Tuberculosis Treatment & Management

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.

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.

Patients with TB who are receiving pyrazinamide should undergo baseline or 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.

DOT is recommended for all patients. Patients on the above regimens as DOT 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.

The chest radiograph below was taken in a patient who had undergone TB treatment.

Pregnancy

Active TB should be treated, even in women in the first stage of pregnancy. Isoniazid, rifampin, and ethambutol may be used. In the United States, pyrazinamide is reserved for women with suspected MDR-TB. Elsewhere in the world, pyrazinamide is commonly used in pregnant women with TB.

Preventive treatment is recommended during pregnancy, especially in the following situations:

• 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 have had a documented tuberculin skin test conversion in the past 2 years

Pregnant women are at an increased risk for isoniazid-induced hepatotoxicity and should undergo monthly 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 have reported that women diagnosed with TB during pregnancy are at an increased risk of having babies who are of low birthweight and small for gestational age. However, preterm birth was not more common in women with TB.^[46]

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. BCG vaccine is not recommended in infants in the United States but is commonly used around the world.

Tuberculosis in children

Isoniazid tablets may be crushed and added to food. Isoniazid liquid without sorbitol should be used to avoid osmotic diarrhea, causing 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 this topic.

Human immunodeficiency virus

Individuals infected with HIV are at an increased risk for TB, beginning within the first year of HIV infection.^[26] Based on historical data, the initiation of antiretroviral therapy (ART) decreases the risk of developing TB in these patients.^[27]

Treatment regimens for active or latent TB in patients with HIV infection are similar to the treatment of individuals who are HIV negative, but dose adjustments may be necessary.^{[47, 48]} 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.

Patients with HIV and TB may develop a paradoxical response 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 survival. The investigators looked at results from 642 patients with a TB/HIV coinfection, to determine the optimal initiation of antiretroviral agents.

In the study, the simultaneous initiation of antiretroviral therapy with TB therapy (429 patients) decreased the death rate over a sequential approach (213 patients), with a mortality rate of 5.4 deaths per 100 person-years (25 deaths) compared with 12.1 deaths per 100 person-years (27 deaths), respectively. The relative reduction was 56%. These results provide further impetus for the integration of TB and HIV services.^[49]

Swaminathan et al compared intermittent (3 times/wk) antitubular treatment regimens in patients with HIV infection and newly diagnosed TB. Patients received either a 6-month, 4-drug regimen or a 9-month, 4-drug regimen. A significantly lower bacteriologic recurrence rate was observed in the 9-month group. Acquired rifampin resistance (ARR) was high, and neither mortality nor ARR was altered by lengthening TB treatment.^[47]

Meningitis

Dexamethasone added to routine 4-drug therapy reduces complications.

Prehospital regimen for TB-drug-related seizures

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. 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.

Once multidrug-resistant tuberculosis (MDR-TB) is suspected due to relevant history or epidemiologic information and after sputum is cultured with anti-TB drug sensitivity, treatment is implemented. Treatment must be started empirically prior to culture results; once results are known modification of therapy is necessary according to susceptibilities. (Costs are many times higher for the treatment of MDR-TB.)

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

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.

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: aminoglycosides (ie, streptomycin, amikacin, capreomycin, kanamycin); fluoroquinolone (ie, levofloxacin, ciprofloxacin, ofloxacin); thioamides such as ethionamide or prothionamide; pyrazinamide; ethambutol; cycloserine; terizodone; or para-aminosalicylic acid.

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

Do not use intermittent therapy.

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 for more than 1 year after surgery.

All patients should be closely observed for 2 years after completion of treatment, with a low threshold for referral to TB centers.

Clusters of MDR-TB with 7-drug resistance have been reported and have a high infectivity rate.

Successful MDR-TB treatment is more likely in association with such factors as a 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 a 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.

In a study by Diacon et al, 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%).^[50]

The diagnosis of 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.

Surgical resection of an infected lung may be considered to reduce the bacillary burden in patients with MDR-TB. Procedures include segmentectomy (rarely used), lobectomy, and pneumonectomy. Pleurectomies for thick pleural peel are rarely indicated. However, intraoperative infection of uninvolved lung tissue has been observed.

Complications include the usual perioperative complications, recurrent disease, and bronchopleural fistulas.

Late complications of pulmonary TB 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. Therefore, retreatment is usually unnecessary, especially after DOT.

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.

Hemoptysis is the most common late complication. Broncholithiasis is the result of spontaneous lymph node migration into the bronchial tree and may be associated with postobstructive pneumonia or esophageal perforation. Bronchiectasis may progress to chronic bronchitis; bleeding from submucosal bronchial veins is usually self-limited.

Fibrothorax is the development of trapped lung due to pleural fibrosis and scarring.

The risk of carcinoma is controversial but should be considered with newly developing clubbing.

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

• Hepatitis
• Peripheral neuropathy
• Retrobulbar optic neuropathy

Patients with a clinically significant result on tuberculin skin testing or a positive IGRA result should receive a course of therapy once active infection and disease are ruled out. Guidelines published by the CDC refer to this as treatment of latent tuberculosis (TB).^[56]

The recommended regimens are listed below:

• Isoniazid 300 mg PO daily for 9 months
• Isoniazid 900 mg PO twice weekly for 9 months (administered as DOT)
• Isoniazid 300 mg PO daily for 6 months

  • Should not be used in patients with fibrotic lesions on chest radiography, patients with HIV, or children
• Isoniazid 900 mg PO twice weekly for 6 months

  • Administered as DOT
  • Should not be used in patients with fibrotic lesions on chest radiography, patients with HIV, or children
• Rifampin 600 mg PO daily for 4 months
• Isoniazid 900 mg PO plus rifapentine 900 mg PO once weekly for 3 months^[57]

  • Administered as DOT
  • Recommended for patients aged 12 years and older who are at high risk for developing TB disease including anyone who has had recent exposure to contagious TB, conversion from negative to positive on a test for TB infection, or a chest X-ray indicating prior TB disease
  • Persons with HIV who are otherwise healthy and not taking antiretrovirals may also use this regimen
  • Consider use of 3-month regimen among populations that are unlikely to complete 9 months of daily therapy (eg, in correctional settings, clinics for recent immigrants, homeless shelters)
  • Use for children aged 2-11 years and patients with underlying conditions associated with TB should be considered on a case-by-case basis
  • Not recommended for children < 2 years, pregnant women or women planning to become pregnant, HIV-infected persons taking antiretrovirals, and 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 3 months of directly observed once-weekly treatment with rifapentine (900 mg) plus isoniazid (900 mg) with 9 months of self-administered daily isoniazid (300 mg) 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.^[51]

Another regimen, rifampin plus pyrazinamide daily for 2 months, is no longer recommended, because of an increased risk for liver toxicity.

Children younger than age 12 years should receive isoniazid for 9 months. The 3-month regimen may be considered for children between 2-11 years on a case-by-case basis. In addition, children younger than age 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.

Household contacts to patients with MDR-TB have a particularly high risk for tuberculosis, 7.8% within 4 years in a study from Lima, Peru.^[52] 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

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. The 2-month combination of pyrazinamide plus rifampin is no longer recommended for patients with HIV.

The BCG vaccine continues to be used throughout much of the world and provides protection mostly until early childhood. Immunity begins to wane as early as 3 months after administration.^[53] As previously noted, use of the BCG vaccine is not recommended in infants in the United States.

On patient discharge, conduct monthly follow-up appointments with the patient for sputum mycobacterial culture and sensitivity.

Because of the prolonged course of anti-TB therapy, inpatient care is excessively costly and impractical. Local county health departments are expert and funded in the care of TB infection.

The public health sector should be notified and involved in cases of TB. 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 antitubercular chemotherapy.

Consult an expert on MDR-TB in cases of multidrug resistance.