How Did Drug-Resistant TB Come to Be?

resistant TB. Getty

Tuberculosis is a disease we can treat. Tuberculosis is a disease we can prevent. It's looking like we are less and less able to treat it.

Little bit by little bit, as the drugs are used - and sometimes misused - to treat TB, we lose the ability to use these drugs. They collect drug resistances. The bacteria collect genes that let them resist the drugs we use to stop TB.

How did this happen?

TB is an old disease.

It is likely as old as humanity, dating back tens of thousands of years.

We didn't have a treatment for this disease until the 1940s. Before then, the disease likely took a billion lives. In the 17th to 19th centuries, 1 in 5 died from TB, likely even more in cities like Paris and London.

Famous figures died from the disease The literary torments of great writers from Franz Kafka to George Orwell to the Brontes to Edgar Alan Poe were tied to TB. Only Poe did not die from it; he watched his loved ones die. The rest lost their lives to the disease.

There wasn't much that could be done for TB. Treatment could be horrible. Some had diseased lung removed. Orwell had his phrenic nerve crushed to paralyze his diaphragm. Others had ping pong balls fill in spaces in their lungs. Kafka could not eat, as TB closed his throat. Otherwise went to the seaside like one Bronte sister did.  Fresh air, good nutrition, and sunlight may have helped a bit, but there wasn't more that could be done.

This is a disease we never want to see be untreatable again. The problem is, if treatments are not properly administered and followed, we risk developing more and more resistance, making TB less and less treatable. These resistances accumulate as the bacteria spreads from person to person.

It's taken doctors and researchers a long time to be able to find effective treatments for TB.

Even so, current treatments require at least 6 months of multiple daily medications.

It took a lot of scientific work to be able to have the treatments we have. In 1943, streptomycin was first isolated - which was then used as the first effective treatment for TB. Researchers soon realized one drug was not enough. TB quickly developed resistance if only one drug was used. There needed to be multiple drugs given for the treatment to be effective. TB had a harder time collecting the resistance genes needed to fight off multiple different drugs.

Many still developed TB again - some from bits of the old infection growing back. Drug courses were long, sometimes up to a year or two, to keep TB from growing back. Until the 1970s saw the use of rifampin, most regimens were at least 18 months. More drugs were added and the regimen was then streamlined. Since 1984, the standard of care has been 6 months of treatment: 4 drugs for 2 months followed by 2 drugs for 4 months, for most cases.

Biologically it's hard to keep resistance at bay

The problem has always been this: Tuberculosis has a high probability of developing resistance.

There is a high bacterial burden. The bacteria can hide where drugs can't reach them and become dormant - standard medications that stop cells from dividing will not stop dormant TB. There is then a high chance one bacterium will mutate. Such spontaneous mutations are common. In fact, as many as 7% of cases relapse.

The problem then has been: many who need access to further drugs for treatment of resistant TB haven't had this access. Those who do not have complete treatment with monitoring and follow up can more easily develop resistant TB. When health systems cannot support TB treatment for all, there is a risk of resistant TB threatening all.

Add to this HIV. The immune suppression caused by HIV makes TB harder to control. The result: a growth in resistance.

Certain drugs matter more

Resistance is worrisome when TB is not responsive to both Isoniazid and Rifampin, the two drugs used for all 6 months of treatment. This is called Multidrug resistant TB or MDR TB. 

Worldwide resistance is a growing problem

By the early 1990s in New York City, 1 in 10 TB cases were resistant. This has improved but an increase in cases has been seen in India, China, and especially Eastern Europe and the ex-Soviet Union. In Eastern Europe, 20% of new TB patients are resistant; rates among those previously treated reach more than 50%. In fact nearly half of TB patient in Minsk, Belarus have resistance.

The problem has been particularly severe in South Africa, which has faced extremely drug resistant TB - XDR TB.  This has also been a problem for China, India, and many other countries. This form of TB is resistant to even further drugs, leaving very few treatment options left. XDR has since developed elsewhere and has been found in 77 countries.

Even more worrisome, Totally Drug Resistant TB has emerged in India, Iran and Italy. These samples are seemingly not responsive to any drugs. 

Not only do many not have access to the drugs needed to successfully treat their TB, but until December 2012, no new novel drugs had been developed for TB since rifampicin in 1963. There have now been two new drugs and others in the pipeline.

We certainly do not want to return to the world of Orwell, the Brontes, Poe, and Kafka.

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