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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 (<5 percent), defined as recurrence of culture positive disease after completion of therapy. The trials discussed below were all performed in HIV-negative persons; however, similar responses can be expected in HIV-infected patients, although many experts choose to prolong therapy for three additional months in this setting. (See "Monitoring the HIV-infected patient on antituberculous medications".) Among patients with monoresistant disease, the choice of therapy varies with the agent to which the isolate is resistant. Isoniazid monoresistance — Tuberculosis resistant to isoniazid (INH) should be treated with a rifamycin ( rifampin or rifabutin), pyrazinamide, and ethambutol for six to nine months, or four months after culture conversion [ 16,17]. This recommendation is based upon trials conducted by the Hong Kong Chest Service/British Medical Research Council, which demonstrated success rates of 95 to 98 percent with this type of regimen among 107 patients with INH-resistant disease [ 18]. Some experts consider continuing isoniazid in the setting of "low-level" INH resistance, ie, resistant to a concentration of 0.2 mcg/mL but sensitive to 2.0 mcg/mL. Some favor adding a fluoroquinolone to this regimen for the duration of therapy [ 19,20]. Moxifloxacin appeared to be a suitable alternative to isoniazid in a study of 328 participants with active pulmonary TB randomized to receive isoniazid or moxifloxacin (in addition to rifampin, pyrazinamide, and ethambutol); culture negativity after eight weeks was comparable between the groups (55 and 60 percent, respectively) [ 20]. (See 'Fluoroquinolones' below.) The optimal regimen for the treatment of isoniazid-resistant TB is not known. In general, for patients from regions with a background level of INH resistance greater than 7 percent and for whom drug susceptibility testing is not available, the use of isoniazid, rifampin, and ethambutol throughout the continuation phase of treatment is an acceptable alternative to isoniazid and rifampin alone [ 21]. Rifampin monoresistance — Rifampin monoresistance most often occurs in HIV-positive patients and represents an uncommon but increasingly frequent clinical problem [22-24]. Rifampin monoresistance may be more likely to develop in HIV-infected patients with advanced immunosuppression (eg, CD4 cell counts <100/microL) treated with highly intermittent (ie, once or twice weekly) regimens [25]. Because rifampin is the cornerstone of all six month regimens, resistance to this drug requires prolongation of treatment. Treatment regimens are based on large trials conducted before the introduction of rifampin, in which success rates of greater than 95 percent were documented with prolonged treatment. Acceptable regimens for rifampin monoresistant disease include [ 26]: Streptomycin, isoniazid, and pyrazinamide given together for nine months. This is the shortest duration regimen with good efficacy for use in rifampin monoresistance, and although it is our preferred regimen, as it has been evaluated in well-conducted clinical trials (in HIV-negative patients), many patients often object to the nine months of injections with their attendant side

effects. Some experts recommend extending treatment to 12 months for HIV-infected patients who do not convert their sputum cultures and clinically improve during the first two months of treatment [16,27]. Isoniazid, pyrazinamide, and ethambutol. The duration of this regimen should be at least 12 months, and some would treat for 18 months after culture conversion. Some recommend adding streptomycin for the first two to three months of treatment, or the addition of a quinolone such as levofloxacin or moxifloxacin throughout. Of the 14 mutant RNA polymerase alleles, which confer resistance to rifampin, nine also confer high-level resistance to rifabutin [28]. Approximately 25 percent of rifampin-resistant clinical isolates are sensitive to rifabutin, which appears as effective clinically as rifampin in short-course regimens for patients with drug-sensitive disease [ 29-31]. However, no data are available regarding short-course, rifabutin-containing regimens in patients with rifabutin-sensitive, but rifampin-resistant disease. Therefore, its use in this setting cannot be recommended at the present time. (See "Epidemiology and molecular mechanisms of drug-resistant tuberculosis" .) Pyrazinamide monoresistance — Single drug-resistance to pyrazinamide requires a nine month regimen of isoniazid and rifampin. This combination is well studied, and has a greater than 96 percent success rate in large trials [ 32-34]. Monoresistance to other agents — Single drug resistance to ethambutol, streptomycin, or second-line agents is of little clinical significance. Patients can still be treated with the standard short course regimen of two months of isoniazid, rifampin, and pyrazinamide followed by four months of isoniazid and rifampin, which yields success rates of around 97 percent [ 35]. (See "Treatment of tuberculosis in HIV-negative patients" .) TREATMENT OF MDR-TB — The management of MDR-TB cases includes treatment of two patient groups: Those who have received one or more previous treatment regimens (ie, patients undergoing retreatment). Those who have contracted drug-resistant strains of M. tuberculosis in the absence of previous antituberculous therapy Chemotherapy — There have been few controlled trials of the therapy of multidrug-resistant tuberculosis; treatment recommendations are based upon experience in patients who had been previously treated and relapsed, as well as prevailing practices at referral centers for MDR cases [ 36]. Even in somewhat resource-limited settings, good outcomes can be achieved with carefully chosen regimens and programs to increase adherence to therapy [ 37,38]. Empiric — In general, treatment of MDR-TB should be guided by drug susceptibility testing (DST) whenever possible. In many parts of the world, however, DST is often not available (at least initially), and empiric therapy must be used. The initial empiric therapy for patients in areas with a known high prevalence of MDR-TB (or for patients who contract TB after contact with a patient with known MDR-TB) should include the standard recommendations plus whatever additional drugs are necessary to assure that at least four drugs effective against the most prevalent drug-resistant strains are included in the regimen [ 26,39]. This may require that six or more drugs be given until drug susceptibility results are obtained. The specific regimens should be tailored based on knowledge of local drug susceptibility patterns. If full drug susceptibility is documented, the additional drugs may be discontinued and standard regimens given until completion. Suggested treatment regimens are listed in the following table ( table 1), and the dosages of second-line agents are given in this table ( table 2). An observational, non-randomized trial demonstrated reasonably successful outcomes with an intensive nine month regimen for MDR-TB using kanamycin (an injectable agent) and gatifloxacin (a quinolone) as the cornerstone of the treatment regimen [40]. However, several caveats must be noted. Gatifloxacin has a high incidence of causing dysglycemia and thus is not widely available. It is likely that similar results could be obtained with moxifloxacin, although it was not evaluated in this study; regimens using ofloxacin have been demonstrated to perform poorly. Rates of resistance to second-line agents in the population studied were low; in many regions multidrug-resistant strains are increasingly resistant to quinolone antibiotics, which could limit the applicability of these findings. In addition, the impact of HIV infection was not assessed in this study. Documented MDR — In patients in whom MDR-TB is documented, the primary principle underlying treatment is to discontinue the drugs to which the isolate is resistant and to add at least two new drugs to which the isolate is susceptible. When resistance is present to at least isoniazid and rifampin, most experts recommend that a parenteral aminoglycoside (streptomycin, kanamycin, amikacin, or capreomycin) and a quinolone ( levofloxacin and moxifloxacin have the most in vitro antituberculosis activity) be added. Treatment with parenteral agents is usually given for six months, and cures rates are high with medical therapy alone (in the 85 percent range) for MDR-TB regimens that include these two classes of drugs. Treatment with at least four effective drugs should be continued for 18 to 24 months [ 26,39]. Management of these difficult cases should be performed by medical personnel with expertise and experience in administering these complicated regimens; in addition, appropriate laboratory facilities to document drug susceptibility and monitor response should be available [ 36]. These regimens should be administered by direct observation. Aminoglycosides — The injectable aminoglycosides may all cause nephrotoxicity and eighth cranial nerve damage; renal function should be assessed regularly, and audiometry performed on a monthly basis. (See "Pathogenesis and prevention of aminoglycoside nephrotoxicity and ototoxicity".) The aminoglycoside is usually given daily or either two or three times per week. Cross-resistance between kanamycin and amikacin is common, but is rarely observed among the other agents in this class. Patients who cannot tolerate repeated intramuscular injections might receive intravenous therapy through an indwelling catheter. Fluoroquinolones — Quinolone antibiotics have considerable in vitro activity against M. tuberculosis and have become widely used in the treatment of MDR-TB [ 41,42]. However, the data from controlled trials to define the exact role of these drugs in the treatment of tuberculosis are limited. Among the newer quinolones, moxifloxacin has the greatest in vitro activity against M. tuberculosis, followed by levofloxacin, and ofloxacin, and ciprofloxacin; moxifloxacin demonstrates bactericidal activity [ 43-45]. Data are conflicting regarding whether substituting moxifloxacin for EMB (in addition to treatment with INH, RIF and PZA) hastens sputum culture conversion at eight weeks

[46,47]. (See "Treatment of tuberculosis in HIV-negative patients", section on 'Fluoroquinolones' .) Moxifloxacin did appear to be a suitable alternative to isoniazid in a study of 328 participants with active pulmonary TB randomized to receive isoniazid or moxifloxacin (in addition to rifampin, pyrazinamide, and ethambutol); culture negativity after eight weeks was comparable between the groups (55 and 60 percent, respectively) [ 20]. Based on these results, moxifloxacin may be a suitable alternative for patients who are intolerant of INH or are infected with INH-resistant M. tuberculosis. A meta-analysis from the Cochrane Database evaluated ten randomized trials including 1178 participants with culture positive pulmonary tuberculosis treated with regimens containing fluoroquinolones [48]. Ciprofloxacin cannot be recommended for treating drug-susceptible or MDR-TB, as use of this agent for treatment of in drug-sensitive tuberculosis was been associated with an increased incidence of relapse and longer time to sputum conversion. No difference was found between sparfloxacin and ofloxacin in treatment of MDR-TB. Adding or substituting levofloxacin to basic regimens in drug-resistant areas had no effect. The quinolones are generally well tolerated; rare complications include tenosynovitis (including reports of Achilles' tendinitis and rupture) and cardiac conduction abnormalities [49,50]. (See "Fluoroquinolones".) Other second line agents — A number of second-line drugs are less active against tuberculosis and have considerable adverse effects, making them difficult to use. (See "Second-line antituberculous therapy".) Ethionamide is a nicotinic acid derivative with structural similarities to isoniazid. It can cause significant gastrointestinal upset, hepatitis, neurologic reactions, and hypothyroidism. One mechanism of isoniazid resistance, mutations in the inhA gene, also is associated with ethionamide resistance. (See "Epidemiology and molecular mechanisms of drug-resistant tuberculosis" .) Para-aminosalicylic acid (PAS) is one of the oldest antituberculosis drugs and inhibits the growth of M. tuberculosis by interfering with folate metabolism. It is difficult to tolerate secondary to nausea, vomiting, and diarrhea, but a recently approved enteric-coated formulation may have fewer gastrointestinal side effects. Cycloserine has been associated with a variety of adverse psychological effects, including psychosis, anxiety, and severe depression. Pyridoxine (vitamin B6) should be co-administered (at a dose of 50 mg for every 250 mg of cycloserine) to reduce the risk of neurotoxicity. Ethionamide has been described as an independent predictor for therapeutic failure among patients with MDR- and XDR-TB [ 51]. Linezolid appears to have modest bactericidal activity in patients with pulmonary TB [ 52-55]. It can penetrate tuberculosis lesions and exert bactericidal activity against bacilli growing in cavities [54]. In a retrospective study of 85 patients with MDR/XDR-TB treated with linezolid for a mean of 221 days, 41 percent experienced major adverse effects requiring discontinuation in 77 percent of cases [ 56]. Twice daily dosing produced more adverse effects than once daily dosing, with no difference in efficacy. The diarylquinoline TMC207 offers a new mechanism of antituberculosis action by inhibiting mycobacterial synthase. Preliminary phase 2 trial results for use of this agent in the setting of MDR-TB appear promising [ 57]. Adjunctive therapies — Uncontrolled trials and anecdotal reports suggest that adjunctive immunotherapy with interferon-gamma (IFNg) may be useful in the management of multidrug-resistant tuberculosis. IFNg is normally produced by CD4+ T lymphocytes and serves to activate alveolar macrophages. Small observational studies suggest benefit in the setting of multidrug-resistant tuberculosis or tuberculosis in the immunocompromised host [58,59]. Small trials of other adjunctive immunotherapy approaches, including IFN alpha, interleukin-2, etanercept, thalidomide, and arginine, have been performed. Although there have been reports of small symptomatic benefits with these adjuncts [ 60], their use outside of clinical trials cannot be recommended. Adherence — Compliance with therapy is crucial, but is particularly difficult for patients with MDR-TB because regimens are prolonged and employ drugs with considerable adverse effects. Directly observed therapy — Directly observed therapy (DOT) is mandatory for all patients with drug-resistant tuberculosis. It insures compliance, thereby eliminating the major cause of treatment failure [ 61]. Regular observation also allows collection of sputum samples, which can be used to provide an objective assessment of clinical response. (See "Adherence to tuberculosis treatment".) Directly observed therapy, short course (DOTS) appears to reduce the transmission and incidence of both drug-susceptible and drug-resistant tuberculosis. The efficacy of DOTS was illustrated by a population-based prospective study of 436 patients with pulmonary tuberculosis treated in southern Mexico between March 1995 and February 2000 [ 62]. In 1996, treatment of TB in the health jurisdiction was changed to the World Health Organization DOTS strategy and the following significant improvements in treatment outcomes were noted: A decrease in the incidence rate of pulmonary TB (from 42 to 19 per 100,000 population) A decreases in the rate of primary drug resistance (from 9.4 to 1.5 per 100,000 population) A decrease in treatment failures (from 11 to 2 percent) A decrease in the rate of MDR-TB (from 10 to 4.3 per 100,000 population) A decrease in MDR-TB, despite treatment that did not include second-line agents, was noted in the South of Vietnam between 1996 and 2001, following implementation of a DOTS strategy in 1989 [ 63]. The prevalence of any drug resistance decreased significantly (36.1 versus 26.3 percent); that of MDR-TB decreased but did not reach significance (3.5 versus 1.8 percent). An accompanying editorial, however, noted the following limitations of the study: the study did not control for the unmeasured effect of treatment of MDR-TB in a growing private medical sector in Vietnam (ie, were these patients being treated with second line agents) and the study used a short time span between data collection periods for a disease that requires decades of intervention to achieve an impact [ 64]. Further studies that control additional variables are needed before we can conclude that DOTS alone will control the spread of MDR-TB.

Serum drug levels — Therapeutic drug level monitoring is not routinely performed. However, low serum levels of antituberculosis drugs have been reported in patients with overt malabsorption and in some patients with HIV infection even in the absence of clinical malabsorption [65,66]. For this reason, monitoring serum drug levels may be useful in patients who do not respond clinically to a directly observed, seemingly appropriate regimen [ 67]. Surgery — Most patients with MDR-TB respond to appropriate chemotherapy. However, patients with sputum cultures positive for longer than three months despite appropriate therapy or with isolates resistant to all of the first-line oral agents have a worse prognosis. These patients may benefit from surgical intervention [ 68-71]. Patients with localized pulmonary disease, which can be completely removed at operation, are most likely to benefit from surgery [68-70]. Drug therapy is often given for one to three months before surgery to try to reduce the bacteriologic burden, but there are no firm guidelines or data about this issue. Resection alone should not be considered curative; patients with MDR-TB should continue the best possible drug regimen for 18 months after surgery. Pregnant women — The optimal approach to treatment of pregnant women with MDR-TB is uncertain. In general, studies performed in Peru have demonstrated that birth outcomes among pregnant women treated for MDR-TB are comparable to those among the general population [ 72], although the experience with treatment of MDR-TB in pregnancy is still small [ 72]. In a case series describing the long-term follow-up of six children with intrauterine exposure to second-line agents during treatment of MDR-TB during pregnancy, there was no evidence of significant toxicity among the children (average age at follow-up 3.7 years); one child was diagnosed with MDR-TB [ 73]. Children — Management of children with MDR-TB is similar to adults. A retrospective case series of 38 children (<15 years of age) in Lima, Peru, examined the adverse effects to therapy and outcome of treatment [ 74]. All children had a supervised individualized treatment regimen (five to seven drugs) based on susceptibility results of their M. tuberculosis isolate, or if this was unavailable, on their source case's isolate, usually a household contact. The following findings were noted: Malnutrition or anemia was present at diagnosis in 45 percent Severe radiographic findings (eg, bilateral or cavitary disease) were present in 29 percent Extrapulmonary disease was present in 13 percent Hospitalization was required initially in 45 percent Adverse effects occurred in 42 percent; however, no events required suspension of therapy for >5 days Cure or probable cure occurred in 36 (95 percent), death occurred in one child, and one child defaulted from therapy This study illustrates that MDR-TB among children can be treated successfully and that treatment is well tolerated with rare adverse events. Outcome — The outcome after treatment of MDR-TB has been evaluated in retrospective reviews from centers in the United States (eg, National Jewish Medical and Research Center [ 1,75]) and in other countries [ 76-78]. The following findings were noted: Patients presenting with MDR-TB had been previously treated with a median of five to six drugs [ 1,75] The overall success rate of patients treated after 1990 was similar in reports from the United States, Turkey, Latvia, and other resource-limited countries (52 to 77 percent) [75-80] Predictors of successful therapy included surgical intervention [75], fluoroquinolone use [ 75,77], and younger age [ 77] The outcome of patients with MDR-TB appears to vary with HIV status. In a retrospective review of 48 cases of MDR-TB, 32 of 33 HIV-seronegative patients were cured, with only one relapse occurring five years after treatment [ 76]. In contrast, all 11 HIV-seropositive patients died during observation. However, only two of the 11 received antiretroviral therapy, and it is possible that early institution of HAART could lead to better outcomes. (See "Monitoring the HIV-infected patient on antituberculous medications".) XDR-TB infection is also a particular problem in HIV-infected patients. In a surveillance study in South Africa, all 44 patients with XDR-TB who were tested for HIV were HIV-positive [ 81]. Fifty-two of 53 patients with XDR-TB died, with a median survival of 16 days from diagnosis. Time to sputum culture conversion is a useful interim indicator of treatment outcome in patients with MDR-TB, as illustrated in a study of 167 Latvian patients who were receiving DOTS for pulmonary MDR-TB [ 82]. Conversion to negative cultures at a median time of 60 days (range 4 to 462 days) occurred in 129 (77 percent) of patients. Thirty-eight patients (23 percent) did not convert. Predictors of a longer conversion time were: Previous treatment of MDR-TB High colony count on initial sputum culture Bilateral cavitation on chest radiography The number of drugs the initial isolate was resistant to at the time of treatment initiation The mortality rate varies depending on whether the individual has been previously treated for compared to newly diagnosed with tuberculosis (14 versus 3 percent) [80]. Management of treatment failure — Treatment failure includes the reappearance of positive cultures after the cultures convert to negative while the patient is receiving treatment OR when cultures do not become negative during the course of treatment (eg, when cultures are still positive at the end of the fourth month with the standard six-month regimen). Treatment failure implies resistance to all of the drugs being administered at the time when failure is diagnosed. Drugsusceptibility testing of the M. tuberculosis isolate is required in order to develop a retreatment regimen.

Retreatment of patients with MDR-TB should be made after careful review of previous medications. This includes patients whose disease is progressing despite compliance with the drug regimen, and patients presenting for treatment who have been noncompliant with previous regimens. The following general principles apply in these settings [ 26]: Any agent taken previously for more than 30 days is likely to have decreased efficacy. An empiric retreatment regimen should include at least four drugs likely to be effective, one of them a parenteral agent. This will usually entail the use of second-line drugs that have increased toxicity compared with first line drugs. Efficacy must be documented by drug-sensitivity studies, and therapy adjusted accordingly. (See "Second-line antituberculous therapy".) Patients considered being at high risk for relapse that have localized disease may benefit from surgical resection. Patients should receive either hospital-based or domiciliary DOT. The implications of treatment failure and further acquired resistance are such that these cases should receive highest priority for DOT. Given the length of therapy, the toxicity, and the expense involved, treatment of MDR-TB should be supervised by persons experienced in this type of care. PREVENTIVE THERAPY FOR CONTACTS — There is obviously no way to determine whether or not a person with a positive tuberculin test has been exposed to a case of drug-resistant tuberculosis without a careful contact investigation, and the role of the health department is vital in this regard. After a thorough contact investigation, an estimate should be made both of the likelihood of recent infection with a resistant strain and the risk of the contact developing active tuberculosis. These factors should then be weighed against the risks of preventive regimens of unknown benefit before therapy is prescribed [ 83]. Exposure to isoniazid monoresistant TB — Contacts of INH monoresistant tuberculosis can be treated for two months with the combination of a rifamycin ( rifampin or rifabutin) plus pyrazinamide [16,84]. A four to six month regimen of a rifamycin alone is acceptable in patients who cannot tolerate pyrazinamide; we favor six months of therapy in this setting. Exposure to rifampin monoresistant TB — Contacts of patients with rifampin monoresistant tuberculosis can be treated with the usual isoniazid regimen given to patients with exposure to drug-sensitive organisms. (See "Treatment of latent tuberculosis infection in HIV-negative adults".) Exposure to multidrug-resistant tuberculosis — Treatment of contacts to MDR cases is difficult because there are few published data concerning the composition, duration, or efficacy of preventive regimens for MDR-TB. Potential regimens that have been suggested (based primarily on animal studies) include pyrazinamide and ethambutol, or pyrazinamide and a quinolone, with drugs given in the doses to treat active disease for 12 months in immunocompromised patients, and at least six months in patients who are immunocompetent [ 84]. (See "Treatment of latent tuberculosis infection in HIV-negative adults" .) PREVENTION OF MDR-TB — The best way to prevent MDR-TB is by prompt institution of appropriate therapy with efforts to guarantee adherence to therapy [ 85]. Proper infection control will also limit spread to others. However, there may be instances in which ongoing contact with cases of multidrug-resistant tuberculosis on a regular basis is unavoidable. This may be the case for selected health care workers in facilities that treat significant numbers of MDR-TB patients. In these instances, consideration may be given to vaccination with Bacille Calmette-Guérin [ 86]. This vaccine is felt to be roughly >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 <30 ml/min or for patients receiving intermittent hemodialysis

10-15 mg/kg/day PO (1g in two doses);

250 mg PO once daily, or 500 mg/dose three times

usually 500-750 mg/day in two doses•

per weekΔ

Second-line drugs Cycloserine

15-20 mg/kg/d PO (1g/day); usually Ethionamide

500-750 mg/day in a single daily dose or two

250-500 mg/dose PO daily

divided doses◊ Streptomycin§

¥

Amikacin/kanamycin§ ¥

Capreomycin Para-aminosalicyclic acid (PAS)

¥

8-12 g/day PO in two or three doses

Levofloxacin

500-1000 mg PO daily

Moxifloxacin

400 mg PO daily

12-15 mg/kg/dose IV or IM two or three times per week (NOT daily) (max 1.5 g per dose) 12-15 mg/kg/dose (IBW) IV or IM two or three times per week (NOT daily) (max 1.5 g per dose) 12-15 mg/kg/dose (IBW) IV or IM two or three times per week (NOT daily) (max 1 g per dose) 4 g/dose, PO twice daily 750-1000 mg per dose PO three times per week (not daily) 400 mg PO daily

CrCl: Creatinine clearance by Cockcroft-Gault equation (See "Calculator: Creatinine clearance estimate by Cockcroft-Gault equation"); PO: by mouth; IV: intravenously; IM: intramuscularly; IBW: ideal body weight. * Doses per weight is based on ideal body weight. For purposes of this document adult dosing begins at age 15 years. • It should be noted that although this is the generally recommended dose, most clinicians with experience using cycloserine indicate that it is unusual for patients to tolerate this amount. Serum concentration measurements are often useful in determining the optimal dose for a given patient. Δ The appropriateness of 250-mg daily doses has not been established. There should be careful monitoring for evidence of neurotoxicity. ◊ The single daily dose can be given at bedtime or with the main meal. § Doses listed for aminoglycosides (streptomycin, kanamycin, amikacin) represent initial doses; subsequent dosing is determined by levels. As these agents are nephrotoxic, consultation with pharmaceutical expertise is warranted to reduce risk of exacerbating renal failure. ¥ Dose: 15 mg/kg per day (maximum 1 g), and 10 mg/kg in persons more that 50 years of age (maximum 750 mg). Usual dose: 750-1000 mg administered intramuscularly or intravenously, given as a single dose 5-7 days/week and reduced to two or three times per week after the first 2-4 months or after culture conversion, depending on the efficacy of the other drugs in the regimen. Modified with permission from: 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. Official Journal of the American Thoracic Society. Copyright © 2003 American Thoracic Society.

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