Further acquisition of drug-resistance in multidrug-resistant tuberculosis during chemotherapy.

*Corresponding author: Mailing address: International Medical Center of Japan, Toyama 1-21-1, Shinjuku-ku, Tokyo 162-8655, Japan. Fax: +81-3-3202-7364, E-mail: [email protected] Multidrug-resistant tuberculosis (MDR-TB) resulting from failure to control primary tuberculosis (1) poses a serious clinical problem. Understanding how an organism can acquire resistance to multiple drugs is essential to prevent the emergence of a multidrug-resistant organism in an individual receiving antituberculous chemotherapy. A 41-year-old man visited a doctor complaining of a left chest pain. A chest radiograph revealed pneumothorax and his sputum was positive for acid-fast bacilli (AFB). He was referred to a hospital in Tokyo in July 2002. The patient had a history of antituberculous chemotherapy from 1992 to 1997 in South Korea with isoniazid (INH), rifamipicin (RFP), ethambutol (EMB), and streptomycin (SM) for 1 month, and then with INH, RFP, EMB, and cycloserine (CS) for 5 years. After the chemotherapy, he still continued to have a productive cough. Four-drug chemotherapy consisting of INH, RFP, pyrazinamide (PZA), and EMB was started in July 2002 (Table 1). Table 2 shows the drug sensitivity to various drugs (Vit Spectrum-SR; Kyokuto Pharmaceutical Industrial Co. Ltd., Tokyo, Japan). The drug sensitivity to PZA was not tested at that time. The isolate was found to be already resistant to INH, RFP, SM, and levofloxacin (LVFX). Therefore, in September 2002, the drugs were immediately changed to PZA, EMB, CS, and ethionamide (TH) and then to five drugs (PZA, EMB, CS, TH, and sparfloxacin [SPFX]) in October 2002. Because the sputa smears remained AFB positive and the symptoms did not improved, the patient received right thoracoplasty in December 2002. The drugs were changed to the four drugs EMB, CS, TH, and SPFX in March 2003. Drug sensitivity testing was conducted in June 2003 (Tables 1 and 2). The isolates were resistant to EMB and TH. The PZA sensitivity test that measures M. tuberculosis pyrazinamidase (PZase), which converts PZA to an active form, was conducted in August 2003, and was negative for both July 2002 and June 2003 isolates; i.e., they were resistant to PZA. The drugs were changed to EMB, CS, p-aminosalicylic acid (PAS), and SPFX in July 2003. The sputum smear was still AFBpositive. He again received pulmonary resection at the left S6 segment in August 2003. After the resection, the smear turned AFB-negative, and he was discharged from the hospital in September 2003. To determine whether isolates in July 2002 and in June 2003 came from a single clone, chromosomal DNA was analyzed by restriction fragment length polymorphism (RFLP) (2) using a IS6110 probe (3) and a trinucleotide