A phase IIb, open-label, randomized controlled dose ranging multi-centre trial to evaluate the safety, tolerability, pharmacokinetics and exposure-response relationship of different doses of delpazolid in combination with bedaquiline delamanid moxifloxacin in adult subjects with newly diagnosed, uncomplicated, smear-positive, drug-sensitive pulmonary tuberculosis.

BACKGROUND: Linezolid is an effective, but toxic anti-tuberculosis drug that is currently recommended for the treatment of drug-resistant tuberculosis. Improved oxazolidinones should have a better safety profile, while preserving efficacy. Delpazolid is a novel oxazolidinone developed by LegoChem Biosciences Inc. that has been evaluated up to phase 2a clinical trials. Since oxazolidinone toxicity can occur late in treatment, LegoChem Biosciences Inc. and the PanACEA Consortium designed DECODE to be an innovative dose-ranging study with long-term follow-up for determining the exposure-response and exposure-toxicity relationship of delpazolid to support dose selection for later studies. Delpazolid is administered in combination with bedaquiline, delamanid and moxifloxacin. METHODS: Seventy-five participants with drug-sensitive, pulmonary tuberculosis will receive bedaquiline, delamanid and moxifloxacin, and will be randomized to delpazolid dosages of 0 mg, 400 mg, 800 mg, 1200 mg once daily, or 800 mg twice daily, for 16 weeks. The primary efficacy endpoint will be the rate of decline of bacterial load on treatment, measured by MGIT liquid culture time to detection from weekly sputum cultures. The primary safety endpoint will be the proportion of oxazolidinone class toxicities; neuropathy, myelosuppression, or tyramine pressor response. Participants who convert to negative liquid media culture by week 8 will stop treatment after the end of their 16-week course and will be observed for relapse until week 52. Participants who do not convert to negative culture will receive continuation phase treatment with rifampicin and isoniazid to complete a six-month treatment course. DISCUSSION: DECODE is an innovative dose-finding trial, designed to support exposure-response modelling for safe and effective dose selection. The trial design allows assessment of occurrence of late toxicities as observed with linezolid, which is necessary in clinical evaluation of novel oxazolidinones. The primary efficacy endpoint is the change in bacterial load, an endpoint conventionally used in shorter dose-finding trials. Long-term follow-up after shortened treatment is possible through a safety rule excluding slow-and non-responders from potentially poorly performing dosages. TRIAL REGISTRATION: DECODE was registered in ClinicalTrials.gov before recruitment start on 22 October 2021 (NCT04550832).

Delamanid in the treatment of multidrug-resistant tuberculosis.

Otsuka has been engaged in anti-tuberculosis drug development efforts for over 30 years, and is the leading private sector funder of tuberculosis (TB) research and development. Delamanid (DLM), discovered by Otsuka's scientists, has been shown to provide benefit with respect to short-term surrogate markers and long-term treatment outcomes, and it has received regulatory approval for treatment of adult pulmonary multidrug-resistant TB (MDR-TB) as one of only two new anti-tuberculosis drugs in the last 40 years. Lack of drug-drug interactions with major antiretrovirals and efficacy against MDR-TB allow DLM's applicability in a wide range of MDR-TB patients. Current and future efforts are focused on replacing less safe and less efficacious second-line drugs with DLM, its contribution to all-oral and/or shortened treatment regimens, and, ultimately, inclusion in a pan-TB regimen. This manuscript provides a brief review of DLM.

Tuberculosis case finding for vaccine trials in young children in high-incidence settings: a randomised trial.

SETTING: A high tuberculosis (TB) burden rural area in South Africa. OBJECTIVE: To compare TB case yield and disease profile among bacille Calmette-Guérin (BCG) vaccinated children using two case-finding strategies from birth until 2 years of age. DESIGN: BCG-vaccinated infants were enrolled within 2 weeks of birth and randomised to 3-monthly home visits for questionnaire-based TB screening plus record surveillance of TB registers, hospital admission and X-ray lists at health facilities for TB suspects and cases (Group 1), or record surveillance (as above) only (Group 2). Both groups received a close-out visit after 2 years. Participants were evaluated for suspected TB disease using standardised investigations. RESULTS: A total of 4786 infants were enrolled: 2392 were randomised to Group 1 and 2394 to Group 2. The case-finding rate was significantly greater in Group 1 (2.2/100 py) than in Group 2 (0.8/100 py), with a case-finding rate ratio of 2.6 (95%CI 1.8-4.0, P < 0.001). Although the proportion of cases with bacteriological confirmation was lower in Group 1, this difference did not reach statistical significance. There was also no significant difference in the proportions with TB symptoms and signs. CONCLUSION: Home visits combined with record surveillance detected significantly more cases than record surveillance with a single study-end visit. The TB case profile did not differ significantly between the two groups.

Early bactericidal activity of delamanid (OPC-67683) in smear-positive pulmonary tuberculosis patients.

BACKGROUND: Delamanid (OPC-67683) is a novel mycolic acid biosynthesis inhibitor active against Mycobacterium tuberculosis at a low minimum inhibitory concentration. METHODS: Forty-eight patients with smear-positive tuberculosis (63% male; 54.7 ± 9.9 kg; 30.7 ± 10.8 years) were randomly assigned to receive delamanid 100, 200, 300 or 400 mg daily for 14 days. Colony forming units (cfu) of M. tuberculosis were counted on agar plates from overnight sputum collections to calculate early bactericidal activity (EBA), defined as fall in log(10) cfu/ml sputum/day. RESULTS: The EBA of delamanid was monophasic and not significantly different between dosages; however, more patients receiving 200 mg (70%) and 300 mg (80%) experienced a response of ≥0.9 log(10) cfu/ml sputum decline over 14 days than those receiving 100 mg (45%) and 400 mg (27%). The average EBA of all dosages combined (0.040 ± 0.056 log(10) cfu/ml sputum/day) was significant from day 2 onward. Delamanid exposure was less than dosage-proportional, reaching a plateau at 300 mg, likely due to dose-limited absorption. Moderate but significant correlation was found between C(max) and EBA, indicating exposure dependence. Delamanid was well tolerated without significant toxicity. CONCLUSIONS: Delamanid at all dosages was safe, well tolerated and demonstrated significant exposure-dependent EBA over 14 days, supporting further investigation of its pharmacokinetics and anti-tuberculosis activity.

Predictive factors for latent tuberculosis infection among adolescents in a high-burden area in South Africa.

SETTING: A high tuberculosis (TB) burden area in South Africa (notification rate for all TB cases 1400 per 100 000 population). OBJECTIVE: To determine the prevalence of and predictive factors associated with latent TB infection in adolescents. DESIGN: Adolescents aged 12-18 years were recruited from high schools, clinical and demographic data were collected, and a tuberculin skin test (TST) and a QuantiFERON®-TB Gold In-Tube (QFT) assay performed. RESULTS: A total of 6363 (58.2%) of 10 942 adolescents at the schools were enrolled. After exclusions, of 5244 participants, 55.2% (95%CI 53.8-56.5) had TST ≥ 5 mm, while 50.9% (49.5-52.2) were QFT-positive. On multivariate analysis, Black/mixed race racial groups, male sex, older age, household TB contact, low income and low education level were predictive factors for both TST- and QFT-positive results. CONCLUSION: About half of the adolescents were found to be latently infected with TB in a high TB burden area with demographic and poverty-related socio-economic factors predicting the risk of TB infection. Adolescents from deprived communities should be considered an important target group for educational interventions by TB control programmes in high-burden settings.

Induced sputum or gastric lavage for community-based diagnosis of childhood pulmonary tuberculosis?

OBJECTIVES: To compare the diagnostic yield of Mycobacterium tuberculosis from induced sputum (IS) and gastric lavage (GL) among children in a community setting. METHODS: Specimen-collection methods for bacteriological confirmation of pulmonary tuberculosis (PTB) were compared during a tuberculosis vaccine trial near Cape Town, South Africa (2001-2006). Children with a tuberculosis contact or compatible symptoms were investigated for suspected PTB. Diagnostic yields from 764 paired IS and GL specimens were compared in 191 culture-confirmed cases. MEASUREMENTS AND MAIN RESULTS: The crude yield of M tuberculosis was 10.4%, n = 108 by IS (5.8%) and n = 127 by GL (6.8%), from a total of 194 cases, of which three had incomplete IS/GL specimen pairs. Agreement between IS and GL was poor (kappa = 0.31). The comparative yield of a single IS sample (38%) was equivalent to a single GL sample (42%), with a difference in yield of -4% (95% CI -15% to +7%). The combined yield of same-day IS and GL specimens (67%) was equivalent to two consecutive GL specimens (66%), with a difference in yield of 1% (95% CI -9% to 11%), but significantly greater than two consecutive IS specimens (55%), with a difference in yield of 12% (95% CI 2% to 21%). The adjusted odds of a M tuberculosis culture were increased by a positive tuberculin skin test or chest radiograph compatible with PTB. CONCLUSIONS: In this community setting, the diagnostic yield of a single IS sample was equivalent to that of a single GL sample. The optimal diagnostic yield may be obtained from paired IS and GL specimens taken on a single day or two GL specimens taken on consecutive days.

Comparison of mantoux skin test with three generations of a whole blood IFN-gamma assay for tuberculosis infection.

SETTING: A rural town in South Africa. OBJECTIVE: To compare the performance of Quanti-FERON assays with the tuberculin skin test (TST) for identifying latent tuberculosis infection (LTBI) in a high TB burden community. DESIGN: In a cross-sectional study in healthy adults, we applied the TST and took blood for the three generations of QuantiFERON assays. RESULTS: Of 358 participants whose results were analysed, 291 (81%) had a TST result of > or = 10 mm induration, and 187 (52%) > or = 15 mm. QuantiFERON-TB was positive in 215 (60%), QuantiFERON-TB Gold in 137 (38%), and QuantiFERON-TB Gold (In-Tube method) in 201 (56%). There was poor agreement between TST and QuantiFERON tests, and between the different generations of QuantiFERON tests (kappa = 0.12-0.50). Of the subset with TST indurations > or = 15 mm, 30-56% had negative QuantiFERON tests. However, positive Quanti-FERON tests were associated with males, who have a higher incidence of TB in this area. CONCLUSION: We showed poor agreement between TST and the different QuantiFERON tests in diagnosing LTBI. The surprising discordance between the Quanti-FERON TB Gold and QuantiFERON TB Gold (In-Tube method) tests needs to be investigated further.

Acceptability of short-course rifampin and pyrazinamide treatment of latent tuberculosis infection among jail inmates.

STUDY OBJECTIVES: To determine whether short-course treatment of latent tuberculosis infection (LTBI) with 2 months of rifampin and pyrazinamide (2RZ) is well tolerated and leads to increased treatment completion among jail inmates, a group who may benefit from targeted testing and treatment for LTBI but for whom completion of > or = 6 months of isoniazid treatment is difficult because of the short duration of incarceration. DESIGN: Prospective cohort. SETTING: Large, urban county jail. PATIENTS: All inmates admitted to the Fulton County Jail who had positive tuberculin skin test results, normal findings on chest radiography, and expected duration of incarceration of at least 60 days. INTERVENTION: Inmates were offered 2RZ via daily directly observed therapy for 60 doses as an alternative to isoniazid therapy. MEASUREMENTS AND RESULTS: We measured the completion of 2RZ treatment and toxicity due to 2RZ treatment during incarceration. From December 14, 1998, through December 13, 1999, 1,360 new inmates had positive tuberculin skin test results and normal findings on chest radiography, and 168 new inmates had an expected duration of incarceration of > or = 60 days. One hundred sixty-six inmates (> 99%) were HIV-negative. Eighty-one inmates (48%) completed 60 doses of 2RZ treatment while incarcerated. Seventy-four inmates (44%) were released before completion. Treatment was stopped in 1 inmate (< 1%) for asymptomatic elevation of asparginine aminotransferase (> or = 10 times normal) and in 12 inmates (7%) for minor complaints. Twenty-one inmates had completed isoniazid treatment in the year before the availability of 2RZ, and 9 inmates completed isoniazid treatment in the year during the availability of 2RZ. CONCLUSIONS: 2RZ was acceptable to and well tolerated by inmates, and led to a marked increase in the number of inmates completing treatment of LTBI during incarceration.

Antituberculosis activity of once-weekly rifapentine-containing regimens in mice. Long-term effectiveness with 6- and 8-month treatment regimens.

The effectiveness of various once-weekly 10 mg/kg rifapentine (P)- containing regimens for treatment of tuberculosis was assessed in mice infected intravenously with 4.3 x 10(6) colony-forming units (cfu) of Mycobacterium tuberculosis H37Rv, and treated 14 d later with various combinations of rifampin (R), P, isoniazid (H), pyrazinamide (Z), ethambutol (E), or streptomycin (S). Control mice treated daily with either 2-mo HRZ + 4-mo HR or 2-mo HRZ + 6-mo HE were rendered spleen and lung culture-negative at 6 mo and 8 mo, respectively. Treatment failure with emergence of R-resistant bacilli occurred in all mice given once-weekly monotherapy with P for 6 mo. Once-weekly PH treatment was successful at 6 mo when it was preceded by a 2-mo daily phase with HRZ. When the initial daily phase was reduced to 2 wk, once-weekly PH-containing treatment was successful, at 6 mo, only if it was supplemented with S during the initial daily and the once-weekly phases, and at 8 mo if it was supplemented with daily H during the once-weekly phase. Without these supplements, once-weekly treatment failed in some mice with selection of R-resistant or H-resistant mutants.

A model of the cost-effectiveness of directly observed therapy for treatment of tuberculosis.

A hypothetical cohort of 25,000 TB patients and their contacts were followed for a 10-year period; rates of treatment default, infectiousness following partial treatment, relapse, hospitalization, and development of drug-resistant TB were included. The average cost per case cured was $16,846 with 15% of patients starting DOT, $17,323 with 100% starting DOT, and $20,106 with none starting DOT. The incremental cost per additional case cured was $24,064 when all patients, started treatment on DOT, indicating that outpatient DOT provides a cost-effective method of improving health outcomes for TB patients and their contacts while controlling direct costs.

Randomised trial of isoniazid versus rifampicin and pyrazinamide for prevention of tuberculosis in HIV-1 infection.

BACKGROUND: Tuberculosis is a common complication of HIV-1 infection, especially in developing countries. Practical and effective chemoprophylaxis regimens for HIV-1-related tuberculosis are needed. Our aim was to test the efficacy of isoniazid versus rifampicin with pyrazinamide for prevention of tuberculosis in HIV-1-positive individuals. METHODS: We compared the efficacy of 6 months of isoniazid with 2 months of rifampicin and pyrazinamide for prevention of tuberculosis in HIV-1-seropositive individuals. Eligible participants were aged 16-77 years, HIV-1 seropositive, had a positive purified-protein derivative (PPD) skin test reaction of at least 5 mm, and had a normal chest radiograph. Participants were randomly assigned partially supervised twice weekly isoniazid for 24 weeks or twice weekly rifampicin and pyrazinamide for 8 weeks. Participants were followed up for up to 4 years for the development of tuberculosis and survival. FINDINGS: Tuberculosis developed in 14 (3.8%) of 370 participants assigned isoniazid and 19 (5.0%) of 380 participants assigned rifampicin and pyrazinamide (Cox model rate ratio 1.3 [95% CI 0.7-2.7]). The Kaplan-Meier estimate of the risk of tuberculosis during the first 10 months after entry was 3.7% among participants who received rifampicin and pyrazinamide compared with 1.0% (p=0.03) among participants who received isoniazid, and 5.4% versus 5.1%, respectively (p=0.9) at 36 months after entry. Higher rates of tuberculosis were observed in people with baseline CD4 percentages (of total lymphocytes) of less than 20 (rate ratio 4.0 [95% CI 1.8-9.0]). There were no significant differences in total mortality at any time. INTERPRETATION: Twice-weekly isoniazid preventive therapy for 6 months or rifampicin and pyrazinamide for 2 months provided similar overall protection against tuberculosis in HIV-1-infected, PPD-positive adults. The better protection among recipients of isoniazid during the first 10 months was most likely secondary to the longer duration of chemoprophylaxis. Preventive therapy for HIV-1-seropositive, PPD-positive individuals could be practical in developing countries with a once weekly clinic visit, but optimum duration of chemoprophylaxis has not been determined.

Rifampin preventive therapy for tuberculosis infection: experience with 157 adolescents.

For persons infected with Mycobacterium tuberculosis resistant to isoniazid (INH), rifampin is recommended for the prevention of active disease. However, the adverse effects and acceptability of this preventive therapy are largely uncharacterized. We prospectively followed 157 high-school students exposed to, and probably infected with, M. tuberculosis strains resistant to INH. All 157 students were prescribed preventive therapy with rifampin (10 mg/kg up to 600 mg daily) for 24 wk. While receiving therapy, 41 (26%) reported one or more adverse effects; of these, 18 had therapy interrupted temporarily, two permanently. Four (2.5%) had alanine aminotransferase elevations greater than two times the upper limit of normal (range, 91 to 161 U/L); of these, one had therapy permanently stopped. Six (3.8%) self-discontinued therapy. No student was found to have active disease during the 2 yr of the study (exact 95% upper confidence limit, 2.2). We assumed that without preventive therapy, seven cases of tuberculosis would have occurred during these 2 yr. Therefore, we estimated that rifampin had a minimum protective effect of 56%. In conclusion, preventive therapy with rifampin was well tolerated and well accepted, and it appears effective in preventing active tuberculosis.

Can physicians treat tuberculosis? Report on a national survey of physician practices.

OBJECTIVES: Researchers examined physicians' treatment strategies for tuberculosis to determine whether they would follow recommendations of the Centers for Disease Control and Prevention and the American Thoracic Society. METHODS: A national survey sampled 1772 physicians. Analyses tested correlates of recommended treatment regimens. RESULTS: Among respondents, 59.4% described a recommended regimen. Specialists; physicians aware of professional publications, treatment recommendations, and reporting requirements; and those having more than 50% of patients in nursing homes were more likely to describe recommended regimens. Physicians who had been in practice longer, relied on personal experience, or had more than 50% of patients receiving Medicaid were less likely to describe recommended regimens. CONCLUSIONS: Physicians who treat tuberculosis require training and support. Policymakers should consider who should treat tuberculosis and how recommended practice should be ensured.

Widespread HIV counseling and testing linked to a community-based tuberculosis control program in a high-risk population.

The aim of the work reported here was to evaluate community-wide screening for HIV infection that was linked to a tuberculosis control program in a population at high risk for both infections. Between May 1990 and August 1992, adults in Cité Soleil, Haiti, were recruited by community health workers at their homes and in clinics for individual, clinic-based counseling and testing for HIV and tuberculosis. All of the screened subjects were offered post-test HIV counseling. Those with active tuberculosis received treatment, while those with latent tuberculosis and HIV infection were offered an opportunity to participate in a trial of antituberculosis chemoprophylaxis. The 10,611 individuals screened for HIV represented 10.0% of the adult population in Cité Soleil. HIV infection was detected in 1,629 (15.4%) and active tuberculosis in 242 (2.3%). Latent M. tuberculosis infection was found in 4,800 (67.5%) of 7,309 community residents who completed tuberculosis screening, 781 (16.3%) of whom were coinfected with HIV. The high prevalence of HIV infection found in this screened population, as compared to other groups undergoing HIV screening in the same community, suggests that people at high risk for HIV infection selectively sought or accepted tuberculosis clinic screening. Also, many people with active tuberculosis were identified earlier in the course of their disease than they would have been in the absence of a screening program. Overall, the results indicate that community-based screening for HIV infection within a tuberculosis control program can result in effective targeting of screening for both infections.

PIP: Findings are reported from an evaluation of community-wide screening for HIV infection linked to a tuberculosis (TB) control program in a population at high risk for both infections. Between May 1990 and August 1992, adults in Cite Soleil, Haiti, were recruited by community health workers at their homes and in clinics for individual, clinic-based counseling and testing for HIV and TB. All screened subjects were offered post-test HIV counseling. Those with active TB received treatment, while those with latent TB and HIV infection were offered an opportunity to participate in a trial of anti-TB chemoprophylaxis. The 10,611 individuals screened for HIV represented 10.0% of the adult population in Cite Soleil. HIV infection was detected among 1629 (15.4%) and active TB in 242 (2.3%). Latent M. tuberculosis infection was found in 4800 (67.5%) of 7309 community residents who completed TB screening, 781 (16.3%) of whom were coinfected with HIV. The high prevalence of HIV infection in this screened population, compared to other groups screened in the same community, suggests that people at high risk for HIV infection selectively sought or accepted TB clinic screening. Also, many people with active TB were identified earlier in the course of their disease than they would have been in the absence of a screening program. Overall, these results indicate that community-based screening for HIV infection within a TB control program can result in the effective targeting of screening for both infections.

[Compliance and tolerance of new antitubercular short-term chemopreventive regimens in childhood--a pilot project]. / Compliance und Toleranz neuer antituberkulotischer Kurzzeit-Chemopräventionsregime im Kindesalter--eine Pilotstudie.

Efficacy of preventive chemotherapy in tuberculosis-infected children depends to a great extend on medical compliance and drug tolerability. Two new short-course chemoprevention-regimes of tuberculosis--four months Rifampin (A) and two months Rifampin plus Pyrazinamide (B)--were compared with the well established regimen of six months Isoniacid (C). 150 children (mean age 3.6 years with Tb conversion) were randomly allocated to these three regimens. 13 patients were non-compliant, in terms of interview, urinary INH-test strips, urine colour and prescription frequency: 7 in group C and 3 in group A and B, respectively. Adverse effects were observed in 5 patients: 3 in group C and 1 in group A and B. 1 child (group B) developed tuberculosis two years after stopping short course chemoprevention. Good compliance (94%) as well as neglectable risks of adverse effects (2%) justify further controlled studies to evaluate the efficacy of short course chemoprevention in childhood.

Purified protein derivative tuberculin and delayed-type hypersensitivity skin testing in migrant farm workers at risk for tuberculosis and HIV coinfection.

OBJECTIVE: To assess the joint use of purified protein derivative (PPD) and delayed-type hypersensitivity (DTH) antigens in screening individuals of unknown HIV serostatus for tuberculosis (TB) preventive therapy eligibility. DESIGN: Population-based survey. METHODS: A group of migrant farm workers were screened for HIV and skin-tested with PPD, tetanus toxoid (TET), Candida albicans (CAN) and mumps (MUM) antigens by the Mantoux method. Anergy was defined as a < or = 2 mm reaction to all four antigens. Eligibility for preventive therapy was defined as a reaction of > or = 5 mm to PPD among HIV-seropositive individuals, > or = 10 mm among HIV-seronegatives, or anergy. RESULTS: A total of 253 out of 271 individuals had sufficient data for analysis. Of these, 15 (5%) were HIV-seropositive; 183 (75%), 175 (72%) and 157 (65%) reacted to TET, CAN, and MUM, respectively, and 113 (47%) were eligible for preventive therapy [108 (44%) PPD-positive, five (2%) anergic]. Use of PPD alone was 95% sensitive for detecting preventive therapy eligibility; PPD plus one DTH antigen was more sensitive (99%) but less specific (range, 69-85%); PPD plus two DTH antigens was most specific (CAN + MUM, 84%; TET + MUM, 93%; and TET + CAN, 100%). CONCLUSIONS: In this population with 5% HIV seroprevalence, testing for anergy did not significantly increase the detection of preventive therapy eligibility. The use of two DTH antigens is very sensitive and specific. These results support the recommendation of joint PPD and anergy testing for the screening of HIV-seropositive individuals. Our data also suggest, however, that for individuals whose HIV serostatus is unknown, anergy testing should be considered as a screening tool only if the prevalence of anergy is expected to exceed the prevalence of PPD positivity.

Nosocomial outbreak of tuberculosis in a renal transplant unit: application of a new technique for restriction fragment length polymorphism analysis of Mycobacterium tuberculosis isolates.

From January 1990 through February 1991, tuberculosis (TB) developed in 10 renal transplant (RT) patients at one hospital; 5 patients died. Possible nosocomial transmission was investigated. Mycobacterium tuberculosis isolates were compared by restriction fragment length polymorphism (RFLP) by a polymerase chain reaction method. The source case occurred in an RT patient (source) who had posttransplant exposure to TB at another hospital. The source patient was rehospitalized on the RT unit; diagnosis of TB and thus isolation precautions were delayed. Epidemiologic and RFLP analysis showed transmission from the source to 5 RT patients and 1 human immunodeficiency virus-infected patient. M. tuberculosis isolates from 4 RT patients had other RFLP patterns. The median incubation period for TB in RT patients was 7.5 weeks (range, 5-11). Bronchoscopy and intubation of the source patient and inadequate ventilation on the RT unit possibly increased transmission. Early detection of TB and effective isolation are essential to prevent nosocomial transmission.

The multidrug-resistant tuberculosis challenge to public health efforts to control tuberculosis.

After years of steady decline, there has been an unprecedented resurgence of tuberculosis (TB) in the United States and outbreaks of multidrug-resistant tuberculosis (MDR-TB). The authors assess the nature, epidemiology, and implications of MDR-TB; provide suggestions for preventing drug resistance among patients with drug-susceptible TB; and offer recommendations for managing patients with MDR-TB. They outline the National Action Plan to Combat MDR-TB. Close collaboration among medical practitioners and staff members of TB control programs is needed to ensure the most effective management of patients with TB and their contacts. This collaboration is one of the most important steps for successful control of MDR-TB.