The seroprevalence of anti-Histoplasma capsulatum IgG antibody among pulmonary tuberculosis patients in seven referral tuberculosis hospitals in Indonesia.

BACKGROUND: Histoplasma capsulatum exposure is rarely suspected in Indonesia. Pulmonary histoplasmosis can occur simultaneously with pulmonary tuberculosis (TB) or as an alternative diagnosis in clinically-diagnosed TB patients with no microbiological evidence of TB. This study aimed to determine the seroprevalence of anti-H. capsulatum IgG antibody among pulmonary TB patients. METHODOLOGY: This was a sub-study of 306 participants from a prospective cohort pulmonary TB study conducted at seven TB referral hospitals in Indonesia. The study population was presumptive pulmonary TB adult patients who underwent microbiological TB examinations and were categorized as drug-sensitive (DS), drug-resistant (DR), and clinically-diagnosed TB. Anti-H. capsulatum IgG antibody levels at baseline were measured using MVista Histoplasma Ab enzyme immunoassays. Data were summarized using descriptive statistics. Bivariate and multivariate logistic regression analysis were performed to assess factors associated with anti-H. capsulatum IgG antibody positive result. RESULTS: 12.7% (39/306) of pulmonary TB patients were positive for anti-H. capsulatum IgG antibodies (DR-TB patients (15.9%, 18/114), DS-TB (13.0%, 15/115), and clinically-diagnosed TB (7.8%, 6/77)). The median unit value of anti-H. capsulatum IgG antibody for all positive samples was 15.7 (IQR 10.2-28.9) EU. This median unit value was higher in clinically-diagnosed TB patients compared to DS-TB or DR-TB patients (38.1 (IQR 25.6-46.6) EU, 19.7 (IQR 12.3-28.9) EU, and 10.9 (IQR 9.2-15.4), respectively). There were 10 patients (3.3%) with anti-H. capsulatum IgG antibody levels above 30 EU. Factors associated with the anti-H. capsulatum IgG antibody positive result were malignancies (OR 4.88, 95% CI 1.09-21.69, p = 0.037) and cavitary lesions (OR 2.27, 95% CI 1.09-4.70, p = 0.028). CONCLUSIONS: Our results provide evidence of exposure to H. capsulatum among pulmonary TB patients in Indonesia. Further studies are needed to provide a comprehensive picture of this fungal disease in other populations and regions to enhance awareness among clinicians and public health officials.

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.

Treatment Strategy for Rifampin-Susceptible Tuberculosis.

BACKGROUND: Tuberculosis is usually treated with a 6-month rifampin-based regimen. Whether a strategy involving shorter initial treatment may lead to similar outcomes is unclear. METHODS: In this adaptive, open-label, noninferiority trial, we randomly assigned participants with rifampin-susceptible pulmonary tuberculosis to undergo either standard treatment (rifampin and isoniazid for 24 weeks with pyrazinamide and ethambutol for the first 8 weeks) or a strategy involving initial treatment with an 8-week regimen, extended treatment for persistent clinical disease, monitoring after treatment, and retreatment for relapse. There were four strategy groups with different initial regimens; noninferiority was assessed in the two strategy groups with complete enrollment, which had initial regimens of high-dose rifampin-linezolid and bedaquiline-linezolid (each with isoniazid, pyrazinamide, and ethambutol). The primary outcome was a composite of death, ongoing treatment, or active disease at week 96. The noninferiority margin was 12 percentage points. RESULTS: Of the 674 participants in the intention-to-treat population, 4 (0.6%) withdrew consent or were lost to follow-up. A primary-outcome event occurred in 7 of the 181 participants (3.9%) in the standard-treatment group, as compared with 21 of the 184 participants (11.4%) in the strategy group with an initial rifampin-linezolid regimen (adjusted difference, 7.4 percentage points; 97.5% confidence interval [CI], 1.7 to 13.2; noninferiority not met) and 11 of the 189 participants (5.8%) in the strategy group with an initial bedaquiline-linezolid regimen (adjusted difference, 0.8 percentage points; 97.5% CI, -3.4 to 5.1; noninferiority met). The mean total duration of treatment was 180 days in the standard-treatment group, 106 days in the rifampin-linezolid strategy group, and 85 days in the bedaquiline-linezolid strategy group. The incidences of grade 3 or 4 adverse events and serious adverse events were similar in the three groups. CONCLUSIONS: A strategy involving initial treatment with an 8-week bedaquiline-linezolid regimen was noninferior to standard treatment for tuberculosis with respect to clinical outcomes. The strategy was associated with a shorter total duration of treatment and with no evident safety concerns. (Funded by the Singapore National Medical Research Council and others; TRUNCATE-TB ClinicalTrials.gov number, NCT03474198.).

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).

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.

Characteristics of Drug-sensitive and Drug-resistant Tuberculosis Cases among Adults at Tuberculosis Referral Hospitals in Indonesia.

As Indonesia's rifampin resistance testing rates are lower than global testing rates per the 2020 WHO global tuberculosis (TB) report, prevalence of multidrug-resistant TB may be underestimated. Our study aimed to evaluate prevalence and patterns of TB drug resistance (DR) within Indonesia. We conducted a cross-sectional analysis of baseline data collected from 2017-2018 as part of a cohort study of adults with presumed pulmonary TB at 7 DR-TB referral hospitals in Indonesia. Bacteriological examinations (acid-fast bacilli, GeneXpert, sputum culture) and drug-susceptibility testing were performed following the guidelines of the National TB Program. Of 447 participants with complete bacteriological examinations, 312 (69.8%) had positive sputum cultures for Mycobacterium tuberculosis. The proportion of MDR and pre-extensively drug-resistant was higher in previously treated compared with newly diagnosed participants (52.5% [73/139] versus 15% [26/173]). Compared with drug-sensitive case, drug-resistant TB was associated with cavities. Given the difference between rates of DR in TB referral hospitals from our study compared with the WHO survey in 2019 that showed 17.7% and 3.3% DR among previously treated and newly diagnosed participants globally, further characterization of Indonesia's TB epidemiology in the general population is needed. Strategies, including public policies to optimize case finding, strengthen capacity for resistance testing, and prevent loss to follow-up will be critical to reduce the burden of TB in Indonesia.

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.

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.

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.

The role of C-Reactive protein as an inflammatory marker to predict prolonged QTc interval in rifampicin-resistant tuberculosis patients: A case-control study.

BACKGROUND: long-term use of anti-tuberculosis drugs (ATD) increases the risk of QTc prolongation, while C-reactive protein (CRP) can be used as an inflammatory marker of Mycobacterium tuberculosis infection.Objective: correlation of CRP on the QTc interval in Rifampicin-resistant tuberculosis (RR-TB) patients with the short regimen. METHODS: An observational study was conducted in Rifampicin-resistant tuberculosis (RR-TB) patients from 2 groups, patients on intensive phase and patients on continuation phase. CRP levels were measured from blood samples and measured automatically using the immunoturbidimetric assay. QTc interval was calculated using electrocardiography. Levels of CRP levels and QTc interval between the 2 groups were analyzed. The statistical analysis used includes the independent t-test, Mann Whitney test, and Rank Spearman test with p = 0.05. RESULTS: Forty-five eligible RR-TB patients were included in this study. CRP levels and QTc intervals between 2 groups (intensive and continuation phase) showed significant difference with p < 0.001 but found no significant correlation of CRP levels and QTc interval in both intensive and continuation phase with p = 0.226 and 0.805, respectively. A higher level of CRP strongly indicated the inflammation caused by RR-TB infection at the early phase of the disease, but not correlated with QTc interval in RR-TB patients. CONCLUSION: Levels of CRP and QTc interval do not correlate in RR-TB patients and can not be used to be the marker of QTc prolongation in RR-TB Patients.

Correlation of inflammatory cytokines on corrected QT interval in rifampicin-resistant tuberculosis patients.

BACKGROUND: The cases of Rifampicin-Resistant Tuberculosis (RR-TB) in our country have increased every year and RR-TB deaths are thought to be caused by prolongation of the QTc interval due to side effects of anti-tuberculosis drugs. Thus, cytokines are needed to be used as early markers of prolongation of the QTc interval in RR-TB patients. OBJECTIVE: This study aims to analyze the correlation of inflammatory cytokines on QTc interval in RR-TB patients who received shorter regimens. METHODS: This study uses a case-control study with a time series conducted in the period September 2019 to February 2020 in one of the referral hospitals for Tuberculosis in Indonesia. Cytokines levels from blood samples were measured using the ELISA method, while QTc intervals were automatically recorded using an electrocardiography machine. The statistical analysis used was the Chi-square test, Man Whitney test, Independence t-test, and Spearman-rank test with p < 0.05. RESULTS: There was no significant correlation between inflammatory cytokines and QTc prolongation in intensive phase which TNF-α value (6.8 pg/ml; r = 0.207; p = 0.281), IL-1ß (20.13 pg/ml; r = 0.128; p = 0.509), and IL-6 (43.17 pg/ml; r = -0.028; p = 0.886). Meanwhile, in the continuation phase, the values for TNF-α (4.79 pg/ml; r = 0.046; p = 0.865), IL-1ß (7.42 pg/ml; r = -0.223; p = 0.406), and IL- 6 (40.61 pg/ml; r = -0.147; p = 0.586). CONCLUSION: inflammatory cytokines (TNF-α, IL-1ß, and IL-6) cannot be used to identify QTc interval prolongation in RR-TB patients who received shorter regimens.

Difficulties with the implemented xpert MTB/RIF for determining diagnosis of pulmonary and extrapulmonary tuberculosis in adults and children.

BACKGROUND AND AIMS: Handling of PTB and EPTB patients with adequate standard detection of MTBC and anti-TB drug sensitivity using accurate and rapid methods could provide good TB management and clinical treatment outcomes. The Xpert MTB/RIF assay is an automated, cartridge-based NAAT that can simultaneously detect MTBC and RIF resistance within 2 h. The aim of this study was to evaluate the implementation of Xpert for determining diagnosis of PTB and EPTB in adults and children. METHODS: A descriptive study was performed using e-TB Manager data from the MDR-TB Clinic at Dr. Soetomo Academic Hospital. Suspected TB cases were from the areas of East Java Province from January 2016 to December 2018. Xpert assay was conducted using standardized criteria for clinically suspected TB, and MTBC-positive results with RR were examined by the culture method using MGIT 960 BACTEC System. RESULTS: A total of 1181 (1181/3009, 39.25%) sputum samples from suspected new MDR-PTB cases tested positive for MTBC with 3.02% RR. Among 3893 sputum samples from previously treated probable MDR-PTB cases tested using Xpert, 1936 (49.73%) were MTBC positive with 13.20% RR. Among 59 new suspected MDR-PTB cases tested using MGIT 960 BACTEC System, 55 tested positive for MTBC, although all RR strains were highly sensitive to amikacin (100%), kanamycin (95%), and ofloxacin (89%). A total of 49 children with suspected PTB were tested using Xpert, revealing low positivity (12%) for MTBC, with all RR strains being rifampicin sensitive (RS). Of the 86 suspected EPTB cases tested using Xpert, very few were MTBC-positive (26%), with 91% RS. CONCLUSIONS: This study revealed that in adults and children with PTB and EPTB, the Xpert assay achieved a low positivity detection rate for MTBC in samples from new or previously treated cases, and this could be the result of many factors.

Nontuberculous mycobacterial species and Mycobacterium tuberculosis complex coinfection in patients with pulmonary tuberculosis in Dr. Soetomo Hospital, Surabaya, Indonesia.

OBJECTIVE/BACKGROUND: The aim of this study was to analyze the detection of nontuberculous mycobacterial (NTM) species derived from sputum specimens of pulmonary tuberculosis (TB) suspects. Increasing prevalence and incidence of pulmonary infection by NTM species have widely been reported in several countries with geographical variation. MATERIALS AND METHODS: Between January 2014 and September 2015, sputum specimens from chronic pulmonary TB suspect patients were analyzed. Laboratory examination of mycobacteria was conducted in the TB laboratory, Department of Clinical Microbiology, Dr. Soetomo Hospital, Surabaya. Detection and identification of mycobacteria were performed by the standard culture method using the BACTEC MGIT 960 system (BD) and Lowenstein-Jensen medium. Identification of positive Mycobacterium tuberculosis complex (MTBC) was based on positive acid-fast bacilli microscopic smear, positive niacin accumulation, and positive TB Ag MPT 64 test results (SD Bioline). If the growth of positive cultures and acid-fast bacilli microscopic smear was positive, but niacin accumulation and TB Ag MPT 64 (SD Bioline) results were negative, then the isolates were categorized as NTM species. MTBC isolates were also tested for their sensitivity toward first-line anti-TB drugs, using isoniazid, rifampin, ethambutol, and streptomycin. RESULTS: From 2440 sputum specimens of pulmonary TB suspect patients, 459 isolates (18.81%) were detected as MTBC and 141 (5.78%) as NTM species. CONCLUSION: From the analyzed sputum specimens, 18.81% were detected as MTBC and 5.78% as NTM species. Each pulmonary TB suspect patient needed clinical settings to suspect causative agents of MTBC and/or NTM species; clinicians have to understand the local epidemiological data for the evaluation of causes of lung infection to determine appropriate therapy.