Continuous infusion of β-lactam antibiotics for all critically ill patients?

Taccone, Fabio Silvio; Laupland, Kevin B.; Montravers, Philippe

doi:10.1007/s00134-016-4241-7

Cited by 13 publications

(9 citation statements)

References 12 publications

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“…However, we do not generally consider that, for a different mode of infusion of the same antibiotic, different indices and targets may apply. When comparing the probability of target attainment between intermittent and continuous infusion, which implies a fundamentally different concentration–time curve, it is usually assumed that the PK/PD index and target remain the same [ 6 , 28 , 35 , 36 , 37 ].…”

Section: Why We Need To Rethink the Use Of Prolonged Infusion Of Beta...mentioning

confidence: 99%

Why We May Need Higher Doses of Beta-Lactam Antibiotics: Introducing the ‘Maximum Tolerable Dose’

2022

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The surge in antimicrobial resistance and the limited availability of new antimicrobial drugs has fueled the interest in optimizing antibiotic dosing. An ideal dosing regimen leads to maximal bacterial cell kill, whilst minimizing the risk of toxicity or antimicrobial resistance. For beta-lactam antibiotics specifically, PK/PD-based considerations have led to the widespread adoption of prolonged infusion. The rationale behind prolonged infusion is increasing the percentage of time the beta-lactam antibiotic concentration remains above the minimal inhibitory concentration (%fT>MIC). The ultimate goal of prolonged infusion of beta-lactam antibiotics is to improve the outcome of infectious diseases. However, merely increasing target attainment (or the %fT>MIC) is unlikely to lead to improved clinical outcome for several reasons. First, the PK/PD index and target are dynamic entities. Changing the PK (as is the case if prolonged instead of intermittent infusion is used) will result in different PK/PD targets and even PK/PD indices necessary to obtain the same level of bacterial cell kill. Second, the minimal inhibitory concentration is not a good denominator to describe either the emergence of resistance or toxicity. Therefore, we believe a different approach to antibiotic dosing is necessary. In this perspective, we introduce the concept of the maximum tolerable dose (MTD). This MTD is the highest dose of an antimicrobial drug deemed safe for the patient. The goal of the MTD is to maximize bacterial cell kill and minimize the risk of antimicrobial resistance and toxicity. Unfortunately, data about what beta-lactam antibiotic levels are associated with toxicity and how beta-lactam antibiotic toxicity should be measured are limited. This perspective is, therefore, a plea to invest in research aimed at deciphering the dose–response relationship between beta-lactam antibiotic drug concentrations and toxicity. In this regard, we provide a theoretical approach of how increasing uremic toxin concentrations could be used as a quantifiable marker of beta-lactam antibiotic toxicity.

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Section: Why We Need To Rethink the Use Of Prolonged Infusion Of Beta...mentioning

confidence: 99%

Why We May Need Higher Doses of Beta-Lactam Antibiotics: Introducing the ‘Maximum Tolerable Dose’

2022

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“…Critically ill patients are at risk to develop ventilator- or hospital-acquired pneumonia (HAP-VAP), which has been associated with impaired outcomes, prolonged duration of mechanical ventilation, increase in the length of stay, and the healthcare costs [1]. In this context, appropriate antibacterial exposure is essential to improve the chances of clinical success and reduce the risk for selection of drug-resistant strains [2].…”

Section: Introductionmentioning

confidence: 99%

Increased β-Lactams dosing regimens improve clinical outcome in critically ill patients with augmented renal clearance treated for a first episode of hospital or ventilator-acquired pneumonia: a before and after study

et al. 2019

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BackgroundAugmented renal clearance (ARC) is recognized as a leading cause of β-lactam subexposure when conventional dosing regimens are used. The main objective was to compare the clinical outcome of ARC patients treated by conventional or increased β-lactam dosing regimens for a first episode of hospital or ventilator-acquired pneumonia (HAP-VAP).MethodsIn this single-center, retrospective study, every ARC patient treated by β-lactam for a first episode of HAP-VAP was included during two 15-month periods, before (Control period) and after (Treatment period) the modification of a local antibiotic therapy protocol. ARC was defined by a 24-h measured creatinine clearance ≥ 150 ml/min. The primary endpoint was defined as a therapeutic failure of the antimicrobial therapy or a HAP-VAP relapse within 28 days. Inverse probability of treatment weight (IPTW) was derived from a propensity score model. Cox proportional hazard models were used to evaluate the association between treatment period and clinical outcome.ResultsDuring the study period, 177 patients were included (control period, N = 88; treatment period, N = 89). Therapeutic failure or HAP-VAP relapse was significantly lower in the treatment period (10 vs. 23%, p = 0.019). The IPTW-adjusted hazard ratio of poor clinical outcome in the treatment period was 0.35 (95% CI 0.15–0.81), p = 0.014. No antibiotic side effect was reported during the treatment period.ConclusionsHigher than licensed dosing regimens of β-lactams may be safe and effective in reducing the rate of therapeutic failure and HAP-VAP recurrence in critically ill augmented renal clearance (ARC) patients.

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“…Patients with pulmonary infection are hypothesised to have a greater primary outcome benefit associated with continuous infusion (compared with intermittent infusion) than patients without pulmonary infection. 8 The analysis for each subgroup will be performed by adding the subgroup variable, as well as its interaction with the intervention as a fixed effect to the main logistic regression model. Within each subgroup, summary measures will include raw counts and percentages within each treatment arm, as well as the OR for treatment effect with a 95% CI.…”

Section: Subgroup Analysesmentioning

confidence: 99%

Statistical analysis plan for the BLING III study: a phase 3 multicentre randomised controlled trial of continuous versus intermittent β-lactam antibiotic infusion in critically ill patients with sepsis

Billot¹,

Lipman²,

Brett³

et al. 2021

Critical Care and Resuscitation

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BACKGROUND: The β-Lactam Infusion Group (BLING) III study is a prospective, multicentre, open, phase 3 randomised controlled trial comparing continuous infusion with intermittent infusion of β-lactam antibiotics in 7000 critically ill patients with sepsis. OBJECTIVE: To describe a statistical analysis plan for the BLING III study. METHODS: The statistical analysis plan was designed by the trial statistician and chief investigators and approved by the BLING III management committee before the completion of data collection. Statistical analyses for primary, secondary and tertiary outcomes and planned subgroup analyses are described in detail. Interim analysis by the Data Safety and Monitoring Committee (DSMC) has been conducted in accordance with a pre-specified DSMC charter. RESULTS AND CONCLUSIONS: The statistical analysis plan for the BLING III study is published before completion of data collection and unblinding to minimise analysis bias and facilitate public access and transparent analysis and reporting of study findings. TRIAL REGISTRATION: ClinicalTrials.gov Registry NCT03212990.

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Continuous infusion of β-lactam antibiotics for all critically ill patients?

Cited by 13 publications

References 12 publications

Why We May Need Higher Doses of Beta-Lactam Antibiotics: Introducing the ‘Maximum Tolerable Dose’

Why We May Need Higher Doses of Beta-Lactam Antibiotics: Introducing the ‘Maximum Tolerable Dose’

Increased β-Lactams dosing regimens improve clinical outcome in critically ill patients with augmented renal clearance treated for a first episode of hospital or ventilator-acquired pneumonia: a before and after study

Statistical analysis plan for the BLING III study: a phase 3 multicentre randomised controlled trial of continuous versus intermittent β-lactam antibiotic infusion in critically ill patients with sepsis

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