Antimycobacterial Drugs



Antimycobacterial Drugs



Classification of Antimycobacterial Drugs





aAlso rifapentine (PRIFTIN).


bAlso clarithromycin (BIAXIN), ciprofloxacin (CIPRO), ethambutol (MYAMBUTOL), rifabutin (MYCOBUTIN), and amikacin.




Overview


This chapter covers drugs used to treat tuberculosis (TB), Mycobacterium avium-intracellulare infections, and leprosy. TB claims a life every 10 seconds, and global mortality rates are increasing despite the use of chemotherapy. Apathy, poverty, and drug resistance are all contributing to our inability to fight this chronic disease, especially in developing countries, where it is most prevalent. The global TB–human immunodeficiency virus (HIV) co-epidemic poses an additional challenge to public health officials and health care professionals. Effective treatment of TB now requires the use of increasingly complex drug regimens for at least 6 months. TB drug research and development efforts have resurged in the past 10 years, and new drugs are undergoing clinical trials. There is an urgent need for novel agents that are active against persistent organisms and thereby shorten the course of treatment.



Mycobacterial Infections


Mycobacteria are acid-fast bacilli that cause a variety of diseases, including TB, leprosy, and localized or disseminated M. avium-intracellulare infections (Box 41-1).



Box 41-1   A Case of Cough, Night Sweats, and Lethargy



Case Presentation


A 42-year-old man is seen at a public health clinic. He reports a productive cough, chills, fever, night sweats, loss of appetite, and feeling tired for the past month. He has a history of knife wounds and was jailed for 3 months after a barroom fight 2 years ago. His chest radiograph shows patchy infiltrates in both upper lobes, and a sputum sample is found to contain acid-fast bacilli. He is given a Mantoux tuberculin skin test, which has a positive result with a 15-mm induration 72 hours later. After completing lab work that will include a complete blood count, liver function tests, and chemistry profile, he will begin standard four-drug therapy for tuberculosis (TB), because the incidence of multiple-drug–resistant TB in his community is low. Liver function tests and a red-green color discrimination test will be conducted every 2 to 4 weeks throughout his treatment. The patient will be isolated until his sputum is negative for tubercle bacilli, and a public health nurse will visit him regularly to provide care and verify adherence to the treatment regimen.



Case Discussion


Tubercle bacilli are transmitted on microdroplets expelled by coughing from persons with active infections. Person-to-person transmission requires close contact with an active case and usually leads to a latent infection. Active infections typically occur months or years later when latent TB emerges as a result of decreased immune function, poor nutrition, physical stress, or other insults. The man in the present case has classic signs and symptoms of TB. The definitive diagnosis is based on finding acid-fast bacilli in sputum and a positive tuberculin test result. Effective therapy will sterilize respiratory secretions in a few weeks or less, but eradication of persistent organisms from infected tissues requires lengthy exposure to antitubercular drugs. The prolonged therapy for this disease often leads to drug toxicity and emergence of drug-resistant organisms. There is an urgent need for new drugs that work more quickly to eradicate TB, and several promising agents are currently being developed.


TB is caused by Mycobacterium tuberculosis. Atypical mycobacteria (e.g., Mycobacterium kansasii and members of the M. avium-intracellulare complex) can cause infections resembling TB. About one third of the world’s population is latently infected (infected asymptomatically) with M. tuberculosis, with 9 million new cases and nearly 2 million deaths annually. In Western countries the incidence of TB declined after the advent of effective drug therapy and improved public health measures, but the emergence of highly drug-resistant organisms has posed new challenges to clinicians.


The goals of TB therapy are to kill tubercle bacilli rapidly, to eliminate persistent bacilli and prevent relapse, and to prevent disease transmission. Isolation of patients with TB in single-person rooms is essential until sputum cultures are negative, and extended isolation may be required to prevent the spread of drug-resistant strains. Multidrug therapy for at least 6 months is required to eradicate the pathogen. Because of the long duration of treatment and difficulties with patient adherence, directly observed therapy (DOT), in which a health care provider observes each drug administration to ensure adherence to the treatment regimen, is the gold standard treatment protocol.


Since the 1980s, the prevalence of multidrug-resistant TB (MDR-TB) and extensively drug-resistant TB (XDR-TB) has been increasing at an alarming rate. MDR-TB is defined as resistance to at least isoniazid and rifampin, and XDR-TB is defined as MDR-TB plus resistance to fluoroquinolones and at least one of the injectable second-line drugs (amikacin, capreomycin, or kanamycin). The treatment of drug-resistant TB necessitates administration of second-line drugs that are less effective and more toxic than first-line drugs. In some cases of resistant TB it may take up to 2 years of therapy to eradicate the pathogen, and many cases of drug-resistant TB are fatal.


M. avium-intracellulare infections are seen most frequently in immunocompromised patients (e.g., those with acquired immunodeficiency syndrome [AIDS]) and often take the form of pulmonary disease, lymphadenitis, or bacteremia. In immunocompetent persons with chronic bronchitis or emphysema, exposure to M. avium-intracellulare can also result in pulmonary infections.


Leprosy, or Hansen’s disease, is relatively common in many parts of the world. It results from infection of the skin and peripheral nervous system with Mycobacterium leprae. Because this organism grows so slowly, the disease exhibits a slow, progressive course over several decades. Contrary to popular opinion, leprosy is not highly contagious, and transmission of infection usually requires prolonged close contact with an infected individual. The disease occurs in two primary forms, lepromatous leprosy and tuberculoid leprosy, each of which has a characteristic pathophysiology and clinical presentation. If leprosy is not treated, it ultimately causes severe deformities and disabilities. Treatment of leprosy can require years of therapy with antimycobacterial agents, although the introduction of newer drugs has enabled the use of shorter courses of therapy for many patients.



Drugs for Mycobacterial Infections


Drugs for Tuberculosis


Drugs initially used to treat most patients with TB are referred to as first-line drugs. They include isoniazid, ethambutol, and pyrazinamide (which are synthetic drugs), and rifampin and streptomycin (which are antibiotics). First-line drugs are discussed later, and some of their properties are shown in Table 41-1.



TABLE 41-1


Pharmacokinetic Properties of Antimycobacterial Drugs*

























































































DRUG ROUTE OF ADMINISTRATION ORAL BIOAVAILABILITY ELIMINATION HALF-LIFE ROUTES OF ELIMINATION
Azithromycin Oral 37% 12 hr Biliary excretion
Ciprofloxacin Oral or IV 75% 4 hr Metabolism; renal excretion
Clarithromycin Oral 62% 5 hr Biliary and renal excretion
Clofazimine Oral 55% 70 days Biliary and fecal excretion
Dapsone Oral Approximately 100% 28 hr† Metabolism; renal excretion
Ethambutol Oral Approximately 100% 3.5 hr Metabolism; renal and fecal excretion
Isoniazid Oral or IM Approximately 100% 2.5 hr† Metabolism; renal excretion
Pyrazinamide Oral Approximately 100% 9.5 hr Metabolism; renal excretion
Rifabutin Oral 16% 45 hr Metabolism; renal and biliary excretion
Rifampin Oral or IV Approximately 100% 2.75 hr Metabolism; renal and biliary excretion
Rifapentine Oral 70% 13 hr Metabolism (active metabolite); renal and biliary excretion
Streptomycin IM NA 2 hr Renal excretion
Thalidomide Oral Approximately 90% 6 hr Metabolism; renal excretion


image


IM, Intramuscular; IV, intravenous; NA, not applicable.


*Values shown are the mean of values reported in the literature.


†The half-lives of dapsone and isoniazid exhibit genetic variation.


Second-line drugs are reserved to treat patients infected with organisms that are resistant to first-line drugs and patients with HIV co-infection. They include rifabutin and rifapentine (other derivatives of rifamycin), fluoroquinolone drugs (see Chapter 40), cycloserine, capreomycin, ethionamide, amikacin, and aminosalicylic acid. Most of the second-line drugs are not discussed further in this chapter.


In persons who have had a relapse of TB after earlier treatment, the choice of drugs is guided by in vitro susceptibility of the infecting mycobacterial strain.



Isoniazid


Isoniazid was developed after studies found that nicotinic acid had a weak antitubercular effect. Investigators tested many nicotinic acid derivatives, and isoniazid (isonicotinic acid hydrazide [INH]) was found to be the most active derivative and subsequently became available for clinical use. The introduction of isoniazid in the early 1950s revolutionized the treatment of this disease, and it has remained the mainstay of most TB regimens for 60 years.



Pharmacokinetics.

Isoniazid is usually given orally and is well absorbed from the gut. The drug is widely distributed to tissues and reaches intracellular concentrations sufficiently high to be effective against organisms inside cells and caseous lesions.


Isoniazid is extensively metabolized, and the parent compound and its metabolites are excreted in the urine. The primary metabolite, acetylisoniazid, is formed by conjugation of acetate with isoniazid in a reaction catalyzed by acetyltransferase, an enzyme whose activity is genetically determined. Slow acetylation is an autosomal recessive trait, and persons with the slow phenotype are homozygous for the slow allele. Persons with the fast phenotype are either heterozygous or homozygous dominant. Because of the different rates of acetylation of isoniazid, persons with the fast phenotype have lower plasma isoniazid concentrations than do persons with the slow phenotype (Fig. 41-1).


image
FIGURE 41-1 Bimodal distribution of plasma isoniazid concentrations. Plasma concentrations of isoniazid were measured 2 hours after the administration of a single 300-mg dose of isoniazid to each member of a general population of human subjects. Subjects with the fast acetylation phenotype showed lower plasma drug concentrations than did subjects with the slow acetylation phenotype.
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Jul 23, 2016 | Posted by in PHARMACY | Comments Off on Antimycobacterial Drugs

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