GYRB - POLYMERASE CHAIN REACTION AND HISTOPATHOLOGIC CHARACTERISTIC FIGURE POTENTIAL FOR DETERMINING DIAGNOSIS OF TUBERCULOUS LYMPHADENITIS.

Background: TB lymphadenitis is still a problem that needs serious treatment. In Indonesia, it was reported that 53% of TB cases were extrapulmonary tuberculosis, with the most cases being Lymphadenitis TB, 11.6%. In children, 43% of extrapulmonary tuberculosis cases are TB lymphadenitis. Diagnosis is quite difficult; a method of determining the diagnosis and appropriate comprehensive treatment is required in managing TB Lymphadenitis. Materials and Methods: In this study, 15 fine needle aspiration biopsy aspirate samples were subjected to molecular examination using the gyrB-polymerase chain reaction method and histopathological observations using the smear method with hematoxylin-eosin staining. Observation of preparations using a microscope with a magnification of 200x. Results: The histopathological characteristics of the fine needle aspiration biopsy aspirate showed positive results in 4 out of 15 samples, with epithelioid cells arranged in a characteristic granuloma structure, necrotic debris was visible, and cells joined together to form multinucleated giant cells as an inflammatory response to Mycobacterium tuberculosis complex infection. In this study, 6 out of 15 (40%) were detected to be positive in the diagnosis based on molecular detection using a specific target gene gyrB - polymerase chain reaction . Conclusion: Characteristic features on histopathological examination associated with gyrB - positive polymerase chain reaction on lymphadenitis fine needle aspiration biopsy aspirate samples can be used as a determinant diagnosis of tuberculous lymphadenitis.

Baseline glycated hemoglobin and potassium level correlated with pretreatment QT-corrected interval among patients with diabetic drug-resistant tuberculosis.

Background: Bedaquiline is a core drug with an optimized background regimen for treating drug-resistant tuberculosis (DR-TB) patients. One of the adverse effects of bedaquiline is QT-corrected (QTc) interval prolongation. TB patients with diabetes mellitus (DM) are more likely to develop QTc interval prolongation during TB treatment than those without DM. This study aimed to correlate baseline electrolyte levels (potassium, calcium, and magnesium), thyroid-stimulating hormone (TSH), body mass index (BMI), blood glucose, glycated hemoglobin (HbA1c), and pretreatment QTc interval among patients with diabetic DR TB who received regimens containing bedaquiline. Methods: It was a prospective study with a cross-sectional design. Blood samples, BMI, and electrocardiogram were collected at baseline before starting the regimen for DR-TB. Pearson correlation was used to correlate between baseline electrolyte level, TSH, BMI, complete blood count, blood glucose, HbA1c, and pretreatment QTc interval. Results: Seventy-two DR-TB patients met the inclusion criteria, half with DM. The blood glucose and HbA1c were significantly higher in patients with DM. Pretreatment QTc interval was similar between the two groups. Levels of calcium, magnesium, TSH, blood glucose, and BMI were not correlated with pretreatment QTc interval. There was a correlation between baseline potassium and HbA1c levels with pretreatment QTc interval (P < 0.05; r = 0.357 and r = -0.376, respectively). Baseline potassium level correlates with the pretreatment QTc interval in those without DM. Conclusion: Baseline HbA1c and potassium levels correlate with pretreatment QTc interval among DR-TB patients with DM. Our study indicates the importance of monitoring HbA1c and potassium levels during DR-TB therapy containing bedaquiline for early detection of QTc prolongation.

Mental Health Status and Its Associated Factors Related to Pulmonary Tuberculosis Patients in Primary Health Care Centre in Surabaya, Indonesia.

BACKGROUND: Mental disorders in TB patients are due to long-term treatment, drug side effects, and relapse. This study aimed to analyse the mental health status among TB patients and its associated factors. METHODS: The study was carried out on 107 Pulmonary TB patients from 5 Primary Healthcare centres in Surabaya, Indonesia. Furthermore, Mental Health Inventory (MHI-18) was used to measure the mental health status. The MHI-18 has four subscales including, anxiety, depression, behaviour control, and positive affection. In addition, the score range of MHI and its subscales is 0-100, where the higher score showed a better mental health status. RESULTS: The results showed no difference in the score of mental health status, anxiety, depression, and positive affect in all factors. However, behaviour control depicted a significant difference between sex and marital status. In conclusion, mental health problems can occur in all TB patients irrespective of their characteristics. CONCLUSION: Screening is required for the prevention of severe disease in the early treatment phase and various factors related to mental health should be considered during the implementation of TB management to optimize treatment outcomes.

Favorable outcome of individual regimens containing bedaquiline and delamanid in drug-resistant tuberculosis: A systematic review.

Background: Drug-resistant tuberculosis (DR-TB) is a public health concern that is difficult to treat, requiring long and complex treatment with highly effective drugs. Bedaquiline and/or delamanid have already shown promising outcomes in patients with DR-TB, increasing the rate of culture conversion and lowering TB-related mortality. Methods: We comprehensively searched and evaluated the effectiveness of individual regimens containing bedaquiline and delamanid on culture conversion and treatment success. We assessed for quality either observational or experimental studies. Results: We identified 14 studies that met the inclusion criteria using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses flowchart with 12 observational and 2 experimental studies. Of 1691 DR-TB patients enrolled in the included studies, 1407 of them concomitantly received regimens containing bedaquiline and delamanid. Overall multidrug resistant (MDR), preextensively drug resistant (XDR), and XDR-TB were seen in 21.4%, 44.1%, and 34.5%, respectively. Of 14 studies, 8 of them reported favorable outcomes including sputum culture conversion and cure rate at the end of treatment, meanwhile 6 studies only reported sputum culture conversion. Sputum culture conversion at the end of the 6th month was 63.6%-94.7% for observational studies, and 87.6%-95.0% for experimental studies. The favorable outcome at the end of treatment was 67.5%-91.4%. With high pre-XDR and XDR cases among DR-TB patients with limited treatment options, regimens containing bedaquiline and delamanid provide successful treatment. Conclusion: In DR-TB patients receiving regimens containing bedaquiline and delamanid, favorable outcomes were high including sputum conversion and cure rate.

Characteristics of Previous Tuberculosis Treatment History in Patients with Treatment Failure and the Impact on Acquired Drug-Resistant Tuberculosis.

Tuberculosis (TB) treatment failure is a health burden, as the patient remains a source of infection and may lead to the development of multi-drug resistance (MDR). Information from cases of treatment failure that develop into MDR, which is related to a history of previous TB treatment, in accordance with the pharmacokinetic aspect, is one important thing to prevent TB treatment failure and to prevent drug resistance. This was an observational descriptive study in an acquired MDR-TB patient who had a prior history of treatment failure. A structured questionnaire was used to collect information. The questionnaire consisted of a focus on the use of TB drug formulas during the treatment period, as well as when and how to take them. This study included 171 acquired MDR-TB patients from treatment failure cases. An amount of 64 patients received the separated TB drug, and 107 patients received the fixed dose combination (FDC) TB drug. An amount of 21 (32.8%) patients receiving separated TB drug and six (5.6%) patients receiving FDC TB drug took their drug in divided doses. In addition, three (4.7%) patients receiving separated TB drug and eight (7.5%) patients receiving FDC TB drug took their drug with food. An amount of 132 out of 171 (77.2%) patients had a history of incorrect treatment that developed into MDR-TB. Education on how to take the correct medication, both the separate version and the FDC TB drug, according to the pharmacokinetic aspect, is important before starting TB treatment.

Development of population pharmacokinetics model and Bayesian estimation of rifampicin exposure in Indonesian patients with tuberculosis.

BACKGROUND: Interindividual variability in the pharmacokinetics (PK) of anti-tuberculosis (TB) drugs is the leading cause of treatment failure. Herein, we evaluated the influence of demographic, clinical, and genetic factors that cause variability in RIF PK parameters in Indonesian TB patients. METHODS: In total, 210 Indonesian patients with TB (300 plasma samples) were enrolled in this study. Clinical data, solute carrier organic anion transporter family member-1B1 (SLCO1B1) haplotypes *1a, *1b, and *15, and RIF concentrations were analyzed. The population PK model was developed using a non-linear mixed effect method. RESULTS: A one-compartment model with allometric scaling adequately described the PK of RIF. Age and SLCO1B1 haplotype *15 were significantly associated with variability in apparent clearance (CL/F). For patients in their 40s, each 10-year increase in age was associated with a 10% decrease in CL/F (7.85 L/h). Patients with the SLCO1B1 haplotype *15 had a 24% lower CL/F compared to those with the wild-type. Visual predictive checks and non-parametric bootstrap analysis indicated good model performance. CONCLUSION: Age and SLCO1B1 haplotype *15 were significant covariates of RIF CL/F. Geriatric patients with haplotype *15 had significantly greater exposure to RIF. The model could optimize TB pharmacotherapy through its application in therapeutic drug monitoring (clinical trial no. NCT05280886).

The Profile of Multidrug Tuberculosis Regimen and Treatment Outcomes in Pulmonary MDR-TB Patients at the Tertiary Referral Hospital Dr. Soetomo, East Java, Indonesia: A Seven-Year Retrospective Study on Bedaquiline.

BACKGROUND: The use of bedaquiline has been reported to minimize the number of lost to follow-up and fewer rejections from the patients. This study is the first to depict the use of bedaquiline. It aims to provide information related to the profile of the MDR-TB drug regimen in the last 7 years with the treatment outcomes of pulmonary MDR-TB patients at a tertiary referral hospital in East Java. METHODS: This study was a retrospective, descriptive, and data analysis on 1053 pulmonary MDR-TB patients in tertiary referral hospital Dr Soetomo, East Java, Indonesia, with the SPSS software version 25 and Microsoft Excel 2021. RESULTS: The study analyzed the  MDR-TB treatment regimen following the latest guidelines from WHO (2020) at a tertiary referral hospital in East Java. This study shows that a bedaquiline-containing regimen started in January 2015 to July 2022 with the percentage of distribution (1, 3, 11, 4, 18, 13, 29, 21)% consecutively in the regimen. The treatment outcome profile of MDR-TB patients shows the average percentage of cured (15%), died (12%), lost-to-follow-up cases (27%), moved to an individualized regimen or a different health facility (42%), and currently in the evaluation stage (4%). Overall from January 2017 to July  2022, the number of LTFU cases decreased (42, 46, 29, 19, 8, 4)%. However, the cured case fluctuated between 2017-2022 (16, 28, 26, 32)%  respectively after Bdq started to be included in the regimen regularly for treating RR/MDR-TB. CONCLUSION: After seven years of study, we revealed an association between adding bedaquiline to the regimen and the treatment success and decreasing lost-to-follow-up cases.

Scoping review: QT interval prolongation in regimen containing bedaquiline and delamanid in patients with drug-resistant tuberculosis.

Background: A regimen containing bedaquiline-delamanid is recommended in management of drug-resistant tuberculosis (DR TB) to increase a success rate. However, this regimen was rare in a clinical setting due to a potential risk of QT prolongation. Several studies have reported the incidence of QT prolongation after administration of this regimen, but the results are inconsistent due to different sample size, study design, and covariate. The aim of this review is to summarize and analyze the published articles related to QT prolongation of bedaquiline and delamanid in PubMed and ScienceDirect databases using a scoping review. Methods: This scoping review was conducted under PRISMA for scoping review. The outcomes of this review were incidence of QT prolongation and death. We found 8 articles to be included in this review. Results: The incidence of QT prolongation was higher for DR TB patients who received a regimen containing bedaquiline and delamanid. However, this review found no clinical symptoms, such as cardiac arrhythmias, torsade de pointes, or even death. DR TB patients, especially the elderly, were at risk for QT prolongation. Special consideration in patients with HIV and low level of potassium should be closely monitored for QT interval. Conclusion: The regular measurement of electrocardiography was highly recommended to evaluate QT interval. Generally, the use of individualized regimen containing bedaquiline and delamanid is relatively safe in DR TB patients.

Line probe assay test in new cases of tuberculosis with rifampicin resistance not detected by Xpert MTB/RIF.

Background: In Indonesia, the National guideline for tuberculosis only recommended taking the DST to check INH resistance only for re-treatment cases of rifampicin-susceptible TB (RS-TB) detected by Xpert MTB/RIF. This study was conducted mainly to evaluate the proportion of isoniazid resistance in new cases of RS-TB according to the Xpert MTB/RIF. Methods: This was an observational descriptive study in RS-TB new patients diagnosed by Xpert MTB/RIF. Sputum samples were examined using first-line LPA and evaluated by culture-based DST. Results of first-line LPA and culture-based DST were compared and presented. Results: Fifty-four new cases of RS-TB (according Xpert MTB/RIF) were enrolled in this study. INH resistance was detected in 4 (7.4%) using FL-LPA and in 5 (9.3%) using culture-based DST. RIF resistance was also found in 1 (1.9%) using FL-LPA and in 2 (3.7%) using culture-based DST. Ethambutol resistance was also detected in 4 (7.4%) using culture-based DST. Conclusion: First-line LPA successfully revealed 4 (7.4%) of Hr-TB in new RS-TB cases detected by the Xpert MTB/RIF. In new cases with RS-TB detected by the Xpert MTB/RIF, FL- LPA can be used as rapid molecular DST to detect RIF and INH resistance followed by culture-based DST to examine other drug resistance.

Proposed Algorithm for Integrated Management of TB-SARS-CoV-2 Co-Infection in a TB-Endemic Country.

Tuberculosis (TB) and COVID-19 have become significant health problems globally, especially in countries with high prevalence. Therefore, this research aims to examine all possibilities and predict the impact of TB-SARS-CoV-2 co-infection to anticipate the cascade effect of both diseases in all sectors. The conceptual strategy of the algorithm in TB-COVID-19 is needed to create an integrated management system. It includes the stages of early detection with accurate and effective methods, as well as the synchronization of TB-COVID-19 health services, starting from primary health facilities to secondary and tertiary referral centers. The algorithm in TB-COVID-19 is crucial to prepare future strategies for PTB co-infection viral respiratory infections other than SARS-CoV-2, ILI, ARI, and SARI. Since the implementation involves all health services, there is a need to integrate the governance of TB-COVID-19 and other comorbidities in good health services based on research and multicentre design.

Treatment Outcomes of Multidrug-Resistant Tuberculosis Patients in East Java, Indonesia: A Retrospective Cohort Analysis.

Background: The drug regimen for the treatment of multidrug-resistant tuberculosis (MDR-TB) has lower potency, is more costly, and has a greater risk of adverse effects than first-line anti-TB drugs. We aimed to compare the treatment outcomes of patients using standard shorter regimen (STR regimen) versus bedaquiline (BDQ)-containing individual regimen in a high TB-burden setting. Methods: This was a retrospective cohort study using secondary data from the medical records in the hospital. The study population were patients with MDR-TB who started treatment in 2016-2018. Treatment outcomes were classified as successful (cured/completed treatment) or unsuccessful (failure/death/loss to follow-up/not evaluated). Categorical data were presented as frequencies and percentage, whereas continuous data were presented as mean± standard deviations. Risk ratio (RR) was obtained by using the Chi-square statistical test with 95% confidence interval (CI) and P < 0.05 set as a significant result. Results: We included 99 patients out of 444 registered patients in 2016-2018. The overall success proportion was 41.4%. Success was more likely in patients who received BDQ regimen than those receiving STR regimen (52.9% vs. 35.4%, RR: 1.496, 95% CI: 0.948-2.362). Factors that influenced the treatment outcomes were smear status and sputum culture status. Conclusions: The success rate of the STR regimen and the BDQ regimen in this study is still below the national and global figures due to the high rate of lost to follow-up. The success was higher in the BDQ regimen, although not statistically significant. Further research is needed on adverse effects, quality of life, and costs during treatment.

Prolonged ICU Stay in Severe and Critically-Ill COVID-19 Patients Who Received Convalescent Plasma Therapy.

Background: Convalescent plasma administration in severe and critically-ill COVID-19 patients have been proven to not provide improvement in patients' outcome, yet it is still widely used in countries with limited resources due to its high availability and safety. This study aims to investigate its effects on ICU mortality, ICU length of stay (LoS), and improvement of oxygen support requirements. Methods: Data of all severe and critically-ill patients in our COVID-19 ICU was collected retrospectively between May and November 2020. We dichotomized the variables and compared outcome data of 48 patients, who received convalescent plasma to 131 patients, receiving standard of care. Data were analyzed using multiple logistic regression to make prediction models of mortality, length of stay, and oxygen support device requirement. Result: Overall mortality rate in our COVID-19 ICU was 55.3%, with a median overall length of stay of 8 (4-11) days. Less patients that received convalescent plasma presented with the need for mechanical ventilation on ICU admission (p < 0.001), but with comparable PaO2 to FiO2 (P/F) ratio (p=0.95). Factors that confounded mortality were obesity (aOR = 14.1; 95% CI (1.25, 166.7); p=0.032), mechanical ventilation (aOR = 333; 95% CI (4.5,1,000); p < 0.001), higher neutrophil-to-lymphocyte ratio (NLR) (aOR = 7.32; 95% CI (1.82, 29.4); p=0.005), and lower P/F ratio (aOR = 7.70; 95% CI (2.04, 29.4); p=0.003). ICU LoS was longer in patients, who had prior history of hypertension (aOR = 2.14; 95% CI (1.05, 4.35); p=0.036) and received convalescent plasma (aOR = 3.88; 95% CI (1.77, 8.05); p < 0.001). Deceased patients, who received convalescent plasma, stayed longer in the ICU with a mean length of stay of 12.87 ± 5.7 days versus 8.13 ± 4.8 days with a significant difference (U = 434; p < 0.000). The chance of improved oxygen support requirements was lower in obese patients (aOR = 9.18; 95%CI (2.0, 42.1); p < 0.004), mechanically ventilated patients (aOR = 13.15; 95% CI (3.75, 46.09); p < 0.001), patients with higher NLR (aOR = 2.5; 95% CI (1.07, 5.85); p=0.034), and lower P/F ratio (aOR = 2.76; 95% CI (1.1, 6.91); p=0.031). Conclusion: The length of stay of patients in the convalescent plasma group was significantly longer than the control group. There was no effect of convalescent plasma in ICU mortality and no improvement was observed in terms of oxygen support requirements.

The Role of Simple Blood Tests and a Modified Chest X-Ray Scoring System in Assessing the Severity Disease and Mortality Risk in COVID-19 Patients in a Secondary Hospital, Indonesia.

Background: Coronavirus disease 2019 (COVID-19) has resulted in millions of mortality cases and significant incremental costs to the healthcare system. Examination of CRP and D-dimer were considered to have higher costs, and the use of simple hematological parameters such as lymphocyte, neutrophil, and white blood cell (WBC) which have more affordable costs would be cost-saving. Radiological imaging complements clinical evaluation and laboratory parameters for managing COVID-19 patients. Therefore, categorizing patients into severe or non-severe becomes more defined, allowing for earlier interventions and decisions of hospital admission or being referred to a tertiary hospital. Purpose: To evaluate the variables correlated with poor outcomes in COVID-19 patients. Patients and Methods: This was a retrospective study on COVID-19 patients in a secondary referral hospital in treating COVID-19 in Indonesia. Demographic, clinical data, laboratory parameters, CXR (analyzed using a modified scoring system), and prognosis were collected through electronic nursing and medical records. Results: This study included 476 hospitalized COVID-19 patients. Severe patients were commonly found with older age (median of 57 vs 40), dyspnea (percentage of 85.2% vs 20.5%), higher CXR score (median of 7 vs 5), higher levels of neutrophil (median of 79.9 vs 68.3), and lower lymphocyte levels (median of 13.4 vs 22.7), compared to non-severe patients. These variables were known to increase the odds of severe disease. Older age (median of 57 vs 48), SpO2 <94% room air (percentage of 87.4% vs 31.5%), higher CXR score (median of 8 vs 5), and higher respiratory rate (median of 25 vs 20) were found higher in death patients and were known to increase the odds of death outcome. Conclusion: The simple blood tests (neutrophil and lymphocyte) and modified CXR scoring system are useful in risk stratification for severe disease and mortality in COVID-19 patients to decide the earlier interventions and treatment.

Comparison Epidemiology between Tuberculosis and COVID-19 in East Java Province, Indonesia: An Analysis of Regional Surveillance Data in 2020.

Tuberculosis and COVID-19 are among the infectious diseases that constitute a public health concern. Therefore, this study aims to examine the recent epidemiology of tuberculosis and COVID-19 in East Java Province, Indonesia, in 2020. Case-based surveillance data were acquired with a retrospective design between January and December 2020 by the East Java Health Officer. The data were analyzed using Quantum Geographic Information System (QGIS) for mapping, and Microsoft Excel for recording. Furthermore, the statistical analysis (Spearman correlation test) was carried out via Statistical Package for Social Science (SPSS) applications. A total number of 38,089 confirmed cases of tuberculosis was recorded, with an incidence rate of 95.49/100,000 population, a case fatality rate (CFR) of 3.6%, and an average treatment success rate of 87.78%. COVID-19 is a new viral disease, with a total of 84,133 confirmed COVID-19 cases in East Java, with an incidence rate of 232.9/100,000 population. The highest incidence rate was found in Mojokerto city, while the lowest was found in Sampang. Furthermore, the CFR values of tuberculosis and COVID-19 were 1.4% and 6.8%, respectively. The regional survey in East Java Province showed that the incidence of tuberculosis remains high. This indicated that the search for active cases and preventive promotion was not completed. Therefore, inter-sectoral collaboration can be adapted to provide suitable tuberculosis health care.

Moxifloxacin concentration correlate with QTc interval in rifampicin-resistant tuberculosis patients on shorter treatment regimens.

Background: Drug-resistant tuberculosis (DR-TB) continues to be a global threat. Moxifloxacin is one of the components of the shorter treatment regimen which is suspected to increase the risk of QT prolongation, although it is also likely to be the most effective against DR-TB. A study to evaluate the correlation between the concentration of moxifloxacin and QTc interval in RR-TB patients who received shorter regimens is needed. Methods: This was an observational study in 2 groups of RR-TB patients on shorter treatment regimens (intensive phase and continuation phase), contain moxifloxacin with body weight-adjusted dose. Blood samples were collected at 2 h after taking the 48th-hour dose and 1 h before taking the 72nd-hour dose. Results: Forty-five RR-TB patients were included in this study. At 2 h after taking the 48th-hour dose, the mean of QTc interval in intensive phase and continuation phase was 444.38 ms vs. 467.94 ms, p = 0.026, while mean of moxifloxacin concentration in intensive phase and continuation phase was 4.3 µg/mL vs. 4.61 µg/mL, p = 0.686). At 1 h before taking the 72nd-hour dose, both moxifloxacin concentration and QTc interval in intensive phase and continuation showed no significant difference with p-value of 0.610 and 0.325, respectively. At 2 h after taking the 48th-dose, moxifloxacin concentration did not correlate with QTc interval, both in intensive phase (p = 0.576) and in continuation phase (p = 0.691). At 1 h before taking the 72nd-hour dose, moxifloxacin concentration also did not correlate with QTc interval in intensive phase (p = 0.531) and continuation phase (p = 0.209). Conclusions: Our study found that moxifloxacin concentration did not correlate with QTc interval, which indicates the safe use of moxifloxacin on QTc interval. In addition to close monitoring of QTc interval, the clinicians should also consider other variables which potentially increase risk for QTc prolongation in DR-TB patients who received shorter treatment regimens.

Simple tuberculosis screening tool using signs, symptoms, and risk factors to reduce the missed opportunity in the older population.

BACKGROUND: There is a growing concern on how to increase tuberculosis (TB) case detection in resource-poor settings. The healthcare facilities routinely providing services to the elderly for chronic diseases often failed to detect TB cases, causing a missed opportunity. This study aimed to develop a simple and sensitive screening tool using signs, symptoms, and risk factors for TB case detection in the elderly. METHODS: This was a cross-sectional study conducted from August to December 2020. A random sample of 302 subjects was taken from the elderly aged ≥ 60 years attending the outpatient polyclinic at Mangunharjo hospital, Madiun, East Java, Indonesia, for a chronic disease problem. The test was developed using 16 TB signs, symptoms, and risk factors. Test performance was assessed by comparing it against the GeneXpert MTB/RIF. RESULTS: Marginal analysis resulted in the optimal cut-point of ≥ 7 for the test, which gave an area under the curve (AUC) of 0.62, with the maximum marginal AUC of 0.04 (p < 0.001). The sensitivity and specificity were 60.26% and 64.29%, meaning 60 TB cases for every 100 elderly with TB would be otherwise left undetected if this screening test did not take place. CONCLUSION: A simple TB screening tool with moderate sensitivity and AUC has been developed using TB signs, symptoms, and risk factors. It can be used as an initial step of the systematic TB screening in the elderly visiting healthcare facilities for routine chronic disease examination, with the additional utility of reducing the missed opportunity.

Correlation of Moxifloxacin Concentration, C-Reactive Protein, and Inflammatory Cytokines on QTc Interval in Rifampicin-Resistant Tuberculosis Patients Treated with Shorter Regimens.

BACKGROUND: Drug-resistant tuberculosis (DR-TB) is a global health concern. QTc prolongation is a serious adverse effect in DR-TB patients receiving a shorter regimen. This study aimed to evaluate the correlation of moxifloxacin concentration, CRP, and inflammatory cytokines with QTc interval in DR-TB patients treated with a shorter regimen. METHODS: This study was performed in 2 groups of rifampicin-resistant (RR-TB) patients receiving shorter regimens. Correlation for all variables was analyzed. RESULTS: CRP, IL-1ß, and QTc baseline showed significant differences between 45 RR-TB patients on intensive phase and continuation phase with p-value of <0.001, 0.040, and <0.001, respectively. TNF-α and IL-6 between RR-TB patients on intensive phase and continuation phase showed no significant difference with p=0.530 and 0.477, respectively. CRP, TNF-α, IL-1 ß, and IL-6 did not correlate with QTc interval in intensive phase (p=0.226, 0.281, 0.509, and 0.886, respectively), and also in continuation phase (0.805, 0.865, 0.406, 0.586, respectively). At 2 hours after taking the 48th-dose, moxifloxacin concentration did not correlate with QTc interval, both in intensive phase (p=0.576) and in continuation phase (p=0.691). At 1 hour before taking the 72nd-hour dose, moxifloxacin concentration also did not correlate with QTc interval in intensive phase (p=0.531) and continuation phase (p=0.209). CONCLUSION: Moxifloxacin concentration, CRP, and inflammatory cytokines did not correlate with QTc interval in RR-TB patients treated with shorter regimens. The use of moxifloxacin is safe but should be routinely monitored and considered the presence of other risk factors for QTc prolongation in RR-TB patients who received shorter regimens.

Development of population pharmacokinetics model of isoniazid in Indonesian patients with tuberculosis.

OBJECTIVES: No population pharmacokinetics (PK) model of isoniazid (INH) has been reported for the Indonesian population with tuberculosis (TB). Therefore, we aimed to develop a population PK model to optimize pharmacotherapy of INH on the basis of therapeutic drug monitoring (TDM) implementation in Indonesian patients with TB. MATERIALS AND METHODS: INH concentrations, N-acetyltransferase 2 (NAT2) genotypes, and clinical data were collected from Dr. Soetomo General Academic Hospital, Indonesia. A nonlinear mixed-effect model was used to develop and validate the population PK model. RESULTS: A total of 107 patients with TB (with 153 samples) were involved in this study. A one-compartment model with allometric scaling for bodyweight effect described well the PK of INH. The NAT2 acetylator phenotype significantly affected INH clearance. The mean clearance rates for the rapid, intermediate, and slow NAT2 acetylator phenotypes were 55.9, 37.8, and 17.7 L/h, respectively. Our model was well-validated through visual predictive checks and bootstrapping. CONCLUSIONS: We established the population PK model for INH in Indonesian patients with TB using the NAT2 acetylator phenotype as a significant covariate. Our Bayesian forecasting model should enable optimization of TB treatment for INH in Indonesian patients with TB.

The espD full gene as a potential biomarker in active pulmonary tuberculosis.

Background: Pulmonary tuberculosis (PTB) is still a major health problem worldwide. The espD has a potential to be a new biomarker because it is important for the espA, espC, and ESX-1 protein secretion system that are actively expressed in active multiplication of Mycobacterium tuberculosis complex. Methods: A total of 55 sputum samples and 41 culture isolates from newly diagnosed PTB patients at Dr. Soetomo Academic Hospital were collected from September 2016 to April 2019. The tested samples using polymerase chain reaction targeted 555 bp of espD gene and sequencing. Clone Manager Version 6 and NCBI BLAST were used to align the gene sequence against wild-type M. tuberculosis. The prediction of T-cell epitope in espD gene was detected by GENETYX. The three-dimensional (3D) structure of espD was modeled by SWISS-MODEL and I-TASSER and was visualized with PyMOL. Results: From 55 sputum samples, 43 (78.18%) showed positive results, and all culture isolates showed positive results. In addition, all sequenced samples showed 100% homolog with M. tuberculosis H37Rv gene without detected variant or mutation. There were four T-cell epitopes that could be obtained. The 3D model had a I-TASSER confidence score of 3.91 with estimated RMSD of approximately 14.5 Å. The structure consists of a main fold of a three-stranded antiparallel ß-sheet and a long α-helix surrounded by several minor secondary structures. Conclusions: This study provides a brief information about the sequence, epitope prediction, and 3D structure of EspD protein from M. tuberculosis strains in Indonesia.

Determinant factors for loss to follow-up in drug-resistant tuberculosis patients: the importance of psycho-social and economic aspects.

BACKGROUND: Drug-resistant tuberculosis (DR-TB) is the barrier for global TB elimination efforts with a lower treatment success rate. Loss to follow-up (LTFU) in DR-TB is a serious problem, causes mortality and morbidity for patients, and leads to wide spreading of DR-TB to their family and the wider community, as well as wasting health resources. Prevention and management of LTFU is crucial to reduce mortality, prevent further spread of DR-TB, and inhibit the development and transmission of more extensively drug-resistant strains of bacteria. A study about the factors associated with loss to follow-up is needed to develop appropriate strategies to prevent DR-TB patients become loss to follow-up. This study was conducted to identify the factors correlated with loss to follow-up in DR-TB patients, using questionnaires from the point of view of patients. METHODS: An observational study with a cross-sectional design was conducted. Study subjects were all DR-TB patients who have declared as treatment success and loss to follow-up from DR-TB treatment. A structured questionnaire was used to collect information by interviewing the subjects as respondents. Obtained data were analyzed potential factors correlated with loss to follow-up in DR-TB patients. RESULTS: A total of 280 subjects were included in this study. Sex, working status, income, and body mass index showed a significant difference between treatment success and loss to follow-up DR-TB patients with p-value of 0.013, 0.010, 0.007, and 0.006, respectively. In regression analysis, factors correlated with increased LTFU were negative attitude towards treatment (OR = 1.2; 95% CI = 1.1-1.3), limitation of social support (OR = 1.1; 95% CI = 1.0-1.2), dissatisfaction with health service (OR = 2.1; 95% CI = 1.5-3.0)), and limitation of economic status (OR = 1.1; 95% CI = 1.0-1.2)). CONCLUSIONS: Male patients, jobless, non-regular employee, lower income, and underweight BMI were found in higher proportion in LTFU patients. Negative attitude towards treatment, limitation of social support, dissatisfaction with health service, and limitation of economic status are factors correlated with increased LTFU in DR-TB patients. Non-compliance to treatment is complex, we suggest that the involvement and support from the combination of health ministry, labor and employment ministry, and social ministry may help to resolve the complex problems of LTFU in DR-TB patients.