Standard dosing of amikacin and gentamicin in critically ill patients results in variable and subtherapeutic concentrations

https://doi.org/10.1016/j.ijantimicag.2015.02.009Get rights and content

Highlights

  • In 90 patients given amikacin (n = 66) or gentamicin (n = 24), an adequate first peak plasma concentration (Cmax) was reached in 17 patients (19%) [16 (24%) for amikacin and 1 (4%) for gentamicin].

  • Only aminoglycoside dosing was associated with an adequate or inadequate first Cmax.

  • For subsequent doses, an adequate amikacin Cmax was reached in 6/27, 3/33, 1/19 and 4/10 patients, respectively.

  • For subsequent doses, an adequate gentamicin Cmax was never reached despite an increase in dosing in 13 patients.

Abstract

Low peak plasma concentrations (Cmax) of amikacin and gentamicin are reported in intensive care unit (ICU) patients after administration of the first dose. The present study aimed to describe the proportion of ICU patients in whom an adequate Cmax was achieved throughout the course of therapy. Septic ICU patients with an indication for intravenous amikacin or gentamicin were eligible for inclusion in this single-centre observational study. The first and subsequent doses and the corresponding Cmax values were recorded. The target Cmax was ≥60 mg/L for amikacin and ≥30 mg/L for gentamicin. Amikacin and gentamicin plasma concentrations were available in 66 and 24 patients, respectively (59 ± 17 years; 79 ± 19 kg; height 169 ± 12 cm; SAPS II score 46 ± 19). Pulmonary, abdominal and urinary tract infections were diagnosed in 64 patients. Culture-positive infection was confirmed in 65 patients (72%). A target first Cmax was achieved in 17/90 patients (19%). For amikacin, the target Cmax was achieved in 16/66 patients (24%) after the initial dose. In the 50 remaining patients, a change in dosing was performed in 14 patients, leading adequate peak plasma level in 2 patients. For gentamicin, the targeted Cmax was achieved in only 1/24 patient (4%) after the initial dose and was never achieved after the third dose. In conclusion, standard dosing of amikacin or gentamicin led to adequate Cmax in only 19% of patients. Subtherapeutic Cmax were not significantly corrected after subsequent doses.

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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