Sex-related disparities in antimicrobial dosing for sepsis may contribute to both treatment failure and drug toxicity, according to an editorial published in the Journal of Intensive Medicine.

Helena Barrasa, MD, of the Osakidetza Basque Health Service, Araba University Hospital Intensive Care Unit, and the Bioaraba Health Research Institute in Vitoria-Gasteiz, Spain, and colleagues reported that standardized antibiotic dosing protocols often overlook sex- and gender-based differences in pharmacokinetics and pharmacodynamics, potentially perpetuating inequities in sepsis outcomes.

The researchers noted that although the influence of biological sex on drug disposition is well established, it remains insufficiently reflected in clinical practice. Women generally have higher body fat, lower muscle mass, and smaller organ sizes than men—factors that affect drug absorption, distribution, and metabolism. Fluctuating estrogen and progesterone levels also modulate key metabolic enzymes such as CYP3A4. These hormonal and physiological differences, compounded by comorbidities and socioeconomic factors, may heighten women’s vulnerability to altered drug concentrations and increased therapeutic or toxic effects.

Women experience up to 30% more adverse drug reactions than men, the researchers noted, due to physiological differences in drug distribution and metabolism. Higher body fat, lower muscle mass, and fluctuating estrogen and progesterone levels alter drug absorption and clearance and increase the risk of overexposure and toxicity. In contrast, younger men more frequently exhibit augmented renal clearance—an accelerated drug elimination process—resulting in subtherapeutic concentrations of renally excreted antibiotics such as beta-lactams, vancomycin, and aminoglycosides.

The researchers emphasized that current methods of estimating renal function, including the Cockcroft–Gault equation, systematically underestimate glomerular filtration rate in women. This inaccuracy complicates individualized dosing and increases the risk of either underdosing or toxicity.

Gender disparities also extended to clinical management. Women with sepsis were less likely to receive early broad-spectrum antibiotics, despite comparable times to antibiotic administration in some cohorts. Population data indicated higher mortality rates among women with septic shock, suggesting that both biological and systemic factors may contribute to outcome differences.

“Recognizing and addressing sex- and gender-related differences in drug dosing represents a critical step toward improving sepsis management,” wrote the authors. They urged the integration of sex and gender variables into pharmacological modeling and clinical trial design and advocated for wider use of therapeutic drug monitoring to individualize dosing and improve safety in critically ill patients.

This study received no specific grant funding, and the authors reported no relevant financial relationships or conflicts of interest.

Source: Journal of Intensive Medicine