Medication Summary
The treatment of tuberculosis (TB) must satisfy the following basic therapeutic principles:
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Any regimen must use multiple drugs to which Mycobacterium tuberculosis is susceptible
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The medications must be taken regularly
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The therapy must continue for a period sufficient to resolve the illness
New cases are initially treated with four drugs: isoniazid, rifampin, pyrazinamide, and either ethambutol or streptomycin. After 2 months, they are then treated with a continuation phase of 4 months with isoniazid and rifampin. Patients requiring retreatment should initially receive at least 5 drugs, including isoniazid, rifampin, pyrazinamide, and at least 2 (preferably 3) new drugs to which the patient has not been exposed. [1]
In three phase III trials, shorter TB treatment regimens were not as effective as standard 6-month regimens. [94, 95, 96, 97, 98] In all of the trials, one of the standard treatment drugs was replaced with a fluoroquinolone. In the first study, ethambutol was replaced with gatifloxacin for 2 months of intensive treatment followed by a 2-month continuation phase. In the shorter regimen group, 21.0% of patients had unfavorable outcomes, compared with 17.2% of patients in the standard regimen group. Rates of recurrence were 14.6% and 7.1% in the two groups, respectively. [95]
The second study involved a 4-month treatment regimen in which moxifloxacin was substituted for isoniazid for 2 months, followed by moxifloxacin and rifapentine twice weekly for 2 months. This shorter regimen was inferior to both a 6-month regimen with moxifloxacin and to a standard 6-month treatment regimen. [96]
In the third study, ethambutol or isoniazid was replaced with moxifloxacin. Favorable outcomes were seen in 85% and 80% of the two moxifloxacin groups, compared with 92% of the standard treatment group. [97]
Antitubercular agents
Class Summary
The goals of TB treatment are to shorten the clinical course of TB, prevent complications, prevent the development of latency and/or subsequent recurrences, and decrease the likelihood of TB transmission. In patients with latent TB, the goal of therapy is to prevent disease progression.
Isoniazid
This is the drug of choice for use in preventive therapy and the primary drug for use in combination therapy for active TB. It is also used in combination with rifapentine for adults and children aged 2 years or older with latent TB as once-weekly DOT therapy for 12 weeks. Its mechanism of action is not fully known, but isoniazid may inhibit the synthesis of mycolic acid, resulting in disruption of the bacterial cell wall. In patients receiving treatment for active TB, pyridoxine 25-50 mg orally once daily should be coadministered to prevent peripheral neuropathy.
Rifampin (Rifadin)
Rifampin is used in combination with at least 1 other antituberculous drug for the treatment of active TB. It inhibits DNA-dependent RNA polymerase activity in bacterial cells but not in mammalian cells. Cross-resistance may occur.
In most susceptible cases, the patient undergoes 6 months of treatment. Treatment lasts for 9 months if the patient's sputum culture result is still positive after 2 months of therapy.
Pyrazinamide
This is a pyrazine analog of nicotinamide that is either bacteriostatic or bactericidal against M tuberculosis, depending on the concentration of drug attained at the site of infection. Pyrazinamide's mechanism of action is unknown. Administer the drug for the initial 2 months of a 6-month or longer treatment regimen for drug-susceptible TB. Treat drug-resistant TB with individualized regimens.
Ethambutol (Myambutol)
Ethambutol diffuses into actively growing mycobacterial cells (eg, tubercle bacilli). It impairs cell metabolism by inhibiting the synthesis of 1 or more metabolites, which in turn causes cell death. No cross-resistance has been demonstrated.
Mycobacterial resistance is frequent with previous therapy. In such cases, use ethambutol in combination with second-line drugs that have not been previously administered. Administer every 24 hours until permanent bacteriologic conversion and maximal clinical improvement are observed. Absorption is not significantly altered by food.
Adverse effects of ethambutol include optic neuritis, which is usually reversible with discontinuation of the drug. During the period when the patient is on a daily dose of 25 mg/kg, monthly eye exams are recommended.
Streptomycin
Streptomycin sulfate, an aminoglycoside, is used for the treatment of susceptible mycobacterial infections. Use this agent in combination with other antituberculous drugs (eg, isoniazid, ethambutol, rifampin).
Although the total period of treatment for TB is a minimum of 6 months, streptomycin therapy is not commonly used for the full duration of therapy, because of toxicity concerns. The drug is recommended when less potentially hazardous therapeutic agents are ineffective or contraindicated.
Levofloxacin (Levaquin)
Levofloxacin, a second-line antituberculous drug, is used in combination with rifampin and other antituberculous agents in treating most cases of multidrug-resistant TB (MDR-TB). A good safety profile with long-term use among the fluoroquinolones has made levofloxacin the preferred oral agent for treating MDR-TB caused by organisms resistant to first-line drugs. Levofloxacin elicits its action through inhibition of bacterial topoisomerase IV and DNA gyrase, which are required for DNA replication, transcription, repair, and recombination.
Moxifloxacin (Avelox)
Moxifloxacin, a second-line antituberculous drug, inhibits the A subunits of DNA gyrase, resulting in inhibition of bacterial DNA replication and transcription. Moxifloxacin can be used for MDR-TB caused by organisms known or presumed to be sensitive to fluoroquinolones or when first-line drugs cannot be used because of intolerance.
Rifapentine (Priftin)
This agent is used twice weekly as part of a multiple drug regimen for 2 months during the intensive phase of TB treatment, then once weekly for 4 months, along with isoniazid or an appropriate agent for susceptible organisms. It is also indicated for adults and children aged 2 years or older with latent TB in combination with isoniazid as once-weekly therapy for 12 weeks. Rifapentine inhibits DNA-dependent RNA polymerase in susceptible strains of M tuberculosis organisms. It should not be used to treat active tuberculosis in individuals with HIV infection or with positive TB cultures after 2 months of treatment.
Ethionamide (Trecator)
Ethionamide is a second-line drug that is bacteriostatic or bactericidal against M tuberculosis, depending on the concentration of the drug attained at the site of infection. It is recommended if treatment with first-line drugs (isoniazid, rifampin) is unsuccessful. Ethionamide can be used to treat any form of active TB. However, it should be used only with other effective antituberculous agents.
Amikacin
Amikacin is a second-line drug used to treat patients with MDR-TB or those who do not tolerate first-line therapies. This agent irreversibly binds to the 30S subunit of bacterial ribosomes, blocking the recognition step in protein synthesis and causing growth inhibition.
Cycloserine
Cycloserine, a second-line TB drug, inhibits cell wall synthesis in susceptible strains of gram-positive and gram-negative bacteria and in M tuberculosis. It is a structural analogue of D-alanine, which antagonizes the role of D-alanine in bacterial cell wall synthesis, inhibiting growth. Like all antituberculosis drugs, cycloserine should be administered in conjunction with other effective TB drugs and not as the sole therapeutic agent
Capreomycin (Capastat)
Capreomycin, which is obtained from Streptomyces capreolus, is a second-line drug that is coadministered with other antituberculous agents in pulmonary infections caused by capreomycin-susceptible strains of M tuberculosis. Capreomycin is used only when first-line agents (eg, isoniazid, rifampin) have been ineffective or cannot be used because of toxicity or the presence of resistant tubercle bacilli.
Rifabutin (Mycobutin)
This is an ansamycin antibiotic derived from rifamycin S. Rifabutin inhibits DNA-dependent RNA polymerase, preventing chain initiation. It is used for TB treatment in individuals on specific HIV medications, when rifampin is contraindicated (most protease inhibitors).
Clofazimine (Lamprene)
Clofazimine inhibits mycobacterial growth, binding preferentially to mycobacterial DNA. It has antimicrobial properties, but its mechanism of action is unknown. It is rarely used to treat MDR-TB. Like all drugs for TB, clofazimine is always used with other antituberculous agents. Clofazimine is available only on a single-patient basis, to physicians who submit an Investigational New Drug (IND) application to the US Food and Drug Administration (FDA).
Para-aminosalicylic acid (Paser)
This is a bacteriostatic agent that is useful as a second-line agent against M tuberculosis. It is most commonly used for MDR-TB or when therapy with isoniazid or rifampin is not possible. It inhibits the onset of bacterial resistance to streptomycin and isoniazid. Administer this agent with other antituberculous drugs.
Bedaquiline (Sirturo)
Bedaquiline is a diarylquinoline that inhibits mycobacterial adenosine 5'-triphosphate (ATP) synthase, an enzyme essential for the generation of energy in Mycobacterium tuberculosis. It is indicated as part of a 24-week multidrug regimen (with at least 4 other antitubercular drugs) in adults and adolescents aged 5 years or older with pulmonary MDR-TB. Therapy with bedaquiline is reserved for use when an effective treatment regimen cannot otherwise be provided. It is not indicated to treat latent, extrapulmonary, or drug-sensitive tuberculosis.
Pretomanid
Nitroimidazooxazine that kills actively replicating M tuberculosis by inhibiting mycolic acid biosynthesis, thereby blocking cell wall production. It is indicated as part of a combination regimen with bedaquiline and linezolid for treatment pulmonary extensively drug-resistant TB (XDR-TB) or treatment-intolerant or nonresponsive MDR-TB in adults.
Delamanid
Delamanid is a dihydro-nitroimidazooxazole derivative. It acts by inhibiting the synthesis of mycobacterial cell wall. The 2019 WHO Consolidated Guidelines on Drug-Resistant Tuberculosis Treatment has a conditional recommendation that delamanid may be included in the treatment of patients with MDR/rifampin-resistant (RR)-TB aged >3 years on longer regimens.
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Acid-fast bacillus smear showing characteristic cording in Mycobacterium tuberculosis.
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This radiograph shows a patient with typical radiographic findings of tuberculosis.
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This is a chest radiograph taken after therapy was administered to a patient with tuberculosis.
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Anteroposterior chest radiograph of a young patient who presented to the emergency department (ED) with cough and malaise. The radiograph shows a classic posterior segment right upper lobe density consistent with active tuberculosis. This woman was admitted to isolation and started empirically on a 4-drug regimen in the ED. Tuberculosis was confirmed on sputum testing. Image courtesy of Remote Medicine (remotemedicine.org).
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Lateral chest radiograph of a patient with posterior segment right upper lobe density consistent with active tuberculosis. Image courtesy of Remote Medicine (remotemedicine.org).
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Pulmonary tuberculosis with air-fluid level.
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Under a high magnification of 15549x, this scanning electron micrograph depicts some of the ultrastructural details seen in the cell wall configuration of a number of Gram-positive Mycobacterium tuberculosis bacteria. As an obligate aerobic organism, M. tuberculosis can only survive in an environment containing oxygen. This bacterium ranges in length between 2-4 microns, with a width between 0.2-0.5 microns. Image courtesy of the Centers for Disease Control and Prevention/Dr. Ray Butler.
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Numerous acid-fast bacilli (pink) from a bronchial wash are shown on a high-power oil immersion.
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Necrotizing granuloma due to tuberculosis shown on low-power hematoxylin and eosin stain. There is central caseous necrosis and a multinucleated giant cell in the central left. Mixed inflammation is seen in the background.
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This chest radiograph shows asymmetry in the first costochondral junctions of a 37-year-old man who presented with cough and fever. Further clarification with computed tomography is needed.
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Axial noncontrast enhanced computed tomography with pulmonary window shows a cavity with an irregular wall in the right apex of a 37-year-old man who presented with cough and fever (same patient as above).
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Coronal reconstructed computed tomography image shows the right apical cavity in a 37-year-old man who presented with cough and fever (same patient as above).
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This posteroanterior chest radiograph shows right upper lobe consolidation with minimal volume loss (elevated horizontal fissure) and a cavity in a 43-year-old man who presented with cough and fever.
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Axial chest computed tomography without intravenous contrast with pulmonary window setting shows a right apical thick-walled cavity and surrounding lung consolidation in a 43-year-old man who presented with cough and fever (same patient as above).
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Coronal reconstructed computed tomography image shows the consolidated, partially collapsed right upper lobe with a cavity that is directly connected to a bronchus in a 43-year-old man who presented with cough and fever (same patient as above).
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The posteroanterior chest radiograph shows a large cavity with surrounding consolidation in the lingular portion of the left upper lobe in a 43-year-old man who presented with cough and hemoptysis. There are also a few nodular opacities in the right mid-lung zone.
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Axial chest computed tomography without intravenous contrast with pulmonary window setting through the mid-chest shows a large, irregular-walled cavity with nodules and air-fluid level and two smaller cavities in a 43-year-old man who presented with cough and hemoptysis (same patient as above). Small, patchy peripheral opacities are also present in the left lower lobe. In the right mid-lung, nodular opacities are in a tree-in-bud distribution, suggestive of endobronchial spread.
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Coronal reconstructed computed tomography image shows the lingular cavity with irregular nodules and right mid-lung nodular opacities in a 43-year-old man who presented with cough and hemoptysis (same patient as above).
