Biology subjects

Young, D. C.

Publications and source records attributed to Young, D. C..

4 recordsLinked to original sources

bioRxiv2025

Population Pharmacokinetics and Probability of Target Attainment Analysis of Vancomycin Following Intermittent and Continuous Infusion in Adults with Cystic Fibrosis

Vancomycin is the drug of choice for treating pulmonary infections caused by methicillinresistant Staphylococcus aureus (MRSA) in people with cystic fibrosis (PwCF). This study characterized the pharmacokinetics (PK) of continuous and intermittent vancomycin infusions following a loading dose using population PK (PopPK) modeling to inform dosing in PwCF. The PopPK model was developed using therapeutic drug monitoring (TDM) data from adult PwCF who received a vancomycin loading dose followed by intermittent, continuous, or both infusion types for MRSA-related pulmonary exacerbations. A total of 212 samples were collected following 90 intermittent and 42 continuous infusions in 21 patients. The final model was a two-compartment model with first-order elimination, incorporating creatinine clearance (CrCL) as a covariate on vancomycin clearance (CL). The estimated CL and volume of distribution were 4.05 L/h/70 kg and 22.5 L/70 kg, respectively. The model was used to predict the probability of target attainment (PTA) following a single intermittent loading dose (500-1500 mg) and continuous infusion (500-6000 mg) over 24 hours. PTA was assessed using efficacy and toxicity thresholds defined by Area Under the Curve0-24 (AUC0-24)/Minimum Inhibitory Concentration (MIC) ratios [≥]400 mg{middle dot}h/L and <650 mg{middle dot}h/L, respectively. At a MIC of 1 {micro}g/mL, a loading dose of 500 mg followed by a 3750 mg continuous infusion achieved PTA targets for efficacy (66.7%) and safety (82.7%). These findings support the use of PopPK modeling to guide vancomycin dosing strategies for MRSA pulmonary infections in PwCF.

pharmacology and toxicology↗

bioRxiv2023

Population Pharmacokinetics and Target Attainment Analysis of Vancomycin after Intermittent Dosing in Adults with Cystic Fibrosis

Vancomycin is the first-line agent to treat pulmonary infections caused by methicillin-resistant Staphylococcus aureus (MRSA) in people with cystic fibrosis (PwCF). However, there is no consensus on vancomycin dosing in this population among health institutions, and there is large variability in dosing regimens across the United States. In this study, we characterized the pharmacokinetics (PK) of vancomycin in PwCF using a population PK approach. The clinical PK data to develop the population PK model was obtained from vancomycin therapeutic monitoring data from PwCF undergoing treatment for infections due to MRSA. The population PK model was then used to perform comprehensive Monte Carlo simulations to evaluate the probability of target attainment (PTA) of 12 different dosing scenarios. The area under the curve to minimum inhibitory concentration ratio (AUC/MIC) [≥] 400 mg*h/L was used as a target for PTA analysis. A total of 181 vancomycin plasma concentrations were included in the analysis. A onecompartment model with first-order elimination best described the data. Weight significantly influenced the vancomycin PK (p < 0.05). In the final model, clearance was estimated as 5.52 L/h/70 kg, and the volume of distribution was 31.5 L/70 kg. The PTA analysis showed that at lower MIC levels (MIC = 1), doses greater than and equal to 1000 mg every 8 hours and 1250 mg every 12 hours resulted in >90% PTA. The PTA results from this study may potentially inform the design of vancomycin dosing regimens to treat pulmonary infections due to MRSA in PwCF.

pharmacology and toxicology↗

bioRxiv2022

Genetic and lipidomic identification of tuberculostearic acid as a controller of mycobacterial membrane compartmentalization

Mycobacteria diverge in a basic way from other bacterial and eukaryotic cells based on their distinct membrane structures. Here we report genome-wide transposon sequencing to discover the controllers of membrane compartmentalization in Mycobacterium smegmatis. cfa, a gene that encodes a putative cyclopropane-fatty-acyl-phospholipid synthase, shows the most significant effect on recovery from a membrane destabilizer, dibucaine. Lipidomic analysis of cfa deletion mutants demonstrates an essential role of Cfa in the synthesis of specific membrane lipids containing a C19:0 monomethyl-branched stearic acid. This molecule, also known as tuberculostearic acid (TBSA), has been intensively studied for decades due to its high level and genus-specific expression in mycobacteria. The proposed Cfa-mediated conversion of an unsaturation to a methylation matched well with its proposed role in lateral membrane organization, so we used new tools to determine the non-redundant effects of Cfa and TBSA in mycobacterial cells. cfa expression regulated major classes of membrane lipids including phosphatidylinositols, phosphatidylethanolamines and phosphatidylinositol mannosides. Cfa localized within the intracellular membrane domain (IMD), where it controls both cellular growth and recovery from membrane fluidization by facilitating subpolar localization of the IMD. Overall, cfa controls lateral membrane partitioning but does not detectably alter orthogonal transmembrane permeability. More generally, these results support the proposed role of the subpolar IMD as a subcellular site of mycobacterial control of membrane function. SignificanceMycobacteria remain major causes of disease worldwide based in part on their unusual membrane structures, which interface with the host. Here we discover the long sought biosynthetic origin of tuberculostearic acid (TBSA), a major fatty acid found selectively in mycobacteria, as well as its role in mycobacterial cells. The lipid is produced by an enzyme called Cfa, whose loss causes a growth defect and slow reformation of a membrane domain near the pole of the rod-shaped cell. Thus, our study offers mechanistic insights to the intrinsic molecular factors critical for mycobacterial plasma membrane partitioning.

microbiology↗

bioRxiv2022

Cell envelope remodeling requires high concentrations of biotin during Mycobacterium abscessus model lung infection

Mycobacterium abscessus is an emerging pathogen resistant to most frontline antibiotics. M. abscessus causes lung infection, predominantly in patients with lung disease or structural abnormalities. To interrogate mechanisms required for M. abscessus survival in the lung, we developed a lung infection model using air-liquid interface culture and performed a screen to identify differentially required genes. In the lung model, synthesis of the cofactor biotin is required due to increased intracellular biotin demand, and pharmacological inhibition of biotin synthesis halts M. abscessus proliferation. Increased quantities of biotin are required to sustain fatty acid remodeling that serves to increase cell envelope fluidity, which in turn promotes M. abscessus survival in the alkaline lung environment. Together, these results indicate that biotin-dependent fatty acid remodeling plays a critical role in pathogenic adaptation to the lung niche and suggests that biotin synthesis and fatty acid metabolism are therapeutic targets for treatment of M. abscessus infection.

microbiology↗