Tuberculosis (TB) Treatment & Management

Updated: Jul 05, 2023
  • Author: Thomas E Herchline, MD; Chief Editor: Michael Stuart Bronze, MD  more...
  • Print

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.


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.


Treatment During Pregnancy

Pregnant patients 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 individuals 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 patients 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 individuals with a positive tuberculin skin test result who have been in close contact with a patient who is smear-positive for pulmonary TB

  • Pregnant patients who had a documented tuberculin skin test conversion during the previous 2 years

Pregnant individuals 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 patients receiving isoniazid.

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

Lin et al reported that individuals 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. [74]


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 often is 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.

Bedaquiline also is a consideration as part of a 4-drug regimen for multidrug-resistant pulmonary tuberculosis in children aged 5 years or older when an effective treatment regimen cannot otherwise be provided.


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 for IRIS and for 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.


Treatment of Tuberculosis Resistant to a Single Drug

The CDC reported that 9.4% of TB cases were resistant to isoniazid in 2018 (16% of these were MDR-TB). [75] TB that is resistant to isoniazid (with or without resistance to streptomycin) can be treated with rifampin, pyrazinamide, and ethambutol for 6 months. Therapy should be extended to 9 months if the patient remains culture-positive after 2 months of treatment.

TB that is resistant to only rifampin (an unusual occurrence) can be treated with isoniazid, a fluoroquinolone (levofloxacin or moxifloxacin), and ethambutol for 12-18 months, depending on clinical response. Therapy should include pyrazinamide for at least the first 2 months of treatment.

A CDC analysis of resistance to pyrazinamide in US cases 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, and extrapulmonary disease. [76, 77] TB resistant to pyrazinamide can be treated with isoniazid and rifampin for 9 months. Ethambutol should be included for the first 2 months of treatment.


Treatment of Multidrug-Resistant Tuberculosis

Multidrug-resistant TB (MDR-TB) refers to isolates that are resistant to both isoniazid and rifampin (and possibly other drugs). When MDR-TB is suspected, because of a relevant history or epidemiologic information, start treatment empirically before culture results become available; obtain molecular drug susceptibility testing, if possible. Once results are known, the regimen is modified according to susceptibilities. (Costs are many times higher for the treatment of MDR-TB.) Never add a single new drug to a failing regimen.

Administer at least 5 drugs for the intensive phase of treatment and at least 4 drugs for the continuation phase (listed in order of preference), as follows [6, 7] :

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).

The intensive-phase treatment for MDR-TB should be 5-7 months, followed by the continuation phase, so that the total duration of treatment is 15-24 months after 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.

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). [78, 79]

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%). [80]

Bedaquiline gained FDA approval in August 2019 for adolescents aged 12 years or older and for children as young as 5 years in May 2020. This approval was based on evidence from a single-arm, open-label, phase 2 study that enrolled 15 pediatric patients with confirmed or probable MDR-TB infection. The patients were treated with the recommended dosage of bedaquiline for 24 weeks in combination with a background regimen. [81]

Provisional guidelines from the CDC include the use of bedaquiline on a case-by-case basis in children, HIV-infected persons, pregnant individuals, persons with extrapulmonary MDR-TB, and patients with comorbid conditions on concomitant medications when an effective treatment regimen cannot otherwise be provided. [82, 83]

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.

In August 2019, the FDA approved pretomanid, a nitroimidazooxazine, for adults with XDR-TB, treatment-intolerant TB, or nonresponsive MDR-TB. Pretomanid kills actively replicating M tuberculosis by inhibiting mycolic acid biosynthesis, thereby blocking cell wall production. Efficacy was primarily demonstrated in a study of 109 patients who were treated with pretomanid plus bedaquiline and linezolid. Of the 107 patients who were evaluated 6 months after the end of therapy, treatment was successful in 95 (89%), far exceeding success rates of previously available treatments. [84, 85]

A CDC analysis of the prevalence, trends, and risk factors for 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 in M tuberculosis cases. [76, 77]

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 rarely are indicated.

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


Treatment of Latent TB

The antimycobacterial rifapentine (Priftin), which was previously approved for use against active pulmonary TB caused by Mycobacterium tuberculosis, has 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 for progression to TB disease. [11, 86]

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). [11, 86]

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 [8, 12] :

  • 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 750-900 mg (based on weight) plus isoniazid 900 mg - Once-weekly for 12 weeks (self-administered or as DOT)

  • No longer recommended - Rifampin plus pyrazinamide daily for 2 months (increased liver toxicity)

Self-administered therapy versus directly observed therapy

A 2017 study reported that self-administered therapy for latent tuberculosis infection (LTBI) may be a viable option for patients when direct medical oversight is unavailable. [87]

As part of an open-label, phase 4 randomized clinical trial, researchers enrolled 1002 patients from outpatient TB clinics in the United States, Spain, Hong Kong, and South Africa between September 2012 and April 2014. Patients with active TB, prior treatment for TB lasting more than 1 week, contact with someone with a resistant form of TB, or prior intolerance to anti-TB agents were excluded. Most enrolled patients (n=774) were in the United States; however, participants were demographically similar between groups. The median age was 36 years, and 48.1% of the patients were women.

Patients were randomly assigned to receive isoniazid or rifapentine once weekly by directly observed therapy (DOT), self-administered therapy (SAT) with weekly text message reminders, or SAT without reminders. The primary objective of the study was to compare treatment adherence, defined as completion of 11 or more doses of medication within 16 weeks. All participants were counseled on correct pill-taking and symptoms of drug toxicity. All patients had monthly follow-up visits both during therapy and for 28 days after the last dose to assess adherence and monitor for adverse events.

The researchers documented overall completion rates of 87.2% (95% confidence interval [CI], 83.1% - 90.5%) in the DOT group, 74.0% (CI, 68.9% - 78.6%) in the SAT group, and 76.4% (CI, 71.3% - 80.8%) in the SAT with reminders group.

Specifically, among US patients, the researchers noted treatment completion rates of 85.4% (CI, 80.4% - 89.4%), 77.9% (CI, 72.7% - 82.6%), and 76.7% (CI, 70.9% - 81.7%), respectively. Using a 15% difference to define noninferiority, the researchers found SAT without reminders to be noninferior to DOT in the United States.

The researchers also found that adverse events were similar among all 3 groups. [87]

Isoniazid plus rifapentine

This combination, approved by the FDA in November 2014, is indicated for patients aged 2 years and older who are at high risk of 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 longer courses of therapy with isoniazid alone. This regimen is not recommended for children under 2 years, individuals who are pregnant or plan 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. [11]

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. [11, 88]

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. [89] 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.


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. [90] As previously noted, use of the BCG vaccine is not recommended in infants in the United States.

In early 2020, Darrah et al reported on the promising efficacy of BCG vaccine administered intravenously rather than intradermally in macaque monkeys. Intravenous immunization resulted in a significantly more robust T-cell response in lung lymph nodes, blood spleen, and bronchoalveolar lavage than traditional intradermal immunization. These findings have not been confirmed in human studies. [91]

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). [92]

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.


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