Antibiotic Pharmacokinetic- Pharmacodynamic

Sepsis continues to be a major cause of morbidity and mortality worldwide. In the United States alone, sepsis accounts for 210,000 deaths annually, at a cost of $17 billion [1]. However this represents only a fraction of the global burden of this syndrome, with an estimated 15–19 million cases per year—the vast majority of which occur in low income countries [2]. Albeit there has been significant investment in developing clinical protocols and guidelines [3], and assessing novel pharmacological interventions [4], 28-day mortality from sepsis in high income countries remains around 20–25% [5, 6]. In addition to short-term mortality, septic patients suffer from numerous complications and are at an increased risk of death for up to 5 years following an acute event [7].

Fundamental principles in managing severe sepsis include early recognition, control of the source of infection, resuscitation with intravenous (IV) fluids, and infusion of vasoactive drugs [3]. Importantly, administration of appropriate broad-spectrum IV antibiotics as soon as possible is now considered a quality of care indicator in the management of this condition [8]. In this respect, the chosen antibiotic agent(s) should have suitable intrinsic bactericidal or bacteriostatic activity against the causative pathogen(s) and be administered in sufficient dose to ensure adequate drug concentrations at the site of infection. While generic critical care guidelines primarily focus on the former requirement, clinicians are generally less certain about adequate dose selection, despite the very real impli-cations for patients.

This uncertainty is primarily a consequence of the marked clinical heterogeneity and multisystem physiological derangement encountered in critical illness, driven by both the underlying pathology and the interventions provided. Anthropometric irregularities, chronic disease, administration of large volumes of IV fluids, use of vasoactive medications, and application of extracorporeal support modalities, in addition to alterations in major native organ function, are common characteristics of this population. These perturbations will significantly impact drug handling, such that antibiotic doses extrapolated from studies in healthy volunteers or ambulatory patients are unlikely to achieve similar drug exposures in this setting. Utilizing the knowledge and experience of numerous global experts in this field, this text aims to comprehensively review the pharmacokinetic/pharmacody-namic considerations concerning antibiotic prescription in the critically ill. Our principal aim is to provide the reader with a complete understanding of these issues, specifically the scientific and clinical imperatives underpinning dose optimization in this setting. In this respect, the subject material ranges from basic antibiotic phar-macokinetic/pharmacodynamic principles, through to dosing considerations in pediatric patients, and those receiving extracorporeal membrane oxygenation (ECMO).

Finally, while these data are critical in ensuring the right dose is selected for a specific patient, it is salient to remind the reader that inadequate antibiotic exposure also has significant ramifications for the wider community. Multidrug resistance is an increasing problem globally, particularly in critical care units [9], and the wide-spread use of antibiotics, in potentially subtherapeutic doses, may in part be to blame [10]. As such, the information provided in this text must be viewed in this context, in that the prescriber has a responsibility not only to their current patient, but also future ones.

We hope you find the information provided herein useful in your everyday practice, as well as stimulating future research and discussion. We are deeply indebted to all of the authors and collaborators involved with this project, as well as the medical, nursing, allied health staff, and patients who have generated much of the data highlighted throughout the text.





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