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Introduction: Sub-Saharan Africa and other low- and middle-income countries (LMICs) have the highest rates of antimicrobial resistance (AMR) driven by high rates of antimicrobial utilization. This is a concern as AMR appreciably increases morbidity, mortality and costs. Pharmacogenetics (PGx) and precision medicine are emerging approaches to combat AMR. Consequently, as a first step there is a need to assess AMR knowledge and attitudes, and knowledge of PGx, among healthcare professionals and use the findings to guide future interventions.Methodology: We conducted a cross-sectional study involving 304 healthcare professionals at tertiary hospitals in Lusaka, Zambia. Structural Equation Modeling (SEM) was used to analyze relationships among latent variables.Results: Overall correctness of answers concerning AMR among healthcare professionals was 60.4% (7/11). Knowledge of pharmacogenetics was low (38%). SEM showed that high AMR knowledge score correlated with a positive attitude toward combating AMR (p < 0.001). Pharmacists had relatively higher AMR knowledge scores (mean = 7.67, SD = 1.1), whereas nurses had lower scores (mean = 5.57, SD = 1.9). A minority of respondents [31.5% (n = 95)] indicated that poor access to local antibiogram data promoted AMR, with the majority [56.5% (n = 190)] responding that poor adherence to prescribed antimicrobials can lead to AMR. Pharmacists had the highest scores for attitude (mean = 5.60, SD = 1.6) whereas nurses had the lowest scores (mean = 4.02, SD = 1.4).Conclusion: AMR knowledge and attitudes, as well as knowledge on PGx among healthcare professionals in Zambia, is sub-optimal and has the potential to affect the uptake of precision medicine approaches to reduce AMR rates. Educational and positive behavioral change interventions are required to address this and in future, we will be seeking to introduce these to improve the use of antimicrobials.

BackgroundPraziquantel (PZQ) is the only drug available for the treatment of all forms of schistosomiasis. New paediatric formulations for the active enantiomer R-PZQ and the racemate PZQ are currently under development. There is however limited drug metabolism and pharmacokinetic data on PZQ available to support these initiatives. Detailed knowledge of PZQ metabolism will enable the use of PBPK modelling to determine appropriate doses for the new formulations in paediatric patients and to predict risks for drug-drug interactions in mass drug administration.MethodsBiotransformation studies on PZQ were conducted in human liver microsomes and recombinant Cytochrome P450s (CYPs). Structure elucidation was inferred from mass spectra. Enzyme kinetic studies to determine the Michaelis-Menten kinetics, Km and Vmax, of the formation of the main metabolites and analysis of clinical samples were determined by LC-MS/MS.ResultsCYP reaction phenotyping studies with HLM and r-CYPs indicate major involvement of CYP1A2, 2 C19, 2D6 and 3A4/5 in the metabolism of R- and S-PZQ. Biotransformation studies showed that PZQ is metabolised to cis-4-OH-PZQ mainly by CYP1A2 and CYP2C19. CYP3A4/5 metabolises PZQ to a mono-hydroxyl metabolite (X-OH-PZQ) whilst CYP2D6 metabolises PZQ to minor novel mono-hydroxyl metabolite (Y-OH-PZQ) both pending structural elucidation by nuclear magnetic resonance. R-PZQ was more rapidly cleared than S–PZQ with variable interindividual AUC and Cmax.Discussion and conclusionThe differential role of CYP1A2 and CYP2C19 and of CYP3A4 and CYP3A5 in the formation the 4-OH-PZQ and the novel X-OH-PZQ respectively are intriguing findings as this has not been reported before in humans. In vitro, cis and not trans 4-OH-PZQ formation has been observed contrary in vivo reports in humans which indicate trans 4-OH-PZQ as the main metabolite. The data will enable us to understand the rapid clearance of PZQ and predict potential drug-drug-gene interactions which may’explain the inter-individual variability of PZQ pharmacokinetics.