The two aims of TB treatment are (1) to prevent morbidity and death by curing TB while preventing the emergence of drug resistance and (2) to interrupt transmission by rendering patients noninfectious. Chemotherapy for TB became possible with the discovery of streptomycin in 1943. Randomized clinical trials clearly indicated that the administration of streptomycin to patients with chronic TB reduced mortality rates and led to cure in the majority of cases. However, monotherapy with streptomycin eventually was associated with the development of resistance to this drug and the resulting failure of treatment. With the introduction into clinical practice of para-aminosalicylic acid (PAS) and isoniazid, it became axiomatic in the early 1950s that cure of TB required the concomitant administration of at least two agents to which the organism was susceptible. Furthermore, early clinical trials demonstrated that a long period of treatment—i.e., 12–24 months—was required to prevent recurrence. The introduction of rifampin (rifampicin) in the early 1970s heralded the era of effective short-course chemotherapy, with a treatment duration of <12 months. The discovery that pyrazinamide, which was first used in the 1950s, augmented the potency of isoniazid/rifampin regimens led to the use of a 6-month course of this triple-drug regimen as standard therapy. DRUGS
Four major drugs are considered first-line agents for the treatment of TB: isoniazid, rifampin, pyrazinamide, and ethambutol (Table 74-2). These drugs are well absorbed after oral administration, with peak serum levels at 2–4 h and nearly complete elimination within 24 h. These agents are recommended on the basis of their bactericidal activity (i.e., their ability to rapidly reduce the number of viable organisms and render patients noninfectious), their sterilizing activity (i.e., their ability to kill all bacilli and thus sterilize the affected tissues, measured in terms of the ability to prevent relapses), and their low rate of induction of drug resistance by selection of mutant bacilli. Two additional rifamycins, rifapentine and rifabutin, are also available in the United States; however, the level of cross-resistance with rifampin is high. For a detailed discussion of the drugs used for the treatment of TB, see Chap. 77.
Because of a lower degree of efficacy and a higher degree of intolerability and toxicity, six classes of second-line drugs are generally used only for the treatment of patients with TB resistant to first-line drugs: (1) the fluoroquinolone antibiotics; (2) the injectable aminoglycosides kanamycin, amikacin, and streptomycin; (3) the injectable polypeptide capreomycin; and the oral agents (4) ethionamide and prothionamide, (5) cycloserine and terizidone (therizidone), and (6) PAS. Streptomycin, formerly a first-line agent, is now rarely used for drug-resistant TB because resistance levels worldwide are high and it is more toxic than the other drugs in the same class; however, the level of cross-resistance with the other injectables is low. Of the quinolones, later-generation agents such as levofloxacin and moxifloxacin are preferred. Gatifloxacin (no longer marketed in several countries, including the United States, because of previously observed dysglycemia) has recently been tested in a 4-month regimen that produced no detectable major side effects; thus, this drug could be reconsidered as a good alternative. Other drugs (referred to by the WHO as “group 5”) whose efficacy is not clearly defined are used in the treatment of patients with TB resistant to most of the first- and second-line agents; these drugs include clofazimine, linezolid, amoxicillin/clavulanic acid, clarithromycin, and carbapenems such as imipenem/cilastatin and meropenem. Today amithiozone (thiacetazone) is used very rarely because it has been associated with severe and at times fatal skin reactions among HIV-infected patients. Two novel drugs belonging to two new antibiotic classes—the diarylquinoline bedaquiline and the nitroimidazole delamanid—have recently been approved for use in severe cases of MDR-TB by stringent regulatory authorities (the U.S. Food and Drug Administration [FDA] and the European Medicine Agency [EMA] in the case of bedaquiline; the EMA and the Pharmaceuticals and Medical Devices Agency of Japan in the case of delamanid). REGIMENS
Standard short-course regimens are divided into an initial, or bactericidal, phase and a continuation, or sterilizing, phase. During the initial phase, the majority of the tubercle bacilli are killed, symptoms resolve, and usually the patient becomes noninfectious. The continuation phase is required to eliminate persisting mycobacteria and prevent relapse. The treatment regimen of choice for virtually all forms of drug-susceptible TB in adults consists of a 2-month initial (or intensive) phase of isoniazid, rifampin, pyrazinamide, and ethambutol followed by a 4-month continuation phase of isoniazid and rifampin (Table 74-3). This regimen can cure TB in more than 90% of patients. In children, most forms of TB in the absence of HIV infection or suspected isoniazid resistance can be safely treated without ethambutol in the intensive phase. Treatment should be given daily throughout the course. However, daily treatment during the intensive phase and intermittently (three times weekly) during the continuation phase is an alternative for patients who can be directly supervised and properly supported. A fully supervised, three-times-weekly regimen throughout the course also can be offered in the absence of HIV infection, although the risk of acquired drug resistance is higher than that among patients treated daily for the full course. In addition, if the infecting strain is resistant to isoniazid, the risks of both acquired resistance and treatment failure are higher with three-times-weekly intensive therapy than with daily treatment in the intensive phase. HIV-infected patients should always receive their initial-phase regimen daily (see below). A continuation phase of once-weekly rifapentine and isoniazid has been shown to be equally effective for HIV-seronegative patients with noncavitary pulmonary TB who have negative sputum cultures at 2 months. Patients with cavitary pulmonary TB and delayed sputum-culture conversion (i.e., those who remain culture-positive at 2 months) should be tested immediately for drug-resistant TB, and a change of regimen should be considered. To prevent isoniazid-related neuropathy, pyridoxine (10–25 mg/d) should be added to the regimen given to persons at high risk of vitamin B6 deficiency (e.g., alcoholics; malnourished persons; pregnant and lactating women; and patients with conditions such as chronic renal failure, diabetes, and HIV infection, which are also associated with neuropathy). A full course of therapy (completion of treatment) is defined more accurately by the total number of doses taken than by the duration of treatment, although the course should not include interruptions of longer than 4 weeks. Specific recommendations on the required number of doses for each of the various treatment regimens have been published jointly by the American Thoracic Society, the Infectious Diseases Society of America, and the CDC. In some developing countries where the ability to ensure adherence to treatment is limited, a continuation-phase regimen of daily isoniazid and ethambutol for 6 months was used in the past. However, this regimen is associated with a higher rate of relapse, failure, and death, especially among HIV-infected patients, and is no longer recommended by the WHO.
Lack of adherence to treatment is recognized worldwide as the most important impediment to cure. Moreover, the tubercle bacilli infecting patients who do not fully adhere to the prescribed regimen are likely to become drug resistant. Both patient- and provider-related factors may affect adherence. Patient-related factors include a lack of belief that the illness is significant and/or that treatment will have a beneficial effect; the existence of concomitant medical conditions (notably alcohol or substance abuse); lack of social support; fear of stigma and discrimination associated with TB; and poverty, with attendant joblessness and homelessness. Provider-related factors that may promote adherence include the support, education, and encouragement of patients and the offering of convenient clinic hours. In addition to specific measures promoting adherence, two other strategic approaches are used: direct supervision of treatment with support to the patient, consisting of incentives and enablers such as meals, travel vouchers, cash transfers, and grants to replace income loss; and provision of fixed-drug-combination products that reduce the number of tablets the patient needs to swallow. Because it is difficult to predict which patients will adhere to the recommended treatment for a disease that has important public as well as individual health implications, all patients should have their therapy directly supervised, especially during the initial phase, with proper social support including education, psychosocial counseling, and material sustainment. In an increasing number of countries, personnel to supervise therapy are usually available through TB control programs of local public health departments and from members of the community who are accepted by the patient to undertake that role and who have been properly educated by health workers. Direct supervision with patient support usually increases the proportion of patients completing treatment in all settings and greatly lessens the chances of failure, relapse, and acquired drug resistance. Fixed-drug-combination products (e.g., isoniazid/rifampin, isoniazid/rifampin/pyrazinamide, and isoniazid/rifampin/pyrazinamide/ethambutol) are available and are strongly recommended as a means of minimizing the likelihood of prescription error and of the development of drug resistance as the result of monotherapy. In some formulations of these combination products, the bioavailability of rifampin has been found to be substandard. Stringent regulatory authorities ensure that combination products are of good quality; however, this type of quality assurance is not always operative in low-income countries. Alternative regimens for patients who exhibit drug intolerance or adverse reactions are listed in Table 74-3. However, severe side effects prompting discontinuation of any of the first-line drugs and use of these alternative regimens are uncommon. The fluoroquinolones moxifloxacin and gatifloxacin have been tested as 4-month treatment-shortening regimens for drug-susceptible TB. Recently published results from these clinical trials failed to show that a 4-month regimen substituting gatifloxacin for ethambutol or moxifloxacin for either ethambutol or isoniazid is noninferior to the standard 6-month regimen. Thus, currently there is no 4-month regimen available for TB treatment. MONITORING TREATMENT RESPONSE AND DRUG TOXICITY
Bacteriologic evaluation through culture and/or smear microscopy is essential in monitoring the response to treatment for TB. In addition, the patient's weight should be monitored regularly and the drug dosage adjusted with any significant weight change. Patients with pulmonary disease should have their sputum examined monthly until cultures become negative to allow early detection of treatment failure. With the recommended regimen, more than 80% of patients will have negative sputum cultures at the end of the second month of treatment. By the end of the third month, the sputum of virtually all patients should be culture negative. In some patients, especially those with extensive cavitary disease and large numbers of organisms, AFB smear conversion may lag behind culture conversion. This phenomenon is presumably due to the expectoration and microscopic visualization of dead bacilli. As noted above, patients with cavitary disease in whom sputum culture conversion does not occur by 2 months require immediate testing for drug resistance. When a patient's sputum cultures remain positive at ≥3 months, treatment failure and drug resistance or poor adherence to the regimen are likely, and testing of drug resistance should guide the choice of the best treatment option (see below). A sputum specimen should be collected by the end of treatment to document cure. If mycobacterial cultures are not practical, then monitoring by AFB smear examination should be undertaken at 2, 5, and 6 months. Smears that are positive after 3 months of treatment when the patient is known to be adherent are indicative of treatment failure and possible drug resistance. Therefore, if not done at the start of treatment, drug susceptibility testing is mandatory at this stage. Bacteriologic monitoring of patients with extrapulmonary TB is more difficult and often is not feasible. In these cases, the response to treatment must be assessed clinically and radiographically.
Monitoring of the response during chemotherapy by nucleic acid amplification technology has not been shown to be suitable. Thus Xpert MTB/RIF should not be used to monitor treatment. Likewise, serial chest radiographs are not recommended because radiographic changes may lag behind bacteriologic response and are not highly sensitive. After the completion of treatment, neither sputum examination nor chest radiography is recommended for routine follow-up purposes. However, a chest radiograph obtained at the end of treatment may be useful for comparative purposes should the patient develop symptoms of recurrent TB months or years later. Patients should be instructed to report promptly for medical assessment if they develop any such symptoms. In addition, an end-of-treatment chest radiograph may reveal earlier the post-TB complications described above.
During treatment, patients should be monitored for drug toxicity. The most common adverse reaction of significance is hepatitis. Patients should be carefully educated about the signs and symptoms of drug-induced hepatitis (e.g., dark urine, loss of appetite) and should be instructed to discontinue treatment promptly and see their health care provider should these symptoms occur. Although biochemical monitoring is not routinely recommended, all adult patients should undergo baseline assessment of liver function (e.g., measurement of serum levels of hepatic aminotransferases and bilirubin). Older patients, those with concomitant diseases, those with a history of hepatic disease (especially hepatitis C), and those using alcohol daily should be monitored especially closely (i.e., monthly), with repeated measurements of aminotransferases, during the initial phase of treatment. Up to 20% of patients have small increases in aspartate aminotransferase (up to three times the upper limit of normal) that are not accompanied by symptoms and are of no consequence. For patients with symptomatic hepatitis and those with marked (five- to sixfold) elevations in serum levels of aspartate aminotransferase, treatment should be stopped and drugs reintroduced one at a time after liver function has returned to normal. Hypersensitivity reactions usually require the discontinuation of all drugs and rechallenge to determine which agent is the culprit. Because of the variety of regimens available, it usually is not necessary—although it is possible—to desensitize patients. Hyperuricemia and arthralgia caused by pyrazinamide can usually be managed by the administration of acetylsalicylic acid; however, pyrazinamide treatment should be stopped if the patient develops gouty arthritis. Individuals who develop autoimmune thrombocytopenia secondary to rifampin therapy should not receive the drug thereafter. Similarly, the occurrence of optic neuritis with ethambutol is an indication for permanent discontinuation of this drug. Other common manifestations of drug intolerance, such as pruritus and gastrointestinal upset, can generally be managed without the interruption of therapy. TREATMENT FAILURE AND RELAPSE
As stated above, treatment failure should be suspected when a patient’s sputum smears and/or cultures remain positive after 3 months of treatment. In the management of such patients, it is imperative that the current isolate be urgently tested for susceptibility to first- and second-line agents. Initial molecular testing for rifampin resistance should be done if the technology is available. When the results of susceptibility testing are based on molecular methods and are expected to become available within a few days, changes in the regimen can be postponed until that time. However, if the patient’s clinical condition is deteriorating, an earlier change in regimen may be indicated. A cardinal rule in the latter situation is always to add more than one drug at a time to a failing regimen: at least two and preferably three drugs that have never been used and to which the bacilli are likely to be susceptible should be added. The patient may continue to take isoniazid and rifampin along with these new agents pending the results of susceptibility tests.
Patients who experience a recurrence after apparently successful treatment (relapse) are less likely to harbor drug-resistant strains (see below) than are patients in whom treatment has failed. Acquired resistance is uncommon among strains from patients in whom relapse follows the completion of a standard short-course regimen. However, pending the results of susceptibility testing, it is prudent to begin the treatment of all patients whose infections have relapsed with a standard regimen containing all four first-line drugs plus streptomycin. In less affluent countries and other settings where facilities for culture and drug susceptibility testing are not yet routinely available and where the prevalence of MDR-TB is low, the WHO recommends that a standard regimen with all four first-line drugs plus streptomycin be used in all instances of relapse and treatment default. Patients with treatment failure and those relapsing or defaulting with a high likelihood of MDR-TB should receive a regimen that includes second-line agents and is based on their history of anti-TB treatment and the drug resistance patterns in the population (Table 74-3). Once drug susceptibility test results are available, the regimen can be adjusted accordingly. DRUG-RESISTANT TB
Strains of M. tuberculosis resistant to individual drugs arise by spontaneous point mutations in the mycobacterial genome that occur at low but predictable rates (10–7–10–10 for the key drugs). Resistance to rifampin is associated with mutations in the rpoB gene in 95% of cases; that to isoniazid with mutations mainly in the katG (50–95% of cases) and inhA (up to 45%) genes; that to pyrazinamide in the pncA gene (up to 98%); that to ethambutol in the embB gene (50–65%); that to the fluoroquinolones in the gyrA–gyrB genes (75–95%); and that to the aminoglycosides mainly in the rrs gene (up to 80%). Because there is no cross-resistance among the commonly used drugs, the probability that a strain will be resistant to two drugs is the product of the probabilities of resistance to each drug and thus is low. The development of drug-resistant TB is almost invariably the result of monotherapy—i.e., the failure of the health care provider to prescribe at least two drugs to which tubercle bacilli are susceptible or of the patient to take properly prescribed therapy. In addition, the use of drugs of substandard quality may cause the emergence of drug resistance. Drug-resistant TB may be either primary or acquired. Primary drug resistance is that which develops in a patient infected from the start by a drug-resistant strain. Acquired resistance is that which develops during treatment with an inappropriate regimen. In North America, Western Europe, most of Latin America, and the Persian Gulf States, rates of primary resistance are generally low and isoniazid resistance is most common. In the United States, although rates of primary isoniazid resistance have been stable at ~7–8%, the rate of primary MDR-TB has declined from 2.5% in 1993 to 1% since 2000. As described above, MDR-TB is an increasingly serious problem in some regions, especially in the states of the former Soviet Union and some countries of Asia (Fig. 74-11). Even more serious is the recently described occurrence of XDR-TB due to MDR strains that are also resistant to any fluoroquinolones and to any of three second-line injectable agents (amikacin, kanamycin, and capreomycin). Creation of drug-resistant TB can be prevented by adherence to the principles of sound treatment: inclusion of at least two qualityassured, bactericidal drugs to which the organism is susceptible; use of fixed-drug-combination products; supervision of treatment with patient support; and verification that patients complete the prescribed course. Transmission of drug-resistant strains can be prevented by implementation of respiratory infection-control measures (see below).
Although the 6-month regimen described in Table 74-3 is generally effective for patients with initial isoniazid-resistant disease, it is prudent to include at least ethambutol and possibly pyrazinamide for the full 6 months and to consider extending the treatment course to 9 months. In such cases, isoniazid probably does not contribute to a successful outcome and could be omitted. In case of documented resistance to both isoniazid and ethambutol, a 9- to 12-month regimen of rifampin, pyrazinamide, and a fluoroquinolone can be used. Any patients whose isolates exhibit resistance to rifampin should be managed as if they had MDR-TB (see below), with the addition of isoniazid if susceptibility to this agent is confirmed via rapid testing or is presumed. MDR-TB, in which bacilli are resistant to (at least) isoniazid and rifampin, is more difficult to manage than is disease caused by drug-susceptible organisms because these two bactericidal drugs are the most potent agents available and because associated resistance to other first-line drugs as well (e.g., ethambutol) is not uncommon. For treatment of MDR-TB, the WHO recommends that in most patients five drugs be used in the initial phase of at least 8 months: a later-generation fluoroquinolone, an injectable agent (the aminoglycosides amikacin or kanamycin or the polypeptide capreomycin), ethionamide (or prothionamide), either cycloserine or PAS, and pyrazinamide. Ethambutol can be added (Table 74-3). Although the optimal duration of treatment is not known, a course of at least 20 months is recommended for previously untreated patients, including the initial phase with an injectable agent, which is usually discontinued at 4 months after culture conversion.
In late 2012, the FDA granted accelerated approval of bedaquiline, a diarylquinoline antibiotic. This new drug, when given for the first 24 weeks (400 mg daily for 2 weeks followed by 200 mg thrice weekly for 22 weeks), has been shown to increase the efficacy of the WHO standard regimen for MDR-TB with faster sputum conversion. Bedaquiline should be used with caution in people >65 years of age and in HIV-infected patients; its use is not advised in children and pregnant women. In early 2014, the European Medical Agency granted accelerated approval of another new agent, the nitroimidazole compound delamanid. Data from a phase 2B clinical trial in which delamanid was added to the WHO-recommended standard MDR-TB regimen have shown increased culture conversion at 2 months. Pending phase 3 trial results and in view of potential side effects of both new drugs (including QT interval prolongation in both cases and hepatotoxicity in the case of bedaquiline), the WHO recommends limiting the use of bedaquiline and delamanid to cases of MDR-TB when an effective WHO-recommended standard MDR-TB regimen cannot be designed because of known resistance, intolerance, or nonavailability of any second-line drugs in the regimen. Patients treated with bedaquiline or delamanid should be counseled, should give informed consent, and should be closely monitored during treatment. In particular, patients with cardiac anomalies such as prolonged QT interval or a history of ventricular arrhythmias should not be given these drugs. Currently, there is no information about simultaneous use of these two agents; therefore, combining them is not recommended.
Finally, a shorter (9-month) regimen consisting of gatifloxacin or moxifloxacin, clofazimine, ethambutol, and pyrazinamide given throughout the treatment period and supplemented by prothionamide, kanamycin, and high-dose isoniazid during an intensive phase of at least 4 months is reportedly effective for MDR-TB in certain settings. Further investigations are necessary to elucidate the role of this shorter regimen in MDR-TB treatment.
Patients with XDR-TB have fewer treatment options and a much poorer prognosis. However, observational studies have shown that aggressive management of cases comprising early drug-susceptibility testing, rational combination of at least five drugs, readjustment of the regimen, strict directly observed therapy, monthly bacteriologic monitoring, and intensive patient support may result in cure and avert death. Table 74-4 summarizes the management of patients with XDR-TB. Some recently published studies regarding the use of linezolid in patients with XDR-TB suggest that, although it carries a high level of toxicity, this drug increases culture conversion.
For patients with localized disease and sufficient pulmonary reserve, lobectomy or pneumonectomy may be considered. Because the management of patients with MDR- and XDR-TB is complicated by both social and medical factors, care of these patients is ideally provided in specialized centers or, in their absence, in the context of programs with adequate resources and capacity, including community support. HIV-ASSOCIATED TB
Several observational studies and randomized controlled trials have shown that treatment of HIV-associated TB with anti-TB drugs and simultaneous use of ART are associated with significant reductions in mortality risk and AIDS-related events. Evidence from randomized controlled trials shows that early initiation of ART during anti-TB treatment is associated with a 34–68% reduction in mortality rates, with especially good results in patients with CD4+ T cell counts of <50/μL. Therefore, the main aim in the management of HIV-associated TB is to initiate anti-TB treatment and to immediately consider initiating or continuing ART. All HIV-infected TB patients, regardless of CD4+ T cell count, are candidates for ART, which optimally is initiated as soon as possible after the diagnosis of TB and within the first 8 weeks of anti-TB therapy. However, ART should be started within the first 2 weeks of TB treatment for patients with CD4+ T cell counts of <50/μL. In general, the standard 6-month daily regimen is equally efficacious in HIV-negative and HIV-positive patients for treatment of drug-susceptible TB. As for any other adult living with HIV (Chap. 97), first-line ART for TB patients should consist of two nucleoside reverse transcriptase inhibitors (NRTIs) plus a nonnucleoside reverse transcriptase inhibitor (NNRTI). Although TB treatment modalities are similar to those in HIV-negative patients, adverse drug effects may be more pronounced in HIV-infected patients. In this regard, three important considerations are relevant: an increased frequency of paradoxical reactions, interactions between ART components and rifamycins, and development of rifampin monoresistance with intermittent treatment. IRIS—i.e., the exacerbation of symptoms and signs of TB—has been described above. Rifampin, a potent inducer of enzymes of the cytochrome P450 system, lowers serum levels of many HIV protease inhibitors and some NNRTIs—essential drugs used in ART. In such cases, rifabutin, which has much less enzyme-inducing activity, has been used in place of rifampin. However, dosage adjustments for rifabutin and protease inhibitors are still being assessed. Several clinical trials have found that patients with HIV-associated TB whose degree of immunosuppression is advanced (e.g., CD4+ T cell counts of <100/μL) are prone to treatment failure and relapse with rifampin-resistant organisms when treated with “highly intermittent” (i.e., once- or twice-weekly) rifamycin-containing regimens. Consequently, it is recommended that all TB patients who are infected with HIV receive a rifampin-containing regimen on a daily basis. Because recommendations are frequently updated, consultation of the following websites is advised: www.who.int/hiv, www.who.int/tb, www.cdc.gov/hiv, and www.cdc.gov/tb. SPECIAL CLINICAL SITUATIONS
Although comparative clinical trials of treatment for extrapulmonary TB are limited, the available evidence indicates that most forms of disease can be treated with the 6-month regimen recommended for patients with pulmonary disease. The WHO and the American Academy of Pediatrics recommend that children with bone and joint TB, tuberculous meningitis, or miliary TB receive up to 12 months of treatment. Treatment for TB may be complicated by underlying medical problems that require special consideration. As a rule, patients with chronic renal failure should not receive aminoglycosides and should receive ethambutol only if serum drug levels can be monitored. Isoniazid, rifampin, and pyrazinamide may be given in the usual doses in cases of mild to moderate renal failure, but the dosages of isoniazid and pyrazinamide should be reduced for all patients with severe renal failure except those undergoing hemodialysis. Patients with hepatic disease pose a special problem because of the hepatotoxicity of isoniazid, rifampin, and pyrazinamide. Patients with severe hepatic disease may be treated with ethambutol, streptomycin, and possibly another drug (e.g., a fluoroquinolone); if required, isoniazid and rifampin may be administered under close supervision. The use of pyrazinamide by patients with liver failure should be avoided. Silicotuberculosis necessitates the extension of therapy by at least 2 months.
The regimen of choice for pregnant women (Table 74-3) is 9 months of treatment with isoniazid and rifampin supplemented by ethambutol for the first 2 months. Although the WHO has recommended routine use of pyrazinamide for pregnant women, this drug has not been recommended in the United States because of insufficient data documenting its safety in pregnancy. Streptomycin is contraindicated because it is known to cause eighth-cranial-nerve damage in the fetus. Treatment for TB is not a contraindication to breast-feeding; most of the drugs administered will be present in small quantities in breast milk, albeit at concentrations far too low to provide any therapeutic or prophylactic benefit to the child.
Medical consultation on difficult-to-manage cases is provided by the U.S. CDC Regional Training and Medical Consultation Centers (www.cdc.gov/tb/education/rtmc/).