The role of infection models and PK/PD modelling for optimising care of critically ill patients with severe infections

Introduction Several reports have shown marked heterogeneity of antibiotic pharmacokinetics (PK) in patients admitted to ICUs, which might potentially affect outcomes. Therefore, the pharmacodynamic (PD) parameter of the efficacy of β-lactam antibiotics, that is, the time that its concentration is above the bacteria minimal inhibitory concentration (T > MIC), cannot be safely extrapolated from data derived from the PK of healthy volunteers. Methods We performed a full review of published studies addressing the PK of intravenous β-lactam antibiotics given to infected ICU patients. Study selection comprised a comprehensive bibliographic search of the PubMed database and bibliographic references in relevant reviews from January 1966 to December 2010. We selected only English-language articles reporting studies addressing β-lactam antibiotics that had been described in at least five previously published studies. Studies of the PK of patients undergoing renal replacement therapy were excluded. Results A total of 57 studies addressing six different β-lactam antibiotics (meropenem, imipenem, piperacillin, cefpirome, cefepime and ceftazidime) were selected. Significant PK heterogeneity was noted, with a broad, more than twofold variation both of volume of distribution and of drug clearance (Cl). The correlation of antibiotic Cl with creatinine clearance was usually reported. Consequently, in ICU patients, β-lactam antibiotic half-life and T > MIC were virtually unpredictable, especially in those patients with normal renal function. A better PD profile was usually obtained by prolonged or even continuous infusion. Tissue penetration was also found to be compromised in critically ill patients with septic shock. Conclusions The PK of β-lactam antibiotics are heterogeneous and largely unpredictable in ICU patients. Consequently, the dosing of antibiotics should be supported by PK concepts, including data derived from studies of the PK of ICU patients and therapeutic drug monitoring.

The current vancomycin therapeutic guidelines recommend the use of only trough concentrations to manage the dosing of adults with Staphylococcus aureus infections. Both vancomycin efficacy and toxicity are likely to be related to the area under the plasma concentration-time curve (AUC). We assembled richly sampled vancomycin pharmacokinetic data from three studies comprising 47 adults with various levels of renal function. With Pmetrics, the nonparametric population modeling package for R, we compared AUCs estimated from models derived from trough-only and peak-trough depleted versions of the full data set and characterized the relationship between the vancomycin trough concentration and AUC. The trough-only and peak-trough depleted data sets underestimated the true AUCs compared to the full model by a mean (95% confidence interval) of 23% (11 to 33%; P = 0.0001) and 14% (7 to 19%; P < 0.0001), respectively. In contrast, using the full model as a Bayesian prior with trough-only data allowed 97% (93 to 102%; P = 0.23) accurate AUC estimation. On the basis of 5,000 profiles simulated from the full model, among adults with normal renal function and a therapeutic AUC of ≥400 mg · h/liter for an organism for which the vancomycin MIC is 1 mg/liter, approximately 60% are expected to have a trough concentration below the suggested minimum target of 15 mg/liter for serious infections, which could result in needlessly increased doses and a risk of toxicity. Our data indicate that adjustment of vancomycin doses on the basis of trough concentrations without a Bayesian tool results in poor achievement of maximally safe and effective drug exposures in plasma and that many adults can have an adequate vancomycin AUC with a trough concentration of <15 mg/liter.

The prescription of pharmaceuticals in the critically ill is complicated by a paucity of knowledge concerning the pharmacokinetic implications of the underlying disease state. Changes in organ function can be dramatic in this population, both as a consequence of the primary pathophysiology and in response to clinical interventions provided. Vascular tone, fluid status, cardiac output and major organ blood flow can be significantly altered from baseline, influencing the volume of distribution and clearance of many commonly prescribed agents. Although measurable endpoints can be used to titrate doses for many drugs in this setting (such as sedatives), for those agents with silent pharmacodynamic indices, enhanced excretory organ function can result in unexpectedly low plasma concentrations, leading to treatment failure. This is particularly relevant to the use of antibacterials in the critically ill, where inadequate, inappropriate and/or delayed prescription can have significant effects on morbidity and mortality. Augmented renal clearance (ARC) refers to enhanced renal elimination of circulating solute and is being described with increasing regularity in the critically ill. However, defining this process in terms of current measures of renal function is problematic, as although the glomerular filtration rate (GFR) is largely considered the best index of renal function, there is no consensus on an upper limit of normal. In addition, the most readily available and accurate estimate of the GFR at the bedside is still widely debated. From a pharmacokinetic point of view, ARC can result in elevated renal elimination and subtherapeutic plasma concentrations of pharmaceuticals, although whether this process solely involves augmented filtration (as opposed to enhanced tubular secretion and/or reabsorption) remains uncertain. The primary contributors to this process are likely to be the innate immune response to infection and inflammation (with its associated systemic and haemodynamic consequences), fluid loading and use of vasoactive medications. The resultant increase in cardiac output and renal blood flow prompts enhanced glomerular filtration and drug elimination. Current evidence suggests that young patients without pre-existing co-morbidity or organ dysfunction who present with trauma are most likely to manifest ARC. As this phenomenon has received little attention in the literature, dose modification has rarely been considered. However, with increasing data supporting the concept, and many investigators demonstrating subtherapeutic concentrations of drugs in the critically ill, consideration of ARC and alternative dosing regimens is now mandatory, both to improve the likelihood of treatment success and to reduce the rate of development of antibacterial resistance.