Variability in plasma rifampicin concentrations and role of SLCO1B1, ABCB1, AADAC2 and CES2 genotypes in Ethiopian patients with tuberculosis.

BACKGROUND: Rifampicin, a key drug against tuberculosis (TB), displays wide between-patient pharmacokinetics variability and concentration-dependent antimicrobial effect. We investigated variability in plasma rifampicin concentrations and the role of SLCO1B1, ABCB1, arylacetamide deacetylase (AADAC) and carboxylesterase 2 (CES-2) genotypes in Ethiopian patients with TB. METHODS: We enrolled adult patients with newly diagnosed TB (n = 119) who had received 2 weeks of rifampicin-based anti-TB therapy. Venous blood samples were obtained at three time points post-dose. Genotypes for SLCO1B1 (c.388A > G, c.521T > C), ABCB1 (c.3435C > T, c.4036A > G), AADACc.841G > A and CES-2 (c.269-965A > G) were determined. Rifampicin plasma concentration was quantified using LC-MS/MS. Predictors of rifampicin Cmax and AUC0-7 h were analysed. RESULTS: The median rifampicin Cmax and AUC0-7 were 6.76 µg/mL (IQR 5.37-8.48) and 17.05 µg·h/mL (IQR 13.87-22.26), respectively. Only 30.3% of patients achieved the therapeutic efficacy threshold (Cmax>8 µg/mL). The allele frequency for SLCO1B1*1B (c.388A > G), SLCO1B1*5 (c.521T > C), ABCB1 c.3435C > T, ABCB1c.4036A > G, AADAC c.841G > A and CES-2 c.269-965A > G were 2.2%, 20.2%, 24.4%, 14.6%, 86.1% and 30.6%, respectively. Sex, rifampicin dose and ABCB1c.4036A > G, genotypes were significant predictors of rifampicin Cmax and AUC0-7. AADACc.841G > A genotypes were significant predictors of rifampicin Cmax. There was no significant influence of SLCO1B1 (c.388A > G, c.521T > C), ABCB1c.3435C > T and CES-2 c.269-965A > G on rifampicin plasma exposure variability. CONCLUSIONS: Subtherapeutic rifampicin plasma concentrations occurred in two-thirds of Ethiopian TB patients. Rifampicin exposure varied with sex, dose and genotypes. AADACc.841G/G and ABCB1c.4036A/A genotypes and male patients are at higher risk of lower rifampicin plasma exposure. The impact on TB treatment outcomes and whether high-dose rifampicin is required to improve therapeutic efficacy requires further investigation.

Correlation of N-acetyltransferase 2 genotype and acetylation status with plasma isoniazid concentration and its metabolic ratio in ethiopian tuberculosis patients.

Unfavorable treatment outcomes for tuberculosis (TB) treatment might result from altered plasma exposure to antitubercular drugs in TB patients. The present study investigated the distribution of the N-Acetyltransferase 2 (NAT2) genotype, isoniazid acetylation status, genotype-phenotype concordance of NAT2, and isoniazid plasma exposure among Ethiopian tuberculosis patients. Blood samples were collected from newly diagnosed TB patients receiving a fixed dose combination of first-line antitubercular drugs daily. Genotyping of NAT2 was done using TaqMan drug metabolism assay. Isoniazid and its metabolite concentration were determined using validated liquid chromatography-tandem mass spectrometry (LC-MS/MS). A total of 120 patients (63 male and 57 female) were enrolled in this study. The mean daily dose of isoniazid was 4.71 mg/kg. The frequency of slow, intermediate, and fast NAT2 acetylators genotypes were 74.2%, 22.4%, and 3.3% respectively. The overall median isoniazid maximum plasma concentration (Cmax) was 4.77 µg/mL and the AUC0-7 h was 11.21 µg.h/mL. The median Cmax in slow, intermediate, and fast acetylators were 5.65, 3.44, and 2.47 µg/mL, respectively. The median AUC0-7 h hour in slow, intermediate, and fast acetylators were 13.1, 6.086, and 3.73 mg•h/L, respectively. The majority (87.5%) of the study participants achieved isoniazid Cmax of above 3 µg/mL, which is considered a lower limit for a favorable treatment outcome. There is 85% concordance between the NAT2 genotype and acetylation phenotypes. NAT2 genotype, female sex, and dose were independent predictors of Cmax and AUC0-7 h (p < 0.001). Our finding revealed that there is a high frequency of slow NAT2 genotypes. The plasma Cmax of isoniazid was higher in the female and slow acetylators genotype group. The overall target plasma isoniazid concentrations in Ethiopian tuberculosis patients were achieved in the majority of the patients. Therefore, it is important to monitor adverse drug reactions and the use of a higher dose of isoniazid should be closely monitored.

Opportunities, associations, and impact of early intravenous to oral antimicrobial switch for hospitalized patients in Ethiopia.

Objective: Short intravenous antimicrobial therapy for 2-3 days followed by its per oral comparable antimicrobial course is a crucial part of the antimicrobial stewardship program. However, nothing is known about this practice in Ethiopian hospitals. Therefore, this study assessed the proportion, associations, and outcomes of early intravenous to per oral antimicrobial switch for patients who were admitted to the three wards of Ambo University Referral Hospital. Method: A hospital-based prospective cohort pilot study was conducted. During the 3-month period, 117 patients met initial inclusion criteria and were followed until Day 3 of intravenous antimicrobial. Of these, 92 (78.6%) subsequently met criteria for early intravenous to per oral switch and are the cohort investigated in this study. Written informed consent was sought from participants and/or parents or guardian for ages 15-17 years. Logistic regression models and independent t-tests were done with a significance of p ⩽ 0.05. Results: Out of 92 study participants, early intravenous to per oral antimicrobial switch was done only for 36 (39.1%). The only independent predictors for lack of early intravenous to per oral antimicrobials switch were poly-pharmacy (adjusted odds ratio = 3.4 at 95% confidence interval, 1.036-11.16; p = 0.044). There was a significant difference in terms of mean length of hospital stay (8.80 ± 3.57 versus 3.17 ± 0.74; p < 0.0001), in-hospital complication rate (95% versus 5%; p < 0.0001), and the mean cost of healthcare in Ethiopian Birrs (652.29 ± 403.29 versus 126.67 ± 29.47; p < 0.0001) between the comparator/early intravenous to per oral not switched and early switched group, respectively. Conclusion: The proportion of early intravenous to per oral antimicrobial switch was unsatisfactory. There was a significant difference between the intervention and comparator groups in terms of length of hospital stay, in-hospital complications, and extra cost. Therefore, implementation of interventions that improve the practice of early intravenous to per oral switch is needed urgently.

Effect of Genetic Variations in Drug-Metabolizing Enzymes and Drug Transporters on the Pharmacokinetics of Rifamycins: A Systematic Review.

Background: Rifamycins are a novel class of antibiotics clinically approved for tuberculosis chemotherapy. They are characterized by high inter-individual variation in pharmacokinetics. This systematic review aims to present the contribution of genetic variations in drug-metabolizing enzymes and transporter proteins to the inter-individual variation of rifamycin pharmacokinetics. Method: We followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement guidelines. The search for relevant studies was done through PubMed, Embase, Web of Science, and Scopus databases. Studies reporting single nucleotide polymorphism in drug transporters and metabolizing enzymes' influence on rifamycin pharmacokinetics were solely included. Two reviewers independently performed data extraction. Results: The search identified 117 articles of which 15 fulfilled the eligibility criteria and were included in the final data synthesis. The single nucleotides polymorphism in the drug transporters SLCO1B1 rs4149032, rs2306283, rs11045819, and ABCB1 rs1045642 for rifampicin, drug metabolizing enzyme AADAC rs1803155 for rifapentine and CES2 c.-22263A>G (g.738A>G) for rifampicin partly contributes to the variability of pharmacokinetic parameters in tuberculosis patients. Conclusion: The pharmacokinetics of rifamycins is influenced by genetic variation of drug-metabolizing enzymes and transporters. Controlled clinical studies are, however, required to establish these relationships.

Non-Prescription Antibiotics Use and Associated Factors Among Drug Retail Outlets in Ambo, Ethiopia: A Cross-Sectional Study.

PURPOSE: To assess the non-prescription use of antibiotics and associated factors in Ambo Town, West Shoa, Oromia, Ethiopia. METHODS: An institutional-based cross-sectional study design supported with the qualitative study was conducted in Ambo Town from February 1 to March 1, 2020. Data were collected using a pretested semi-structured questionnaire and in-depth interview guide questions. Simple random sampling was used to select retail outlets and systematic random sampling to select study participants. The data analysis was done using SPSS and univariate and multivariate binary logistic regression analysis was performed to identify factors associated with non-prescription use of antibiotics. Thematic framework analysis was applied for the qualitative data. RESULTS: From the 421 study sample, a total of 399 participants were interviewed with a 94.8% response rate. Among the study participants, 214 (53.6) were males, 228 (57.1%) were married, 191 (47.9%) were orthodox by religion, and 343 (86%) were Oromo by ethnicity. One hundred seventy-two (43.1%; 95% CI: 38.6, 48.1) of the participants had used non-prescribed antibiotics. Being male [AOR=2.21 95% CI: 1.276, 3.835], residing in rural area [AOR=3.659, 95% CI: 1.479, 9.054], holding diploma [AOR=0.120, 95% CI: 0.025, 0.591], and hold BSC degree [AOR=0.050, 95% CI: 0.007, 0.378], and being farmer [AOR=0.034, 95% CI: 0.004, 0.285] showed significant association with the non-prescription use of antibiotics. CONCLUSION: This study concluded that the non-prescription use of antibiotics 172 (43.1%) was relatively high. Being male, residing in a rural area, holding a diploma, BSc degree, and being a farmer were significantly associated with non-prescription use of antibiotics. So, West Shoa Zone regulatory body should actively focus on the prevention of non-prescription use of antibiotics through health communication and public awareness on the demerits of non-prescription use of antibiotics.

The Impact of First-Line Anti-Tubercular Drugs' Pharmacokinetics on Treatment Outcome: A Systematic Review.

BACKGROUND: Tuberculosis remains the major public health problem besides tremendous efforts to combat it. Most tuberculosis patients are treated with a standard dose of first-line anti-TB drugs. The cure rate, however, varies from patient to patient. Various factors have been related to anti-TB treatment failure. In recent years, studies associating lower plasma concentrations of anti-TB drugs with poor treatment outcomes are emerging although the results are inconclusive. OBJECTIVE: Investigate the impact of first-line anti-tubercular drugs pharmacokinetics on treatment outcome. METHODS: A systematic search of Pubmed, EMBASE, Web of Science, and the Cochrane Library for articles published in the English language between January 2010 to June 2020 was conducted to identify eligible studies describing associations of first-line anti-tubercular drug pharmacokinetics with treatment outcomes. The primary outcomes considered were pharmacokinetics parameter results and its association with treatment outcome. RESULTS: The search identified 1754 articles of which twelve articles; ten prospective observational studies and two controlled clinical trials fulfilled the eligibility criteria. The majority of the studies showed target concentrations for the first-line anti-tubercular drugs below the current standard range. Among the twelve studies, eleven studies assessed rifampicin pharmacokinetics of which eight reported association of drug concentration and treatment outcomes. Similarly, four out of eight and three out of seven reported drug concentration and treatment outcome association for isoniazid and pyrazinamide, respectively. Despite the low plasma concentration, a favorable treatment outcome was achieved for the bulk of the patients. Irrespective of the inconsistency, an increase in exposure to rifampicin improved the outcome, and lower rifampicin, isoniazid, and pyrazinamide concentration are associated with poor outcome. No data are available for ethambutol associating its pharmacokinetics with treatment outcomes. CONCLUSION: The pharmacokinetics of first-line antitubercular drugs can influence treatment outcomes. Further controlled clinical studies are, however, required to establish these relationships.