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The article discusses the influence of pharmacokinetic variability in patients who have tuberculosis along with other diseases and the importance of therapeutic drug monitoring (TDM) to manage tuberculosis in such patients. It notes the need for enabling access to TDM and recommends that the World Health Organization (WHO) provide guidance on TDM use.

The unique medical and socio-economic situation in each country affected by TB creates different epidemiological contexts, thus providing exploitable loopholes for the spread of the disease. Country-specific factors such as comorbidities, health insurance, social stigma or the rigidity of the health system complicate the management of TB and the overall outcome of each patient. First-line TB drugs are administered in a standardized manner, regardless of patient characteristics other than weight. This approach does not consider patient-specific conditions such as HIV infection, diabetes mellitus and malnutrition, which can affect the pharmacokinetics of TB drugs, their overall exposure and response to treatment. Therefore, the 'one-size-fits-all' approach is suboptimal for dealing with the underlying inter-subject variability in the pharmacokinetics of anti-TB drugs, further complicated by the recent increased dosing regimen of rifampicin strategies, calling for a patient-specific methodology. In this context, therapeutic drug monitoring (TDM), which allows personalized drug dosing based on blood drug concentrations, may be a legitimate solution to address treatment failure. This review focuses on rifampicin, a critical anti-TB drug, and examines its suitability for TDM and the socio-economic factors that may influence the implementation of TDM in clinical practice in resource-limited settings, illustrated by Tanzania, thereby contributing to the advancement of personalized TB treatment., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.)

Background: The end tuberculosis (TB) strategy requires a novel patient treatment approach contrary to the one-size-fits-all model. It is well known that each patient's physiology is different and leads to various rates of drug elimination. Therapeutic drug monitoring (TDM) offers a way to manage drug dosage adaptation but requires trained pharmacologists, which is scarce in resource-limited settings., Objective: We will develop an automated clinical decision support system (CDSS) to help practitioners with the dosage adaptation of rifampicin, one of the essential medical drugs targeting TB, that is known for large pharmacokinetic variability and frequent suboptimal blood exposure. Such an advanced system will encourage the spread of a dosage-individualization culture, including among practitioners not specialized in pharmacology. Thus, the objectives of this project are to (1) develop the appropriate population pharmacokinetic (popPK) model for rifampicin for Tanzanian patients, (2) optimize the reporting of relevant information to practitioners for drug dosage adjustment, (3) automate the delivery of the report in line with the measurement of drug concentration, and (4) validate and implement the final system in the field., Methods: A total of 3 teams will combine their efforts to deliver the first automated TDM CDSS for TB. A cross-sectional study will be conducted to define the best way to display information to clinicians. In parallel, a rifampicin popPK model will be developed taking advantage of the published literature, complemented with data provided by existing literature data from the Pan-African Consortium for the Evaluation of Antituberculosis Antibiotics (panACEA), and samples collected within this project. A decision tree will be designed and implemented as a CDSS, and an automated report generation will be developed and validated through selected case studies. Expert pharmacologists will validate the CDSS, and finally, field implementation in Tanzania will occur, coupled with a prospective study to assess clinicians' adherence to the CDSS recommendations., Results: The TuberXpert project started in November 2022. In July 2024, the clinical study in Tanzania was completed with the enrollment of 50 patients to gather the required data to build a popPK model for rifampicin, together with a qualitative study defining the report design, as well as the CDSS general architecture definition., Conclusions: At the end of the TuberXpert project, Tanzania will possess a new tool to help the practitioners with the adaptation of drug dosage targeting complicated TB cases (TB or HIV, TB or diabetes mellitus, and TB or malnutrition). This automated system will be validated and used in the field and will be proposed to other countries affected by endemic TB. In addition, this approach will serve as proof of concept regarding the feasibility and suitability of CDSS-assisted TDM for further anti-TB drugs in TB-burdened areas deprived of TDM experts, including second-line treatments considered important to monitor., International Registered Report Identifier (irrid): DERR1-10.2196/58720., (©Yann Thoma, Annie E Cathignol, Yuan J Pétermann, Margaretha L Sariko, Bibie Said, Chantal Csajka, Monia Guidi, Stellah G Mpagama. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 21.10.2024.)

Background: Poor glycemic control during tuberculosis (TB) treatment is challenging, as the optimum treatment strategy remains unclear. We assessed hyperglycemia severity using glycated hemoglobin (HbA1c) test and predictors of severe hyperglycemia at the time of TB diagnosis in three resources-diverse regions in Tanzania., Methods: This was a substudy from a large cohort study implemented in three regions of Tanzania. TB individuals with diabetes mellitus (DM) (prior history of DM or newly diagnosed DM) were assessed for hyperglycemic levels using HbA1c test and stratified as mild (<53 mmol/mol), moderate (≥53-<86 mmol/mol), and severe (≥86 mmo/mol)., Results: From October 2019 to September 2020, 1344 confirmed TB individuals were screened for DM and 105 (7.8%) individuals had dual TB/DM and were assessed for glycemic levels. Of these, 69 (67.7%) had a prior history of DM and 26 (24.8%) were living with human immunodeficiency virus. Their mean age was 49.0 (±15.0) years and 56.2% were male. The majority (77.1%) had pulmonary TB, and 96.2% were newly diagnosed TB individuals. HbA1c test identified 41(39.0%), 37 (35.2%), and 27 (25.7%) individuals with severe, moderate, and mild the hyperglycaemia respectively. Female sex (odds ratio [OR]: 3.55, 95% confidence interval [CI]: 1.06-11.92, P = 0.040) and previous history of DM (OR: 3.71, 95% CI: 1.33-10.33, P = 0.013) were independent risk factors for severe hyperglycemic at the time of TB diagnosis., Conclusion: By integrating early HbA1c testing, a substantial proportion of individuals with severe hyperglycemia were identified. HbA1c testing can be recommended to identify and triage patients requiring personalized intensified DM management in resource-limited programmatic settings., Competing Interests: None

Background: Suboptimal exposure to antituberculosis (anti-TB) drugs has been associated with unfavourable treatment outcomes. We aimed to investigate estimates and determinants of first-line anti-TB drug pharmacokinetics in children and adolescents at a global level., Methods: We systematically searched MEDLINE, Embase and Web of Science (1990-2021) for pharmacokinetic studies of first-line anti-TB drugs in children and adolescents. Individual patient data were obtained from authors of eligible studies. Summary estimates of total/extrapolated area under the plasma concentration-time curve from 0 to 24 h post-dose (AUC 0-24 ) and peak plasma concentration ( C max ) were assessed with random-effects models, normalised with current World Health Organization-recommended paediatric doses. Determinants of AUC 0-24 and C max were assessed with linear mixed-effects models., Results: Of 55 eligible studies, individual patient data were available for 39 (71%), including 1628 participants from 12 countries. Geometric means of steady-state AUC 0-24 were summarised for isoniazid (18.7 (95% CI 15.5-22.6) h·mg·L -1 ), rifampicin (34.4 (95% CI 29.4-40.3) h·mg·L -1 ), pyrazinamide (375.0 (95% CI 339.9-413.7) h·mg·L -1 ) and ethambutol (8.0 (95% CI 6.4-10.0) h·mg·L -1 ). Our multivariate models indicated that younger age (especially <2 years) and HIV-positive status were associated with lower AUC 0-24 for all first-line anti-TB drugs, while severe malnutrition was associated with lower AUC 0-24 for isoniazid and pyrazinamide. N -acetyltransferase 2 rapid acetylators had lower isoniazid AUC 0-24 and slow acetylators had higher isoniazid AUC 0-24 than intermediate acetylators. Determinants of C max were generally similar to those for AUC 0-24 ., Conclusions: This study provides the most comprehensive estimates of plasma exposures to first-line anti-TB drugs in children and adolescents. Key determinants of drug exposures were identified. These may be relevant for population-specific dose adjustment or individualised therapeutic drug monitoring., Competing Interests: Conflict of interest: H.S. Schaaf reports grants from the NIH/IMPAACT; and honoraria from Ann Lake publications (sponsored by Johnson & Johnson) for an educational publication on the management of MDR-TB in children. A. Bekker reports grants from IMPAACT, UNITAID; lecture honoraria from Sandoz; support for attending PENTA PIM meeting; and received generic LPV/r, 3TC and ABC for the PETITE study. D.J. Bell reports support for attending a meeting from ViiV pharmaceuticals; and attendance fees for an advisory board meeting from ViiV pharmaceuticals. L. Choo reports grants from the UKRI MRC DFID Wellcome NIHR Joint Global Health Trials, TB Alliance Support for trial drug purchase and UKRI COVID-19 Grant Extension Allocation Award. P. Denti reports a grant for WHO expert review for TB drugs in children. S.M. Graham reports participation on a data safety monitoring board for the TB CHAMP trial; and leadership roles as a co-chair for the Guidelines Development Committee of the WHO updated recommendations and consolidated guidelines on child and adolescent TB, and as a core member for the WHO Child and Adolescent TB Working Group. S.K. Heysell reports grants from the NIH, DANIDA and EDTCP; royalties or licences from UpToDate; and honoraria for lectures from Henry Stewart Talks. A. Kwara reports a grant from the NIH/NICHD. V. Mave reports grants from the NIH and CDC. C.A. Peloquin reports a grant from the NIH. V. Roy reports a grant from the Delhi State TB Association; and leadership roles as a member of the Delhi State TB Association and the MAMC TB Committee. E.M. Svensson reports grants from the NWO personal Veni, IMI UNITE4TB consortium, TB Alliance, UNITAID BenefitKids consortium, WHO expert review, NIH support for IMPAACT studies, Blueprint, Probex, ACTG study Clo-FAST, Janssen Pharmaceuticals, EDCTP support PanTB-HM and Legochem; and leadership or fiduciary roles in the ISOP DI&E committee and BenNeLux PMX organising committee. U. Thatte reports participation on a data safety monitoring board for an ICMR TB trial. T.A. Thomas reports grants from the NIH and the University of Virginia. D.J. Touw reports a grant from Chiesi; consulting fees from Pure IMS and Sanguin; and participation on a data safety monitoring board for the FORMAT trial. A. Turkova reports grants from the UKRI MRC DFID Wellcome NIHR Joint Global Health Trials and MRC Grants for core funding of the Medical Research Council Clinical Trials Unit at the UCL; and TB Alliance Support for SHINE trial drug purchase. All of this work was declared by the authors to be outside the submitted work. All other authors declare no competing interests., (Copyright ©The authors 2023.)

Introduction: Poor quality of health care services remains an important challenge in health care delivery systems. Here, we validate clinical audit tools and describe audit results of selected clinical standards related to communicable disease (CD) and non-communicable disease (NCD) integration at the primary health care level., Methodology: A multi-methods approach, including a retrospective cohort and cross-sectional design, was deployed concurrently at Health Centres. Separate evaluators assessed the Health Centres using an audit tool and the inter-rater/inter-observer reliability was estimated. The extent of adherence to clinical standards was measured in proportions for: infection prevention control, tuberculosis (TB) diagnosis including advanced TB/Human Immunodeficiency Virus (HIV), the diagnosis of chronic lung diseases, and the bidirectional screening and clinical management of TB and Diabetes Mellitus (DM)., Results: The inter-rater reliability for the clinical audit tools based on 130 individuals' charts was 99.5% (CI:99-100). The total estimated maximum score for infection prevention control was 114 and on average health centres scored 42 (37%). Only 3 (4%) of 80 individuals' medical charts with unexplained productive cough were evaluated for TB. None of the 24 individuals with HIV infection medical charts had vitals measured and only 6 (25%) patients with advanced HIV had a TB test performed, whereas 4 (17%) had a cryptococcal antigen test, and 1 (4%) had a chest radiograph. Also, 24 patients' chart from documented HIV negative with chronic cough had no records of spirometry or peak flowmeter or a chest radiograph. However, a diagnosis of asthma and chronic obstructive pulmonary disease as made in 17 (71%) and 7 (29%), respectively. TB was confirmed for 102 patients among whom only 12(12%) were screened for DM. The DM clinics had no TB presumptive registers. Patients with TB/DM (n=2) had a glycated haemoglobin (HbA1c) measurement done and received appropriate management., Conclusion and Recommendation: The developed clinical audit tools were reliable and could contribute to quality measurement for metrics-related integration of CD and NCD in Tanzania. Further investigations will determine if the clinical audit tools widely used in cycles can improve the quality of care in health care delivery systems., (© The East African Health Research Commission 2023.)

Early and accurate diagnosis and rigorous clinical and microbiological monitoring of multidrug-resistant tuberculosis (MDR-TB) treatment can curb morbidity and mortality. While others are still under evaluation, the World Health Organization has recommended few novel molecular methods for MDR-TB diagnosis only. We present current molecular methods for diagnosis and monitoring of MDR-TB treatment in TB-endemic settings. A systematic meta-narrative review was conducted according to the RAMESES recommendations. Electronic databases were searched for relevant articles published in English language from January 2013 to June 2018. Based on predefined criteria, two independent reviewers extracted the key messages from relevant articles. Disagreement between them was resolved through discussion and the involvement of a third reviewer, if needed. Key messages were synthesized to create the meta-narratives for method's accuracy, drug-susceptibility capability, and laboratory infrastructure required. We included 33 articles out of 1213 records retrieved, of which 16 (48%) and 12 (36%) were conducted in high- and low-TB-endemic settings, respectively. Xpert ® MTB/RIF, GenoType MTBDRplus, GenoType MTBDRsl, FlouroType™ MTBDR, TB TaqMan ® array card, and DNA sequencers can accurately guide effective treatment regimens. Molecular bacterial load assay quantifies mycobactericidal impact of these regimens. Although they present inherent advantages compared to the current standard of care, they carry important limitations to implementation and/or scale-up. Therefore, considerable effort must now be directed to implementation and health systems research to maximize these forecasted benefits for individual patient's health outcomes., Competing Interests: None

Background: Tanzania is one of the countries confronting a multidrug-resistant tuberculosis (MDR-TB) epidemic., Research: Research studies on drug susceptibility testing (DST) for second-line TB drugs given to Tanzanian MDR-TB patients has demonstrated mycobacterial resistance to important MDR-TB drugs, such as ethionamide, ofloxacin, amikacin, kanamycin, and pyrazinamide. Likewise, pharmacokinetic studies have shown a high frequency of patients with circulating serum drug levels below the expected ranges, especially for levofloxacin and kanamycin - key drugs in MDR-TB treatment that also affect ex-vivo plasma drug activity., Recommendations: We suggest using molecular diagnostic assays, such as the GenoType MTBDRplus test, and inhA and/or katG genotypic results to optimize MDR-TB treatment. Quantitative drug susceptibility can guide the selection of options for second-line anti-TB drugs. The TB drug assay, an alternative biomarker for therapeutic drug monitoring, can identify patients who have extensively drug-resistant TB or are exposed to suboptimal serum drug levels of, specifically, levofloxacin and kanamycin., Competing Interests: Competing Interests: None declared., (© The East African Health Research Commission 2018.)

Settings: Kibong'oto Infectious Diseases Hospital, Kilimanjaro, Tanzania., Objective: Characterise multidrug-resistant tuberculosis (MDR-TB)-treated cases during the scaling up of molecular diagnostics using Xpert MTB/RIF and GenoType MTBDRplus., Design: Retrospective cohort study., Results: A total of 223 MDR-TB patients were referred to the Kibong'oto Infectious Disease Hospital from January 2013 through December 2014. Four cities-Dar es Salaam, Mbeya, Mwanza, and Tanga-contributed 144 (65%) of referrals. Of the total referred patients, HIV coinfection was found in 92 (41%) and 180 (81%) had history of previous TB treatment. Molecular drug susceptibility testing (DST) contributed 201 (91%) of referrals and resulted in a shorter time from diagnosis to start of treatment, 30 days (95% confidence interval [CI], 26-37), compared to conventional phenotypic DST, 212 days (95% CI, 151-272; P <.001). Molecular DST found higher proportions of MDR-TB children and people living with HIV without prior treatment, 5 (12%) and 24 (56%), respectively, compared to those with previous treatment for TB, 4 (2%) and 68 (38%), respectively. The median CD4 count correspondingly was 131 cells/μl (IQR, 109-131) and 200 cells/μl (IQR, 94-337) for MDR-TB diagnosed by phenotypic and molecular diagnostics ( P =.70). Despite the more rapid time to treatment initiation among patients diagnosed by molecular DST, treatment outcomes, including time to sputum culture conversion, did not differ compared to those diagnosed with conventional phenotypic DST. Regardless of the method of diagnosis, MDR-TB/HIV coinfected patients who died had lower CD4 counts (mean 86 ± 87 cells/μl) than survivors (mean 274 ± 224 cells/μl; P =.02)., Conclusion: Molecular diagnostics appear to speedup the time to treatment initiation, but may not improve other treatment outcomes., Competing Interests: Competing Interests: None declared., (© The East African Health Research Commission 2017.)

Little is known about plasma drug concentrations relative to quantitative susceptibility in patients with multidrug-resistant tuberculosis (MDR-TB). We previously described a TB drug activity (TDA) assay that determines the ratio of the time to detection of plasma-cocultured Mycobacterium tuberculosis versus control growth in a Bactec MGIT system. Here, we assess the activity of individual drugs in a typical MDR-TB regimen using the TDA assay. We also examined the relationship of the TDA to the drug concentration at 2 h (C2) and the MICs among adults on a MDR-TB regimen in Tanzania. These parameters were also compared to the treatment outcome of sputum culture conversion. Individually, moxifloxacin yielded superior TDA results versus ofloxacin, and only moxifloxacin and amikacin yielded TDAs equivalent to a -2-log killing. In the 25 patients enrolled on a regimen of kanamycin, levofloxacin, ethionamide, pyrazinamide, and cycloserine, the C2 values were found to be below the expected range for levofloxacin in 13 (52%) and kanamycin in 10 (40%). Three subjects with the lowest TDA result (<1.5, a finding indicative of poor killing) had significantly lower kanamycin C2/MIC ratios than subjects with a TDA of ≥1.5 (9.8 ± 8.7 versus 27.0 ± 19.1; P = 0.04). The mean TDAs were 2.52 ± 0.76 in subjects converting to negative in ≤2 months and 1.88 ± 0.57 in subjects converting to negative in >2 months (P = 0.08). In Tanzania, MDR-TB drug concentrations were frequently low, and a wide concentration/MIC range was observed that affected plasma drug activity ex vivo. An opportunity exists for pharmacokinetic optimization in current MDR-TB regimens, which may improve treatment response.