PROCAARE: RELATED EPIDEMICS--TUBERCULOSIS--RIFAMPIN RESISTANCE

[Albert Shaw <ashaw@usa.healthnet.org>]

KEYWORDS: TUBERCULOSIS/ RESISTANCE/ RIFAMPIN/ RIFABUTIN/ PROPHYLAXIS
======================================================================

Reference: Bishai, W.R., Graham, N.M.H., Harrington, S., Page, C., 
Moore-Rice, K., Hooper, N., Chaisson, R.E. (1996).  Brief report: 
rifampin-resistant tuberculosis in a patient receiving rifabutin 
prophylaxis.  New Engl. J. Med. 334: 1573-6.

This report describes the case of a 35 year old man with AIDS and a CD4 
count of 7/mm3.  The patient presented with a two-month history of fever, 
sweats, cough, dyspnea and weight loss; chest x-ray revealed hilar 
adenopathy without infiltrates, and sputum smears demonstrated numerous 
acid-fast bacilli.  M. tuberculosis was subsequently cultured, and this 
isolate was sensitive to INH, rifampin, pyrazinamide, ethambutol, and 
streptomycin.

The patient received six months of directly observed therapy, beginning 
with INH/ rifampin/ pyrazinamide/ ethambutol daily for 16 days, then 
twice a week for 6 weeks, followed by INH/ rifampin twice a week for 33 
doses.  Cultures were negative for M. tuberculosis after 2 months of 
treatment.

Nine months after the beginning of antituberculous therapy, a follow-up 
chest radiograph was normal, and sputum smears and cultures were negative 
at 10 months.  The patient subsequenly saw a new physician who prescribed 
rifabutin (300 mg qD) for Mycobacterium avium complex prophylaxis.  Two 
months later, fever, cough and dyspnea along with diffuse interstitial 
infiltrates on chest x-ray were reported, and the patient died of 
respiratory failure.   M. tuberculosis resistant to rifampin and 
rifabutin, but sensitive to INH, pyrazinamide, ethambutol, and 
streptomycin was isolated from sputum.  

DNA restriction fragment length polymorphism (RFLP) analyses revealed 
that the M. tuberculosis strains from the first and second episodes of 
tuberculosis were virtually identical, implying a clonal genetic 
relationship between the strains.  Sequence determination of the M. 
tuberculosis rpoB gene demonstrated a point mutation in the resistant 
strain commonly found in other rifampin-resistant isolates.  This 
mutation and RFLP pattern was rare in the community (only 2 of 101 
isolates) and no epidemiologic link between the patient and subjects with 
an apparently similar strain could be established.  Thus, it seems 
unlikely that the patient was reinfected with the resistant M. 
tuberculosis, and a reasonable hypothesis would implicate relapsed 
disease with rifabutin use potentially selecting for acquired rifampin 
resistance (if rifabutin use were sporadic, acquired resistance might be 
even more likely).

This report emphasizes the difficulties of tuberculosis treatment in the 
setting of AIDS.  In addition, the importance of screening patients for 
active mycobacterial infection prior to the institution of rifabutin 
prophylaxis appears clear, as it seems most likely that selection 
pressures imposed by rifabutin contributed to the acquisition of resistance.