Multidrug-resistant tuberculosis (MDRTB) is a growing problem globally and can be difficult to manage clinically. It is especially difficult to treat in areas where adequate drug susceptibility testing, appropriate second-line drugs, and support services are unavailable. Unfortunately, it is in these set-tings that the incidence of MDRTB is increasing.
Even in resource-rich settings, MDRTB presents clinical and logistic challenges, because the treatment is long and requires the use of several relatively toxic drugs. Over the past 2 decades, experience in the treatment of MDRTB has grown, even if new drug development has not kept pace.
In this article, we will explore the epidemiology, diagnosis, and management of MDRTB, based on our collective experience managing this disease in the United States, Peru, Haiti, and Russia.1
MDRTB is defined as tuberculosis caused by strains of Mycobacterium tuberculosis that have documented in vitro resistance to at least isoniazid and rifampin.2 Such resistance is clinically significant because these 2 drugs represent the most powerful antituberculous agents currently available.
Once the mycobacterium is no longer susceptible to killing by these drugs, management of the disease becomes more complicated, because the remaining drugs are less effective and more toxic.3 Resistance to other combinations of drugs--polyresistance--is generally easier to eradicate.
Resistance to antituberculous drugs can occur in 1 of 2 ways. Acquired drug resistance occurs when the patient is infected with a strain that is initially susceptible but becomes resistant during the course of inadequate therapy. Organisms that have acquired resistance to an antituberculous drug (such as isoniazid) are not sufficiently suppressed by other companion drugs (such as rifampin and pyrazinamide) to prevent resistant organisms from predominating, which leads to treatment failure. These companion drugs may be unavailable, or they may be prescribed inappropriately, taken incorrectly, or malabsorbed.
Organisms already resistant to one drug can acquire additional resistance mutations to another drug. If these organisms are not suppressed by other agents, resistance increases in a stepwise fashion.
The other type of resistance, known as primary resistance, occurs when a patient becomes infected with a strain that is already drug-resistant. Both primary and acquired resistance are responsible for the increase in MDRTB seen globally.4 The contribution of primary resistance to the global pandemic is probably underestimated, since most patients do not undergo drug susceptibility testing before receiving therapy for tuberculosis.5
MDRTB is a significant problem in many countries and has been documented in all countries that have been surveyed.6 In some areas, known as "hotspots," there is a high prevalence (more than 3% of tuberculosis cases) of MDRTB. These areas include the Dominican Republic, Latvia, and parts of the former Soviet Union.7 In the United States, persons from these areas are at increased risk for MDRTB.
In addition, immigrants, students, and visitors from areas such as Mexico, India, the Far East, and especially the Philippines are at higher risk for MDRTB.Other risk groups include persons with HIV infection and those who are known contacts of persons with MDRTB.8
The incidence of MDRTB appears to be declining in the United States and in other countries where the incidence of tuberculosis is declining; however, the incidence of MDRTB appears to be increasing in many other parts of the world where tuberculosis is less well controlled.9 However, since an increasing proportion of persons with tuberculosis in the United States, Canada, Western Europe, and Australia are foreign-born, the problem of MDRTB is universal, and an international approach is needed.10
The only way to diagnose MDRTB is by testing an isolate from the patient to determine whether the mycobacteria can grow in the presence of isoniazid, rifampin, and other antituberculous agents.11 Conventional testing methods usually require the growth of mycobacteria in solid culture media, a process that can take up to 2 months. Growth characteristics are then compared between cultures that contain drugs and those that do not.
More rapid radiometric methods can also be used, in which mycobacteria are inoculated into a radiolabeled broth, with and without drug, then growth in the broth is measured.12 Genotypic methods for detecting specific genetic mutations responsible for certain types of drug resistance are available and allow for more rapid testing to be performed.13 Genotypic methods are especially useful for rifampin resistance. However, not all known genetic mutations are accounted for in resistance testing, thus limiting this modality.
The treatment for MDRTB is more difficult than that for its pan-susceptible counterpart.14 Because isoniazid and rifampin cannot be used, less powerful agents--the second-line drugs--are required. These drugs are less potent, so a larger number of drugs are needed for a longer time. Table 1 lists the drugs used for treating MDRTB and the usual dosages.
To cure patients of MDRTB, multidrug regimens consisting of a minimum of 4 or 5 drugs to which the infecting strain has documented susceptibility ideally should be used for a minimum of 18 to 24 months.15 A daily injectable medication should be used until negative sputum cultures have been documented for at least 6 months. Our strategy for building a regimen is as follows16:
Use ethambutol or pyrazinamide if susceptibility to the drug has been documented.
Include an injectable agent until sputum cultures are negative for a minimum of 6 months.
Use a fluoroquinolone (especially moxifloxacin or gatifloxacin) whenever possible.
Add other second-line agents to reach a minimum of 4 or 5 drugs.
If there is severe parenchymal damage, high-grade resistance, or clinically advanced disease, consider the use of reinforcing agentsthat show in vitro evidence of antimycobacterial activity. Surgery is also used for select patients with localized lung destruction.
Because successful treatment is critical, therapy must be directly observed and should be given a minimum of 6 days per week.In addition to antituberculous therapy, all patients should receive oral pyridoxine, 50 mg/d.
While awaiting results of drug susceptibility testing, it is often necessary to institute empiric therapy, depending on the clinical status of the patient. When initiating empiric therapy, it is important to build on a solid foundation of at least 4 or 5 agents to which the infecting strain is likely to be susceptible. Knowledge of local resistance patterns and the patient's known contacts, and avoidance of drugs that the patient has previously received are important principles in the design of empiric therapy. Regimens are usually adjusted once drug susceptibility test results are available.17
CASE PRESENTATIONSDesigning a treatment regimen
Case 1: LR was a 41-year-old man with tuberculosis, who presented with cough, fever, and weight loss. His chest radiograph demonstrated biapical cavitation, fibrosis, and infiltrates (Figure 1).He was started on a regimen of isoniazid, rifampin, pyrazinamide, and ethambutol, but he continued to have symptoms, and his sputum smears remained positive.
A sputum specimen was sent for drug susceptibility testing. While awaiting the results, the patient was given empiric MDRTB treatment with streptomycin, ciprofloxacin, ethionamide, cycloserine, and para-aminosalicylic acid.
Two months later, his symptoms had improved and his sputum specimen was smear-negative. Drug susceptibility tests confirmed resistance to isoniazid and rifampin; pyrazinamide and ethambutol were added to his regimen, and para-aminosalicylic acid was discontinued. He continued to respond well, and streptomycin was stopped after 6 negative sputum cultures were obtained. He completed a total of 24 months of therapy, during which sputum smears and cultures remained negative.
1. Farmer P, Furin J, Shin S. Managing multidrug-resistant tuberculosis. J Respir Dis. 2000;21:53-56.
2. Iseman MD, Madsen LA. Drug-resistant tuberculosis. Clin Chest Med. 1989;10:341-353.
3. Iseman MD. Management of multidrug- resistant tuberculosis. Chemotherapy. 1999; 45(suppl 2):3-11.
4. Chevrel-Dellagi D, Abderrahman A, Haltiti R, et al. Large-scale DNA fingerprinting of Mycobacterium tuberculosis strains as a tool for epidemiologic studies of tuberculosis. J Clin Microbiol. 1993;31:2446-2450.
5. Crofton J, Chaulet P, Maher D. Guidelines on the Management of Drug-Resistant Tuberculosis. Geneva: World Health Organization; 1996.
6. Pablos-Mendez A, Raviglione MC, Laszlo A, et al. Global surveillance for antituberculosis drug resistance, 1994-1997. World Health Organization-International Union against Tuberculosis and Lung Disease Working Group on Anti-tuberculosis Drug Resistance Surveillance. N Engl J Med. 1998;338:1641-1649.
7. World Health Organization. Anti-tuberculosis drug resistance in the world: the WHO/ IUATLD global project on antituberculosis drug resistance surveillance 2000. Geneva: World Health Organization; 2000.
8. Centers for Disease Control. Meeting the challenge of multidrug-resistant tuberculosis: summary of a conference. MMWR. 1992; 41(RR-11):49-57.
9. Program in Infectious Disease and Social Change. The Global Impact of Drug Resistant Tuberculosis. Boston: Harvard Medical School and the Open Society Institute; 1999.
10. Farmer P, Bayona J, Becerra M, et al. The dilemma of MDR-TB in the global era. Int J Tuberc Lung Dis. 1998;2:869-876.
11. Heifets LB, Cangelosi GA. Drug susceptibility testing of Mycobacterium tuberculosis: a neglected problem at the turn of the century. Int J Tuberc Lung Dis. 1999;3:564-581.
12. Grange JM, Festenstein F. The human dimension of tuberculosis control. Tuber Lung Dis. 1993;74:219-222.
13. Drobniewski FA, Wilson SM. New biomolecular assays must be tested by direct study in the developing world. BMJ. 1998;316:940.
14. Goble M, Iseman MD, Madsen LA, et al. Treatment of 171 patients with pulmonary tuberculosis resistant to isoniazid and rifampin. N Engl J Med. 1993;328:527-532.
15. Iseman MD. A Clinician's Guide to Tuberculosis. Philadelphia: Lippincott Williams & Wilkins; 2000.
16. Partners In Health, Harvard Medical School, the Bill and Melinda Gates Foundation. A DOTS-Plus Handbook: Guide to the Community-Based Treatment of MDR TB. Boston: Partners In Health; 2002.
17. Mukherjee J, Shin S, Furin J, et al. New challenges in the clinical management of multidrug-resistant tuberculosis. Infect Dis Clin Pract. 2003;11:329-339.
18. Furin JJ, Mitnick CD, Shin SS, et al. Occurrence of serious adverse effects in patients receiving community-based therapy for multidrug-resistant tuberculosis. Int J Tuberc Lung Dis. 2001;5:648-655.
19. Farmer P, Kim JY. Community based approaches to the control of multidrug resistant tuberculosis: introducing "DOTS-plus." BMJ. 1998;317:671-674.
20. Partners In Health, Harvard Medical School, the Bill and Melinda Gates Foundation. Dots-Plus at a Glance: Protocols and Norms for the Management of Multidrug- Resistant Tuberculosis. Boston: Partners In Health; 2003.
21. Centers for Disease Control. Outbreak of multidrug-resistant tuberculosis--Texas, California, and Pennsylvania. MMWR. 1990; 39: 369-372.
22. Farmer P, Leandre F, Mukherjee JS, et al. Community-based approaches to HIV treatment in resource-poor settings. Lancet. 2001; 358:404-409.
23. Mukherjee J, Joseph K, Rich M, et al. Clinical and programmatic considerations in the treatment of MDR-TB in children: a series of 16 patients from Lima, Peru. Int J Tuberc Lung Dis. 2003;7:637-644.
24. Shin S, Guerra D, Rich M, et al. Treatment of multidrug-resistant tuberculosis during pregnancy: a report of 7 cases. Clin Infect Dis. 2003;36:996-1003.
25. Pomerantz M, Madsen L, Goble M, Iseman M. Surgical management of resistant mycobacterial tuberculosis and other mycobacterial pulmonary infections. Ann Thorac Surg. 1991;52:1108-1112.
26. Iseman MD. Tailoring a time-bomb. Inadvertent genetic engineering. Am Rev Respir Dis. 1985;132:735-736.
27. Mitnick C, Bayona J, Palacios E, et al. Community-based therapy for multidrug- resistant tuberculosis in Lima, Peru. N Engl J Med. 2003;348:119-128.
28. Palacios E, Guerra D, Llaro K, et al. The role of the nurse in the community-based treatment of multidrug-resistant tuberculosis (MDR-TB). Int J Tuberc Lung Dis. 2003;7:343-346.