Multidrug-resistant Tuberculosis Treatment Outcomes Research Articles

Predictive model of unfavorable outcomes for multidrug-resistant tuberculosis.

ABSTRACTOBJECTIVE to analyze the temporal trend, identify the factors related and elaborate a predictive model for unfavorable treatment outcomes for multidrug-resistant tuberculosis (MDR-TB).METHODS Retrospective cohort study with all cases diagnosed with MDR-TB between the years 2006 and 2015 in the state of São Paulo. The data were collected from the state system of TB cases notifications (TB-WEB). The temporal trend analyzes of treatment outcomes was performed through the Prais-Winsten analysis. In order to verify the factors related to the unfavorable outcomes, abandonment, death with basic cause TB and treatment failure, the binary logistic regression was used. Pictorial representations of the factors related to treatment outcome and their prognostic capacity through the nomogram were elaborated.RESULTS Both abandonment and death have a constant temporal tendency, whereas the failure showed it as decreasing. Regarding the risk factors for such outcomes, using illicit drugs doubled the odds for abandonment and death. Besides that, being diagnosed in emergency units or during hospitalizations was a risk factor for death. On the contrary, having previous multidrug-resistant treatments reduced the odds for the analyzed outcomes by 33%. The nomogram presented a predictive model with 65% accuracy for dropouts, 70% for deaths and 80% for failure.CONCLUSIONS The modification of the current model of care is an essential factor for the prevention of unfavorable outcomes. Through predictive models, as presented in this study, it is possible to develop patient-centered actions, considering their risk factors and increasing the chances for cure.

Health-related quality of life of patients with multidrug-resistant tuberculosis in Yemen: prospective study

BackgroundSubstantial efforts are currently focused on investigating and developing new multidrug-resistant tuberculosis (MDR-TB) drugs and diagnostic methods. In Yemen, however, the evaluation of health-related quality of life (HRQoL) and the effect of current MDR-TB treatment on the QoL are commonly ignored. This study evaluated the HRQoL during and after treatment and identified the risk factors that are predictive of HRQoL score differences.MethodA prospective cohort study was conducted in four of the five main MDR-TB centres in Yemen. The patients confirmed with MDR-TB completed the SF-36 V2 survey at the beginning of treatment, end of treatment (continous phase) and at the 1 year follow-up after completing treatment. A total normal base score (NBS) of < 47 reflects impairment of functions, whereas a mental component summary (MCS) score of < 43 indicates a risk of depression.ResultAt the beginning of treatment, the mean scores for all health domains were < 47 NBS points (PF = 40.7, RP = 16.1, BP = 21.6, GH = 28.3, VT = 14.55, SF = 25.9, RE = 13.7, and MH = 14.7). At the completion of treatment, all eight health domains increase compare to beginning of treatment (PF = 59.3, RP = 31.1, BP = 40.9, GH = 48.5, VT = 30.5, SF = 46.6, RE =26.6 & MH = 27.7), but a follow-up duration of 1 year after completing treatment showed decreased NBS points in all domains (PF = 51.5, RP = 30.6, BP = 39.1, GH = 47.8, VT = 30.2, SF = 43.7, RE =26.4 & MH = 27.2). Age, history of streptomycin use, baseline lung cavity, marital status and length of sickness before MDR-TB diagnosis were predictive of in PCS score differences, whereas, age, smoking, baseline lung cavity, stigma, residence, marital status and length of sickness before MDR-TB diagnosis were predictive of MCS scores differences.ConclusionThe length of sickness before DR-TB diagnosis was found to be predictive of the trends in both PCS and MCS scores. Despite the positive outcome of MDR-TB treatment, the low HRQoL scores obtained for all heath domains and especially for mental health reflect a high depression status of patients even after 1 year of completing therapy. Moreover, the poor HRQoL, particularly regarding mental health, of study participants at the end of treatment demands the need for urgent attention from national tuberculosis control programme managers. Therefore, the Yemen Ministry of Health and the National Tuberculosis Control Programme should implement an intervention programme to enhance HRQoL at the end of treatment to avoid any further negative consequences of MDRTB in patients after treatment. Moreover, The HRQoL data of patients with MDR-TB must be collected at the different stages of MDR-TB treatment to provide an additional parameter for assessing the effectiveness of the treatment programme.Trial registrationSNOYEM 1452. Registered 01 February 2013.

Impact of universal drug susceptibility testing and effective management of multidrug-resistant tuberculosis in Taiwan.

BackgroundThe treatment outcomes of multidrug-resistant tuberculosis (MDR-TB) patients in the 1990s in Taiwan was not satisfactory. To strengthen programmatic management of drug-resistant tuberculosis (PMDT), Taiwan MDR-TB Consortium (TMTC) was established in 2007. We assess the performance and epidemiologic impact of TMTC.Methodology/Principle findingsWe analyzed the trends of proportion of TB cases with drug susceptibility testing, enrollment of MDR-TB patients into TMTC and outcomes of treatment of all MDR-TB patients in Taiwan from 2007–2016. We computed the trends of both incidence and prevalence of MDR-TB from 2007–2016. We assessed the trends of MDR-TB among both new and recurrent TB cases. The proportion of TB cases with drug susceptibility testing results increased from 24.2% in 2007 to 97.9% in 2016. Of the 1,452 MDR-TB patients who were eligible for TMTC care, 1,197 (82.4%) were enrolled in TMTC, in whom 82.9% had treatment success. MDR-TB incidence was 9.0 cases per million in 2007, which declined to 4.6 cases per million in 2016 (p<0.0001). MDR-TB prevalence decreased from 19.4 cases per million in 2007 to 8.4 cases per million in 2016 (p<0.0001). The proportion of MDR-TB among new TB cases decreased from 1.4% in 2010 to 1.0% in 2016 (p = 0.039); and that among recurrent TB cases from 9.0% in 2010 to 1.8% in 2016 (p<0.0001).ConclusionsWe concluded that effective PMDT have had a significant impact on the epidemic of drug-resistant TB in Taiwan.

Improved Fluoroquinolone-Resistant and Extensively Drug-Resistant Tuberculosis Treatment Outcomes

BackgroundTreatment outcomes of multidrug-resistant tuberculosis (MDR TB) remain poor, particularly for fluoroquinolone-resistant (FQ-R) MDR TB. The aim of this study was to determine treatment outcomes and factors associated with failure of MDR TB treatment, focusing on FQ resistance.MethodsMedical records were retrospectively reviewed of patients diagnosed and treated for MDR TB from January 2005 through December 2017 at Severance Hospital, South Korea.ResultsOf a total of 129 patients with MDR TB, 90 (69.8%) cases were FQ-sensitive (FQ-S) and 39 (30.2%) were FQ-R. FQ-R MDR TB was associated with more severe clinical symptoms, including cavitary lesions and bilateral disease, and tended to require treatment with a greater number of drugs for a longer period of time than FQ-S MDR TB. Linezolid (51.3% vs 7.8%, P < .001), bedaquiline (20.5% vs 8.9%, P = .083), and delamanid (10.3% vs 5.6%, P = .452) were more frequently used in FQ-R cases. Overall, 95/124 patients (76.6%) had favorable treatment outcomes, and we did not detect a significant difference between FQ-R and FQ-S (FQ-S 65/87, 74.7%, vs FQ-R 30/37, 81.1%; P = .443). Old age, low body mass index, smoking, and malignancy—but not FQ resistance or extensively drug-resistant (XDR) TB—were associated with poor clinical outcomes.ConclusionsOverall, 76.6% of MDR TB patients had successful treatment outcomes. Effective drug combinations and appropriate use of new drugs may improve treatment outcomes of FQ-R MDR and XDR TB. Poor clinical outcomes were more related to the patients’ general condition rather than FQ resistance or XDR.

Impact of Xpert MTB/RIF assay on multidrug-resistant tuberculosis treatment outcomes in a health district in South Africa.

Xpert MTB/RIF assay rapidly diagnoses rifampicin resistance, enabling early initiation of second-line tuberculosis (TB) treatment. However, the impact of an earlier multidrug-resistant TB (MDR-TB) diagnosis on treatment outcomes is unknown. To compare MDR-TB treatment outcomes in cases diagnosed with smear/culture and Xpert. This was a retrospective cohort study with cohorts defined by the diagnostic assay used in presumptive TB cases. Data were extracted from a drug-resistant (DR)-TB register including cases from January 2012 to June 2014. Treatment outcomes were assessed at recorded endpoints or after 2 years for those completing treatment. A total of 718 cases were enrolled into the study. Cure rates were 43.4% (n=158) for the smear/culture cohort and 33.5% (n=118) for the Xpert cohort (p&lt;0.01). Xpert diagnosis (adjusted risk ratio (aRR) 0.65; p=0.02) and male gender (aRR 0.66; p=0.04) were associated with cure outcome. Xpert diagnosis increased time to sputum culture conversion from 4 to 5 months (log-rank test p=0.01). Time to treatment initiation was not associated with treatment success in logistic regression analysis. Despite rapid treatment initiation, MDR-TB treatment outcomes were poorer in patients diagnosed with Xpert MTB/RIF assay than in the smear/culture cohort, and they were also poorer in men than in women. Additional studies are required to assess possible factors influencing DR-TB outcomes.

Effect of reliance on Xpert MTB/RIF on time to treatment and multidrug-resistant tuberculosis treatment outcomes in Tanzania: a retrospective cohort study.

During 2009-2013, Xpert MTB/RIF testing was decentralized in Tanzania. Standardized treatment of multidrug-resistant/rifampicin-resistant tuberculosis (MDR/RR-TB) was centralized at the Kibong'oto Infectious Diseases Hospital. Initially, Xpert MTB/RIF results were confirmed and complemented with phenotypic drug susceptibility testing before MDR-TB treatment was started. Since 2013, the decision to start MDR-TB treatment in patients with RR-TB relied on Xpert MTB/RIF results. A retrospective cohort study of predictors of unsuccessful treatment outcomes (including death, lost to follow-up and treatment failure) was carried out. During the study period, 201 patients started MDR-TB treatment. The number of patients starting MDR-TB treatment increased over time. Out of 201 patients, 48 (23.9%) had an unsuccessful treatment outcome. The median time between sample collection and MDR-TB treatment initiation was reduced from 155 d (IQR 40-228) in the 2009-2012 period to 26 d (IQR 13-64) in 2013. Patients who started MDR-TB treatment in 2013 were more likely (adjusted OR 2.3; 95% CI 1.1-4.7; p=0.02) to have an unsuccessful treatment outcome. Xpert MTB/RIF testing increased enrolment on MDR-TB treatment. Reliance on Xpert MTB/RIF results to start MDR-TB treatment reduced time to treatment. However, treatment outcomes did not improve.

Predictors of Treatment Outcomes among Multidrug Resistant Tuberculosis Patients in Tanzania.

Background According to World Health Organization (WHO) the final multidrug resistant tuberculosis (MDRTB) treatment outcome is the most important direct measurement of the effectiveness of the MDRTB control program. Literature review has shown marked diversity in predictors of treatment outcomes worldwide even among the same continents. Therefore, findings could also be different in Tanzanian context, where the success rate is still lower than the WHO recommendation. This study sought to determine the predictors of treatment outcomes among MDRTB patients in Tanzania in order to improve the success rate. Methodology This was a retrospective cohort study, which was conducted at Kibong'oto Infectious Diseases Hospital (KIDH) in Tanzania. Patients' demographic and clinical parameters were collected from the MDRTB registry and clinical files. Then, a detailed analysis was done to determine the predictors of successful and unsuccessful MDRTB treatment outcomes. Results Three hundred and thirty-two patients were diagnosed and put on MDRTB treatment during the year 2009 to 2014. Among them, males were 221 (67%), and 317 (95.48%) were above 18 years of age, mean age being 36.9 years. One hundred and sixty-one patients (48.5%) were living in Dar es Salaam. The number of MDRTB patients has increased from 16 in 2009 to 132 in 2014. Majority of patients (75.7%) had successful treatment outcomes. The following predictors were significantly associated with MDRTB cure: presence of cavities in chest X-rays (aOR 1.89, p value 0.002), low BMI (aOR 0.59, p value 0.044), and resistance to streptomycin (aOR 4.67, p value 0.007) and ethambutol (aOR 0.34, p value 0.041). Smoking and presence of cavities in chest X-rays were associated with MDRTB mortality, aOR 2.31, p value 0.043 and aOR 0.55, p value 0.019, respectively. Conclusion The study indicated that overall number of MDRTB patients and the proportion of successful treatment outcomes have been increasing over the years. The study recommends improving nutritional status of MDRTB patients, widespread antismoking campaign, and close follow-up of patients with ethambutol resistance.

Treatment outcomes for multidrug-resistant tuberculosis in Eastern Taiwan.

Objectives:The objective of this study is to evaluate the treatment outcomes of patients with multidrug-resistant tuberculosis (MDR-TB) under special programmatic management in Eastern Taiwan over the past 10 years.Materials and Methods:All newly diagnosed MDR-TB patients and MDR-TB patients enrolled previously with persistent positive cultures were included in this study, from May 2007 to April 2017, in Eastern Taiwan. A panel of pulmonologists designed the initial MDR-TB regimens. Subsequently, regimens were adjusted according to drug susceptibility test results for second-line drugs. Mobile teams were organized for treatment support, and several measures were adapted to safeguard effective treatment support.Results:A total of 178 patients with bacteriological confirmed pulmonary MDR-TB were identified, of whom 167 had treatment outcomes when the study was conducted. Of these 167 patients, 120 (71.9%) were cured, 11 (6.5%) completed therapy (78.4% had successful treatment), 25 (15.0%) died, 9 (5.4%) had treatment failure, none were transferred out, and 2 (1.2%) were lost to follow-up. Surgery was performed on 8 (4.8%).Conclusions:This is an analysis of the treatment outcomes after adopting the Directly Observed Treatment, Short-course Plus program to treat MDR-TB patients in Eastern Taiwan. We had a low proportion of loss-to-follow-up, resulting in a high treatment success rate. This program serves as an effective model in providing quality care to patients with MDR-TB.

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.

Bedaquiline and delamanid in the treatment of multidrug-resistant tuberculosis: Promising but challenging.

Improving treatment outcomes in multidrug‐resistant tuberculosis (MDR‐TB) is partly hampered by inadequate effective antitubercular agents. Development of bedaquiline and delamanid has potentially changed the treatment landscape for MDR‐TB. This review provides an update on the progress of these novel antitubercular agents. We review published studies aimed at evaluating clinical efficacy and effectiveness of bedaquiline and delamanid. Five prospective clinical studies and seven retrospective studies on bedaquiline showed that patients treated with a bedaquiline‐containing regimen had a high culture conversion rate ranging from 65 to 100% and a satisfactory treatment outcome. The combined use with linezolid might add to the effectiveness of bedaquiline. Controversies about bedaquiline resistance are discussed. Three clinical trials have reported outcomes on delamanid and showed that introducing delamanid to a background regimen improved culture conversion rate at 2 months from 29.6% to more than 40%. A higher favorable treatment rate was also observed among patients who received delamanid for more than 6 months, but about a quarter of patients defaulted in the control group. Seven retrospective studies were summarized and found a treatment benefit as well. More reliable evidence from randomized clinical trials reporting on the treatment outcomes is needed urgently to support a strong recommendation for the use of delamanid. Advances in the combined use of bedaquiline and delamanid are also reviewed, and the combination may be well tolerated but requires electrocardiograph monitoring.

Substitution of ethambutol with linezolid during the intensive phase of treatment of pulmonary tuberculosis: a prospective, multicentre, randomised, open-label, phase 2 trial

Linezolid improves the treatment outcomes of multidrug-resistant tuberculosis substantially. We investigated whether use of linezolid instead of ethambutol increases the proportion of sputum culture conversion at 8 weeks of treatment in patients with pulmonary tuberculosis. We did a phase 2, multicentre, randomised, open-label trial for patients with pulmonary tuberculosis at the three affiliated hospitals to Seoul National University and National Medical Center (Seoul-Seongnam, South Korea). Patients, aged 20-80 years, with a positive sputum for pulmonary tuberculosis, but without resistance to rifampicin, and current treatment administered for 7 days or fewer, were randomly assigned at a 1:1:1 ratio into three groups. The control group received ethambutol (2 months) with isoniazid, rifampicin, and pyrazinamide. The second group used linezolid (600 mg/day) for 2 weeks and the third group for 4 weeks instead of ethambutol for 2 months. We used a minimisation method to randomise, and stratified according to institution, cavitation on chest radiographs, and diabetes. The primary endpoint was the proportion of patients with negative culture conversion of sputum in liquid media after 8 weeks of treatment. The results of this trial were analysed primarily in the modified intention-to-treat population. The trial is registered with ClinicalTrials.gov, number NCT01994460. Between Feb 19, 2014, and Jan 13, 2017, a total of 429 patients were enrolled and 428 were randomly assigned into either the control group (142 patients), the linezolid 2 weeks group (143 patients), or the linezolid 4 weeks group (143 patients). Among them, 401 were eligible for primary efficacy analyses. In the modified intention-to-treat analyses, negative cultures in liquid media at 8 weeks of treatment were observed in 103 (76·9%) of 134 control patients, 111 (82·2%) of 135 in the linezolid 2 weeks group, and 100 (75·8%) of 132 in the linezolid 4 weeks groups. The difference from the control group was 5.4% (95% CI -4·3 to 15·0, p=0·28) for the linezolid 2 weeks group and -1·1% (-11·3 to 9·1, p=0·83) for the linezolid 4 weeks group. Numbers of patients who experienced at least one adverse event were similar across the groups (86 [62·8%] of 137 in control, 79 [57·2%] of 138 in the linezolid 2 weeks group, and 75 [62·0%] of 121 in the linezolid 4 weeks group). Resistance to linezolid was not identified in any patient. Higher rates of culture conversion at 8 weeks of treatment with short-term use of linezolid were not observed. However, safety analyses and the resistance profile suggested the potential role of linezolid in shortening of treatment for drug-susceptible tuberculosis. Ministry of Health and Welfare, South Korea.

Rapid drug susceptibility testing and treatment outcomes for multidrug-resistant tuberculosis in Peru.

The detection of multidrug-resistant tuberculosis (MDR-TB) using rapid drug susceptibility testing (DST) has increased steadily in recent years in Peru, from 9216 tests in 2010 to 27 021 tests in 2015. Research examining the impact of rapid DST on treatment outcomes is required. To evaluate the association between rapid DST use (nitrate reductase assay, microscopic observation drug susceptibility assay [MODS] and GenoType® MTBDRplus) and treatment outcomes and mortality in MDR-TB patients in Peru. Retrospective cohort study of patients diagnosed with pulmonary MDR-TB between 2010 and 2013 (with treatment outcomes up to December 2015) using the electronic registry of the Peruvian National TB Programme. A total of 2671 MDR-TB patients were included; the median age was 27 years, 2.8% were co-infected with the human immunodeficiency virus. Use of rapid DST was associated with a 40% increase in the adjusted odds of treatment success (aOR 1.40, 95%CI 1.19-1.64) and a 54% reduction in mortality (aOR 0.46, 95%CI 0.33-0.64). Higher treatment success rates were driven by MODS and GenoType® MTBDRplus testing (aORs for unsuccessful outcomes respectively 0.68 and 0.66). The use of rapid DST (MODS and MTBDRplus) to diagnose MDR-TB was associated with a reduction in the odds of death and a substantial increase in the odds of treatment success.

Current treatment of multidrug resistant tuberculosis in Ethiopia: an aggregated and individual patients\u2019 data analysis for outcome and effectiveness of the current regimens

BackgroundThe programmatic management of Multidrug-resistant tuberculosis (MDR-TB) is entirely based on a WHO recommended long-term, 18–24 month lasting treatment regimen. However, growing evidence shows that low treatment success rate and high rates of adverse events are associated with this regimen. Up to date, the MDR-TB treatment outcome is not sufficiently understood in Ethiopia. Therefore, this analysis aimed to determine the pooled estimates of successful (cure, completed, or both), and poor outcomes (death, failure, and lost to follow ups).MethodA systematic search was performed to identify eligible studies reporting MDR-TB treatment outcomes in Ethiopia. Relevant studies for our analysis were retrieved from PubMed database search, Google Scholar and institutional repository sites of Ethiopian universities up to March 15, 2018. The primary outcome was treatment success, referring to a composite of cure and treatment completion. A random effect model was used to calculate pooled estimates.ResultsSix studies reporting treatment outcome on the 1993 MDR-TB patients were included in this analysis. Of the cases, the 1288 and 442 patients had a successful and poor outcome, respectively. In the pooled analysis, treatment success was observed in 59.2% (95%CI, 48.1–70.4) of patients, while 23.3% (95%CI, 19.7–27.0%) of patients had a poor outcome. in sub-group analysis,46.1% (95%CI, 34.2–58.0) were cured, 12.8% (5.7–20.0) treatment completed, 14.3% (11.5–17.2) died, 7.5% (3.7–11.3) lost to follow up, and 1.6% (1.1–2.2%) experienced treatment failure. The 25.0% (14.6–35.5) patients whose treatment outcome was not assessed (on treatment or transfer-out).ConclusionThe result of this study highlight treatment success among MDR-TB is below acceptable range. To update the current treatment regimen, the levels of evidence need to be replicated through meticulous surveillance systems.Trial registrationStudy protocol registration: CRD42018090711.

Treatment correlates of successful outcomes in pulmonary multidrug-resistant tuberculosis: an individual patient data meta-analysis

Treatment outcomes for multidrug-resistant tuberculosis remain poor. We aimed to estimate the association of treatment success and death with the use of individual drugs, and the optimal number and duration of treatment with those drugs in patients with multidrug-resistant tuberculosis. In this individual patient data meta-analysis, we searched MEDLINE, Embase, and the Cochrane Library to identify potentially eligible observational and experimental studies published between Jan 1, 2009, and April 30, 2016. We also searched reference lists from all systematic reviews of treatment of multidrug-resistant tuberculosis published since 2009. To be eligible, studies had to report original results, with end of treatment outcomes (treatment completion [success], failure, or relapse) in cohorts of at least 25 adults (aged >18 years). We used anonymised individual patient data from eligible studies, provided by study investigators, regarding clinical characteristics, treatment, and outcomes. Using propensity score-matched generalised mixed effects logistic, or linear regression, we calculated adjusted odds ratios and adjusted risk differences for success or death during treatment, for specific drugs currently used to treat multidrug-resistant tuberculosis, as well as the number of drugs used and treatment duration. Of 12 030 patients from 25 countries in 50 studies, 7346 (61%) had treatment success, 1017 (8%) had failure or relapse, and 1729 (14%) died. Compared with failure or relapse, treatment success was positively associated with the use of linezolid (adjusted risk difference 0·15, 95% CI 0·11 to 0·18), levofloxacin (0·15, 0·13 to 0·18), carbapenems (0·14, 0·06 to 0·21), moxifloxacin (0·11, 0·08 to 0·14), bedaquiline (0·10, 0·05 to 0·14), and clofazimine (0·06, 0·01 to 0·10). There was a significant association between reduced mortality and use of linezolid (-0·20, -0·23 to -0·16), levofloxacin (-0·06, -0·09 to -0·04), moxifloxacin (-0·07, -0·10 to -0·04), or bedaquiline (-0·14, -0·19 to -0·10). Compared with regimens without any injectable drug, amikacin provided modest benefits, but kanamycin and capreomycin were associated with worse outcomes. The remaining drugs were associated with slight or no improvements in outcomes. Treatment outcomes were significantly worse for most drugs if they were used despite in-vitro resistance. The optimal number of effective drugs seemed to be five in the initial phase, and four in the continuation phase. In these adjusted analyses, heterogeneity, based on a simulated I2 method, was high for approximately half the estimates for specific drugs, although relatively low for number of drugs and durations analyses. Although inferences are limited by the observational nature of these data, treatment outcomes were significantly better with use of linezolid, later generation fluoroquinolones, bedaquiline, clofazimine, and carbapenems for treatment of multidrug-resistant tuberculosis. These findings emphasise the need for trials to ascertain the optimal combination and duration of these drugs for treatment of this condition. American Thoracic Society, Canadian Institutes of Health Research, US Centers for Disease Control and Prevention, European Respiratory Society, Infectious Diseases Society of America.

Treatment outcome of multidrug-resistant tuberculosis in Japan \u2013 the first cross-sectional study of Japan tuberculosis surveillance data

BackgroundMultidrug resistant-tuberculosis (MDR-TB) is a major global health concern. Its treatment requires toxic medications, is longer and costlier than drug-susceptible TB, and often results in productivity losses and poor outcomes. In Japan, a TB middle-burden country, reports on treatment outcome of MDR-TB patients have only been institution-based. We thus sought to shed some light on the nationwide treatment status and outcome of MDR-TB patients in Japan.MethodsCharacteristics and treatment status and outcome of MDR-TB patients notified between 2011 and 2013 were evaluated using the data from the Japan TB Surveillance (JTBS) system. Since the treatment outcome from the surveillance data was not directly linked to any clinical records or drug susceptible test results, we also analyzed the treatment duration of MDR-TB cases in an attempt to validate our results.ResultsBetween 2011 and 2013, a total of 172 MDR-TB patients had been notified to the JTBS as MDR-TB. 68.6% (118/172) were males and 70.9% (122/172) were Japan-born – however, over the study period, the proportions of foreign-born, of those in the age group 15–64 years old and of new cases have increased. The overall treatment completion rate was 57.0%, however, when restricted to patients aged 64 years old and below, the rate improved to 71.6%. Treatment duration of 29.2% of those patients who had been recorded as “treatment completed” in fact fell short of the 540 days, the minimum duration as recommended by the Japanese guideline.ConclusionsIncreasing proportion of new cases, and of younger age groups among the MDR-TB patients indicate new transmissions. Better strategies for early detection and containment of MDR-TB are urgently needed. The overall treatment completion rate was 57.0% over the three-year study period. However, when restricting the result to those aged 64 years old and below, the rate improved to 71.6%, which was comparable to similarly industrialized countries. Due to the limitations of the JTBS data, a comprehensive survey of all MDR-TB patients may be necessary to provide more concrete evidence for decision-making.

CURRENT STRATEGIES IN THE TREATMENT OF MULTIDRUG-RESISTANT TUBERCULOSIS

Objective: The objective of the study was to analyze and review the current knowledge about the principles of treatment of multidrug-resistant tuberculosis (MDR-TB), World Health Organization treatment regimen to treat MDR-TB, mechanism of resistance, and risk factors for emergence of resistance, and novel antitubercular drugs (ATDs) available and control measures to improve treatment outcomes of MDR-TB.Methods: Various articles were reviewed from PubMed and other databases and were analyzed to write the review.Results: Mycobacterium is a largely curable infectious disease if proper treatment should be followed. The success of the treatment depends on the designing of proper treatment regimen and patient adherence to that medication.Conclusion: Mycobacterium tuberculosis is now the most lethal infectious pathogen. Drug resistance has become a major problem in the treatment of TB. In MDR-TB, the bacteria is resistant to at least isoniazid (INH) and rifampicin (RIF), and in extensively drug-resistant TB the bacteria is resistant to INH, RIF, any fluoroquinolone, and at least one of three injectable second-line drugs for TB such as kanamycin, capreomycin, and amikacin. More recently, a more worrying situation has emerged with the description of M. tuberculosis strains that have been found resistant to all antibiotics that were available for testing, a situation labeled as totally drug resistant-TB. Other reasons like poor planning by the authorities and the government may also result in the emergence of resistant strain. Rather than the effective chemotherapy and the moderately protective vaccine, new anti-TB agents, and novel controlled release nanoparticulate system like polymeric nanocarrier systems containing existing ATDs are urgently needed to decrease the global incidence of TB.

The relationship between social support, treatment interruption and treatment outcome in patients with multidrug-resistant tuberculosis in China: a mixed-methods study.

Multidrug-resistant tuberculosis (MDR-TB) has been a major threat for successful TB control. We examined the relationship between social support and treatment outcomes in MDR-TB patients and evaluated barriers to social support. Retrospective cohort study with MDR-TB patients enrolled in the Global Fund programme between 1 January 2009 and 30 June 2014 in Zhejiang, China. We reviewed all MDR-TB patients' diagnoses and treatment outcomes. In-depth interviews were conducted with 10 community health workers and 10 patients. Pathway analysis was employed to examine the association between social support and treatment outcomes, and the mediating effect of medication adherence on their relationship. Of 218 participants, 144 (66%) were successfully treated and 59 (27%) had poor treatment adherence. Directly observed therapy (DOT) had an indirect positive effect on treatment success, mediating through medication adherence (β=0.541, P=0.008; β=0.538, P<0.001). Financial support had both a direct (β=0.769, P<0.001) and an indirect positive effect on treatment success, which was mediated by a self-reported social support scale (β=0.541, P=0.008; β=0.538, P<0.001). The interviews indicated poor performance of DOT. Patients often suffered from substantial stigma, but were not provided with psychological support. DOT and financial support were effective strategies for improving successful treatment outcomes in MDR-TB patients, but they were delivered not considering patients' perspectives. There is an urgent need for consistent and specific psychological support for MDR-TB patients in their communities.

Impact of pyrazinamide resistance on multidrug-resistant tuberculosis in Karakalpakstan, Uzbekistan.

The World Health Organization (WHO) recommends the inclusion of pyrazinamide (PZA) in treatment regimens for multidrug-resistant tuberculosis (MDR-TB) unless resistance has been confirmed. To investigate the association between PZA susceptibility and MDR-TB treatment outcome among patients treated with a PZA-containing regimen and whether the duration of the intensive phase of the PZA-containing regimen affected treatment outcome. We conducted a retrospective cohort study including all eligible MDR-TB patients starting treatment in 2003-2013 in the TB programme in Karakalpakstan, Uzbekistan. PZA drug susceptibility testing (DST) using liquid culture was performed, and outcomes were classified according to the WHO 2013 definitions. Of 2446 MDR-TB patients included, 832 (34.0%) had an available baseline PZA DST result, 612 (73.6%) of whom were PZA-resistant. We found no association between treatment success and PZA susceptibility (adjusted odds ratio [aOR] 0.86, 95%CI 0.51-1.44, P = 0.6) in patients treated with PZA. Furthermore, among patients with no baseline PZA DST result, no evidence was seen of an association between treatment success and PZA treatment duration (aOR 0.86, 95%CI 0.49-1.51, P = 0.6). Treatment of MDR-TB with a standard PZA regimen does not appear to improve treatment outcomes, regardless of PZA susceptibility or duration of treatment.

Drug‐resistant tuberculosis: An update on disease burden, diagnosis and treatment

The emergence of antimicrobial resistance against Mycobacterium tuberculosis, the leading cause of mortality due to a single microbial pathogen worldwide, represents a growing threat to public health and economic growth. The global burden of multidrug-resistant tuberculosis (MDR-TB) has recently increased by an annual rate of more than 20%. According to the World Health Organization approximately only half of all patients treated for MDR-TB achieved a successful outcome. For many years, patients with drug-resistant tuberculosis (TB) have received standardized treatment regimens, thereby accelerating the development of MDR-TB through drug-specific resistance amplification. Comprehensive drug susceptibility testing (phenotypic and/or genotypic) is necessary to inform physicians about the best drugs to treat individual patients with tailor-made treatment regimens. Phenotypic drug resistance can now often, but with variable sensitivity, be predicted by molecular drug susceptibility testing based on whole genome sequencing, which in the future could become an affordable method for the guidance of treatment decisions, especially in high-burden/resource-limited settings. More recently, MDR-TB treatment outcomes have dramatically improved with the use of bedaquiline-based regimens. Ongoing clinical trials with novel and repurposed drugs will potentially further improve cure-rates, and may substantially decrease the duration of MDR-TB treatment necessary to achieve relapse-free cure.

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.