Antibiotics in critically ill patients: a systematic review of the pharmacokinetics of β-lactams

Joao Gonçalves-Pereira, Pedro Póvoa, Joao Gonçalves-Pereira, Pedro Póvoa

Abstract

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.

Figures

Figure 1
Figure 1
ICU patients present pharmacokinetic changes of antibiotics that may alter bacterial exposure. Concentration-time curve of antibiotics in healthy volunteers (left panel). A large volume of distribution (Vd) (middle panel) is often present in ICU patients, leading to decreased maximum concentration (Cmax) but a longer half-life (T1/2) and eventually higher time that the antibiotic concentration is above the bacteria minimum inhibitory concentration (T > MIC). The antibiotic area under the concentration time curve (AUC) remains virtually the same. An increase in drug clearance (Cl) (right) is associated with decreases in AUC, T1/2 and T > MIC. Straight dotted lines-bacteria minimum inhibitory concentration.
Figure 2
Figure 2
Flow diagram illustrating the selection of studies included in this review.
Figure 3
Figure 3
Heterogeneity of volume of distribution in litres of β-lactam antibiotics in ICU patients. Open circles: volume of distribution in healthy volunteers [44,51,89-92]; filled squares: weighted means of volume of distribution in the studies; straight lines: ranges of the means of volume of distribution in the studies.

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