Time to sputum culture conversion and its associated factors among drug-resistant tuberculosis patients: a systematic review and meta-analysis.

OBJECTIVE: We aimed to evaluate the sputum culture conversion time of DR-TB patients and its related factors. METHODS: PubMed, The Cochrane Library, Embase, CINAHL, Web of Science, CNKI, Wan Fang, CBM and VIP databases were electronically searched to collect studies on sputum culture conversion time in patients with DR-TB. Meta-analysis was performed by using the R 4.3.0 version and Stata 16 software. RESULTS: A total of 45 studies involving 17373 patients were included. Meta-analysis results showed that the pooled median time to sputum culture conversion was 68.57 days (IQR 61.01,76.12). The median time of sputum culture conversion in patients with drug-resistant tuberculosis was different in different WHO regions, countries with different levels of development and different treatment schemes. And female (aHR = 0.59,95%CI: s0.46,0.76), alcohol history (aHR = 0.70,95%CI:0.50,0.98), smoking history (aHR = 0.58,95%CI:0.38,0.88), history of SLD use (aHR = 0.64,95%CI:0.47,0.87), BMI < 18.5 kg/m2 (aHR = 0.69,95%CI:0.60,0.80), lung cavity (aHR = 0.70,95%CI:0.52,0.94), sputum smear grading at baseline (Positive) (aHR = 0.56,95%CI:0.36,0.87), (grade 1+) (aHR = 0.87,95%CI:0.77,0.99), (grade 2+) (aHR = 0.81,95%CI:0.69,0.95), (grade 3+) (aHR = 0.71,95%CI:0.61,0.84) were the related factor of sputum culture conversion time in patients with DR-TB. CONCLUSION: Patients with DR-TB in Europe or countries with high level of economic development have earlier sputum culture conversion, and the application of bedaquiline can make patients have shorter sputum culture conversion time. Female, alcohol history, smoking history, history of SLD use, BMI < 18.5 kg/m2, lung cavity, sputum smear grading at baseline (Positive, grade 1+, grade 2+, grade 3+) may be risk factors for longer sputum culture conversion time. This systematic review has been registered in PROSPERO, the registration number is CRD42023438746.

Ceftriaxone efficacy for Mycobacterium avium complex lung disease in the hollow fiber and translation to sustained sputum culture conversion in patients.

BACKGROUND: Only 35.6%-50.8% of patients with Mycobacterium avium complex (MAC) pulmonary disease achieve sustained sputum culture conversion (SSCC) on treatment with the azithromycin-ethambutol-rifabutin standard of care (SOC). We tested the efficacy of ceftriaxone, a ß-lactam with a lung penetration ratio of 12.18-fold. METHODS: We mimicked lung concentration-time profiles of seven ceftriaxone once-daily doses for 28 days in the hollow fiber system model of intracellular MAC (HFS- MAC). Monte Carlo experiments were used for dose selection.We also compared the once-daily ceftriaxone monotherapy to three-drug SOC against five MAC clinical isolates in HFS-MAC using γ (kill)-slopes. Results were translated to SSCC rates. RESULTS: Ceftriaxone killed 1.02-3.82 log10 cfu/mL in dose-response studies. Ceftriaxone 2G once-daily was identified as the optimal dose. Ceftriaxone killed all five strains below day 0 versus 2/5 for SOC. The median γ (95% confidence interval) was 0.49(0.47-0.52) log10 cfu/mL/day for ceftriaxone and 0.38(0.34-0.43) log10 cfu/mL/day for SOC. In patients, the SOC was predicted to achieve SSCC rates of 39.3%(36%-42%) at 6 months (similar to meta-analyses results). The SOC SSCC was 50% at 8.18(3.64-27.66) months versus 3.58(2.20-7.23) months for ceftriaxone. Thus, ceftriaxone shortened time-to-SSCC 2.35-fold compared to SOC. CONCLUSION: Ceftriaxone is a promising agent for creation of short-course chemotherapy.

Prognostic accuracy of time to sputum culture conversion in predicting cure in extensively drug-resistant tuberculosis patients: a multicentre retrospective observational study.

BACKGROUND: There was a lack of information about prognostic accuracy of time to sputum culture conversion (SCC) in forecasting cure among extensively drug-resistant tuberculosis (XDR-TB) patients. Therefore, this study evaluated the prognostic accuracy of SCC at various time points in forecasting cure among XDR-TB patients. METHODS: This retrospective observational study included 355 eligible pulmonary XDR-TB patients treated at 27 centers in Pakistan between 01-05-2010 and 30-06-2017. The baseline and follow-up information of patients from treatment initiation until the end of treatment were retrieved from electronic nominal recording and reporting system. Time to SCC was analyzed by Kaplan-Meier method, and differences between groups were compared through log-rank test. Predictors of time to SCC and cure were respectively evaluated by multivariate Cox proportional hazards and binary logistic regression analyses. A p-value < 0.05 was considered statistically significant. RESULTS: A total of 226 (63.6%) and 146 (41.1%) patients respectively achieved SCC and cure. Median time to SCC was significantly shorter in patients who achieved cure, 3 months (95% confidence interval [CI]: 2.47-3.53), than those who did not (median: 10 months, 95% CI: 5.24-14.76) (p-value < 0.001, Log-rank test). Patient's age > 40 years (hazards ratio [HR] = 0.632, p-value = 0.004), baseline sputum grading of scanty, + 1 (HR = 0.511, p-value = 0.002), + 2, + 3 (HR = 0.523, p-value = 0.001) and use of high dose isoniazid (HR = 0.463, p-value = 0.004) were significantly associated with early SCC. Only SCC at 6 month of treatment had statistically significant association with cure (odds ratio = 15.603, p-value < 0.001). In predicting cure, the sensitivities of SCC at 2, 4 and 6 months were respectively 41.8% (95%CI: 33.7-50.2), 69.9% (95%CI: 61.7-77.2) and 84.9% (95%CI: 78.1-90.3), specificities were respectively, 82.8% (95%CI: 76.9-87.6), 74.6% (95%CI: 68.2-80.4) and 69.4% (95%CI: 62.6-75.5) and prognostic accuracies were respectively 65.9% (95%CI: 60.7-70.8), 72.7% (95%CI: 67.7-77.2) and 75.8% (95%CI: 71.0-80.1). CONCLUSION: In forecasting cure, SCC at month 6 of treatment performed better than SCC at 2 and 4 months. However, it would be too long for clinicians to wait for 6 months to decide about the regimen efficacy. Therefore, with somewhat comparable prognostic accuracy to that SCC at 6 month, using SCC at 4 month of treatment as a prognostic marker in predicting cure among XDR-TB patients can decrease the clinicians waiting time to decide about the regimen efficacy.

Time for culture conversion and its associated factors in multidrug-resistant tuberculosis patients at a tertiary level hospital in Peshawar, Pakistan.

Objectives: This study aimed to assess the time to sputum culture conversion (SCC) and its determinants among multidrug-resistant tuberculosis (MDR-TB) patients. Methods: This cross-sectional study was conducted from January 2019 to January 2020. A total of 252 MDR-TB patients presenting at a tertiary level teaching hospital in Peshawar, Khyber Pakhtunkhwa (KP), were included. The patient's demographic and clinical data were collected using a structured questionnaire. Time to SCC was calculated from the initiation of treatment till the patient had two consecutive negative cultures. The Cox proportional-hazards analysis was performed to check strength and association between the determinants and time for SCC. Results: Out of 252 MDR-TB patients enrolled, sputum culture conversion was observed in 76.6% of the patients by the end of six months. While, 19.0% of the patients failed to achieve negative culture and remained positive after interim report of their treatment. Age > 45 years (HR = 15.22; 95% CI: 7.27-31.83; p<0.001), female gender (6.22; 2.90-13.36; p<0.001), BMI < 18.5 kg/m2 (10.28; 5.25-20.11; p<0.001), weight loss (0.03; 0.01-0.06; p<0.001), smoking (0.10; 0.05-0.21; p<0.001), diabetes mellitus (0.02; 0.00-0.04 p<0.001) and disease severity on chest X-ray (CXR) (0.03; 0.01-0.09; p<0.001) were the significant determinants of delayed sputum culture conversion. Conclusion: MDR-TB patients with older age, low BMI, weight loss, diabetes, smokers and those with disease severity on CXR are less likely to respond to treatment as they displayed delayed SCC. Therefore, such patients should be meticulously followed up for successful management.

Depression and recovery of IL-17A secretion in mitogen responses in patients with active tuberculosis-a prospective observational study.

BACKGROUND/PURPOSE: T-helper cell 17 (Th17) is a distinct subset of CD4+ T lymphocytes that is important in the pathogenesis of Mycobacterium tuberculosis infection. This study aims to investigate the characteristics of interleukin (IL)-17A and Th17-related cytokines after stimulation with phytohemagglutinin in patients with active tuberculosis (TB). METHODS: This prospective cohort study enrolled patients with culture-confirmed active TB. QuantiFERON-TB Gold In-Tube (QFT-GIT) assay was performed upon TB diagnosis and at 2 months after TB treatment. Their non-TB-specific secretion of IL-17A and Th17-related cytokines were measured in supernatants of mitogen tubes in QFT-GIT and compared to those of active TB contacts with or without latent TB infection. We analyzed the association between IL-17A secretions and TB presentation and treatment outcomes. RESULTS: A total of 108 patients with TB and 64 non-TB cases were enrolled. The secretion of IL-17A, IL-21, IL-23, and IL-6 were lower in active TB patients upon TB diagnosis. In active TB patients, lower IL-17A secretions were associated with higher grades of sputum smear. In the multivariate analysis, lower IL-17A secretions served as an independent factor associated with 2-month culture non-conversion (odds ratio 23.04, 95% confidence interval [CI] 1.69-84.78) and on-treatment mortality (hazard ratio 28.54, 95% CI 1.30-99.25). The levels of IL-23, and IL-6 significantly increased after 2 months of anti-TB treatment. CONCLUSION: The non-TB-specific IL-17A secretions were lower in active TB patients upon TB diagnosis and associated with higher disease severity and worse treatment outcomes. Trend of recovery of the depressed Th17-related cytokines was noted after effective anti-TB treatment.

Understanding the drug exposure-response relationship of bedaquiline to predict efficacy for novel dosing regimens in the treatment of multidrug-resistant tuberculosis.

AIMS: To externally validate an earlier characterized relationship between bedaquiline exposure and decline in bacterial load in a more difficult-to-treat patient population, and to explore the performances of alternative dosing regimens through simulations. METHODS: The bedaquiline exposure-response relationship was validated using time-to-positivity data from 233 newly diagnosed or treatment-experienced patients with drug-resistant tuberculosis from the C209 open-label study. The significance of the exposure-response relationship on the bacterial clearance was compared to a constant drug effect model. Tuberculosis resistance type and the presence and duration of antituberculosis pre-treatment were evaluated as additional covariates. Alternative dosing regimens were simulated for tuberculosis patients with different types of drug resistance. RESULTS: High bedaquiline concentrations were confirmed to be associated with faster bacterial load decline in patients, given that the exposure-effect relationship provided a significantly better fit than the constant drug effect (relative likelihood = 0.0003). The half-life of bacterial clearance was identified to be 22% longer in patients with pre-extensively drug-resistant (pre-XDR) tuberculosis (TB) and 86% longer in patients with extensively drug-resistant (XDR) TB, compared to patients with multidrug-resistant (MDR) TB. Achievement of the same treatment response for (pre-)XDR TB patients as for MDR TB patients would be possible by adjusting the dose and dosing frequency. Furthermore, daily bedaquiline administration as in the ZeNix regimen, was predicted to be as effective as the approved regimen. CONCLUSION: The confirmed bedaquiline exposure-response relationship offers the possibility to predict efficacy under alternative dosing regimens, and provides a useful tool for potential treatment optimization.

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

BACKGROUND: Few 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. METHODS: This 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. RESULTS: In 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. CONCLUSIONS: MDR-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.

Time to Sputum Culture Conversion and Treatment Outcomes Among Patients with Isoniazid-Resistant Tuberculosis in Atlanta, Georgia.

BACKGROUND: Although isoniazid-resistant tuberculosis is more common than multidrug-resistant tuberculosis, it has been much less studied. We examined the impact of isoniazid resistance and treatment regimen, including use of a fluoroquinolone, on clinical outcomes. METHODS: A retrospective cohort study among patients with sputum culture-positive tuberculosis was performed. Early fluoroquinolone (FQ) use was defined as receiving ≥5 doses during the first month of treatment. The primary outcome was time to sputum culture conversion (tSCC). A multivariate proportional hazards model was used to determine the association of isoniazid resistance with tSCC. RESULTS: Among 236 patients with pulmonary tuberculosis, 59 (25%) had isoniazid resistance. The median tSCC was similar for isoniazid-resistant and -susceptible cases (35 vs 29 days; P = .39), and isoniazid resistance was not associated with tSCC in multivariate analysis (adjusted hazard ratio = 0.83; 95% confidence interval [CI], .59-1.17). Early FQ use was higher in isoniazid-resistant than -susceptible cases (20% vs 10%; P = .05); however, it was not significantly associated with tSCC in univariate analysis (hazard ratio = 1.48; 95% CI, .95-2.28). Patients with isoniazid-resistant tuberculosis were treated with regimens containing rifampin, pyrazinamide, and ethambutol +/- a FQ for a median of 9.7 months. Overall, 191 (83%) patients were cured. There was no difference in initial treatment outcomes; however, all cases of acquired-drug resistance (n = 1) and recurrence (n = 3) occurred among patients with isoniazid-resistant tuberculosis. CONCLUSIONS: There was no significant association with isoniazid resistance and tSCC or initial treatment outcomes. Although patients with isoniazid-resistant tuberculosis had a high cure rate, the cases of recurrence and acquired drug resistance are concerning and highlight the need for longer-term follow-up studies.

Comparison of Sputum-Culture Conversion for Mycobacterium bovis and M. tuberculosis.

Current US guidelines recommend longer treatment for tuberculosis (TB) caused by pyrazinamide-resistant organisms (e.g., Mycobacterium bovis) than for M. tuberculosis TB. We compared treatment response times for patients with M. bovis TB and M. tuberculosis TB reported in the United States during 2006-2013. We included culture-positive, pulmonary TB patients with genotyping results who received standard 4-drug treatment at the time of diagnosis. Time to sputum-culture conversion was defined as time between treatment start date and date of first consistently culture-negative sputum. We analyzed 297 case-patients with M. bovis TB and 30,848 case-patients with M. tuberculosis TB. After 2 months of treatment, 71% of M. bovis and 65% of M. tuberculosis TB patients showed conversion of sputum cultures to negative. Likelihood of culture conversion was higher for M. bovis than for M. tuberculosis, even after controlling for treatment administration type, sex, and a composite indicator of bacillary burden.

Early interventions for diabetes related tuberculosis associate with hastened sputum microbiological clearance in Virginia, USA.

BACKGROUND: Diabetes complicates tuberculosis (TB) treatment including a prolonged time of sputum culture conversion to negative growth. Since 2013 in Virginia, interventions early in the treatment course have used therapeutic drug monitoring and dose correction for isoniazid and rifampin after 2 weeks of TB treatment in patients with diabetes along with nurse manager initiated diabetes education and linkage to care. METHODS: A retrospective cohort study of the state TB registry was performed for patients initiating drug-susceptible pulmonary TB treatment that were matched for age, gender, chest imaging and sputum smear status to compare time to sputum culture conversion and other clinical outcomes in the pre-and post-intervention groups. RESULTS: Three hundred sixty-three patients had documented time to sputum culture conversion in the pre-and post-intervention periods, including 56 (15%) with diabetes. Seventy-four (57%) of all patients with diabetes were ≥60 years of age at treatment initiation. Twenty-six patients with diabetes were matched in each group. Mean time to sputum culture conversion in the post-intervention group was 42 ± 22 days compared to the pre-intervention group of 62 ± 31 days (p = 0.01). In the post-intervention group 21 (80%) of patients with diabetes had culture conversion by 2 months compared to 13 (50%) in the pre-intervention group (p = 0.04). CONCLUSIONS: Early interventions for diabetes related TB in the programmatic setting may hasten sputum culture conversion.

Prevalence and Impact of Diabetes Mellitus Among Patients with Active Pulmonary Tuberculosis in South Korea.

OBJECTIVE: South Korea has an increasing prevalence of diabetes and a relatively high burden of tuberculosis. We aimed to determine the prevalence of diabetes in patients with active pulmonary tuberculosis (PTB) and examine the effect of diabetes on tuberculosis treatment outcomes. SETTING AND DESIGN: Data from patients ≥30 years diagnosed with and treated for PTB between January 2010 and December 2012 at Severance Hospital, a 2000-bed tertiary referral hospital in Seoul, South Korea, were analyzed and compared with data from a contemporaneous general population sample extracted from KNHANES V. RESULTS: Diabetes prevalence was 24.2% (252/1044) among patients with PTB and 11.6% (1700/14,655) among controls. Diabetes [odds ratios (OR) 2.56, 95% confidence interval (CI) 1.56-4.21, P < 0.001], male sex (OR 1.93, 95% CI 1.08-3.44, P = 0.027), and cavitary disease (OR 2.08, 95% CI 1.29-3.35, P = 0.003) were significant risk factors for 2-month culture positivity. Diabetes was the only factor associated with unsuccessful treatment outcomes (OR 1.67, 95% CI 1.03-2.70, P = 0.039). CONCLUSION: The prevalence of diabetes was markedly higher in patients with PTB than in a sample of the general South Korean population. Diabetes may delay sputum conversion and adversely affect treatment outcomes; detection and management of diabetes in patients with PTB is crucial.

Sputum culture conversion and its predictors among drug-resistant pulmonary tuberculosis patients in eastern Ethiopia.

BACKGROUND: Evidence of time to culture conversion is used to predict the time of cure from the disease and the overall drug-resistant tuberculosis (TB) treatment duration. Even though evidence about sputum culture conversion is enormous in TB treatment, no study has yet been done in our areas, where cases are common. The study aimed to assess the time to sputum conversion and its predictors among drug-resistant TB patients from October 2013 to September 2021 in eastern Ethiopia. METHODOLOGY: A retrospective cohort study was conducted in eastern Ethiopia among 273 drug-resistant TB patients who were treated from October 2013 to September 2021 at Dire Dawa City and Harari regional treatment centres. The Kaplan-Meier method was used to estimate the median time of sputum culture conversion. Cox proportional hazards regression was employed to detect the predictors of sputum culture conversion. An adjusted hazard ratio (aHR) with 95% confidence interval (CI) was used to determine the strength and significance of the association. RESULTS: Of the 273 drug-resistant TB patients, the sputum culture of 216 (79.12%) patients became negative in a median time of 3 months (interquartile range 2-7). The time to sputum culture conversion was negatively associated with underweight (aHR 0.65 [95% CI 0.49 to 0.90]) and poor adherence (aHR 0.41 [95% CI 0.24 to 0.69]). The time to sputum culture conversion was also positively associated with patients resistant to two or more drugs (aHR 1.58 [95% CI 1.07 to 2.32]) and patients receiving a short treatment regimen (aHR 2.24 [95% CI 1.10 to 2.55]). CONCLUSIONS: A shorter culture conversion rate was observed compared with the median time recommended by the World Health Organization. Being underweight, poor adherence to treatment, resistance to two or more drugs and receiving a short treatment regimen were found to be predictors of time to sputum culture conversion. Implementing nutrition assessment, counselling and support of drug adherence may improve sputum culture conversion.

Impact of isoniazid monoresistance on overall and vulnerable patient populations in Taiwan.

Isoniazid is an early bactericidal anti-tuberculosis (TB) agent and isoniazid mono-resistance TB is the most prevalent drug-resistant TB worldwide. Concerns exist regarding whether resistance to isoniazid would lead to delayed culture conversion and worst outcomes. From January 2008 to November 2017, adult culture-positive pulmonary TB patients receiving isoniazid, rifampicin, pyrazinamide, and ethambutol were identified through Taiwan Center for Disease Control database and were followed until the end of 2017. Primary outcomes included time to sputum culture conversion (SCC) within two months. Secondary outcomes included death and unfavourable outcomes at the end of 2nd month. A total of 37,193 drug-susceptible and 2,832 isoniazid monoresistant pulmonary TB patients were identified. Compared with no resistance, isoniazid monoresistance was not associated with a delayed SCC (HR: 0.99, 95% CI: 0.94─1.05, p = 0.8145), a higher risk of 2-month mortality (HR: 1.19, 95% CI: 0.92─1.53, p = 0.1884), and unfavourable outcomes at 2nd month (OR: 1.05, 95% CI: 0.97─1.14, p = 0.2427). Isoniazid monoresistance was associated with delayed SCC (HR: 0.90, 95% CI: 0.83─0.98, p = 0.0099) and a higher risk of unfavourable outcomes (OR:1.18, 95% CI: 1.05─1.32, p = 0.0053) in patients aged between 20 and 65, and delayed SCC in patients without underlying comorbidities (HR: 0.90, 95% CI: 0.81─0.98, p = 0.0237). Isoniazid mono-resistant TB had a comparable outcome with drug-susceptible TB at the end of the intensive phase. Healthy, and non-elderly patients were more likely to had culture persistence, raising concerns about disease transmission in these subgroups and warranting early molecular testing for isoniazid resistance.

Efficacy and safety of the all-oral bedaquiline-containing regimen as treatment for pediatric multidrug/rifampicin-resistant tuberculosis: a multicenter, retrospective, cohort study.

OBJECTIVE: The study aimed to observe the efficacy and safety of an all-oral bedaquiline (BDQ)-containing regimen for pediatric multidrug/rifampicin-resistant tuberculosis (MDR/RR-TB) through a multicenter, retrospective study in China. METHODS: In the study, pediatric patients receiving all-oral BDQ-containing regimen (BDQ group) with clinical matched control group were included, the control group received an injection-containing regimen. The treatment outcomes and the incidence of adverse events (AEs) were compared and analyzed. RESULTS: 79 pediatric patients were enrolled, including 37 cases in BDQ group and 42 cases in the control group, the median age was 12 {8-16} and 11 {9-15} in both groups respectively. Favorable treatment outcome and cure rate in BDQ group were significantly higher than those in control group (100%vs 83.3%, p 0.03; 94.6%vs 63.3%, p 0.00). Median time of sputum culture conversion in BDQ group was significantly shorter than that in the control group (4 weeks vs 8 weeks, p 0.00). The incidence of AEs in the BDQ group was significantly less than that in the control group (48.6% vs 71.4%, p 0.03). No AEs leading to treatment discontinuation of BDQ occurred. CONCLUSIONS: The all-oral BDQ-containing regimens may be effective and safe in the Chinese pediatric population.

Metformin reduces the risk of poor treatment outcomes among individuals with rifampicin-resistant tuberculosis and type-2 diabetes mellitus.

We conducted a retrospective cohort study among individuals with rifampicin-resistant tuberculosis and diabetes to determine the association between metformin use and tuberculosis treatment outcomes. We found that individuals with metformin use had a significantly lower risk of poor tuberculosis treatment outcomes (adjusted RR=0.25, 95%CI 0.06 - 0.95) compared to those without.

The effect of undernutrition on sputum culture conversion and treatment outcomes among people with multidrug-resistant tuberculosis: a systematic review and meta-analysis.

OBJECTIVES: We aimed to evaluate the effect of undernutrition on sputum culture conversion and treatment outcomes among people with multidrug-resistant tuberculosis (MDR-TB). METHODS: We searched for publications in the Medline, Embase, Scopus, and Web of Science databases. We conducted a random-effect meta-analysis to estimate the effects of undernutrition on sputum culture conversion and treatment outcomes. Hazard ratio (HR) for sputum culture conversion and odds ratio (OR) for end-of-treatment outcomes, with 95% CI, were used to summarize the effect estimates. Potential publication bias was checked using funnel plots and Egger's tests. RESULTS: Of the 2358 records screened, 63 studies comprising a total of 31,583 people with MDR-TB were included. Undernutrition was significantly associated with a longer time to sputum culture conversion (HR 0.7, 95% CI 0.6-0.9, I2 = 67·1%), and a higher rate of mortality (OR 2.8, 95% CI 2.1-3.6, I2 = 21%) and unsuccessful treatment outcomes (OR 1.8, 95% CI 1.5-2.1, I2 = 70%). There was no significant publication bias in the included studies. CONCLUSION: Undernutrition was significantly associated with unsuccessful treatment outcomes, including mortality and longer time to sputum culture conversion among people with MDR-TB. These findings have implications for supporting targeted nutritional interventions alongside standardized TB drugs.

Acquired drug resistance during the turnaround time for drug susceptibility testing impacts outcome of tuberculosis.

BACKGROUND: The impacts of acquired resistance to first-line drugs other than rifampicin during turnaround time (TAT) for drug susceptibility testing (DST) on tuberculosis (TB) treatment are unclear. METHOD: We performed a prospective cohort study to test acquired resistance to isoniazid, ethambutol and pyrazinamide during TAT for DST as risk factors for prolonged time to sputum culture conversion (SCC) and treatment failure in China. Participants included had a baseline DST result for a Mycobacterium tuberculosis (Mtb) isolate collected at TB diagnosis and a follow-up DST result for a Mtb isolate collected upon baseline DST results availability. Acquired drug resistance was identified by comparing baseline and follow-up DST results. RESULTS: This study included 65 patients with acquired resistance Mtb isolates and 130 patients with consistent drug susceptibility profiles. Cox proportional hazard regression analysis demonstrated acquired isoniazid resistance (aHR 0.50, 95%CI: 0.29-0.85) and acquired pyrazinamide resistance (aHR 0.54, 95%CI: 0.36-0.81) were associated with prolonged time to SCC. Moreover, acquired isoniazid resistance (aOR 7.64, 95%CI: 2.39-16.08) and acquired pyrazinamide resistance (aOR 5.71, 95%CI: 2.31-14.12) were independently associated with treatment failure. CONCLUSION: Acquired resistance to isoniazid and/or pyrazinamide during TAT for DST was associated with prolonged time to SCC as well as treatment failure.

Comparative effectiveness of individualized longer and standardized shorter regimens in the treatment of multidrug resistant tuberculosis in a high burden country.

Objective: To compare the effectiveness of second line injectables containing shorter (duration 9-12 months) and longer treatment regimens (LTR, duration ≥ 20 months) among multidrug-resistant tuberculosis (MDR-TB) patients with no documented resistance and history of treatment with any second-line anti-TB drug (SLD) for ≥ 1 month. Methods: This was an observational cohort study of MDR-TB patients treated at eight PMDT units in Pakistan. Patients' data from baseline until treatment outcomes were collected from Electronic Nominal Recording and Reporting System. The treatment outcomes of "cured" and "treatment completed" were grouped together as successful, whereas "death," "treatment failure," and "lost to follow-up" were collectively grouped as unsuccessful outcomes. Time to sputum culture conversion (SCC) was analyzed using the Kaplan-Meier method and the differences between groups were compared through the log-rank test. Multivariate Cox proportional hazards and binary logistic regression analyses were used to find predictors of time to SCC and unsuccessful treatment outcomes. A p-value < 0.05 was considered statistically significant. Results: A total 701 eligible MDR-TB patients [313 treated with shorter treatment regimen (STR) and 388 treated with LTR at eight centres in Pakistan were evaluated]. Time to achieve SCC was significantly shorter in STR group [mean: 2.03 months, 95% confidence interval (CI):1.79-2.26] than in LTR group (mean: 2.69 months, 95% CI: 2.35-3.03) (p-value<0.001, Log-rank test). Treatment success was higher in STR (83.7%) than in LTR (73.2%) group (p-value <0.001) due to high cure (79.9% vs. 70.9%, p-value = 0.006) and low death (9.9% vs. 18.3%, p-value = 0.002) rates with STR. Treatment with STR emerged the only predictor of early SCC [adjusted Hazards ratio (aHR) = 0.815, p-value = 0.014], whereas, patient's age of 41-60 (OR = 2.62, p-value<0.001) and >60 years (OR = 5.84, p-value<0.001), baseline body weight of 31-60 (OR = 0.36, p-value = 0.001) and >60 kg (OR = 0.23, p-value <0.001), and treatment with LTR (OR = 1.88, p-value = 0.001) had statistically significant association with unsuccessful treatment outcomes. Conclusion: STR exhibited superior anti-microbial activity against MDR-TB. When compared LTR, treatment with STR resulted in significantly early SCC, high cure, and lower death rates among MDR-TB patients who had no documented resistance and history of treatment with any SLD ≥ 1 month.

Standard versus high dose of rifampicin in the treatment of pulmonary tuberculosis: a systematic review and meta-analysis.

OBJECTIVES: A growing amount of evidence suggests that the rifampicin dosing currently recommended for tuberculosis treatment could be associated with inadequate exposure and unfavourable outcomes. We aimed to compare clinical and microbiological efficacy and safety outcomes of standard and higher rifampicin dosing. METHODS: Data sources were MEDLINE, Google Scholar and the Cochrane Library. This was a systematic review and meta-analysis that included experimental or observational studies comparing 8-week sputum culture conversion, treatment failure, or safety outcomes in naïve patients with pulmonary tuberculosis treated with standard (10 mg/kg) or higher doses of rifampicin. RESULTS: Of a total of 9683 citations screened, eight randomized controlled trials were included, accounting for 1897 subjects; the risk of bias was low in three studies, high in two and intermediate in three. At week 8 a higher proportion of patients in the high-dose group obtained a sputum culture conversion than those in the standard dose group (83.7% versus 80.6%, RR 1.06; 95%CI 1.01-1.12, p 0.028); this result was confirmed in the sub-analysis including patients treated with a rifampicin dose of ≥20 mg/kg, but not in those treated with 11-19 mg/kg. Events of treatment failure at end of treatment showed no significant difference between the two groups (RR 0.84; 95%CI 0.59-1.21, p 0.362). In the analysis evaluating safety outcome, the difference in the occurrence of a grade 3 or 4 liver toxicity or adverse drug reactions leading to discontinuation was not significant at the statistical analysis among the groups (7.2% versus 5.4%, RR 1.19; 95%CI 0.81-1.73, p 0.370, and 1.5% versus 0.6%, RR 2.31; 95%CI 0.65-8.21, p 0.195, respectively). No statistical heterogeneity among studies was observed for each outcome. CONCLUSIONS: High doses of rifampicin were associated with an increased rate of sputum culture conversion at 8 weeks of treatment, particularly in patients receiving ≥20 mg/kg.

Treatment Outcomes of Extensively Drug-Resistant Tuberculosis in Pakistan: A Countrywide Retrospective Record Review.

Background: The current study is conducted with the aim to the fill the gap of information regarding treatment outcomes and variables associated with unsuccessful outcome among XDR-TB patients from Pakistan. Methods: A total of 404 culture confirmed XDR-TB patients who received treatment between 1st May 2010 and June 30, 2017 at 27 treatment centers all over Pakistan were retrospectively followed until their treatment outcomes were reported. A p-value <0.05 reflected a statistical significant association. Results: The patients had a mean age 32.9 ± 14.1 years. The overall treatment success rate was 40.6% (95% confidence interval [CI]:35.80-45.60%). A total of 155 (38.4%) patients were declared cured, 9 (2.2%) completed treatment, 149 (36.9%) died, 60 (14.9%) failed treatment and 31 (7.7%) were lost to follow up (LTFU). The results of the multivariate binary logistic regression analysis revealed that the patients' age of >60 years (OR = 4.69, 95%CI:1.57-15.57) and receiving high dose isoniazid (OR = 2.36, 95%CI:1.14-4.85) had statistically significant positive association with death, whereas baseline body weight >40 kg (OR = 0.43, 95%CI:0.25-0.73) and sputum culture conversion in the initial two months of treatment (OR = 0.33, 95%CI:0.19-0.58) had statistically significant negative association with death. Moreover, male gender had statistically significant positive association (OR = 1.92, 95%CI:1.04-3.54) with LTFU. Conclusion: The treatment success rate (40.6%) of XDR-TB patients in Pakistan was poor. Providing special attention and enhanced clinical management to patients with identified risk factors for death and LTFU in the current cohort may improve the treatment outcomes.