Mycobacterium tuberculosis, also known as Koch’s bacillus, is a species of pathogenic bacteria that is the causative agent of tuberculosis. It was first discovered in 1882 by Robert Koch1.
The bacterium has an unusual, waxy coating on its cell surface primarily due to the presence of mycolic acid. This coating makes the cells impervious to Gram staining, and as a result, M. tuberculosis can appear weakly Gram-positive. Acid-fast stains such as Ziehl–Neelsen, or fluorescent stains such as auramine are used instead to identify M. tuberculosis with a microscope1.
The physiology of M. tuberculosis is highly aerobic and requires high levels of oxygen. Primarily a pathogen of the mammalian respiratory system, it infects the lungs. The most frequently used diagnostic methods for tuberculosis are the tuberculin skin test, acid-fast stain, culture, and polymerase chain reaction.
Tuberculosis (TB) is a contagious infection that mainly affects the lungs but can also affect any other organ including bone, brain, and spine. It spreads through infected droplets, released in the air by coughing, sneezing, etc., by the affected individual. It usually spreads after prolonged exposure with the infected individual. Immunocompromised individuals are at higher risk of contracting the infection.
Drugs used for the treatment of tuberculosis:
| Class | Drug Name | Mechanism of action |
|
First-Line Drugs | Isoniazid (INH) | Inhibits mycolic acid synthesis by targeting InhA and KasA enzymes, essential for mycobacterial cell wall synthesis |
| Rifampin (RIF) | Inhibits bacterial RNA synthesis by binding to the β-subunit of DNA-dependent RNA polymerase, preventing RNA elongation | |
| Ethambutol (EMB) | Inhibits arabinogalactan synthesis by targeting the enzyme arabinosyl transferase (EmbB), which is involved in cell wall synthesis | |
| Pyrazinamide (PZA) | Converted into its active form, pyrazinoic acid (POA), which disrupts mycobacterial membrane transport and energy production by inhibiting the enzyme fatty acid synthase I (FASI) and interfering with membrane potential | |
| Rifabutin (RBT) | Similar to rifampin, these inhibit bacterial RNA synthesis by binding to the β-subunit of DNA-dependent RNA polymerase, preventing RNA elongation. | |
| Rifapentine (RPT) | ||
|
Second-Line Drugs | Streptomycin (SM) | Inhibit bacterial protein synthesis by binding to the 30S ribosomal subunit, causing misreading of mRNA codons and premature termination of translation. |
| Amikacin (AMK) | ||
| Kanamycin (KM) | ||
| Capreomycin (CPM) | Inhibits bacterial protein synthesis by binding to the 70S ribosome and interfering with the formation of the 70S initiation complex. | |
| Levofloxacin (LVX) | Inhibit bacterial DNA gyrase and topoisomerase IV, enzymes essential for DNA replication, transcription, and repair. | |
| Moxifloxacin (MXF) | ||
| Gatifloxacin (GFX) | ||
| Ethionamide (ETH) | Inhibit mycolic acid synthesis by targeting the enzyme enoyl-acyl carrier protein reductase (InhA), involved in fatty acid biosynthesis. | |
| Prothionamide (PTH) | ||
| Cycloserine (CS) | Inhibits bacterial cell wall synthesis by competitively inhibiting enzymes L-alanine racemase and D-alanyl-D-alanine ligase, which are involved in peptidoglycan biosynthesis | |
| Para-aminosalicylic acid (PAS) | Inhibits bacterial folic acid synthesis by acting as a competitive inhibitor of dihydropteroate synthase (DHPS) and dihydrofolate reductase (DHFR), enzymes involved in the production of tetrahydrofolic acid, which is essential for DNA synthesis | |
| Linezolid (LZD) | Inhibits bacterial protein synthesis by binding to the 50S ribosomal subunit, preventing the formation of a functional 70S initiation complex | |
| Clofazimine (CFZ) | Binds to bacterial DNA, disrupting its structure and function; also interferes with cell membrane potential, causing the generation of reactive oxygen species that damage bacterial cells | |
| Bedaquiline (BDQ) | Inhibits mycobacterial ATP synthase (F-ATPase), an enzyme essential for ATP production and energy metabolism | |
| Delamanid (DLM) | Inhibits mycolic acid synthesis by targeting the enzyme enoyl-acyl carrier protein reductase (InhA), involved in fatty acid biosynthesis, and disrupting the formation of methoxy- and keto-mycolic acids | |
|
Pretomanid (PRT) | Converted into reactive nitrogen species (RNS) under hypoxic conditions, which disrupts mycobacterial membrane transport and energy production, damages bacterial DNA, and inhibits cell respiration |
Phases and Drugs of Tuberculosis Treatment
| Treatment Phase | Duration | Drugs |
|---|---|---|
| Intensive | 2 months | Isoniazid (H), Rifampicin (R), Pyrazinamide (Z), Ethambutol (E) OR Isoniazid (H), Rifampicin (R), Pyrazinamide (Z), Streptomycin (S) |
| Continuous | 4-7 months OR 9-10 months (for INH-resistant TB) | Isoniazid (H), Rifampicin (R) OR Isoniazid (H) only (for INH-resistant TB) |
During the intensive phase, which lasts for two months, patients are typically prescribed a four-drug regimen of isoniazid, rifampicin, pyrazinamide, and either ethambutol or streptomycin. The continuous phase follows the intensive phase and lasts for 4-7 months, during which patients receive a two-drug regimen of isoniazid and rifampicin. The continuous phase may be extended to 9-10 months for patients with isoniazid-resistant TB treated with isoniazid alone. The duration of both phases may vary depending on the severity of the infection and the patient’s response to treatment.
Isoniazid (H): A Key Drug in Tuberculosis Treatment
Isoniazid is a prodrug activated by the enzyme catalase-peroxidase, coded by the gene KatG. Its active metabolite inhibits ketoenoylreductase, an enzyme essential for mycolic acid synthesis, a vital component of the mycobacterial cell wall. This drug is effective against both intra- and extra-cellular mycobacteria, demonstrating bacteriostatic action against resting organisms and bactericidal action against rapidly multiplying ones. Isoniazid is widely distributed in the body and penetrates the cerebrospinal fluid effectively.
Isoniazid (INH) is an antibiotic used primarily as a first-line agent in the treatment of tuberculosis. Its mechanism of action is quite interesting. Here’s a summarized explanation of its mechanism of action:
Targeting Mycolic Acid Synthesis: Isoniazid is a prodrug and requires activation by the bacterial catalase-peroxidase enzyme, KatG. Once activated, it interferes with the synthesis of mycolic acid, a component of the bacterial cell wall.
Inhibition of Enzyme: The activated form of isoniazid forms a complex with NAD (Nicotinamide Adenine Dinucleotide) to produce an INH-NAD adduct. This adduct then binds to and inhibits the enzyme enoyl-acyl carrier protein reductase (InhA), which is involved in the synthesis of mycolic acid.
Cell Wall Disruption: As a result of the inhibition of mycolic acid synthesis, the bacterial cell wall becomes weak, leading to bacterial cell lysis and death.
Here’s a visual representation of the mechanism of action of Isoniazid (INH):
- The KatG enzyme activates Isoniazid (INH).
- The activated INH forms a complex with NAD to produce the INH-NAD adduct.
- This adduct inhibits the InhA enzyme.
- The disruption of the InhA enzyme leads to a disruption in mycolic acid synthesis.
- As a result, the bacterial cell wall becomes weak, leading to bacterial cell death.
Rifampicin (R): A Powerful Bactericidal Agent
Rifampicin is a derivative of rifamycin and works by inhibiting DNA-dependent RNA polymerase, resulting in bactericidal activity against dividing and non-dividing mycobacteria. This antibiotic penetrates various barriers, including the blood-brain and placental barriers, and is effective against intra- and extra-cellular bacilli. Rifampicin is unique in its ability to kill dormant bacteria in solid caseous lesions. Additionally, it is utilized in leprosy treatment and as a prophylactic drug for meningococcal and staphylococcal carrier states.
Pyrazinamide (Z): Sterilizing Activity Against Slowly Replicating Bacteria
Pyrazinamide is a weakly bactericidal drug, exhibiting its most significant activity against slowly replicating bacteria in acidic environments, such as intracellular sites and areas of inflammation. This drug demonstrates the highest sterilizing activity among anti-mycobacterial antibiotics and is effective only against intracellular mycobacteria.
Ethambutol (E): A Bacteriostatic Agent for Mycobacterium
Ethambutol is a bacteriostatic agent that inhibits the synthesis of arabinogalactan, a component of the mycobacterial cell wall, by blocking arabinosyl transferase. This drug is distributed throughout the body but does not penetrate the cerebrospinal fluid effectively.
Streptomycin (S): A Tuberculocidal Aminoglycoside
Streptomycin is an aminoglycoside antibiotic with tuberculocidal properties. Administered via intramuscular injection, it is active only against extra-cellular bacteria and is not hepatotoxic. Streptomycin is contraindicated during pregnancy.
Second-Line Anti-Tubercular Agents
In cases where patients are resistant to first-line drugs or are intolerant to them, second-line anti-tubercular agents are employed. These drugs are generally more toxic and less effective, but they play a crucial role in managing drug-resistant TB cases.
Fluoroquinolones
This class of drugs includes ofloxacin, moxifloxacin, and levofloxacin, which are effective against both Mycobacterium tuberculosis and Mycobacterium avium complex (MAC) in AIDS patients. They inhibit bacterial DNA gyrase and topoisomerase IV, thus disrupting DNA replication and transcription.
Injectable Aminoglycosides
Kanamycin and amikacin are two injectable aminoglycosides used in the treatment of multi-drug resistant (MDR) tuberculosis. They act by binding to bacterial 30S ribosomal subunit, causing errors in protein synthesis and ultimately leading to bacterial death.
Polypeptide Antibiotics
Capreomycin is an injectable polypeptide antibiotic used in the treatment of MDR-TB. It inhibits bacterial protein synthesis by binding to the 50S ribosomal subunit, leading to bacterial cell death. However, capreomycin can cause ototoxicity, nephrotoxicity, hypokalemia, and hypomagnesemia as side effects.
Newer Macrolides
Azithromycin and clarithromycin are effective against non-tubercular atypical mycobacteria. They inhibit bacterial protein synthesis by binding to the 50S ribosomal subunit, preventing peptide chain elongation.
Thioamides
Ethionamide is a tuberculostatic drug that can cause hepatitis, optic neuritis, and hypothyroidism. It shares a similar mechanism of action with isoniazid, and bacteria resistant to isoniazid are cross-resistant to ethionamide. It can also be used in the treatment of leprosy.
Cycloserine
This cell wall synthesis inhibitor can cause neuropsychiatric adverse effects. Its mechanism of action involves the inhibition of an enzyme called D-alanine racemase. This enzyme is essential for synthesising the bacterial cell wall, specifically for forming peptidoglycan. Cycloserine binds to the D-alanine racemase enzyme and disrupts its function, inhibiting cell wall synthesis in TB bacteria. By blocking the formation of the peptidoglycan layer, the bacterial membrane becomes weak and more susceptible to damage, ultimately leading to cell death.
Para-Amino Salicylic Acid (PAS)
PAS is a bacteriostatic drug related to sulfonamides and acts through a similar mechanism. It can cause kidney, liver, and thyroid dysfunction as side effects.
New Drugs for Tuberculosis/New Antitubercular Drugs
Bedaquiline: An inhibitor of mycobacterial ATP synthase, bedaquiline is used as part of multi-drug therapy in adults with pulmonary MDR-TB. It can cause QT prolongation as a side effect.
Delamanid: A nitroimidazole compound (similar to metronidazole) that inhibits mycolic acid synthesis, delamanid can be used in the treatment of extensively drug-resistant (XDR) tuberculosis. The major adverse effect of delamanid is QT prolongation.
Pretomanid: used in combination with bedaquiline and linezolid for the treatment of pulmonary extensively drug-resistant tuberculosis (XDR-TB) in adults. It is a diarylquinoline compound that targets the bacterial ATP synthase enzyme, disrupting the production of energy in TB bacteria. This is taken orally once every day and can cause side effects such as nausea, vomiting, headache, and diarrhea.
Treatment of Tuberculosis: RNTCP 2016 Guidelines
Under the Revised National Tuberculosis Control Program (RNTCP) 2016 guidelines, combination chemotherapy is administered under direct observation (DOTS; Directly Observed Treatment Short-course chemotherapy) to prevent the emergence of drug resistance.
Drug-sensitive tuberculosis cases are divided into two categories:
- Category I: New patients who have not been exposed to anti-tubercular agents or have taken anti-tubercular drugs for less than one month.
- Category II: Old cases who have previously taken anti-tubercular drugs for more than one month (relapse, treatment after default, treatment failure, or chronic cases).
Category I Treatment Regimen
The Category I regimen consists of an intensive phase followed by a continuation phase. The intensive phase includes 2 months of isoniazid (H), rifampicin (R), pyrazinamide (Z), and ethambutol (E), followed by a continuation phase of 4 months of isoniazid and rifampicin.
The regimen is represented as: 2(HRZE) / 4(HR)
Category II Treatment Regimen
The Category II regimen is for patients who have been previously treated for TB and is designed to address potential drug resistance. It consists of an intensive phase and a continuation phase. The intensive phase includes 2 months of isoniazid (H), rifampicin (R), pyrazinamide (Z), ethambutol (E), and streptomycin (S), followed by 1 month of isoniazid, rifampicin, pyrazinamide, and ethambutol. The continuation phase consists of 5 months of isoniazid, rifampicin, and ethambutol.
The regimen is represented as: 2(HRZES) / 1(HRZE) / 5(HRE)
Treatment of Multi-drug Resistant Tuberculosis (MDR-TB)
The management of MDR-TB requires a combination of first-line and second-line anti-tubercular drugs. The World Health Organization (WHO) recommends an individualized treatment regimen based on drug susceptibility testing (DST) results, with a minimum of five effective drugs during the intensive phase, including pyrazinamide, a fluoroquinolone, and at least one injectable aminoglycoside (e.g., amikacin or kanamycin).
The intensive phase typically lasts for 8 months, followed by a continuation phase without injectable drugs for an additional 12 to 20 months. The total treatment duration for MDR-TB is at least 20 months, but it can be extended based on individual patient response.
Treatment of Extensively Drug-resistant Tuberculosis (XDR-TB)
XDR-TB is a more severe form of drug-resistant TB that is resistant to at least one fluoroquinolone and one injectable second-line agent. Treatment of XDR-TB is complex and requires a combination of first-line, second-line, and newer anti-tubercular drugs, including bedaquiline and delamanid, based on drug susceptibility testing results.
The treatment duration for XDR-TB is typically longer than that of MDR-TB and may last up to 24 months or more. Treatment success rates are lower for XDR-TB compared to MDR-TB, and the management of XDR-TB often requires the expertise of specialized centers and multidisciplinary teams.
The treatment of tuberculosis involves a combination of first-line and second-line anti-tubercular drugs, depending on the patient’s drug susceptibility and prior treatment history. The use of directly observed treatment (DOTS) and adherence to treatment guidelines is crucial to prevent the development of drug resistance and ensure successful treatment outcomes.
Atypical mycobacterial infections
Atypical mycobacterial infections necessitate the administration of prophylactic measures, with clarithromycin or azithromycin being recommended for Mycobacterium avium complex (MAC) in individuals whose CD4 count is below 50μl. The treatment of MAC entails the REC regimen which involves the use of rifabutin in combination with ethambutol and clarithromycin/azithromycin. Azithromycin, due to its long half-life, can be used as a once-weekly dose instead of the daily dose of clarithromycin for prophylaxis of MAC. In addition to clarithromycin and azithromycin, quinolones such as ciprofloxacin, levofloxacin, moxifloxacin, and gatifloxacin, as well as amikacin, have demonstrated efficacy against atypical mycobacteria.
Disclaimer: This article is for informational purposes only and does not constitute medical advice. Always seek the advice of a healthcare provider with any questions regarding a medical condition.
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