Potential benefits of therapeutic drug monitoring for beta-lactam antibiotics in augmented renal clearance patients: a case report.

Augmented renal clearance (ARC) is commonly described in critically ill patients, making drug pharmacokinetics even harder to predict in this population. This case report displays the value of therapeutic drug monitoring (TDM) of piperacillin/tazobactam (PTZ) in this population. We identified two patients with ARC and intermittent administration of PTZ who took part in a prospective, descriptive study conducted at Hôpital du Sacré-Cœur de Montréal. Both had plasma samples drawn at peak, middle, and end of their dosing intervals of PTZ. Minimal inhibitory concentrations (MICs) of 4 and 8 mg/L were chosen to evaluate therapeutic target attainment at middle and end of dosing interval. The first patient was a 52-year-old male with a renal clearance rate estimated at 147 mL/min who received 3.375 g PTZ every 6 h. The second patient, a 49-year-old male, had an estimated renal clearance rate of 163 mL/min and received the same regimen. Both patients had piperacillin concentrations above the target MICs at middle of the dosing interval, but they failed to reach a trough concentration above 8 mg/L. The present case report showcases two patients with subtherapeutic PTZ concentrations despite strict following of local administration protocols. This suboptimal administration could not only lead to treatment failure, but also to the selection and growth of resistant pathogens. Implementing TDM would offer the possibility to adjust drug regimens in real-time and prevent situations like these from occurring.

Pharmacogenomic markers of metoprolol and α-OH-metoprolol concentrations: a genome-wide association study.

Aim: Few genome-wide association studies (GWASs) have been conducted to identify predictors of drug concentrations. The authors therefore sought to discover the pharmacogenomic markers involved in metoprolol pharmacokinetics. Patients & methods: The authors performed a GWAS of a cross-sectional study of 993 patients from the Montreal Heart Institute Biobank taking metoprolol. Results: A total of 391 and 444 SNPs reached the significance threshold of 5 × 10-8 for metoprolol and α-OH-metoprolol concentrations, respectively. All were located on chromosome 22 at or near the CYP2D6 gene, encoding CYP450 2D6, metoprolol's main metabolizing enzyme. Conclusion: The results reinforce previous findings of the importance of the CYP2D6 locus for metoprolol concentrations and confirm that large biobanks can be used to identify genetic determinants of drug pharmacokinetics at a GWAS significance level.

Breeding for adaptation to climate change: genomic selection for drought response in a white spruce multi-site polycross test.

With climate change, increasingly intense and frequent drought episodes will be affecting water availability for boreal tree species, prompting tree breeders and forest managers to consider adaptation to drought stress as a priority in their reforestation efforts. We used a 19-year-old polycross progeny test of the model conifer white spruce (Picea glauca) replicated on two sites affected by distinct drought episodes at different ages to estimate the genetic control and the potential for improvement of drought response in addition to conventional cumulative growth and wood quality traits. Drought response components were measured from dendrochronological signatures matching drought episodes in wood ring increment cores. We found that trees with more vigorous growth during their lifespan resisted better during the current year of a drought episode when the drought had more severe effects. Phenotypic data were also analyzed using genomic prediction (GBLUP) relying on the genomic relationship matrix of multi-locus gene SNP marker information, and conventional analysis (ABLUP) based on validated pedigree information. The accuracy of predicted breeding values for drought response components was marginally lower than that for conventional traits and comparable between GBLUP and ABLUP. Genetic correlations were generally low and nonsignificant between drought response components and conventional traits, except for resistance which was positively correlated to tree height. Heritability estimates for the components of drought response were slightly lower than for conventional traits, but similar single-trait genetic gains could be obtained. Multi-trait genomic selection simulations indicated that it was possible to improve simultaneously for all traits on both sites while sacrificing little on gain in tree height. In a context of rapid climate change, our results suggest that with careful phenotypic assessment, drought response may be considered in multi-trait improvement of white spruce, with accelerated screening of large numbers of candidates and selection at young age with genomic selection.

Genomic selection for resistance to spruce budworm in white spruce and relationships with growth and wood quality traits.

With climate change, the pressure on tree breeding to provide varieties with improved resilience to biotic and abiotic stress is increasing. As such, pest resistance is of high priority but has been neglected in most tree breeding programs, given the complexity of phenotyping for these traits and delays to assess mature trees. In addition, the existing genetic variation of resistance and its relationship with productivity should be better understood for their consideration in multitrait breeding. In this study, we evaluated the prospects for genetic improvement of the levels of acetophenone aglycones (AAs) in white spruce needles, which have been shown to be tightly linked to resistance to spruce budworm. Furthermore, we estimated the accuracy of genomic selection (GS) for these traits, allowing selection at a very early stage to accelerate breeding. A total of 1,516 progeny trees established on five sites and belonging to 136 full-sib families from a mature breeding population in New Brunswick were measured for height growth and genotyped for 4,148 high-quality SNPs belonging to as many genes along the white spruce genome. In addition, 598 trees were assessed for levels of AAs piceol and pungenol in needles, and 578 for wood stiffness. GS models were developed with the phenotyped trees and then applied to predict the trait values of unphenotyped trees. AAs were under moderate-to-high genetic control (h 2: 0.43-0.57) with null or marginally negative genetic correlations with other traits. The prediction accuracy of GS models (GBLUP) for AAs was high (PAAC: 0.63-0.67) and comparable or slightly higher than pedigree-based (ABLUP) or BayesCπ models. We show that AA traits can be improved and that GS speeds up the selection of improved trees for insect resistance and for growth and wood quality traits. Various selection strategies were tested to optimize multitrait gains.