Pharmacokinetics and pharmacodynamics of high-dose isoniazid for the treatment of rifampicin- or multidrug-resistant tuberculosis in Indonesia.

BACKGROUND: Pharmacokinetic data on high-dose isoniazid for the treatment of rifampicin-/multidrug-resistant tuberculosis (RR/MDR-TB) are limited. We aimed to describe the pharmacokinetics of high-dose isoniazid, estimate exposure target attainment, identify predictors of exposures, and explore exposure-response relationships in RR/MDR-TB patients. METHODS: We performed an observational pharmacokinetic study, with exploratory pharmacokinetic/pharmacodynamic analyses, in Indonesian adults aged 18-65 years treated for pulmonary RR/MDR-TB with standardized regimens containing high-dose isoniazid (10-15 mg/kg/day) for 9-11 months. Intensive pharmacokinetic sampling was performed after ≥2 weeks of treatment. Total plasma drug exposure (AUC0-24) and peak concentration (Cmax) were assessed using non-compartmental analyses. AUC0-24/MIC ratio of 85 and Cmax/MIC ratio of 17.5 were used as exposure targets. Multivariable linear and logistic regression analyses were used to identify predictors of drug exposures and responses, respectively. RESULTS: We consecutively enrolled 40 patients (median age 37.5 years). The geometric mean isoniazid AUC0-24 and Cmax were 35.4 h·mg/L and 8.5 mg/L, respectively. Lower AUC0-24 and Cmax values were associated (P < 0.05) with non-slow acetylator phenotype, and lower Cmax values were associated with male sex. Of the 26 patients with MIC data, less than 25% achieved the proposed targets for isoniazid AUC0-24/MIC (n = 6/26) and Cmax/MIC (n = 5/26). Lower isoniazid AUC0-24 values were associated with delayed sputum culture conversion (>2 months of treatment) [adjusted OR 0.18 (95% CI 0.04-0.89)]. CONCLUSIONS: Isoniazid exposures below targets were observed in most patients, and certain risk groups for low isoniazid exposures may require dose adjustment. The effect of low isoniazid exposures on delayed culture conversion deserves attention.

Management of drug-resistant tuberculosis in Indonesia: a four-year cascade of care analysis.

Background: In Indonesia, drug resistance testing for TB largely relies on Xpert MTB/RIF, and it is unknown what proportion of drug-resistant (DR) TB is adequately diagnosed and treated. Methods: We conducted a cascade of care analysis on a cohort of presumptive rifampicin-resistant (RR) TB patients registered in 2015-2018 in a tertiary hospital in Indonesia. Estimated incidences of (presumptive) DR-TB cases were assumption-based using global reports. Data on diagnosis and consecutive cascades steps, including their timing were collected from national electronic registers, and medical records. We described a secondary cascade for patients receiving treatment not supported by phenotypic drug susceptibility testing (pDST). Factors associated with delay and loss between diagnosis and treatment were identified using logistic regression. Findings: Less than a third of estimated incident TB cases at risk of DR-TB were identified as presumptive DR-TB case and tested, and 9.8% (982/10,065) of estimated true DR-TB cases was diagnosed. Of those diagnosed, only 45.1% (443/982) had treatment regimens supported by pDST results, but this did not significantly influence treatment outcomes. Only 25.5% (250/982) of diagnosed patients completed all steps of the cascade including successful treatment. Delays between diagnosis and treatment were substantial, and more common among those referred from a primary healthcare facility, and among those who were employed, living outside of Bandung, and reporting engagement with the private sector. Interpretation: The DR-TB care cascade in this urban setting in Indonesia is characterized by substantial attrition and delays. Strategies to increase access to DR-TB diagnosis accompanied by optimisation of clinical care could substantially improve outcomes and reduce onward transmission. Funding: Radboud university medical center and University of Otago.

Clinical presentation, management, and outcome of suspected central nervous system infections in Indonesia: a prospective cohort study.

BACKGROUND: Little is known about the etiology, clinical presentation, management, and outcome of central nervous system (CNS) infections in Indonesia, a country with a high burden of infectious diseases and a rising prevalence of HIV. METHODS: We included adult patients with suspected CNS infections at two referral hospitals in a prospective cohort between April 2019 and December 2021. Clinical, laboratory, and radiological assessments were standardized. We recorded initial and final diagnoses, treatments, and outcomes during 6 months of follow-up. RESULTS: Of 1051 patients screened, 793 were diagnosed with a CNS infection. Patients (median age 33 years, 62% male, 38% HIV-infected) presented a median of 14 days (IQR 7-30) after symptom onset, often with altered consciousness (63%), motor deficits (73%), and seizures (21%). Among HIV-uninfected patients, CNS tuberculosis (TB) was most common (60%), while viral (8%) and bacterial (4%) disease were uncommon. Among HIV-infected patients, cerebral toxoplasmosis (41%) was most common, followed by CNS TB (19%), neurosyphilis (15%), and cryptococcal meningitis (10%). A microbiologically confirmed diagnosis was achieved in 25% of cases, and initial diagnoses were revised in 46% of cases. In-hospital mortality was 30%, and at six months, 45% of patients had died, and 12% suffered from severe disability. Six-month mortality was associated with older age, HIV, and severe clinical, radiological and CSF markers at presentation. CONCLUSION: CNS infections in Indonesia are characterized by late presentation, severe disease, frequent HIV coinfection, low microbiological confirmation and high mortality. These findings highlight the need for earlier disease recognition, faster and more accurate diagnosis, and optimized treatment, coupled with wider efforts to improve the uptake of HIV services.

Insights from the molecular mechanism of pyrazinamide to mutated pyrazinamidase linked to the pncA gene in clinical isolates of Mycobacterium tuberculosis.

This study aims to conduct a comprehensive molecular dynamics strategy to evaluate whether mutations found in pyrazinamide monoresistant (PZAMR) strains of Mycobacterium tuberculosis (MTB) can potentially reduce the effectiveness of pyrazinamide (PZA) for tuberculosis (TB) treatment. Five single point mutations of pyrazinamidase (PZAse), an enzyme which is responsible for the activation of prodrug PZA into pyrazinoic acid, found in MTB clinical isolates, namely His82Arg, Thr87Met, Ser66Pro, Ala171Val, and Pro62Leu, were analyzed by the dynamics simulations both in the apo state (unbound state) and in the PZA bound state. The results showed that the mutation of His82 to Arg, Thr87 to Met, and Ser66 to Pro in PZAse affects the coordination state of the Fe2+ ion, which is a cofactor required for enzyme activity. These mutations change the flexibility, stability, and fluctuation of His51, His57, and ASP49 amino acid residues around the Fe2+ ion, culminating in an unstable complex and dissociation of PZA from the PZAse binding site. However, mutations of Ala171 to Val and Pro62 to Leu were found to have no effect on the complex's stability. Based on the results, PZAse mutations of His82Arg, Thr87Met, and Ser66Pro culminated in weak binding affinity for PZA and caused significant structural deformations that led to PZA resistance. Future structural and functional studies, as well as investigations into other aspects of drug resistance in PZAse, will require experimental clarification.Communicated by Ramaswamy H. Sarma.

The effect of M. tuberculosis lineage on clinical phenotype.

Six lineages of Mycobacterium tuberculosis sensu stricto (which excludes M. africanum) are described. Single-country or small observational data suggest differences in clinical phenotype between lineages. We present strain lineage and clinical phenotype data from 12,246 patients from 3 low-incidence and 5 high-incidence countries. We used multivariable logistic regression to explore the effect of lineage on site of disease and on cavities on chest radiography, given pulmonary TB; multivariable multinomial logistic regression to investigate types of extra-pulmonary TB, given lineage; and accelerated failure time and Cox proportional-hazards models to explore the effect of lineage on time to smear and culture-conversion. Mediation analyses quantified the direct effects of lineage on outcomes. Pulmonary disease was more likely among patients with lineage(L) 2, L3 or L4, than L1 (adjusted odds ratio (aOR) 1.79, (95% confidence interval 1.49-2.15), p<0.001; aOR = 1.40(1.09-1.79), p = 0.007; aOR = 2.04(1.65-2.53), p<0.001, respectively). Among patients with pulmonary TB, those with L1 had greater risk of cavities on chest radiography versus those with L2 (aOR = 0.69(0.57-0.83), p<0.001) and L4 strains (aOR = 0.73(0.59-0.90), p = 0.002). L1 strains were more likely to cause osteomyelitis among patients with extra-pulmonary TB, versus L2-4 (p = 0.033, p = 0.008 and p = 0.049 respectively). Patients with L1 strains showed shorter time-to-sputum smear conversion than for L2. Causal mediation analysis showed the effect of lineage in each case was largely direct. The pattern of clinical phenotypes seen with L1 strains differed from modern lineages (L2-4). This has implications for clinical management and could influence clinical trial selection strategies.

Identification of Significant Pathogenic Nontuberculous Mycobacteria Species from Presumptive TB Patients Using Partial hsp65 Gene Sequencing.

Purpose: To date, the diagnosis of nontuberculous mycobacteria (NTM) disease primarily relies on clinical symptoms and radiological features. Our objective was to apply a sequence-based analysis method by using partial gene sequencing of heat shock protein 65 (hsp65) to identify NTM species. Patients and Methods: A total of 32 stored isolates obtained from individuals suspected of having pulmonary NTM infection were subjected to solid Ogawa culture. Genomic DNA from each sample was extracted and used in a conventional polymerase chain reaction (PCR) targeting a specific region of hsp65 gene. Identified amplicons from the PCR were then subjected to targeted sequencing. Analysis of the obtained hsp65 sequence was performed using DNA Baser tool. The consensus sequences obtained were compared to references in the GenBank NCBI database to determine NTM species. Results: We identified several important NTM species which posses opportunistic characteristics. M. abscessus and M. chelonae are the most frequent NTM species identified in this study (40.63% and 18.75%, respectively). These two species have the potential to cause significant infections in human, ranging from opportunistic pulmonary infection to localized skin infection. Additionally, pathogenic NTM members of M. fortuitum group (MFG), M. avium, M. intracellulare, M. kansasii, and M. celatum were also found among all identified species. Conclusion: Sequence-based analysis is a promising method for identifying species of NTM. The hsp65 gene has a high discriminatory power to identify opportunistic pathogen NTM species in specimens in Indonesia. Consequently, hsp65 partial gene sequencing is considerable as an alternative and reliable approach for NTM speciation.

The effect of M. tuberculosis lineage on clinical phenotype.

Eight lineages of Mycobacterium tuberculosis sensu stricto are described. Single-country or small observational data suggest differences in clinical phenotype between lineages. We present strain lineage and clinical phenotype data from 12,246 patients from 3 low-incidence and 5 high-incidence countries. We used multivariable logistic regression to explore the effect of lineage on site of disease and on cavities on chest radiography, given pulmonary TB; multivariable multinomial logistic regression to investigate types of extra-pulmonary TB, given lineage; and accelerated failure time and Cox proportional-hazards models to explore the effect of lineage on time to smear and culture-conversion. Mediation analyses quantified the direct effects of lineage on outcomes. Pulmonary disease was more likely among patients with lineage(L) 2, L3 or L4, than L1 (adjusted odds ratio (aOR) 1.79, (95% confidence interval 1.49-2.15), p<0.001; aOR=1.40(1.09-1.79), p=0.007; aOR=2.04(1.65-2.53), p<0.001, respectively). Among patients with pulmonary TB, those with L1 had greater risk of cavities on chest radiography versus those with L2 (aOR=0.69(0.57-0.83), p<0.001) and L4 strains (aOR=0.73(0.59-0.90), p=0.002). L1 strains were more likely to cause osteomyelitis among patients with extra-pulmonary TB, versus L2-4 (p=0.033, p=0.008 and p=0.049 respectively). Patients with L1 strains showed shorter time-to-sputum smear conversion than for L2. Causal mediation analysis showed the effect of lineage in each case was largely direct. The pattern of clinical phenotypes seen with L1 strains differed from modern lineages (L2-4). This has implications for clinical management and could influence clinical trial selection strategies.

The development of the national tuberculosis research priority in Indonesia: A comprehensive mixed-method approach.

Ranked second in global tuberculosis (TB) incidence, Indonesia has developed a National Strategy for TB Prevention and Control 2020-2024 to accelerate the TB elimination program. Research and innovation are key pillars to support the program and need to be prioritised. This study aimed to develop updated national TB research priorities in Indonesia. This study was a mixed-methods study consisting of an open survey, a published literature survey, and Delphi survey. The open survey invited all related TB stakeholders to answer (a) the main barriers of the TB program and (b) the need for studies to support TB elimination. The published literature survey retrieved scientific articles published in national and international journals between 2015 and 2020 to identify gaps between published research and the current national strategy for TB control. The online survey and literature survey informed a panel of TB experts in a two-phase Delphi Survey to select the top 10 priority research topics. We identified 322 articles and analysed 1143 open survey responses. Through two-phases Delphi surveys, top ten research categories were listed: early TB detection; diagnosis and treatment of DR-TB; contact investigation; case detection and treatment of child TB; TB preventive therapy; government policy; laboratory for drug-sensitive- and drug-resistant-TB diagnosis; treatment adherence; diagnostic tool development; and community empowerment. This study also found the gap between stakeholders' interests and the importance of translating research into policy and practice. TB research priorities have been identified through the involvement of various stakeholders. The combination of an online survey, a published literature survey, and a Delphi survey was a rigorous methodology and was fit to build a systematic consensus about the priority of TB research.

Transcriptional Biomarkers for Treatment Monitoring of Pulmonary Drug-Resistant Tuberculosis: Protocol for a Prospective Observational Study in Indonesia.

Many blood-based gene expression biomarkers for monitoring tuberculosis (TB) treatment have been suggested so far, but promising biomarker results for drug-resistant TB treatment response have not been studied. This protocol presents a prospective observational study in Indonesia to profile the human blood transcriptome for predicting the response to drug-resistant TB treatment, focusing on pulmonary TB, and to adapt the specific RNA signature to the qRT-PCR platform. Longitudinal blood samples will be collected from 44 subjects with rifampicin resistant TB, confirmed by Xpert MTB/RIF, and 52 healthy controls. RNA-Seq will be performed to identify changes in the transcriptome following TB treatment. A discriminative RNA signature will be chosen and translated into a score for use in a quantitative PCR-based assay. This study will provide crucial information to guide the discovery and design of a clinically implementable tool to monitor the response of TB treatment.

The Role of Amino Acids in Tuberculosis Infection: A Literature Review.

Recently, there was an abundance of studies being conducted on the metabolomic profiling of tuberculosis patients. Amino acids are critical metabolites for the immune system, as they might contribute to providing nutrients for the host intracellular pathway. In tuberculosis, several amino acids play important roles in both the mycobacteria infection mechanism and the host. Individual studies showed how the dynamics of metabolite products that result from interactions between Mycobacterium tuberculosis (Mtb) and the host play important roles in different stages of infection. In this review, we focus on the dynamics of amino-acid metabolism and identify the prominent roles of amino acids in the diagnostics and treatment of tuberculosis infection. Online resources, including PubMed, ScienceDirect, Scopus, and Clinical Key, were used to search for articles with combination keywords of amino acids and TB. The inclusion criteria were full-text articles in English published in the last 10 years. Most amino acids were decreased in patients with active TB compared with those with latent TB and healthy controls. However, some amino acids, including leucine, isoleucine, valine, phenylalanine, aspartate, and glutamate, were found to be at higher levels in TB patients. Additionally, the biomarkers of Mtb infection included the ratios of kynurenine to tryptophan, phenylalanine to histidine, and citrulline to arginine. Most amino acids were present at different levels in different stages of infection and disease progression. The search for additional roles played by those metabolomic biomarkers in each stage of infection might facilitate diagnostic tools for staging TB infection.

Omics Biomarkers for Monitoring Tuberculosis Treatment: A Mini-Review of Recent Insights and Future Approaches.

Poor sensitivity of sputum conversion for monitoring tuberculosis (TB) treatment that makes identification of a non-sputum-based biomarker is urgently needed. Monitoring biomarkers in TB treatment is used to decide whether critical thresholds have been reached and helps clinicians to conclude the therapeutic success. In this mini review, we highlight recent studies on omics-related contributes to identifying of a novel biomarker as surrogate markers for the cure and predicting future reactivation risk following TB treatment. We catalogue the studies published to seek the progress made in transcriptomics, proteomics, and metabolomics in pulmonary TB. We also discuss how integrative multi-omics data will provide further understanding and effective TB treatment, such as revealing the interrelationships at multiple molecular levels, facilitating the identification of biologically interconnected processes, and accelerating precision medicine in TB treatment. However, proper validation in prospective longitudinal studies with long-term follow-up and outcome assessment must be conducted before the biomarkers are utilized in clinical practice.

A case of endocarditis and spondylodiscitis associated with Mycobacterium tuberculosis.

Tuberculosis (TB) is a global health problem, in which the majority of cases occur in population-dense developing countries. Despite advances in various diagnostic TB modalities, extrapulmonary TB remains a challenge due to complexities related to its diagnostic approach. Hereby, we present a rare case of endocarditis and spondylodiscitis associated with Mycobacterium tuberculosis (MTB). This case report highlighted the challenges faced in diagnosing blood culture-negative infective endocarditis (BCNIE). We also emphasized the importance of considering MTB as etiology of BCNIE, particularly in endemic TB areas.

Development of Nucleic Acid Lateral Flow Immunoassay for Rapid and Accurate Detection of Chikungunya Virus in Indonesia.

Chikungunya fever is an arboviral disease caused by the Chikungunya virus (CHIKV). The disease has similar clinical manifestations with other acute febrile illnesses which complicates differential diagnosis in low-resource settings. We aimed to develop a rapid test for CHIKV detection based on the nucleic acid lateral flow immunoassay technology. The system consists of a primer set that recognizes the E1 region of the CHIKV genome and test strips in an enclosed cassette which are used to detect amplicons labeled with FITC/biotin. Amplification of the viral genome was done using open-source PCR, a low-cost open-source thermal cycler. Assay performance was evaluated using a panel of RNA isolated from patients' blood with confirmed CHIKV (n = 8) and dengue virus (n = 20) infection. The open-source PCR-NALFIA platform had a limit of detection of 10 RNA copies/ml. The assay had a sensitivity and specificity of 100% (95% CI: 67.56% - 100%) and 100% (95% CI: 83.89% - 100%), respectively, compared to reference standards of any positive virus culture on C6/36 cell lines and/or qRT-PCR. Further evaluation of its performance using a larger sample size may provide important data to extend its usefulness, especially its utilization in the peripheral healthcare facilities with scarce resources and outbreak situations.

Are neighbourhoods of tuberculosis cases a high-risk population for active intervention? A protocol for tuberculosis active case finding.

BACKGROUND: Indonesia has the second largest tuberculosis (TB) burden globally. Attempts to scale-up TB control efforts have focused on TB households. However, in most high burden settings, considerable Mycobacterium tuberculosis (Mtb) transmission occurs outside TB households. A better understanding of transmission dynamics in an urban setting in Indonesia will be crucial for the TB Control Program in scaling up efforts towards elimination of TB in a more targeted way. Therefore, the study aims to measure TB prevalence and incidence in household contacts and neighbourhoods in the vicinity of known TB cases and to assess their genomic and epidemiological relatedness. METHODS AND ANALYSIS: Individuals (~1000) living in the same household as a case diagnosed with pulmonary TB (n = 250) or in a neighbouring household (~4500 individuals) will be screened for TB symptoms and by chest x-ray. Two sputum samples will be collected for microbiological analysis from anyone with a productive cough. Any person found to have TB will be treated by the National TB Control Program. All those with no evidence of TB disease will have a repeat screen at 12 months. Whole-genome sequencing (WGS) and social network analysis (SNA) will be conducted on Index cases and contacts diagnosed with TB.

A public health intervention package for increasing tuberculosis notifications from private practitioners in Bandung, Indonesia (INSTEP2): A cluster-randomised controlled trial protocol.

Background. A significant proportion of tuberculosis (TB) patients globally make their initial visit for medical care to either an informal provider or a private practitioner, and many are not formally notified. Involvement of private practitioners (PPs) in a public-private mix for TB (TB-PPM) provides an opportunity for improving TB control. However, context-specific interventions beyond public-private agreements and mandatory notification are needed. In this study we will evaluate whether a tailored intervention package can increase TB notifications from PPs in Indonesia. Methods. This is a cluster-randomized trial of a multi-component public health intervention. 36 community health centre (CHC) areas will be selected as study locations and randomly allocated to intervention and control arms (1:1). PPs in the intervention areas will be identified using a mapping exercise and recruited into the study if they are eligible and consent. They will receive a tailored intervention package including in-person education about TB management along with bimonthly electronic refreshers, context-specific selection of referral pathways, and access to a TB-reporting app developed in collaboration with the National TB programme. The primary hypothesis is that the intervention package will increase the TB notification rate. The primary outcome will be measured by collecting notification data from the CHCs in intervention and control arms at the end of a 1-year observation period and comparing with the 1-year pre-intervention. The primary analysis will be intention-to-treat at the cluster level, using a generalised mixed model with repeated measures of TB notifications for 1 year pre- and 1 year post-intervention. Discussion. The results from this study will provide evidence on whether a tailored intervention package is effective in increasing the number of TB notifications, and whether the PPs refer presumptive TB cases correctly. The study results will guide policy in the development of TB-PPM in Indonesia and similar settings.

Cerebrospinal fluid IL-1ß is elevated in tuberculous meningitis patients but not associated with mortality.

Inflammation contributes to the pathophysiology and high mortality of tuberculous meningitis. The IL-1ß pathway has been implicated in immunopathology and could be a target for host-directed therapy. IL-1ß was elevated in the cerebrospinal fluid (CSF) of 225 HIV-uninfected tuberculous meningitis patients in Indonesia compared to controls, but did not predict subsequent mortality, nor did IL-6 or IL-1Ra. Furthermore, genetic loci known to regulate IL1B gene expression did not predict mortality in 443 tuberculous meningitis patients, although two of these loci did predict CSF IL-1ß concentrations. Collectively, these data argue against a role for IL-1ß targeted host-directed therapy in tuberculous meningitis.

Microbiological Testing of Gastric Aspirate Improves the Diagnosis of Pulmonary Tuberculosis in Unconscious Adults with TB Meningitis.

Conventional sputum collection for TB diagnosis is difficult in TB meningitis patients since most of them are admitted with decreased consciousness. It is assumed that unconscious patients swallow their sputum; therefore, gastric aspiration can replace sputum collection in unconscious patients. A prospective study was conducted to see whether examining gastric aspirate could increase the diagnosis certainty of pulmonary TB in such subjects. The inclusion criteria were age 18-60 years, decreased level of consciousness, and use of a nasogastric tube. Subjects who had taken antituberculosis drugs for more than 3 days were excluded. Gastric lavage was performed in the morning after an overnight fast. Specimens were examined for direct smear, culture, and rapid molecular testing. Demographic, clinical, chest X-ray, and laboratory data were also recorded. During the study period, 31 subjects were available. The positivity rates for microbiological tests were 19.3%, 41.9%, and 48.4% for smear, culture, and rapid molecular testing, respectively. All positive smears were confirmed by either culture or rapid molecular testing. Gastric lavage can be considered a tool for improving extraneural TB diagnosis in unconscious patients.

Evaluation of Xpert MTB-RIF guided diagnosis and treatment of rifampicin-resistant tuberculosis in Indonesia: A retrospective cohort study.

BACKGROUND: Rifampicin-resistant tuberculosis (RR-TB) is largely underdetected in Indonesia. Xpert MTB/RIF (Xpert) has recently been introduced, prioritizing patients at risk of RR-TB, followed by phenotypic drug-susceptibility (DST) if rifampicin resistance is detected. OBJECTIVE: This study investigated Xpert-based management of presumptive RR-TB cases under routine practice in West Java, Indonesia. METHODS: We examined all records of patients tested with Xpert in the referral hospital for West Java in 2015-2016. We measured loss across a limited cascade of care, time to Xpert diagnosis and the commencement of initial second-line treatment, and identified factors associated with diagnostic and treatment delay. Additionally, we analyzed the appropriateness of treatment according to DST results. RESULTS: Of 3415 patients with presumptive RR-TB, 3215 (94%) were tested by Xpert, of whom 339 (10.5%) were diagnosed as RR-TB. 288 (85%) of 339 RR-TB patients started initial second-line TB treatment, with 48 (14%) patients being lost between diagnosis and pre-treatment assessment. Second-line treatment was commenced at a median of 41 days (IQR 29-70) after RR-TB diagnosis. Delays in both diagnosis and treatment initiation were observed in 104 (52%) of 201 RR-TB patients with identifiable referral date. Rural residence was associated with delay to diagnosis (adjusted OR 2.7; 95%CI 1.5-5.2) and treatment initiation (adjusted OR 2.0; 1.2-3.4). Of 162 patients with available DST result, 107 (66%) had multidrug-resistant tuberculosis (MDR-TB) and 32 (20%) had either pre-extensively drug resistant (pre-XDR) or extensively drug resistant tuberculosis (XDR-TB). We estimated that with the current algorithm 41% of pre-XDR or XDR-TB patients are diagnosed, and 33% of them started on an appropriate treatment regimen. CONCLUSIONS: Many patients with Xpert-diagnosed RR-TB either do not start MDR-TB treatment or encountered diagnostic and treatment delays under programmatic conditions in Indonesia, and most pre-XDR and XDR-TB cases remain undiagnosed. Further expansion and ongoing quality improvement of RR-TB services are urgently needed.