Clinical trial NCT02413892: Impact of a Loading Dose of Caspofungin in Invasive Candidiasis in ICU Patients
Official title: Impact of a Loading Dose of Caspofungin on Pharmacokinetic and Pharmacodynamic Parameters Target Achievements for Severe Candida Infections in ICU Patients
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Candida Infections
Lead sponsor: Outcome Rea
Sponsor class: OTHER
Collaborators: name: Assistance Publique - Hôpitaux de Paris
First posted: 2015-04-10
Enrollment: 15
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: PROBABILITY_SAMPLE
Study population: All consecutive patients for whom the decision to start antifungal therapy with caspofungin loading dose was taken

Brief summary: Echinocandins are the drug of choice in severe candida infections. Efficacy of echinocandins is related to concentration and area under the curve (AUC) of the drug.

Available pharmacokinetic studies found that concentration of echinocandins mainly caspofungin is sub-optimal in severe candida infections in intensive care unit (ICU) patients.

Higher dose of caspofungin has been proven to be safe in critically ill patients but its impact on the ability to reach PK/PD target is unknown.

The aim of this study is to evaluate the impact of a loading dose of caspofungin on PK/PD parameters within the first 24-hours.

Detailed description: Invasive fungal infections are associated to a high mortality rate in ICU, partly because of a delayed treatment.

PK/PD targets for caspofungin are the peak concentration over minimal inhibitory concentration (MIC) ratio which should reach 10 and the area under the inhibitory curve (AUIC) which should be over 200. High distribution volume in ICU patients and increase of MICs due to extensive use of antifungal agents make optimal concentration difficult to obtain. High doses up to 150mg of caspofungin have been reported to be safe. Thus, in our unit, a loading dose of 140mg of caspofungin is a standard practice but was never rigorously evaluated.

The aim of the present study is to measure the impact of a loading dose of 140mg of caspofungin on the pharmacokinetic parameters in the first 24 hours of treatment.

The AUIC and maximal concentration (CMax) / (MIC) according to the recovered yeasts will be measured. The investigators also planned a Monte-Carlo simulation using MICs obtained from clinically relevant candida strains isolated in Bichat and Grenoble hospitals in order to evaluate the percentage of patients appropriately treated within the first 24 hours according to Candida species and previous use of antifungals.

Recovered strains from epidemiological studies will be used for PKPD modelling and will use s. A second Monte-Carlo simulation will be done using data from the Amarcand 2 study.

All MICs will be determined using E-test ( Biomerieux® KIT's) without specifying any breakpoints as MICs and not breakpoints per se will be used.

Eligibility criteria: Inclusion Criteria:

* Patient hospitalized in intensive care
* Age\> 18 years
* Patient with a central catheter
* Patient with invasive mechanical ventilation
* Patient receiving more than 0.1 mcg / kg / min of adrenaline or noradrenaline
* Patient treated for proven (positive blood cultures or positive specimen obtained during a surgical or percutaneous puncture) or suspected (risk factor, extra digestive colonization, absence of other uncontrolled bacterial infections, candida score\> 3) invasive candidiasis.
* Patient affiliated to medical insurance

Exclusion Criteria:

* Expected length of stay under 48H
* Age \<18 years
* Pregnant or breastfeeding women
* Limited or sustained life support therapy
* Patient unable to legally consent
* History of Allergy, hypersensitivity or intolerance to echinocandins or Drug excipients

Primary outcomes:
measure: Area Under the inhibitory curve (AUIC)
timeFrame: 24 hours after the loading dose
Secondary outcomes:
measure: Peak concentration over MIC (Cmax/MIC)
timeFrame: 2 hours avec the loading dose
Other outcomes:
Locations:
city: Paris
country: France
facility: Reanimation Medicale et Infectieuse-Hopital Bichat
Study officials:
affiliation: Assistance Publique - Hôpitaux de Paris
name: Jean-Francois TIMSIT, Professor
role: PRINCIPAL_INVESTIGATOR
References:
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citation: Sinnollareddy M, Peake SL, Roberts MS, Lipman J, Roberts JA. Using pharmacokinetics and pharmacodynamics to optimise dosing of antifungal agents in critically ill patients: a systematic review. Int J Antimicrob Agents. 2012 Jan;39(1):1-10. doi: 10.1016/j.ijantimicag.2011.07.013. Epub 2011 Sep 16.
citation: Nguyen TH, Hoppe-Tichy T, Geiss HK, Rastall AC, Swoboda S, Schmidt J, Weigand MA. Factors influencing caspofungin plasma concentrations in patients of a surgical intensive care unit. J Antimicrob Chemother. 2007 Jul;60(1):100-6. doi: 10.1093/jac/dkm125. Epub 2007 May 24.
citation: Bailly S, Gautier-Veyret E, Le MP, Bouadma L, Andremont O, Neuville M, Mourvillier B, Sonneville R, Magalhaes E, Lebut J, Radjou A, Smonig R, Wolff M, Massias L, Dupuis C, Timsit JF. Impact of Loading Dose of Caspofungin in Pharmacokinetic-Pharmacodynamic Target Attainment for Severe Candidiasis Infections in Patients in Intensive Care Units: the CASPOLOAD Study. Antimicrob Agents Chemother. 2020 Nov 17;64(12):e01545-20. doi: 10.1128/AAC.01545-20. Print 2020 Nov 17.