Antibiotic Concentration in Critically ill intensive care unit (ICU) patients in Sweden

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Background Antibiotic therapy has the major impact on morbidity and mortality in severe sepsis and septic shock (Kumar, Roberts et al. 2006; Bagshaw, Lapinsky et al. 2009). Rapid killing of bacteria is considered important to limit the infection and systemic inflammatory response. Pharmacokinetic data for most antibiotics are obtained in healthy human volunteers. Hence, it is unclear if adequate antibiotic concentrations in plasma are achieved in critically ill patients with infections, especially on the first day of treatment when benefits of adequate dosed antibiotics are greatest. This is unfortunate, since the outcome in ICU patients depends on early, accurate and adequately dosed antibiotic treatment. Underdosing antibiotics leads to the no or limited effect against infectious agents with the risk of lack of infection control as well as risk of emergence of multi-resistant strains. Overdosing antibiotics increases the risk of toxicity without providing additional benefit. There are several reasons for variations in drug concentration in ICU. Large changes in total body water may be seen due to intravenous fluids given during resuscitation (Liu, Thompson et al. 2011). Moreover, changes are seen in plasma protein levels (Investigators, Finfer et al. 2011) permeability between the different compartments, liver function, (Macnab, Macrae et al. 1986) renal function (White, Hassoun et al. 2013) and renal tubular function (Wen, Peng et al. 2011). In addition, critically ill patients treated with continuous renal replacement therapy (CRRT) in severe renal impairment that alters the excretion of the drugs with predominantly renal clearance (Lau, Kronfol et al. 1987). Thus, to date it is unknown what proportion of the ICU patients have adequate plasma concentrations of antibiotics, whether antibiotic concentrations change during the first days and if the pharmacokinetics of these drugs is affected by the critical illness and / or intensive care. Hypothesis Plasma concentrations of antibiotics in ICU patients during the first 72 hours after initiation of treatment are too low to provide adequately dosed antibacterial therapy. Method In a prospective multicenter study, concentrations of cefotaxime, piperacillin-tazobactam, meropenem, ciprofloxacin, gentamicin, tobramycin, amikacin and vancomycin in the plasma will be measured twice daily for 3 days after the initiation of treatment in intensive care patients with suspected infection. Participating centers are: the general ICU, the cardiothoracic ICU and the burns ICU at Uppsala university hospital, and general ICUs at County hospitals in Eskilstuna, Vasteras, Karlstad, and Gavle, as well as the general ICU at Karolinska University Hospital Huddinge. Demographic, clinical, laboratory and microbiological data will be collected. Antibiotic concentrations in each patient with positive cultures will be compared with the MIC for the isolated bacteria from the same patient.