Drugs Acting on Mycobacteria – A Brief Overview from the Perspective of Internal Medicine
a) Isoniazid
Isoniazid is bactericidal for replicating bacteria and bacteriostatic for non-replicating bacteria. It is activated by mycobacterial catalase-peroxidase (KatG) and inhibits the InhA gene product—a reductase involved in mycolic acid synthesis. Mutations in the KatG or InhA genes result in resistance to isoniazid, which was observed in 15% of patients with M. tuberculosis worldwide in 2013. Isoniazid is well absorbed orally and metabolized through acetylation in the liver. Major side effects include hepatitis, neuropathy (the risk of which is reduced by concomitant pyridoxine administration), and hypersensitivity reactions.
b) Rifampicin
Rifampicin inhibits DNA-dependent RNA polymerase and is bactericidal against replicating bacteria. It is also active in necrotic foci where mycobacteria have low replication rates, making it crucial for sterilization and sputum culture conversion. Resistance to rifampicin is often associated with the RNA polymerase beta-subunit and is common in multidrug-resistant TB (MDR-TB). Rifampicin is well absorbed orally and metabolized in the liver by the microsomal cytochrome P450 system. It is a potent inducer of several P450 isoenzymes, leading to numerous drug interactions. Common side effects include hepatitis, flu-like symptoms, and hypersensitivity reactions. Rifampicin typically causes urine and other body fluids to turn orange.
c) Pyrazinamide
The exact mechanism of pyrazinamide is not fully understood but includes the inhibition of fatty acid synthase and ribosomal trans-translation. Pyrazinamide is often bacteriostatic but can be bactericidal against persisting bacteria active at low pH levels. Primary resistance to pyrazinamide is rare, but MDR-TB strains are often resistant, and primary resistance is characteristic of Mycobacterium bovis strains. Pyrazinamide is well absorbed orally and metabolized in the liver. Side effects include nausea, hepatitis, asymptomatic hyperuricemia, and myalgias.
d) Ethambutol
Ethambutol is a bacteriostatic agent. It inhibits arabinosyltransferase, which is involved in the synthesis of arabinogalactan—a component of the mycobacterial cell wall. Resistance to ethambutol is usually observed in the presence of resistance to other anti-mycobacterial agents, such as MDR-TB strains. Ethambutol is absorbed orally but poorly penetrates cerebrospinal fluid (CSF) and is excreted by the kidneys. The main side effect is optic neuritis, resulting in the loss of red-green color discrimination and reduced visual acuity. Ethambutol can also cause hepatitis.
e) Streptomycin
Streptomycin belongs to the aminoglycoside group, sharing their mechanism of action and side effects. It is administered intramuscularly (IM).
These drugs are the cornerstone of anti-tuberculosis therapy, each with specific mechanisms of action, absorption characteristics, and side effects. Proper administration and monitoring are essential to ensure efficacy and manage resistance and adverse effects.
e) Other Antituberculosis Agents
Second-line Drugs
When multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains of tuberculosis (TB) are identified, second-line drugs are employed. These include aminoglycosides (amikacin, capreomycin, and kanamycin) and fluoroquinolones (moxifloxacin and levofloxacin).
Other oral second-line drugs include:
- Cycloserine: Known for its neuropsychiatric side effects.
- Ethionamide and Prothionamide: Ineffective in cases of InhA-mediated resistance, but they penetrate well into the cerebrospinal fluid (CSF). Their side effects include gastrointestinal disturbances, hepatotoxicity, and neurotoxicity.
- Para-aminosalicylic acid: Known to cause rash and gastrointestinal symptoms.
Linezolid can also be used and penetrates well into the CSF. Meropenem with clavulanate is used in rare cases. New drugs developed for XDR-TB treatment include delamanid and bedaquiline. Their side effects include QT interval prolongation and heart rhythm disturbances, necessitating careful risk assessment when used alongside other drugs with similar side effects (e.g., fluoroquinolones).
f) Clofazimine
Clofazimine is used against Mycobacterium leprae and resistant strains of M. tuberculosis. Its mechanism of action might involve the induction of oxidative stress, and it has weak bactericidal activity. Clofazimine is variably absorbed after oral administration and is excreted via bile. Side effects include gastrointestinal disturbances, dry eyes and skin, and skin hyperpigmentation, particularly in individuals with darker skin.