From the Guidelines
The guidance document for beta-lactam therapeutic drug monitoring (TDM) with extended infusion should prioritize targeting a threshold of 50-70% for fT>MIC to predict clinical response, as supported by the most recent and highest quality study by Guilhaumou et al. 1. When creating the guidance document, it is essential to acknowledge the limitations of the available studies, including small sample sizes, patients receiving concomitant antibiotics, heterogeneous infection types, and frequently missing MIC data for the causative pathogens.
- The study by Guilhaumou et al. 1 highlights the importance of continuous beta-lactam administration in critically ill patients, demonstrating an improvement in clinical cure rates and a trend towards reducing 30-day hospital mortality.
- Another study by Falagas et al. 1 suggests that prolonged infusion of beta-lactam antibiotics is associated with mortality reduction, with a meta-analysis showing 10.8% mortality in patients treated by prolonged infusion compared to 16.8% in patients treated by intermittent perfusion.
- The guidance should emphasize that TDM may be particularly valuable for:
- Critically ill patients with sepsis
- Those with altered pharmacokinetics (such as augmented renal clearance, obesity, or renal dysfunction)
- When treating resistant organisms where achieving adequate drug exposure is challenging
- Monitoring should ideally occur after steady state is reached (typically after 3-4 doses) and should include consideration of both efficacy and potential toxicity.
- The pharmacokinetic/pharmacodynamic relationship of beta-lactams is time-dependent, which is why extended infusions are used to optimize the time above MIC, but appropriate TDM can help confirm whether these extended infusion strategies are achieving the desired exposure targets in individual patients.
From the Research
Important Notes and Caveats
- The majority of studies identified thresholds for the time the free concentration of the drug remains above the minimum inhibitory concentration (MIC) during the dosing interval (fT>MIC) of between 20% and 30% to predict mortality benefit, although there were several limitations in the study design, including small numbers of subjects, receipt of active concomitant antibiotics, multiple infection types, and lack of MIC data for the causative pathogen 2, 3.
- A majority of the studies identified thresholds for the time the free concentration of the drug remains above the minimum inhibitory concentration (MIC) during the dosing interval (fT>MIC) of between 50% and 70% to predict clinical response, although there were several limitations in the study design, including small numbers of subjects, receipt of active concomitant antibiotics, multiple infection types, and lack of MIC data for the causative pathogen 2, 3.
- There is currently no evidence to determine what threshold for the time the free concentration of the drug remains above the minimum inhibitory concentration (MIC) during the dosing interval (fT>MIC) to use as a target for TDM in extended-infusion beta-lactam dosing 2, 4.
- Therapeutic drug monitoring (TDM) of beta-lactam antibiotics is recommended to address the variability in exposure observed in critical illness, and TDM-guided dosing has been associated with improved clinical cure, microbiological cure, treatment failure, and target attainment 5.
- Extended and continuous infusions of beta-lactam antibiotics are well tolerated in children and improve achievement of pharmacokinetic-pharmacodynamic targets with similar or superior clinical outcomes, particularly in infections associated with high MICs 6.
Limitations of Available Studies
- Small numbers of subjects
- Receipt of active concomitant antibiotics
- Multiple infection types
- Lack of MIC data for the causative pathogen
- Limited evidence regarding relevant patient outcomes