In a patient's fight against tuberculosis—the bacterial lung disease that kills more people annually than any infectious disease besides HIV— doctors have more than 10 drugs from which to choose. Most of those didn't work for Uvistra Naidoo, a South African doctor who contracted the disease in his clinic. For those who contract the disease now, maybe none of them will.

A new paper published earlier this week in the Centers for Disease Control and Prevention's Emerging Infectious Diseases journal warns that the first cases of "totally drug-resistant" tuberculosis have been found in South Africa and that the disease is "virtually untreatable."

Like many bacterial diseases, tuberculosis has been evolving to fend off many effective antibiotics, making it more difficult to treat. But even treatable forms of the disease are particularly tricky to cure; drug sensitive strains must be treated with a six-month course of antibiotics. Tougher cases require long-term hospitalization and a regimen of harsh drugs that can last years.

Naidoo, then an avid runner, says he continued training for months with the disease, which affects more than 389,000 South Africans annually (about one fourth of Africa's cases), according to the World Health Organization. It wasn't until he went to visit his family in Durban (he had been working with TB patients in a pediatric clinic in Cape Town) that his family noticed he had lost more than 30 pounds.

"I had flu symptoms and chest pains, but I was still running so I didn't think anything was wrong," he says. But when he went in for an X-ray, doctors found that his entire right lung had filled with fluid. Within weeks, he was on his deathbed as his body wasn't responding to the most commonly prescribed antibiotics.

"One night I nearly passed away—it didn't look good," he says.

His father, also a physician, suggested that he may have had an emerging MDR, or a multi drug-resistant strain of TB. The emergence of MDR and its even more dangerous cousin, XDR (extremely drug-resistant TB), have pushed tuberculosis cure rates in the country from a high of 73 percent in 2008 down to 53 percent in 2010.

Naidoo survived the night and doctors eventually found a treatment regimen that worked, but he was in and out of the hospital for three years, and the drugs' side effects were almost unbearable, he says. He developed Stevens-Johnson Syndrome, a complication that causes layers of skin to separate from each other and can be deadly. He regularly bled from his eyes. He fell into a deep depression.

"The TB doesn't feel like it's killing you, but the drugs do. I am a doctor and was informed that the drugs you take make you feel worse," he says. "My case was three years long. I don't think the average patient has that kind of patience."

At King George V hospital in Durban—one of South Africa's most popular TB clinics, which specifically treats XDR patients—the 200 beds are always full, and there's a four- to six-week waitlist for new patients.

William Bishai, of the Johns Hopkins Center for TB Research Laboratory and head of the KwaZulu-Natal Research Institute for Tuberculosis and HIV in South Africa, works with Naidoo and says his commitment to getting better is uncharacteristic in South Africa. TB is particularly easy to contract among people who have compromised immune systems due to HIV infection—a group that makes up about 12 percent of the country's population.

"There's a co-infection problem with HIV—a lot of XDR patients also have HIV and have to take eight TB drugs in addition to their HIV retrovirals," he says. "The average uneducated person would be prone to giving up. There have been a number of suicides at King George V."

Partial treatment of TB is one of the most important causes of drug resistance, says Karin Weyer, coordinator of the World Health Organization's Stop TB department on drug resistance. Any time a patient stops treatment, surviving bacteria have already been exposed to some level of antibiotics and are more likely to be resistant if the patient relapses, she says.

"The most important aspect of this is that we get the patient cured the first time around," Weyer says. "Every time a patient has to get treated again, you run the risk of amplifying resistance."

That has led to the cases of totally drug-resistant tuberculosis (TDR) described in the Emerging Infectious Diseases journal. Paul van Helden, director of South Africa's Centre of Excellence for Biomedical TB Research and one of the authors of the study, says it was only a matter of time before tuberculosis developed resistances to the last remaining effective antibiotics. TDR has previously been found in India, Iran, and Italy, but appears to be most prevalent in South Africa.

"How long it's been out there is anyone's guess. We found nine cases in one small area; obviously it's something that's been out there for a while," he says.

Patients are rarely tested for a particular strain of tuberculosis, so it's unclear how prevalent TDR is worldwide. Major health organizations have yet to even define the parameters necessary for a case of tuberculosis to be considered TDR.

Bishai says van Helden's paper suggests that "TDR is extensive in South Africa."

"It's gone relatively unrecognized," he says. "This is evidence that it's emerged and is spreading—we're playing with fire here."

Drug-resistant TB isn't just a South African problem. In the early '90s, there was an outbreak of MDR in a New York City hospital. During that outbreak, 32 patients caught MDR over the course of a few months and 29 of them died. That outbreak was eventually controlled, but more than 100 cases of MDR have been detected in the United States over the past eight years, and there have been high-profile outbreaks in Peru, Russia, and India over the past decade.

Despite the high death rate during the New York City outbreak, public health officials were able to keep MDR from escaping into the general population, a task that took a concerted effort and many millions of dollars, van Helden says. South Africa, doesn't have that luxury.

"The fact that New York City managed the outbreak suggests we can contain it, but the cost was phenomenal," van Helden says. "We don't have the same resources as the U.S. South Africa is going to go through a lot of strain trying to combat this problem."

But while tuberculosis appears to be getting more nefarious by the year, Bishai and other experts are more optimistic about humanity's chances for fighting TB than they are about some other drug-resistant bacteria. Global TB rates have been declining for years, and in the most developed countries, there are very few tuberculosis deaths. In the United States, 529 people died of TB in 2009 (the most recent year for which data is available from the CDC). About 10,000 Americans contract the disease each year.

Today, 22 "high burden" countries (including South Africa) account for 80 percent of the world's TB cases, according to WHO. But the organization's most recent report notes that the "global burden of TB remains enormous." The disease killed 1.4 million people in 2011.Because of that burden, pharmaceutical companies are working on new drugs to treat it—which can't be said for some more innocuous bacteria that have developed drug resistances, such as gonorrhea.

In December, the FDA approved bedaquiline, the first new class of TB drug to be developed in more than 40 years. The drug will likely be approved in South Africa sometime this year. It's unclear whether the new drug will be effective against TDR, but scientists are optimistic.

Weyer says bedaquiline is a good start, but if more new drugs aren't quickly developed, TB will develop resistance to that drug as well.

"The only game-changing effects will happen once we have enough drugs to put completely new treatment regiments into use," she says. "It's encouraging we have a few drugs in the pipeline, but we need several new ones, with new mechanisms of action, to protect against new resistances."

In the meantime, researchers are working on getting better at identifying TDR, so doctors will know what they're up against if one of their patients has a highly resistant strain of TB. A lab can easily test whether a strain is resistant to the so-called "first line" of TB drugs, but detecting more highly resistant forms of the bacteria is more difficult.

"There are not yet accepted assays for detecting resistance against second-line drugs," van Helden says. Often, doctors will have to wait months to determine whether a patient is actually responding to treatment. That's what happened in Naidoo's case: For a while, he was taking drugs that weren't having any affect on his disease.

Today, Naidoo has permanent lung scarring, but he's otherwise healthy. The scars on his skin have begun to fade, and he recently started running again. He says the experience has allowed him to become a better TB doctor because he can empathize with patients. But many of his colleagues who have been infected as a result of their work have left the field.

"Doctors and nurses are exposed so routinely to sick patients," he says. "We put our lives at risk every day."