Browsing by Author "Sariko, Margaretha"

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    Rifampicin Exposure in Tuberculosis Patients with Comorbidities in Sub‑Saharan Africa: Prioritising Populations for Treatment—A Systematic Review and Meta‑analysis
    (Clinical Pharmacokinetics, 2025-07-03) Bibie Said; Yuan Pétermann; Howlett, Patrick; Guidi, Monia; Yann Thoma; Violet Dismas Kajogoo; Sariko, Margaretha; Scott, Heysell; Jan‑Willem Alffenaar; Mpolya, Emmanuel; Mpagama, Stellah
    Emerging evidence suggests that comorbidities like human immunodeficiency virus (HIV) infection, diabetes mellitus (DM), and malnutrition in tuberculosis (TB) patients can alter drug concentrations, thereby affecting the treatment outcomes. For these populations, personalised strategies such as therapeutic drug monitoring (TDM) may be essential. We investigated the variations of drug levels within comorbid populations and analysed the differences in patterns observed between sub-Saharan Africa (SSA) and non-SSA regions.We performed a systematic review and meta-analysis of rifampicin drug pharmacokinetics (PK) through searches of major databases from 1980 to December 2023. A random-effects meta-analysis model using R-studio version 4.3.2 was conducted to estimate pooled serum rifampicin exposure (area under the concentration-time curve [AUC], and peak maximum concentration [Cmax ]) between patients with TB-HIV infection, and TB-DM. Results From 3300 articles screened, 24 studies met inclusion criteria, contributing 33 comorbidity subgroups for meta- analysis. In SSA, 14 subgroups assessed rifampicin PK in TB-HIV, 1 in TB-DM, and none in TB-malnutrition. The pooled mean Cmax was below the recommended range (8–24 mg/L) for all subgroups. For TB-HIV, the pooled Cmax was 5.59 mg/L, 95% CI (4.59–6.59), I2 = 97% for SSA populations and 5.59 mg/L, 95% CI (3.65; 6.59) for non-SSA populations. The Cmax for TB-DM in SSA (9.60 ± 4.4 mg/L) exceeded non-SSA (4.27 mg/L, 95% CI [2.77–5.76]). The lowest AUC was in TB-HIV (SSA, 29.09 mg/L h, 95% CI [21.06; 37.13, I2 = 91%]). High variability and heterogeneity (I2 >90%) were observed, with most studies (20/23) showing low bias.
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    State of the art of real-life concentration monitoring of rifampicin and its implementation contextualized in resource-limited settings: the Tanzanian case
    (Oxford University Press, 2024-11-14) Petermann, Yuan; Said, Bibie; Cathignol, Annie; Sariko, Margaretha; Thoma, Yann; Mpagama, Stellah; Csajka, Chantal; Guidi, Monia
    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.
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    Whole genome sequencing-based drug resistance predictions of multidrug-resistant Mycobacterium tuberculosis isolates from Tanzania
    (Oxford University Press, 2022-04-21) Mbelele, Peter; Utpatel, Christian; Sauli, Elingarami; Mpolya, Emmanuel; Mutayoba, Beatrice; Barilar, Ivan; Dreyer, Viola; Merker, Matthias; Sariko, Margaretha; Swema, Buliga; Mmbaga, Blandina; Gratz, Jean; Addo, Kennedy; Pletschette, Michel; Niemann, Stefan; Houpt, Eric; Mpagama, Stellah; Heysell, Scott
    Background: Rifampicin- or multidrug-resistant (RR/MDR) Mycobacterium tuberculosis complex (MTBC) strains account for considerable morbidity and mortality globally. WGS-based prediction of drug resistance may guide clinical decisions, especially for the design of RR/MDR-TB therapies. Methods: We compared WGS-based drug resistance-predictive mutations for 42 MTBC isolates from MDR-TB pa tients in Tanzania with the MICs of 14 antibiotics measured in the Sensititre™ MycoTB assay. An isolate was phenotypically categorized as resistant if it had an MIC above the epidemiological-cut-off (ECOFF) value, or as susceptible if it had an MIC below or equal to the ECOFF. Results: Overall, genotypically non-wild-type MTBC isolates with high-level resistance mutations (gNWT-R) cor related with isolates with MIC values above the ECOFF. For instance, the median MIC value (mg/L) for rifampicin gNWT-R strains was .4.0 (IQR 4.0–4.0) compared with 0.5 (IQR 0.38–0.50) in genotypically wild-type (gWT-S, P,0.001); isoniazid-gNWT-R .4.0 (IQR 2.0–4.0) compared with 0.25 (IQR 0.12–1.00) among gWT-S (P= 0.001); ethionamide-gNWT-R 15.0 (IQR 10.0–20.0) compared with 2.50 (IQR; 2.50–5.00) among gWT-S (P, 0.001). WGS correctly predicted resistance in 95% (36/38) and 100% (38/38) of the rifampicin-resistant isolates with ECOFFs .0.5 and .0.125 mg/L, respectively. No known resistance-conferring mutations were present in genes associated with resistance to fluoroquinolones, aminoglycosides, capreomycin, bedaquiline, delamanid, linezolid, clofazimine, cycloserine, or p-amino salicylic acid. Conclusions: WGS-based drug resistance prediction worked well to rule-in phenotypic drug resistance and the absence of second-line drug resistance-mediating mutations has the potential to guide the design of RR/MDR-TB regimens in the future.