Introduction
Tuberculosis has been diagnosed in over a billion humans throughout the world and has led to the most deaths by any infectious disease in history. Despite being both curable and preventable for decades, it is still a leading cause of death - the second most infectious cause of mortality after COVID-19 in 2021. Following the first positive results over a century ago, treatments for tuberculosis have developed significantly, but Mycobacterium Tuberculosis (MTB) has adapted over time, and resultantly the efficacy of certain regimens and procedures has decreased. This article will explore the basic history of treatments as well as the methods for tackling tuberculosis, and identify how antibiotic resistance and other factors have led to the evolution of the way humans tackle this disease and how our scientific methods have adapted accordingly.
Initial (Surgical) Treatments
Tuberculosis (TB) is an ancient infectious disease, having existed long before the invention of antibiotics, and therefore the use of chemical or natural substances were not generally considered viable treatments. Prior to the modern antibiotic style of treatment, many patients were referred to institutions called sanatoria. This did not necessarily improve the patient’s own health, but was done more so as a protective measure or quarantine, due to the airborne nature of MTB. These institutions essentially isolated those who had contracted this disease, so as to reduce the probability of them transmitting the bacterium to the healthy population. This practice of isolation is carried out in hospital wards to this day, yet despite this, it is estimated that 1.8 billion of the world’s population are carriers of the bacteria but only about 1 in 200 have active TB (i.e. are infectious). Following the discovery by Robert Koch in 1882 of tuberculosis’ aetiological agent (the bacterium that causes TB) the disease was understood better, and treatments which used surgical techniques were developed over the course of the next few decades. One technique initially used was Pulmonary resection, where surgeons would physically remove the lobes infected with MTB. This had limited success as it had no guarantee of removing all the bacteria from the lungs, and was fatal for many patients post operation.
A much more promising and successful technique emerged from French physicians, who observed the positive effect of spontaneous pneumothoraces (collapsed lungs) on patients who were suffering from active TB. Carlo Forlanini soon developed a surgical treatment to induce a pneumothorax within a patient, by injecting liquid nitrogen and oxygen into the pleural space (this is the cavity that exists between the lungs and underneath the chest wall). Collapsing or deflating a lung allowed the tuberculosis cavities to be closed off. This not only allowed the lung to ‘rest’ but also caused the bacteria themselves to arrest, a consequence of little to no oxygen entering the collapsed lung. Despite being a revolutionary step forward and becoming a widely popular treatment, there were many drawbacks. Firstly, scientists and physicians were unable to confirm efficacy of this treatment, since no official clinical trial was run, and many centres were reporting variable results despite valid procedures having been carried out at the reporting hospitals. Furthermore, there were huge risks of inducing a pneumothorax and it often left patients disfigured or even dead. This procedure showed progress in tackling the disease, however it was not a viable solution for the greater issue.
Bacillus Calmette-Guerin
Other scientists had begun developing other forms of tackling the disease. Another bacterium closely related to MTB called Mycobacterium Bovis, causes a similar disease in cattle and other animals. A French doctor named Calmette explored using this bacterium as a possible vaccine, and trialled orally administering an attenuated version of Mycobacterium Bovis. Again, over the course of several decades, this was honed and improved. It is now commonly known as the Bacillus Calmette-Guerin (BCG) and is injected. Many clinical trials have taken place, and although they do have variable results depending on geographic location and ethnic factors, the general efficacy of the BCG vaccine is high: on average it reduces the risk of TB by 50%. This vaccine is still used widely to this day; however, it is not a treatment, simply a mitigating element, and does not help those who already have the disease.
Streptomycin Monotherapy
Antibiotics caused a revolution in modern medical treatments, following the discovery of the naturally occurring antibiotic, penicillin, by Alexander Fleming in 1928. These drugs were used extensively in countering bacterial infections and preventing disease. Their effectiveness naturally led to the thought of it as a viable method to counter Mycobacterium Tuberculosis. Many drugs were trialled, but none were considered effective until the usage of streptomycin in 1944, whose efficacy was such that it seemed a definitive treatment for tuberculosis had been discovered. The discoverer, Selman Waksman, received the Nobel prize "for his discovery of streptomycin, the first antibiotic active against tuberculosis". Streptomycin enters the bacteria and irreversibly binds to ribosomes (which synthesise proteins, crucial for all biological processes). Though the process is not fully understood, the general understanding by microbiologists is that the drug inhibits protein synthesis within the bacterium, which results in the death of the cell. One thing to note is that the substance does not target only bacterial ribosomes, and therefore it can lead to significant side effects within humans when used in higher concentrations. These can be relatively mild - fever, rashes and vomiting - but can also include kidney and ear toxicity.
Finally, after various treatments and vaccines having been made, it seemed that a cure had been found, albeit a long course lasting several months. However, after a few years of widespread use of streptomycin, by 1952 some patients’ conditions were seemingly unaffected by the use of the drug. This was a result of acquired antibiotic resistance - a topic which deserves an article of its own. In simple terms, bacteria adapt over time and become resistant to the antibacterial substances they are exposed to. The greater the exposure to these drugs, the greater the chance of these resistant attributes occurring within the general population. Consequently, with streptomycin being the only active drug being administered for this infection, Drug-Resistant Tuberculosis (DR TB) became widespread.
Combination Therapy and Multi-drug Regimens
The presence of antibiotic resistance has been the single most influential factor in the method of treatment for TB and its variants. Once DR TB had become a prevalent issue, the first multi drug regimens were used. Various new antibiotics were and are used in these regimens, namely isoniazid and rifampin, and they all have varying mechanisms of action. For example, some inhibit cell wall or protein synthesis while others cause depolarisation of cell membranes. These all work together to provide a stronger, and more effective treatment, but must be carefully balanced. In the right proportions, these drugs will complement each other and compensate for any immunity the bacteria might have to specific drugs in the regimens. In the wrong proportions, and in large amounts, these drugs can fail to treat the TB effectively and again have toxic effects on the human body. Treatment courses typically last for 6-9 months and contain 4-5 drugs. The drug combinations that are used depend on various factors. TB Specialists tailor the treatment to the patient, making it incredibly effective.
Some more developed strains require a more informed decision on the combination of drugs used. Whilst treating the patient with a group of broad-spectrum antibiotics, microbiologists grow multiple cultures of the bacterium in laboratories. These are then attacked with varying regimens, and this can reveal what if any drugs the MTB could be resistant to, and which combination of drugs act against the growth of the infection the best. One drawback with this culture method, is that MTB is a comparatively slow growing bacterium. This means that growing and testing cultures in laboratories takes a long period of time, during which the patient’s condition can deteriorate. However, diet and rest can help to maintain the patient until the best combination is found.
Whole Gene Sequencing (WGS)
Whole Gene Sequencing is one of the more recent developments in microbiology and biochemistry, and it is something that is not extensively used yet in medical practice. It is a concept that has evolved massively and has led to and aided research in new disciplines, such as gene therapy. One application that has been explored in recent years is the whole gene sequencing of TB strains. This yields much information about how the bacterium in each person varies by the slightest mutation. More importantly, this vast amount of data can be manipulated and analysed to predict what drugs the bacteria has immunity to and also which it is susceptible to. Despite the extremely complicated nature of this process, it has over a 90% sensitivity for accurately predicting the resistance to all front-line drugs, barring pyrazinamide. This process is expensive, but it is faster than letting the cultures grow and testing them so it provides a quicker solution to finding the best combination of drugs tailored to the patient.
Concluding Remarks
Once again, due to antibiotic resistance, the efficacy of modern combination therapies and multi drug regimens are decreasing slowly but surely. This is again due to the bacteria adapting to form strains known as multi-drug-resistant tuberculosis which are resistant to several of the main antibiotics used in the varying regimens. Although we can discover and implement new synthetic antibiotics in regimens, this does not escape the cycle, and could result in even stronger strains of TB being formed.
From surgically deflating lungs a century ago to now sequencing the genetic identity of tuberculosis, treatments have developed which have saved countless lives. With great investment into research into alternate treatments, concepts such as bacteriophages may soon become regular treatments, however ultimately, with great advancements and leaps forward taking place in medical science, it is hard to definitively say what the future of treatments holds.
Further Reading
An interesting paper, with chest x-ray images of patients:
Imtiyaz Basher’s article on the MediSphere Journal website -