Standard dosing of amikacin and gentamicin in critically ill patients results in variable and subtherapeutic concentrations
Introduction
Early and appropriate treatment of infections is a priority in the management of intensive care unit (ICU) patients and could reduce mortality rates in patients with severe sepsis or septic shock [1], [2]. Therefore, empirical broad-spectrum anti-infective therapy, often using multiple agents, is recommended for the initial treatment of severe sepsis [3]. Although some specific anti-infective combinations remain controversial, a survival improvement has been reported with the use of combination therapy in patients with septic shock [4], [5]. Therefore, aminoglycosides are often given as part of empirical therapy for severe sepsis and septic shock, especially when Gram-negative bacteria are suspected [6].
One of the main conditions for aminoglycoside therapy to be efficient is to achieve therapeutic drug concentrations at the site of infection [7]. As tissue concentrations of anti-infective drugs cannot be routinely measured, plasma concentrations are classically used as a surrogate to confirm the appropriateness of dosing and anti-infective exposure. From a pharmacodynamic perspective, for aminoglycosides the ratio between the peak plasma concentration (Cmax) and the minimum inhibitory concentration (MIC) of the infecting pathogen (Cmax/MIC) is considered as the best index of bacterial killing and the subsequent success of anti-infective treatment [8]. Maximum antibacterial activity is achieved when Cmax is 8–10 times greater than the MIC [9], [10], [11]. Although the ratio of the area under the concentration–time curve from 0–24 h (AUC0–24) to the MIC (AUC0–24/MIC) for the first dose is also correlated with maximum aminoglycoside activity [12], for convenience peak concentrations are used for therapeutic concentration monitoring [13]. Despite a large possible distribution of MICs for different pathogens, recent French recommendations for the use of aminoglycosides targeted Cmax of 30–40 mg/L and 60–80 mg/L for gentamicin and amikacin, respectively [14]. These recommendations are closest to the recommended peak concentrations in recent publications [15], [16], [17]. As aminoglycosides are nephrotoxic, residual plasma concentrations should be monitored to minimise the likelihood of nephrotoxicity and ototoxicity [13], [14].
Although the pharmacokinetics of aminoglycosides in ICU patients has previously been described, studies on optimal dosing regimens for patients with sepsis have had several limitations [18], [19]. Many factors can influence the pharmacokinetics of different anti-infective drugs [20]. Indeed, alterations in the volume of distribution, plasma albumin concentration, increased cardiac output, increased blood volume, and paradoxical renal and hepatic clearance increase can be observed in the early stage of severe sepsis and are frequently observed in ICU patients [20]. Some studies have previously shown a low aminoglycoside concentration in the early phase of therapy in ICU patients [17], [21]. Taccone et al. [17] and de Montmollin et al. [15] recently reported 30% and 33% of patients with a first amikacin Cmax of <60 mg/L after a first dose of 25 mg/kg, respectively. Gálvez et al. [16] compared three initial doses of amikacin (15, 25 and 30 mg/kg) and reported a target Cmax of >60 mg/L in 0%, 39% and 76% of patients, respectively. Unfortunately, neither of these previous studies provided concentration data for the subsequent doses of aminoglycosides. Therefore, to address this deficiency in the literature, an observational study was performed to describe the proportion of ICU patients achieving target peak plasma aminoglycoside concentrations after the first dose as well as after subsequent aminoglycoside doses.
Section snippets
Materials and methods
This was a single-centre observational cohort study. As this was a non-interventional study to assess the daily practice of aminoglycoside monitoring in the ICU of Nîmes University Hospital (Nîmes, France), approval by the Comité de Protection des Personnes was not required according to French law. Therefore, the study was approved by the Institutional Review Board of Nîmes University Hospital and was declared to the Commission nationale de l’informatique et des liberté (CNIL). For this reason,
Patients
From 2 June 2013 to 29 November 2013, 325 patients (197 male; age 61 ± 17 years; SAPS II score 40.4 ± 20.2; length of stay in the ICU 7.9 ± 12.6 days; mortality rate 30%) were admitted to the ICU. Among them, 130 patients (87 male) were administered aminoglycosides (Fig. 1). Tobramycin was given to 6 patients who did not participate and in another 34 patients a concentration from the first dose of aminoglycosides was not available; thus, 90 eligible patients were included in the study (Fig. 1). The
Discussion
The present study assessed the daily practice of amikacin and gentamicin administration relative to a French aminoglycoside dosing guideline [14]. A first Cmax was performed in 90 of 130 patients administered aminoglycosides. An adequate first Cmax was reported in only 17 (19%) of 90 patients (16/66 for amikacin and 1/24 for gentamicin). For subsequent doses, when Cmin and Cmax were monitored, dose changes were not commonly performed, leading to adequate Cmax being observed in only 25% of
Conclusion
The present study showed that standard dosing of amikacin or gentamicin led to adequate Cmax in only 19% of patients. A first insufficient dose is associated with subsequent subtherapeutic doses. This emphasises the importance of the first dose to detect a subtherapeutic regimen and potentially adapt the following doses. This brings into question the appropriateness of current dosing recommendations and supports the initiation of aminoglycoside therapy with higher doses in ICU patients with
Funding
JAR is funded in part by an Australian National Health and Medical Research Council Fellowship [APP1048652]. This study was performed with the help of the research team of the University Hospital of Nîmes (Nîmes, France).
Competing interests
None declared.
Ethical approval
As this was a non-interventional study to assess the daily practice of aminoglycoside monitoring in the ICU of Nîmes University Hospital (Nîmes, France), approval by the Comité de Protection des Personnes was not required according to French law. Therefore, the study was approved by the Institutional Review Board of Nîmes University Hospital [IRB 13/10-02] and was declared to the Commission nationale de l’informatique et liberté [CNIL # 1713434]. For this reason, the need for written informed
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