The goals of TB treatment include: controlling the spread of TB, reducing the development of drug resistance, and preventing relapse to active disease.9 A four-drug regimen comprised of isoniazid, pyrazinamide, rifampin, and ethambutol is initiated in suspected active TB infection.9 The combination therapy prevents selecting out drug-resistant organisms. Typical treatment for active disease includes an initial 2 month phase of four drugs and a continuation phase of 4 months (18 weeks) with two drugs.9 First-line drug treatment regimens for TB recommended by the Center for Disease Control and Prevention are listed in Table 27-1. This continuation phase is extended to 7 months in the following patient groups: cavitary pulmonary TB with positive-sputum culture at the end of 2-month initial phase, if the initial phase did not include pyrazinamide, and those taking isoniazid-rifapentine once-weekly regimens who have positive-sputum cultures at the end of initial phase.9 Directly observed therapy is recommended in patients receiving regimens of five times per week or less.9 Ethambutol can be safely discontinued after drug susceptibility reveals the TB is susceptible to isoniazid and rifampin.9 Baseline laboratory values before initiating treatment include: liver function tests, creatinine, bilirubin, and platelets. Routine monitoring of these parameters is not needed unless they are abnormal initially or clinical situation warrants rechecking.9 For example, if any symptoms of liver toxicity are found at follow-up visits, this situation would warrant rechecking of baseline labs. Treatment in children is generally the same regimens as in adults with the exception that ethambutol is not included.9
Latent TB infection treatment should not be initiated until active disease has been ruled out. Latent TB infection is recommended to be treated with isoniazid monotherapy for 9 months unless contraindicated.7 Acceptable latent TB infection treatment regimens are shown in Table 27-2. In children daily or twice-weekly isoniazid for 9 months is the preferred regimen.7 Baseline laboratory monitoring is not always indicated for patients receiving latent TB therapy.7 Patients taking isoniazid for treatment of latent disease who are over the age of 35 should have baseline liver function tests.10 This group is at higher risk for liver toxicity.10 The following populations should have the same baseline and routine laboratory monitoring as listed above in the active disease section: HIV-positive patients, pregnant women, postpartum women (3 months of delivery), chronic liver disease, and regular alcohol users.7
Effectiveness of TB therapy is determined by AFB smears and cultures. Sputum cultures should be sent for AFB staining and microscopic examination every 1 to 2 weeks until two consecutive smears are negative. This provides early evidence of a response to treatment. If sputum cultures continue to be positive after 2 months, drug susceptibility testing should be repeated, and serum concentration of the drugs should be checked.
Patient nonadherence is a serious problem with TB therapy. The most effective way to achieve adherence is with directly observed therapy (DOT). DOT also provides opportunities to observe the patient for toxicity, thus improving overall care.
Hepatotoxicity should be suspected in patients whose transaminases exceed five times the upper limit of normal or whose bilirubin is significantly elevated and in patients with symptoms such as nausea, vomiting, and jaundice. At this point, the offending agent(s) should be discontinued.
Isoniazid is a first-line agent against latent TB and also one of the first-line drugs in combination therapy for active TB. Isoniazid (INH) inhibits production of mycolic acids, which form a large part of the mycobacterial cell wall.11 Metabolism of isoniazid occurs by acetylation and may be affected by genetic differences in slow and fast acetylators.11 Currently there are no recommendations in testing for genetic differences that affect treatment. Dosing is typically 300 mg once daily or 900 mg for the once, twice, and three times weekly regimens in adults.9 Caution should be used with this agent in patients with significant liver disease.9 Pyridoxine (vitamin B6) 25 to 50 mg daily is recommended to be taken with isoniazid to help prevent drug-induced peripheral neuropathy.9 Adverse effects of isoniazid include: rash, neuropathy, gastrointestinal upset, and hepatotoxicity.9 Isoniazid-induced hepatitis is rare, but rates are increased in the elderly, pregnant women, postpartum women, alcohol abusers, patients with underlying liver disease, and when used in combination with rifampin.9-12 Isoniazid should be discontinued immediately and not used again with confirmation of INH-induced hepatitis.9 Ten to twenty percent of patients will have benign liver function tests elevations if all patients were monitored.11
Rifampin is a first-line agent against active TB, when used in combination. Rifampin inhibits DNA-dependent RNA polymerase in bacterial cells.11,13 Dosing is 600 mg for once daily and twice or three times weekly regimens in adults.9 Rifabutin and rifapentine are other rifamycins which can be used in place of rifampin.9 All three rifamycins have drug interactions with significant induction of cytochrome P-450, however rifabutin is a less potent enzyme inducer.9 Rifampin, rifabutin, and rifapentine can significantly induce cytochrome P-450 and increases metabolism of several drugs including: oral anticoagulants, anticonvulsants, antiretrovirals, cyclosporine, oral contraceptives, and others.11,13 The alternative rifamycins can also be used with intolerance to rifampin.9 Adverse reactions to rifamycins include: pruritus, rash, gastrointestinal upset, flu-like syndrome, and rare hepatotoxicity.9,13 Rifamycins also give urine, sweat, and tears a harmless reddish-orange color.11
Pyrazinamide (PZA) is a first-line agent for active TB, when used in combination. PZA exerts its effects against dormant organisms inside macrophages.9 Mechanism of action is uknown.14 Dosing is 20 to 25 mg/kg/d in adults rounded to the nearest 500 mg tablets.9 PZA is contraindicated in patients with severe liver disease and acute gout attacks. Caution should be taken in those with a history of gout.14 Adverse reactions include: hepatotoxicity, gastrointestinal upset, and hyperuricemia.11,14 Baseline liver function tests should be performed in patients with preexisting liver disease and if used with rifampin. 9,14
Ethambutol is a first-line treatment of active tuberculosis, when used in combination. Ethambutol targets mycobacterial arabinosyl transferase to inhibit cell wall production.11 Ethambutol is added to the TB regimen to prevent rifampin resistance. Dosing in adults is 15 to 20 mg/kg/d rounded to the nearest dose using whole tablets (100 mg, 400 mg).9 Dose adjustments are required for renal dysfunction.9,15 Ethambutol is contraindicated in patients with optic neuritis as well as with those who would have difficulty determining visual acuity (children).15 Ethambutol can cause retrobulbar neuritis, which presents as decreased visual acuity or red-green color blindness.9,15 This can occur in one or both eyes and typically at higher doses.9 Patients should have baseline visual acuity and color blindness assessed as well as continued monitoring for this adverse effect.9
All patients diagnosed with HIV should receive TB testing at diagnosis.4 Patients with HIV and other immunocompromised hosts may be managed with chemotherapeutic agents similar to those utilized in immunocompetent individuals, although treatment is extended to 9 months. Highly intermittent regimens (twice or once weekly) are not recommended for HIV-positive TB patients.
HIV-positive patients can have a paradoxical reaction when antiretroviral therapy is initiated in TB-positive patients.4 It is possibly thought to be a recovery of the immune response. It is often an exaggerated inflammatory response and self-limited. It can be treated with nonsteroidal anti-inflammatory or corti-costeroids.4
Drug interactions with rifamycins are important in this patient population. Interactions among rifamycins, HIV-protease inhibitors, and nonnucleoside reverse transcriptase inhibitors are common and require dose and frequency modifications. Rifabutin provides an alternative rifamycin in this case but careful attention still must be paid to drug adjustments.16
Drug therapy is warranted in pregnant women with active TB. Treatment in pregnant patients with latent TB is more controversial. Patients with latent TB who are HIV positive or who have recently been infected with latent TB infection should be considered for treatment.7 All pregnant and postpartum women should have baseline liver function tests before therapy initiation due to physiological increased risk for hepatotoxicity.9 The first-line drug regimen in pregnancy consists of isoniazid, rifampin, and ethambutol. Pyrazinamide is not recommended due to potential concerns for safety in this population.9 Known teratogens that should not be used include several second-line drugs: streptomycin, kanamycin, amikacin, and capreomycin.9 Patients taking TB therapy can breastfeed.9
There are no standardized treatment regimens for multidrug resistant (MDR) TB. Treatment of MDR-TB is based on the patient's previous drug therapy, exposure history, geographic resistance patterns, and drug-susceptibility data. One important principle in multidrug resistant TB is to never change one drug at a time.9 Two or more new drugs should be added to a regimen to lessen the likelihood of further resistance development.9
Treatment of MDR-TB consists of second-line antituberculosis drugs. Examples of second-line agents are cycloserine, ethionamide, streptomycin, amikacin/kanamycin, capreomycin, p-Aminosalicylic acid (PAS), and select fluoroquinolones.