In the pre-antibiotic era, the gold standard treatment for the lung disease tuberculosis (TB) was plenty of rest and fresh air. Facilities to house TB patients, known as sanatoria, sprang up in Europe and North America in the late 19th century, usually up mountains or in isolated forests. Although no controlled studies have established the effectiveness of any of the interventions they applied, the existence of sanatoria led to the long-term removal of infectious patients from the community. With the discovery of streptomycin in the 1940’s and isoniazid in the 1950’s, the antibiotic age heralded the end of an era for a disease which mankind has lived with since ancient times*. Or so we thought.
A number of factors contributed to making the microbe Mycobacterium tuberculosis such a long-standing human pathogen, including its small infectious dose, waxy outer coat and its ability to withstand our immune response. Breathing in as few as five bacteria is enough to become infected, and for many this will be the end of the story, with the crafty microbe hiding out in the lungs, in what we call a latent infection, with full blown disease kept at bay by our immune system.
People with latent TB are not infectious so, providing the immune system can maintain the status quo, all is fine. And this is what is happening in the lungs of about one third of the world’s population, more than two billion people. It is when this status quo breaks down that all hell breaks loose. The devastating pandemic that is HIV and AIDS is one of the major reasons why a disease most people think was eradicated in the 1950’s now kills over 4,500 people every day.
So if TB is such a problem, and one third of the world’s population are latently infected with M. tuberculosis, why don’t we just put everyone on a course of antibiotics? This is where the microbes slow growth and waxy coat come in. Because M. tuberculosis is actually a very difficult bug to kill. The ‘short course’ of treatment is usually two months of treatment with four antibiotics, followed by taking two of the antibiotics for a further four months. Because the drugs are fairly old, they can have pretty bad side effects, so what has happened is patients stopping their treatment partway. And what happens when we don’t finish a course of antibiotics? The bugs become resistant.
Multi-drug resistant M. tuberculosis (MDR-TB) are defined as being resistant to two of the frontline drugs. MDR-TB takes even longer to treat and can only be cured with second-line drugs, which are more expensive and have more side effects. As a result, we have seen the emergence of extremely-drug resistant M. tuberculosis (XDR-TB), which are essentially strains of MDR-TB that have become resistant to some of the second-line drugs.
Recently, Zarir Udwadia and colleagues reported the emergence of totally drug resistant M. tuberculosis (TDR-TB) in India.** This is not the first time TDR-TB has been described; there have been small clusters reported in Italy and Iran. Worryingly, they found:
1. The strains were resistant to all first-line and second-line drugs recommended by the World Health Organization (WHO) for treatment of TB.
2. Three of the patients had received erratic, unsupervised second-line drugs, added individually and often in incorrect doses, from multiple private practitioners.
Another paper by Udwadia and colleagues suggests the recent Indian cases may be the tip of the iceberg. They surveyed over 106 private GPs practicing in Dharavi, a large slum in Mumbai, which covers an area of approximately 1.75 sq. kilometers, and has a population of over 2.5 million, asking them*** how they would treat TB. Just 6 of the respondents wrote a prescription with a correct drug regimen and only 3 of the 106 could write an appropriate prescription for treating MDR-TB. They concluded:
“Strategies to control TB through public sector health services will have little impact if inappropriate management of TB patients in private clinics continues unabated. ….Ignoring the private sector could worsen the epidemic of multidrug-resistant and extensively drug-resistant forms of TB.”
Treatment options for XDR-TB and TDR-TB are pretty limited, and may come down to a choice of surgically removing the sections of infected lung, or confining infectious patients so they cannot spread their drug-resistant microbes to anyone else. But in resource-limited countries that bear the brunt of TB, a more realistic scenario is that patients with drug-resistant TB are sent home to their families to die, infecting those caring for them in the process.
Recently Prof Keertan Dheda and Prof Giovanni Migliori suggested in an article published in The Lancet that perhaps the time has come to bring back sanatoria to provide state-of-the-art palliative care to dying patients in a safe and dignified setting. In this way, destitute people for whom treatment has failed could voluntarily reside on a long-term basis with social, educational, and recreational facilities, and receive good nutrition and care within an infection-controlled setting, thereby reducing transmission within the community and to family members.
“We have now come full circle and once again there are large numbers of patients for whom there are no effective antituberculosis drugs. The pool of untreatable cases is accumulating and will need swift action to avoid a human catastrophe.”
So while the world’s media and governments are obsessing over a potentially lethal strain of flu locked away in a couple of laboratories, a public health disaster continues to unfold beneath our very noses. If only similar efforts could be directed to trying to control the spread of TB.
* Skeletal remains show prehistoric humans had TB, and researchers have found tubercular decay in the spines of Egyptian mummies (Zink A, Sola C, Reischl U, Grabner W, Rastogi N, Wolf H, Nerlich A (2003). Characterization of Mycobacterium tuberculosis Complex DNAs from Egyptian Mummies by Spoligotyping. J Clin Microbiol 41 (1): 359—67. doi:10.1128/JCM.41.1.359-367.2003.).
** Although this is not the first time TDR-TB has been described; there have been small clusters reported in Italy and Iran a few years ago.
*** The questions were:
1. Please write a prescription for a previously untreated adult case of sputum-positive pulmonary tuberculosis weighing 50 kg.
2. Please write a prescription for a previously untreated adult case of multidrug-resistant tuberculosis resistant to isoniazid and rifampicin and weighing 50 kg.