Model-informed precision dosing of beta-lactam antibiotics and ciprofloxacin in critically ill patients: a multicentre randomised clinical trial

Abstract

Purpose: Individualising drug dosing using model-informed precision dosing (MIPD) of beta-lactam antibiotics and ciprofloxacin has been proposed as an alternative to standard dosing to optimise antibiotic efficacy in critically ill patients. However, randomised clinical trials (RCT) on clinical outcomes have been lacking.

Methods: This multicentre RCT, including patients admitted to the intensive care unit (ICU) who were treated with antibiotics, was conducted in eight hospitals in the Netherlands. Patients were randomised to MIPD with dose and interval adjustments based on monitoring serum drug levels (therapeutic drug monitoring) combined with pharmacometric modelling of beta-lactam antibiotics and ciprofloxacin. The primary outcome was ICU length of stay (LOS). Secondary outcomes were ICU mortality, hospital mortality, 28-day mortality, 6-month mortality, delta sequential organ failure assessment (SOFA) score, adverse events and target attainment.

Results: In total, 388 (MIPD n = 189; standard dosing n = 199) patients were analysed (median age 64 [IQR 55-71]). We found no significant differences in ICU LOS between MIPD compared to standard dosing (10 MIPD vs 8 standard dosing; IRR = 1.16; 95% CI 0.96-1.41; p = 0.13). There was no significant difference in target attainment before intervention at day 1 (T1) (55.6% MIPD vs 60.9% standard dosing; p = 0.24) or at day 3 (T3) (59.5% vs 60.4%; p = 0.84). There were no significant differences in other secondary outcomes.

Conclusions: We could not show a beneficial effect of MIPD of beta-lactam antibiotics and ciprofloxacin on ICU LOS in critically ill patients. Our data highlight the need to identify other approaches to dose optimisation.

Keywords: Beta-lactam antibiotics; Ciprofloxacin; Critically ill; Model-informed; Precision dosing.

Fig. 1

Patient flow in the DOLPHIN trial. AB antibiotic; SDD selective decontamination of the digestive track; T1 first moment of blood sampling. Patients were excluded from analyses if they did not comply to the inclusion criteria e.g. no informed consent was gathered. Patients were furthermore excluded if they met an exclusion criterium within the first 24 h of therapy, before sampling was performed

Fig. 2

Study flow and dose advice given. ICU intensive care unit; MIP model-informed precision dosing; MD medical doctor; T1, first moment of antibiotic sampling, 1 day after initiation of antibiotic; T3, second moment of sampling, 48 h after T1; T5, third moment of sampling, 48 h after T3. (1) Patients in the ICU were sampled in the morning, after a logistical route the sample was analysed in the laboratory and the analytical results were imported into the analysing software. (2) A Bayesian prediction was made using previously published population PK models. Dose adjustments were simulated, after which a final dose advice was chosen. (3) The bedside physician (MD) was informed of the dosing advice. (4) The dosing of the antibiotic was altered by the physician. In the bottom panel, the given dose advice are reported. Doses could be increased, decreased or kept equal. Equal doses were advised when the target was attained or when the maximum daily dose was achieved

Fig. 3

Alluvial plot of target attainment over time. T1, first moment of antibiotic sampling, 1 day after initiation of antibiotic; T3, second moment of sampling, 48 h after T1; T5, third moment of sampling, 48 h after T3