/publications/issue/2008/2008-11/2008-11-8748

Treatment Goals for Drug-Resistant Tuberculosis

Author: Cheryl A. Grandinetti, PharmD


Dr. Grandinetti is a senior clinical research pharmacist at the National Cancer Institute, National Institutes of Health, Rockville, Maryland. The views expressed are those of the author and not those of any government agency.


Tuberculosis (TB), with cases dating as far back as 4000 bc, remains a major global health concern.1 In 2003, the World Health Organization (WHO) estimated 8.7 million new cases of TB in existence and over 2 million deaths resulted from TB.2 In 2007, the Centers for Disease Control and Prevention (CDC) reported 13,293 active TB cases in the United States, with the rate highest in foreign-born persons and racial and ethnic minorities. It is the leading opportunistic infection causing death in HIV-positive individuals.3

High-Risk Populations

Groups at high risk for TB include employees and residents of long-term care facilities, hospitals, clinics, and correctional institutions; racial and ethnic minorities; HIV-infected patients; alcoholics and illicit drug users; individuals with low socioeconomic status; and those in close contact with known or suspected TB cases.4 Mycobacterium tuberculosis is the most common infecting organism. Definitive diagnosis requires a positive culture or a positive acid-fast smear. Clinicians should treat patients empirically until susceptibility results are available.5

Primary disease, or clinical illness occurring immediately following infection, generally occurs in younger patients who have developing immune systems and are more susceptible to infection. Although considered a severe infection, primary TB is not usually transmissible. Most infected patients have asymptomatic latent infection; approximately 10% progress to active TB within 2 years. Microorganisms may lie dormant for several years and reactivate to produce a transmissible secondary TB. TB may infect the lungs or other extrapulmonary sites, such as the gastrointestinal and urinary tracts, central nervous system, and bone marrow.4

Active TB treatment goals include curing the infection and preventing spread in the community. Treatment with a single drug can lead to development of drug-resistant TB. Multidrug regimens rid extracellular organisms from the sputum, decrease infectivity, kill slowly dividing organisms in the caseating macrophages and activated granulomas, and minimize resistance. Standard first-line combination regimens (Table 1) have an 8-week initiation phase followed by a 4- to 7-month continuation phase. The duration of therapy depends upon the severity and site of infection at diagnosis and sputum culture results after 2 months of therapy.

Table 1
Drug Regimens for Pulmonary Tuberculosis

Initial Phase

Continuation Phase

Regimen

Schedule

Regimen

Duration

Isoniazid, rifampin, pyrazinamide, ethambutol

Once daily for 5a or 7 days/week for 8 weeks

Isoniazid, rifampin

Once daily for 5a or 7 days/week for 18 weeks

Isoniazid, rifampin

Once daily for 2 days/week for 18 weeksb

Isoniazid, rifapentine

Once weekly for 18 weeksb

Isoniazid, rifampin, pyrazinamide, ethambutol

Once daily for 5a or 7 days/week for 2 weeks, followed by once daily for 2 days/week for 6 weeksb

Isoniazid, rifampin

Once daily for 2 days/week for 18 weeksb

Isoniazid, rifapentine

Once weekly for 18 weeksb

Isoniazid, rifampin, pyrazinamide, ethambutol

3 times weekly for 8 weeksb

Isoniazid, rifampin

3 times weekly for 18 weeksb

Isoniazid, rifampin, ethambutolc

Once daily for 5a or 7 days/week for 8 weeks

Isoniazid, rifampin

Once daily for 5a or 7 days/week for 31 weeks

Isoniazid, rifampin

Twice weekly for 31 weeksb

a Drugs may be given 5 days/week when directly observed therapy is used.
b Patients on regimens less than 7 days should receive directly observed therapy.
c Pyrazinamide is associated with potentially lethal hepatotoxicity and should be avoided in patients with severe liver disease or gout.
Adapted from reference 11.


Once active disease is ruled out, patients should start therapy for latent TB infection (LTBI) to prevent them from developing TB disease. The preferred treatment of LTBI includes 9 months of isoniazid, given daily or intermittently (Table 2). Daily rifampin for 4 months is an alternative in patients who are intolerant to isoniazid or who have been exposed to isoniazid-resistant organisms.4,5

Clinicians should prescribe and dispense no more than a 1-month supply of medication to patients on selfadministered therapy. In addition, they should provide pyridoxine to prevent isoniazid-induced peripheral neuropathy in patients who are malnourished, pregnant, or coinfected with HIV, or have alcoholism or diabetes.

Clinicians should perform monthly follow-up visits; monitor for signs and symptoms of active TB, adverse reactions, and medication adherence; and educate patients about the condition and its treatment. HIV infection, history of liver disease, regular alcohol use, current or recent pregnancy (within 3 months), and concurrent hepatotoxic medications are signals for clinicians to perform baseline liver function tests (LFTs) before and periodically during therapy. Symptomatic patients with LFTs 3 times the upper limit of normal and asymptomatic patients with LFTs 5 times the upper limit of normal should not take isoniazid. Culture results and chest x-rays are used to monitor response to therapy. Clinicians should suspect drug resistance and nonadherence if symptoms do not improve during the first 2 months of therapy or worsen after improving initially, or culture results remain positive after 2 months of treatment or culture results become positive after being negative.4

Poor adherence is the most common cause of treatment failure and is associated with emergence of drug resistance. Other causes of treatment failure include inappropriate drug therapy choice, treatment duration, and toxicity. Drug-resistant strains cause higher mortality rates, treatment failures, relapse, acquired drug resistance, and greater community harm in the long term.2,6,7

In 2004, WHO estimated in existence 242,794 cases of multidrug-resistant TB (MDR-TB), defined as resistance to at least isoniazid and rifampin. In the United States, the CDC reported 116 cases of MDR-TB in 2006 (the most recent year for which data are available).3 Alternative regimens are used for treating drug-resistant TB. Isoniazid-resistant TB is generally treated with a combination of rifampin, ethambutol, and pyrazinamide for 6 months, or rifampin and ethambutol for 12 months. Lengthening the course or adding second-line agents, such as moxifloxacin and levofloxacin, are methods employed to strengthen regimens. Other secondline agents include capreomycin, amikacin, streptomycin, ethionamide, and cycloserine.5,8

Table 2
Latent Tuberculosis Treatment Regimens

Regimen

Schedule

Isoniazid

Daily for 9 monthsa

Twice weekly for 9 monthsb

Daily for 6 monthsc

Twice weekly for 6 monthsb,c

Rifampin

Daily for 4 monthsd

a Preferred regimen.
b Patients should receive directly observed therapy.
c Not recommended in patients with HIV, previous tuberculosis, or children.
d Alternative for patients who cannot tolerate or are resistant to isoniazid.
Adapted from reference 11.


A New Threat

In addition, a newly identified threat, extensive drug-resistant TB (XDR-TB), compounds this global health problem. XDR-TB is resistant to at least isoniazid and rifampin, in addition to any fluoroquinolone, and at least 1 of the 3 intravenous second-line treatments (capreomycin, kanamicin, and amikacin).9 Although XDR-TB is rare, it is much more difficult to treat, as fewer effective treatments are available. Successful outcomes depend on the extent of drug resistance, the severity of the disease, and the patient's immune status.8

Directly observed therapy (DOT), a strategy used to help patients adhere to treatment, decreases drug resistance, relapse, and mortality rates, and improves cure rates. In DOT, a health care worker or another designated person watches the patient swallow each prescribed dose.10 DOT is crucial in patients with drug-resistant infections, patients with LTBI who are at high risk for developing active TB, and all patients on intermittent regimens. These patients may be more likely to miss doses and are susceptible to treatment failure.8

Summary

Effective therapy is critical to the public health response and control of TB. The majority of treatment failure cases and drug resistance arise from poor patient adherence and inappropriate therapy choice. Thus, pharmacists can play an important role by monitoring the appropriateness of the regimen, adverse events, follow-up visits, and medication adherence, and educating the patient on medication use.

References

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  2. Aziz MA, Wright A, Laszlo A, et al. Epidemiology of antituberculosis drug resistance (the Global Project on Anti-tuberculosis Drug Resistance Surveillance): an updated analysis. Lancet. 2006;368(9553):2142-2154.
  3. Centers for Disease Control and Prevention (CDC). Trends in tuberculosis--United States, 2007. MMWR Morb Mortal Wkly Rep. 2008;57(11):281-285.
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  5. Drugs for tuberculosis. Treat Guidel Med Lett. 2007;5(55):15-22.
  6. Lew W, Pai M, Oxlade O, Martin D, Menzies D. Initial drug resistance and tuberculosis treatment outcomes: systematic review and meta-analysis. Ann Intern Med. 2008; 149(2):123-134.
  7. Zignol M, Hosseini MS, Wright A, et al. Global incidence of multidrug-resistant tuberculosis. J Infect Dis. 2006;194(4):479-485.
  8. Maartens G, Wilkinson RJ. Tuberculosis. Lancet. 2007; 370(9604):2030-2043.
  9. Fair E, Hopewell PC, Pai M. International Standards for Tuberculosis Care: revisiting the cornerstones of tuberculosis care and control. Expert Rev Anti Infect Ther. 2007;5(1):61-65.
  10. Clark PM, Karagoz T, Apikoglu-Rabus S, Izzettin FV. Effect of pharmacist-led patient education on adherence to tuberculosis treatment. Am J Health Syst Pharm. 2007;64(5):497-505.
  11. American Thoracic Socety; CDC; Infectious Diseases Society of America. Treatment of tuberculosis. MMWR Recomm Rep. 2003; 52(RR-11):1-77.