Pathenogenic bacteria are becoming resistant to antibiotics. This includes tuberculosis (TB), a bacterial disease that takes its place as one of the ‘Big Three’ infectious diseases, along with malaria and HIV. All three exhibit an unparalleled capacity to become resistant. Is the era of being able to treat bacterial disease with antibiotics coming to an end?

But tuberculosis is a disease of the Victorians, right? Wrong. Today, Mycobacterium tuberculosiscauses more deaths in adults than any other infectious disease apart from AIDS, killing 1.3 million people in 2012 alone. Around one-third of the world population is infected with TB. Going by various pseudonyms like consumption, the King’s evil, and scrofula to name a few, TB has been found in the skeletons of our most ancient ancestors, and its symptoms were first described by Hippocrates over 2,000 years ago. This bacterial disease has truly conquered the world.

It was thought that humans would be cured of TB shortly after the 1950s, when combination therapy using several antibiotics was introduced. However, in the past few years, the trend in TB infection has reversed, and it is on the rise once again. This time, TB is ready. Many strains are resistant, and some are resistant to everything we have to throw at them (multiple or extremely drug resistant TB, MDR and XDR TB). With millions of people dying each year, the race is on to get TB back under control.

BECOMING RESISTANT

In 2013, half of all TB cases in Eastern Europe were multiple-drug resistant (MDR) — the highest proportion yet. Resistance to an antibiotic is a case of the right mutation at the right time. Some bacteria have a neat trick — they can make copies of a gene with a beneficial mutation in it and directly transfer it to another bacterial cell. Bacteria do ‘have sex’ too, but they call it horizontal gene transfer. The recent outbreaks in Pneumococcus in North America are thought to be driven by bacteria that first swapped genes for vaccine resistance, and then for antibiotic resistance. Scary stuff.

One of the interesting things about TB, however, is that it does not seem to share its genes. The only way for a colony to acquire a beneficial mutation is through a single mutation event, followed by large-scale replication of that individual until its descendants take over the colony, outcompeting other strains. Despite this, TB becomes resistant very quickly. In 1946, a new antibiotic was introduced, and two years later, over 85% of cases were resistant.

Russia, in particular, is a hotspot for drug resistant TB. In 2004, 12% of TB cases were detected in prisons. Bearing in mind that prisoners account for 0.5% of the population, this figure is staggering. But cases of TB are not confined to Russian prisons; a similar trend is found worldwide, including US and UK prisons.

Other groups of people that have a high rate of MDR-TB infection are those living in poverty, HIV patients, and intravenous drug users. The connection is clear: high transmission rates, poor, compromised immunity, and lack of adherence to the treatment regime.

Evolutionary biology came to the rescue in explaining this link. Mutations for a new adaptation can result in reduced fitness. In the case of a bacterium, the mutation for resistance may reduce its growth rate, for example. Only when there are nice benign conditions can that bacteria outcompete fitter non-mutants. As it replicates, compensatory mutations accumulate, until it is resistant and competitive.

TB may be able to capitalise on this evolutionary process. The treatment takes place over many months, which leaves plenty of time for many resistant mutants to arise. This places everybody on the treatment at risk. In the immunocompromised groups, failure to regularly take the antibiotics and the defective immune response can provide an easy life for the bacteria. Populations of TB within the body can grow vast, with only small doses of antibiotic reaching cells and the body does not induce an aggressive immune response. Within these populations, the mutants are able to thrive, and with such a large population size, one is bound to develop. Furthermore, in poverty-stricken, high-density human populations there is more than ample opportunity to infect other individuals. Even poorly adapted bacteria can do it, which unfortunately streamlines their transmission rates. Now, they are free to infect healthy individuals.

Is this how TB is doing it? Some microbiologists report fitness deficits in resistant bacteria and others find none. Other factors may play into drug resistance, particularly to do with the socioeconomic backgrounds of high-risk patients. A time lag in diagnosis, a reluctance or inability to finish the antibiotic course, and frequent contact with other infected individuals can mean that a very large population with mutants may already be present before the administration of the drugs.

CONTROLLING TB

So how can public health services stop the transmission of drug resistant TB? Top of the list is getting the patients to take their course of drugs properly, as patients who adhere to the antibiotic treatment are likely to be cured. Is it possible to make the course shorter? Or to get better at finding and diagnosing high risk TB cases? Incentivising the patients through more education, or offering money or food to those who regularly come to the clinic has also been explored. Unstable living conditions, childcare, lack of access to good health centres, and general sickness seem to make even cash in hand not much of a motivation. The World Health Organisation (WHO) has made tuberculosis one of its current focuses, declaring it a major global health emergency. They employ directly-observed treatment strategy (DOTS), where patients are watched by a health professional as they take their drugs each day. This seems effective and the WHO considers it a great success, however there are some cases where it (perhaps understandably) demoralises the participants.

Of course, the ideal would be some fantastic new antibiotic, or an effective, cheap vaccine. (The currently available BCG vaccine doesn’t have high success rates and makes diagnosis difficult). Research for these is ongoing. There is some evidence to suggest that a multi-strain vaccine is the way to go, but most developing TB drugs and vaccines are not making it through the clinical trials.

It is not all bad news though, as infection rates are slowing and mortality rates are decreasing. According to the WHO, the global mortality rate had fallen by 45% in 2012 from 1990. Integrating what is known about the biology of TB and the social background to TB infection is critical. Drugs and vaccines can never be completely effective without considering the conditions of the people who will take them, and with TB infecting 8.6 million people every year, we had better get a move on.