Bacterial Folate Antagonists, Fluoroquinolones, and Other Antibacterial Agents

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Chapter 49 Antimycobacterial Agents

Abbreviations
AIDS Acquired immunodeficiency syndrome
CNS Central nervous system
CSF Cerebral spinal fluid
DNA Deoxyribonucleic acid
DOT Directly observed therapy
GI Gastrointestinal
HIV Human immunodeficiency virus
IM Intramuscular
INH Isoniazid (isonicotinic acid hydrazide)
IV Intravenous
LTBI Latent TB infection
MAC Mycobacterium avium complex
MDR Multi-drug resistance
PAS p-Aminosalicylic acid
POA Pyrazinoic acid
PZA Pyrazinamide
PZase Nicotinamidase/pyrazinamidase
RNA Ribonucleic acid
TB Tuberculosis
WHO World Health Organization
XDR-TB Extensive drug-resistant TB

Therapeutic Overview

The genus Mycobacterium consists of relatively slow-growing, obligate aerobic bacilli with a unique lipid-rich cell wall that allows these organisms to take up basic dyes and resist decolorization with acid-alcohol (“acid-fast” organisms). The acid-fast cell wall of Mycobacterium contains a large amount of glycolipids. A waxy lipid called mycolic acid makes up approximately 60% of the cell wall and makes it relatively impermeable. The major human mycobacterial pathogens are the virulent M. tuberculosis and M. leprae, while most mycobacteria inhabit soil and water and only occasionally cause human disease. For example, M. avium complex (MAC) causes infections among highly immunocompromised patients with human immunodeficiency virus (HIV) infection (CD4+ T lymphocyte counts of <75/μL) and in persons with abnormal lung anatomy or physiology. More rapidly growing non-tuberculous mycobacteria can cause skin and soft-tissue infection after trauma or surgery (e.g., M. chelonae or M. fortuitum) or after exposure to salt water (M. marinum). This chapter focuses on agents used to treat M. tuberculosis, M. leprae, and M. avium complex.

Tuberculosis (TB) is transmitted person to person by airborne droplet nuclei, which are small particles (1 to 5μ diameter). TB classically is a pulmonary disease, but disseminated and extrapulmonary disease, especially among immunocompromised persons, also occurs.

Tuberculosis has emerged as a global public health epidemic and is the second leading cause of death worldwide caused by an infectious disease. In 2005, the World Health Organization (WHO) estimated that more than 8 million persons developed active disease, and more than 1.5 million deaths occurred, mostly in resource-poor

countries. Overall, it is estimated that one third of the people in the world are currently infected with the TB bacillus. In the United States there was a resurgence of TB between 1985 and 1992, largely because of underfunding and decline of the public health infrastructure. With increased attention and funding, since 1992 there has been a decline in the number of TB cases in the United States to 14,097 TB cases in 2005 (4.8 per 100,000 population). The global epidemic of TB has impacted the United States, where most cases now occur among foreign-born persons. There are great racial/ethnic disparities among case rates. For individuals born in the United States, in 2005, the rate among African-Americans was almost eight times that of Caucasians.

Treatment of TB is much different than treatment of other diseases because of its public health implications. The provider has the responsibility for prescribing an appropriate regimen and ensuring that treatment is completed. Directly observed therapy (DOT) is recommended for all patients with active TB disease and can help ensure higher completion rates (Fig. 49-1), decrease risk for emergence of resistance, and enhance TB control. DOT is generally provided by public health agencies. Active TB should never be treated with a single drug because of the risk of emergence of resistance; therefore multidrug therapy is required. The minimum length of therapy is 6 to 9 months. Patients with drug resistance, especially multidrug resistance (MDR) (i.e., resistance to at least isoniazid and rifampin) require longer therapy. MDR-TB is associated with much higher morbidity and mortality. Drug resistance is an important factor in determining the appropriate therapeutic regimen. Patients who are infected with M. tuberculosis (latent TB infection, or LTBI) are at risk for progressing to active disease. This can be greatly reduced by treating persons with LTBI who are at high or increased risk for progression to active disease (e.g., HIV infection, other illnesses that increase risk of progression, recent infection, or recent immigration from high TB endemic area).

More recently, extensively drug-resistant TB (XDR-TB) has emerged, which is resistant to the two best first-line drugs, the fluoroquinolones, and to at least one of the three alternatives: amikacin, kanamycin, or capreomycin. Because of the resistance, patients with XDR-TB have more limited therapeutic choices and poorer outcomes.

Leprosy, also caused by a mycobacterium, is rare in the United States and Canada but is not uncommon in developing countries. Approximately 410,000 new cases were reported in 2004, compared with 804,000 in 1998. According to the WHO, 290,000 cases were being treated at the beginning of 2005. India, Brazil, and Nepal have the highest prevalence of the disease, while the largest number of cases exists in Southeast Asia. Transmission is thought to occur by the respiratory route, because the nasal discharge from patients with untreated multibacillary leprosy often contains large numbers of bacilli. Transmission may occasionally occur through direct skin contact. In the United States, leprosy is seen primarily among immigrants, although small pockets occur in Texas, Hawaii, and Louisiana. M. leprae is the causative organism, which multiplies very slowly with a generation time of 12.5 days and an incubation period of years. Clinical manifestations depend on the infected person’s immune response to M. leprae. Skin and peripheral nerves in cooler areas of the body are most commonly affected. Prompt recognition is key to limiting morbidity caused by irreversible nerve damage. The disease is curable with multidrug therapy.

Therapeutic Overview
Tuberculosis
Tuberculosis is a huge global health problem; the second leading cause of death due to an infectious disease worldwide.
More than 8 million new cases and 1.5 million deaths occur annually.
M. tuberculosis is an aerobic organism.
M. tuberculosis can cause latent infection and active pulmonary or extrapulmonary disease.
Combinations of drugs are used for active disease; a single drug can be used for latent infection.
Long-term treatment is needed (at least 6-9 months).
Bacterial resistance is of growing importance.
Multidrug-resistant tuberculosis is associated with increased morbidity and mortality.
Directly observed therapy is an important component in treatment.
Leprosy (Hansen’s disease)
Leprosy is caused by M. leprae, an aerobic acid-fast bacillus organism.
M. leprae grows extremely slowly with a long incubation period (average 2-4 years).
It is a chronic disease; clinical manifestations depend upon immune responses.
Long-term treatment is needed, usually with multidrug therapy.
Leprosy “reactions” can result from immunologically mediated acute inflammatory responses.
Mycobacterium avium complex (MAC) disease
Disseminated MAC most commonly occurs in patients with advanced HIV/AIDS.
Pulmonary infections are also seen in HIV-seronegative individuals, particularly with underlying or chronic pulmonary disease.
Treatment requires a multidrug regimen for prolonged periods.
Prophylaxis is indicated in patients with advanced HIV infection.

The incidence of invasive (i.e., disseminated) MAC disease among HIV-infected persons in the United States has decreased markedly in recent years because of the use of highly active antiretroviral therapy and MAC prophylaxis. In immunocompetent individuals, MAC most commonly causes pulmonary disease among those with underlying or chronic lung disease.

A summary of the characteristics and issues associated with tuberculosis, leprosy, and MAC is presented in the Therapeutic Overview Box.

Mechanisms of Action

Anti-Tuberculosis Drugs

Anti-TB drugs can be categorized on the basis of whether they are first- or second-line agents (see Major Drug Classes Box). They are divided into three groups based on their mechanism of action.

Inhibition of Cell Wall Synthesis: Isoniazid (INH)

INH is a bactericidal agent that is thought to inhibit mycolic acid synthesis. Mycolic acids are a major constituent of mycobacterial cell walls (along with arabinogalactan and peptidoglycan). The mode of action of INH is complex, and a current model is shown in Figure 49-3. INH is a prodrug that has to be activated by the M. tuberculosis catalase-peroxidase enzyme encoded by the katG gene. Deletions or mutations in this gene may account for 40% to 50% of clinical INH-resistant isolates. Other mechanisms of resistance may include mutations in three other genes. inhA and kasA code for mycolic acid biosynthetic enzymes, and mutations are found in some INH-resistant isolates. ahpC has also been associated with some INH resistance strains, but its role is unclear.

Pyrazinamide (PZA) is active only against M. tuberculosis and M. africanum; it is inactive against M. bovis and nontuberculous mycobacteria. PZA is active at a low pH (e.g., pH 5), is bactericidal, and has excellent sterilizing activity against semidormant bacteria. PZA is thought to enter M. tuberculosis by passive diffusion and is then converted to the active metabolite pyrazinoic acid (POA) by nicotinamidase/pyrazinamidase (PZase). The target of POA may involve fatty acid synthase I and disruption of mycobacterial membranes by acid (Fig. 49-4). Selected mutations in the PZase gene (pncA) are associated with PZA resistance in M. tuberculosis.

The mechanism of action of ethambutol is not well understood. It is thought to interfere with mycobacterial cell wall synthesis by inhibiting synthesis of polysaccharides and transfer of mycolic acids to the cell wall. The target is thought to be encoded by a three-gene operon (embC, embA, embB) that produces arabinosyl transferases that mediate polymerization of arabinose into arabinogalactan, particularly embB. Resistance to ethambutol is most common among M. tuberculosis isolates that are also resistant to INH and rifampin (i.e., MDR strains), probably because of mutations in embB. Ethambutol is effective only on actively dividing mycobacteria.

Anti-M. avium Complex (MAC) Drugs

Clarithromycin and azithromycin have excellent activity against MAC, and these macrolides are the cornerstone of therapy. They can be used in both prevention and treatment of disease (see Chapter 47). Ethambutol is usually combined with clarithromycin (or azithromycin) for treatment of MAC infections, especially among HIV-infected patients with disseminated MAC. Rifabutin can also be used to prevent MAC in HIV-infected patients who are unable to take macrolide drugs, and it can also be used in combination with other agents. Amikacin and the fluoroquinolones also have activity against MAC and are discussed in Chapters 47 and 48, respectively.

Pharmacokinetics

Key pharmacokinetic parameters are summarized in Table 49-1 and in Chapters 47 and 48.

Anti-Tuberculosis Drugs

First Line

INH is well absorbed orally and is widely distributed, with peak concentrations achieved in pleural, peritoneal, and synovial fluids. Cerebrospinal fluid (CSF) concentrations are approximately 20% of plasma levels but can increase to 100% with meningeal inflammation. INH is metabolized by a liver N-acetyltransferase, and the rate of acetylation determines its concentration in plasma and its half-life. As discussed in Chapter 2, slow acetylation is inherited as an autosomal recessive trait. The average plasma concentration of drug in rapid acetylators is half of that in slow acetylators. However, there is no evidence that these differences are therapeutically important if INH is administered once daily, because plasma levels are well above inhibitory concentrations.

Rifampin is well absorbed orally and widely distributed, achieving therapeutic concentrations in lung, liver, bile, bone, and urine and entering pleural, peritoneal, and synovial fluids and CSF, tears, and saliva. Its high lipid solubility enhances its entrance into phagocytic cells, where it kills intracellular bacteria. Rifampin is metabolized in the liver to a desacetyl derivative that is biologically active. Unmetabolized drug is excreted in bile and reabsorbed from the gastrointestinal (GI) tract into the enterohepatic circulation; the deacetylated metabolite is poorly reabsorbed with eventual elimination in urine and from the GI tract. Rifampin induces its own metabolism by inducing the expression of cytochrome P450s, resulting in increased biliary excretion with continued therapy. Induction of metabolism results in reduction of the plasma life by 20% to 40% after 7 to 10 days of therapy. Patients with severe liver disease may require dose reduction, but dose adjustment is not necessary in renal failure. Oral bioavailability of rifabutin is less than that of rifampin, and the plasma half-life is approximately 10 times greater. Rifabutin is more lipid soluble than rifampin and is extensively distributed. Rifabutin also induces its own metabolism but has less of an effect on cytochrome P450s. Rifapentine