Association between augmented renal clearance, antibiotic exposure and clinical outcome in critically ill septic patients receiving high doses of β-lactams administered by continuous infusion: a prospective observational study

https://doi.org/10.1016/j.ijantimicag.2017.11.013Get rights and content

Highlights

  • In patients with augmented renal clearance, PK/PD targets may not be reached using high-dose continuous-infusion β-lactams.

  • Mean CLCr values ≥170 mL/min remain associated with higher rates of subexposure for β-lactams.

  • Subexposure<4×MIC is associated with higher rates of therapeutic failure.

Abstract

This study assessed whether augmented renal clearance (ARC) impacts negatively on antibiotic concentrations and clinical outcomes in patients treated by high-dose β-lactams administered continuously. Over a 9-month period, all critically ill patients without renal impairment treated by one of the monitored β-lactams for a documented infection were eligible. During the first 3 days of antibiotic therapy, every patient underwent 24-h CLCr measurements and therapeutic drug monitoring. The main outcome was the rate of β-lactam underdosing, defined as a free drug concentration <4 × MIC of the known pathogen. Secondary outcomes were rates of subexposure for β-lactams and therapeutic failure. The performance of CLCr in predicting underdosing was assessed by a ROC curve, and multivariable logistic regression was performed to determine risk factors for subexposure and therapeutic failure. A total of 79 patients were included and 235 samples were analysed. The rate of underdosing<4×MIC was 12%, with a significant association with CLCr (P <0.0001). A threshold of CLCr ≥ 170 mL/min had a sensitivity and specificity of 0.93 (95% CI 0.77–0.99) and 0.65 (95% CI 0.58–0.71) for predicting β-lactam underdosing<4×MIC. Mean CLCr values ≥170 mL/min were significantly associated with subexposure<4xMIC [OR = 10.1 (2.4–41.6); P = 0.001]. Patients with subexposure<4×MIC presented higher rates of therapeutic failure [OR = 6.3 (1.2–33.2); P = 0.03]. Mean CLCr values ≥170 mL/min remain a risk factor for subexposure to β-lactams despite high doses of β-lactams administered continuously. β-Lactam subexposure was associated with higher rates of therapeutic failure in septic critically ill patients.

Introduction

In critically ill patients, early initiation of appropriate antimicrobial therapy in sepsis and septic shock is one of the major determinants of outcome [1]. According to current practice, β-lactams are the most commonly prescribed antimicrobial agents in intensive care settings [2]. β-Lactam antibiotics exhibit time-dependent bacterial killing, such that optimal response in severe infections is achieved when the free drug concentration remains above the minimum inhibitory concentration (MIC) of the targeted organism(s) (fT>MIC) for a defined portion of the dosing interval [3]. Given the concentration-dependent selection pressure, a pharmacokinetic/pharmacodynamic (PK/PD) target greater than four times the MIC throughout the entire dosing period (100%fT>4×MIC) has been suggested to achieve microbiological eradication and to prevent the growth of resistant subpopulations [4], [5], [6]. However, these results were not confirmed in larger prospective studies and the optimal PK/PD exposure remains to be determined [7].

Moreover, optimising antimicrobial therapy still represents a complex challenge given the wide and unpredictable variability of antibiotic concentrations in critically ill patients [7], [8], [9]. A ‘one dose fits all’ approach could be especially problematic in patients with augmented renal clearance (ARC), potentially leading to subtherapeutic drug exposure and higher rates of clinical failure [10], [11], [12], [13]. In this context, recent data suggested that standard intermittent dosing is unlikely to achieve optimal antibiotic exposure in most patients with ARC [14]. Although several studies suggested a significant improvement in PK/PD target attainment and clinical success rates with high doses of β-lactams administered continuously or by prolonged infusion, evidence regarding relevant clinical outcomes in critical care patients with ARC is still limited [15], [16].

The main objective of this study was to determine whether ARC impacts negatively on PK/PD target attainment in patients treated by high doses of β-lactams administered continuously for a first infection in a surgical intensive care unit (ICU). The secondary objective was to test the association between ARC, subexposure to β-lactams and clinical outcome.

Section snippets

Study design

This prospective, single-centre, observational study was conducted in a 25-bed Surgical and Trauma ICU of CHU Pellegrin, a university hospital in Bordeaux (France), over a 9-month period (December 2016 to August 2017). Antimicrobial agent assays were performed by the university-affiliated pharmacological laboratory. Ethical approval was obtained from the Institutional Review Board (Comité de Protection des Personnes Sud-Ouest et Outre Mer III, Bordeaux, France), which waived the need for

Study population

Over the study period, 79 patients were included in the analysis. The rate of therapeutic failure was 16% (13/79). Nine patients died over the study period, two of them before end of study. No death was related to an infectious disease. The study flowchart is given Fig. 1. The main characteristics of the population, infections and outcome data are presented Table 1.

Association between creatinine clearance and β-lactam underdosing

Over the study period, 235 samples were analysed (2 samples of piperacillin were not analysed because of excessive delivery time or

Discussion

This study aimed to assess the correlation between CLCr values, subexposure to β-lactams and clinical outcome in critically ill patients receiving high doses of β-lactams administered continuously. Despite a large pharmacokinetic variability, the results suggested that (i) mean CLCr values of ≥170 mL/min were associated with higher rates of underdosing<4×MIC and (ii) subexposure<4×MIC was associated with higher rates of therapeutic failure.

This is a major concern as therapeutic failure has been

Conclusion

This study suggests that patients with CLCr ≥ 170 mL/min remain at risk of subexposure for β-lactams despite high doses of β-lactams administered continuously. Subexposure to β-lactams was associated with higher rates of therapeutic failure in patients treated for a first microbiologically documented infection in a surgical ICU. This study emphasises the need for TDM in patients with ARC, especially when targeting less-susceptible pathogens or surgical infections with limited penetration of

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