were treated correctly, that is referral to a health-care provider without any antibiotics or steroids. Others were instead treated for bronchitis or pneumonia with antibiotics and/or steroids, including some 10% with quinolones, despite the restrictions on their use.
“In 2013, regulations were further tightened, with anti-tuberculosis drugs (isoniazid, rifampicin, ethambutol, and pyrazinamide) and some fluoroquinolones (such as moxifloxacin and levofloxacin, used in the treatment of tuberculosis) listed on a newly created Schedule H1. For H1 drugs, pharmacies require both a prescription from a qualified medical practitioner and a separate register.”
Also of note was that 60% of the referrals were to private doctors and the remaining 40% were to the public, government sector. A patient was referred to a directly observed treatment, short-course (DOTS) centre in only three instances. Directly observed therapy is critically important to ensure compliance, especially when a patient has to take multiple medications over a period of many months. If they stop prematurely, the bacteria will develop resistance.
Personal perspective
The findings above resonated with me because in 2011, I was invited to spend five weeks in rural, northern India studying drug resistant TB with my daughter, who researched that for her MPH thesis. It was an eye-opening experience. We worked with two hospitals, one private and one government, and saw significant differences in care.
There are barriers to care beyond what one in practice might imagine here. For example, patients sometimes traveled for days, rather than hours, over difficult mountain terrain, to reach the hospital. Directly observed therapy, aka DOTS, which is the standard of care, is often not possible. We learned that instead of watching a patient take each dose of anti-TB meds, “DOTS” at one of the hospitals was what they called giving a patient a one month supply of medication and asking them to return the leftovers. Patients kept their tattered TB records with them and often had their X-rays as well. Another problem we saw was that if a patient was failing treatment or relapsed, only one new drug was added to their regimen, despite recommendations to the contrary, which fuels resistance.
What are standard infection control precautions and airborne isolation in the U.S. was non-existent in India, due to the prohibitive cost.
Disturbingly, patients often went doctor shopping to private physicians in the community who were less likely to follow standard treatment courses. And often, as patients traveled long distances for work, they could not get consistent care at any one specific site.
Resistance is also driven by having subtherapeutic drug levels, either from the recommended doses being too low or from variations in formulations. An important new model shows that patient variability in a drug’s metabolism (pharmacokinetics) accounts for a significant number of emerging MDR cases. Per Dr. Tawanda Gumbo,“Patients receiving the same treatment regimens and doses show different drug concentration–time profiles, which also differ between days in the same patient.” INH and Rifampin, the mainstays of first-line TB therapy, showed a genetic influence in their metabolism, but two other drugs, ethambutol and pyrazinamide, were more affected by a patient’s weight.
Another critically important factor, the lack of adequate diagnostics, often comes into play, as was brought up last month by Drs. Lee Schroeder, Timothy Amukele, and Madhu Pai. In our little hospital in northern India, I saw that TB cultures and sensitivities were essentially unobtainable. Every specimen that was sent came back saying the media was “overgrown” and telling us to submit another specimen. Without reliable and timely sensitivities, physicians were forced to treat based on clinical response and often resorted to second line, more toxic antibiotics. It became a vivid lesson in the realities of rural practice and of the factors—social, economic, educational and geographic—that lead to the emergence of multi-drug resistant and XDR-TB.
Conclusion
Without a global, coordinated and aggressive response involving both the public and private sectors, we will lose the battle against TB and it will again become the world-wide scourge that it was before the discovery and development of antibiotics in 1944.
The complexities of this undertaking are daunting, and range from developing simple diagnostic tests that don’t require sophisticated equipment or training, to better education, to social support and treatment of related conditions like malnutrition and HIV. We are seeing more cases of MDR and XDR (essentially untreatable) TB emerging as effective drugs are being misused, yet there is little antibiotic development occurring, as it is not a profitable endeavor for pharmaceutical companies.
The problems highlighted by these studies in India are universal problems, not limited to India. It’s heartening to see this research was a collaborative effort between different universities in different countries, with funding from philanthropic and government groups.
*1 Study collaborators: IMS Health Inc; Central TB division, Government of India; World Health Organization, India Country Office; Bill and Melinda Gates Foundation
*2 Study collaborators: McGill International TB Centre, World Bank, Harvard Medical School, Access Health International, Johns Hopkins University, and Institute for Socio-Economic Research on Development and Democracy, India
