Vycke Yunivita

Background: High-dose rifampicin could potentially shorten tuberculosis preventive therapy (TPT) and improve outcomes. We aimed to characterize population pharmacokinetics of standard- and high-dose rifampicin for TPT among individuals with tuberculosis infection. Methods: Intensive and sparse pharmacokinetic substudies were conducted in Indonesia, Canada, and Vietnam within the 2R2 randomized trial, which compared 2 months of high-dose rifampicin at 20 mg/kg/day (2R20) or 30 mg/kg/day (2R30) with 4 months of standard-dose rifampicin at 10 mg/kg/day (4R10) in adults and adolescents aged ≥ 10 years. Venous blood samples were collected after 4 weeks of treatment. Rifampicin pharmacokinetics were analyzed using nonlinear mixed-effects modeling in NONMEM. Results: Among 1368 trial participants, 440 were included in model development (51 intensive and 389 sparse sampling), with 191 (43%) assigned to 4R10, 159 (36%) to 2R20, and 90 (20%) to 2R30. A 1-compartment model with saturable hepatic extraction and transit-compartment absorption best described rifampicin pharmacokinetics. All disposition parameters were allometrically scaled using fat-free mass. Country-specific differences, particularly variation in drug formulation, were associated with lower bioavailability in Canada {−21.8% (95% confidence interval [CI] −27.9 to −18.0%)} and Vietnam (−12.3% [95% CI −17.7 to −7.9%]) compared with Indonesia. The 24-hour area under the concentration–time curve increased more than proportionally with dose and was higher across treatment arms in Indonesia, followed by Vietnam and Canada. Conclusions: High-dose rifampicin for TPT resulted in greater-than-proportional increases in exposure due to nonlinear clearance at higher doses. Substantial between-country variability in exposure was observed, which may have been due to multiple factors, including differences in country-specific formulations, fat-free mass, and unmeasured confounders.

Tuberculosis (TB) is a major global health concern, especially in vulnerable populations, such as pregnant women. Changes in the immune system in pregnancy may impair the individual’s ability to withstand this infection. The objective of this scoping review was to systematically map the available literature regarding alteration of the immune response, specifically cytokines profiles, in pregnant women with or without TB. We conducted a systematic search of four databases (PubMed, EBSCO, ScienceDirect, and Scopus). Studies reporting on cytokine measurements in pregnant women with TB were included. Two reviewers independently screened titles/abstracts and full texts against predefined eligibility criteria. Data were charted on study characteristics, population, and reported cytokine outcomes. From 1.320 records, 14 studies were ultimately included based on the exclusion and inclusion criteria. Pregnant women with TB were shown to have reduction in adaptive proinflammatory response, mainly by the decrease of IFN-γ and IL-2 levels in the latter stage of pregnancy. However, this still remains conflicted due to several studies that state otherwise. Other cytokines, such as IL-6 and IL-17, and TGF-β, show a notable depletion in the concentration suggesting the enhancement of the vulnerability of pregnant individuals. Interestingly, there is a rise in the number and function of innate immune cells, which can be seen from the elevated levels of proinflammatory cytokines, including IP-10, MCP-2, and antiinflammatory cytokine, which is IL-1ra. This scoping review provides an overview of the current evidence landscape. It highlights methodological heterogeneity and inconsistent reporting as major challenges in drawing definitive conclusions. The findings underscore the need for more standardized, longitudinal studies to clarify the immune dynamics in pregnant women with TB. This map can guide future primary research and systematic reviews.

Background: Tuberculous meningitis (TBM) is the most common central nervous system (CNS) infection caused by “ Mycobacterium tuberculosis ,” leading to significant neurological deficits and high mortality rates. Effective treatment is essential to control the infection. This literature review aims to evaluate recent advancements in anti-tuberculosis therapy for TBM, focusing on optimizing treatment regimens. Methods: This literature review primarily draws from studies available in the PubMed and Scopus databases on TBM regimens, focusing on publications that evaluate higher doses or novel drug therapies. Key search terms included “tuberculous meningitis,” “anti-tuberculosis therapy,” and “novel treatment regimens.” Results: Findings suggest that while standard tuberculosis (TB) regimens are effective for pulmonary TB, they may be suboptimal for TBM due to limited CNS drug penetration. Recent investigations propose higher drug doses and novel medications to enhance efficacy in TBM treatment. Conclusion: The review highlights the need for TBM-specific treatment regimens with optimized dosing and new drug formulations to improve patient outcomes. Further research is needed to validate these emerging therapies.

Introduction: Tuberculosis (TB) patients with a history of ATT therapy are associated with changes in IL-17 levels, lymphocyte counts, and neutrophil counts. Increased IL-17 levels, lymphocyte counts and neutrophil counts indicate colonisation of Candida sp. fungus. Changes in the immune response in TB patients with Candida sp. colonisation may cause complications of TB that affect the treatment success rate. Methods: This research was designed for observational analytical study with a cross-sectional design. 59 subjects are divided into 3 groups, consisting of 21 TB-positive people with Candida sp. colonisation, 21 TB-positive people without Candida sp. colonisation, and 17 TB-negative people with Candida sp. colonisation. Plasma IL-17 levels are examined using the ELISA test, while the lymphocyte and neutrophil counts are seen from previous study examinations (AFFECT). Results: The plasma IL-17 levels in the TB-positive group with Candida sp. colonisation were 24.05 pg/ml (IQR 21.77-30.50). The plasma IL-17 levels in the TB-positive group without Candida sp colonisation were 23.08 pg/ml (IQR 19.11-32.46). The plasma IL-17 levels in the TB-negative group with Candida sp. colonisation is 20.72 pg/ml (IQR 18.51-22.84) pg/ml, (p=0.046). However, there are no statistically significant difference was observed in lymphocyte and neutrophil counts (p=0.078). Conclusions: The differences in IL-17 levels that occur in the TB group with Candida sp colonisation may serve as an immunological signal suggesting the need for fungal assessment if the TB patients do not improve their treatment outcome after undergoing ATT for over 6 months.

Introduction: Systemic Lupus Erythematosus (SLE) is a chronic autoimmune inflammatory disease with a high risk of tuberculosis (TB) infection, especially in those living in TB-endemic areas. Isoniazid (INH), an anti-tuberculosis drug, is recommended as preventive therapy in TB susceptible groups, however, its use in SLE is still controversial. SLE patients are more likely to have compromised liver function which can influence the kinetic of INH. The aim of the study was to explore the pharmacokinetic profile of INH and acetylator status in SLE patients. Methods: This was a descriptive observational study with a purposive sampling technique, including adult female SLE at Dr. Hasan Sadikin Hospital Bandung, conducted in January - August 2023. Inclusion criteria were SLE patients in remission with no TB infection; whereas the exclusion criteria were INH allergy, liver or kidney disorders, pregnant or lactating patients, and malignancy. Pharmacokinetic data was collected from six blood collection time points (0, 1, 2, 3, 4, and 8 hours) after 10 days of daily INH 300 mg administration on an empty stomach. Results: In total, 20 female SLE patients were included. The C_max value was 8.73 (2.55– 18.27) mg/L and AUC_0-24 was 28.01 (8.82– 79.40) mg.h/L. Conclusion: In terms of pharmacokinetic features, preventive isoniazid (INH) daily use of 300mg in SLE is sufficient to provide the prospect of protection from TB. These findings suggest that INH prophylaxis may be a viable strategy for TB prevention in SLE patients, warranting further investigation into long-term safety and efficacy.

Background: Tuberculous meningitis (TBM) is the most common central nervous system infection of Mycobacterium tuberculosis (M.tb). The infection will cause focal neurological deficits and can be fatal, so that it will increase the morbidity and mortality rates. Adequate treatment is needed so that the drug can reach the center of infection. Not all anti-tuberculosis (TB) drugs can effectively cross the blood–brain and blood-cerebrospinal fluid barriers. The use of higher doses is expected to be able to work on the center of infection effectively. However, the use of higher doses will also increase the risk of drug-induced liver injury, which requires temporary discontinuation of the suspected drug. Methods: This scientific work aims to determine the penetration rate of first-line anti-TB drugs that are often used in patients infected with M.tb, especially TBM. Journal searches were performed on PubMed/PMC and BioMed Central/BMC search engines with the appropriate keywords. Critical appraisal analysis was carried out in selected journals. CSF sampling can be done to establish the diagnosis of TBM. CSF characteristics in TBM include lymphocyte pleocytosis, increased protein levels, and decreased glucose levels. Results: The results of CSF analysis depend on the volume of CSF used, the delivery of the sample, and the technical expertise of the clinician. If clinically, a patient is suspected of having TBM even though the results of CSF analysis show negative results for M.tb bacteria, a drug regimen can be given immediately to prevent worsening of the patient’s condition. Bacterial cultures may be performed as treatment progresses. Based on the penetration rate of anti-TB drugs in the CSF, isoniazid (INH), pyrazinamide, and fluoroquinolones, especially levofloxacin, are drugs with fairly good CSF penetration. Conclusion: The use of INH is beneficial because it has high bactericidal activity. Gatifloxacin and ciprofloxacin, which are included in the fluoroquinolone class of drugs, are safe to use even though their CSF penetration is not as good as levofloxacin.

Background/Objectives: Studies show that SNPs in ABCB1 rs2032582 and SLCO1B1 rs4149015 affect the PK profile of moxifloxacin, a key drug for MDR-TB. This study aimed to assess the genotype frequencies of ABCB1 rs2032582 and SLCO1B1 rs4149015; describe moxifloxacin AUC_0–24 and C_max; and evaluate the association between genotype variations and moxifloxacin AUC_0–24 and C_max, corrected for the effect of other determinants in MDR-TB patients in Indonesia. Methods: The genotypes were identified using DNA sequencing. Plasma samples for PK analysis were collected at either two or four timepoints post-dose, at steady state. AUC_0–24 values were assessed with a limited sampling formula. A multivariate linear regression analysis identified the determinants for moxifloxacin AUC_0–24 and C_max. Results: We recruited 204 MDR-TB patients for PG analysis, with 80 providing PK samples. The majority of the ABCB1 and SLCO1B1 genotypes were wildtype (GG), 41.7% and 93.6%, respectively. The geometric mean AUC_0–24 for moxifloxacin was 78.6 mg·h/L and that for C_max was 6.1 mg/L. No statistically significant difference in exposure to moxifloxacin could be shown between the genotypes. Sex, age, and dose in mg/kg/body weight were significant determinants of the AUC_0–24 of moxifloxacin. Conclusions: The major genotype of ABCB1 rs2032582 and SLCO1B1 rs4149015 was wildtype, and the exposure to moxifloxacin was high but not related to the studied genotype in an Indonesian population.

Corona Virus Disease-19 (COVID-19) yang disebabkan oleh Severe Acute Respiratory Syndrome Corona Virus 2 (SARS-CoV-2) menyebar dengan cepat di seluruh dunia. Para peneliti berupaya untuk menemukan terapi untuk penyakit ini. Strategi penemuan terapi ini salah satunya dengan menggunakan obat di luar indikasi asalnya (drug repurposing) yang lebih cepat diperoleh dan terjangkau dibandingkan penemuan obat baru. Hasil skrining terhadap obat yang sudah tersedia dan senyawa alami, menunjukkan hesperidin dan diosmin memiliki potensi untuk menginhibisi siklus hidup SARS-CoV-2. Hesperidin dan Diosmin dalam bentuk Micronized Purified Flavonoid Fraction (MPFF), sebelumnya digunakan sebagai pengobatan insufisiensi vena kronik. Tujuan penulisan kajian ini yaitu untuk mengkaji potensi hesperidin dan diosmin dalam menginhibisi jalur infeksi COVID-19. Metode yang digunakan pada kajian pustaka ini yaitu metode tinjauan pustaka naratif dengan pencarian literatur melalui database Google Scholar, Pubmed, dan ScienceDirect. Hasil kajian yang dilakukan menunjukkan dari 2012 jurnal didapatkan 16 jurnal in silico yang menunjukkan target pengobatan pada infeksi COVID-19 pada hesperidin dan diosmin diantaranya dapat menghambat reseptor Angiotensin Converting Enzyme 2 (ACE2) yang menjadi tempat SARS-CoV-2 berikatan dengan sel inang, menghambat aktivitas Transmembrane Serine Protease 2 (TMPRSS2), menghambat proses proteolitik dengan menghambat enzim 3Clpro, menghambat aktivitas RNA dependent RNA polymerase (RdRp) yang menghambat pembentukan protein struktural SARS-CoV-2. Selain itu, hesperidin dapat menghambat aktivitas protein virus nucleocapsid dan menghambat sitokin pro-inflammatory. Sebagai kesimpulan, hesperidin dan diosmin dapat menjadi kandidat yang potensial dalam menginhibisi COVID-19.