Bureau of Tuberculosis Control

Multidrug-Resistant Tuberculosis

TB Fact Sheet 4c

The emergence of multidrug-resistant tuberculosis (MDRTB) -- specifically, disease caused by Mycobacterium tuberculosis isolates resistant to at least isoniazid and rifampin -- has been well documented. During the early 1990s, nosocomial outbreaks (characterized by delayed diagnosis and inadequate treatment regimens) contributed to rising rates of MDRTB in New York City (NYC) and elsewhere in the United States.^1,2 Since then, however, because of improved infection control practices and the increased availability of directly observed therapy (DOT) programs for the treatment of tuberculosis (TB) disease, the number of new cases of MDRTB in NYC has declined dramatically.³

The following principles have helped physicians detect initial drug resistance and prevent the emergence of additional drug resistance in patients with suspected or confirmed TB disease:

• • Always test the patient's isolate for drug susceptibility. Send samples to a laboratory that has extensive experience in drug-susceptibility testing. For free drug-susceptibility testing at the NYC Department of Health and Mental Hygiene mycobacteriology laboratory, call 311.
• • Never add a single drug to a failing regimen. If the patient is not clinically improving, or if the cultures are still positive after 3 months of therapy, add at least two -- and preferably three -- new antituberculosis medications to which the strain is likely to be susceptible.

Treatment regimens for MDRTB

Although the number of patients with MDRTB in NYC has decreased, these patients remain difficult to treat. They often require extended hospital stays and/or rehospitalization. Standardized regimens cannot be developed for MDRTB, and good data are lacking on the efficacy of non-standard regimens. The following general rules will help the physician tailor a treatment regimen for the patient who is known or suspected to have MDRTB:⁴

• • Always treat patients with MDRTB under a program of daily DOT to ensure adherence.
• • Consult with a physician experienced in the care of patients with MDRTB. For referral to a specialist at the NYC Department of Health and Mental Hygiene, Bureau of TB Control, call 311.
• • Treat patients with TB (including MDRTB) with a regimen of at least two -- and preferably three to five -- medications to which the mycobacterial strain is reported to be susceptible.
• • Continue treating patients with MDRTB for a minimum of 18 months after culture conversion to negative; treat those with HIV infection or cavitary disease for as long as 24 months after culture conversion. Treatment must be daily, not intermittent.
• • Prescribe an aminoglycoside (e.g., streptomycin, kanamycin, amikacin) or capreomycin from the start of therapy and for at least 6 months after cultures convert to negative.⁵
• • Counsel women with MDRTB who are of childbearing age to avoid pregnancy; explain the risk that second-line medications may cause fetal abnormalities.
• • Surgical resection can play an important role in the management of selected cases. Criteria for resection include extensive drug resistance, poor response to medical treatment, and disease that is sufficiently localized so that respiratory function will not be crippled when the diseased portion of the lung is removed.⁶

Monitoring treatment for MDRTB

The physician should carefully monitor the treatment of patients with MDRTB.

• • Monthly clinical evaluations. Every month, the physician (and nurse) should evaluate the patient to monitor response and adherence to treatment and to detect any adverse reactions. Monthly sputum samples for acid-fast bacilli (AFB) smear and culture should be collected from patients who have pulmonary disease.⁷
• • Therapeutic drug monitoring (TDM). Soon after treatment is started, whenever the regimen is changed, and in the event that the patient deteriorates clinically, the physician should consider monitoring the serum levels of antituberculosis medications in order to maintain the appropriate concentration of each drug for maximum efficacy and minimum toxicity.⁸ TDM is especially important for cycloserine (which has limited efficacy and potentially severe toxicity) and for the fluoroquinolones (which may demonstrate variable absorption).
• • Managing adverse reactions to second-line medications. Occasionally, even though the regimen is not failing, a patient has a severe adverse reaction. This can be managed as follows:

IF	THEN
Reaction is caused by a single, identifiable medication	Omit the medication or Substitute a new, previously unused agent for the offending drug9
Cause of the adverse reaction cannot be readily identified	Discontinue all medications and then test the medications by reintroducing them one at a time, under hospitalization if necessary. (To prevent emergence of additional drug resistance, do not keep the patient on a single drug for more than a week.)

Post-treatment evaluation for MDRTB

After completing treatment for MDRTB, patients should be evaluated at 4, 8, 12, 18 and 24 months. Post-treatment evaluation should include the following: symptom review, AFB smear and culture, drug-susceptibility testing, and chest radiographs (if disease was pulmonary).⁴

Notes and References

1. Centers for Disease Control. Nosocomial transmission of multidrug-resistant tuberculosis among HIV-infected persons, Florida and New York, 1988-1991. MMWR 1991;40:585-91.
2. Frieden TR, Sherman LF, Maw KL, et al. A multi-institutional outbreak of highly drug-resistant tuberculosis. JAMA 1996;276:1229-35.
3. New York City Department of Health, Tuberculosis Control Program. Information Summary 1998.
4. For recommendations on treatment of patients with MDRTB, consult NYC Department of Health, TB Control Program, Clinical Policies and Protocols, 3rd edition, 1999.
5. In some cases--for example, if there is extensive disease or slow conversion of sputum cultures--it may be necessary to continue the injectable medication despite the risk of ototoxicity or nephrotoxicity.
6. Harkin TJ, Harris WH. Treatment of multidrug-resistant tuberculosis. In: Rom WN, Garay SM, eds. Tuberculosis. New York, NY: Little, Brown and Company, 1996;843-850.
7. See TB Fact Sheet 2c: Monitoring sputum during TB treatment.
8. Peloquin CA. Using therapeutic drug monitoring to dose the antimycobacterial drugs. Clin in Chest Med 1997;18(1):79-87.
9. Because the regimen is not failing, adding one drug in this setting does not increase the risk of drug resistance.

For further information, call 311.