We are conducting a study to learn more about how lab test results can help the treatment of TB that cannot be treated by the most important TB medicines. Sometimes lab results show that a certain medicine will not treat the TB germs that a patient has, but another, very similar medicine will. When this happens, clinicians are not sure what to do. We have designed a study that will let us know if those similar medicines that seem to treat TB in the lab will work in real people.We are conducting a study to learn more about how lab test results can help the treatment of TB that cannot be treated by the most important TB medicines. Sometimes lab results show that a certain medicine will not treat the TB germs that a patient has, but another, very similar medicine will. When this happens, clinicians are not sure what to do. We have designed a study that will let us know if those similar medicines that seem to treat TB in the lab will work in real people. We are conducting a study to learn more about how lab test results can help the treatment of TB that cannot be treated by the most important TB medicines. Sometimes lab results show that a certain medicine will not treat the TB germs that a patient has, but another, very similar medicine will. When this happens, clinicians are not sure what to do. We have designed a study that will let us know if those similar medicines that seem to treat TB in the lab will work in real people. We are conducting a study to learn more about how lab test results can help the treatment of TB that cannot be treated by the most important TB medicines. Sometimes lab results show that a certain medicine will not treat the TB germs that a patient has, but another, very similar medicine will. When this happens, clinicians are not sure what to do. We have designed a study that will let us know if those similar medicines that seem to treat TB in the lab will work in real people. We are conducting a study to learn more about how lab test results can help the treatment of TB that cannot be treated by the most important TB medicines. Sometimes lab results show that a certain medicine will not treat the TB germs that a patient has, but another, very similar medicine will. When this happens, clinicians are not sure what to do. We have designed a study that will let us know if those similar medicines that seem to treat TB in the lab will work in real people. We are conducting a study to learn more about how lab test results can help the treatment of TB that cannot be treated by the most important TB medicines. Sometimes lab results show that a certain medicine will not treat the TB germs that a patient has, but another, very similar medicine will. When this happens, clinicians are not sure what to do. We have designed a study that will let us know if those similar medicines that seem to treat TB in the lab will work in real people. We are conducting a study to learn more about how lab test results can help the treatment of TB that cannot be treated by the most important TB medicines. Sometimes lab results show that a certain medicine will not treat the TB germs that a patient has, but another, very similar medicine will. When this happens, clinicians are not sure what to do. We have designed a study that will let us know if those similar medicines that seem to treat TB in the lab will work in real people. We are conducting a study to learn more about how lab test results can help the treatment of TB that cannot be treated by the most important TB medicines. Sometimes lab results show that a certain medicine will not treat the TB germs that a patient has, but another, very similar medicine will. When this happens, clinicians are not sure what to do. We have designed a study that will let us know if those similar medicines that seem to treat TB in the lab will work in real people. We are conducting a study to learn more about how lab test results can help the treatment of TB that cannot be treated by the most important TB medicines. Sometimes lab results show that a certain medicine will not treat the TB germs that a patient has, but another, very similar medicine will. When this happens, clinicians are not sure what to do. We have designed a study that will let us know if those similar medicines that seem to treat TB in the lab will work in real people. We are conducting a study to learn more about how lab test results can help the treatment of TB that cannot be treated by the most important TB medicines. Sometimes lab results show that a certain medicine will not treat the TB germs that a patient has, but another, very similar medicine will. When this happens, clinicians are not sure what to do. We have designed a study that will let us know if those similar medicines that seem to treat TB in the lab will work in real people.  

Protocol summary
Background: Multidrug-resistant (MDR) tuberculosis (TB) is defined by resistance to the two most important anti-TB drugs, isoniazid (INH) and rifampin (RIF). Without these first-line drugs, MDR TB must be treated with so-called second-line drugs (SLDs) that are less effective, more toxic, and more expensive. MDR TB is difficult to treat, requiring 20 months or more of at least four different drugs. Cure rates range from <50% to >75%, averaging 60%-65% (1,2). To cure more patients, decrease mortality, and prevent transmission to others, treatment should include at least four effective drugs based on timely drug susceptibility testing (DST). However, relatively few laboratories test SLDs, and ones that do usually test one representative drug from each category of closely related drugs because resistance to one is generally thought to confer resistance to the other(s). There are, however, many examples of closely related drugs with differing antimicrobial activities reflected in DSTs.

Laboratories have found differences in DST results among the rifamycins, RIF and rifabutin (RBT); the fluoroquinolones, ofloxacin and moxifloxacin; and the second-line injectable agents, kanamycin, amikacin, and capreomycin. In a related finding, isolates resistant to 0.2 mcg/ml INH, the worldwide standard, may be susceptible to INH at higher concentrations. Additionally, some laboratories have reported discrepancies between the results of genotypic testing for RIF resistance, performed using molecular technologies that identify mutations in the rpoB region of the Mycobacterium tuberculosis (M. tb) genome, and culture-based phenotypic testing for RIF resistance. In the Preserving Effective Tuberculosis Treatment Study (PETTS), 32% of rifampin-resistant isolates were susceptible to rifabutin, 41% of kanamycin-resistant isolates were susceptible to capreomycin, and 45% of isolates resistant to 0.2 mcg/ml isoniazid were susceptible to 1.0 or 5.0 mcg/ml. Other in vitro studies have demonstrated much lower inhibitory concentrations for moxifloxacin than for ofloxacin, suggesting very different breakpoints for resistance (3,4). Considering all 4 pairs, these situations are relatively common in MDR TB cases. Whether these in vitro results translate into clinical efficacy is completely unknown. At present, when the causative organism is resistant to one of a closely related group of antibiotics, there is no direct clinical evidence to support treating the patient with a different antibiotic from the same group when the isolate is susceptible in vitro to the different drug. Similarly, it is unknown if RIF retains its clinical efficacy when there is a discrepancy between genotypic markers and phenotypic susceptibility test results. Given the severely limited treatment options in MDR TB patients, it would be exceedingly useful to determine whether these in vitro results translate into evidence for clinically meaningful activity.