Sputum Culture Conversion Rate Research Articles

A Moxifloxacin-based Regimen for the Treatment of Recurrent, Drug-sensitive Pulmonary Tuberculosis: An Open-label, Randomized, Controlled Trial.

The substitution of moxifloxacin for ethambutol produced promising results for improved tuberculosis treatment outcomes. We conducted an open-label, randomized trial to test whether a moxifloxacin-containing treatment regimen was superior to the standard regimen for the treatment of recurrent tuberculosis. The primary and secondary outcomes were the sputum culture conversion rate at the end of 8 weeks and the proportion of participants with a favorable outcome, respectively. We enrolled 196 participants; 69.9% were male and 70.4% were co-infected with human immunodeficiency virus (HIV). There was no significant difference between the study groups in the proportion of patients achieving culture conversion at the end of 8 weeks (83.0% [moxifloxacin] vs 78.5% [control]; P = .463); however, the median time to culture conversion was significantly shorter (6.0 weeks, interquartile range [IQR] 4.0-8.3) in the moxifloxacin group than the control group (7.9 weeks, IQR 4.0- 11.4; P = .018). A favorable end-of-treatment outcome was reported in 86 participants (87.8%) in the moxifloxacin group and 93 participants (94.9%) in the control group, for an adjusted absolute risk difference of -5.5 (95% confidence interval -13.8 to 2.8; P = .193) percentage points. There were significantly higher proportions of participants with Grade 3 or 4 adverse events (43.9% [43/98] vs 25.5% [25/98]; P = .01) and serious adverse events (27.6% [27/98] vs 12.2% [12/98]; P = .012) in the moxifloxacin group. The replacement of ethambutol with moxifloxacin did not significantly improve either culture conversion rates at the end of 8 weeks or treatment success, and was associated with a higher incidence of adverse events. NCT02114684.

Treatment outcome of multidrug-resistant tuberculosis with modified DOTS-plus strategy: A 2 years' experience.

Background:Multidrug-resistant tuberculosis (MDR-TB) is a global health problem with notoriously difficult and challenging treatment. This study determined treatment outcome in patients of MDR-TB with modified DOTS-Plus strategy.Methods:Ninety-eight consecutive MDR-TB patients treated with standardized regimen according to modified DOTS-Plus strategy aligned to the existing national DOTS-Plus guidelines with relevant modifications proposed by Chennai consensus were analyzed prospectively. Treatment included monthly follow-up with clinical, radiological, and bacteriological assessment (sputum smear advised monthly till conversion then quarterly; culture for Mycobacterium tuberculosis at 0, 4, 6, 12, 18, and 24 months), ensuring adherence, intense health education, and monitoring of adverse events (AEs). Patients' outcome was considered as cure when at least two of the last three cultures (all three or last two) were negative and as failure when the same were positive.Results:Favorable and unfavorable outcomes in this cohort were reported to be 71/98 (72.4%) and 27/98 (27.6%) (failure – 10 [10.2%], default – 7 [7.1%], and expiry – 10 [10.2%]), respectively. Sputum smear and culture conversion rate were 75/81 (92.5%) and 71/81 (87.7%), respectively. Major AEs were experienced in only 17.4% of patients.Conclusions:MDR-TB can be cured successfully with modified DOTS-Plus strategy and requires much effort from both the patients and health-care workers. It can be an alternative model for treating MDR-TB patients in private sector.

Cigarette smoking and culture conversion in patients with susceptible and M/XDR-TB.

Tuberculosis (TB) is a leading cause of morbidity and mortality worldwide. Active cigarette smoking may have a significant impact on treatment responses to anti-tuberculosis treatment. To ascertain the effect of smoking on Mycobacterium tuberculosis sputum culture conversion rates following treatment initiation in patients with susceptible, multidrug-resistant and extensively drug-resistant TB (M/XDR-TB). Sputum cultures of smoking and non-smoking patients with pulmonary TB (PTB) treated at a referral centre in Germany were evaluated. Between January 2012 and March 2017, 247 patients with PTB treated at the Medical Clinic of Research Center Borstel, Borstel, Germany, were included in the study. Of 247 patients, 65 (26.3%) were infected with multidrug-resistant strains of M. tuberculosis (MDR-TB). Sputum culture examinations were performed on a weekly basis. Active smoking (n = 111; time to culture conversion [TCC] 50.7 days, interquartile range [IQR] 26.5-73.0) and former smoking (n = 72; TCC 43.1 days, IQR 19.8-56.0) significantly delayed culture conversion rates (P < 0.001) when compared with never smoking (n = 64; TCC 33.2 days, IQR 8.0-50.3). Delay in TCC among smoking, non-MDR-TB patients (n = 138; TCC 47.3 days, IQR 19.0-89.0) was comparable with non-smoking, MDR-TB patients (n = 20; TCC 53.0 days, IQR 18.0-71.0). The shortest TCC was observed in non-smoking, non-MDR-TB patients (n = 44; TCC 33.0 days, IQR 10.0-48.5), whereas the longest was seen in smoking, MDR-TB patients (n = 45; TCC 60.7 days, IQR 33.3-89.0); P < 0.001). Active cigarette smoking and, to a lesser extent, former cigarette smoking, substantially delayed culture conversion in PTB.

800. Drug-Resistant TB: An Experience From Qatar

BackgroundDrug-resistant tuberculosis (DR-TB) is an important issue for public health. This study was conducted to evaluate the characteristics, treatment outcome, and risk factors associated with 223 DR-TB cases in the State of Qatar.MethodsA descriptive records-based retrospective study was conducted on patients registered at Communicable Disease Centre (CDC), Qatar to all consecutive microbiologically confirmed tuberculosis cases for the period January 2010–March 2015. Demographic and clinical data extracted included: patient’s age, sex, and country of origin; disease site (pulmonary or extra-pulmonary); presence of comorbidities, HIV/AIDS status, previous chemoprophylaxis and/or previous treatment for TB, and anti-TB drug resistance the resistance pattern of isolated mycobacteria. The sputum culture conversion rate and treatment outcome was assessed for the patient who completed their treatment in QatarResultsOf 3,301 patients with positive M. tuberculosis culture were analyzed; 223 (6.7%) were resistant to one or more first-line drugs, to isoniazid in 3.1% (n = 102), streptomycin in 1.2% (n = 41), rifampicin in 0.2% (n = 6), ethambutol in 0.15% (n = 5), and multi-drug resistance in 1.2% (n = 38) of patients. Among the resistant TB patients, more common demographic characteristics were former resident of Indian subcontinent (64.1%). A history of anti-TB treatment was not a risk factor with drug resistance in our cohort. Only 111 (49.7%) patients were tested for HIV antibodies and the results were all negative. There was significant correlation between the type of drug-resistance and CXR finding (23.3% had cavity—P = 0.019). Sputum culture conversion to negative at 2 month of therapy was 94% (n = 101), whereas 122 cases lost follow-up. The outcome of treatment was assessed for 85 resistant cases with follow-up after completion of treatment, show cure rate of 97.6%, and relapse of 2.4%. However, 137 cases (61.4% from total) they left the country before completion of therapy.ConclusionDrug-resistant TB in Qatar is influenced by migration, especially from the Indian subcontinent, where the patients were probably infected. Rapid sputum sampling performed in the early stages of the disease, patient isolation, and drug susceptibility testing should be the standard of care to avoid further transmission and improve TB control.Disclosures All authors: No reported disclosures.

794. Infectivity of Smear-Positive Pulmonary TB After 2 Weeks of Rifampicin-based Anti-Tuberculous Therapy

BackgroundPulmonary tuberculosis (TB) remains one of the leading infectious causes of morbidity and mortality worldwide. Most data showed that infectiousness of pulmonary TB diminishes rapidly after 2 weeks of effective anti-tuberculous therapy and the bacilli seen in the smear after 2 weeks are most likely nonviable. We aim to assess this hypothesis by doing sputum culture after 2 weeks of therapy to assess the viability of the bacilli in the smear.MethodsA prospective cohort study was conducted on patients admitted to Communicable Disease Centre (CDC), Qatar with smear positive pulmonary tuberculosis during the period November 2013–November 2014. We repeated sputum smear and culture after 2 weeks of rifampicin based regimen to assess the infectivity. Demographic and clinical characteristics of patients was evaluated and compared with smear and culture conversion rate.ResultsNinety-five cases were included in the study. All had sputum smear and culture after 2 weeks of supervised rifampicin based therapy (Table 1). Sputum culture at two weeks of treatment was positive in 91 cases (95.7%) and only four cases were culture negative after 2 weeks. Demographic and clinical characteristics were compared with the culture status after 2 weeks, found Patient from Indian subcontinent and symptoms duration more than 1 month are less likely to clear infection after 2 weeks with P-value 0.01 and 0.009, respectively (Table 2). The calculated mean for sputum smear and culture conversion rate was 4 and 8 weeks, respectively. The presence of cough and the duration of symptoms were associated significantly with rapid sputum conversion (P < 0.05); however, the presence of cavity on CXR had no statistical significant effect (Table 3). ConclusionMajority of our patients in the study have positive TB culture after two weeks of rifampicin based anti-tuberculosis therapy. So, discontinuation of the isolation after 2 weeks of treatment assuming that bacilli in the smear are nonviable may not be safe.Disclosures All authors: No reported disclosures.

RELATIONSHIP BETWEEN IN VITRO CLARITHROMYCIN SUSCEPTIBILITY AND SPUTUM CULTURE CONVERSION WITH ADD-ON AMIKACIN LIPOSOME INHALATION SUSPENSION (ALIS) FOR TREATMENT OF REFRACTORY MYCOBACTERIUM AVIUM COMPLEX (MAC) LUNG DISEASE

RELATIONSHIP BETWEEN IN VITRO CLARITHROMYCIN SUSCEPTIBILITY AND SPUTUM CULTURE CONVERSION WITH ADD-ON AMIKACIN LIPOSOME INHALATION SUSPENSION (ALIS) FOR TREATMENT OF REFRACTORY MYCOBACTERIUM AVIUM COMPLEX (MAC) LUNG DISEASE

Impact of integrated psycho-socio-economic support on treatment outcome in drug resistant tuberculosis – A retrospective cohort study

ObjectiveTo assess the impact of providing integrated psycho-socio-economic support to drug resistant tuberculosis (DRTB) patients on the treatment outcome under programmatic conditions. Study designRetrospective cohort study. SettingAn urban district TB centre in India under the Revised National Tuberculosis Control Programme. ParticipantsA cohort of 123 patients who started DRTB treatment between June 2010 and May 2013. MethodsPatients started on treatment for DRTB between June 2010 and May 2013 who were provided with the integrated support package for at least 3 months formed the supported group while the other patients of the cohort formed the non-supported group. The treatment outcomes and sputum culture conversion rates were compared between the two groups. ResultsThe supported group consisted of 60 patients and the non-supported group of 63 patients. The treatment success rate was found to be significantly higher in the supported group (65% vs 46.03%; p=0.0349). Support duration was significantly associated with lower incidence of death [HR 0.876, 95% CI 0.811–0.947; p=0.0009] and loss to follow up [OR: 0.752, 95% CI 0.597–0.873; p=0.0023]. The treatment failure rate was higher in the supported group (16.66% vs 4.76%) with 60% of the failures in the supported group occurring after 24 months of compliant treatment. There was no significant association found between support duration and treatment failure or sputum culture conversion. ConclusionIntegrated support seems to significantly increase the treatment success rate and improve survival and treatment adherence of DRTB patients. However, early diagnosis and effective pharmacotherapy are crucial for reducing treatment failures.

Treatment responses in multidrug-resistant tuberculosis in Germany.

Excellent treatment outcomes have recently been reported for patients with multi/extensively drug-resistant tuberculosis (M/XDR-TB) in settings where optimal resources for individualised therapy are available. To ascertain whether differences remain in treatment responses between patients with M/XDR-TB and those with non-M/XDR-TB. Patients with TB were prospectively enrolled between March 2013 and March 2016 at five hospitals in Germany. Treatment was conducted following current guidelines and individualised on the basis of drug susceptibility testing. Two-month and 6-month sputum smear and sputum culture conversion rates were assessed. A clinical and radiological score were used to assess response to anti-tuberculosis treatment. Non-M/XDR-TB (n = 29) and M/XDR-TB (n = 46) patients showed similar rates of microbiological conversion: 2-month smear conversion rate, 90% vs. 78%; culture conversion rate, 67% vs. 61%; time to smear conversion, 19 days (IQR 10-32) vs. 31 days (IQR 14-56) (P = 0.066); time to culture conversion, 39 days (IQR 17-67) vs. 39 days (IQR 6-85) (P = 0.191). Both clinical and radiological scores decreased after the introduction of anti-tuberculosis treatment. There were no significant differences in scores between the two groups until 6 months of treatment. Under optimal clinical conditions, with the availability of novel diagnostics and a wide range of therapeutic options for individualised treatment, patients with M/XDR-TB achieved 6-month culture conversion rates that were compatible with those in patients with non-M/XDR-TB.

The effect of metformin on culture conversion in tuberculosis patients with diabetes mellitus.

Background/AimsPatients with diabetes mellitus (DM) and tuberculosis (TB) have increased morbidity and a high risk of treatment failure or recurrence. It is important to manage both diseases simultaneously. Among anti-diabetic drugs, metformin inhibits intracellular growth of mycobacteria. Therefore, we examined the effects of metformin on TB treatment, especially in patients with DM.MethodsThis retrospective cohort study included patients with culture-positive pulmonary TB diagnosed between 2011 and 2012. The primary study outcome was sputum culture conversion after 2 months of treatment.ResultsOf 499 patients diagnosed with culture-positive pulmonary TB, 105 (21%) had DM at diagnosis. Among them, 62 (59.5%) were treated with metformin. Baseline characteristics, except for the presence of chronic renal disease, were not significantly different between the metformin and non-metformin groups. Metformin treatment had no significant effect on sputum culture conversion (p = 0.60) and recurrence within 1 year after TB treatment completion (p = 0.39). However, metformin improved the sputum culture conversion rate in patients with cavitary pulmonary TB, who have higher bacterial loads (odds ratio, 10.8; 95% confidence interval, 1.22 to 95.63).ConclusionsAmong cavitary pulmonary TB patients with DM, metformin can be an effective adjunctive anti-TB agent to improve sputum culture conversion after 2 months of treatment.

Factors affecting time to sputum culture conversion and treatment outcome of patients with multidrug-resistant tuberculosis in China

BackgroundFew prospective cohort studies, none in China, have investigated the relationship between treatment outcomes of multidrug-resistant tuberculosis (MDR-TB) patients and sputum culture conversion. Factors affecting the time of the culture conversion throughout the whole course of the treatment have rarely been investigated.MethodsThis study was performed in four cities in Jiangsu province, China. MDR-TB patients were consecutively enrolled between December 2011 and March 2014. Rates of sputum culture conversion were calculated and Cox proportional-hazards model was performed. Factors contributing to sputum culture conversion were investigated.ResultsIn all, 139 MDR-TB patients with treatment outcomes were enrolled. Median time to culture conversion among those who converted was 91.5 days (interquartile range, 34.0–110.8 days). After multivariable analysis, smoking (HR = 0.44; 95% CI: 0.23–0.83), drinking (HR = 0.41; 95% CI: 0.21–0.81), ofloxacin resistance (HR = 0.43; 95% CI: 0.24–0.76) and sputum smear grade > 1 (HR = 0.51; 95% CI: 0.31–0.83) were less likely to have culture conversion.ConclusionsMDR-TB patients who smoke, drink, have ofloxacin resistance, or a high smear grade are less likely to respond to treatment and should be meticulously followed up.

Intermittent Antibiotic Therapy for Recurrent Nodular Bronchiectatic Mycobacterium avium Complex Lung Disease.

Intermittent, three-times-weekly oral antibiotic therapy is recommended for the initial treatment of noncavitary nodular bronchiectatic (NB) Mycobacterium avium complex (MAC) lung disease. However, intermittent therapy is not recommended for patients who have been previously treated. We evaluated 53 patients with recurrent noncavitary NB MAC lung disease who underwent antibiotic treatment for ≥12 months with daily therapy (n = 26) or intermittent therapy (n = 27) between January 2008 and December 2015. Baseline characteristics were comparable between daily therapy and intermittent therapy groups. Sputum culture conversion rates did not differ between daily therapy (21/26, 81%) and intermittent therapy (22/27, 82%) groups. Compared to the etiologic organism at the time of previous treatment, recurrent MAC lung disease was caused by the same MAC species in 38 patients (72%) and by a different MAC species in 15 patients (28%). Genotype analysis in patients with sequenced paired isolates revealed that 86% (12/14) of cases with same species recurrence were due to reinfection with a new MAC genotype. In conclusion, most recurrent noncavitary NB MAC lung disease cases were caused by reinfection rather than relapse. Intermittent antibiotic therapy is a reasonable treatment strategy for recurrent noncavitary NB MAC lung disease.

Sputum Smear and Culture Conversion in Multidrug Resistance Tuberculosis Patients in Seven Districts of Central Gujarat, India: A Longitudinal Study.

Objectives:To know the sputum smear and culture conversion among multidrug resistance tuberculosis (MDR-TB) patients.Materials and Methods:The longitudinal cohort study was conducted for 142 MDR-TB patients registered in 2010 under Revised National Tuberculosis Control Programme of Vadodara region. Three follow-ups were taken for sputum and culture examination, at completion of 6, 12, and 24 months of treatment. Individuals were interviewed to know the reasons for missed dose and default.Results:The sputum smear and culture conversion rate was 43.4%, 47.7%, and 57% at 6 months, 12 months, and 24 months of follow-up, respectively. Treatment default rate was highest (15.2%) within initial 6 months of therapy. The mean time to sputum smear and culture conversion was 120.27 days and 125.02 days, respectively.Conclusions:Most of patients who were culture positive at 6 months remained so even after 12 months. There was not much difference in the time taken for culture and sputum conversion.

Treatment outcomes of macrolide-susceptible Mycobacterium abscessus lung disease

Mycobacterium abscessus lung disease is difficult to treat due to inducible resistance to macrolides. However, 15%–20% of isolates are macrolide susceptible. In 14 patients with macrolide-susceptible M. abscessus lung disease, all isolates had nonfunctional erm(41) gene, and sputum culture conversion rate was achieved in 93% (13/14) following antibiotic therapy.

Isoniazid Monoresistance and Rate of Culture Conversion among Patients in the State of Georgia with Confirmed Tuberculosis, 2009-2014.

Isoniazid-monoresistant tuberculosis (INH-monoresistant TB) is the most common drug-resistant TB type in the United States; however, its impact on TB treatment outcomes is not clear. This study aims to understand 1) factors associated with INH-monoresistant TB and 2) the association between INH monoresistance and response to TB treatment. We studied all patients with TB (age, ≥15 yr) reported to the Georgia State Electronic Notifiable Disease Surveillance System (SENDSS) from 2009 to 2014. INH-monoresistant TB was defined as a Mycobacterium tuberculosis isolate resistant to isoniazid only. Time to sputum culture conversion was defined as the time (measured in days) from TB treatment initiation to the date of the first consistently negative culture result reported to the SENDSS. Logistic regression and Cox proportional hazard models were used to estimate the odds and hazard rate of sputum culture conversion, all-cause mortality, and poor TB outcome among patients with INH-monoresistant TB. Among 1,141 culture-confirmed patients with available drug susceptibility testing results, 998 (87.5%) were susceptible to TB first-line drugs, and 143 (12.5%) were patients with INH-monoresistant TB. In multivariable analysis, male sex (adjusted odds ratio [aOR], 1.62; 95% confidence interval [CI], 1.01-2.67) and homelessness (aOR, 5.55; 95% CI, 3.38-9.17) were associated with higher odds of INH-monoresistant TB. In the same multivariable model, older age (≥65 yr old) (aOR, 0.21; 95% CI, 0.07-0.55) and miliary disease (aOR, 0.19; 95% CI, 0.01-0.96) were associated with lower odds of INH-monoresistant TB. Among 1,116 patients with pulmonary TB, the median time to sputum culture conversion was 30 days (interquartile range, 13-58). The rate of culture conversion was similar among patients with and without INH monoresistance (adjusted cause-specific hazard ratio, 1.15; 95% CI, 0.95-1.40). INH-monoresistant TB was not significantly associated with poor TB treatment outcomes (aOR, 1.61; 95% CI, 0.67-3.70) or mortality during TB treatment (aOR, 1.72; 95% CI, 0.58-4.94). Our findings suggest that compared with drug-susceptible TB, patients in Georgia with INH-monoresistant TB have a similar response to TB treatment including culture conversion rate, final TB treatment outcome, and all-cause mortality.

Follow up of Drug-Resistant Pulmonary Tuberculosis Patients in a DRTB Center in First Fifteen Months of Treatmen

Background and Objective: Multidrug-resistant tuberculosis (MDR-TB) is defined as resistant to both INH and Rifampicin with or without resistance to other first-line antitubercular drugs. The aim of the study was to assess the sputum culture conversion rate during first 12 months of treatment in drug-resistant TB patients, to assess the impact of comorbid illnesses and other factors on culture conversion by following up the patients up to 15 months after initiation of treatment. Materials and Methods: This was a prospective study comprising of 142 diagnosed patients of drug-resistant TB admitted in this center from April 2014 to March 2015 for treatment initiation, excluding extrapulmonary TB and already diagnosed extensively drug-resistant tuberculosis (XDR-TB). After pretreatment evaluation, standard second-line antitubercular drug (CAT-IV) was started. Patients were followed up in first 15 months of treatment. Results of sputum culture for mycobacteria at 3rd, 4th, 5th, 6th, 7th, 9th and 12th months after treatment initiation were analyzed. Results: Sputum culture for mycobacteria was converted negative within one year in 95 cases (67%); whereas 18 patients died during follow up, 27 defaulted and 2 patients switched over to CAT-V after development of extended drug-resistance during follow up. Conclusion: Though drug-resistant tuberculosis (DRTB) is one of the biggest challenges to public health program in India, treatment with standardized second-line drugs under RNTCP have a favorable outcome as indicated by sputum culture conversion of as many as 67% of patients within one year in this study.

Meta-analyses and the evidence base for microbial outcomes in the treatment of pulmonary Mycobacterium avium-intracellulare complex disease.

To perform a systematic review and meta-analysis of the level of funding support and the sputum culture conversion rates in pulmonary Mycobacterium avium-intracellulare complex (P-MAC) disease in adult patients without cystic fibrosis or HIV infection, treated with recommended antibiotic regimens. We performed a literature search to identify clinical trials, prospective studies and registries that reported outcomes in P-MAC patients. Studies that reported P-MAC diagnosis and treatments based on established guidelines met the inclusion criteria and were examined for bias and quality. We modified existing quality scales and came up with a 10 star quality score. Outcomes meta-analysed were sputum conversion incidence ratios (IR) and their 95% CI, weighted for study quality. Twenty-one studies that examined 28 regimens, including 2534 patients in intent-to-treat analyses and 1968 in per-protocol analyses, were identified. The study quality mean ± SD scores were 5.4 ± 2.2 out of 10 stars. Only two (9.5%) studies received public funding. There was significant heterogeneity of microbial effect among treatment regimens (I2 > 40%; P > 0.001). The pooled IR for sustained sputum conversion was 0.54 (95% CI 0.45-0.63) for macrolide-containing regimens versus 0.38 (0.25-0.52) with macrolide-free regimens. Prolonging therapy duration beyond 12 months was associated with an average decline in sputum conversion to 22% (95% CI 1%-44%). Researchers working on P-MAC therapy have received very little public funding support. As a result, the evidence base for treatment guidelines is based on studies of relatively small numbers of patients in low-quality studies. Nevertheless, these studies showed poor sputum conversion rates in patients receiving recommended treatment regimens.

Polymorphisms in the vitamin D receptor gene are associated with reduced rate of sputum culture conversion in multidrug-resistant tuberculosis patients in South Africa.

BackgroundVitamin D modulates the inflammatory and immune response to tuberculosis (TB) and also mediates the induction of the antimicrobial peptide cathelicidin. Deficiency of 25-hydroxyvitamin D and single nucleotide polymorphisms (SNPs) in the vitamin D receptor (VDR) gene may increase the risk of TB disease and decrease culture conversion rates in drug susceptible TB. Whether these VDR SNPs are found in African populations or impact multidrug-resistant (MDR) TB treatment has not been established. We aimed to determine if SNPs in the VDR gene were associated with sputum culture conversion among a cohort of MDR TB patients in South Africa.MethodsWe conducted a prospective cohort study of adult MDR TB patients receiving second-line TB treatment in KwaZulu-Natal province. Subjects had monthly sputum cultures performed. In a subset of participants, whole blood samples were obtained for genomic analyses. Genomic DNA was extracted and genotyped with Affymetrix Axiom Pan-African Array. Cox proportional models were used to determine the association between VDR SNPs and rate of culture conversion.ResultsGenomic analyses were performed on 91 MDR TB subjects enrolled in the sub-study; 60% were female and median age was 35 years (interquartile range [IQR] 29–42). Smoking was reported by 21% of subjects and most subjects had HIV (80%), were smear negative (57%), and had cavitary disease (55%). Overall, 87 (96%) subjects initially converted cultures to negative, with median time to culture conversion of 57 days (IQR 17–114). Of 121 VDR SNPs examined, 10 were significantly associated (p<0.01) with rate of sputum conversion in multivariable analyses. Each additional risk allele on SNP rs74085240 delayed culture conversion significantly (adjusted hazard ratio 0.30, 95% confidence interval 0.14–0.67).ConclusionsPolymorphisms in the VDR gene were associated with rate of sputum culture conversion in MDR TB patients in this high HIV prevalence setting in South Africa.

Effectiveness and safety of bedaquiline-containing regimens in the treatment of MDR- and XDR-TB: a multicentre study.

Large studies on bedaquiline used to treat multidrug-resistant (MDR-) and extensively drug-resistant tuberculosis (XDR-TB) are lacking. This study aimed to evaluate the safety and effectiveness of bedaquiline-containing regimens in a large, retrospective, observational study conducted in 25 centres and 15 countries in five continents.428 culture-confirmed MDR-TB cases were analysed (61.5% male; 22.1% HIV-positive, 45.6% XDR-TB). MDR-TB cases were admitted to hospital for a median (interquartile range (IQR)) 179 (92-280) days and exposed to bedaquiline for 168 (86-180) days. Treatment regimens included, among others, linezolid, moxifloxacin, clofazimine and carbapenems (82.0%, 58.4%, 52.6% and 15.3% of cases, respectively).Sputum smear and culture conversion rates in MDR-TB cases were 63.6% and 30.1%, respectively at 30 days, 81.1% and 56.7%, respectively at 60 days; 85.5% and 80.5%, respectively at 90 days and 88.7% and 91.2%, respectively at the end of treatment. The median (IQR) time to smear and culture conversion was 34 (30-60) days and 60 (33-90) days. Out of 247 culture-confirmed MDR-TB cases completing treatment, 71.3% achieved success (62.4% cured; 8.9% completed treatment), 13.4% died, 7.3% defaulted and 7.7% failed. Bedaquiline was interrupted due to adverse events in 5.8% of cases. A single case died, having electrocardiographic abnormalities that were probably non-bedaquiline related.Bedaquiline-containing regimens achieved high conversion and success rates under different nonexperimental conditions.

Efficacy and Safety of Bedaquiline and Delamanid in the Treatment of Tuberculosis: a Focus on Multidrug-resistant Tuberculosis

The emergence of multi-drug resistant tuberculosis (MDR-TB) poses a major difficulty in controlling TB worldwide. More potent TB drugs, higher cost, and longer duration of treatment are necessary for MDR-TB compared with drug-sensitive TB. However, currently available TB drugs have been used for more than 40 years. Therefore, a novel anti-TB drug is required for the treatment of MDR-TB. This study was aimed at assessing the efficacy and safety of bedaquiline and delamanid and determining the therapeutic validity of them in controlling MDR-TB. A literature search of original studies published in PubMed, MEDLINE, and Scopus until August 2015 was conducted using the terms ‘bedaquiline OR delamanid’ AND ‘efficacy OR safety’ AND ‘tuberculosis’ to identify the clinical trials regarding bedaquiline or delamanid in TB. Six and four clinical studies regarding bedaquiline and delamanid, respectively, were examined in this review. The treatment durations of bedaquiline and delamanid in the selected studies were from 2 weeks to 32 weeks. The higher falls in log10 colony forming units (CFU)/mL during the treatment period were observed in the regimens including bedaquiline than in the standard anti-TB regimen. The median time to sputum-culture conversion (TTC) of the bedaquiline group was shorter than that of the placebo group. The sputum-culture conversion rate of the delamanid group was higher than that of the placebo group. In the included studies, serious adverse effects were not reported due to bedaquiline or delamanid. However, their uses were more highly associated with potential QT-interval prolongation. The clinical trials suggest that the uses of bedaquiline or delamanid with other anti-TB medications were at least efficacious and safe in the treatment of MDR-TB at this point.

Substitution of ethambutol with linezolid during the intensive phase of treatment of pulmonary tuberculosis: study protocol for a prospective, multicenter, randomized, open-label, phase II trial

BackgroundLinezolid, an oxazolidinone, substantially improves treatment outcomes of multidrug-resistant tuberculosis and extensively drug-resistant tuberculosis. We started a trial to test whether the use of linezolid instead of ethambutol could increase the rate of sputum culture conversion as of 8 weeks of treatment in patients with drug-susceptible tuberculosis.Methods/designThis is a phase II, multicenter, randomized study with three arms. We are enrolling patients with pulmonary tuberculosis without rifampicin resistance screened by the Xpert MTB/RIF® assay. The standard treatment arm uses isoniazid (6 months), rifampicin (6 months), pyrazinamide (2 months), and ethambutol (2 months). Experimental arm 1 uses linezolid (600 mg/day) for 4 weeks instead of ethambutol. Experimental arm 2 uses linezolid (600 mg/day) for 2 weeks instead of ethambutol. The primary outcome is the sputum culture conversion rate on liquid media after 2 months of treatment. Secondary outcomes include the sputum culture conversion rate on solid media after 2 months of treatment, time to sputum culture conversion on liquid and solid media, cure rate, and treatment success rate. The frequencies of total adverse events (AEs) and serious AEs will be described and documented. Based on an α = 0.05 level of significance, a power of 85%, a 15% difference in the culture conversion rate after 2 months between the control arm and experimental arm 1 (75% vs. 90%), a 10% default (loss to follow-up) rate, and a 10% culture failure, the required number per arm was calculated to be 143 (429 in total).DiscussionThis trial will reveal the effectiveness and safety of 2 or 4 weeks of use of linezolid instead of ethambutol for patients with drug-susceptible pulmonary tuberculosis. If a new regimen including linezolid shows a higher culture conversion rate by week 8, and is safe, it could be tested as a 4-month antituberculosis treatment regimen in the future.Trial registrationClincalTrials.gov, NCT01994460. Registered on 13 November 2013.