Antibacterial dosing in intensive care: Pharmacokinetics, degree of disease and pharmacodynamics of sepsis

Treatment of sepsis remains a significant challenge with persisting high mortality and morbidity. Early and appropriate antibacterial therapy remains an important intervention for such patients. To optimise antibacterial therapy, the clinician must possess knowledge of the pharmacokinetic and pharmacodynamic properties of commonly used antibacterials and how these parameters may be affected by the constellation of pathophysiological changes occurring during sepsis. Sepsis, and the treatment thereof, increases renal preload and, via capillary permeability, leads to 'third-spacing', both resulting in higher antibacterial clearances. Alternatively, sepsis can induce multiple organ dysfunction, including renal and/or hepatic dysfunction, causing a decrease in antibacterial clearance. Aminoglycosides are concentration-dependent antibacterials and they display an increased volume of distribution (V-d) in sepsis, resulting in decreased peak serum concentrations. Reduced clearance from renal dysfunction would increase the likelihood of toxicity. Individualised dosing using extended interval dosing, which maximises the peak serum drug concentration (C-max)/minimum inhibitory concentration ratio is recommended. beta-Lactams and carbapenems are time-dependent antibacterials. An increase in Vd and renal clearance will require increased dosing or administration by continuous infusion. If renal impairment occurs a corresponding dose reduction may be required. Vancomycin displays predominantly time-dependent pharmacodynamic properties and probably requires higher than conventionally recommended doses because of an increased V-d and clearance during sepsis without organ dysfunction. However, optimal dosing regimens remain unresolved. The poor penetration of vancomycin into solid organs may require alternative therapies when sepsis involves solid organs (e.g. lung). Ciprofloxacin displays largely concentration-dependent kill characteristics, but also exerts some time-dependent effects. The V-d of ciprofloxacin is not altered with fluid shifts or over time, and thus no alterations of standard doses are required unless renal dysfunction occurs. In order to optimise antibacterial regimens in patients with sepsis, the pathophysiological effects of systemic inflammatory response syndrome need consideration, in conjunction with knowledge of the different kill characteristics of the various antibacterial classes. In conclusion, certain antibacterials can have a very high V-d, therefore leading to a low C-max and if a high peak is needed, then this would lead to underdosing. The Vd of certain antibacterials, namely aminoglycosides and vancomycin, changes over time, which means dosing may need to be altered over time. Some patients with serum creatinine values within the normal range can have very high drug clearances, thereby producing low serum drug levels and again leading to underdosing. Copyright © 2010 Elsevier Inc. All rights reserved.

Energy and calcium stores are preserved in girls and young women with CF, independent of disease severity: An explanation for the 'gender gap'?

Bioenergetics differ between males and females of many species. Human females apportion a substantial proportion of energy resources towards gynoid fat storage, to support the energetic burden of reproduction. Similarly, axial calcium accrual is favoured in females compared with males. Nutritional status is a prognostic indicator in cystic fibrosis (CF), but girls and young women are at greater risk of death despite equivalent nutritional status to males. The aim of this study was to compare fat (energy) and calcium stores (bone density) in males and females with CF over a spectrum of disease severity. Methods: Fat as % body weight (fat%) and lumbar spine (LS) and total body (TB) bone mineral density (BMD) were measured using dual absorption X-ray photometry in 127(59M) control and 101(54M) CF subjects, aged 9–25 years. An equation for predicted age at death had been determined using survival data and history of pulmonary function for the whole clinic, based on a trivariate normal model using maximum likelihood methods (1). For the CF group, a disease severity index (predicted age at death) was calculated from the derived equations according to each subjects history of pulmonary function, current age, and gender. Disease severity was classified according to percentile of predicted age at death (‘mild’ ≥75th, ‘moderate’ 25th–75th, ‘severe’ ≤25th percentile). Wt for age z-score was calculated. Serum testosterone and oestrogen were measured in males and females respectively. Fat% and LSBMD were compared between the groups using ANOVA. Results: There was an interaction between disease severity and gender: increasing disease severity was associated with greater deficits in TB (p=0.01), LSBMD (p