Additional drug resistance in Mycobacterium tuberculosis isolates from resected cavities among patients with multidrug-resistant or extensively drug-resistant pulmonary tuberculosis.

The pathogenesis of increasing drug resistance among patients with multidrug-resistant or extensively drug-resistant tuberculosis undergoing treatment is poorly understood. Increasing drug resistance found among Mycobacterium tuberculosis recovered from cavitary isolates compared with paired sputum isolates suggests pulmonary cavities may play a role in the development of worsening tuberculosis drug resistance.

Comprehensive treatment of extensively drug-resistant tuberculosis.

BACKGROUND: Extensively drug-resistant tuberculosis has been reported in 45 countries, including countries with limited resources and a high burden of tuberculosis. We describe the management of extensively drug-resistant tuberculosis and treatment outcomes among patients who were referred for individualized outpatient therapy in Peru. METHODS: A total of 810 patients were referred for free individualized therapy, including drug treatment, resective surgery, adverse-event management, and nutritional and psychosocial support. We tested isolates from 651 patients for extensively drug-resistant tuberculosis and developed regimens that included five or more drugs to which the infecting isolate was not resistant. RESULTS: Of the 651 patients tested, 48 (7.4%) had extensively drug-resistant tuberculosis; the remaining 603 patients had multidrug-resistant tuberculosis. The patients with extensively drug-resistant tuberculosis had undergone more treatment than the other patients (mean [+/-SD] number of regimens, 4.2+/-1.9 vs. 3.2+/-1.6; P<0.001) and had isolates that were resistant to more drugs (number of drugs, 8.4+/-1.1 vs. 5.3+/-1.5; P<0.001). None of the patients with extensively drug-resistant tuberculosis were coinfected with the human immunodeficiency virus (HIV). Patients with extensively drug-resistant tuberculosis received daily, supervised therapy with an average of 5.3+/-1.3 drugs, including cycloserine, an injectable drug, and a fluoroquinolone. Twenty-nine of these patients (60.4%) completed treatment or were cured, as compared with 400 patients (66.3%) with multidrug-resistant tuberculosis (P=0.36). CONCLUSIONS: Extensively drug-resistant tuberculosis can be cured in HIV-negative patients through outpatient treatment, even in those who have received multiple prior courses of therapy for tuberculosis.

[Impact of surgical intervention in the treatment of pulmonary tuberculosis]. / Aktueller Stellenwert der Chirurgie in der Therapie der Lungentuberkulose.

The different modalities in the treatment of tuberculosis (TB) changed within the last century. With the beginning of the era of effective antibiotic treatment, indication for surgical methods became rare. The combination of different classes of antibiotics to treat TB is most often effective but several multi-drug-resistant germs were created, leading to the need of surgical resection as adjuvant treatment. The aim of this review is to summarize the current role of surgical therapy in treating TB.

Predicting treatment failure risk in a Chinese Drug-Resistant Tuberculosis with surgical therapy: Development and assessment of a new predictive nomogram.

BACKGROUND: The aim of this study was to develop and internally validate a treatment failure risk nomogram in a Chinese population of patients with Drug-Resistant Tuberculosis with surgical therapy. METHODS: We developed a prediction model based on a dataset of 132 drug-resistant tuberculosis (DR-TB) patients. The least absolute shrinkage and selection operator regression model was used to optimize feature selection for the treatment failure risk model. Multivariable logistic regression analysis was applied to build a predicting model incorporating the feature selected in the least absolute shrinkage and selection operator regression model. Discrimination, calibration, and clinical usefulness of the predicting model were assessed using the C-index, calibration plot, and decision curve analysis. Internal validation was assessed using the bootstrapping validation. FINDINGS: Predictors contained in the prediction nomogram included Lesion, Treatment history, Recurrent chest infection (RCI) and Multidrug-resistant tuberculosis (MDR-TB) or Extensively drug-resistant tuberculosis (XDR-TB). The model displayed good discrimination with a C-index of 0.905 and good calibration. A high C-index value of 0.876 could still be reached in the interval validation. Decision curve analysis showed that the nomogram was clinically useful when an intervention was decided at the treatment failure possibility threshold of 1%. INTERPRETATION: This study developed a novel nomogram with relatively good accuracy to help clinicians access the risk of treatment failure in MDR/XDR-TB patients when starting surgery. With an estimate of individual risk, clinicians and patients can make more suitable decisions regarding surgery. This nomogram requires external validation, and further research is needed to determine whether the nomogram is appropriate for predicting surgery risk in MDR/XDR-TB patients.

Adjunctive resectional lung surgery for extensively drug-resistant tuberculosis.

Extensively drug-resistant (XDR) tuberculosis (TB) poses significant management challenges as there are limited pharmacological treatment options for cure. Adjunctive resectional lung surgery decreases case-fatality rates for some patients with multidrug-resistant tuberculosis (MDR-TB), but its use has not been well documented for patients with XDR-TB. We describe 17 XDR-TB patients treated with surgery as part of their case management in Latvia during 1999-2005. One patient had no previous TB treatment history, 10 were previously treated for drug-susceptible TB and six were previously treated for MDR-TB. Mycobacterium tuberculosis isolates from the 17 patients were resistant to a mean of 9.2 drugs. Due to failure of pharmacological therapy, one due to a large cavity and one due to pulmonary haemorrhage, 15 patients were treated with surgery. Despite failure of pharmacological treatment in 15 out of 17 patients, eight (47%) were cured with adjunctive surgical treatment. Surgery should be explored as a possible treatment option for patients with XDR-TB.

Treatment outcomes and long-term survival in patients with extensively drug-resistant tuberculosis.

RATIONALE: The increasing worldwide incidence of extensively drug-resistant tuberculosis (XDR-TB) has emerged as a threat to public health and tuberculosis (TB) control. Treatment outcomes have varied among studies, and data on long-term survival are still scarce. OBJECTIVES: To retrospectively assess the burden, clinical characteristics, treatment outcomes, and long-term survival rate of patients with XDR-TB in a cohort of patients with HIV-negative multidrug-resistant tuberculosis (MDR-TB) in South Korea. METHODS: Medical records were reviewed of patients newly diagnosed with or retreated for MDR-TB from 2000 to 2002. The cohort was monitored for 3 to 7 years after the initiation of treatment. Initial treatment outcomes and cumulative survival rates were analyzed, and predictors of treatment success and survival were defined. MEASUREMENTS AND MAIN RESULTS: Of 1,407 patients with MDR-TB 75 (5.3%) had XDR-TB at treatment initiation. The default rate was high (453/1,407; 32%), and patients with XDR-TB had lower treatment success (29.3 vs. 46.2%; P = 0.004) and higher all-cause (49.3 vs. 19.4%; P < 0.001) and TB-related disease mortality (41.3 vs. 11.8%; P < 0.001) than other patients with MDR-TB. The presence of XDR-TB significantly affected treatment success (odds ratio, 0.23; 95% confidence interval [CI], 0.08-0.64; P = 0.005), all-cause mortality (hazards ratio, 3.25; 95% CI, 1.91-5.53; P < 0.001), and TB-related mortality (hazards ratio, 4.45; 95% CI, 2.48-8.00; P < 0.001) on multivariate analyses. CONCLUSIONS: XDR-TB occurred in a substantial proportion of patients with MDR-TB in South Korea, and was the strongest predictor of treatment outcomes and long-term survival in patients with MDR-TB. Adequate TB control policies should be implemented to prevent the further development and spread of drug resistance.

Modern Collapse Therapy for Pulmonary Tuberculosis.

Multidrug-resistant tuberculosis (TB), extensively drug-resistant TB, and TB-human immunodeficiency virus (HIV) coinfection require a special approach in anti-TB treatment. Most patients cannot be successfully cured by conventional chemotherapy alone. They need a modern approach using minimally invasive therapeutic and surgical techniques. The novel approaches of collapse therapy techniques and minimally invasive osteoplastic thoracoplasty increase the effectiveness of complex anti-TB therapy. Achieving the required selective collapse of lung tissue in destructive pulmonary TB, especially in cases of drug resistance and/or HIV coinfection, leads to bacteriologic conversion, cavity closure, and successful cure.

Treatment outcomes for HIV-uninfected patients with multidrug-resistant and extensively drug-resistant tuberculosis.

BACKGROUND: Multidrug-resistant (MDR) tuberculosis (TB) is more difficult to treat than is drug-susceptible TB. To elucidate the optimal therapy for MDR TB, we assessed the treatment outcomes and prognostic factors for patients with MDR TB. METHODS: This study included patients who received an individualized treatment regimen for MDR TB at Samsung Medical Center, a tertiary referral hospital in Seoul, Korea, from January 1995 through December 2004. To identify the prognostic factors related to favorable treatment outcomes, univariate comparison and multiple logistic regression were performed. RESULTS: Of 155 patients, 18 (12%) had newly diagnosed MDR TB, 81 (52%) had previously received treatment with first-line drugs, and 56 (36%) had received treatment with second-line drugs. The isolated strains were resistant to a median of 5 drugs. Twenty-seven patients (17%) had extensively drug-resistant (XDR) TB at the start of treatment. Outcome assessment revealed that 102 patients (66%) were cured or completed therapy. The treatment success rates did not differ significantly between patients with non-XDR MDR TB and those with XDR TB (66% vs. 67%). Surgical resection was performed more frequently for patients with XDR TB than for those with non-XDR MDR TB (48% vs. 17%). Combined surgical resection, body mass index >/=18.5 (calculated as the weight in kilograms divided by the square of the height in meters), use of >4 effective drugs, and a negative sputum smear result were independent predictors of a favorable outcome. CONCLUSIONS: Early aggressive treatment comprising at least 4 effective drugs and surgical resection, when indicated, may improve the outcome for patients with MDR TB or XDR TB.

Bilateral cavitary multidrug- or extensively drug-resistant tuberculosis: role of surgery.

OBJECTIVES: Cavitary disease and bilateral lesions are among the risk factors for poor outcome of pulmonary tuberculosis (TB). Our aim was to explore the value and limits of surgery in patients with advanced TB. METHODS: A retrospective study of 57 consecutive patients who underwent thoracic surgery for culture-positive bilateral cavitary pulmonary TB was performed. Forty-four (77.2%) patients were men and 13 (22.8%) patients were women; their ages were in the range of 18-61 years. Twenty-two (38.6%) patients had multidrug-resistant (MDR) TB and 35 (61.4%) patients had extensively drug-resistant (XDR) TB confirmed with cultures. On admission, 49 (86.0%) patients had sputum smear microscopy positive for acid-fast bacilli. The main indication for surgery was treatment failure manifested as contagious persisting cavities despite best available therapy. The surgical procedures included combinations of pulmonary resections of different levels, selective thoracoplasties and/or endobronchial valve treatment. The operations were performed consecutively, starting with the most affected side. TB therapy preceded the operation for a minimum of 6 months and was continued after the operation on the basis of the patient's susceptibility to drugs for Mycobacterium tuberculosis. RESULTS: We performed 121 operations: 42 in 22 patients with MDR TB (1.9 operations per patient) and 79 procedures in 35 patients with XDR TB (2.3 operations per patient). No deaths occurred in the 1st year. Two late deaths followed, 1 unrelated to and 1 due to TB progression. Ten major complications (1 complication per patient) developed: main bronchus stump fistula (n = 4), prolonged air leak (n = 3), respiratory failure (n = 2) and wound seroma (n = 1). At the 1-month follow-up visit, sputum smear conversion was observed in 11 (68.8%) patients with MDR and in 15 (45.5%) patients with XDR TB. At the late (20-36 months) follow-up visit, culture negativity was achieved in 21 (95.5%) patients with MDR TB and in 23 (65.7%) patients with XDR TB (P = 0.015). CONCLUSIONS: Thoracic surgery may significantly improve patients' outcomes and even result in a cure in a good portion of patients with bilateral cavitary MDR and XDR TB and should be considered as the essential element of multimodality treatment for MDR and XDR TB, even in patients with bilateral cavitary disease and borderline respiratory reserves.

Pulmonary resection in the treatment of multidrug-resistant tuberculosis: A case series.

Multidrug-resistant (MDR) and extensive drug-resistant (XDR) tuberculosis (TB) are significant health problems throughout the world. Although the main treatment is medical, adjunctive surgical resection may increase the chance of cure in selected patients with MDR-TB or XDR-TB. This study aimed to present a case series of patients who underwent surgical resection for MDR-TB.Between March 2008 and November 2011, surgical resection was performed on 54 patients including 34 with MDR-TB and 20 with XDR-TB at the Departments of Surgery of Shanghai Public Health Clinical Center (Shanghai), Henan Chest Hospital (Henan), and Anhui Chest Hospital (Henan). Preoperative sputum smear samples were positive for 28 patients and sputum quantitative polymerase chain reaction was positive for 32. Patients were treated according to a standard therapy protocol for a mean of 4.2 months before the operation. The variables that affected treatment outcomes were identified through multivariate regression analysis.Fifty-four patients were operated for MDR-TB with localized disease usually complicated by cavity formation or destroyed lung. Thirty-seven were males and 17 were females. Median age was 37.8 (range, 20-75) years. Lobectomy was performed in 46 patients and pneumonectomy in 8. Muscle flaps were used in 36 of the patients with lobectomy and 8 with pneumonectomy. Various complications occurred in 6 (11.1%) patients, including bronchopleural fistula in 1 patient, bleeding in 2 patients, and prolonged air leak in 2 patients. A favorable outcome was achieved in 47 patients (87%) who underwent surgical resection. Higher body mass index (BMI) was associated with better outcome (odds ratio = 0.537, 95% confidence interval: 0.310-0.928, P = .026).Patients with MDR-TB had good treatment outcomes after adjunctive pulmonary resection, and with few complications. Higher BMI was related to a favorable outcome.

Retrospective study of clinical and lesion characteristics of patients undergoing surgical treatment for Pulmonary Tuberculosis in Georgia.

OBJECTIVES: Our aim was to retrospectively compare clinical data and characteristics of removed lesions of the cohort of patients undergoing therapeutical surgery for their tuberculosis. DESIGN AND METHODS: Demographic and epidemiological details, clinical data, data on the surgery performed, macroscopic characteristics of the TB lesions removed, and outcome were recorded retrospectively from the 137 patients who underwent therapeutical surgery for their TB in Tbilisi, Georgia during 2014 and 2015. RESULTS: Men represented 70% of the included patients, presented more comorbidities and underwent operation earlier in terms of days between diagnostic and surgery. Women underwent operation at younger ages, and in MDR/XDR-TB cases, showed higher percentages of sputum conversion at >2 months and of fresh necrosis in the surgical specimens, suggesting a worse evolution. Half of cases were MDR/XDR-TB cases. In spite of being considered microbiologically cured according to WHO, a non despricable percentage of cases showed viable bacilli in the surgical specimen. Even if no causality could be statistically demonstrated, differences could be encountered according to gender and drug susceptibility of the responsible strains. CONCLUSIONS: According to our results, host factors such as gender, type of necrosis found in the lesions, size of lesions and presence of viable bacilli in the surgical specimen, should be included in future studies on therapeutical surgery of TB. As most of studies are done in MDR/XDR-TB, more data on DS-TB operated cases are needed. Our results also highlight that, in spite of achieving the microbiologically cured status, sterilization might not occur, and thus new biomarkers and new methods to evaluate the healing process of TB patients are urgently needed and radiological assays should be taken into account.

When There's No Cure: My Brother's Battle With Drug-Resistant TB.

As the incidence of tuberculosis has waned, so has investment in new tests and treatments-and that may prove to be a mistake.

[Interest of collapse therapy in pulmonary extensively drug-resistant tuberculosis]. / Intérêt de la collapsothérapie dans la tuberculose pulmonaire ultra-résistante.

Extensively drug-resistant (XDR) tuberculosis is rare in France. Treatment of XDR tuberculosis is difficult and therapeutic failures are frequent. Surgery is considered as one of the therapeutic options, but is of little use regarding its high morbi-mortality. We report successful treatment of a XDR tuberculosis case with a 21-month antibiotic regimen followed by a surgical collapse therapy because of persistence of a large cavity. No relapse was observed after five years. Surgery in the XDR tuberculosis treatment is discussed.

[Adjuvant surgical resection for multidrug-resistant tuberculosis: A review]. / Chirurgie et tuberculose multi/ultrarésistante : une revue de la littérature réhabilite une intervention adjuvante à l'antibiothérapie chez des patients sélectionnés.

INTRODUCTION: The frequency of multi and extensively drug resistant pulmonary tuberculosis (MDR/XDR-TB) is increasing worldwide, with major issues related to treatment modalities and outcome. In this setting, the exact benefits associated with surgical resection are still unknown. METHODS: We performed a literature review to determine the indications, morbidity, mortality and bacteriological success associated with the surgical management of MDR/XDR-TB patients. RESULTS: Altogether, 177 publications dealing with surgical resection and MDR/XDR-TB have been analyzed, including 35 surgical series and 24 cohort studies summarized in one meta-analysis. The surgical series reported success rates from 47% to 100%, complication rates from 0 to 29%, and mortality rates from 0 to 8%. The published meta-analysis reported a statistically significant association between surgical resection and treatment success (OR 2.24, IC95% 1.68-2.97). However, all these studies were associated with selection bias. International consensual guidelines included a multidisciplinary assessment in a reference centre, a personalized and prolonged antibiotic treatment and a medico-surgical discussion on a case-to-case basis. PERSPECTIVES: These guidelines are now applied for the management of patients with MDR/XDR-TB in our centre. Further studies are required to avoid further increase in the burden of MDR/XDR-TB and to establish the optimal timing of medical and surgical treatments.

Autologous mesenchymal stromal cell infusion as adjunct treatment in patients with multidrug and extensively drug-resistant tuberculosis: an open-label phase 1 safety trial.

BACKGROUND: Novel treatment options are urgently needed for multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis, which are associated with immune dysfunction and poor treatment outcomes. Mesenchymal stromal cells (MSCs) are immunomodulatory and adjunct autologous treatment with bone marrow-derived MSCs might improve clinical outcome by transforming chronic inflammation into productive immune responses. Our aim was to assess the safety of infusion of autologous MSCs as an adjunct treatment in patients with tuberculosis. METHODS: 30 patients with microbiologically confirmed MDR or XDR tuberculosis were treated with single-dose autologous bone marrow-derived MSCs (aimed for 1×10(6) cells per kg), within 4 weeks of the start of antituberculosis-drug treatment in a specialist centre in Minsk, Belarus. Inclusion patients were those with pulmonary tuberculosis confirmed by sputum smear microscopy, culture, or both; MDR or XDR tuberculosis confirmed by drug-susceptibility testing to first-line and second-line drugs; age older than 21 years to 65 years or younger; and absence of lesion compatible with a malignant process or ongoing tuberculosis in organs other than the lungs and pleura. In addition to the inclusion criteria, patients were excluded if they were pregnant, coinfected with HIV, or infected with hepatitis B, C, or both. The primary endpoint was safety measured by MSC-infusion related events; any tuberculosis-related event within the 6 month observation period that related to a worsening of the underlying infectious disease, measured by conversion of Mycobacterium tuberculosis culture or microscopic examination; or any adverse event defined clinically or by changes in blood haematology and biochemistry variables, measured monthly for 6 months after MSC infusion per protocol. This study is registered with the German Clinical Trials Registry, number DRKS00000763. FINDINGS: The most common (grade 1 or 2) adverse events were high cholesterol levels (14 of 30 patients), nausea (11 of 30 patients), and lymphopenia or diarrhoea (ten of 30 patients). There were no serious adverse events reported. We recorded two grade 3 events that were transitory-ie, increased plasma potassium ion concentrations in one patient and a transitory grade 3 γ-glutamyltransferase elevation in another patient. INTERPRETATION: MSCs as an adjunct therapy are safe and can now be explored further for the treatment of patients with MDR or XDR tuberculosis in combination with standard drug regimens. Adjunct treatment with MSCs needs to be evaluated in controlled phase 2 trials to assess effects on immune responses and clinical and microbiological outcomes.

Favorable outcomes for multidrug and extensively drug resistant tuberculosis patients undergoing surgery.

BACKGROUND: New approaches are needed in the treatment of multidrug-resistant and extensively drug-resistant pulmonary tuberculosis (M/XDR-PTB). We evaluated the role of adjunctive surgical therapy in the treatment of M/XDR-PTB in the setting of directly observed treatment strategy (DOTS)-Plus implementation. METHODS: We conducted an observational cohort study consisting of M/XDR-PTB patients who underwent thoracic surgery at the National Tuberculosis Center in Tbilisi, Georgia between October 2008 and February 2011. Indications for surgery included presence of M/XDR-PTB, localized pulmonary disease, fit to undergo surgery, and either medical treatment failure or such extensive drug resistance that failure was likely. Second-line anti-tuberculosis medical therapy was administered per World Health Organization (WHO) recommendations. RESULTS: Seventy-five patients (51 MDR, 24 XDR) with PTB underwent adjunctive thoracic surgery. Median age was 30 years and average duration of preoperative M/XDR-PTB medical therapy was 342 days. The following surgical procedures were performed: pneumonectomy (11%), lobectomy (54%), and segmentectomy (35%). Mean postoperative follow-up time was 372 days. Of 72 patients with evaluable outcomes, 59 (82%) had favorable outcomes including 90% of MDR and 67% of XDR-TB patients. There was no postoperative mortality; postoperative complications occurred in 7 patients (9%). Risk factors for poor treatment outcomes in univariate analysis included bilateral disease, XDR, increasing effective drugs received, positive preoperative sputum culture, and major postoperative surgical complication. CONCLUSIONS: Patients with M/XDR-PTB undergoing adjunctive thoracic surgery had high rates of favorable outcomes, no surgical-related mortality, and low rates of complications. Adjunctive surgery appears to play an important role in the treatment of select patients with M/XDR-PTB.

Multidrug-resistant pulmonary tuberculosis: surgical challenges.

Multidrug-resistant tuberculosis (MDR-TB) continues to be a significant public health problem worldwide. The treatment of MDR-TB consists mainly of chemotherapy. However, surgery has been reported to be an effective adjunctive therapy in selected cases. This article discusses the scope of the problem of MDR-TB and the most accepted modern standard therapy. The indications for surgical intervention as well as an analysis of the results of this therapy are also discussed.

Pulmonary resection for extensively drug resistant tuberculosis in Kwazulu-Natal, South Africa.

BACKGROUND: Extensively drug resistant tuberculosis (XDR-TB) has been reported in 58 countries around the world and has emerged as a major public health challenge. Our objective was to determine the impact of pulmonary resection on XDR-TB treatment outcomes in a resource-constrained setting. METHODS: We conducted a retrospective case review of 11 patients with XDR-TB who were referred for pulmonary resection between January 2007 and June 2010 at a tertiary care referral hospital in South Africa. Two pneumonectomies and three upper lobectomies were performed. Occurrence of surgical complications and TB treatment outcome were assessed. RESULTS: No perioperative mortality or major morbidity was noted. All patients achieved sputum conversion, with 4 regarded as "cured." One patient defaulted on treatment, but subsequently returned and is regarded as a probable cure. CONCLUSIONS: We describe pulmonary resection for XDR-TB management in Africa. Although the initial cohort of XDR-TB patients from Tugela Ferry demonstrated nearly complete mortality, our results demonstrate the potential of adjuvant surgical methods in XDR-TB treatment. With appropriate chemotherapy and timely adjuvant surgery, patients with XDR-TB localized to lobe or lung may achieve a "cure" with low morbidity and mortality. Consequently, this approach may be the most cost effective treatment for patients suitable for lung resection.

Surgical treatment of drug-resistant tuberculosis.

The global emergence and spread of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis has led to the re-examination of surgery as a possible adjunctive treatment. We present the case of a 26-year-old HIV-seronegative patient with XDR pulmonary tuberculosis refractory to medical therapy. Surgical resection of the patient's solitary cavitary lesion was done as adjunctive treatment, and a successful outcome with a combination of surgery and drug therapy was achieved. We review the history of surgical therapy for tuberculosis and reports of its role in treatment of MDR and XDR tuberculosis. 26 case series and cohort studies were included, and together showed that surgical resection is beneficial in the treatment of drug-resistant tuberculosis. However, the results might not be applicable in all settings because investigations were observational and typically included patients with less severe disease, and all surgeries were done at specialised thoracic-surgery centres. Well designed studies are needed to establish the efficacy of surgery in treatment of drug-resistant tuberculosis.