Treatment Of Multi-drug Resistant Pulmonary Tuberculosis Research Articles

Expert consensus on surgical treatment of multidrug-resistant and rifampicin-resistant pulmonary tuberculosis in China (2022 edition)

The cure rate of multidrug-resistant and rifampicin-resistant pulmonary tuberculosis in the world is about 60%, and timely surgical intervention can increase the cure rate to more than 85%. The treatment of multidrug-resistant and rifampicin-resistant pulmonary tuberculosis requires multidisciplinary involvement of tuberculosis department, thoracic surgery department, imaging department, laboratory department and other disciplines to significantly reduce its morbidity and mortality. Although the World Health Organization has defined the role and status of surgery in the treatment of multidrug-resistant and rifampicin-resistant pulmonary tuberculosis, there are significant differences in the cognition and diagnosis and treatment methods of domestic clinicians on multidrug-resistant and rifampicin-resistant pulmonary tuberculosis. Therefore, it is urgent to develop expert consensus on surgical treatment of multidrug-resistant and rifampicin-resistant pulmonary tuberculosis for clinicians to learn from in clinical diagnosis and treatment practice. The Chinese Society for Tuberculosis,Chinese Medical Association organized experts in tuberculosis thoracic surgery to write the first draft of consensus based on the expert suggestion on surgical diagnosis and treatment of multidrug-resistant pulmonary tuberculosis written by the European Office of the World Health Organization in 2014 and the 2019 version of China's multidrug-resistant and rifampicin-resistant pulmonary tuberculosis expert consensus, and combined with China's national situation. This consensus systematically elaborated seven aspects, including surgical indications, contraindications to surgery, conditions and timing of surgery, surgical methods and indications of various surgical procedures, preoperative and postoperative chemotherapy, treatment of surgical complications, and perioperative management of patients with multidrug-resistant and rifampin-resistant pulmonary tuberculosis. After discussion and voting by experts, six recommendations were formed, aiming to provide reference for clinicians in the treatment of multidrug-resistant and rifampin-resistant pulmonary tuberculosis and further improve the standardized diagnosis and treatment level of multidrug-resistant and rifampin-resistant pulmonary tuberculosis in China.

Discovery and preclinical evaluations of JBD0131, a novel nitrodihydro-imidazooxazole anti-tuberculosis agent

Multidrug-resistant pulmonary tuberculosis (MDR-TB) is a major health problem worldwide. The treatment for MDR-TB requires medications for a long duration (up to 20–24 months) with second-line drugs resulting in unfavorable outcomes. Nitroimidazoles are promising antimycobacterial agents known to inhibit both aerobic and anaerobic mycobacterial activity. Delamanid and pretomanid are two nitroimidazoles approved by the regulatory agencies for MDR-TB treatment. However, both agents possess unsatisfactory absorption and QTc prolongation. In our search for a safer nitroimidazole, we discovered JBD0131 (2). It exhibited excellent anti-mycobacterial activity against M. tuberculosis H37Rv in vitro and in vivo, improved PK and absorption, reduced QT prolongation potential of delamanid. JBD0131 is currently in clinical development in China for pulmonary tuberculosis (CTR20202308).

Treatment of multidrug-resistant pulmonary tuberculosis with delamanid based on Japanese guideline recommendations.

In Japan, a new anti-tuberculous drug, delamanid, was recognized as the drug of choice to treat multi-drug resistant pulmonary tuberculosis in July 2014. We treated 28 cases of multidrug-resistant tuberculosis (MDR-TB) and three cases of extensively drug-resistant tuberculosis (XDR-TB) with delamanid from July 2014 to June 2018at our hospital. There were 21 men and 10 women, with the mean age of 48 and 37 years, respectively. We used an average of 4.4 sensitive anti-tuberculous drugs for the MDR-TB cases and 4.7 for the XDR-TB cases with delamanid. We used linezolid in 19 of 31 cases, although it has not been recognized as an anti-tuberculous drug in Japan. On electrocardiography, QTc prolongation of more than 450ms was seen in two cases (6.4%), but they were asymptomatic, thus the treatment with delamanid could be continued. In 10 cases, surgical resection was performed. We completed the treatment in 20 cases and continued the treatment in seven cases; however, the treatment was discontinued in four cases because of side effects. In all cases, the sputum cultures were negative. Delamanid is a relatively safe drug with few side effects. However, some patients could not continue it because of difficulty of use in combination, therefore delamanid should be prescribed considering the side effects of all therapies in the regimen.

Clinical-morphological characteristics of surgical treatment of multidrug-resistant pulmonary tuberculosis in the last 10 years

Objective — to analyze the surgical activity in cases of pulmonary MDR-TB taking into account laboratory parameters over a 10-years period (based on the materials of a highly specialized NIFP clinic).Materials and methods. A retrospective study of surgical activity for pulmonary tuberculosis, in particular multidrug-resistant was performed for a 10-years period. A total of 1.038 operations were carried out, 366 of them (35.3 %) with pulmonary MDR-TB. All cases of multidrug-resistance have been verified microbiologically. During the study period, the dynamics of the annual frequency of operations and their types in pulmonary MDR-TB was analyzed, and also the frequency of different types of operations depending on the clinical and morphological form of MDR-TB, morphological activity in various forms of lung lesions, taking into account histological findings. The results of a microbiological study of the resistance profile of mycobacteria were taken into account.Results and discussion. The annual total number of operations for pulmonary TB has been presented and among them — the percentage of MDR-TB cases over a 10-year follow-up period. It is shown that overall the surgical activity has slightly decreased, while the specific weight of operations at MDR-TB is quite stable. The change in the types of surgical interventions in cases of MDR-TB has been established over time, in particular, the reduction in the number of large operations such as pneumonectomy, which the authors associate with the improvement of both the regimens of anti-tuberculosis chemotherapy, and with the introduction of video-assisted minimally invasive surgical procedures into surgical practice. Dependence of the type of surgical intervention on the clinical-morphological form of pulmonary TB and the degree of morphological activity of a specific inflammatory process at the time of surgery was analyzed.Tuberculomas and fibro-cavernous TB are prevailed among operated patients with MDR-TB, and in most cases of these forms of pulmonary TB the activity of tuberculous inflammation remains, 83 and 97 % respectively, according to morphological features.It was established that the microbiological detection of multidrug-resistant strains of MBT in the NIFP clinic in cases of pulmonary MDR-TB with surgical treatment was effective only in a third of all cases.Conclusions. In the past 10 years, the trend of reducing the number of pneumonectomies and increasing the number of operations of a more radical nature has been observed in surgery of pulmonary MDR-TB. Surgical interventions are indicated mainly in fibro-cavernous TB and pulmonary tu­­berculomas. According to the results of the morphological study, at the time of the operation, the activity of a specific process is retained in more than 80 % of cases, which indicates the need for complex, including surgical, treatment of such patients.

Clinical analysis of 64 cases of multidrug resistant pulmonary tuberculosis

Objective To explore the effect of previous treatment on the efficacy of multidrug resistant pulmonary tuberculosis (MDR-TB) patients. Methods From February 2015 to February 2017, 64 cases with MDR-TB who received treatment in the First Hospital of Ninghai were collected.All patients received antituberculous therapy for 6 months.The clinical data were retrospectively analyzed.The factors that influence the efficacy of MDR-TB patients were evaluated by multivariate logistic regression analysis. Results After standard chemotherapy for MDR-TB patients, the incidence of chest radiographic lesions in primary and relapsed MDR-TB patients was 18 cases(81.82%) and 21 cases(50.00%), respectively.There was statistically significant difference between the two groups (χ2=22.835, P<0.05). The cavity closure rate of MDR-TB patients after primary treatment and relapse was 54.55% and 40.48%, respectively, and there was significant difference between the two groups (χ2=8.693, P<0.05). After standard chemotherapy for MDR-TB patients, the cure rates of primary and recurrent MDR-TB patients were 18 cases(81.82%) and 23 cases (54.76% ), respectively, there was statistically significant difference between the two groups (χ2=21.791, P<0.05). Conclusion The effect of initial treatment of MDR-TB is better than recurrent MDR-TB, so it is necessary to strengthen the surveillance of drug resistance in patients with tuberculosis and to find the disease as soon as possible.Early treatment of MDR-TB is the best option for patients. Key words: Tuberculosis, multidrug resistant; Tuberculosis; Treatment outcome

Analysis of adverse drug reactions in multidrug-resistant pulmonary tuberculosis patients

Objective To analyze the adverse drug reactions (ADR) during the standardized treatment of multidrug-resistant pulmonary tuberculosis (MDR-PTB), and to evaluate its impact on treatment outcomes. Methods A retrospective study was carried out on 305 MDR-PTB patients. Medical records of clinical treatment and laboratory examinations were collected, and the ADR data were analyzed.Chi-square test or Fisher exact test was used for discontinuous variables, and t test or non-parametric test was used for continuous variables. Results Among 305 MDR-PTB patients , 282 (92.5%) had at least one ADR. The major ADR were gastrointestinal reaction (46.9%), thyroid dysfunction (41.3%), hypokalemia (34.1%), renal injury (29.8%), hematological system impairment (21.6%), hepatotoxicity (19.0%), arthralgia or courbature (11.1%), and ototoxicity and vestibular dysfunction (8.5%). Sex, age, native place, the history of using second-line TB drugs or the history of diabetes mellitus had no significant effect on the incidence of ADR (all P>0.05). As per the Naranjo causality assessment of ADR, 34 patients had definite, 236 had probable, 12 had possible and 0 had doubtful causal relations. Among the 282 cases with ADR, 175 (62.1%) patients continued the original treatment regimen, 89 (31.6%) patients changed or stopped ADR-related drugs, only 18 (6.4%) cases stopped MDR-PTB treatment. The episodes of ADR had no significant effect on the treatment outcomes (P>0.05). Conclusions Although ADR are common in MDR-PTB patients during the treatment course, most of the ADR can be managed. Through timely monitoring and appropriate treatment of ADR, most of the patients could continue MDR-PTB treatment. Key words: Tuberculosis, pulmonary; Tuberculosis, multidrug-resistant; Therapy; Adverse drug reactions

Bedaquiline in multidrug-resistant pulmonary tuberculosis GENESIS-SEFH drug evaluation report.

Multidrug-resistant pulmonary tuberculosis (MDR-TB) is a disease affecting pulmonary parenchyma and tracheobronchial tree due to organisms which shows high-level resistance to both isoniazid and rifampicin, with or without resistance to other anti-TB drugs. Extensively drug-resistant tuberculosis (XDR-TB) is characterized for in vitro resistance to isoniazid and rifampicin plus any fluoroquinolone and at least one injectable drug (capreomycin, amikacin or kanamycin). In 2013, among the world reported cases of pulmonary tuberculosis, 450,000 were MDR-TB or XDR-TB. Almost 60% of them were located at India, China and Russian Federation. In Spain, in 2012, 6,046 cases of tuberculosis were reported, with a 3.9-4.3% proportion of MDR-TB; and approximately 6% of them could be XDRTB, a higher ratio than other occidental countries. MDRTB poses special challenges on his treatment. Curation rate is around 62% and mortality reaches 11%. Male gender, alcoholism, quinolone resistance and positive smear at diagnosis are poor prognostic factors. In XDRTB, curation rates falls to 43.7% and mortality reaches 20.8%. Current treatment of MDR-TB needs to be individualized, being guided by antibiogram and including in the first 6 months an injectable drug (amikacin, kanamycin, capreomycin, streptomycin) and a fluoroquinolone (levofloxacin, moxifloxacin or ofloxacin) during the complete course of treatment. Treatment should include at least 4 effective agents and should continue 18 months after obtaining negative cultures2. Bedaquiline (Sirturo®, Lab. Janssen), is a new diarylquinoline approbed by FDA (December 2012) according to the accelerated approval pathway, intended to facilitate and expedite development and review of new drugs to address unmet medical need in the treatment of a serious or life threatening condition, based on a surrogate endpoint or an intermediate clinical endpoint and clinical benefit that can be verified by post approval studies. Bedaquiline was approved by EMA in March 2014 after an orphan drug designation in 2005. Bedaquiline is available in 100 mg tablets. The recommended dosage is 400 mg once daily during weeks 1 and 2, and 200 mg per day three times per week (with at least 48 hours between doses) weeks 3 to 24. Bedaquiline tablets should be taken with food, in order to increase oral bioavailability (by about 2-fold). Tablets should be swallowed whole with a glass of water. Bedaquiline efficacy and safety in children younger than 18 years and in adults older than 65 years has not been established yet. Dosage adjustment in patients with mild or moderate renal impairment is not needed. In patients with creatinine clearance < 30 ml/min, terminal renal disease requiring hemodialysis, peritoneal dialysis or mild or moderate hepatic impairment bedaquiline should be used with caution. In patients with severe hepatic impairment, bedaquiline is not recommended.

Multidrug-resistant tuberculosis treatment with linezolid-containing regimen

The following is a case of multidrug-resistant pulmonary tuberculosis (MDR-TB) that was treated successfully with a linezolid-containing regimen. It was found that linezolid is an efficient medicine for MDR-TB treatment with an acceptable side effect profile. Treatment was maintained for 18months, and closely monitoring toxicities did not reveal evidence of any neurologic adverse effects. However, despite our expectation, thrombocytopenia was seen after 2years follow-up.

Correction: Multidrug Resistant Pulmonary Tuberculosis Treatment Regimens and Patient Outcomes: An Individual Patient Data Meta-analysis of 9,153 Patients

Correction: Multidrug Resistant Pulmonary Tuberculosis Treatment Regimens and Patient Outcomes: An Individual Patient Data Meta-analysis of 9,153 Patients

Multidrug resistant pulmonary tuberculosis treatment regimens and patient outcomes: an individual patient data meta-analysis of 9,153 patients.

Treatment of multidrug resistant tuberculosis (MDR-TB) is lengthy, toxic, expensive, and has generally poor outcomes. We undertook an individual patient data meta-analysis to assess the impact on outcomes of the type, number, and duration of drugs used to treat MDR-TB. Three recent systematic reviews were used to identify studies reporting treatment outcomes of microbiologically confirmed MDR-TB. Study authors were contacted to solicit individual patient data including clinical characteristics, treatment given, and outcomes. Random effects multivariable logistic meta-regression was used to estimate adjusted odds of treatment success. Adequate treatment and outcome data were provided for 9,153 patients with MDR-TB from 32 observational studies. Treatment success, compared to failure/relapse, was associated with use of: later generation quinolones, (adjusted odds ratio [aOR]: 2.5 [95% CI 1.1-6.0]), ofloxacin (aOR: 2.5 [1.6-3.9]), ethionamide or prothionamide (aOR: 1.7 [1.3-2.3]), use of four or more likely effective drugs in the initial intensive phase (aOR: 2.3 [1.3-3.9]), and three or more likely effective drugs in the continuation phase (aOR: 2.7 [1.7-4.1]). Similar results were seen for the association of treatment success compared to failure/relapse or death: later generation quinolones, (aOR: 2.7 [1.7-4.3]), ofloxacin (aOR: 2.3 [1.3-3.8]), ethionamide or prothionamide (aOR: 1.7 [1.4-2.1]), use of four or more likely effective drugs in the initial intensive phase (aOR: 2.7 [1.9-3.9]), and three or more likely effective drugs in the continuation phase (aOR: 4.5 [3.4-6.0]). In this individual patient data meta-analysis of observational data, improved MDR-TB treatment success and survival were associated with use of certain fluoroquinolones, ethionamide, or prothionamide, and greater total number of effective drugs. However, randomized trials are urgently needed to optimize MDR-TB treatment. Please see later in the article for the Editors' Summary.

Roxithromycin for multidrug-resistant pulmonary tuberculosis

Objective To observe and assess the efficacy of roxithromycin sustained-release capsules com-bined with other anti-tuberculosis drugs in the treatment of multidrug-resistant pulmonary tuberculosis ( MDR-PTB ).Methods 120 patients with MDR-PTB were selected as the subjecs of this study and then were randomly divided intostudy group and control group,60 for each group.The control group received sparfloxacin,amikacin,and other three kindsof anti-tuberculosis drugs as anti-tuberculosis scheme,and the study group received roxithromycin for 12 months inaddition to the therapies used in the control group.Results At the end of the third month,the sputum negative conversionrate was 64％ in the study group and 42％ in the control group,with a statistical significance ( ~=5.52,P＜ 0.05 ).Atthe end of treatment,the sputum negative conversion rate was 91％ in the study group and 72％ in the control group,witha significant difference ( x2=6.62,P＜ 0.01 ).The rate of lesion absorption was 89％ in the study group and 70％ in thecontrol group,with a statistical significance ( x2=6.14,P ＜ 0.05 ).Conclusions Roxithromycin sustained-releasecapsules combined with other anti-tuberculosis drugs is efficacious in the treatment of MDR-PTB and plays a role inpromoting sputum negative conversion,lesion absorption,and cavity closure. Key words: Tuberculosis, pulmonary; Multidrug resistance; Roxithromycin sustained-release capsules; Efficacy

Efficiency of surgical treatment of multidrug-resistant Pulmonary Tuberculosis within the DOTS-PLUS program

Efficiency of the surgical treatment of pulmonary tuberculosis for multidrug-resistant (MDR TB) tuberculosis patients was analyzed. Seventy DOTS-PLUS patients with various clinical forms of pulmonary tuberculosis and Mycobacterium resistance from 3 to 8 antituberculosis drugs have been operated. Positive clinical results have been achieved for 65 (92,8%) patients. Indications for surgical treatment for patients with MDR TB have been developed. To ensure positive outcomes of the surgical interventions, main objective is the development of so-called a favorable preoperative environment during the preoperative phase. It includes switching on intensive chemotherapy and pathogenetic methods of treatment.

Subcutaneously administered interferon-gamma for the treatment of multidrug-resistant pulmonary tuberculosis

We evaluated the clinical and laboratory effects of subcutaneously administered interferon-gamma (IFN-gamma) in the treatment of chronic and advanced multidrug-resistant tuberculosis (MDR-TB). Eight patients with sputum smear and culture persistently positive MDR-TB were subcutaneously administered 2 million international units of recombinant human IFN-gamma three times a week for 24 weeks (72 doses total) between December 2002 and May 2003. Subjects also received a customized drug regimen containing second- and third-line antituberculosis agents based upon drug susceptibility testing and previous treatment history. Body weight remained stable or slightly decreased in all subjects during the study period, and none displayed radiographic improvement on serial chest computed tomography scanning. Sputum smears and cultures remained positive for all patients, and there was no increase in the mean time to yield a positive culture (from 16.5+/-6.4 to 11.8+/-4.9 days). There was no enhancement of cell-mediated immune responses in terms of production of IFN-gamma or IL-10, or of composition of lymphocytes among peripheral blood mononuclear cells. In four patients, therapy was discontinued because of adverse reactions. In patients with chronic and advanced MDR-TB, subcutaneous IFN-gamma treatment did not result in improvement in clinical, radiologic, microbiologic, or immunologic parameters.

Surgical Treatment of Multidrug-resistant Pulmonary Tuberculosis

Background : Recently, medical treatment of multi-drug resistant pulmonary tuberculosis has been unsuccessful. Through analyzing the cases with surgical treatment, we hope to provide some help in treating multi-drug resistant pulmonary tuberculosis in the future. Material and Method : A retrospective review was performed with 138cases of surgical treatment of multi-drug resistant tuberculosis during 10years from January 1994 to December 2003 at National Masan Hospital. Results : The ratio of men to women, 5.1:1 indicates that there were more incidences in men. The number of the resistant drugs was 5.3 with a mean age of 42.6 years. Cavitary lesions on the plain chest X-rays were seen in 94cases (68.1%). 128cases had positive sputum culture preoperatively. Types of operations were 24 pnemonectomies, 83 lobectomies, 10 bilobectomies, 19 lobectomies with segmentectomies or wedge resections, 1 wedge resection, and 1 carvenoplasty. There was no death after operation. There were 6cases of air leakage over a week, 6cases of postoperative bleeding, 8cases of bronchopleural fistula and empyema, 16cases of dead space, 1case of atelectasis, 1case of wound infection, 1case of cyst as postoperative complication. Postoperative complication showed higher long-term negative conversion rate of 92.8%. Conclusion : There has been many discussions about operative indications, postoperative drug regimens, length of postoperative chemotherapy. In our study, we showed higher long-term success rate of postoperative chemotherapy with pulmonary resection on multi-drug resistant pulmonary tuberculosis.

The Adjunctive Role of Resectional Surgery for the Treatment of Multidrug-Resistant Pulmonary Tuberculosis

Background : Many patients with isoniazid and rifampin-resistant pulmonary tuberculosis have organisms that are also resistant to other first-line drugs. Despite of aggressive retreatment chemotherapy, the results are often unsuccessful, with a failure rate approaching 40%. Recently, there has been a revival of resectional surgery for the treatment of multidrug-resistant pulmonary tuberculosis. Methods : A retrospective analyses of the case records and radiographic findings were done. Between January 1991 and December 1995, 14 human immunodeficiency virus (HIV)-seronegative patients with multidrug-resistant pulmonary tuberculosis were selected for resection to supplement chemotherapy. All patients had organisms resistant to many of the first-line drugs, including both isoniazid and rifampin. Results : Despite of aggressive therapy for median duration of 9.5 months, 12 of the 14 patients (86%) were still sputum smear and/or culture positive at the time of surgery. The disease was generally extensive. Although main lesions of the disease including thick-walled cavities were localized in one lung, lesser amounts of contralateral disease were demonstrated in 10 of 14 (71%). Types of surgery performed were pneumonectomy including extrapleural pneumonectomy in six patients, lobectomy or lobectomy plus in six patients, and segmentectomy in two patients. The resected lung appeared to have poor function ; preoperative perfusion lung scan showed only 4.8% of the total perfusion to the resected portion of the lung. There were no operative deaths. Two patients had major postoperative complications including empyema with bronchopleural fistula and prolonged air leak, respectively. Of the 14 patients, 13 (93%) remained sputum-culture-negative for M. tuberculosis for a median duration of 23 months and one remained continuously sputum smear and culture positive for M. tuberculosis. Conclusion : On the basis of comparison with historical controls, adjunctive resectional surgery appears to play a significant beneficial role in the management of patients with multidrug-resistant pulmonary tuberculosis if the disease is localized and there are adequate reserve in pulmonary function.