Charles: This is Charles Prober. Morgan: And Morgan Theis. Charles: And for this video, we're going to talk about resistance among TB infections, so resistance, drug resistance, a very important topic because it dramatically affects how we treat different patients. The timeline and the patient that Morgan has drawn is going to help us describe different scenarios about how to treat patients who have different kinds of TB in terms of the resistance pattern. This little person we've diagnosed as having a TB infection based upon their clinical presentation and some of the laboratory tests we did, which we talked about in another video. And when the patient starts their therapy, especially if they're in a developing world, where the Xpert RIF test is available - that's that molecular test that we described in another video that identifies that TB is present, it's on a molecular assay, and that that particular TB is resistant to rifampin. If that's the case, then that's going to immediately modify how we treat this patient with their TB infection. But let's assume that the expert test is negative. Morgan: OK. Charles: And we have a TB infection that we've diagnosed. We take cultures of the sputum, and we know that those cultures are going to come back in 4 weeks or 6 weeks. It takes a bit of time. Those cultures are also going to be tested. The bacteria are going to be tested for sensitivity to the antituberculose agents, but we're not going to have that information out for about 6 weeks, because that's how long it takes the TB to grow. Morgan: OK, so here's my little culture plate that's trying to grow out that sputum. Charles: Perfect. While we're waiting for the culture results and sensitivity testing to come back, we need to start therapy for this TB infection. The standard therapy is using all of the first-line drugs that you've listed in the top right-hand corner that we referred to before as RIPE: the rifampin, isoniazid, pyrazinamide, and ethambutol. Morgan: OK. Charles: The rifampin and isoniazid, or INH, are used for a full 6 months if this turns out to be a sensitive TB bug. They're both used for 6 months. The pyrazinamide and ethambutol are used for the first 2 months of that 6-month interval. That's the standard therapy. Now let's consider we've got the culture results that have come back from that sputum, and we're 6 weeks into this treatment, and we discover from those culture results that the organism, the TB, is resistant to one of our TB agents. The most common resistance would be to INH, but they can be resistant to any of the different first-line drugs. If the organism turns out to be resistant to INH, we will stop the INH because it won't do much good, and we'll either just continue the three drugs for a longer period of time or we may add a fluoroquinolone. If the TB turns out to be resistant to rifampin based upon that sensitivity testing, we'll stop the rifampin and may continue the other three drugs and maybe even add something like streptomycin. Morgan: So the idea here is that if whatever drug this particular TB organism is resistant to, you're going to stop using it, and you're going to continue with the other ones. You may consider adding a secondary drug, and you might consider a longer treatment. Charles: All correct, yes. Charles: So if the bugs are resistant, the TB is resistant to both INH and rifampin, the term that is used for that resistance is MDR, which stands for multiple drug-resistant TB. These are becoming increasingly important around the world. It turns out that the countries that have the most MDR isolates are five countries in the world, and those include China, India, Pakistan, the Russian Federation countries, and South Africa. That's only five countries, and they have the largest amount of MDR-TB. The final type of resistant TB that I would like to mention is called XDR-TB, which stands for extreme drug resistant. XDR-TB is less common than MDR-TB but more serious because it's harder to treat because they're resistant to multiple drugs that are either first-line anti-TB drugs or second-line, which you've also put in the right-hand corner of this picture. They're more difficult to treat, and in fact, the mortality rate for this XDR-TB is much higher. But let's assume that we do the sensitivity testing when the sputum comes back positive at 6 weeks or so and they turn out to be sensitive, and we're continuing on with just a standard RIPE therapy. But then as we're checking the sputum cultures, as we want to do on a regular basis, when you get out to 3 months, it turns out the sputum culture is still positive. It should not be still positive. You should have a negative sputum culture by about 2 months or so, or even earlier. Morgan: Right, because you've been treating the TB. Charles: Exactly. Morgan: OK. Charles: So if it's still positive, there is one or two possibilities. One is the TB has developed resistance to one of the anti-tuberculose agents, in which case, you'll have to modify therapy. And you'll know it's resistant because you tested sensitivity again. The other possibility is it's just a slow responder, that the patient continues to have positive sputums even though the bugs are sensitive, are killed by the antibiotics you're using, and it's just slow. Under either circumstance, therapy, you'll have to anticipate modifying therapy. If it's resistant, you'll change the anti-tuberculose agents and treat the patient longer. If it's sensitive, you'll just anticipate treating the patient longer than the standard 6 months. Then the final scenario that I would like to mention is all goes well for the 6 months of therapy. The patient's chest X-ray gets better. They look well, and you believe you have cured the infection. Morgan: OK, so here at 6 months ... Charles: All is good. Morgan: ... my patient is happy. Charles: Exactly. Morgan: And cured, supposedly. Charles: But the scenario that I'll now describe is several months or even years later, that happy patient becomes sad again because the patient has a relapse of the infection. The signs and symptoms of TB reappear. Now, that may be because the patient's initial infection was never completely eradicated and it just came back, or it may be that the patient acquired a new TB infection from somebody else, so it's a completely different TB infection, so it's not really relapse in that case. It's re-infection, but nonetheless, the symptoms have relapsed. Morgan: So how could you tell the difference? If a patient who was treated for their original TB then years later presented with TB again, how could you tell if it was a relapse of their original bug or a new infection with a new bug? Charles: That's a great question, and the only way you'd be able to tell the difference is if you had both TB bugs in your laboratory available to retest, and you can do molecular testing on the two bugs and see if their DNA is the same or different. If the DNA is the same, then it's a relapse because it's the same bug. If the DNA is different, then it's a reinfection. Morgan: Oh, great. So you really can figure that out. Charles: Exactly.