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Chapter: Modern Pharmacology with Clinical Applications: Drugs Used in Tuberculosis and Leprosy

Second-Line Antituberculous Drugs

Para-aminosalicylic Acid (PAS), like the sulfonamides , is a structural analogue of p-aminobenzoic acid (PABA).




Para-aminosalicyclic Acid


Para-aminosalicylic Acid (PAS), like the sulfonamides , is a structural analogue of p-aminobenzoic acid (PABA). It is a folate synthesis an-tagonist that interferes with the incorporation of PABA into folic acid. PAS is bacteriostatic, and in vitro, most strains of M. tuberculosis are sensitive to a concentra-tion of 1  μg/mL. The antibacterial activity of PAS is highly specific for M. tuberculosis; it is not effective against other mycobacterium species.


PAS is readily absorbed from the GI tract and is widely distributed throughout body fluids except cere-brospinal fluid. It penetrates tissues and reaches high concentrations in the tuberculous cavities and caseous tissue. Peak plasma levels are reached within 1 to 2 hours of drug administration, and the drug has a half-life of about an hour. PAS is primarily metabolized by hepatic acetylation. When combined with isoniazid, PAS can function as an alternative substrate and block hepatic acetylation of isoniazid, thereby increasing free isoniazid levels. Both the acetylated and unaltered drug are rapidly excreted in the urine. The concentration of PAS in urine is high and may result in crystalluria.


Use of PAS has diminished over the years following the introduction of more effective drugs, such as ri-fampin and ethambutol. At present, therapy with PAS is limited to the treatment of MDR tuberculosis. Problems with primary resistance, poor compliance due to GI intolerance, and lupuslike reactions have further discouraged its use.





Ethionamide (Trecator) is a derivative of isonicotinic acid and is chemically related to isoniazid. It is a sec-ondary agent used in combination when primary agents are ineffective or contraindicated; it is a bacteriostatic antituberculosis agent. Its exact mechanism of action is unknown but is believed to involve inhibition of oxygen-dependent mycolic acid synthesis. It is thought that mutations in the region of the (inhA) gene that are involved in mycolic acid synthesis can cause both isoni-azid and ethionamide resistance.


Ethionamide is well absorbed following oral admin-istration. It is rapidly and widely distributed to all body tissues and fluids, including the cerebrospinal fluid. Metabolism of ethionamide is extensive, and several di-hydropyridine metabolites are produced. Less than 1% of the drug is eliminated in the urine unchanged.


GI disturbances, including nausea, vomiting, and in-tense gastric irritation, are frequent. In addition, ethion-amide may cause a wide range of neurological side effects, such as confusion, peripheral neuropathy, psy-chosis, and seizures. Neurological effects can be mini-mized by pyridoxine supplementation. Other rare side effects include gynecomastia, impotence, postural hy-potension, and menorrhagia.




Cycloserine is a broad-spectrum antibiotic produced by Streptomyces orchidaceus. It is structural analogue of D-alanine and acts through a competitive inhibition of the D-alanine that is involved in bacterial cell wall synthesis. Cycloserine is inhibitory to M. tuberculosis and active against Escherichia coli, S. aureus, and Enterococcus, Nocardia, and Chlamydia spp. It is used in the treatment of MDR tuberculosis and is useful in renal tuberculosis, since most of the drug is excreted unchanged in the urine.


Cycloserine is readily absorbed orally and distributes throughout body fluids including the cerebrospinal fluid. The concentrations of cycloserine in tissues, body fluids, and the cerebrospinal fluid are approximately equal to the plasma level. Cycloserine is partially metabolized, and 60 to 80% is excreted unchanged by the kidney.


Neurological symptoms, which tend to appear in the first week of therapy, consist of dizziness, confusion, ir-ritability, psychotic behavioral changes, and even suici-dal ideation. Cycloserine is contraindicated in patients with underlying psychiatric and seizure disorders. Other side effects include occasional peripheral neuropathy and low magnesium levels.




Rifabutin (Mycobutin), an antibiotic related to ri-fampin, shares its mechanism of action, that is, inhibi-tion of RNA polymerase. Rifabutin has significant ac-tivity in vitro and in vivo against M. avium-intracellular complex (MAC) isolates from both HIV-infected and non–HIV-infected individuals. It has better activity against MAC organisms than rifampin. Rifabutin is ac-tive against M. tuberculosis, including some rifampin-resistant strains, such as M. leprae and M. fortuitum. It has a spectrum of activity against gram-positive and gram-negative organisms similar to that of rifampin. The mo-lecular basis for resistance to rifabutin is shared by both rifampin and rifabutin; this explains the virtually com-plete cross-resistance that occurs between these drugs.


Rifabutin is well absorbed orally, and peak plasma concentrations are reached in 2 to 3 hours. Because of its lipophilicity, rifabutin achieves a 5- to 10-fold higher concentration in tissues than in plasma. The drug has a half-life range of 16 to 96 hours and is eliminated in urine and bile.


Rifabutin appears as effective as rifampin in the treatment of drug-susceptible tuberculosis and is used in the treatment of latent tuberculosis infection either alone or in combination with pyrazinamide. Clinical use of rifabutin has increased in recent years, especially in the treatment of HIV infection. It is a less potent inducer of cytochrome 450 enzymes pathways than ri-fampin and results in less drug interaction with the protease inhibitors and nonnucleoside reverse tran-scriptase inhibitors. Rifabutin is therefore commonly substituted for rifampin in the treatment of tuberculosis in HIV-infected patients. Another important use of ri-fabutin in the HIV-infected population is prevention and treatment of disseminated MAC.

The adverse effects that most frequently result in discontinuation of rifabutin include GI intolerance, rash, and neutropenia. Rifabutin levels will be increased with concurrent administration of fluconazole and clar-ithromycin, resulting in anterior uveitis, polymyalgia syndrome, and a yellowish-tan discoloration of the skin (pseudojaundice). Other adverse reactions are similar to those of rifampin, such as hepatitis, red-orange dis-coloration of body fluids, and drug interactions due to effects on the hepatic P450 cytochrome enzyme system.




Rifapentine is an analogue of rifampin that is active against M. tuberculosis and M. avium. Rifapentine’s mechanism of action, cross-resistance, hepatic induction of P450 enzymes, drug interactions, and toxic profile are similar to those of rifampin. It has been used in the treatment of tuberculosis caused by rifampin-susceptible strains.





Capreomycin (Capastat) is a polypeptide antibiotic de-rived from Streptomyces capreolus. It is bacteriostatic against most strains of M. tuberculosis, including the MDR strain. In addition, it is active against M. kansasii, M. avium, and in high concentrations, some gram-positive and gram-negative bacteria. Like other antitu-bercular drugs, resistance to capreomycin occurs rapidly if the drug is used alone. There is no cross-resistance be-tween streptomycin and capreomycin, but some isolates resistant to capreomycin are resistant to viomycin.


Capreomycin is poorly absorbed from GI tract and so must be given parenterally. It is excreted mainly un-changed in the urine following glomerular filtration. Capreomycin is a used as a second-line agent in combi-nation with other drugs. It appears to be particularly useful in multidrug regimens for the treatment of drug-resistant tuberculosis, especially with streptomycin re-sistance. Capreomycin is associated with ototoxicity and nephrotoxicity, and these adverse effects can be severe in patients with preexisting renal insufficiency.


Amikacin and Kanamycin


Amikacin and kanamycin  have been used in the treatment of tuberculosis. Amikacin is very active against several mycobacterium species; however, it is expensive and has significant toxicity. It is consid-ered in the treatment of MDR tuberculosis after strep-tomycin and capreomycin. An additional use of amikacin is in the treatment of disseminated MAC in AIDS patients. There is no cross-resistance between streptomycin and other aminoglycosides; most M. tu-berculosis strains that are resistant to streptomycin aresensitive to kanamycin. The latter drug may be pre-ferred over viomycin due to its lower toxicity.




Viomycin is a complex polypeptide antibiotic that is ac-tive against MDR strains of tuberculosis. Cross-resist-ance between viomycin and kanamycin is less frequent than between viomycin and capreomycin.




Clofazimine has some activity against M. tuberculosis and is used as a last resort drug for the treatment of MDR tuberculosis. It is primarily used in the treatment of M. leprae and M. avium-intracellulare. Further details are discussed later, under the treatment of leprosy.




The macrolide antibiotics  clar-ithromycin and azithromycin have demonstrated in vitro activity against mycobacteria, although they have limited activity against M. tuberculosis. Clarithromycin is four times as active as azithromycin against M. avium-intracellulare in vitro. Azithromycin’s lower potency may be compensated for by its greater intracellular pen-etration and its two-fold higher tissue levels than plasma levels. Clarithromycin with azithromycin, in combination with other drugs, has gained an important role in the prevention and treatment of MAC in HIV-infected patients.





Thiacetazone is active against many strains of M. tuber-culosis. It is not marketed in the United States. However, because of its low cost, it is used as a first-line agent in East Africa, especially in combination with compounds such as isoniazid. The most common side effects of thiacetazone include GI intolerance and de-velopment of rashes. It causes significant ototoxicity, es-pecially when coadministered with streptomycin. Life-threatening hypersensitivity reactions, such as hepatitis, transient marrow aplastic syndromes, neutropenia, and thrombocytopenia, have been reported.


Quinolones: Ciprofloxacin, Levofloxacin and Ofloxacin


Most of the fluoroquinolones antibiotics  have activity against M. tuberculosis and M. avium-intracellulare. Ciprofloxacin, ofloxacin, and levofloxacin inhibit 90% of the strains of susceptible tubercula bacilli at concentrations of less than 2  μg/mL. Levofloxacin is preferred because it is the active L-optical isomer of ofloxacin and is approved for once-daily use. Thequinolones act by inhibition of bacterial DNA gyrase. Resistance is the result of spontaneous mutations in genes that either change the DNA gyrase or decrease the ability of the drug to cross the cell membrane.


Quinolones are important recent additions to the therapeutic agents used against M. tuberculosis, espe-cially in MDR strains. Clinical trials of ofloxacin in com-bination with isoniazid and rifampin have indicated ac-tivity comparable to that of ethambutol. In addition, quinolones, particularly ciprofloxacin, are used as part of a combined regimen in HIV-infected patients.


β-Lactam and Clavulanate Antibiotics


All mycobacteria produce β-lactamase. In vitro, several β-lactamase-resistant antibiotics or a combination of a β-lactam with β-lactamase inhibitors, such as clavulanic acid, are active against M. tuberculosis and nontubercu-lous mycobacteria. However, the activity of β-lactam agents against intracellular mycobacteria is generally poor. The β-lactam agents may be useful in the treat-ment of MDR tuberculosis in combination with other antitubercular drugs but never as monotherapy.


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