Treatment of isoniazid-resistant tuberculosis with isoniazid, rifampin, ethambutol, and pyrazinamide for 6 months.

SETTING: In 1992 the Seattle-King County Department of Public Health Tuberculosis Clinic began to treat patients with isoniazid-resistant tuberculosis with a regimen of isoniazid, rifampin, pyrazinamide, and ethambutol daily for 6 months. OBJECTIVE: To conduct a review of clinical and bacteriological outcomes of treatment for patients who received the four-drug, 6-month regimen for isoniazid-resistant tuberculosis. DESIGN: A retrospective review of medical records of TB cases meeting the study criteria, a Mycobacterium tuberculosis isolate resistant to isoniazid, and intent to treat with a 6-month course of isoniazid, rifampin, pyrazinamide, and ethambutol. RESULTS: Through December 1999, 44 consecutive patients with isoniazid-resistant, rifampin-susceptible tuberculosis were started on the four-drug, 6-month daily regimen. Among 42 patients followed until completion of therapy, three required changes in the regimen due to side effects. There was one case of drug-induced hepatotoxicity. Among 39 patients with pulmonary involvement, 37 converted sputum cultures from positive to negative within 2 months of starting treatment. There were no treatment failures. On passive follow-up of at least 2 years on all patients, two patients relapsed. The single patient with bacteriological relapse did not develop further drug resistance. CONCLUSION: The regimen of isoniazid, rifampin, pyrazinamide, and ethambutol given daily for 6 months produced successful outcomes when used in a public health tuberculosis clinic as routine therapy for isoniazid-resistant tuberculosis.     

Clinical trial of two short-course (6-month) regimens and a standard regimen (12-month) chemotherapy in retreatment of pulmonary tuberculosis in Pakistan. Results 18 months after completion of treatment (Lahore Tuberculosis Study)

This study compared the efficacy and tolerability of two 6-month daily regimens of isoniazid and rifampin in combination with either pyrazinamide or ethambutol (RHZ and RHE regimens) against a standard daily regimen of streptomycin, isoniazid, and ethambutol (SHE regimen) given for 6 months followed by isoniazid and ethambutol for an additional 6 months. Only previously treated sputum positive patients suffering from active pulmonary tuberculosis were entered into the study. Three hundred and fifty-eight patients were admitted to the study and 267 (75%) completed chemotherapy. Eighty-five percent of RHZ-regimen and 82% of RHE-regimen patients achieved sputum culture negativity compared to 55% of patients in SHE regimen. Successfully treated patients were followed up for 18 months, and among these, all 3 treatment regimens showed broadly similar levels of culture negativity at the end of the follow-up period. Final therapeutic outcome was based on sputum culture results obtained throughout the follow-up period, and no statistically significant difference in relapse rate was noticed in the 3 regimens. Severe drug intolerance necessitated discontinuation of therapy in only 2 patients.     

Intermittent treatment regimens in pulmonary tuberculosis

The author reviews various methods of intermittent chemotherapy for newly discovered cases of pulmonary tuberculosis and for retreatment of chronic patients excreting resistant bacilli. In the clinical use of intermittent therapy, drugs for oral administration (isoniazid, rifampicin, ethambutol, and pyrazinamide) and the injectable agent streptomycin appear to be particularly suitable. A period of daily treatment followed by twice-weekly drug administration results in nearly 100% sputum conversion. Also, there are fewer side effects than with the standard daily treatment. On the other hand, the once-weekly regimen using isoniazid and streptomycin appears to be less effective, even when a third drug is added. There is a low rate of sputum conversion and a higher risk of bacteriological relapse, particularly in patients who rapidly inactivate isoniazid. The use of rifampicin and ethambutol strengthens the regimen, particularly for patients resistant to previously used drugs. The characteristics of groups of patients under intermittent therapy can be important for the incidence of intolerance and toxicity. Smaller total quantities of drugs are likely to produce less toxicity than conventional daily regimens. Treatment beyond 1 year with regimens including intermittent methods appears to be unnecessary. If rifampicin or pyrazinamide are included, treatment of less than 1 year is usually sufficient for the majority of patients. Also, patients seem to accept intermittent therapy better than a daily regimen, and statistics show nearly 90% adherence to supervised intake of drugs. The use of intermittent therapy requires a very good monitoring system, but it can help overcome the deficiencies of the daily regimen and reduce not only drug costs and the length of institutional stays but total medical care expenses for pulmonary tuberculosis patients. As intermittent therapy — whether one- or two-phase — is still controversial and, until now, not fully refined, it still requires further research.     

Bactericidal activity of streptomycin, isoniazid, rifampin, ethambutol, and pyrazinamide alone and in combination against Mycobacterium Tuberculosis.

Log-phase cultures of Mycobacterium tuberculosis in Tween-albumin medium were exposed to streptomycin, isoniazid, rifampin, ethambutol, and pyrazinamide in concentrations in the range likely to be present in serum during treatment of patients. The bactericidal activity of the drugs was measured as the decrease in viable counts at 4 and 7 days. The activity of single drugs was highest for streptomycin and next highest for rifampin and isoniazid, but ethambutol only started to kill after 4 days. When exposed to 2 drugs, bactericidal synergism was found with streptomycin/isoniazid and isoniazid/ethambutol; additivity, with streptomycin/rifampin; indifference, with isoniazid rifampin and streptomycin/ethambutol; and antagonism, with rifampin/ethambutol and isoniazid/pyrazinamide. When cultures were exposed to the 3 drugs, isoniazid, rifampin, and ethambutol, marked antagonism was found between isoniazid and rifampin, whereas the addition of isoniazid or an increase in its concentration increased the bactericidal activity.     

Supervised intermittent chemotherapy for pulmonary tuberculosis in a rural area of China

In order to ensure regularity of ambulatory treatment of new cases of pulmonary tuberculosis, a fully supervised intermittent chemotherapy regimen was tried in two rural counties of Beijing. The bare-foot doctors of the village health co-operatives were designated to administer and supervise treatment. The regimen consisted of isoniazid and streptomycin daily for 1 month, then every 3 days for 5 months and then every 5 days for a total of 12 or 18 months. For smear-negative cases the daily phase was omitted. The compliance rate among 229 patients in 1 year was 99.4%. The sputum conversion rate among 104 cases harbouring sensitive bacilli was 95.2%. Discontinuation of the regimen due to side-effects as necessary in 3 cases (1.3%). Since 1979, this treatment programme has been adopted in the whole rural area of Beijing, and the coverage rate among newly diagnosed smear-positive cases in 1983 reached 90%. A reserve regimen consisting of rifampicin and ethambutol for patients who do not convert their sputum after 6 months of treatment with isoniazid and streptomycin was added. The overall conversion rate achieved in 1981 was 97.8%. The average overall cost of drugs for each patient treated in this treatment programme was 49 yuan (RMB), about $24.00 U.S.     

Prospective comparative study of ofloxacin or ethambutol for the treatment of pulmonary tuberculosis.

The efficacy of ofloxacin, rifampicin and isoniazid was prospectively compared with the regimen of ethambutol, rifampicin and isoniazid for the primary treatment of pulmonary tuberculosis in 124 patients. All drugs were given orally daily for nine months. Culture conversion rates three months after starting treatment were 98 percent in the ofloxacin group and 94 percent in the ethambutol group; by six months all patients in both groups were culture-negative. Significant radiological improvement of pulmonary infiltrates was observed in 83 percent of the ofloxacin group and 85 percent of the ethambutol group one year after starting treatment. No relapse in either group was observed during a two-year follow-up period after the cessation of chemotherapy. Ofloxacin appears to be as useful as ethambutol in the treatment of pulmonary tuberculosis when either drug is combined with isoniazid and rifampicin.     

Superiority of enviomycin or streptomycin over ethambutol in initial treatment of lung disease caused by Mycobacterium avium complex

The rate of sputum conversion (continuously negative cultures for six months or more) was compared among four regimens given to 83 patients with moderately advanced, cavitary lung disease caused by Mycobacterium avium complex untreated previously. The regimens of rifampin + isoniazid + enviomycin and rifampin + isoniazid + streptomycin appeared to be superior to the regimen of rifampin + isoniazid + ethambutol. No statistically significant difference was observed between the regimens rifampin + isoniazid + enviomycin and rifampin + isoniazid + streptomycin.     

Utilization of antituberculosis drugs expressed in defined daily doses in Klenovnik Hospital in the period between 1983 and 1987

In this paper the utilization of antituberculosis drugs was analyzed in defined daily doses per 1000 bed-days (DDD/1000 BD) in the Hospital for Pulmonary Diseases and Tuberculosis, Klenovnik, from 1983 to 1987. The utilization of these drugs increased from 894 DDD/1000 BD in 1983 to 1112 DDD/1000 BD in 1984, and then decreased to 1077 DDD/1000 BD in 1986; but in 1987 it again increased to 1270 DDD/1000 BD. During the research period the following drugs were prescribed: ethambutol, rifampin, pyrazinamide, streptomycin, isoniazid, and two combinations of drugs: a combination of isoniazid with pyridoxine and a combination of ethambutol, isoniazid and pyridoxine. For the whole of that period the use of ethambutol, isoniazid with pyridoxine and rifampin made up more than 85% of the general utilization of antituberculosis drugs, while other drugs were prescribed in lesser quantities. The data presented indicate that tuberculosis in Klenovnik hospital was in most cases treated with ethambutol, the combination of isoniazid with pyridoxine, and rifampin.     

A four-drug regimen for initial treatment of cavitary disease caused by Mycobacterium avium complex

Forty-six patients with positive sputum cultures for Mycobacterium avium complex and cavitary disease were placed on a 4-drug regimen consisting of isoniazid, rifampin, and ethambutol daily and streptomycin twice weekly. Forty-two (91.3%) converted their sputum to negative and 4 (8.7%) failed to convert. All of the 4 nonconverters had prior subtotal gastrectomy. Twenty-two patients were available for long-term follow-up: 12 patients completed 24 months of chemotherapy, all experienced sputum conversion, but 2 reactivated, 1 at 9 and the other at 27 months after termination of chemotherapy. These 2 patients had prior subtotal gastrectomy. Ten patients completed 18 months of chemotherapy with sputum conversion, 2 of these reactivated but had not had prior subtotal gastrectomy. In this group of patients, subtotal gastrectomy appeared to be an adverse risk factor for both initial treatment response and reactivation in pulmonary disease caused by Mycobacterium avium complex.     

Weekly moxifloxacin and rifapentine is more active than the denver regimen in murine tuberculosis

RATIONALE: Treatment of tuberculosis with an efficacious once-weekly regimen would be a significant achievement in improving patient adherence. Currently, the only recommended once-weekly continuation phase regimen of isoniazid plus rifapentine (10 mg/kg) is inferior to standard twice-weekly therapy with isoniazid plus rifampin and is, therefore, restricted to non-high-risk patients. The substitution of moxifloxacin, a new 8-methoxyfluoroquinolone, for isoniazid and an increase in the dose of rifapentine could augment the activity of once-weekly regimens. METHODS: To test this hypothesis we evaluated the sterilizing activity of improved once-weekly rifapentine-based continuation phase regimens in a murine model that mimics the treatment of high-risk patients with tuberculosis. The bactericidal activity of standard daily therapy and standard intermittent therapy ("Denver" regimen) was also assessed to evaluate the effect of intermittent drug administration during the initial phase of therapy. RESULTS: After 2 mo of treatment, lung colony-forming unit counts were 1 log(10) lower in mice treated with standard daily therapy than with the Denver regimen. During the continuation phase, the sterilizing activity of once-weekly moxifloxacin plus rifapentine (15 mg/kg) was significantly greater than that of the predominantly twice-weekly Denver regimen of isoniazid plus rifampin. No significant difference in sterilizing activity was detected between once-weekly isoniazid plus rifapentine (15 mg/kg) and the Denver regimen. CONCLUSIONS: These results suggest that the efficacy of the once-weekly isoniazid plus rifapentine continuation phase regimen can be increased by substituting moxifloxacin for isoniazid and by increasing the dose of rifapentine to a clinically acceptable level of 15 mg/kg.     

Pulmonary disease due to Mycobacterium xenopi in a renal allograft recipient: report of a case and review

A 39-year-old man with pulmonary disease due to Mycobacterium xenopi is described. He had received prednisone and azathioprine for 5 years and prednisone in combination with cyclosporin A for 1 year in an effort to prevent rejection of his renal transplant. Shortly after the renal allograft was removed because of chronic rejection, the patient developed dyspnea and a decrease in vitality. He had no history of preexisting lung disease. A chest roentgenogram showed multiple nodular infiltrates in both lungs. M. xenopi was cultured from three sputum samples. The organism was susceptible to isoniazid, streptomycin, ethambutol, rifampin, pyrazinamide, and ethionamide. The patient was treated successfully with isoniazid, ethambutol, and rifampin for 3 months and with isoniazid in combination with rifampin for an additional 9 months, while he was maintained on continuous ambulatory peritoneal dialysis (CAPD). The literature on mycobacterial disease, especially in renal transplant recipients and patients on CAPD, is reviewed.     

Response to chemotherapy of pulmonary infection due to Mycobacterium kansasii.

Chemotherapy of pulmonary disease due to Mycobacterium kansaii has not always been successful, and resectional surgery has been used frequently in the treatment of this infection. To ascertain the impact of new antimicrobial agents on the treatment of M. kansaii infection, we reviewed the clinical courses of 59 patients treated between 1971 and 1974. Over-all, 92 per cent of patients converted their sputum cultures while receiving drugs, with only one patient undergoing surgical resection. Regimens containing rifampin were universally effective in both initial and retreatment cases; however, they offered no significant advantage over monrifampin regimens in initial treatment cases. In vitro resistance to isoniazid and ethambutol did not adversely affect the results of treatment with these drugs. Owing to the effectiveness of current chemotherapy, parameters such as age, underlying lung disease, or extent of disease were not related to the outcome of therapy. Because 90 per cent of the conversions in successful regimens occur within 4 to 6 months of beginning therapy, patients whose cultures remain positive should be considered for alternate drugs. Because the frequency of relapse after current chemotherapy is not yet clear, and because rifampin appears to be particularly advantageous in retreatment programs, rifampin should be reserved for this role. The total course of treatment should probably span at least 18 months, or 6 months beyond any cultural or radiographic evidence of activity.     

The bioavailability of isoniazid, rifampin, and pyrazinamide in two commercially available combined formulations designed for use in the short-course treatment of tuberculosis

The bioavailability of isoniazid, rifampin, and pyrazinamide in 2 combined formulations of the 3 drugs (Rifater) for use primarily in the short-course chemotherapy of tuberculosis has been studied in Chinese patients in Singapore and Hong Kong. One formulation, containing 50 mg isoniazid, 120 mg rifampin, and 300 mg pyrazinamide per tablet is suitable for daily use, whereas the other, containing higher proportions of isoniazid and pyrazinamide, is designed for intermittent treatment, each tablet containing 125 mg isoniazid, 100 mg rifampin, and 375 mg pyrazinamide. Appropriate dosages for the Chinese patients, whose average weight was approximately 50 kg, were 5 and 6 tablets, respectively. Plasma concentrations of the 3 drugs after giving such dosages of the 2 combined formulations were compared in 16 patients, 8 in Singapore and 8 in Hong Kong, by means of a crossover study, with the concentrations obtained when identical doses of the 3 drugs were given using standard separate drug formulations. The concomitant urinary excretions of the drugs and their major metabolites were also estimated. Very similar results were obtained whether the drugs were given as the combined preparations or in their standard separate formulations, demonstrating the excellent bioavailability of all 3 drugs in each of the 2 combined formulations.     

Increasing drug resistance of Mycobacterium tuberculosis isolates in Ontario, Canada, 1987-1998.

We examined trends in resistance to first-line antituberculous agents for Mycobacterium tuberculosis strains isolated in Ontario, Canada from 1987 through 1998 (n=8069). The proportions resistant were as follows: isoniazid, 9.6%; rifampin, 1.9%; streptomycin, 4. 9%; ethambutol, 1.3%; and pyrazinamide, 1.7%. Resistance to isoniazid has increased markedly since 1990, whereas resistance to streptomycin, ethambutol, and pyrazinamide increased from 1997 through 1998. Resistance to both isoniazid and rifampin did not increase. The incidence of persistence and reactivation (early or late treatment failure) was 1-2 per 100 person-years (PY) in the first 7-12 months and 0.3-0.9 per 100 PY from 13 months to 5 years thereafter. For initially susceptible strains, the incidence of resistance to isoniazid was 0.11 per 100 PY and for and rifampin was 0.06 per 100 PY in the first year and negligible thereafter, with an overall risk of 0.14% for isoniazid and 0.10% for rifampin. Resistance of M. tuberculosis to antituberculous agents, and in particular to isoniazid, is a growing problem in Ontario and is higher than elsewhere in Canada.     

Comparison of a daily and three intermittent retreatment regimens for pulmonary tuberculosis administered under programme conditions

One daily and 3 thrice weekly retreatment regimens given for 12 months under programme conditions were compared. The daily regimen was rifampicin and ethambutol (RE7). The three intermittent regimens also contained rifampicin and ethambutol: one of them, rifampicin and ethambutol throughout (RE3); the next one supplemented with pyrazinamide for the first 3 months (REZ3); the last one supplemented with prothionamide for the first 3 months (REPt3). The pyrazinamide containing regimen was subdivided into ordinary and high dose groups. The subjects for retreatment were those who have had, at least, more than 6 months of initial triple chemotherapy of isoniazid, PAS and streptomycin at the health centres, and failed to convert to bacteriologically negative status. Among 419 patients who were available for sensitivity tests before commencing retreatment, 393 (94.3%) were resistant to isoniazid. Six hundred and seventy-four patients (674) were allocated randomly to the regimens: 64 patients were excluded due to various pretreatment reasons and 109 did not complete 12 months of chemotherapy. There remain 501 patients who completed their retreatment. As assessed at 12 months, a bacteriologically favourable response was achieved in 68% of 135 RE7 patients, 62% of 129 RE3 patients, 74% of 132 REZ3 patients, and in 79% of 108 REPt3 patients. Adverse reactions were uncommon: 4% in RE7, 5% in RE3 and 9% in REZ3, but 32% in REPt3. Relapse rates during 2 years after termination of chemotherapy were 15% in RE7, 14% in RE3 and REZ3, and 26% in REPt3, as calculated by life table analysis.     

The results of 9-month isoniazid-rifampin therapy for pulmonary tuberculosis under program conditions in San Francisco

The outcome of treatment for pulmonary tuberculosis using isoniazid and rifampin for 9 months supplemented by ethambutol for the initial 2 months was evaluated in a cohort of 233 patients. All patients had sputum cultures positive for Mycobacterium tuberculosis sensitive to isoniazid and rifampin. Of the 233 patients, 200 completed the regimen without change. Four patients had adverse reactions necessitating discontinuation and four became pregnant and had ethambutol substituted for rifampin. All eight were treated successfully with altered regimens. Ten patients were lost to follow-up, seven died, and eight were transferred to other jurisdictions. No patients failed to convert their sputum during therapy. At completion of therapy, three patients (1.5%) were found to have positive sputum. Follow-up 6 months after completion of treatment in 174 successfully treated patients revealed four (2.3%) with positive sputum. No further relapses were detected on evaluation 12 months after treatment was completed. All seven patients who failed therapy or relapsed were retreated successfully using the same regimen. These data provide a reference standard against which newer treatment regimens, such as the 6-month regimen currently in use, can be compared. In addition, the value of routine evaluations in detecting relapses at the time treatment is completed and 6 months later was substantiated, but 12-month follow-up was not useful.     

Treatment of tuberculosis infection

Tuberculosis is a chronic bacterial infection caused by Mycobacterium tuberculosis. It continues as an important cause of morbidity and mortality worldwide, especially in impoverished countries and where human immunodeficiency virus infection is endemic. The modern treatment of tuberculosis is based on the administration of effective drugs. Regimens do not differ for pulmonary and extra-pulmonary tuberculosis. In order to prevent the emergence of drug-resistant organisms, which is present initially in very small numbers, at least two effective drugs are always required. Short-course therapy has been developed to mitigate the consequences of patient default. It is best considered as consisting of two phases. An initial 2-month intensive phase of daily therapy should include isoniazid, rifampin, ethambutol and pyrazinamide. A consolidation phase of daily therapy with isoniazid and rifampin should be continued for an additional 4 months, preferably more for special clinical circumstances. This standardized drug strategy is successful only if the resources conserved by shortening treatment are used to maintain patient compliance. Completely supervised regimens have been also developed with success. Defaults lead not only to treatment failure but also the emergence and transmission of drug-resistant organisms. Treatment of confirmed or suspected drug-resistant tuberculosis is difficult and should only be made on experts consultation. More difficult to use and/or less effective than first line drugs, second line drugs could be chosen and associated. However drug toxicities should be monitored, with greatest concern to hepatitis. Follow-up of patients must be organised until 2 years after the completion of therapy to detect relapses. Treatment includes prophylactic measures which are a major modality for decreasing the spread of infection.     

抗结核药物诱导结核分支杆菌形成L型及其特性的观察

目的 观察常用抗结核药物对结核分支杆菌L型的诱导作用以及结核分支菌L型在非高渗透压培养基内的某些特性及其抗菌药物敏感性,探讨结核分支菌L型形成的机制及其在结核病的发生、诊断及治疗上的意义。方法 将结核分支杆菌接种于含有利福平、异烟肼、乙胺丁醇的非高渗透压培养基内,逐日在显微镜下观察结构分支杆菌L型的形成情况。L型形成后将培养物过滤,获得结核分支杆菌L型纯培养物并对其形态、培养、抗菌药物敏感性、结核分支杆菌特异性基因等进行观察。结果 结核分支杆菌在常规药敏试验浓度的利福平、异烟肼、乙胺丁醇的作用下均可形成L型。结核分支杆菌L型对这些抗结核药物不再敏感,但对链霉素、红霉素、氧氟沙星、诺氟沙星等抗菌药物均敏感。结核分支杆菌L型在非高渗透压培养基内呈圆球或不规则形态的细胞,单个、成双或链状排列,沉于培养基底部生长,不粘附瓶壁,不运动,抗酸染色阴性,革兰染色阴性或阳性,保留了结核分支杆菌特异性PCR引物基因序列。结论 利福平、异烟肼、乙胺丁醇虽然能够杀灭结核分支杆菌细菌型,但也能够诱导其形成L型而造成这些抗结核药物对结核治疗无效。非高渗培养基传代培养的结核分支杆菌L型保留了与其亲代细菌型一致的PCR引物基因序列,以致可用结核分支杆菌特异性PCR鉴定。根据结核分支杆菌L型的药物敏感性特点,建议在使用抗结核药物治疗中须注意其L型的形成和联合使用结核分支杆菌L型敏感的抗菌药物进行治疗。     

Intermittent chemotherapy in pulmonary tuberculosis — Current aspects

A critical review of the application of various methods of intermittent chemotherapy in the initial treatment of tuberculosis and retreatment of far advanced pulmonary tuberculosis has been presented. Not all drugs are suitable for intermittent chemotherapy in clinical practice, but the introduction in the last years of new drugs in the treatment of tuberculosis, especially rifampicin and ethambutol made possible the application of intermittent chemotherapy also for the groups of patients with far advanced chronic pulmonary tuberculosis with resistant bacilli. For intermittent chemotherapy isoniazid, rifampicin, ethambutol and streptomycin are particularly suitable in clinical practice. The intermittent chemotherapy should be applied only under strict supervision, as it requires a very good monitoring organization system. Still some problems of intermittent chemotherapy in tuberculosis are unsolved and require further studies, but the perspectives of this type of treatment seems to be very promising.     

Tuberculoid tenosynovitis and carpal tunnel syndrome caused by mycobacterium szulgai

Mycobacterium szulgai, a scotochromogenic mycobacterium, is a newly recognized pathogen of man and has been reported to cause pulmonary infections, olecranon bursltis and cervical adenitis. We isolated M. szulgai from granulomatous tissue removed at surgery from a young florist with the carpal tunnel syndrome. The organism was susceptible to ethambutol and rifampin but resistant to isoniazid. Cure was achieved by debridement and chemotherapy with ethambutol and rifampin. Neither the source in our patient nor the natural habitat of M. szulgai is known. Because it resembles M. gordonae and M. flavescens, common scotochromogenic mycobacteria in tapwater, care must be taken to avoid dismissing M. szulgai as a contaminant when it is isolated from tissue.