Context

For the past near century, antibiotics have seemed almost like miracle drugs, transforming diseases that had once been synonymous with a death sentence into minor inconveniences in daily life. After their initial discovery in 1928, antibiotics soon became the preferred treatment for many bacterial infections, making it possible for many patients of gruesome disease to make a full recovery. Tuberculosis was no different. 

Caused by the bacteria Mycobacterium tuberculosis, tuberculosis symptoms often include chest pain, fever, chills, aches and pains, and cough accompanied by phlegm and blood. Evidence of tuberculosis has been found in mummified remains from as early as 2400 BCE (Barberis et al., 2017), and the disease was considered an epidemic throughout the 18th and 19th centuries across Europe and North America (Daniel, 2006) and even today ranks as the second deadliest infectious disease with 1.8 million deaths yearly, surpassed only by Covid-19 (Winny, 2022). When left untreated, i.e. before antibiotic intervention was possible, mortality rates consistently hovered around 50% (WHO, 2022). The introduction of vaccines and antibiotic treatments, however, turned the tides.

Current Treatment Methods

The first case of tuberculosis being treated with antibiotics was recorded in 1944 when, just months after its discovery by scientists Albert Schatz, Elizabeth Bugie, and Selman Waksman,   streptomycin was administered to a young woman with tuberculosis and produced dramatic results. The initial distribution was slow and limited due to a lack of supplies, but after the discovery of orally-administered isoniazid and rifamycins in 1952 and 1957 respectively, the tide finally turned for what had been a multi-millennium battle against tuberculosis (Daniel, 2006).

Today, the common course of treatment lasts between six to twelve months and uses a combination of four common antibiotics: isoniazid, rifampin, pyrazinamide, and ethambutol (Rutgers University, 2024). In some cases, short-term chemotherapy is also used. Tuberculosis vaccination also became widespread after World War II and though not completely effective, the combination of treatment and prevention strategies dramatically reduced both incidence and mortality rates (Riva, 2014).

Rise of Resistance

Although some severe cases required more toxic drug combinations, the majority responded well to treatment. Concerns over antibiotic resistance began to arise in the late 1980s and early 1990s when tuberculosis infections grew rapidly during the AIDS pandemic (Keshavjee & Farmer, 2012). Tuberculosis has long shown rapid adaptive abilities, with many strains developing mutations and showing resistance to individual drugs or early antibiotics. Much more dangerous Multidrug-Resistant (MDR) cases began to increase in prevalence during the AIDS pandemic as patients initially improved on antibiotic treatments only to relapse with strains that resisted most if not all common treatment regimens. The first incidence of highly virulent MDR tuberculosis was recorded in the 1970s, later causing an outbreak in New York City that lasted throughout the late 1980s and early 1990s and eventually accounted for 15% of all cases in the country (Keshavjee & Farmer, 2012).

MDR cases refer to strains resistant to two or more of the common antibiotics used in treatment: isoniazid and rifampin. More specifically, two more serious forms of MDR tuberculosis are classified as pre-extensively drug-resistant (pre-XDR) and extensively drug-resistant tuberculosis (XDR) which, though rare, are resistant to nearly all drugs used in treatment. (CDC, 2023). The first case of XDR tuberculosis was reported in November 2005 (CDC, 2007), and infections have been rapidly increasing.

Although Mycobacterium tuberculosis can naturally mutate quickly and become randomly resistant, the antibiotic resistance issue is still largely manmade. The primary cause of resistance is non-adherence, where patients fail to complete their treatment or fail to follow all steps before “completing” their regimen (Palomino & Martin, 2014). Given the length of treatments and the fact that MDR treatment may last as long as two years, non-adherence rates are unsurprisingly high. Additionally, the expense of treatments and lack of access in some communities can make adherence nearly impossible. When bacteria are incompletely eradicated, small populations can survive and potentially develop mutations. Additionally, sublethal levels of antibiotic exposure may induce mutations or put evolutionary pressure that selects for resistant bacteria, allowing them to eventually reinfect the patient (Nguyen, 2016).

Future Projections

Both MDR and XDR are now serious concerns to human and global health. Between 2010-2019, XDR cases increased by 22.5% with a total of 25,060 new reports globally. In some countries, MDR tuberculosis makes up nearly 38% of all tuberculosis cases (Bu et al., 2023). In 2021 alone, roughly 134,000 cases with some level of resistance were reported and projections predict an upward trend to come (Gupta et al., 2024).

Furthermore, tuberculosis, especially resistant strains, represents a global discrepancy in health equality. Initial research was largely conducted in wealthy countries and the distribution of treatments reflected this wealth disparity. Yet despite continuing to ravage the global population, funding for research and resources was cut dramatically as cases declined in wealthy countries with US federal cuts bringing research to a near halt (Keshavjee & Farmer, 2012). Epidemics persisted in countries with lower average incomes despite tuberculosis becoming extremely rare in other countries. Global health efforts were frequently deemed too costly and as MDR cases reflect a similar disparity. Whereas efforts to stop outbreaks in the US and across Europe were efficient and effective, similar measures have not been seen in lower-income countries where such measures would prove “too costly” (Keshavjee & Farmer, 2012). A global burden remains; if left untreated, resistant tuberculosis will only continue to spread and mutate.

Despite a potentially troublesome forecast, many solutions have been proposed to try to prevent a major MDR tuberculosis outbreak. Promising research on bacteriophage therapy, for example, has recently emerged, though data on MDR tuberculosis specifically is still significantly lacking (Allué-Guardia et al., 2021). Amongst the most widely recognized is the “Six Month Global Regimen” first proposed by the World Health Organization (WHO) in 2022. The plan consists of a six month treatment plan with a concoction of three to four drugs: pretomanid, bedaquiline, linezolid, and moxifloxacin in some cases (BPaLM). The regimen is predicted to be used in the majority of drug-resistant forms of tuberculosis by 2026, with estimates of roughly 78% of cases (Gupta et al., 2024). In the WHO Global Tuberculosis Report 2023, evidence from one randomized controlled trial showed “much-improved treatment success rates with the 6-month BPaLM regimen (89%) compared with previous standard-of-care regimens (52%), as well as lower levels of treatment failure, death and loss to follow-up” (WHO, 2023).

References

Allué-Guardia, A., Saranathan, R., Chan, J., & Torrelles, J. B. (2021). Mycobacteriophages as potential therapeutic agents against drug-resistant tuberculosis. International Journal of Molecular Sciences, 22(2), 735. https://doi.org/10.3390/ijms22020735

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Bu, Q., Qiang, R., Fang, L., Peng, X., Zhang, H., & Cheng, H. (2023). Global trends in the incidence rates of MDR and XDR tuberculosis: Findings from the global burden of disease study 2019. Frontiers in Pharmacology, 14. National Library of Medicine. https://doi.org/10.3389/fphar.2023.1156249

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Nguyen, L. (2016). Antibiotic resistance mechanisms in M. tuberculosis: an update. Archives of Toxicology, 90(7), 1585–1604. National Library of Medicine. https://doi.org/10.1007/s00204-016-1727-6

Palomino, J., & Martin, A. (2014). Drug resistance mechanisms in mycobacterium tuberculosis. Antibiotics, 3(3), 317–340. National Library of Medicine. https://doi.org/10.3390/antibiotics3030317

Winny, A. (2022, August 15). The other pandemic: Why TB deserves your attention | Johns Hopkins | Bloomberg School of Public Health. Publichealth.jhu.edu. https://publichealth.jhu.edu/2022/the-other-pandemic-why-tb-deserves-your-attention

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