Tuberculosis (TB) Treatment & Management

Updated: Sep 19, 2017
  • Author: Thomas E Herchline, MD; Chief Editor: Michael Stuart Bronze, MD  more...
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Treatment

Approach Considerations

Isolate patients with possible tuberculosis (TB) infection in a private room with negative pressure (air exhausted to outside or through a high-efficiency particulate air filter). Medical staff must wear high-efficiency disposable masks sufficient to filter the tubercle bacillus. Continue isolation until sputum smears are negative for 3 consecutive determinations (usually after approximately 2-4 wk of treatment). Unfortunately, these measures are neither possible nor practical in countries where TB is a public health problem.

Drug therapy

For initial empiric treatment of TB, start patients on a 4-drug regimen: isoniazid, rifampin, pyrazinamide, and either ethambutol or streptomycin. Once the TB isolate is known to be fully susceptible, ethambutol (or streptomycin, if it is used as a fourth drug) can be discontinued. [1]

Patients with TB who are receiving pyrazinamide should undergo baseline and periodic serum uric acid assessments, and patients with TB who are receiving long-term ethambutol therapy should undergo baseline and periodic visual acuity and red-green color perception testing. The latter can be performed with a standard test, such as the Ishihara test for color blindness.

After 2 months of therapy (for a fully susceptible isolate), pyrazinamide can be stopped. Isoniazid plus rifampin are continued as daily or intermittent therapy for 4 more months. If isolated isoniazid resistance is documented, discontinue isoniazid and continue treatment with rifampin, pyrazinamide, and ethambutol for the entire 6 months. Therapy must be extended if the patient has cavitary disease and remains culture-positive after 2 months of treatment.

Directly observed therapy (DOT) is recommended for all patients. With DOT, patients on the above regimens can be switched to 2- to 3-times per week dosing after an initial 2 weeks of daily dosing. Patients on twice-weekly dosing must not miss any doses. Prescribe daily therapy for patients on self-administered medication.

Monitoring

Patients diagnosed with active TB should undergo sputum analysis for Mycobacterium tuberculosis weekly until sputum conversion is documented. Monitoring for toxicity includes baseline and periodic liver enzymes, complete blood cell (CBC) count, and serum creatinine.

Seizures from isoniazid overdose

A special regimen exists for patients with TB who are actively seizing or who have overdosed on antimycobacterial medication. In these patients, overdose with isoniazid should be suspected. The administration of diazepam can be attempted to control seizure activity, but IV pyridoxine is the drug of choice, in a gram-for-isoniazid-ingested-gram dose. If the ingested dose is unknown, 5 g of pyridoxine can be used empirically. For patients who are awake and alert, an oral dose of activated charcoal (1 g/kg) with sorbitol can be administered.

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Treatment During Pregnancy

Pregnant women with active TB should be treated, even in the first stage of pregnancy. Isoniazid, rifampin, and ethambutol may be used. In the United States, pyrazinamide is reserved for women with suspected multidrug-resistant TB (MDR-TB). Elsewhere in the world, pyrazinamide is commonly used in pregnant women with TB. Streptomycin should not be used, because it has been shown to have harmful effects on the fetus.

Preventive treatment is recommended during pregnancy, especially in the following types of patients:

  • Pregnant women with a positive tuberculin skin test result who are HIV seropositive or who have behavioral risk factors for HIV infection but who decline HIV testing
  • Pregnant women with a positive tuberculin skin test result who have been in close contact with a patient who is smear-positive for pulmonary TB
  • Pregnant women who had a documented tuberculin skin test conversion during the previous 2 years

Pregnant women are at an increased risk for isoniazid-induced hepatotoxicity and should undergo monthly alanine aminotransferase (ALT) monitoring while on treatment. This risk continues 2-3 months into the postpartum period. Pyridoxine should also be administered to pregnant women receiving isoniazid.

Breastfeeding can be continued during preventive therapy. Many experts recommend supplemental pyridoxine for the breastfed infant.

Lin et al reported that women diagnosed with TB during pregnancy are at an increased risk of having babies who are of low birthweight and are small for their gestational age. However, preterm birth was not more common in women with TB. [72]

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Treatment in Children

Most children with TB can be treated with isoniazid and rifampin for 6 months, along with pyrazinamide for the first 2 months if the culture from the source case is fully susceptible.

For postnatal TB, many experts increase the treatment duration to 9 or 12 months because of the possible impaired immune system in children younger than 12 months. Bacillus Calmette-Guérin (BCG) vaccine is not recommended in infants in the United States but is commonly used around the world.

Isoniazid tablets may be crushed and added to food. Isoniazid liquid without sorbitol should be used to avoid osmotic diarrhea, which can cause decreased absorption.

Rifampin capsules may be opened and the powder added to food. If rifampin is not tolerated, it may be taken in divided doses 20 minutes after light meals.

Ethambutol is often avoided in young children because of difficulties monitoring visual acuity and color perception. However, studies show that ethambutol (15 mg/kg) is well tolerated and can prevent further resistance if the child is infected with a resistant strain. Go to Pediatric Tuberculosis for complete information on treatment of children.

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Treatment in HIV-Infected Patients

Treatment regimens for active or latent TB in patients with HIV infection are similar to those used in HIV-negative patients, but dose adjustments may be necessary. [2, 3] The most significant differences involve the avoidance of rifampin in patients who are on protease inhibitors. Rifabutin may be used in place of rifampin in such patients.

Antiretroviral therapy

Patients with HIV and TB may develop a paradoxical response (immune reconstitution inflammatory syndrome [IRIS]) when starting antiretroviral therapy. This response has been attributed to a stronger immune response to M tuberculosis. Clinical findings include fever, worsening pulmonary infiltrates, and lymphadenopathy.

However, in an open-label, randomized trial, Abdool Karim et al concluded that the initiation of antiretroviral therapy during TB therapy significantly improved patient survival. In this study, the mortality rate with simultaneous initiation of antiretroviral therapy and TB therapy was 5.4 deaths per 100 person-years (25 deaths in 429 patients), compared with 12.1 deaths per 100 person-years (27 deaths in 213 patients) with antiretroviral therapy started after the completion of TB therapy, a relative reduction of 56%. [4]

Subsequent studies by these and other researchers found that starting antiretroviral therapy early (eg, within 4 weeks after the start of TB treatment) reduced progression to AIDS and death. In patients with higher CD4+ T-cell counts, however, deferring initiation of antiretroviral therapy until the continuation phase of TB treatment may be a reasonable strategy, because the risks of IRIS and of adverse events that necessitate switching of antiretroviral drugs are lower with later initiation of antiretroviral therapy. [5]

Treatment length and recurrence rate

Swaminathan et al reported a significantly lower bacteriologic recurrence rate with 9 months, instead of 6 months, of an intermittent (3 times/wk) 4-drug regimen in patients with HIV infection and newly diagnosed TB. Mortality was similar in both groups. The rate of acquired rifampin resistance was high in both groups and was not altered by the longer TB treatment. [2]

Tuberculous meningitis

In patients with tuberculous meningitis, dexamethasone added to routine 4-drug therapy reduces complications.

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Treatment of Multidrug-Resistant TB

When MDR-TB is suspected, because of a relevant history or epidemiologic information, treatment is initiated after sputum specimens are drawn for culture and sensitivity testing; however, treatment must be started empirically before culture results become available. Once results are known, the regimen is modified according to susceptibilities. (Costs are many times higher for the treatment of MDR-TB.)

The complexity of MDR-TB treatment lies in the futility of using isoniazid and rifampin. Isoniazid has the strongest antibactericidal action and significantly contributes to making patients rapidly noninfectious; rifampin has unique antibacterial properties against dormant bacilli that are no longer in the active phase of replication.

When initiating treatment, utilize at least 3-5 previously unused drugs for which there is in vitro susceptibility. Levofloxacin, which is a fluoroquinolone, has been shown to be best suited long-term and should be included in the regimen.

Never add a single new drug to a failing regimen. Administer at least 3 (preferably 4-5) of the following medications, according to drug susceptibilities:

  • An aminoglycoside - Ie, streptomycin, amikacin, capreomycin, kanamycin
  • A fluoroquinolone - Ie, levofloxacin, ciprofloxacin, ofloxacin
  • A thioamide - Eg, ethionamide, prothionamide
  • Pyrazinamide
  • Ethambutol
  • Cycloserine
  • Terizidone
  • Para-aminosalicylic acid
  • A diarylquinoline: Bedaquiline

Consider rifabutin as a substitute for rifampin, as approximately 15% of rifampin-resistant strains are rifabutin sensitive.

Successful MDR-TB treatment is more likely in association with such factors as lower prior patient exposure to anti-TB drugs, a higher number of anti-TB drugs to which the infection is still susceptible, and a shorter time since the first TB diagnosis (indicating less advanced disease).

Continue treatment for MDR-TB for 18-24 months after sputum culture conversion. The drugs should be prescribed daily (no intermittent therapy), and the patient should always be on DOT. Weekend DOT may not be possible; therefore, giving self-administered oral drugs on Saturdays and Sundays may be reasonable. All patients should be closely observed for 2 years after completion of treatment, with a low threshold for referral to TB centers.

Novel drugs for TB are currently under development and may prove valuable for treatment of MDR-TB. The diarylquinoline antimycobacterial, bedaquiline (Sirturo), was approved by the FDA in December 2012 as part of a 22-week multidrug regimen for pulmonary MDR-TB. Approval was based on phase 2 data that showed bedaquiline significantly improved time to sputum culture conversion and included 2 consecutive negative sputum cultures collected at least 25 days apart during treatment. At week 24, sputum culture conversion was observed in 77.6% of patients in the bedaquiline treatment group compared with 57.6% of patients in the placebo treatment group (p = 0.014). [73, 74]

In another phase II study by Diacon et al, bedaquiline (TMC207) added to standard therapy for MDR-TB reduced the time to conversion to a negative sputum culture compared with placebo and increased the proportion of patients with conversion of sputum culture (48% vs 9%). [75]

Provisional guidelines from the Centers for Disease Control and Prevention (CDC) include use of bedaquiline for FDA-approved and off-label uses. In addition to the approved indication as part of at least a 4-drug regimen for treatment multidrug-resistant tuberculosis, the guidelines include use on a case-by-case basis for children, HIV-infected persons, pregnant women, persons with extrapulmonary MDR TB, and patients with comorbid conditions on concomitant medications when an effective treatment regimen cannot otherwise be provided. [76, 77]

The diagnosis of extensively drug-resistant TB (XDR-TB) is established with an isolate that is resistant to isoniazid, rifampin, at least 1 of the quinolones, and at least 1 injectable drug. Treatment options for XDR-TB are very limited, and XDR-TB carries a very high mortality rate.

A CDC analysis of the prevalence, trends, and risk factors for initial resistance to pyrazinamide in Mycobacterium tuberculosis complex (MTBC) cases in the United States showed that such resistance increased from 2% in 1999 to 3.3% in 2009. Pyrazinamide monoresistance was associated with younger age, Hispanic ethnicity, HIV infection, extrapulmonary disease, and normal chest radiograph and inversely associated with Asian and Black race, substance use, homelessness, and residence in a correctional facility. [78, 79]

In the same CDC analysis, pyrazinamide polyresistance was associated with Hispanic ethnicity, Asian race, previous TB diagnosis, and normal chest x-ray and inversely associated with age 45 years and older. Pyrazinamide resistance in multidrug-resistant cases was associated with female sex and previous TB diagnosis. Bacterial lineage, rather than host characteristics, was the primary predictor of pyrazinamide resistance ijn M tuberculosis cases. [78, 79]

Surgical resection

Surgical resection of an infected lung may be considered to reduce the bacillary burden in patients with MDR-TB. Surgery is recommended for patients with MDR-TB whose prognosis with medical treatment is poor. Surgery can be performed with a low mortality rate (< 3%), with prolonged periods of a chemotherapeutic regimen used for more than 1 year after surgery.

Procedures include segmentectomy (rarely used), lobectomy, and pneumonectomy. Pleurectomies for thick pleural peel are rarely indicated.

Intraoperative infection of uninvolved lung tissue has been observed in resections. Complications include the usual perioperative complications, recurrent disease, and bronchopleural fistulas.

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Treatment of Latent TB

The antimycobacterial rifapentine (Priftin), which was previously approved for use against active pulmonary TB caused by Mycobacterium tuberculosis, has now been approved by the US Food and Drug Administration (FDA) for use, in combination with isoniazid, in the treatment of latent TB infection. Therapy was approved for patients aged 2 years or older who are at high risk of progression to TB disease. [80, 8]

FDA approval for the new indication was partially based on a randomized study of more than 6000 patients in which a 12-dose, once-weekly regimen of directly observed therapy (DOT) with rifapentine plus isoniazid was compared with a regimen consisting of 9 months of self-administered daily isoniazid. The cumulative rate of tuberculosis disease development was 0.16% in the rifapentine-isoniazid group (5 out of 3074 patients), compared with 0.32% in the isoniazid group (10 out of 3074 patients). [80, 8]

Patients with a clinically significant result on tuberculin skin testing or a positive interferon-gamma release assay (IGRA) result should receive a course of therapy for latent TB, once active infection and disease are ruled out. Recommended regimens for latent TB published by the US Centers for Disease Control and Prevention (CDC) are as follows [6] :

  • Isoniazid 300 mg - Daily for 9 months
  • Isoniazid 900 mg - Twice weekly for 9 months (administered as DOT)
  • Isoniazid 300 mg - Daily for 6 months (should not be used in patients with fibrotic lesions on chest radiography, patients with HIV infection, or children)
  • Isoniazid 900 mg - Twice weekly for 6 months (administered as DOT; should not be used in patients with fibrotic lesions on chest radiography, patients with HIV infection, or children)
  • Rifampin 600 mg - Daily for 4 months
  • Rifapentine 900 mg plus isoniazid 900 mg - Once-weekly for 12 weeks (administered as DOT)
  • No longer recommended - Rifampin plus pyrazinamide daily for 2 months (increased liver toxicity)

Isoniazid plus rifapentine

A newer regimen for latent TB is isoniazid 900 mg plus rifapentine 900 mg once weekly for 12 weeks (administered as DOT). [7] This combination was approved by the FDA in November 2014 for patients aged 2 years and older who are at high risk for developing active TB disease(including those in close contact with active TB patients, patients who have had a recent conversion to a positive tuberculin skin test, HIV-infected patients, and those with pulmonary fibrosis on radiograph).

Consider using this 12-dose regimen among populations that are unlikely to complete 9 months of daily therapy (eg, in correctional settings, clinics for recent immigrants, homeless shelters). Use in children aged 2-11 years and patients with underlying conditions associated with TB should be considered on a case-by-case basis.

This regimen is not recommended for children under 2 years, pregnant women or women planning to become pregnant, or patients whose TB infection is presumed to be the result of exposure to a person with TB disease that is resistant to 1 of the 2 drugs.

The PREVENT TB Study compared this regimen with 9 months of self-administered, daily isoniazid (300 mg) therapy for latent tuberculosis. The combination therapy was shown to be as effective as isoniazid alone in preventing tuberculosis and had a higher treatment-completion rate. [8]

Isoniazid therapy in children

Children younger than 12 years should receive isoniazid for 9 months. In addition, children younger than 5 years who have close contact with a person who has active TB should be started on isoniazid, even if the results on skin testing are negative; preventive therapy can be stopped if the results on repeat skin testing are negative 2-3 months after last contact with a culture-positive source case. Alternatively, children aged 2-11 years may receive DOT with weight-base dosing of once-weekly rifapentine plus isoniazid for 12 weeks. [7, 8]

MDR-TB and patient contacts

Household contacts of patients with MDR-TB have a particularly high risk for tuberculosis, 7.8% within 4 years in a study from Lima, Peru. [81] Limited data are available on regimens for the treatment of patients exposed to MDR-TB. However, if treatment is initiated, at least 2 drugs should be given, and the index isolate should be susceptible to all drugs used

Therapy in patients with HIV infection

Recommended regimens in patients with HIV infection include rifampin alone daily for 4 months or isoniazid, daily or twice weekly, for 9 months. Patients on antiretroviral therapy may need rifabutin instead of rifampin because of potential drug interactions.

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Prevention and Consultations

The BCG vaccine continues to be used throughout much of the world and usually provides protection until early childhood. Immunity begins to wane, however, as early as 3 months after administration. [82] As previously noted, use of the BCG vaccine is not recommended in infants in the United States.

In a meta-analysis of eight randomized controlled studies involving a total of 10,320 patients aged 15 years or younger, Ayieko et al found that isoniazid prophylaxis reduced the risk of developing TB, with a pooled risk ratio (RR) of 0.65 (P  = 0.004). However, isoniazid had no effect in children who initiated treatment at 4 months of age or earlier. When those patients were excluded, isoniazid prophylaxis reduced the risk of developing TB by 59% (RR, 0.41; P < 0.001). [83]

The public health sector should be notified and involved in cases of TB. Local county health departments are expert and funded in the care of TB infection. Consultation with a primary care, pulmonology, internal medicine, or infectious disease specialist prior to initiating therapy is helpful, and it may be appropriate for this consultant to manage the antituberculous chemotherapy. Consult an expert on MDR-TB in cases of multidrug resistance.

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Long-Term Monitoring

After completion of treatment for pulmonary TB, patients remain at risk for late complications, which include relapse, aspergilloma, bronchiectasis, broncholithiasis, fibrothorax, and possibly carcinoma. A copy of the chest radiograph at the time of completion of therapy should be provided to the patient to facilitate the diagnosis of late complications.

The relapse rate following appropriate completed therapy is only 0-4% and occurs within the first 2 years after completion. Aspergilloma is a fungus ball that develops in a residual lung abnormality (eg, pneumatocele, bulla, bleb, cyst). It may appear as a crescent sign on chest radiographs. Other superinfections may manifest with an air-fluid level (seen in the image below) and often contain mixed bacteria, including anaerobes.

Pulmonary tuberculosis with air-fluid level. Pulmonary tuberculosis with air-fluid level.

Hemoptysis is the most common late complication. Bleeding from submucosal bronchial veins is usually self-limited.

Other complications include the following:

  • Broncholithiasis - The result of spontaneous lymph node migration into the bronchial tree; may be associated with postobstructive pneumonia or esophageal perforation
  • Chronic obstructive pulmonary disease (COPD) - Bronchiectasis may progress to COPD
  • Fibrothorax - The development of trapped lung due to pleural fibrosis and scarring
  • Cancer - The risk of carcinoma is controversial but should be considered with newly developing clubbing

Adverse effects of antibiotic therapy in TB can be severe. They include the following:

  • Hepatitis
  • Peripheral neuropathy
  • Retrobulbar optic neuropathy
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