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Epidemiologic Notes and Reports Multi-Drug-Resistant Tuberculosis -- North Carolina

A 32-year-old male presented at a hospital emergency room on March 31, 1984, complaining of nausea and vomiting, abdominal pain, headache, and neck stiffness. He was admitted and a tentative diagnosis of viral encephalitis was made. His condition rapidly deteriorated; he became comatose and was transferred to another hospital 4 days later for further evaluation and treatment. A lumbar puncture on April 3 revealed bright yellow cerebrospinal fluid (CSF) with 3.8 g/dl protein, 37 mg/dl glucose, 118 rbc's, and 311 wbc's (100% mononuclear cells). A computerized tomography scan of the head showed marked hydrocephalus. The chest radiograph revealed bilateral lower lobe infiltrates and a mass in the left hilar area. The patient's condition worsened, and he died on April 20, 1984.

Autopsy findings revealed basilar meningitis, extensive acute encephalomalacia of the basal ganglia and brain stem, obstructive hydrocephalus, and left hilar lymph node caseation and necrosis. Staining of material from the brain demonstrated acid-fast organisms in isolated necrotic foci. On July 18, 1984, the North Carolina State Laboratory reported identification of Mycobacterium tuberculosis from a brain-tissue-culture specimen taken at autopsy. On August 15, 1984, the laboratory reported identification of M. tuberculosis from a culture of the CSF obtained on April 3. Drug-susceptibility studies showed the organism to be resistant to isoniazid (INH), rifampin (RIF), ethambutol (EMB), and streptomycin (SM).

The patient received no anti-tuberculosis drugs while hospitalized. Both the patient and his family gave no history of treatment for tuberculosis. A review of the tuberculosis records systems in North Carolina and South Carolina also revealed no history of prior treatment for tuberculosis.

Subsequent investigation revealed that the patient had resided in North Carolina for approximately 1 year immediately preceding his death. During this time, he was in contact with three other persons with infectious, drug-resistant tuberculosis. Two of these persons had M. tuberculosis isolates with the same pattern of quadruple drug resistance. Table 1 shows the dates of the patients' first TB diagnosis in chronological order. Three of the four patients died from tuberculosis. Patient 4 had the fatal meningitis case reported here.

The four patients knew one another and had interacted closely. Patients 1 and 2 were living together in May 1978 when Patient 1 was first diagnosed with tuberculosis. Patient 3, until his death, was the proprietor of an entertainment establishment often frequented by the other three. From about June 1983 until April 1984, Patients 1 and 4 lived in adjoining apartments in a small, four-unit converted house. Both had a history of alcohol abuse.

The available information suggests that Patient 1 transmitted quadruple-drug-resistant organisms to Patient 4 between June 1983 and February 1984. Progression from infection to disease was rapid and resulted in fatal tuberculous meningitis in less than 1 year.

After the initial diagnoses, the first three cases were difficult to manage because of the patients' alcohol abuse and the drug-resistant nature of the infections. Cumulatively, Patients 1, 2, and 3 were admitted 14 times to state tuberculosis hospitals. They continued to have positive smears and cultures and were lost to followup for long periods.

The treatment of Patients 1 and 3 was further complicated by delayed, conflicting, or possibly overlooked laboratory reports. Multiple medical providers and laboratories were involved in their care, and a review of records suggests that information may not have been uniformly shared.

Ten contacts of Patient 1 were evaluated with a Mantoux tuberculin skin test during 1978. Patient 2 was the only person with a significant skin-test reaction ( 10 mm) found among these contacts, and she was not put on tuberculosis preventive therapy. Within the following year, she developed disease, which subsequently was found to be resistant to INH, EMB, and SM, suggesting that she was infected by Patient 1 when he had not yet acquired resistance to RIF. Among her five contacts, one reactor was found and was started on INH preventive therapy.

During October 1980, 13 close contacts of Patient 3 were tested, and six, including his wife and two children, had a significant reaction. Four of the six were started on INH preventive therapy. Fifty-four contacts who worked with Patient 3 were also tuberculin tested, and seven of these had significant reactions.

From October 1984 through December 1985, there was extensive contact investigation around the four cases. Over 415 contacts were evaluated in North Carolina, South Carolina, and the District of Columbia. Fifty-six contacts had significant skin-test reactions. Twenty-nine of these reactors were started on INH preventive therapy. Although no new cases of tuberculosis (disease) were found as a result of contact investigations, a brother of Patient 2, living in Washington, D.C., was diagnosed with pulmonary tuberculosis in June 1984. Susceptibility tests showed the brother's organisms to be resistant to INH and SM. Reported by JA Jones, RV Berry, MD, K Scott, MD, M Swift, Tuberculosis Control Br, JN MacCormack, MD, State Epidemiologist, Div of Health Svcs, North Carolina Dept of Human Resources; RC Baxley, C Boner, Davidson County Health Dept; C Pozsik, Tuberculosis Control Div, R Parker, DVM, State Epidemiologist, South Carolina Dept of Health and Environmental Control; H Swann, MD, Div of Tuberculosis Control, M Levy, MD, State Epidemiologist, Bur of Preventive Svcs, District of Columbia Dept of Human Svcs; Div of Tuberculosis Control, Center for Prevention Svcs, CDC.

Editorial Note

Editorial Note: Transmission of drug-resistant tuberculosis in families and households (1) and in a shelter for the homeless (2) has been previously documented, and community outbreaks of drug-resistant tuberculosis have been reported in Mississippi (3) and in California, Montana, Nevada, and Utah (4). Although phage typing was not done in this investigation, the epidemiologic evidence and similar patterns of drug resistance suggest that Patient 1 (who ultimately died) infected Patients 2 and 4 with multi-drug-resistant tuberculosis and may have infected Patient 3; two additional deaths resulted. Noncompliance with therapy recommendations as well as poor communication among health care providers in various institutional settings contributed to treatment failures in Patients 1, 2, and 3.

This report calls attention to the problems that drug-resistant disease continues to pose to contemporary tuberculosis control programs. To address these problems, tuberculosis control programs should emphasize the following when monitoring all tuberculosis patients:

! continuity and completion of therapy, including direct

observation of therapy for patients who are unwilling or unable to take an unsupervised course of therapy; ! effective communication among all health care providers, both

within and outside of the health department; ! careful surveillance of mycobacteriology laboratory reports;

and ! thorough contact investigations surrounding each case of

tuberculosis. One of the purposes of most tuberculosis contact investigations is to identify persons infected with tuberculosis so that they can be evaluated for preventive therapy. The current standard preventive therapy regimen is INH for 6 to 12 months. In the case of INH-resistant tuberculosis, preventive therapy with 1 year of RIF or INH is considered an acceptable option since INH may be effective in vivo even in the case of laboratory failure (5). However, the contacts in this episode may have been infected with organisms resistant to both INH and RIF, in which case INH and/or RIF preventive therapy would probably not have been effective in preventing disease. These contacts then are at risk of developing drug-resistant disease in the future and of transmitting drug-resistant organisms to others. Health departments should establish special surveillance for such contacts. Certainly, the further spread of these quadruply resistant organisms should be prevented.

This report also points out the need for a readily available, rapid diagnostic test for tuberculosis. There was a 4-month hiatus between culturing the CSF from Patient 4 and the report of drug-resistant M. tuberculosis. Faster laboratory techniques for culturing and obtaining drug susceptibility results might have enabled providers to diagnose tuberculosis and institute appropriate therapy early enough to prevent this patient's death.


  1. Steiner M, Chaves AD, Lyons HA, Steiner P, Portugaleza C. Primary drug-resistant tuberculosis: report of an outbreak. N Engl J Med 1970;283:1353-8.

  2. CDC. Drug-resistant tuberculosis among the homeless--Boston. MMWR 1985;34:429-31.

  3. CDC. Drug-resistant tuberculosis--Mississippi. MMWR 1977;26:417-8,423.

  4. CDC. Interstate outbreak of drug-resistant tuberculosis involving children--California, Montana, Nevada, Utah. MMWR 1983;32:516-8.

  5. American Thoracic Society, CDC. Treatment of tuberculosis and

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