Lentis, Antibiotics in India

Introduction

Antibiotic resistance has been studied since the inception of the antibiotic in 1909.1] Resistance is a complex biologic process in which bacteria adapt genetic changes to withstand specific kinds of antibiotics. Indian superbugs [NDM-1 and VRSA have spread to cause global implications. Pharmaceutical companies, health regulators, local chemists, doctors, and educators compete to determine health regulation.

Origin and Background

History of Antibiotics

Paul Ehrlich, an early antibiotic pioneer, theorized a ‘magic bullet’ which could selectively target diseases and “exert their full action on the parasite harbored within the organism.” In 1909, his discovery of the first antibiotic, compound 606 or Salvarsan, began the antibiotic era. Salvarsan, used to treat syphilis, was the most consumed antibiotic until the 1920’s.1] Salvarsans’ popularity was overtaken by [Alexander Fleming’s discovery of Penicillin in 1928.2] Shortly after, [Bayer Pharmaceuticals discovered Prontosil, a sulfonamide, which was marketed as the treatment to “all conditions.”[3] In 1949, strains of bacteria were found to be resistant to penicillin and sulfonamides.[4] Pharmaceutical companies responded to the growing concern of antibiotic resistance by creating new antibiotics.[5]

Antibiotic Mechanism

Antibiotics work by inhibiting DNA replication and bacterial replication. Antibiotics are only used on bacteria; they do not affect viral infections. Resistance occurs by either a genetic mutation or by accepting resistant genes from other bacteria.[6] Bacteria can mutate to allow the bacterial replicative machinery to be unaffected by the antibiotic, degrade the antibiotic molecules, or eject the antibiotic. With overuse of the antibiotic, resistant bacteria will outlive non-resistant bacteria, replicate freely, and spread genetic antibiotic resistance.[7]

Indian Superbugs

India’s problem with antibiotic use has led to the creation of superbugs. Superbugs are bacterial strains which have several antibiotic resistances, usually to the strongest antibiotics.

In 2009, A Swedish national fell ill with an antibiotic-resistant bacterial infection that he acquired in New Delhi, India.8] No conventional antibiotics were able to treat his infection of [Klebsiella pneumoniae. His specific strain contained a gene referred to as New Delhi metallo-beta-lactamase-1 (NDM-1).[9] By 2015, strains appeared in more than 70 countries.[10]

In 2006, strains of vancomycin-resistant Staphylococcus aureus (VRSA) were found in an Indian hospital’s water supply. VRSA is a “death sentence” because vancomycin is one of the strongest antibiotics. Many people died from infected wound dressings citation. VRSA spread to other city centers in other Indian regions.[11]

Environmental Factors

High Burden of Disease

The mortality rate of infectious diseases in India is 416.75 per 100,000 persons. The Ministry of Health in India is responsible for handling public health outbreaks but lacks appropriate public health infrastructure. Control of tuberculosis, visceral leishmaniasis, and malaria have been inadequate according to WHO standards. The increased morbidity in India warrants rampant use of antibiotics, contributing to antibiotic resistance. [12]

Human Bacteria Transfer

Bacteria can spread from human contact. Humans internally create bacteria and spread them in hospitals, nursing homes, or the general community. Human bacterial transfer in India is augmented by India’s large population: 1.33 billion people.13] Many of India’s residents live in cities like [Mumbai and Kolkata -  the two densest populated cities in the world.[14] The ease of bacterial transfer coupled with increased human contact within cities allows resistant bacteria to rapidly proliferate.

Ecological Bacteria Transfer

Bacteria can travel through animals, water, and food. Livestock can develop bacteria internally source. Animal feces containing bacteria compose fertilizer and leak into water sources, spreading resistance to humans through food and drink.[15]

Pollution in rivers also spreads bacteria. There are no standards to monitor antibiotic residues from pharmaceutical industrial pollution in India. The antibiotic resistance gene (NDM-1) was identified in several major rivers in India. Wastewater treatment plants serving antibiotic manufacturing facilities also spread resistant genes via water consumption.[16]

Participants in Rising Antibiotic Resistance

World Health Organization

The WHO’s primary focus is to direct international health within the United Nations' standards. In India, this means holding pharmaceutical companies and practices to international standards.17] Standards include inspections designed to ensure compliance with [Good Manufacturing Practices (GMP) and Good Clinical Practices (GCP).[18] The WHO also operates the South East Asia Regulatory Network (SEARN) as an effort to increase access to high-quality medical products in South East Asia, including India.[17]

Central Drugs Standard Control Organization

The Central Drugs Standard Control Organization (CDSCO), under the Ministry of Health & Welfare, is the national regulatory committee headed by the Drugs Controller General of India. Their mission is to “safeguard and enhance public health by assuring the safety, efficacy and quality of drugs, cosmetics and medical devices.”[19] In 2014 they initiated a Five Year Plan - “Make in India” - funding approximately US$273 million to strengthen India’s regulatory structure. This effort is in part to bolster India’s status as an international pharmaceutical distributor. The Plan also attempts to mitigate dishonest practices by the State Licensing Authorities.[20] However, compared to other countries the CDSCO is grossly understaffed and struggles to regulate the antibiotic industry source.

Pharmaceutical Companies

India is the 3rd largest pharmaceutical market in terms of volume and 71% of its market share focuses on generic drugs.21] Minimal patent laws allow large pharmaceutical companies to promptly recreate generic antibiotic drugs. [Lupin Ltd, the third largest drug manufacturer, has a mission statement of achieving its vision of becoming a transnational company;” Pfizer, one of the largest global pharmaceutical companies, states, “working together for a healthier world.”[22][23]  Mainly, these companies aim to best serve their profits. This is evident by various cases of CDSCO infractions and antibiotic recalls.

Associated Chambers of Commerce and Industry of India

Associated Chambers of Commerce and Industry of India (ASSOCHAM) is a lobbying group that has been formed by large pharmaceutical companies within India. Their mission statement is “the knowledge architects for Indian corporations.”[24] They are currently promoting increased regulation of the drug market. This pushes the long-term corporate agenda by allowing Indian pharmaceuticals to generate revenue on an international stage.

All India Organization of Chemists and Druggists

The All India Organization of Chemists and Druggists **(**AIOCD) is an organization of over 100,000 local chemists and pharmacists that serves the provinces of India.[25] This is the relatively unorganized and unregulated side of the Indian pharmaceutical industry. AIOCD seeks to promote less regulation and fight standardization legislation. They cite “accept[ing] and gift[ing] donations to the … Government” as a strategy. A local chapter in Tamil Nadu recently prevented E-Pharmacies from being deployed.[26] Local druggists continue to profit and supply India’s uneducated and lower-class population with antibiotics of subpar quality.

Individual Local Pharmacists

Local druggists will also further their agenda by marketing religion or spirituality to convince consumers to buy their products over regulated antibiotics.[27] Over 97% of Indians are religious.[28]

Universal Immunization Programme

A direct cause for overuse of antibiotics is the lack of childhood vaccinations in India.29] Vaccinations immunize children from many antibiotic-required illnesses. The Ministry of Health and Family Welfare created the [Universal Immunization Programme (UIP) to combat the meager 44% of vaccinated children in India.[30] The UIP offers cash incentives to rural families that vaccinate their children.[31]

Religious Anti-Vaccination

Many Indians are opposed to vaccination on religious grounds. India’s 80% Hindu population opposes vaccination because of conceived bovine origins. Hindus consider cows sacred and want, “the Government to] look into alternatives that are from plant-based derivatives.”[32] Additionally, the 15% Muslim population, consider vaccinations '['haram'', or forbidden.[33] Dr. Abdul Katme, Head of the Islamic Medical Association, states that “all vaccines are derived from animals and human tissue, which make them haram.”[34]

Local Doctors

Many doctors in India are paid on a commission based on the number of patients they see. As a result, doctors are incentivized to see as many patients as possible leading to an overprescription of antibiotics. Dr. Punjani says, “[Indian] doctors think it can’t hurt to prescribe more antibiotics.”[35] In 2015, pharmacy employees in Haryana were interviewed on their medical expertise. One participant explained “If someone asks for a medicine by name, then I will give it to them. [Even without a prescription?] Yes.” The employee had a high school education, with no concentration in the medical field.[36]

Hospitals

There is a lack of importance placed on resistance prevention in government hospitals. Few hospitals in India have infectious diseases and infection control specialists. The majority of private and corporate hospitals are in denial, either purposefully or due to ignorance. Dr. Ghafur says he has "come across many hospital administrators in India claiming zero infection in their hospitals. It is sad to say that many of these hospitals do not have the necessary microbiology laboratory support or trained infection control specialists to look for resistance. The claim of zero infection is in fact an innocent advertisement of the lack of necessary infection control infrastructure in that hospital". [37]

Patients

Patients have been conditioned by doctors to always ask for antibiotics for any sickness, be it viral or bacterial. A local doctor says, “patients who come in complaining about a cough, sinus pressure, or earache and leave disappointed because I didn’t prescribe an antibiotic. But antibiotics can’t cure everything.”[38] Sometimes, patients will not leave the doctor’s office without an antibiotic prescription, potentially following the sociological phenomenon of social trust. Dr. Laxminarayan says, “patients feel safer and mentally better if they take an antibiotic – even if it has no effect.”[35] Rising average incomes also contribute to increased patient expectations.[38]

Chennai Declaration

Dr. Abdul Ghafur founded the Chennai Declaration in 2012 to develop a five-year plan on combating antibiotic resistance. The main action was categorizing specific antibiotics as ‘restricted’ to minimize overprescription.[39] The Chennai Declaration also developed several marketing strategies to prevent antibiotic overuse. Their ‘Red Line’ initiative indicates specific antibiotics should only be taken with a prescription.[40] Through education, they hope to change the public’s perception and overuse of antibiotics.

Conclusion

Since the inception of antibiotics, resistance has been a pressing issue. This issue is profoundly personified in India’s antibiotic regulation. The drug Amoxicillin, a common prescription antibiotic in the USA, costs $0.40 a pill, whereas in India, lovoxine, a similar generic drug, costs only $0.09 a pill.[41][42] The difference in price is enforced by the degree of regulation in the two countries. In India, many social groups compete to push different regulatory agendas. Antibiotics are often misused, resulting in deadly international superbugs.  Future research on novel antibiotic strains can stem resistant outbreaks and social movements can educate India’s population to minimize outbreak conditions. A true understanding of the antibiotic crisis in India is pertinent to the international bacterial resistance.

References

• ↑ a b Yarnell, A. (2018). Salvarsan. Chemical Engineering and News, 83(25). Retrieved from http://cen-cc-origin.acs.org/articles/83/i25/Salvarsan.html
• ↑ Tan, S., & Tatsumura, Y. (2015). Alexander Fleming (1881–1955): Discoverer of Penicillin. Singapore Medical Journal, 56(07), 366-367. doi:10.11622/smedj.2015105
• ↑ Thomas E. Brock, Fred, E., & Domagk, G. (1986). A Contribution to the Chemotherapy of Bacterial Infections. Reviews of Infectious Diseases, 8(1), 163-166. http://www.jstor.org/stable/4453817
• ↑ Sing, T. B. (1949). Acquired Resistance to Fatty Acids and Sulfanilamide of Certain Trichophyton-Strains. Dermatology, 99(4), 231-238. doi:10.1159/000257234
• ↑ Antibiotics: An overview. (2013). https://www.khanacademy.org/science/health-and-medicine/current-issues-in-health-and-medicine/antibiotics-and-antibiotic-resistance/a/antibiotics-an-overview
• ↑ U.S. Food and Drug Administration. (2018, March). Antimicrobial Resistance - Animation of Antimicrobial Resistance (video). https://www.fda.gov/AnimalVeterinary/SafetyHealth/AntimicrobialResistance/ucm584286.htm
• ↑ Antibiotic resistance. (2018, February). https://www.who.int/news-room/fact-sheets/detail/antibiotic-resistance
• ↑ Mohapatra, P. R. (2013). Metallo-β-lactamase 1 - why blame New Delhi & India? The Indian Journal of Medical Research, 137(1): 213–215.
• ↑ Yong D, Toleman MA, Giske CG, et al (2009). "Characterization of a New Metallo-β-Lactamase Gene, blaNDM-1, and a Novel Erythromycin Esterase Gene Carried on a Unique Genetic Structure in Klebsiella pneumoniae Sequence Type 14 from India". Antimicrobial Agents and Chemotherapy (12): 5046-54. doi:10.1128/AAC.00774-09.
• ↑ Johnson A, Woodford N (01 April 2013). "Global spread of antibiotic resistance: the example of New Delhi metallo-β-lactamase (NDM)-mediated carbapenem resistance". Journal of Medical Microbiology 62: 499-513. doi:10.1099/jmm.0.052555-0
• ↑ Gaddad, S., Thati, V., & Shivannavar, C. (2011). Vancomycin resistance among methicillin resistant Staphylococcus aureus isolates from intensive care units of tertiary care hospitals in Hyderabad. The Indian Journal of Medical Research, 134(5), 704. doi:10.4103/0971-5916.91001
• ↑ Laxminarayan, R. (2016). Antibiotic Resistance in India: Drivers and Opportunities for Action. PLOS Medicine. https://journals.plos.org/plosmedicine/article/file?id=10.1371/journal.pmed.1001974&type=printable.
• ↑ Orgi. (n.d.). Census of India Website : Office of the Registrar General & Census Commissioner, India. Retrieved from http://www.censusindia.gov.in/
• ↑ Mumbai, Kota among world's most crowded cities. (2017, May). https://timesofindia.indiatimes.com/city/mumbai/mumbai-kota-among-worlds-most-crowded-cities/articleshow/58844092.cms
• ↑ Bengtsson-Palme, J., Kristiansson, E., & Larsson, D. G. (2017). Environmental factors influencing the development and spread of antibiotic resistance. FEMS Microbiology Reviews, 42(1). doi:10.1093/femsre/fux053
• ↑ Sumanth Gandra, Jyoti Joshi, Anna Trett, Anjana Sankhil Lamkang, and Ramanan

Laxminarayan. 2017. Scoping Report on Antimicrobial Resistance in India.

Washington, DC: Center for Disease Dynamics, Economics & Policy

• ↑ a b What we do. (2018, May 30). https://www.who.int/about/what-we-do/en
• ↑ Gupta, M., Dr, Shridhar, M., Dr, Singh, G., Dr, & Khadem, A., Dr. (2017). Medicines Regulation. WHO Drug Information, 31(3), 387-401. https://www.who.int/medicines/publications/druginformation/issues/WHO_DI_31-3_RegSystemIndia.pdf.
• ↑ https://www.who.int/medicines/publications/druginformation/issues/WHO_DI_31-3_RegSystemIndia.pdf
• ↑ Singh, G., Dr. (n.d.). Strengthening of Drug Regulatory System in India viz. (i) Central Drugs Standard Control Organisation (CDSCO); and (ii) States’ Drug Regulatory System. (Rep. No. DCGI/MISC/2014 (223))
• ↑ Sector Survey: Pharmaceuticals. (2017). http://www.makeinindia.com/article/-/v/sector-survey-pharmaceuticals
• ↑ Lupin Pharmaceutical - About Us. (2010). http://www.lupinpharmaceuticals.com/mission.htm
• ↑ Pfizer - Working Together for a Healthier World. (2014). https://www.pfizer.com.my/
• ↑ Varma, U. (n.d.). ASSOCHAM - About Us. http://www.assocham.org/aboutus.php
• ↑ Lekharu, D. (2016). Working with frontline private providers: Innovations in scaling up collaboration and regulation (pp. 1-92, Rep.). Mumbai, India: World Health Organization.
• ↑ Objectives of the Association. (n.d.). ://www.tncda.com/
• ↑ McGraw, P., J. A. Schwartz, and P. E. Tetlock. 2012. “From the Commercial to the Communal: Reframing Taboo Trade-offs in Religious and Pharmaceutical Marketing.” Journal of Consumer Research 39 (Jun.): 157–173.
• ↑ The Global Religious Landscape (p. 6, Rep.). (2012). Washington DC: Pew Research Center.
• ↑ Ginsburg, A. S., & Klugman, K. P. (2017). Vaccination to reduce antimicrobial resistance. The Lancet Global Health, 5(12). doi:10.1016/s2214-109x(17)30364-9
• ↑ Laxminarayan, R., & Ganguly, N. K. (2011). India’s Vaccine Deficit: Why More Than Half Of Indian Children Are Not Fully Immunized, And What Can—And Should—Be Done. Health Affairs, 30(6), 1096-1103. doi:10.1377/hlthaff.2011.0405
• ↑ Johri, M., Chandra, D., Koné, G. K., Dudeja, S., Sylvestre, M., Sharma, J. K., & Pahwa, S. (2015). Interventions to increase immunization coverage among children 12–23 months of age in India through participatory learning and community engagement: Pilot study for a cluster randomised trial. BMJ Open, 5(9). doi:10.1136/bmjopen-2015-007972
• ↑ Shagar, L. (2016, July). Hindu groups want vaccines without beef gelatine. The Star. https://www.thestar.com.my/news/nation/2016/07/28/hindu-groups-want-vaccines-without-beef-gelatine/#c5zoFghaszeEAjol.99
• ↑ Zissis, C. (2007). India's Muslim Population. Council on Foreign Relations. https://www.cfr.org/backgrounder/indias-muslim-population.
• ↑ Orac. (2007). Muslims shouldn't be vaccinated. Respectful Insolence. https://respectfulinsolence.com/2007/01/30/muslims-shouldnt-be-vaccinated/.
• ↑ a b Bhutia, Lhendup (15 July 2016). "How India Became The Antibiotics Capital Of The World And Wasted The Wonder Cure". Huffington Post.
• ↑ Barker, A. K., Brown, K., Ahsan, M., Sengupta, S., & Safdar, N. (2017). What drives inappropriate antibiotic dispensing? A mixed-methods study of pharmacy employee perspectives in Haryana, India. BMJ Open, 7(3). doi:10.1136/bmjopen-2016-013190
• ↑ Abdul Ghafur K (March 2010). "An obituary- On the Death of antibiotics!". Journal of Association of Physicians of India. 58.
• ↑ a b Antibiotics: When you need them and when you don't | Prevention. UT Southwestern Medical Center. (2016, June 23). https://utswmed.org/medblog/antibiotics-resistance-proper-use/
• ↑ Ghafur A, Mathai D, Muruganathan A, Jayalal J A, Kant R, Chaudhary D, Prabhash K, Abraham O C, Gopalakrishnan R, Ramasubramanian V, Shah S N, Pardeshi R, Huilgol A, Kapil A, Gill J, Singh S, Rissam H S, Todi S, Hegde B M, Parikh P (2013). "The Chennai declaration: A roadmap to tackle the challenge of antimicrobial resistance". Indian J Cancer 50: 71-73.
• ↑ Team C. (2014). ""Chennai Declaration": 5-year plan to tackle the challenge of anti-microbial resistance". Indian J Med Microbiol 32: 221-8.
• ↑ Amoxicillin. https://www.goodrx.com/amoxicillin
• ↑ Lovoxine. https://www.indiamart.com/proddetail/lovoxine-levofloxacin-500mg-tablets-12367916548.html

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