Linezolid is important for treating infections caused by Gram-positive bacteria resistant to first-line agents. Severe infections often require empirical therapy before pathogen identification and susceptibility testing. This evaluation aims to compare different empirical linezolid dosing strategies in intensive care unit (ICU) patients to improve pharmacokinetic/pharmacodynamic target attainment while minimising toxicities. Three dosing strategies were compared: (i) standard dosing, (ii) therapeutic drug monitoring (TDM)-guided dosing, and (iii) a theoretical model-informed precision dosing (MIPD) strategy based on Bayesian forecasting with a population pharmacokinetic model. Each scenario was combined with an ICU-specific minimal inhibitory concentration (MIC) distribution comprising more than 19,000 isolates collected over 10 years. Data from 117 critically ill patients with 2184 TDM samples were available. Linezolid resistance was highest in ICU isolates (9.6%) compared with isolates from the intermediate care unit (4.3%), general wards (3.6%), and emergency room (1.6%). Among ICU isolates, resistance increased significantly over the 10-year study period, from 6.3% in 2015 to 11.4% in 2024. Empirical target attainment was 36.6% with standard dosing and 48.5% with TDM-guided dose adaptation, in two different ICU cohorts that showed 35.9% and 59.4% baseline target attainment, respectively. Theoretical MIPD projected target attainment in 71.4-81.6% of patients. After excluding resistant isolates, the corresponding values were 40.5%, 53.7%, and 79.0-90.3%, respectively. Integrating a large contemporary ICU-specific MIC distribution with patient-level pharmacokinetic data, our results suggest MIPD may represent a promising strategy improving target attainment, in contrast to standard regimens and TDM-guided dosing which failed to achieve adequate target exposure in ICU patients.

This narrative review highlights that tuberculosis (TB) treatment succeeds or fails at the regimen level, rather than based on individual drugs. The central challenge is to sustain effective multidrug pressure across a pathogen population in heterogeneous microenvironments. In drug-susceptible TB, rifampicin-based combinations achieve high cure rates; however, prolonged treatment duration, drug toxicity, and treatment interruptions drive resistance. In drug-resistant TB, newer agents like bedaquiline, nitroimidazoles, and repurposed linezolid enable shorter, all-oral regimens, yet durability depends on preventing resistance while maintaining effective exposure. Here, we review the available information on anti-TB drugs, concentrating on the physiological states of pathogen, resistance fitness landscapes, and regimen-level pharmacodynamics. These concepts are considered as complementary perspectives for understanding treatment response and directing future research. First, we map how drug classes distribute activity across pathogen physiological states, thereby establishing the need for mechanistic complementarity. Second, we conceptualize resistance as a constrained evolutionary outcome shaped by mutation supply and fitness costs, as illustrated by resistance to bedaquiline, pretomanid, and linezolid. Third, we integrate lesion pharmacokinetics and combination-response landscapes to demonstrate how spatial drug gradients and microenvironment-specific interactions can guide regimen prioritisation. These concepts are interpreted with WHO target regimen profiles to identify principles for protecting high-value core drugs as finite global assets.

PVL-positive ψUSA300 CA-MRSA is increasingly identified in Japan and is primarily associated with skin and soft tissue infections; respiratory infections caused by this clone remain rare. We report a 49-year-old healthy woman with lung abscess and empyema caused by PVL-positive ψUSA300, successfully treated with vancomycin and linezolid. This case expands the known clinical spectrum of ψUSA300 and underscores the need for CA-MRSA consideration in otherwise healthy patients with severe pulmonary infections.

Antimicrobial resistance (AMR) varies across hospitals, patient populations, and care settings, limiting the clinical utility of aggregate surveillance data. We characterized bacterial distribution and antimicrobial resistance at a tertiary hospital in Zigong, southwestern China, during 2023-2025, with explicit stratification by age and care setting.

The phenomenon of deuterium kinetic isotope effects has been occasionally leveraged to design new drugs that have altered drug metabolism and pharmacokinetics relative to their nondeuterated versions. However, it is difficult to know a priori which drugs and exploratory drug candidates would benefit from this drug design strategy. To address this, 10 drugs (amodiaquine, astemizole, cravacitinib, dextromethorphan, ezlopitant, febuxostat, glyburide, linezolid, naproxen, and rosiglitazone) and their deuterated analogs were systematically evaluated for kinetic isotope effects on their metabolism catalyzed by several cytochrome P450 enzymes. Trends could be observed for reaction type in that isotope effects could be observed for some hydroxylation and O-dealkylation reactions, but not for amine N-dealkylation reactions. No trends were apparent across the enzymes and substrates in that the same enzyme could show meaningful isotope effects for some drugs but not others, and substrates could show isotope effects catalyzed by some enzymes and not others. Thus, when considering leveraging deuteration as a drug design strategy intended to alter the metabolism and/or pharmacokinetics of a compound, at this time it cannot be predicted whether a suitable effect will be gained, and evaluation will depend on synthesizing and testing deuterated analogs. SIGNIFICANCE STATEMENT: Deuteration has become a strategy in drug design. In this study, it is demonstrated that for some substrates, P450 enzymes, and reaction types, deuterium isotope effects that would meaningfully impact drug clearance can be observed while for others this is not the case.

Data integrating hand bioburden and antimicrobial resistance with genomic characterisation among Aboriginal schoolchildren remains limited. Hand imprint samples were collected from 60 Orang Asli schoolchildren in Kelantan, Malaysia, immediately before and after handwashing, three months after a one-day educational intervention. Selected pre-handwashing Staphylococcus isolates underwent antimicrobial susceptibility testing, and four multidrug-resistant Staphylococcus arlettae isolates underwent whole-genome sequencing. Mean left-hand and median right-hand bioburden, expressed as log10 colony forming units(CFUs)/plate, were lower after handwashing, but neither comparison was statistically significant after Holm adjustment. Escherichia coli/Shigella complex recovery decreased from 21/60 participants (35.0%) to none (Holm-adjusted p < 0.001). Resistance to penicillin, fusidic acid and erythromycin was frequent, while most isolates were susceptible to linezolid and rifampicin. Sequencing identified msr(A) and dfrG in all four isolates, mph(C) in three, partial arginine catabolic mobile element (ACME)-associated sequences in all four, and the rep24c replicon belonging to the replication initiation protein family RepA_N in two. Genotype-phenotype concordance was partial: ResFinder detected no corresponding acquired resistance determinants for several resistant or intermediate phenotypes. These exploratory findings describe immediate bacterial recovery and selected isolates' resistance and genomic features; they do not establish the effectiveness of the earlier educational intervention.