Early, appropriate antibacterial therapy is a key factor in effectively managing septic critically ill patients (1). The prescriber must not only employ an agent of appropriate spectrum, but also in an adequate dose to achieve bacterial eradication at the site of infection. However, the relationship between drug administration and therapeutic success is complex in the critically ill, such that a patient's physiology heavily influences the way drugs distribute into tissue and are eliminated. This represents a significant challenge to the emergency or intensive care physician, and in this manner, personalising therapy, through a greater understanding of how a drug will behave in an individual patient, is likely to lead to improved outcomes.
In this edition of Anaesthesia and Intensive Care there are three articles that nicely describe some of the barriers to optimal antibacterial prescription in the critically ill. Together they contribute key information in improving our understanding of how to recognise, and treat, patients 'at-risk' of subtherapeutic drug exposure.
The first article describes some of the key fluid shifts that routinely occur in critically ill patients (2), while the second (3) highlights that we can now measure cardiac output in a relatively easy, noninvasive fashion. This work is in keeping with that of McLean et al, recently published in this journal4. The third paper (5) emphasises that 'package insert' doses of vancomycin (1.0 g bd) are not enough to fill the extra fluid compartments that Sanchez et al describe. Separately, and synergistically, each paper provides important insight into optimising individual antibacterial therapy.
Sanchez et al describes the haemodynamic changes observed after fluid resuscitation for septic shock (2). As stated by the authors, "fluid resuscitation can increase hydrostatic pressure, inducing accumulation of interstitial fluid and worsening of tissue oedema". The physiochemical properties of a molecule will determine the consequences of these effects on distribution. Antibacterials such as the [beta]-lactams, aminoglycosides and glycopeptides "go where the water goes", meaning that in the acute resuscitation phase of critical illness, these drugs will be preferentially 'dragged' into the interstitial space by extra-vascular movement of free fluid. This in turn means that the volume of distribution ([V.sub.d]) of such drugs is much higher than would be the case if there were no 'leaky' capillaries. Notably, distribution into a larger [V.sub.d] will result in lower serum concentrations for any...