What clindamycin dose should be administered by continuous infusion during combination therapy with rifampicin? A prospective population pharmacokinetics study.

BACKGROUND: Despite its important drug-drug interaction, combined clindamycin/rifampicin therapy may achieve effective plasma clindamycin concentrations, provided clindamycin is administered by continuous infusion. However, the precise clindamycin dose remains unknown. OBJECTIVES: This study was undertaken to determine the daily clindamycin dose to be administered by continuous infusion in combination with rifampicin to achieve effective plasma clindamycin concentrations. PATIENTS AND METHODS: Two plasma clindamycin concentrations were determined prospectively for 124 patients with bone-and-joint infections treated with continuously infused clindamycin. Twenty patients received clindamycin monotherapy, 19 clindamycin combined with rifampicin and 85 received clindamycin successively without and with rifampicin. A population pharmacokinetic model was developed using NONMEM 7.5. Monte Carlo simulations were run to determine which regimens obtained clindamycin concentrations of at least 3 mg/L. RESULTS: A linear one-compartment model with first-order elimination accurately described the data. Clindamycin distribution volume was not estimated. Mean clindamycin clearances with rifampicin and without, respectively, were 33.6 and 10.9 L/h, with 12.8% interindividual variability. The lowest daily clindamycin dose achieving plasma concentrations of at least 3 mg/L in >90% of the patients, when combined with rifampicin, was 4200 mg/24 h. CONCLUSIONS: Our results support continuous infusion of 4200 mg of clindamycin/24 h, in combination with rifampicin. This high-dose regimen requires therapeutic drug monitoring-guided dose adaptation.

Defining standard and high dosages for ß-lactam agents administered by intermittent, prolonged or continuous infusion: a PK/PD simulation study.

BACKGROUND: The new definitions of antimicrobial susceptibility categories proposed by EUCAST in 2020 require the definition of standard and high dosages of antibiotic. For injectable ß-lactams, standard and high dosages have been proposed for short-infusion regimens only. OBJECTIVES: To evaluate dosages for ß-lactams administered by prolonged infusion (PI) and continuous infusion (CI). METHODS: Monte Carlo simulations were performed for seven injectable ß-lactams: aztreonam, cefepime, cefotaxime, cefoxitin, ceftazidime, piperacillin and temocillin. Various dosage regimens based on short infusion, PI or CI were simulated in virtual patients. Pharmacokinetic (PK) profiles and PTAs were obtained based on reference population PK models, as well as PK/pharmacodynamic targets and MIC breakpoints proposed by EUCAST. Alternative dosage regimens associated with PTA values similar to those of recommended dosages up to the breakpoints were considered acceptable. RESULTS: Adequate PTAs were confirmed for most EUCAST short-infusion dosage regimens. A total of 9 standard and 14 high dosages based on PI (3 to 4 h) or CI were identified as alternatives. For cefepime and aztreonam, only PI and CI regimens could achieve acceptable PTAs for infections caused by Pseudomonas spp.: 2 g q8h as PI of 4 h or 6 g/24 h CI for cefepime; 2 g q6h as PI of 3 h or 6 g/24 h CI for aztreonam. CONCLUSIONS: These alternative standard and high dosage regimens are expected to provide antibiotic exposure compatible with new EUCAST definitions of susceptibility categories and associated MIC breakpoints. However, further clinical evaluation is necessary.

Caspofungin sequestration in a polyacrylonitrile-derived filter: Increasing the dose does not mitigate sequestration.

OBJECTIVES: Critically ill patients frequently require continuous renal replacement therapy. Echinocandins are recommended as first-line treatment of candidemia. Preliminary results suggested echinocandin sequestration in a polyacrylonitrile filter. The present study aimed to determine whether increasing the dose might balance sequestration. METHODS: An STX filter (Baxter-Gambro) was used. A liquid chromatography-mass spectrometry method was used for dosage of caspofungin. In vitro drug disposition was evaluated by NeckEpur (Neckepur, Versailles, France) technology using a crystalloid medium instead of diluted/reconstituted blood, focusing on the disposition of the unbound fraction of drugs. Two concentrations were assessed. RESULTS: At the low dose, the mean measured initial concentration in the central compartment (CC) was 5.1 ± 0.6 mg/L. One hundred percent of the initial amount was eliminated from the CC within the 6-h session. The mean total clearance from the CC was 9.6 ± 2.5 L/h. The mean percentages of elimination resulting from sequestration and diafiltration were 96.0 ± 5.0 and 4.0 ± 5.2%, respectively. At high dose, the mean measured initial concentration in the CC was 13.1 mg/L. One hundred percent of the initial amount was eliminated from the CC within the 6-h session. The mean total clearance from the CC was 9.5 L/h. The mean percentages of elimination resulting from sequestration and filtration were 88.5% and 11.5%, respectively. CONCLUSION: Increasing the dose does not mitigate caspofungin sequestration in the STX filter. The results raise caution about the simultaneous use of caspofungin and polyacrylonitrile-derived filters. Intermittent modes of renal replacement therapy might be considered. For sensitive species, fluconazole might be an alternative.

An innovative ethosuximide granule formulation designed for pediatric use: Comparative pharmacokinetics, safety, tolerability, and palatability profile versus reference syrup.

Ethosuximide, the first-line therapy for childhood absence epilepsy, is currently formulated as a syrup (Zarontin®, Pfizer) with a bitter taste and high sugar content, poorly adapted to children, and a ketogenic diet. The collaborative European FP7 project KIEKIDS aimed at developing an innovative sugar-free, tasteless formulation convenient for pediatric use. This dual Phase-I study evaluated two granule formulations based on lipid multiparticulate (LMP) technology. Two panels of 6 healthy adult volunteers underwent a randomized, placebo-controlled, partly blinded, 3-way cross-over trial, comparing ethosuximide granules A or B with placebo granules and syrup at single 10 mg/kg doses. Corresponding plasma pharmacokinetic profiles of ethosuximide were compared, along with palatability, safety, and tolerability. The LMP granule A proved suboptimal due to bitterness and adherence to beaker walls, while the optimized granule B revealed excellent palatability, similar to placebo granules, and low adherence to glass. The relative bioavailability of granules A versus syrup, based on dose-normalized Cmax and AUC0-∞ was 93.7% [90% CI: 76.3-115.1] and 96.1% [91.0-101.5], respectively. For granules B it was 87.6% [81.6-94.0] and 92.5% [88.5-96.6], respectively, with slightly delayed tmax of 0.75 h [0.5-4.05] compared to syrup 0.5 h [0.3-0.8]. Tolerability visual analog scales revealed a trend for statistically non-significant improvement versus syrup at peak (30 min) for transient dizziness (both granules), fatigue (granules A), and anxiety (granules B). The innovative ethosuximide granule formulation B achieves a suitable profile for pediatric use, being sugar-free, tasteless, bioequivalent, and well-tolerated while enabling precise adjustment to body weight.

Population Pharmacokinetics of Orally Administered Clindamycin to Treat Prosthetic Joint Infections: A Prospective Study.

A population PK model of clindamycin orally administered to patients with prosthetic joint infections (PJIs) was developed using NONMEM 7.5. Monte-Carlo simulations were run to determine the probability of obtaining bone clindamycin concentrations equal to at least the MIC or four times the MIC for several MIC values and dosing regimens. One hundred and forty plasma concentrations prospectively obtained from 20 patients with PJIs were used. A one-compartment model with first-order absorption and elimination appropriately described the data. Mean PK-parameter estimates (F being the bioavailability) were: apparent clearance, CL/F = 23 L/h, apparent distribution volume, V/F = 103 l and absorption rate constant, Ka = 3.53/h, with respective interindividual variabilities (coefficients of variation) of 14.4%, 8.2% and 59.6%. Neither goodness-of-fit curves nor visual predictive checks indicated bias. The currently recommended 600 mg q8h regimen provided a high probability of obtaining concentrations equal to at least the MIC, except for MIC ≥ the clinical breakpoint for Staphylococcus spp. (0.25 mg/L). For such MIC values, higher daily doses and q6h regimens could be considered.

Empirical Antibiotic Therapy for Gram-Negative Bacilli Ventilator-Associated Pneumonia: Observational Study and Pharmacodynamic Assessment.

Background: Strong evidence suggests a correlation between pharmacodynamics (PD) index and antibiotic efficacy while dose adjustment should be considered in critically ill patients due to modified pharmacokinetic (PK) parameters and/or higher minimum inhibitory concentrations (MICs). This study aimed to assess pharmacodynamic (PD) target attainment considering both antibiotics serum concentrations and measured MICs in these patients. Method: A multicentric prospective open-label trial conducted in 11 French ICUs involved patients with Gram-negative bacilli (GNB) ventilator-associated pneumonia (VAP) confirmed by quantitative cultures. Results: We included 117 patients. Causative GNBs were P. aeruginosa (40%), Enterobacter spp. (23%), E. coli (20%), and Klebsiella spp. (16%). Hence, 117 (100%) patients received ß-lactams, 65 (58%) aminoglycosides, and two (1.5%) fluoroquinolones. For ß-lactams, 83% of the patients achieved a Cmin/MIC > 1 and 70% had a Cmin/MIC > 4. In the case of high creatinine clearance (CrCL > 100 mL/min/1.73 m2), 70.4% of the patients achieved a Cmin/MIC ratio > 1 versus 91% otherwise (p = 0.041), and 52% achieved a Cmin/MIC ratio > 4 versus 81% (p = 0.018). For aminoglycosides, 94% of the patients had a Cmax/MIC ratio > 8. Neither ß-lactams nor aminoglycosides PK/PD parameters were associated clinical outcomes, but our data suggest a correlation between ß-lactams Cmin/MIC and microbiological success. Conclusion: In our ICU patients treated for GNB VAP, using recommended antibiotic dosage led in most cases to PK/PD targets attainment for aminoglycosides and ß-lactams. High creatinine clearance should encourage clinicians to focus on PK/PD issues.

Automated HPLC-MS/MS assay for the simultaneous determination of ten plasma antibiotic concentrations.

Therapeutic drug monitoring (TDM) of antibiotics (ATB) in patients with serious bacterial infections allows optimization of the efficacy of the treatment while reducing the risk of toxicity. Notably, early measurement of plasma beta-lactam concentration has been shown to be associated with reduced mortality in intensive care patients. In this context, a rapid, robust, and accurate assay method is essential for daily TDM. A fully automated procedure for quantification of the plasma concentrations of ten ATB was developed. The ATB were divided into two calibration pools, with Pool 1: aztreonam, ceftobiprole, cefoxitin, avibactam, tazobactam and Pool 2: metronidazole, ceftriaxone, daptomycin, ceftolozane, moxifloxacin. Sample preparation consisting of acetonitrile plasma protein precipitation and H20 dilution was applied to all analytes. This procedure was carried out by an automated sample preparation system directly coupled to a liquid chromatography-tandem mass spectrometry (LC-MS/MS) system. Since the instrument extracts sample n while sample n-1 is in the LC-MS/MS system, the delay between obtaining the results for two samples corresponds to the analytical run time, which is less than 7 min. The method was validated according to the Food and Drug Administration guidelines. The method was sensitive (lower limit of quantification 0.1-1 mg/L, depending on the ATB), accurate (intra/inter-assay bias -14.8 to 14.2 %) and precise (intra/inter-assay CVs 1.27 to 16.3 %). Application of the TDM assay was illustrated by the report of an intensive care patient treated with the ceftazidime/aztreonam/avibactam combination. Four assays were performed in 8 days with results returned within 24 h to quickly manage the dose regimen in this patient. An automated, simple, rapid, robust LC-MS/MS analysis was developed and validated for the simultaneous quantification of plasma concentrations of 10 ATB and was applied with success to perform TDM. This method provides a shorter turnaround time than classic sample batch-based analytical methods.

Systemic bis-phosphinic acid derivative restores chloride transport in Cystic Fibrosis mice.

Mutations in the Cystic Fibrosis Transmembrane Conductance Regulator gene (CFTR) are responsible for Cystic Fibrosis (CF). The most common CF-causing mutation is the deletion of the 508th amino-acid of CFTR (F508del), leading to dysregulation of the epithelial fluid transport in the airway's epithelium and the production of a thickened mucus favoring chronic bacterial colonization, sustained inflammation and ultimately respiratory failure. c407 is a bis-phosphinic acid derivative which corrects CFTR dysfunction in epithelial cells carrying the F508del mutation. This study aimed to investigate c407 in vivo activity in the F508del Cftrtm1Eur murine model of CF. Using nasal potential difference measurement, we showed that in vivo administration of c407 by topical, short-term intraperitoneal and long-term subcutaneous route significantly increased the CFTR dependent chloride (Cl-) conductance in F508del Cftrtm1Eur mice. This functional improvement was correlated with a relocalization of F508del-cftr to the apical membrane in nasal epithelial cells. Importantly, c407 long-term administration was well tolerated and in vitro ADME toxicologic studies did not evidence any obvious issue. Our data provide the first in vivo preclinical evidence of c407 efficacy and absence of toxicity after systemic administration for the treatment of Cystic Fibrosis.

In Vivo Efficacy of Voriconazole in a Galleria mellonella Model of Invasive Infection Due to Azole-Susceptible or Resistant Aspergillus fumigatus Isolates.

Aspergillus fumigatus is an environmental filamentous fungus responsible for life-threatening infections in humans and animals. Azoles are the first-line treatment for aspergillosis, but in recent years, the emergence of azole resistance in A. fumigatus has changed treatment recommendations. The objective of this study was to evaluate the efficacy of voriconazole (VRZ) in a Galleria mellonella model of invasive infection due to azole-susceptible or azole-resistant A. fumigatus isolates. We also sought to describe the pharmacokinetics of VRZ in the G. mellonella model. G. mellonella larvae were infected with conidial suspensions of azole-susceptible and azole-resistant isolates of A. fumigatus. Mortality curves were used to calculate the lethal dose. Assessment of the efficacy of VRZ or amphotericin B (AMB) treatment was based on mortality in the lethal model and histopathologic lesions. The pharmacokinetics of VRZ were determined in larval hemolymph. Invasive fungal infection was obtained after conidial inoculation. A dose-dependent reduction in mortality was observed after antifungal treatment with AMB and VRZ. VRZ was more effective at treating larvae inoculated with azole-susceptible A. fumigatus isolates than larvae inoculated with azole-resistant isolates. The concentration of VRZ was maximal at the beginning of treatment and gradually decreased in the hemolymph to reach a Cmin (24 h) between 0.11 and 11.30 mg/L, depending on the dose. In conclusion, G. mellonella is a suitable model for testing the efficacy of antifungal agents against A. fumigatus.

Development of a dosing-adjustment tool for fluoroquinolones in osteoarticular infections: The Fluo-pop study.

Fluoroquinolones efficacy depend on both the drug exposure and the level of drug resistance of the bacteria responsible for the infection. Specifically for the Staphylococcus species, which is the microorganism mainly involved in osteoarticular infections (OAI), in-vitro data reported that an AUC/MIC ratio above 115 h maximizes drug efficacy. However, data on OAI patients are lacking and a simple approach to access AUCs is still a clinical issue. We conducted a prospective, single-center study in 30 OAI patients hospitalized in the Rennes University Hospital to model ofloxacin pharmacokinetics and to define a limited sampling strategy (LSS) suitable for ofloxacin and levofloxacin treatments. Modeling was conducted with the Monolix software. The final model was externally validated using levofloxacin data. Monte-Carlo simulations were used to evaluate the probability of target attainment (PTA) of different dosing regimens. Two hundred and ninety-seven (297) ofloxacin concentrations were available for the pharmacokinetic modeling. Ofloxacin pharmacokinetics was best described using a bicompartmental model with a first order elimination, and a transit compartment model absorption. CKD-EPI and sex explained half of ofloxacin pharmacokinetic variability. For LSS, the 0, 1 h and 3 h sampling scheme resulted in the best approach both for BID and TID dosages (R2 adjusted = 91.1% and 95.0%, outliers = 4.8% and 5.0%, respectively). PTA allows choosing the best drug and dosage according to various hypotheses. A simple 3-sample protocol (pre-dose, 1 h after intake and 3 h after intake) to estimate ofloxacin and levofloxacin AUC allows optimal drug dosage for the treatment of osteoarticular infections.

Conditional Non-parametric Bootstrap for Non-linear Mixed Effect Models.

PURPOSE: Non-linear mixed effect models are widely used and increasingly integrated into decision-making processes. Propagating uncertainty is an important element of this process, and while standard errors (SE) on pa- rameters are most often computed using asymptotic approaches, alternative methods such as the bootstrap are also available. In this article, we propose a modified residual parametric bootstrap taking into account the different levels of variability involved in these models. METHODS: The proposed approach uses samples from the individual conditional distribution, and was implemented in R using the saemix algorithm. We performed a simulation study to assess its performance in different scenarios, comparing it to the asymptotic approximation and to standard bootstraps in terms of coverage, also looking at bias in the parameters and their SE. RESULTS: Simulations with an Emax model with different designs and sigmoidicity factors showed a similar coverage rate to the parametric bootstrap, while requiring less hypotheses. Bootstrap improved coverage in several scenarios compared to the asymptotic method especially for the variance param-eters. However, all bootstraps were sensitive to estimation bias in the original datasets. CONCLUSIONS: The conditional bootstrap provided better coverage rate than the traditional residual bootstrap, while preserving the structure of the data generating process.

Influence of the clindamycin administration route on the magnitude of clindamycin-rifampicin interaction: a prospective pharmacokinetic study.

OBJECTIVES: An important clindamycin-rifampicin pharmacokinetic (PK) interaction has been reported, but the potential influence of the clindamycin administration route on that interaction is unknown. This prospective, observational, comparative PK study was undertaken to characterize and analyse the impact of the route, comparing the rifampicin enzyme-inductor effects on clindamycin clearance (CLclin) for oral versus intravenous (IV) administration. METHODS: Patients with bone-and-joint infections (BJIs) were treated with clindamycin monotherapy (n = 20) or clindamycin-rifampicin combination therapy (n = 19). Patients received continuous IV clindamycin infusion for 2-6 weeks, followed by an oral regimen. Liquid chromatography-mass spectrometry was used to measure plasma clindamycin concentrations at the end of IV and after 2 weeks of oral treatment. The ratios of the mean CLclin for the combination and monotherapy groups were calculated for IV (Riv) and oral (Rpo) routes, with the final ratio, Rf = Rpo/Riv, representing the fold change of the rifampicin-inducing effect from the IV to the oral route. RESULTS: Comparing monotherapy with combination-therapy groups, the former's median steady-state concentration was two-fold higher after IV administration (8.49 versus 3.82 mg/L, p < 0.001) and its median AUC0-8h was 12 times higher after oral intake (37.7 versus 3.1 mg.h/L, p < 0.001). Riv, Rpo and Rf were 2.68, 18.8 and 7.0 respectively. CONCLUSION: The magnitude of this interaction was markedly increased by oral intake, questioning the use of oral treatment for difficult-to-treat infections like BJIs. Nevertheless, the clindamycin-rifampicin combination seems possible provided that clindamycin is administered by continuous IV infusion.

Unintentional artenimol/piperaquine overdose in two children occurring without evidence of subsequent cardiotoxicity.

At the emergency department of the Robert-Debré children's hospital in Paris, France, artenimol/piperaquine (AP) has been the first-line antimalarial treatment since September 2012. Most children receive the first dose at the hospital and return home if, after 1 hour's observation, there have been no episodes of vomiting. Here we report the case of two children, aged 11 years and 5 years, respectively, in whom the entire cumulative 3 days' treatment course combined was accidentally administered instead of just the first-day treatment dose. Serum piperaquine levels were measured between Hour 40 (H40) and Day 29 (D29) post-ingestion for the first patient, and between H17 and D7 for the second patient. Corrected QT (QTc) values were measured between H12 and D20 for the first patient and between H17 and H64 for the second patient. Despite reports of adverse electrophysiological events, AP overdose occurred without consequence on the QTc interval or clinical cardiac state in these two children.

Deficient mitophagy pathways in sickle cell disease.

Sickle cell disease (SCD) is characterised by chronic haemolysis and oxidative stress. Herein, we investigated 30 SCD patients and found 40% with elevated mitochondria levels (SS-mito+ ) in their mature red blood cells, while 60% exhibit similar mitochondria levels compared to the AA group (SS-mito- ). The SS-mito+ patients are characterised by higher reticulocytosis and total bilirubin levels, lower foetal haemoglobin, and non-functional mitochondria. Interestingly, we demonstrated decreased levels of mitophagy inducers, PINK1 and NIX, and higher levels of HSP90 chaperone in their red cells. Our results highlighted for the first time an abnormal retention of mitochondria in SCD linked with mitophagy-related proteins.

Pharmacokinetic and Pharmacodynamic Optimization of Antibiotic Therapy in Cystic Fibrosis Patients: Current Evidences, Gaps in Knowledge and Future Directions.

Antibiotic therapy is one of the main treatments for cystic fibrosis (CF). It aims to eradicate bacteria during early infection, calms down the inflammatory process, and leads to symptom resolution of pulmonary exacerbations. CF can modify both the pharmacokinetic (PK) and pharmacodynamic (PD) profiles of antibiotics, therefore specific PK/PD endpoints should be determined in the context of CF. Currently available data suggest that optimal PK/PD targets cannot be attained in sputum with intravenous aminoglycosides. Continuous infusion appears preferable for ß-lactam antibiotics, but optimal concentrations in sputum are unlikely to be reached, with some possible exceptions such as meropenem and ceftolozane. Usual doses are likely suboptimal for fluoroquinolones and linezolid, whereas daily doses of 45-60 mg/kg and 200 mg could be convenient for vancomycin and doxycycline, respectively. Weekly azithromycin doses of 22-30 mg/kg could also be appropriate for its anti-inflammatory effect. The difficulty with achieving optimal concentrations supports the use of combined treatments and the inhaled administration route, as very high local concentrations, concomitantly with low systemic exposure, can be obtained with the inhaled route for aminoglycosides, colistin, and fluoroquinolones, thus minimizing the risk of toxicity.

Pharmacokinetic study (phase I-II) of a new dobutamine formulation in preterm infants immediately after birth.

BACKGROUND: Dobutamine is particularly suited to treatment of haemodynamic insufficiency caused by increased peripheral vascular resistance and myocardial dysfunction in the preterm infant. Knowledge of the elimination half-life is essential to estimate the steady state when its efficacy/safety can be evaluated. METHODS: Analysis of pharmacokinetic data in ten preterm newborns treated with a new neonatal formulation of dobutamine (IMP) after screening for haemodynamic insufficiency within the first 72 h from birth. Blood samples were withdrawn at the end of IMP infusion and at a random time after the end of infusion (5 min, 15 min, 45 min, 2 h and 6 h). IMP concentration in each sample was measured by ultra-high performance liquid chromatography with electrochemical detection. RESULTS: Median duration of IMP infusion was 37.7 h (IQR 21.2). Calculated IMP half-life ranged between 3.06 and 36.1 min (median 10.6 min), leading to a time to reach the steady-state concentration between 15 min and >2 h. Adverse events were not related to IMP. CONCLUSIONS: The wide variability in dobutamine metabolism in preterm infants requires awareness about the risk of under- or overtreatment. A delay of up to 3 h might be required before drawing blood samples to evaluate the effective dose. IMPACT: Small trials suggest dobutamine as the optimal drug in the preterm infant with haemodynamic insufficiency after birth. Age-related differences in drug pharmacokinetics may result in suboptimal treatments. The lack of formal studies in preterms results in inadequate data on efficacy and safety. This study provides data on the variability of the elimination half-life of dobutamine in the very preterm infant during transitional circulation. There is a wide variation in the time to reach the plasma concentration corresponding to steady state, the moment when its efficacy/safety can be reliably evaluated. This information is crucial for planning future trials on cardiovascular support.

Are we correctly treating invasive candidiasis under continuous renal replacement therapy with echinocandins? Preliminary in vitro assessment.

There is major concern regarding the pharmacokinetics of drugs under continuous renal replacement therapy (CRRT), including anti-infectious agents and more especially antifungal agents. From a regulatory viewpoint, only dialysis and filtration are considered meanwhile there is growing evidence that adsorption may also significantly alter the pharmacokinetics of anti-infectious agents. Adsorption results from a complex drug-filter interaction and might be considered an unexpected adverse effect induced by CRRT. Measurement of total plasma concentrations instead of the unbound, free, active concentrations in in vitro as well as in clinical studies hides this major adverse effect, which may jeopardise the therapeutic effect and even result in treatment failure. Noteworthy, minimal inhibitory concentrations (MIC) of anti-infectious agents are performed using solid and liquid medium without proteins testing only the antimicrobial activity of the free fraction of drugs. In a new in vitro model using crystalloid solution instead of blood, we report data supporting the assumption that the assessment of the disposition of the free fraction of caspofungin and micafungin unveils adverse effects of ST150® filter, which might eventually result in non-detectable drug concentrations and treatment failure. From a technical viewpoint, we conclude the measurement of the free fraction of drugs that largely bound to plasma proteins, including caspofungin and micafungin, should be considered instead of total plasma concentrations to assess all effects induced by filters used in CRRT.

Elimination of fluconazole during continuous renal replacement therapy. An in vitro assessment.

INTRODUCTION: Continuous renal replacement therapy (CRRT) efficiently eliminates fluconazole. However, the routes of elimination were not clarified. Adsorption of fluconazole by filters is a pending question. We studied the elimination of fluconazole in a model mimicking a session of CRRT in humans using the NeckEpur® model. Two filters were studied. METHODS: The AV1000®-polysulfone filter with the Multifiltrate Pro. Fresenius and the ST150®-polyacrylonitrile filter with the Prismaflex. Baxter-Gambro were studied. Continuous filtration used a flowrate of 2.5 L/h in post-dilution only. Session were made in duplicate. Routes of elimination were assessed using the NeckEpur® model. RESULTS: The mean measured initial fluconazole concentration (mean ± SD) for the four sessions in the central compartment (CC) was 14.9 ± 0.2 mg/L. The amount eliminated from the CC at the end of 6 h-session at a 2.5 L/h filtration flowrate for the AV1000®-polysulfone and the ST150®-polyacrylonitrile filters were 90%-93% and 96%-94%, respectively; the clearances from the central compartment (CC) were 2.5-2.6 and 2.4-2.3 L/h, respectively. The means of the instantaneous sieving coefficient were 0.94%-0.91% and 0.99%-0.91%, respectively. The percentages of the amount eliminated from the CC by filtration/adsorption were 100/0%-95/5% and 100/0%-100/0%, respectively. CONCLUSION: Neither the ST150®-polyacrylonitrile nor the AV1000®-polysulfone filters result in any significant adsorption of fluconazole.