Genetic analysis of resistance and PK/PD model-based study of Moxifloxacin and Levofloxacin in multi-drug resistant tuberculosis patients attending hospitals in Southern Ethiopia
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Date
2023-06
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Addis Ababa University
Abstract
Background: Multi-drug resistant tuberculosis (MDR-TB) has hindered the therapeutic success of TB.
Patient, drug, and pathogen-related factors are critical to understanding, characterizing, and predicting
drug resistance, which help to tailor drug dosing taking into account inter-individual differences and
patient needs. The highly active World Health Organization (WHO) Group A fluoroquinolones, FQs
(moxifloxacin, MXF, and levofloxacin, LFX), exhibit inter-individual pharmacokinetic variability (IIV) that
may result in low drug exposure. The 24-hour area under the concentration-time curve over the minimum
inhibitory concentration (AUC0-24/MIC) is a strong predictor of FQ exposure and positive treatment
outcome. Ethiopia is one of the world nations with a high prevalence of MDR-TB. However, there is a lack
of data on factors affecting MDR-TB treatment success and one-size-fits-all scenario is the single most
common therapeutic strategy of TB in Ethiopia.
Objective: This dissertation aimed to study treatment outcome and its predictors, characterize and predict
MXF and LFX resistance in MDR-TB patient population using phenotypic and genotypic methods as well
as a PK/PD model-based study.
Methodology: A prospective observational study of 80 MDR-TB patients was carried out. Treatment
outcomes in patients receiving MXF-and LFX-based regimens were compared at the end of treatment. We
determined the plasma concentrations of MXF and LFX and their PK parameters. A PK/PD (AUC0-
24/MIC) analysis to predict the recommended probability of target attainment (PTA) was carried out for
IV
both drugs. The potential patient covariates which impact the model estimated PK profiles were also
screened. Drug resistance was characterized by phenotypic and genotypic methods, and the association
between patient and pathogen related variables, FQ-resistance and treatment outcome were evaluated.
Result: The total treatment success in this study was lower than the report in previous local and
international studies. The LFX-based MDR-TB regimen outperformed the MXF-based regimen.
Unsuccessful treatment outcome was predicted by a delayed culture conversion rate, history of alcohol
intake, lesion of lung cavities, serum levels of creatinine (Cr.). A one-compartment model with adjustments
was fit to the LFX and MXF concentrations. Cr. and body mass index (BMI) were covariates identified to
have impact on clearance and apparent volume distribution (Vd) of LFX and MXF, respectively. Exposures
to LFX and MXF were lower in study participants than in other settings. However, LFX-treated groups
experienced higher drug levels and exposure with dose. Nine clinical isolates (11.3%) were resistant
overall, all of which were at least resistant to FQs, while 3 were resistant to both FQs and injectable drugs.
Mutation in gyrA 94 was identified in 5 isolates. The MIC values were associated with patient treatment
outcomes. Cavitary lesion and serum creatinine predict FQ-resistant tuberculosis.
Conclusion: Exposure to either LFX or MXF may be inadequate, but LFX appears to provide better
treatment outcomes. Patient clinical and behavioral variables can predict drug exposure, drug resistance
and the overall treatment outcome. Even though the line probe assay (LPA) showed a moderate level of
resistance in Ethiopian patients, genotypic test results do not always correlate well with phenotypic results.
The actual drug resistance level could be higher than anticipated. Higher MIC values of clinical isolates
correlate with a higher risk of treatment failure. In such scenarios, dosage optimization may improve
outcome. GyrA mutation is associated with FQ-resistance in Ethiopian patients. Further controlled clinical
studies are needed to establish optimal doses and exposure of FQs.
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Keywords
Fluoroquinolones, multi-drug resistant tuberculosis, population pharmacokinetics, treatment outcome, gyrA sequencing