High creatinine clearance in critically ill patients with community-acquired acute infectious meningitis

<p>Abstract</p> <p>Background</p> <p>A high dose of anti-infective agents is recommended when treating infectious meningitis. High creatinine clearance (CrCl) may affect the pharmacokinetic / pharmacodynamic relationships of anti-infective drugs eliminated by the kidneys. We recorded the incidence of high CrCl in intensive care unit (ICU) patients admitted with meningitis and assessed the diagnostic accuracy of two common methods used to identify high CrCl.</p> <p>Methods</p> <p>Observational study performed in consecutive patients admitted with community-acquired acute infectious meningitis (defined by >7 white blood cells/mm³ in cerebral spinal fluid) between January 2006 and December 2009 to one medical ICU. During the first 7 days following ICU admission, CrCl was measured from 24-hr urine samples (24-hr-UV/P creatinine) and estimated according to Cockcroft-Gault formula and the simplified Modification of Diet in Renal Disease (MDRD) equation. High CrCl was defined as CrCl >140 ml/min/1.73 m² by 24-hr-UV/P creatinine. Diagnostic accuracy was performed with ROC curves analysis.</p> <p>Results</p> <p>Thirty two patients were included. High CrCl was present in 8 patients (25%) on ICU admission and in 15 patients (47%) during the first 7 ICU days for a median duration of 3 (1-4) days. For the Cockcroft-Gault formula, the best threshold to predict high CrCl was 101 ml/min/1.73 m² (sensitivity: 0.96, specificity: 0.75, AUC = 0.90 ± 0.03) with a negative likelihood ratio of 0.06. For the simplified MDRD equation, the best threshold to predict high CrCl was 108 ml/min/1.73 m² (sensitivity: 0.91, specificity: 0.80, AUC = 0.88 ± 0.03) with a negative likelihood ratio of 0.11. There was no difference between the estimated methods in the diagnostic accuracy of identifying high CrCl (p = 0.30).</p> <p>Conclusions</p> <p>High CrCl is frequently observed in ICU patients admitted with community-acquired acute infectious meningitis. The estimated methods of CrCl could be used as a screening tool to identify high CrCl.</p

Implications of augmented renal clearance in critically ill patients

Critically ill patients can display markedly abnormal physiological parameters compared with those in ward-based or ambulatory settings. As a function of both the underlying inflammatory state and the interventions provided, these patients manifest substantial changes in their cardiovascular and renal function that are not always immediately discernable using standard diagnostic tests. Impaired renal function is well documented among such individuals; however, even patients with normal serum creatinine concentrations might display elevated glomerular filtration rates, a phenomenon we have termed augmented renal clearance (ARC). This finding has important ramifications for the accurate dosing of renally eliminated drugs, given that most pharmaceutical dosing regimens were validated outside the critical care environment. Empirical approaches to dosing are unlikely to achieve therapeutic drug concentrations in patients with ARC, placing them at risk of suboptimal drug exposure and potential treatment failure. With an increasing appreciation of this phenomenon, alternative dosing strategies will need to be investigated

Clinical implications of antibiotic pharmacokinetic principles in the critically ill

Successful antibiotic therapy in the critically ill requires sufficient drug concentrations at the site of infection that kill or suppress bacterial growth. The relationship between antibiotic exposure and achieving the above effects is referred to as pharmacokinetics/pharmacodynamics (PK/PD). The associated indices therefore provide logical targets for optimal antibiotic therapy. While dosing regimens to achieve such targets have largely been established from studies in animals and non-critically ill patients, they are often poorly validated in the ICU. Endothelial dysfunction, capillary leak, altered major organ blood flow, deranged plasma protein concentrations, extremes of body habitus, the application of extracorporeal support modalities, and a higher prevalence of intermediate susceptibility, independently, and in combination, significantly confound successful antibiotic treatment in this setting. As such, the prescription of standard doses are likely to result in sub-therapeutic concentrations, which in turn may promote treatment failure or the selection of resistant pathogens. This review article considers these issues in detail, summarizing the key changes in antibiotic PK/PD in the critically ill, and suggesting alternative dosing strategies that may improve antibiotic therapy in these challenging patients