Augmented renal clearance, antibiotic exposure & clinical outcome: What is the impact on septic patients receiving high doses of β-lactams in ICU?
Augmented Renal Clearance [ARC] poses a significant risk of antibiotic sub-exposure and in turn, can be a cause of therapeutic failure leading to increased ICU length of stay, morbidity and mortality; and promote antimicrobial resistance. The aim of the study was to determine the impact of ARC on PK/PD target attainment in patients with high doses of β-lactams administered by continuous infusion; and to assess the relationship between ARC, sub-exposure for β-lactams and clinical outcome.
This prospective, single-centre, observational study took place over 9 months in a Surgical and Trauma ICU in a University Hospital in Bordeaux, France. Therapeutic drug monitoring [TDM] for the six β-lactam antibiotics and measurement of CrCl formed the biochemical basis of the analysis. Subexposure was defined as fT>MIC <100% and underdosing as plasma levels ≤X4MIC. The antibiotics evaluated in this study were Cefazolin, Cefotaxime, Cefepime, Ceftazidime, Piperacillin/Tazobactam and Meropenem. Patients were excluded if they died within 15 days of the end of the antibiotic course.
- No patient had sub-exposure<MIC, and 20% had sub-exposure<4xMIC. Patients with sub-exposure<4xMIC presented higher rates of therapeutic failure (OR: 6.3 [1.2 – 33.2], p = 0.03).
- Sub-exposure<4xMIC was related with ARC (OR = 10.1 [2.4 – 41.6], p <0.05) but not with treatment failure.
- CrCl of ≥170ml/min was found to be predictive of sub-exposure<4xMIC, having a sensitivity of 0.93 (95% CI: 0.77-0.99) and a specificity of 0.65 (95% CI: 0.58-0.71). ROC curve yielded a discrimination factor of 0.84 (95%CI: 0.77 – 0.91; p < 0.0001). They identified an inconclusive grey zone of CrCL for predicting β-lactam under-dosing, which was between 170 and 240 ml/min (a third of samples).
- β-lactam under-dosing was associated with higher MIC, younger age and higher weight.
- None of the deaths were related to infection.
- This was a single-centre study conducted in a specific population.
- Potential bias by predominant prescription of piperacillin.
- Adverse effects were not recorded with the 4xMIC target.
- High percentage of patients received combination therapy which can alter the 24h- CrCl and drug levels.
- CrCl and TDM were performed only in the first 72h, which could overestimate glomerular filtration rate and underestimate drug accumulation.
Take home message
Patients with ARC are at risk of sub-exposure. The role of TDM in managing patients with ARC (or at risk); and the effectiveness and safety of a higher MIC target should be scrutinised by randomised controlled trials.
Article review for the ESICM Journal Review Club on behalf of the Antimicrobial Use-WG provided by Dr. Ryan Seguna and Dr. Barbara Borgatta.
Carrié C, Petit L, d’Houdain N, Sauvage N, Cottenceau V, Lafitte M, Foumenteze C, Hisz Q, Menu D, Legeron R, Breilh D, Sztark F. 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. Int J Antimicrob Agents. 2018 Mar;51(3):443-449. doi: 10.1016/j.ijantimicag.2017.11.013.