Tuberculosis Treatments Have Always Been Controversial

In the 19th century, tuberculosis (TB) was called the “romantic disease”. The people recovering from TB, often famous writers and artists, were a staple of Victorian literature and art.

John Keats and his poems often reflect themes of transience, beauty, and mortality. His famous poem "Ode to a Nightingale" is an example of his exploration of the fleeting nature of life and the longing for immortality.

"La Bohème" by Giacomo Puccini, an opera tells the story of young bohemian artists in Paris, one of whom, Mimì, suffers from tuberculosis.

In the novel "Wuthering Heights" by Emily Bront?, the character of Catherine is associated with the image of a recovering patient. Her illness and eventual death are pivotal to the story, and her spectral presence influences the characters and the tone of the novel.

But, the effect of the disease on mortality rates was far from picturesque: four million people died of TB in England and Wales between 1851 and 1910. Today, tuberculosis is the second leading cause of death after COVID-19 worldwide. The incidence rate (100,000 new cases per year) is predicted to have increased by 3.6% between 2020 and 2021, with 1.6 million deaths in 2021.

TB has had an atypical path of treatment

Doctors, in the early 19th century believed that foul air caused tuberculosis. Despite Robert Koch’s discovery of the TB germ,?Mycobacterium tuberculosis?in 1882, the foul-air theory continued to shape treatments. The high premium placed on ‘pure’ air as a therapeutic tool informed the growth of special hospitals known as “sanatoriums”. These were situated in rural locations to maximize the exposure of patients to sunlight and fresh air, but also to segregate them from the general population.

This fear of contagion was deeply ingrained in society, and the notion of isolating TB patients in these remote facilities was not only a medical strategy but also a reflection of the widespread dread of the disease. Families and communities were terrified of tuberculosis, which was often referred to as the "white plague" or the "great white scourge" due to its deadly and highly contagious nature.

In the 1930s, artificial pneumothorax was a somewhat controversial and temporary treatment approach for tuberculosis. It involved collapsing or partially deflating a lung, which was believed to reduce the strain on the lung affected by tuberculosis, allowing it to heal.

Antibiotics finally came in the late 1940s and was the game changer for TB.

Available treatment options include drugs as “first-line” or “second-line” depending on the patient and the profile of TB drug resistance.

Treatment regimens are typically predefined; but, there’s an big problem - drug resistance.

The ability of TB to resist anti-TB drugs represents a major barrier to TB diagnosis, treatment, and eradication efforts.

How drug resistance came into play?

Mycobacterium tuberculosis?has a conserved genome driving a paradigm of a near-perfect host-pathogen relationship. Phylogenetic inferences reveal that there are seven global lineages of?M.tb?strains that have co-evolved with human populations under sympatric and allopatric host-pathogen combinations. These?M.tb?strain lineages differ in their geographic distribution, biological fitness, virulence and their propensity to acquire drug resistance

One of the mechanisms through which Mycobacterium tuberculosis can evolve drug resistance is by undergoing mutations in specific genes.

One example is a mutation in the?rpoB?gene, which encodes the beta subunit of the bacterium's RNA polymerase enzyme. In non-resistant TB, rifampin binds the beta subunit of RNA polymerase and disrupts transcription elongation. Mutation in the?rpoB?gene changes the sequence of amino acids and the eventual conformation, or arrangement, of the beta subunit. In this case, rifampin can no longer bind or prevent transcription, and the bacterium is resistant.

Other mutations make the bacterium resistant to various drugs. For example, there are many mutations that confer resistance to isoniazid (INH), including in the genes?katG,?inhA,?ahpC?and others. Amino acid replacements in the NADH binding site of InhA result in INH resistance by preventing the inhibition of mycolic acid biosynthesis, which the bacterium uses in its cell wall. Mutations in the?katG?gene make the enzyme catalase peroxidase unable to convert INH to its biologically active form. INH is ineffective and the bacterium is resistant.?The discovery of new molecular targets is essential to overcome drug-resistance problems.

In some TB bacteria, the acquisition of these mutations can be explained by other mutations in the DNA recombination, recognition and repair machinery. Mutations in these genes allow the bacteria to have a higher overall mutation rate and to accumulate mutations that cause drug resistance more quickly.

Multidrug-resistant TB (MDR-TB) has a mortality rate of about 15% with treatment, which further depends on a number of factors, including:

1. How many drugs the organism is resistant to (the fewer the better)
2. How many drugs the patient is given (patients treated with five or more drugs do better)
3. How co-operative the patient is with treatment (treatment is arduous and long, and requires persistence and determination on the part of the patient)
4. Whether the patient is?HIV-positive?or not (HIV co-infection is associated with increased mortality)
5. The stage at which Tb was diagnosed (with more delay, the disease can progress and become more severe, making it harder to treat effectively)

Speaking of which, we at Cambrian used the Blood and Tissue DNA kit from Bronchoalveolar lavage (BAL). The presence of MTb was analyzed and correlated to the presence of the disease.

Know more here.

We have been surveilling drug-resistant tuberculosis for 25 years

The Global Project on Anti-Tuberculosis Drug Resistance Surveillance, hosted by WHO since 1994, stands as the world's oldest and largest antimicrobial resistance surveillance system. Over the past 25 years, it has provided a common platform for assessing drug-resistant tuberculosis on local, regional, and global levels.

The Global Project on Anti-Tuberculosis Drug Resistance Surveillance has achieved remarkable milestones. It includes a comprehensive analysis of trends in over 100 countries, spanning the past two decades, with 65 of these nations amassing three or more years of data. These analyses have closely examined per capita rates of multidrug-resistant tuberculosis (MDR TB) and tracked trends from 1999 to 2014. Additionally, the project has explored the complex association between MDR tuberculosis and HIV infection, revealing varying patterns across different regions. While a positive correlation has been observed in Eastern European countries, global data do not consistently establish a definitive link between HIV infection levels and the prevalence of MDR tuberculosis.

Looking ahead to the next decade of antituberculosis-drug resistance surveillance, we anticipate significant developments to address key challenges. Molecular technologies, such as Xpert MTB/RIF, are increasingly integrated into surveys, simplifying logistics, reducing costs, and improving detection of rifampin resistance. These molecular technologies are expected to replace conventional testing methods in the future, including high-throughput sequencing-based technologies.

The use of molecular technologies can resolve ongoing challenges in monitoring drug-resistance trends, allowing for continuous surveillance, precise mapping of resistance levels within countries, and rapid detection of hot-spot regions. Rifampin and isoniazid, as powerful first-line antituberculosis drugs, remain essential, but shorter treatment regimens involving fluoroquinolones and pyrazinamide are under evaluation and could shape the future of tuberculosis treatment.

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