NCLEX: Antimycobacterial Drugs

Mycobacteria are rod-shaped aerobic bacilli that multiple slowly, every 18 to 24 hours in vitro. Their cell walls contain mycolic acids, which give the genus its name. Mycolic acids are very long-chain, β-hydroxylated fatty acids. Mycobacteria produce highly lipophilic cell walls that stain poorly with Gram stain. Once stained, the bacilli are not decolorized easily by acidified organic solvents. Hence, the organisms are called “acid-fast bacilli.” Mycobacterial infections classically result in the formation of slow growing, granulomatous lesions that cause tissue destruction anywhere in the body.

Mycobacterium tuberculosis can cause latent tuberculosis infection (LTBI) and the disease known as tuberculosis (TB). [Note: In LTBI, the patient is infected with M. tuberculosis but does not have any signs or symptoms of active TB disease.] TB is the leading infectious cause of death worldwide, and over 2 billion people already have been infected (roughly 10 million are in the United States). Increasing in frequency are diseases caused by nontuberculosis mycobacteria (NTM). These species include M. avium-intracellulare, M. chelonae, M. abscessus, M. kansasii, and M. fortuitum. Finally, M. leprae causes leprosy.

TB treatment generally includes four first-line drugs. Second-line drugs are typically less effective, more toxic, and less extensively studied. They are used for patients who cannot tolerate the first-line drugs or who are infected with resistant TB. No drugs are specifically developed for NTM infections. Macrolides, rifamycins, and aminoglycosides are frequently included, but NTM regimens vary widely by organism.

Antimycobacterial Drugs


Focus topic: Antimycobacterial Drugs

M. tuberculosis is slow growing and requires treatment for months to years. LTBI can be treated for 9 months with isoniazid (INH) monotherapy or with 12 once-weekly doses of INH (900 mg) and rifapentine (900 mg). In contrast, active TB disease must be treated with several drugs. Treatment for drug-susceptible TB lasts for at least 6 months, while treatment of multidrug-resistant TB (MDR-TB) typically lasts for about 2 years.

A. Strategies for addressing drug resistance

Populations of M. tuberculosis contain small numbers of organisms that are naturally resistant to a particular drug. Under selective pressure from inadequate treatment, especially from monotherapy, these resistant TB can emerge as the dominant population. Multidrug therapy is employed to suppress these resistant organisms. The first-line drugs isoniazid, rifampin, ethambutol, and pyrazinamide are preferred because of their high efficacy and acceptable incidence of toxicity. Rifabutin or rifapentine may replace rifampin under certain circumstances. Active disease always requires treatment with multidrug regimens, and preferably three or more drugs with proven in vitro activity against the isolate. Although clinical improvement can occur in the first several weeks of treatment, therapy is continued much longer to eradicate persistent organisms and to prevent relapse.

Standard short-course chemotherapy for tuberculosis includes isoniazid, rifampin, ethambutol, and pyrazinamide for 2 months (the intensive phase), followed by isoniazid and rifampin for 4 months (the continuation phase; Once susceptibility data are available, the drug regimen can be individually tailored. Second-line regimens for MDR-TB (TB resistant to at least isoniazid and rifampin) normally include an aminoglycoside (streptomycin, kanamycin, or amikacin) or capreomycin (all injectable agents), a fluoroquinolone (typically levofloxacin or moxifloxacin), any first-line drugs that remain active, and one or more of the following: cycloserine, ethionamide, or p-aminosalicylic acid. For extensively drug resistant TB (XDR-TB), clofazimine, linezolid, and other drugs may be employed empirically.

Patient adherence can be low when multidrug regimens last for 6 months or longer. One successful strategy for achieving better treatment completion rates is directly observed therapy, also known as DOT. Patients take their medications while being watched by a member of the health care team. DOT has been shown to decrease drug resistance and to improve cure rates. Most public health departments offer DOT services.

Antimycobacterial Drugs

Antimycobacterial Drugs


B. Isoniazid

Isoniazid [eye-so-NYE-a-zid], along with rifampin, is one of the two most important TB drugs.

  • Mechanism of action: Isoniazid is a prodrug activated by a mycobacterial catalase–peroxidase (KatG). Isoniazid targets the enzymes acyl carrier protein reductase (InhA) and β-ketoacyl-ACP synthase (KasA), which are essential for the synthesis of mycolic acid. Inhibiting mycolic acid leads to a disruption in the bacterial cell wall.
  • Antibacterial spectrum: Isoniazid is specific for treatment of M. tuberculosis, although M. kansasii may be susceptible at higher drug concentrations. Most NTM are resistant to INH. The drug is particularly effective against rapidly growing bacilli and is also active against intracellular organisms.
  • Resistance: Resistance follows chromosomal mutations, including 1) mutation or deletion of KatG (producing mutants incapable of prodrug activation), 2) varying mutations of the acyl carrier proteins, or 3) overexpression of the target enzyme InhA. Crossresistance may occur between isoniazid and ethionamide.
  • Pharmacokinetics: Isoniazid is readily absorbed after oral administration. Absorption is impaired if isoniazid is taken with food, particularly high-fat meals. The drug diffuses into all body fluids, cells, and caseous material (necrotic tissue resembling cheese that is produced in tuberculous lesions). Drug concentrations in the cerebrospinal fluid (CSF) are similar to those in the serum. Isoniazid undergoes N-acetylation and hydrolysis, resulting in inactive products. [Note: Isoniazid acetylation is genetically regulated, with the fast acetylators exhibiting a 90-minute serum half-life, as compared to 3 to 4 hours for slow acetylators.] Excretion is through glomerular filtration and secretion, predominantly as metabolites. Slow acetylators excrete more of the parent compound.
  • Adverse effects: Hepatitis is the most serious adverse effect associated with isoniazid. If hepatitis goes unrecognized, and if isoniazid is continued, it can be fatal. The incidence increases with age (greater than 35 years old), among patients who also take rifampin, or among those who drink alcohol daily. Peripheral neuropathy (manifesting as paresthesia of the hands and feet) appears to be due to a relative pyridoxine deficiency. This can be avoided by supplementation of 25 to 50 mg per day of pyridoxine (vitamin B6). Central nervous system (CNS) adverse effects can occur, including convulsions in patients prone to seizures. Hypersensitivity reactions with isoniazid include rashes and fever. Because isoniazid inhibits the metabolism of carbamazepine and phenytoin, isoniazid can potentiate the adverse effects of these drugs (for example, nystagmus and ataxia).

Antimycobacterial Drugs

Antimycobacterial Drugs

C. Rifamycins: rifampin, rifabutin, and rifapentine

Rifampin, rifabutin, and rifapentine are all considered rifamycins, a group of structurally similar macrocyclic antibiotics, which are first-line oral agents for tuberculosis.

1. Rifampin: Rifampin [ri-FAM-pin] has broader antimicrobial activity than isoniazid and can be used as part of treatment for several different bacterial infections. Because resistant strains rapidly emerge during monotherapy, it is never given as a single agent in the treatment of active tuberculosis.

  • Mechanism of action: Rifampin blocks RNA transcription by interacting with the β subunit of mycobacterial DNA-dependent RNA polymerase.
  • Antimicrobial spectrum: Rifampin is bactericidal for both intracellular and extracellular mycobacteria, including M. tuberculosis, and NTM, such as M. kansasii and Mycobacterium avium complex (MAC). It is effective against many gram-positive and gram-negative organisms and is used prophylactically for individuals exposed to meningitis caused by meningococci or Haemophilus influenzae. Rifampin also is highly active against M. leprae.
  • Resistance: Resistance to rifampin is caused by mutations in the affinity of the bacterial DNA-dependent RNA polymerase gene for the drug.
  • Pharmacokinetics: Absorption is adequate after oral administration. Distribution of rifampin occurs to all body fluids and organs. Concentrations attained in the CSF are variable, often 10% to 20% of blood concentrations. The drug is taken up by the liver and undergoes enterohepatic recycling. Rifampin can induce hepatic cytochrome P450 enzymes and transporters, leading to numerous drug interactions. Unrelated to its effects on cytochrome P450 enzymes, rifampin undergoes autoinduction, leading to a shortened elimination half-life over the first 1 to 2 weeks of dosing. Elimination of rifampin and its metabolites is primarily through the bile and into the feces; a small percentage is cleared in the urine. [Note: Urine, feces, and other secretions have an orange-red color, so patients should be forewarned. Tears may even stain soft contact lenses orange-red.]
  • Adverse effects: Rifampin is generally well tolerated. The most common adverse reactions include nausea, vomiting, and rash. Hepatitis and death due to liver failure are rare. However, the drug should be used judiciously in older patients, alcoholics, or those with chronic liver disease. There is a modest increase in the incidence of hepatic dysfunction when rifampin is co-administered with isoniazid. When rifampin is dosed intermittently, especially with doses of 1.2 g or greater, a flu-like syndrome can occur, with fever, chills, and myalgia, sometimes extending to acute renal failure, hemolytic anemia, and shock.
  • Drug interactions: Because rifampin induces a number of phase I cytochrome P450 enzymes and phase II enzymes, it can decrease the half-lives of coadministered drugs that are metabolized by these enzymes. This may necessitate higher dosages for coadministered drugs, a switch to drugs less affected by rifampin, or replacement of rifampin with rifabutin.

Antimycobacterial Drugs

Antimycobacterial Drugs

Antimycobacterial Drugs

2. Rifabutin: Rifabutin [rif-a-BYOO-tin], a derivative of rifampin, is preferred for TB patients co-infected with the human immunodeficiency virus (HIV) who are receiving protease inhibitors (PIs) or several of the non-nucleoside reverse transcriptase inhibitors (NNRTIs). Rifabutin is a less potent inducer (approximately 40% less) of cytochrome P450 enzymes, thus lessening certain drug interactions. Rifabutin has adverse effects similar to those of rifampin but can also cause uveitis, skin hyperpigmentation, and neutropenia.

3. Rifapentine: Rifapentine [rih-fa-PEN-teen] has activity greater than that of rifampin in animal and in vitro studies, and it also has a longer half-life. In combination with isoniazid, rifapentine may be used once weekly in patients with LTBI and in select HIV-negative patients with minimal pulmonary TB.

D. Pyrazinamide

Pyrazinamide [peer-a-ZIN-a-mide] is a synthetic, orally effective short course agent used in combination with isoniazid, rifampin, and ethambutol. The precise mechanism of action is unclear. Pyrazinamide must be enzymatically hydrolyzed by pyrazinamidase to pyrazinoic acid, which is the active form of the drug. Some resistant strains lack the pyrazinamidase enzyme. Pyrazinamide is active against tuberculosis bacilli in acidic lesions and in macrophages. The drug distributes throughout the body, penetrating the CSF. Pyrazinamide may contribute to liver toxicity. Uric acid retention is common but rarely precipitates a gouty attack. Most of the clinical benefit from pyrazinamide occurs early in treatment. Therefore, this drug is usually discontinued after 2 months of a 6-month regimen.

E. Ethambutol

Ethambutol [e-THAM-byoo-tole] is bacteriostatic and specific for mycobacteria. Ethambutol inhibits arabinosyl transferase—an enzyme important for the synthesis of the mycobacterial cell wall. Ethambutol is used in combination with pyrazinamide, isoniazid, and rifampin pending culture and susceptibility data. [Note: Ethambutol may be discontinued if the isolate is determined to be susceptible to isoniazid, rifampin, and pyrazinamide.] Ethambutol is well distributed throughout the body. Penetration into the CNS is minimal, and it is questionably adequate for tuberculous meningitis. Both the parent drug and metabolites are primarily excreted in the urine. The most important adverse effect is optic neuritis, which results in diminished visual acuity and loss of ability to discriminate between red and green. The risk of optic neuritis increases with higher doses and in patients with renal impairment. Visual acuity and color discrimination should be tested prior to initiating therapy and periodically thereafter. Uric acid excretion is decreased by ethambutol, and caution should be exercised in patients with gout.

Antimycobacterial Drugs

F. Alternate second-line drugs

Streptomycin [strep-toe-MY-sin], para-aminosalicylic [a-mee-noesal-i-SIL-ik] acid, capreomycin [kap-ree-oh-MYE-sin], cycloserine [sye-kloe-SER-een], ethionamide [e-thye-ON-am-ide], fluoroquinolones, and macrolides are second-line TB drugs. In general, these agents are less effective and more toxic than the first-line agents.

Antimycobacterial Drugs

  • Streptomycin: Streptomycin, an aminoglycoside antibiotic, was one of the first effective agents for TB. Its action appears to be greater against extracellular organisms. Infections due to streptomycin-resistant organisms may be treated with kanamycin or amikacin, to which these bacilli usually remain susceptible.
  • Para-aminosalicylic acid: Para-aminosalicylic acid (PAS) was another one of the original TB medications. From the early 1950s until well into the 1960s, isoniazid, PAS, plus streptomycin was the standard 18-month treatment regimen. While largely replaced by ethambutol for drug-susceptible TB, PAS remains an important component of many regimens for MDR-TB.
  • Capreomycin: This is a parenterally administered polypeptide that inhibits protein synthesis. Capreomycin is primarily reserved for the treatment of MDR-TB. Careful monitoring is necessary to minimize nephrotoxicity and ototoxicity.
  • Cycloserine: This is an orally effective, tuberculostatic drug that disrupts d-alanine incorporation into the bacterial cell wall. It distributes well throughout body fluids, including the CSF. Cycloserine is primarily excreted unchanged in urine. Accumulation occurs with renal insufficiency. Adverse effects involve CNS disturbances (for example, lethargy, difficulty concentrating, anxiety, and suicidal tendency), and seizures may occur.
  • Ethionamide: This is a structural analog of isoniazid that also disrupts mycolic acid synthesis. The mechanism of action is not identical to isoniazid, but there is some overlap in the resistance patterns. Ethionamide is widely distributed throughout the body, including the CSF. Metabolism is extensive, most likely in the liver, to active and inactive metabolites. Adverse effects that limit its use include nausea, vomiting, and hepatotoxicity. Hypothyroidism, gynecomastia, alopecia, impotence, and CNS effects also have been reported.
  • Fluoroquinolones: The fluoroquinolones, specifically moxifloxacin and levofloxacin, have an important place in the treatment of multidrug-resistant tuberculosis. Some NTM also are susceptible.
  • Macrolides: The macrolides azithromycin and clarithromycin are included in regimens for several NTM infections, including MAC. Azithromycin may be preferred for patients at greater risk for drug interactions (clarithromycin is a both a substrate and inhibitor of cytochrome P450 enzymes).
  • Bedaquiline: Bedaquiline [bed-AK-wi-leen], an ATP synthase inhibitor, is the first in a new class of drugs approved for the treatment of MDR-TB. Bedaquiline is administered orally, and it is active against many types of mycobacteria. Bedaquiline may cause QT prolongation, and monitoring of the electrocardiogram is recommended. This agent is a CYP3A4 substrate, and administration with strong CYP3A4 inducers (for example, rifampin) should be avoided.

 Antimycobacterial Drugs

 Antimycobacterial Drugs


Antimycobacterial Drugs: DRUGS FOR LEPROSY

Focus topic: Antimycobacterial Drugs

Leprosy (or Hansen’s disease) is uncommon in the United States; however, worldwide it is a much larger problem. Leprosy can be treated effectively with dapsone and rifampin, adding clofazimine in multibacillary cases.

A. Dapsone

Dapsone [DAP-sone] is structurally related to the sulfonamides and similarly inhibits dihydropteroate synthetase in the folate synthesis pathway. It is bacteriostatic for M. leprae, and resistant strains may be encountered. Dapsone also is used in the treatment of pneumonia caused by Pneumocystis jirovecii in immunosuppressed patients. The drug is well absorbed from the gastrointestinal tract and is distributed throughout the body, with high concentrations in the skin. The parent drug undergoes hepatic acetylation. Both parent drug and metabolites are eliminated in the urine. Adverse reactions include hemolysis (especially in patients with glucose-6-phosphate dehydrogenase deficiency), methemoglobinemia, and peripheral neuropathy.

B. Clofazimine

Clofazimine [kloe-FAZ-i-meen] is a phenazine dye. Its mechanism of action may involve binding to DNA, although alternative mechanisms have been proposed. Its redox properties may lead to the generation of cytotoxic oxygen radicals that are toxic to the bacteria. Clofazimine is bactericidal to M. leprae, and it has potentially useful activity against M. tuberculosis and NTM. Following oral absorption, the drug accumulates in tissues, allowing intermittent therapy but does not enter the CNS. Patients typically develop a pink to brownish-black discoloration of the skin and should be informed of this in advance. Eosinophilic and other forms of enteritis, sometimes requiring surgery, have been reported. Clofazimine has some anti-inflammatory and anti-immune activities. Thus, erythema nodosum leprosum may not develop in patients treated with this drug.





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