Delivering precision antimicrobial therapy through closed-loop control systems

Rawson, Timothy M; O’Hare, Dermot; Herrero, Pau; Sharma, Sanjiv; Moore, Luke; Barra, Eoghan de; Roberts, Jason A.; Gordon, Anthony; Hope, William; Georgiou, Pantelis; Cass, Anthony E. G.; Holmes, Alison

doi:10.1093/jac/dkx458

Cited by 33 publications

(31 citation statements)

References 115 publications

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“…Actually, various forms of point of care testing are currently being developed and prototypes are being experimented with. The use of biosensor technologies has been proposed, superficially explored and the first results are promising [52][53][54]. In the latter study, elegant microneedle-based biosensors were used for betalactam detection.…”

Section: Technologies Used For Tdmmentioning

confidence: 99%

Diagnostic and medical needs for therapeutic drug monitoring of antibiotics

Mabilat

Gros

Nicolau

et al. 2019

Eur J Clin Microbiol Infect Dis

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Therapeutic drug monitoring (TDM) of antibiotics has been practiced for more than half a century, but it is still not widely applied for infected patients. It has a traditional focus on limiting toxicity of specific classes of antibiotics such as aminoglycosides and vancomycin. With more patients in critical care with higher levels of sickness severity and immunosuppression as well as an increasingly obese and ageing population, an increasing risk of suboptimal antibiotic exposure continues to escalate. As such, the value of TDM continues to expand, especially for beta-lactams which constitute the most frequently used antibiotic class. To date, the minimum inhibitory concentration (MIC) of infectious microbes rather than classification in terms of susceptible and resistant can be reported. In parallel, increasingly sophisticated TDM technology is becoming available ensuring that TDM is feasible and can deliver personalized antibiotic dosing schemes. There is an obvious need for extensive studies that will quantify the improvements in clinical outcome of individual TDM-guided dosing. We suggest that a broad diagnostic and medical investigation of the TDM arena, including market analyses and analytical technology assessment, is a current priority.

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Section: Technologies Used For Tdmmentioning

confidence: 99%

Diagnostic and medical needs for therapeutic drug monitoring of antibiotics

Mabilat

Gros

Nicolau

et al. 2019

Eur J Clin Microbiol Infect Dis

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“…Nevertheless, timely availability of appropriate antimicrobial assays could be problematic, as TDM programs for cefepime or other beta-lactam antibiotics are not yet widespread. To this end, biosensor technology could offer an alternative by providing real-time monitoring of antimicrobials in a minimally invasive fashion (30).…”

Section: Discussionmentioning

confidence: 99%

Target-Controlled Infusion of Cefepime in Critically Ill Patients

Jonckheere

Neve

Verbeke

et al. 2019

Antimicrob Agents Chemother

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Attainment of appropriate pharmacokinetic-pharmacodynamic (PK-PD) targets for antimicrobial treatment is challenging in critically ill patients, particularly for cefepime, which exhibits a relative narrow therapeutic-toxic window compared to other beta-lactam antibiotics. Target-controlled infusion (TCI) systems, which deliver drugs to achieve specific target drug concentrations, have successfully been implemented for improved dosing of sedatives and analgesics in anesthesia. We conducted a clinical trial in an intensive care unit (ICU) to investigate the performance of TCI for adequate target attainment of cefepime. Twenty-one patients treated with cefepime according to the standard of care were included. Cefepime was administered through continuous infusion using TCI for a median duration of 4.5 days. TCI was based on a previously developed population PK model incorporating the estimated creatinine clearance based on the Cockcroft-Gault formula as the input variable to calculate cefepime clearance. A cefepime blood concentration of 16 mg/liter was targeted. To evaluate the measured versus predicted plasma concentrations, blood samples were taken (median of 10 samples per patient), and total cefepime concentrations were measured using ultraperformance liquid chromatography-tandem mass spectrometry. The performance of the TCI system was evaluated using Varvel criteria. Half (50.3%) of the measured cefepime concentrations were within ±30% around the target value of 16 mg liter−1. The wobble was 11.4%, the median performance error (MdPE) was 21.1%, the median absolute performance error (MdAPE) was 32.0%, and the divergence was −3.72% h−1. Based on these results, we conclude that TCI is useful for dose optimization of cefepime in ICU patients. (This study has been registered at ClinicalTrials.gov under identifier NCT02688582.)

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“…Drug therapy outcomes are improved using MIPD for drugs with narrow therapeutic indices (TIs) in difficult-to-dose patients for whom the clinical stakes are high, such as anti-microbial use in patients who are hemodynamically unstable critically ill (Rawson et al, 2018). The most successful MIPD approach is the use of population pharmacokinetic/pharmacodynamic models (pop PK/PD) with Bayesian priors that are updated postdose with plasma concentrations from therapeutic drug monitoring (TDM) to generate PK parameters for the drug in the individual patient, thus allowing Bayesian forecasting of the dose needed to obtain the target plasma concentration.…”

Section: Case 4: Precision Dosingmentioning

confidence: 99%