Diagnosis, treatment, and prevention of drug-resistant tuberculosis

Official reprint from UpToDate

®

www.uptodate.com

Back | Print

Diagnosis, treatment, and prevention of drug-resistant tuberculosis Author Neil W Schluger, MD

Section Editor C Fordham von Reyn, MD

Deputy Editor Elinor L Baron, MD, DTMH

Last literature review version 19.1: January 2011 | This topic last updated: January 6, 2011 (More) INTRODUCTION — Tuberculosis remains one of the leading causes of morbidity and mortality throughout the world. Its management has become more complex because of increased resistance to commonly used antituberculosis drugs. (See "Epidemiology and molecular mechanisms of drug-resistant tuberculosis".) The diagnosis and therapy of patients infected with drug-resistant strains of M. tuberculosis will be reviewed here. Prevention and chemoprophylaxis of drug-resistant tuberculosis is covered briefly; the treatment of nonresistant tuberculosis is discussed in more detail elsewhere. (See "Treatment of tuberculosis in HIV-negative patients" .) Treatment of drug-resistant tuberculosis can be difficult, and may necessitate the use of second-line drugs or resectional surgery. Therefore, management of patients with resistant disease should only be undertaken by, or in very close consultation with, experts in this area. Good patient outcomes depend upon a rapid and accurate diagnosis, and the institution, administration, and monitoring of proper therapy [1]. DEFINITIONS — The different types of drug-resistant tuberculosis are defined as follows [ 2]: Drug-resistant tuberculosis refers to M. tuberculosis that is resistant to one of the first-line antituberculosis drugs: isoniazid, rifampin, pyrazinamide, or ethambutol. Multidrug-resistant tuberculosis (MDR-TB) refers to M. tuberculosis that is resistant to at least isoniazid and rifampin, and possibly additional chemotherapeutic agents. Extensively drug-resistant tuberculosis (XDR-TB) refers to M. tuberculosis that is resistant to at least isoniazid and rifampin (as in MDR-TB) and is also resistant to fluoroquinolones and either aminoglycosides ( amikacin, kanamycin) or capreomycin, or both. "Primary" resistance refers to drug resistance in a patient who has never received antituberculosis therapy. "Secondary" resistance refers to the development of drug resistance during or following chemotherapy for previously drug-susceptible tuberculosis. DIAGNOSIS — The presenting clinical and radiographic features of drug-resistant tuberculosis are comparable with drug-susceptible disease. While drug susceptibility data are pending, a careful history must be obtained before treatment begins for any clues that drug resistance may be an issue of concern. All patients with suspected or confirmed TB should be offered voluntary counseling and testing for HIV. (See "Epidemiology, clinical manifestations, and diagnosis of tuberculosis in HIV-infected patients" and "Treatment of pulmonary tuberculosis in the HIV-infected patient".) History — Demographic and historical features that should raise the suspicion of drug-resistant tuberculosis include [3-5]: Previous treatment for active tuberculosis, particularly if therapy was self-administered Tuberculosis treatment failure or relapse in a patient with advanced HIV infection who was treated with an intermittent anti-TB regimen Acquisition of tuberculosis in a region with known high rates of drug resistance, such as Russia, Kazakhstan, Tajikistan, and others Contact with a patient with drug-resistant tuberculosis Failure to respond to empiric therapy, particularly if adherence to therapy has been documented Multiple courses of fluoroquinolone therapy for treatment of symptoms consistent with community-acquired pneumonia later proven to be tuberculosis In cases in which prior antituberculosis therapy has been prescribed, the clinician must obtain a complete record of all previous cultures, drug susceptibility testing results, and treatment. Culture and sensitivity — The diagnosis of drug-resistant tuberculosis has traditionally been dependent on the collection and processing of adequate specimens for culture and sensitivity testing prior to the institution of therapy [ 6]. Sputum cultures are positive in 85 to 90 percent of cases of pulmonary tuberculosis, and every attempt should be made to collect adequate material before treatment is initiated. If a patient cannot produce an expectorated sputum sample, sputum induction should be performed. If an adequate sample is still not produced, bronchoscopy may provide diagnostic material for culture in a significant number of cases, although the risks of nosocomial transmission of potentially drug-resistant tuberculosis must be weighed against the benefits of the procedure [7]. The absence of conversion of a positive to a negative smear during treatment is a potentially useful marker for suspect drug resistance. However, smear conversion is not always a useful determining factor for identifying patients with MDR-TB. In one study of 93 adults in Peru, persistent 60 day smear positivity had a positive predictive value for detecting multidrug resistance of 67 percent

[8]. Restricting drug susceptibility testing to those who continue to be smear positive after a trial of first-line therapy is unlikely to decrease the transmission of MDR-TB in the community. In patients with exclusively extrapulmonary disease, samples of involved tissue (eg, lymph nodes, bone, blood) should be obtained for culture and sensitivity testing as well as pathology. Susceptibility testing for first- and second-line agents should be performed at a reliable reference laboratory. Improvements in culture techniques and molecular diagnosis (eg, nucleic acid amplification assays) permit more rapid identification of antibiotic resistance than was possible when solid medium alone was used for mycobacterial growth [ 9-11]. (See "Diagnosis of tuberculosis in HIV-negative patients", section on 'Nucleic acid amplification'.) Rapid testing Nucleic acid tests — Rapid testing using molecular techniques can speed the diagnosis and control of MDR-TB infection: The assay GeneXpert MTB/RIF is an automated nucleic acid amplification test for M. tuberculosis and rifampin resistance (rpoB gene). In a study including 1730 patients with suspected tuberculosis, the test correctly identified 98 percent of patients with smear positive tuberculosis and 72 percent of patients with smear negative/culture positive tuberculosis [ 12]. The accuracy for identification of rifampin resistance was 98 percent. The assay is simple to perform with minimal training, is not prone to cross-contamination, and requires minimal biosafety facilities. Results are available in two hours. The assay MTBDRplus is a molecular probe capable of detecting rifampin and isoniazid resistance mutations (rpoB gene for rifampin resistance; katG and inhA genes for isoniazid resistance) [13]. In an evaluation of 536 smear positive specimens from patients at risk for MDR-TB in South Africa, the molecular probe was ≥99 percent sensitive and specific for multidrug TB resistance compared with standard drug susceptibility testing; results were available in 1 to 2 days. Since the assay does not depend on culture, it yielded results even in specimens that were contaminated or had no growth. Molecular testing was successful even when the AFB smear was negative. Direct DNA sequencing analysis of sputum specimens is also a useful method for detection of drug-resistant TB, and results may be available in four days [ 14]. While these assays hold promise for the early and rapid detection of drug resistance, limitations of these tests include cost, identification of only rifampin or isoniazid resistance, and inability to identify which patients are “sputum smear positive” for infection control and treatment monitoring purposes. Culture based tests — Microscopic observation drug susceptibility (MODS) and thin layer agar (TLA) are tests in which drug-free and drug-containing media (liquid for MODS, solid for TLA) are inoculated with patient specimens and cultures are microscopically examined for early growth [ 15]. Growth of M. tuberculosis in or on a drug-free media indicates a positive culture, whereas growth in or on both drug-free and drug-containing media indicates resistance. MODS is faster than automated liquid culture (results can be available in as little as seven days) and can be used in smear-positive and smear-negative cases. The WHO has recommended that MODS be used as an interim diagnostic tool while the capacity for other tools, including drug susceptibility and automated liquid culture, are developed. CHEMOTHERAPY OF MONORESISTANT DISEASE — Effective therapy for drug sensitive and isoniazid monoresistant tuberculosis is associated with very high (>95 percent) success rates, defined by bacteriologic and clinical response, and low relapse rates (70 to 80 percent protective when given to children, and is most useful in preventing meningitis and disseminated disease. Efficacy in persons first immunized as adults is expected to be substantially lower [87]. Use of the BCG vaccine for the prevention of MDR-TB is not well established and should be employed only as a measure of last resort, since the ability to perform screening tuberculin examinations will be lost after the vaccine is administered. (See "BCG vaccination".) In the United States, federal authority can also issue regulations to prevent the introduction, transmission, or interstate spread of communicable diseases; infectious TB is deemed a quarantinable disease [ 88]. Use of UpToDate is subject to the Subscription and License Agreement

REFERENCES 1.

Goble M, Iseman MD, Madsen LA, et al. Treatment of 171 patients with pulmonary tuberculosis resistant to isoniazid and rifampin. N Engl J Med 1993; 328:527.

2.

WHO. Laboratory XDR-TB definitions. Geneva: Meeting of the global XDR TB task force 2006.

3.

Wright A, Zignol M, Van Deun A, et al. Epidemiology of antituberculosis drug resistance 2002-07: an updated analysis of the Global Project on Anti-Tuberculosis Drug Resistance Surveillance. Lancet 2009; 373:1861.

4.

Long R, Chong H, Hoeppner V, et al. Empirical treatment of community-acquired pneumonia and the development of fluoroquinolone-resistant tuberculosis. Clin Infect Dis 2009; 48:1354.

5.

http://www.who.int/tb/publications/global_report/2009/update/en/index.html.

6.

Diagnostic Standards and Classification of Tuberculosis in Adults and Children. This official statement of the American Thoracic Society and the Centers for Disease Control and Prevention was adopted by the ATS Board of Directors, July 1999. This statement was endorsed by the Council of the Infectious Disease Society of America, September 1999. Am J Respir Crit Care Med 2000; 161:1376.

7.

Schluger NW, Rom WN. Current approaches to the diagnosis of active pulmonary tuberculosis. Am J Respir Crit Care Med 1994; 149:264.

8.

Fitzwater SP, Caviedes L, Gilman RH, et al. Prolonged infectiousness of tuberculosis patients in a directly observed therapy short-course program with standardized therapy. Clin Infect Dis 2010; 51:371.

9.

Heifets L. Mycobacteriology laboratory. Clin Chest Med 1997; 18:35.

10. Telenti A, Imboden P, Marchesi F, et al. Direct, automated detection of rifampin-resistant Mycobacterium tuberculosis by polymerase chain reaction and single-strand conformation polymorphism analysis. Antimicrob Agents Chemother 1993; 37:2054. 11. Williams DL, Spring L, Gillis TP, et al. Evaluation of a polymerase chain reaction-based universal heteroduplex generator assay for direct detection of rifampin susceptibility of Mycobacterium tuberculosis from sputum specimens. Clin Infect Dis 1998; 26:446. 12. Boehme CC, Nabeta P, Hillemann D, et al. Rapid molecular detection of tuberculosis and rifampin resistance. N Engl J Med 2010; 363:1005. 13. Barnard M, Albert H, Coetzee G, et al. Rapid molecular screening for multidrug-resistant tuberculosis in a high-volume public health laboratory in South Africa. Am J Respir Crit Care Med 2008; 177:787. 14. Choi JH, Lee KW, Kang HR, et al. Clinical efficacy of direct DNA sequencing analysis on sputum specimens for early detection of drug-resistant Mycobacterium tuberculosis in a clinical setting. Chest 2010; 137:393. 15. Minion J, Leung E, Menzies D, Pai M. Microscopic-observation drug susceptibility and thin layer agar assays for the detection of drug resistant tuberculosis: a systematic review and meta-analysis. Lancet Infect Dis 2010; 10:688. 16. Prevention and treatment of tuberculosis among patients infected with human immunodeficiency virus: principles of therapy and revised recommendations. Centers for Disease Control and Prevention. MMWR Recomm Rep 1998; 47:1. 17. Cattamanchi A, Dantes RB, Metcalfe JZ, et al. Clinical characteristics and treatment outcomes of patients with isoniazid-monoresistant tuberculosis. Clin Infect Dis 2009; 48:179. 18. Five-year follow-up of a controlled trial of five 6-month regimens of chemotherapy for pulmonary tuberculosis. Hong Kong Chest Service/British Medical Research Council. Am Rev Respir Dis 1987; 136:1339. 19. Clinical policies and protocols. Chest Clinics, Bureau of Tuberculosis Control, New York City Department of Health. 20. Dorman SE, Johnson JL, Goldberg S, et al. Substitution of moxifloxacin for isoniazid during intensive phase treatment of pulmonary tuberculosis. Am J Respir Crit Care Med 2009; 180:273. 21. World Health Organization. Treatment of tuberculosis: Guidelines --- 4th ed, Geneva 2010. p. 35-36. whqlibdoc.who.int/publications/2010/9789241547833_eng.pdf (Accessed May 3, 2010). 22. Sandman L, Schluger NW, Davidow AL, Bonk S. Risk factors for rifampin-monoresistant tuberculosis: A case-control study. Am J Respir Crit Care Med 1999; 159:468. 23. Lutfey M, Della-Latta P, Kapur V, et al. Independent origin of mono-rifampin-resistant Mycobacterium tuberculosis in patients with AIDS. Am J Respir Crit Care Med 1996; 153:837. 24. Nolan CM, Williams DL, Cave MD, et al. Evolution of rifampin resistance in human immunodeficiency virus-associated tuberculosis. Am J Respir Crit Care Med 1995; 152:1067. 25. Vernon A, Burman W, Benator D, et al. Acquired rifamycin monoresistance in patients with HIV-related tuberculosis treated with once-weekly rifapentine and isoniazid. Tuberculosis Trials Consortium. Lancet 1999; 353:1843. 26. Blumberg HM, Burman WJ, Chaisson RE, et al. American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America: treatment of tuberculosis. Am J Respir Crit Care Med 2003; 167:603. 27. Controlled trial of 6-month and 9-month regimens of daily and intermittent streptomycin plus isoniazid plus pyrazinamide for pulmonary tuberculosis in Hong Kong. The results up to 30 months. Am Rev Respir Dis 1977; 115:727. 28. Grassi C, Peona V. Use of rifabutin in the treatment of pulmonary tuberculosis. Clin Infect Dis 1996; 22 Suppl 1:S50. 29. Schwander S, Rüsch-Gerdes S, Mateega A, et al. A pilot study of antituberculosis combinations comparing rifabutin with rifampicin in the treatment of HIV-1 associated tuberculosis. A single-blind randomized evaluation in Ugandan patients with HIV-1 infection and pulmonary tuberculosis. Tuber Lung Dis 1995; 76:210. 30. McGregor MM, Olliaro P, Wolmarans L, et al. Efficacy and safety of rifabutin in the treatment of patients with newly diagnosed pulmonary tuberculosis. Am J Respir Crit Care Med 1996; 154:1462. 31. Gonzalez-Montaner LJ, Natal S, Yongchaiyud P, Olliaro P. Rifabutin for the treatment of newly-diagnosed pulmonary tuberculosis: a multinational, randomized, comparative study versus Rifampicin. Rifabutin Study Group. Tuber Lung Dis 1994; 75:341. 32. Short-course chemotherapy in pulmonary tuberculosis. A controlled trial by the British Thoracic and Tuberculosis Association. Lancet 1975; 1:119. 33. Stead WW, Dutt AK. Chemotherapy for tuberculosis today. Am Rev Respir Dis 1982; 125:94. 34. Dutt AK, Jones L, Stead WW. Short-course chemotherapy of tuberculosis with largely twice-weekly isoniazid-rifampin. Chest 1979; 75:441. 35. Combs DL, O'Brien RJ, Geiter LJ. USPHS Tuberculosis Short-Course Chemotherapy Trial 21: effectiveness, toxicity, and acceptability. The report of final results. Ann Intern Med 1990; 112:397. 36. Iseman MD. Treatment of multidrug-resistant tuberculosis. N Engl J Med 1993; 329:784. 37. Mitnick CD, Shin SS, Seung KJ, et al. Comprehensive treatment of extensively drug-resistant tuberculosis. N Engl J Med 2008; 359:563. 38. Guidelines for the Programmatic Management of Drug-Resistant Tuberculosis (monograph). World Health Organization, Geneva 2006. 39. Drugs for tuberculosis. Treat Guidel Med Lett 2004; 2:83. 40. Van Deun A, Maug AK, Salim MA, et al. Short, highly effective, and inexpensive standardized treatment of multidrug-resistant tuberculosis. Am J Respir Crit Care Med 2010; 182:684. 41. Peloquin CA. Quinolones and tuberculosis. Ann Pharmacother 1996; 30:1034. 42. Yew WW, Chan CK, Chau CH, et al. Outcomes of patients with multidrug-resistant pulmonary tuberculosis treated with ofloxacin/levofloxacin-containing regimens. Chest 2000; 117:744. 43. Hu Y, Coates AR, Mitchison DA. Sterilizing activities of fluoroquinolones against rifampin-tolerant populations of Mycobacterium tuberculosis. Antimicrob Agents Chemother 2003; 47:653.

44. Gosling RD, Uiso LO, Sam NE, et al. The bactericidal activity of moxifloxacin in patients with pulmonary tuberculosis. Am J Respir Crit Care Med 2003; 168:1342. 45. Pletz MW, De Roux A, Roth A, et al. Early bactericidal activity of moxifloxacin in treatment of pulmonary tuberculosis: a prospective, randomized study. Antimicrob Agents Chemother 2004; 48:780. 46. Burman WJ, Goldberg S, Johnson JL, et al. Moxifloxacin versus ethambutol in the first 2 months of treatment for pulmonary tuberculosis. Am J Respir Crit Care Med 2006; 174:331. 47. Conde MB, Efron A, Loredo C, et al. Moxifloxacin versus ethambutol in the initial treatment of tuberculosis: a double-blind, randomised, controlled phase II trial. Lancet 2009; 373:1183. 48. Ziganshina LE, Vizel AA, Squire SB. Fluoroquinolones for treating tuberculosis. Cochrane Database Syst Rev 2005; :CD004795. 49. Khaliq Y, Zhanel GG. Fluoroquinolone-associated tendinopathy: a critical review of the literature. Clin Infect Dis 2003; 36:1404. 50. Fish DN. Fluoroquinolone adverse effects and drug interactions. Pharmacotherapy 2001; 21:253S. 51. Migliori GB, Lange C, Centis R, et al. Resistance to second-line injectables and treatment outcomes in multidrug-resistant and extensively drug-resistant tuberculosis cases. Eur Respir J 2008; 31:1155. 52. Alcalá L, Ruiz-Serrano MJ, Pérez-Fernández Turégano C, et al. In vitro activities of linezolid against clinical isolates of Mycobacterium tuberculosis that are susceptible or resistant to first-line antituberculous drugs. Antimicrob Agents Chemother 2003; 47:416. 53. Ntziora F, Falagas ME. Linezolid for the treatment of patients with [corrected] mycobacterial infections [corrected] a systematic review. Int J Tuberc Lung Dis 2007; 11:606. 54. Dietze R, Hadad DJ, McGee B, et al. Early and extended early bactericidal activity of linezolid in pulmonary tuberculosis. Am J Respir Crit Care Med 2008; 178:1180. 55. Schecter GF, Scott C, True L, et al. Linezolid in the treatment of multidrug-resistant tuberculosis. Clin Infect Dis 2010; 50:49. 56. Migliori GB, Eker B, Richardson MD, et al. A retrospective TBNET assessment of linezolid safety, tolerability and efficacy in multidrug-resistant tuberculosis. Eur Respir J 2009; 34:387. 57. Diacon AH, Pym A, Grobusch M, et al. The diarylquinoline TMC207 for multidrug-resistant tuberculosis. N Engl J Med 2009; 360:2397. 58. Condos R, Rom WN, Schluger NW. Treatment of multidrug-resistant pulmonary tuberculosis with interferon-gamma via aerosol. Lancet 1997; 349:1513. 59. Suárez-Méndez R, García-García I, Fernández-Olivera N, et al. Adjuvant interferon gamma in patients with drug - resistant pulmonary tuberculosis: a pilot study. BMC Infect Dis 2004; 4:44. 60. Achkar JM, Casadevall A, Glatman-Freedman A. Immunological options for the treatment of tuberculosis: evaluation of novel therapeutic approaches. Expert Rev Anti Infect Ther 2007; 5:461. 61. Schluger N, Ciotoli C, Cohen D, et al. Comprehensive tuberculosis control for patients at high risk for noncompliance. Am J Respir Crit Care Med 1995; 151:1486. 62. DeRiemer K, García-García L, Bobadilla-del-Valle M, et al. Does DOTS work in populations with drug-resistant tuberculosis? Lancet 2005; 365:1239. 63. Huong NT, Lan NT, Cobelens FG, et al. Antituberculosis drug resistance in the south of Vietnam: prevalence and trends. J Infect Dis 2006; 194:1226. 64. Nardell EA, Mitnick CD. Are second-line drugs necessary to control multidrug-resistant tuberculosis? J Infect Dis 2006; 194:1194. 65. Peloquin CA, Nitta AT, Burman WJ, et al. Low antituberculosis drug concentrations in patients with AIDS. Ann Pharmacother 1996; 30:919. 66. Sahai J, Gallicano K, Swick L, et al. Reduced plasma concentrations of antituberculosis drugs in patients with HIV infection. Ann Intern Med 1997; 127:289. 67. Peloquin CA. Therapeutic drug monitoring of the antimycobacterial drugs. Clin Lab Med 1996; 16:717. 68. Sung SW, Kang CH, Kim YT, et al. Surgery increased the chance of cure in multi-drug resistant pulmonary tuberculosis. Eur J Cardiothorac Surg 1999; 16:187. 69. Souilamas R, Riquet M, Barthes FP, et al. Surgical treatment of active and sequelar forms of pulmonary tuberculosis. Ann Thorac Surg 2001; 71:443. 70. Pomerantz BJ, Cleveland JC Jr, Olson HK, Pomerantz M. Pulmonary resection for multi-drug resistant tuberculosis. J Thorac Cardiovasc Surg 2001; 121:448. 71. Somocurcio JG, Sotomayor A, Shin S, et al. Surgery for patients with drug-resistant tuberculosis: report of 121 cases receiving community-based treatment in Lima, Peru. Thorax 2007; 62:416. 72. Palacios E, Dallman R, Muñoz M, et al. Drug-resistant tuberculosis and pregnancy: treatment outcomes of 38 cases in Lima, Peru. Clin Infect Dis 2009; 48:1413. 73. Drobac PC, del Castillo H, Sweetland A, et al. Treatment of multidrug-resistant tuberculosis during pregnancy: long-term follow-up of 6 children with intrauterine exposure to second-line agents. Clin Infect Dis 2005; 40:1689. 74. Drobac PC, Mukherjee JS, Joseph JK, et al. Community-based therapy for children with multidrug-resistant tuberculosis. Pediatrics 2006; 117:2022. 75. Chan ED, Laurel V, Strand MJ, et al. Treatment and outcome analysis of 205 patients with multidrug-resistant tuberculosis. Am J Respir Crit Care Med 2004; 169:1103. 76. Burgos M, Gonzalez LC, Paz EA, et al. Treatment of multidrug-resistant tuberculosis in San Francisco: an outpatient-based approach. Clin Infect Dis 2005; 40:968. 77. Tahaoğlu K, Törün T, Sevim T, et al. The treatment of multidrug-resistant tuberculosis in Turkey. N Engl J Med 2001; 345:170. 78. Leimane V, Riekstina V, Holtz TH, et al. Clinical outcome of individualised treatment of multidrug-resistant tuberculosis in Latvia: a retrospective cohort study. Lancet 2005; 365:318.

79. Espinal MA, Kim SJ, Suarez PG, et al. Standard short-course chemotherapy for drug-resistant tuberculosis: treatment outcomes in 6 countries. JAMA 2000; 283:2537. 80. Nathanson E, Lambregts-van Weezenbeek C, Rich ML, et al. Multidrug-resistant tuberculosis management in resource-limited settings. Emerg Infect Dis 2006; 12:1389. 81. Gandhi NR, Moll A, Sturm AW, et al. Extensively drug-resistant tuberculosis as a cause of death in patients co-infected with tuberculosis and HIV in a rural area of South Africa. Lancet 2006; 368:1575. 82. Holtz TH, Sternberg M, Kammerer S, et al. Time to sputum culture conversion in multidrug-resistant tuberculosis: predictors and relationship to treatment outcome. Ann Intern Med 2006; 144:650. 83. Management of persons exposed to multidrug-resistant tuberculosis. MMWR Recomm Rep 1992; 41:61. 84. Targeted tuberculin testing and treatment of latent tuberculosis infection. This official statement of the American Thoracic Society was adopted by the ATS Board of Directors, July 1999. This is a Joint Statement of the American Thoracic Society (ATS) and the Centers for Disease Control and Prevention (CDC). This statement was endorsed by the Council of the Infectious Diseases Society of America. (IDSA), September 1999, and the sections of this statement. Am J Respir Crit Care Med 2000; 161:S221. 85. Nathanson E, Nunn P, Uplekar M, et al. MDR tuberculosis--critical steps for prevention and control. N Engl J Med 2010; 363:1050. 86. The role of BCG vaccine in the prevention and control of tuberculosis in the United States. A joint statement by the Advisory Council for the Elimination of Tuberculosis and the Advisory Committee on Immunization Practices. MMWR Recomm Rep 1996; 45:1. 87. von Reyn CF, Vuola JM. New vaccines for the prevention of tuberculosis. Clin Infect Dis 2002; 35:465. 88. Markel H, Gostin LO, Fidler DP. Extensively drug-resistant tuberculosis: an isolation order, public health powers, and a global crisis. JAMA 2007; 298:83.

GRAPHICS Potential regimens for the management ofpatients with drug-resistant pulmonary tuberculosis Pattern of drug resistance

Suggested regimen

Duration of treatment, months

Comments In BMRC trials, 6-mo regimens have yielded ≥95% success rates

RIF, PZA, EMB (a FQN INH (± SM)

may strengthen the regimen forpatients with

despite resistance to INH if four drugs were used in the initial 6

extensive disease)

phase and RIF plus EMB or SM was used throughout.* Additional studies suggested that results were best if PZA was also used throughout the 6 mo •. INH should be stopped in cases of INH resistance (see text for additional discussion) In such cases, extended treatment is needed to lessen the risk of

INH and RIF

FQN, PZA, EMB, IA,

(± SM)

±alternative agent

relapse. In cases with extensive disease, the use of an additional 18-24

agent (alternative agents) may be prudent to lessen the risk of failure and additional acquired drug resistance. Resectional surgery may be appropriate (see text).

INH, RIF (±

FQN (EMB or PZA if

SM), and EMB

active), IA, and two

or PZA

alternativeagents

Use of the first-line agents to which there is susceptibility. Add 24

two or more alternative agents in case of extensive disease. Surgery should be considered (see text). Daily and three times weekly regimens of INH, PZA, and SM given for 9 mo were effective in a BMRC trialΔ.

INH, PZA, EMB (a FQN RIF

may strengthen the regimen forpatients with

However,extended use of an injectable agent may not be 9-12

more extensive disease)

feasible. It is not known if EMB would be as effective as SM in these regimens. An all-oral regimen for 12 mo should be effective. But for more extensive disease and/or to shorten duration, an injectable agent maybe added in the initial 2 mo of therapy.

BMRC: British Medical ResearchCouncil; EMB: ethambutol; FQN: fluoroquinolone; IA: injectable agent;INH: isoniazid; PZA: pyrazinamide; RIF: rifampin; SM: streptomycin.FQN: fluoroquinolone; most experience involves ofloxacin, levofloxacin,or ciprofloxacin. IA: injectable agent; may include aminoglycosides(streptomycin, amikacin, or kanamycin) or the polypeptide capreomycin. Alternative agents: ethionamide, cycloserine, p-aminosaliclyic acid,clarithromycin, amoxicillin/clavulanate, linezolid. * Mitchison DA, Nunn Aj. Influence of initial drug resistance on the response to short-course chemotherapy of pulmonary tuberculosis. Am Rev Respir Dis 1986; 133:423-430. • Hong Kong Chest Service, British Medical Research Council. Five-year follow-up of a controlled trial of five, 6 month regimens of chemotherapy for tuberculosis. Am Rev Respir Dis 1987;136:1339-1342. Δ Hong Kong Chest Service, British Medical Research Council. Controlled trial of 6-monthand 9-month regimens of daily and intermittent streptomycin plus isoniazid plus pyrazinamide for pulmonary tuberculosis in Hong Kong. Am Rev Respir Dis 1977;115:727-735. Am J Respir CritCare Med 2003; 167:603

Doses of antituberculosis drugs for adults*

Drug

Daily dosing (normal renal function)

Dosing patients with CrCl