Treatment Goals for Drug-Resistant Tuberculosis

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 casesdating as far back as 4000 bc,remains a major global healthconcern.¹ In 2003, the World HealthOrganization (WHO) estimated 8.7 millionnew cases of TB in existence andover 2 million deaths resulted fromTB.² In 2007, the Centers for DiseaseControl and Prevention (CDC) reported13,293 active TB cases in theUnited States, with the rate highest inforeign-born persons and racial andethnic minorities. It is the leadingopportunistic infection causing deathin HIV-positive individuals.³

High-Risk Populations

Groups at high risk for TB includeemployees and residents of long-termcare facilities, hospitals, clinics, and correctionalinstitutions; racial and ethnicminorities; HIV-infected patients; alcoholicsand illicit drug users; individualswith low socioeconomic status; andthose in close contact with known orsuspected TB cases.⁴ Mycobacteriumtuberculosis is the most commoninfecting organism. Definitive diagnosisrequires a positive culture or a positiveacid-fast smear. Clinicians should treatpatients empirically until susceptibilityresults are available.⁵

Primary disease, or clinical illnessoccurring immediately following infection,generally occurs in younger patientswho have developing immune systemsand are more susceptible to infection.Although considered a severe infection,primary TB is not usually transmissible.Most infected patients have asymptomaticlatent infection; approximately 10%progress to active TB within 2 years.Microorganisms may lie dormant forseveral years and reactivate to producea transmissible secondary TB. TB mayinfect the lungs or other extrapulmonarysites, such as the gastrointestinaland urinary tracts, central nervous system,and bone marrow.⁴

Active TB treatment goals include curingthe infection and preventing spreadin the community. Treatment with asingle drug can lead to development ofdrug-resistant TB. Multidrug regimensrid extracellular organisms from thesputum, decrease infectivity, kill slowlydividing organisms in the caseating macrophagesand activated granulomas, andminimize resistance. Standard first-linecombination regimens (Table 1) havean 8-week initiation phase followed bya 4- to 7-month continuation phase. Theduration of therapy depends upon theseverity and site of infection at diagnosisand sputum culture results after 2months of therapy.

Table 1

Drug Regimens for Pulmonary Tuberculosis

Initial Phase

Continuation Phase

Regimen

Schedule

Regimen

Duration

Isoniazid, rifampin, pyrazinamide, ethambutol

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

Isoniazid, rifampin

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

Isoniazid, rifampin

Once daily for 2 days/week for 18 weeks^b

Isoniazid, rifapentine

Once weekly for 18 weeks^b

Isoniazid, rifampin, pyrazinamide, ethambutol

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

Isoniazid, rifampin

Once daily for 2 days/week for 18 weeks^b

Isoniazid, rifapentine

Once weekly for 18 weeks^b

Isoniazid, rifampin, pyrazinamide, ethambutol

3 times weekly for 8 weeks^b

Isoniazid, rifampin

3 times weekly for 18 weeks^b

Isoniazid, rifampin, ethambutolc

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

Isoniazid, rifampin

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

Isoniazid, rifampin

Twice weekly for 31 weeks^b

^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 latentTB infection (LTBI) to prevent themfrom developing TB disease. The preferredtreatment of LTBI includes 9months of isoniazid, given daily or intermittently(Table 2). Daily rifampin for 4months is an alternative in patients whoare intolerant to isoniazid or who havebeen exposed to isoniazid-resistantorganisms.^4,5

Clinicians should prescribe and dispenseno more than a 1-month supplyof medication to patients on selfadministeredtherapy. In addition, theyshould provide pyridoxine to preventisoniazid-induced peripheral neuropathyin patients who are malnourished,pregnant, or coinfected with HIV, orhave alcoholism or diabetes.

Clinicians should perform monthlyfollow-up visits; monitor for signs andsymptoms of active TB, adverse reactions,and medication adherence; andeducate patients about the conditionand its treatment. HIV infection, historyof liver disease, regular alcohol use,current or recent pregnancy (within 3months), and concurrent hepatotoxicmedications are signals for cliniciansto perform baseline liver function tests(LFTs) before and periodically duringtherapy. Symptomatic patients withLFTs 3 times the upper limit of normaland asymptomatic patients withLFTs 5 times the upper limit of normalshould not take isoniazid. Cultureresults and chest x-rays are used tomonitor response to therapy. Cliniciansshould suspect drug resistance and nonadherenceif symptoms do not improveduring the first 2 months of therapyor worsen after improving initially, orculture results remain positive after 2months of treatment or culture resultsbecome positive after being negative.⁴

Poor adherence is the most commoncause of treatment failure and is associatedwith emergence of drug resistance.Other causes of treatment failureinclude inappropriate drug therapychoice, treatment duration, and toxicity.Drug-resistant strains cause higher mortalityrates, treatment failures, relapse,acquired drug resistance, and greatercommunity harm in the long term.^2,6,7

In 2004, WHO estimated in existence242,794 cases of multidrug-resistantTB (MDR-TB), defined as resistance toat least isoniazid and rifampin. In theUnited States, the CDC reported 116cases of MDR-TB in 2006 (the mostrecent year for which data are available).³ Alternative regimens are usedfor treating drug-resistant TB. Isoniazid-resistantTB is generally treated witha combination of rifampin, ethambutol,and pyrazinamide for 6 months, orrifampin and ethambutol for 12 months.Lengthening the course or adding second-line agents, such as moxifloxacinand levofloxacin, are methods employedto strengthen regimens. Other secondlineagents include capreomycin, amikacin,streptomycin, ethionamide, andcycloserine.^5,8

Table 2

Latent Tuberculosis Treatment Regimens

Regimen

Schedule

Isoniazid

Daily for 9 months^a

Twice weekly for 9 months^b

Daily for 6 months^c

Twice weekly for 6 months^b,c

Rifampin

Daily for 4 months^d

^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 isoniazidand rifampin, in addition to any fluoroquinolone,and at least 1 of the 3 intravenoussecond-line treatments (capreomycin,kanamicin, and amikacin).⁹Although XDR-TB is rare, it is muchmore difficult to treat, as fewer effectivetreatments are available. Successfuloutcomes depend on the extent of drugresistance, the severity of the disease,and the patient's immune status.⁸

Directly observed therapy (DOT), astrategy used to help patients adhereto treatment, decreases drug resistance,relapse, and mortality rates, andimproves cure rates. In DOT, a healthcare worker or another designatedperson watches the patient swalloweach prescribed dose.¹⁰ DOT is crucialin patients with drug-resistant infections,patients with LTBI who are athigh risk for developing active TB, andall patients on intermittent regimens.These patients may be more likely tomiss doses and are susceptible to treatmentfailure.⁸

Summary

Effective therapy is critical to the publichealth response and control of TB. Themajority of treatment failure cases anddrug resistance arise from poor patientadherence and inappropriate therapychoice. Thus, pharmacists can playan important role by monitoring theappropriateness of the regimen, adverseevents, follow-up visits, and medicationadherence, and educating the patient onmedication use.

References

• Zink AR, Sola C, Reischl U, et al. Characterization of Mycobacterium tuberculosis complex DNAs from Egyptian mummies by spoligotyping. J Clin Microbiol. 2003;41(1):359-367.
• 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.
• Centers for Disease Control and Prevention (CDC). Trends in tuberculosis--United States, 2007. MMWR Morb Mortal Wkly Rep. 2008;57(11):281-285.
• Potter B, Rindfleisch K, Kraus CK. Management of active tuberculosis. Am Fam Physician. 2005;72(11):2225-2232.
• Drugs for tuberculosis. Treat Guidel Med Lett. 2007;5(55):15-22.
• 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.
• Zignol M, Hosseini MS, Wright A, et al. Global incidence of multidrug-resistant tuberculosis. J Infect Dis. 2006;194(4):479-485.
• Maartens G, Wilkinson RJ. Tuberculosis. Lancet. 2007; 370(9604):2030-2043.
• 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.
• 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.
• American Thoracic Socety; CDC; Infectious Diseases Society of America. Treatment of tuberculosis. MMWR Recomm Rep. 2003; 52(RR-11):1-77.