Strategies against multidrug-resistant tuberculosis

Abstract

Pulmonary tuberculosis can be cured by 6 months chemotherapy, consisting of isoniazid (INH), rifampicin (RFP), pyrazinamide (PZA), and etahanbutol (EB). However, the patients with pulmonary tuberculosis caused by multidrug-resistant tuberculosis (MDR-TB) bacilli, defined as resistance to at least INH and RFP, poorly respond to this regimen. Therefore, the epidemic of MDR-TB in the community is a major threat to tuberculosis control. According to the interim report of the survey of drug-resistant tuberculosis carried out by Tuberculosis Research Committee Japan in 2002, the prevalence of MDR-TB among new cases, previously treated cases and combined cases was 0.9%, 9.9% and 2.1%, respectively. Thus, the latest Japanese prevalence of MDR-TB was as high as the median prevalence of 72 geographical settings in the world, reported in the WHO/IUATLD Global Project on Drug Resistance Tuberculosis Surveillance, 1994-1999. In Japan, there is still an estimated 2,000 cases of MDR-TB patients. In the last meeting of the Japanese Society for Tuberculosis, an outbreak of MDR-TB in tuberculosis wards was reported, and a careful infection control of MDR-TB was recognized again. To work out the strategy for the elimination of MDR-TB, two issues were taken up in this symposium. First, not to make new MDR-TB cases, an intervention in the development and spread of MDR-TB was discussed. Second, the effectiveness of conventional anti-tuberculosis chemotherapy and pulmonary resection in the treatment of patients with MDR-TB was reevaluated, and a new approach for the treatment of chronic cases was also discussed. Dr. Koji Sato (National Amamiwakouen Sanatorium) surveyed the number of patients with MDR-TB in 72 hospitals with tuberculosis wards, and examined the clinical characteristics of chronic cases who had been expecting MDR-TB bacilli in the sputum for more than 5 years. One hundred and twenty-one of 149 chronic cases (81%) in this study were sputum-smear positive. Thirty-seven of them (25%) were outpatients. Thus, the high risk of MDR-TB transmission and the difficulties of infection control of chronic cases were reported. Dr. Yuka Sasaki (National Hospital Organization Chiba East National Hospital) conducted the questionnaire survey to the ordinance-designated cities and National Sanatoria Hospitals in Japan. Only a few contacts of patients with MDR-TB received preventive treatment, mainly due to the difficulties of diagnosis of latent MDR-TB infections and no effective treatment regimens. She pointed out the importance of preventive treatment guideline for contacts of patients with MDR-TB. Dr. Masako Wada (Research Institute of Tuberculosis, Japan Anti-Tuberculosis Association) examined the details of acquired MDR-TB cases. Among 2,375 pulmonary tuberculosis patients newly treated in Fukujuji Hospital form 1991 to 2002, 4 cases had developed drug resistance to INH and RFP during treatment. First case was initially INH mono-resistant, which had treated with INH, RFP and EB. Second case had received a sequential mono-therapy after serious adverse reaction. The remaining two cases were supposed to be reinfected with MDR-TB during treatment. This study indicated the importance of improvement of treatment guideline for patients with adverse drug reactions and infection control of MDR-TB in the sanatoria hospitals, in addition to the avoidance of sequential mono-therapy. Unlike the treatment of drug susceptible tuberculosis, it is not possible to develop a standard treatment regimen for MDR-TB. To know the treatment outcome by the number of susceptible drugs included in each regimen, Dr. Takayuki Nagai (Osaka Prefectural Medical Center for Respiratory and Allergic Diseases) reviewed the 37 patients with pulmonary MDR-TB, knowing the results of susceptibility testing to all 11 anti-tuberculosis drugs, such as INH, RFP, PZA, EB, streptomycin (SM), kanamycin (KM), Enviomycin (EVM), Ethionamide (TH), Cycloserine (CS), Para-aminosalicylic acid (PAS) and levofloxacin (LVFX). Among 11 patients who had received at least 3 susceptible drugs of PZA, LVFX and aminoglycoside, 10 patients (90.9%) had favorable response, converting their sputum cultures to negative at 2 months after the start of chemotherapy. He said that surgical interventions should be considered for any cases, which will not be effectively treated by the regimens including PZA, LVFX and aminoglycoside. Dr. Yuzo Sagara (National Hospital Organization Tokyo National Hospital) reviewed the surgical outcome of 28 patients with pulmonary MDR-TB with sufficient follow up data. All 8 patients, whose lung lesions had been completely removed, had achieved sputum-culture conversion after surgery and in combination with adequate chemotherapy. Even among 20 patients who still have some lesions after surgery, 14 patients (70.0%) had negative results of sputum cultures. Thus, it is shown that surgical intervention is a major treatment approach to MDR-TB. Finally, Dr. Koh Nakata (Niigata University Medical Dental Hospital) reported a clinical trial of activated autologous T lymphocytes transfusion to chronic cases. This immunotherapy was well tolerated by all 3 patients. Two patients had responded to this treatment and their sputum culture had become negative for 3-5 months. The host immune upregulation was proved by the tuberculin skin test conversion and the increment of IFN-γ production by peripheral blood in response to EAST-6 antigen. It was shown that activated T lymphocyte transfusion might be an effective treatment measure for some chronic cases, by enhancing the host antimycobacterial defense systems. MDR-TB control strategies should be primarily aimed at preventing the emergence of new cases. The rational approach devised by each panelist in this symposium will be the first step to containing the further spread of MDR-TB. 1. Current status of patients with multidrug resistant tuberculosis (MDR-TB) in the long term in Japan: Koji SATO (National Amamiwakouen Sanatorium), Masashi MORI (National Hospital Organization Tokyo National Hospital) We surveyed the number of MDR-TB cases in Japan. Four hundreds and eighty-seven cases (4.8%) of 10,208 tuberculosis patients registered in 72 hospitals were MDR-TB. Of them, 149 cases (30.6%) had been expecting MDR-TB bacilli in sputum for a long time more than 5 years. We examined the clinical profiles of these so called chronics. There were 33 females and 116 males. Ninety-eight (65.8%) of them were more than 60 years old. Thirty-seven (24.8%) were out patients. Among 103 cases with the reports of chest X-ray examination, 76 cases (73.8%) had cavity formations. Of them, 24 cases (64.9%) were sputum-smear positive. Difficulties of management and treatment of chronics were recognized again. 2. Chemoprophylaxis for contacts of patients with multidrug-resistant tuberculosis: Yuka SASAKI (Department of Thoracic Disease, National Hospital Organization Chiba East National Hospital) The Chemoprophylaxis to the contacts of patients with multidrug-resistant tuberculosis was considered. The questionnaire survey was conducted to the ordinance-designated cities in Japan. Chemoprophylaxis was performed in 2.4% of contacts of patients with multidrug-resistant tuberculosis, and in the contacts, 20 cases were diagnosed as tuberculosis in the ordinance-designated cities for the past five years. Chemoprophylaxis to the contacts of patients with multidrug-resistant tuberculosis is not carried out positively from many problems in National Sanatoria Hospitals. The present condition is troubled by the correspondence to the contacts of patients with multidrug-resistant tuberculosis. 3. Retrospective examination of treatment failures in newly diagnosed cases, whose strain had acquired multidrug resistance in initial treatment: Masako WADA (Research Institute of Tuberculosis, Japan Anti-Tuberculosis Association) Not to make a new multidrug resistant tuberculosis case, what should we do for it? First of all, we should treat all new pulmonary tuberculosis cases with 6-month regimen using INH, RFP, EB and PZA, if pyrazinamid is not contraindicated. In this review, two cases of far-advanced multidrug resistant pulmonary tuberculosis patients were presented. One patient received left pneumectomy with chemotherapy of second line anti-tuberculosis drugs, and she had been cured after the completion of 24-month chemotherapy. The other patients died due to massive hemoptysis with chronic respiratory failure at the age of 30 years old. It was supposed the critical different subject to their fates was the timing of reference to a specialist for tuberculosis treatment. Among 2,608 newly diagnosed pulmonary tuberculosis patients from 1 January 1991 to 31 December 2002, only 4 cases (0.15%) had treatment failures with the emergence of multidrug resistance. First case infected with INH resistant strain was treated with INH, RFP and EB without PZA. Second case complicated with tuberculous pyothorax was also treated with above three drugs regimen. Third case had suffered from a serious skin adverse reaction, and then she had a sequential mono-therapy. The remaining case was suspected to have re-infected with MDR-TB strain. We should initially treat all pulmonary tuberculosis patients with four drugs regimen. When the treatment failure had occurred due to drug resistant strain, adverse drug reactions or other reasons, it is essential to consult with a specialist for tuberculosis treatment. It should be never done to add antituberculosis drugs one by one to the case of treatment failure. 4. Treatment outcomes of multidrug-resistant tuberculosis: Takayuki NAGAI, Tetsuya TAKASHIMA, Izuo TSUYUGUCHI (Osaka Prefectural Medical Center for Respiratory and Allergic Diseases) [Objective] To study the results of anti-tuberculosis chemotherapy of the patients with diagnoses of MDR-TB in our hospital and determine the adequate chemotherapy regimen for MDR-TB.