Treatment of drug-resistant tuberculosis can be difficult, and may necessitate ..... Diagnostic Standards and Classifica
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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
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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