Publications by authors named "Isabel Spriet"

136 Publications

Interaction between flucloxacillin and azoles: is isavuconazole next?

Mycoses 2021 Sep 23. Epub 2021 Sep 23.

Department of Pharmaceutical and Pharmacological Sciences, KU Leuven and Pharmacy Department, University Hospitals Leuven, Leuven, Belgium.

Background: Isavuconazole is a triazole antifungal drug, approved for the treatment of invasive aspergillosis and mucormycosis. It has been previously reported that an interaction between flucloxacillin and voriconazole may lead to subtherapeutic voriconazole exposure, when used concomitantly. Since isavuconazole is also metabolized via cytochrome P450 enzymes, the same interaction may be expected.

Objectives: We aim to document exposure to isavuconazole in patients concomitantly treated with flucloxacillin.

Patients: We report two patients treated with both isavuconazole and flucloxacillin, in whom we determined isavuconazole concentrations.

Results: Low isavuconazole trough concentrations (< 1 mg/L) were observed in two patients under concomitant treatment with flucloxacillin.

Conclusions: In combination with flucloxacillin, low isavuconazole concentrations were observed but an adequate isavuconazole exposure may be reached with dose augmentation. Therapeutic drug monitoring of isavuconazole is recommended to ensure an adequate exposure.
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http://dx.doi.org/10.1111/myc.13373DOI Listing
September 2021

Population pharmacokinetics of cefazolin in maternal and umbilical cord plasma, and simulated exposure in term neonates.

J Antimicrob Chemother 2021 Sep 9. Epub 2021 Sep 9.

Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium.

Background: Intra-partum cefazolin is used to prevent group B Streptococcus (GBS) vertical transmission in mothers allergic to penicillin without a history of anaphylaxis.

Objectives: To investigate the maternal cefazolin dose-exposure relationship and subsequent maternal and neonatal target attainment at delivery.

Methods: Data were obtained from 24 healthy, GBS-colonized pregnant women (20-41 years), undergoing vaginal delivery (gestational age ≥37 weeks). During labour, all women received a 2 g cefazolin IV infusion. Eight hours later, eight women received another 1 g in the event of delayed (>8 h) delivery. Next to maternal plasma concentrations (up to 10 per dosing interval, until delivery), venous and arterial umbilical cord concentrations were determined at delivery. Target attainment in maternal/neonatal plasma was set at 1 mg/L for 60% of the dosing interval (unbound cefazolin, worst-case clinical breakpoint). A population pharmacokinetic (popPK) model was built (NONMEM 7.4). ClinicalTrials.gov Identifier: NCT01295606.

Results: At delivery, maternal blood and arterial umbilical cord unbound cefazolin concentrations were >1 mg/L in 23/24 (95.8%) and 11/12 (91.7%), respectively. The popPK of cefazolin in pregnant women was described by a two-compartment model with first-order elimination. Two additional compartments described the venous and arterial umbilical cord concentration data. Cefazolin target attainment was adequate in the studied cohort, where delivery occurred no later than 6.5 h after either the first or the second dose. PopPK simulations showed adequate maternal and umbilical cord exposure for 12 h following the first dose.

Conclusions: PopPK simulations showed that standard pre-delivery maternal cefazolin dosing provided adequate target attainment up to the time of delivery.
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http://dx.doi.org/10.1093/jac/dkab329DOI Listing
September 2021

Letermovir exposure in transplant patients with end-stage renal disease on renal replacement therapy.

J Antimicrob Chemother 2021 Sep 2. Epub 2021 Sep 2.

Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium.

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http://dx.doi.org/10.1093/jac/dkab316DOI Listing
September 2021

Bacteriophage Therapy for Difficult-to-Treat Infections: The Implementation of a Multidisciplinary Phage Task Force ().

Viruses 2021 Aug 5;13(8). Epub 2021 Aug 5.

Department of Trauma Surgery, University Hospitals Leuven, 3000 Leuven, Belgium.

In times where only a few novel antibiotics are to be expected, antimicrobial resistance remains an expanding global health threat. In case of chronic infections caused by therapy-resistant pathogens, physicians have limited therapeutic options, which are often associated with detrimental consequences for the patient. This has resulted in a renewed interest in alternative strategies, such as bacteriophage (phage) therapy. However, there are still important hurdles that currently impede the more widespread implementation of phage therapy in clinical practice. First, the limited number of good-quality case series and clinical trials have failed to show the optimal application protocol in terms of route of administration, frequency of administration, treatment duration and phage titer. Second, there is limited information on the systemic effects of phage therapy. Finally, in the past, phage therapy has been applied intuitively in terms of the selection of phages and their combination as parts of phage cocktails. This has led to an enormous heterogeneity in previously published studies, resulting in a lack of reliable safety and efficacy data for phage therapy. We hereby present a study protocol that addresses these scientific hurdles using a multidisciplinary approach, bringing together the experience of clinical, pharmaceutical and molecular microbiology experts.
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http://dx.doi.org/10.3390/v13081543DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8402896PMC
August 2021

Development and validation of a Screening Tool to Evaluate and Warrant Anticoagulation Treatment prior to Discharge in inpatients with Atrial Fibrillation (STEWARD-AF).

Int J Med Inform 2021 Aug 17;154:104555. Epub 2021 Aug 17.

Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium; Pharmacy Department, University Hospitals Leuven, Leuven, Belgium. Electronic address:

Objective: Anticoagulation is highly effective for stroke prevention in atrial fibrillation (AF), reducing the risk by about 64%. Despite overwhelming evidence in support of anticoagulation, up to 40% of AF patients remain untreated. We aimed to develop and validate STEWARD-AF: a Screening Tool to Evaluate and Warrant Anticoagulation Treatment prior to Discharge in Atrial Fibrillation.

Materials And Methods: STEWARD-AF was developed by integrating information extracted from the electronic health record (EHR). A stepwise decision process was applied, based on AF diagnosis, estimated CHADS-VASc-score and anticoagulant use. A priority score was assigned accordingly, ranging from 0 (no risk) to 5 (highest risk of undertreatment). A cross-sectional study was performed to assess the accuracy of STEWARD-AF. Criterion and tool validity were ascertained by determining sensitivity and specificity, compared to a manual check of the EHR in an inpatient sample (n = 800). Consistency regarding the priority score was determined by estimating Cohen's kappa.

Results: A tool to screen for un(der)treated AF was developed and embedded into the EHR. Sensitivity and specificity for AF diagnosis were 98.4% and 87.6%, respectively. Overall sensitivity and specificity for identification of a CHADS-VASc-score ≥ 2 was 97.7% and 72.7%. Sensitivity and specificity to determine the presence of anticoagulant treatment was at least 87.8% and 97.1% There was good agreement for the priority score (κ 0.74 (unweighted); 0.66 (weighted)).

Conclusions: STEWARD-AF was able to identify untreated AF inpatients reliably and with a high sensitivity. Nearly no patients were missed. We will now implement this AF-screening tool in clinical practice to improve the use of anticoagulation and reduce the risk of stroke.
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http://dx.doi.org/10.1016/j.ijmedinf.2021.104555DOI Listing
August 2021

Global guideline for the diagnosis and management of rare yeast infections: an initiative of the ECMM in cooperation with ISHAM and ASM.

Lancet Infect Dis 2021 Aug 19. Epub 2021 Aug 19.

Department of Clinical Microbiology and Immunology, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.

Uncommon, or rare, yeast infections are on the rise given increasing numbers of patients who are immunocompromised or seriously ill. The major pathogens include those of the genera Geotrichum, Saprochaete, Magnusiomyces, and Trichosporon (ie, basidiomycetes) and Kodamaea, Malassezia, Pseudozyma (ie, now Moesziomyces or Dirkmeia), Rhodotorula, Saccharomyces, and Sporobolomyces (ie, ascomycetes). A considered approach to the complex, multidisciplinary management of infections that are caused by these pathogens is essential to optimising patient outcomes; however, management guidelines are either region-specific or require updating. In alignment with the One World-One Guideline initiative to incorporate regional differences, experts from diverse geographical regions analysed publications describing the epidemiology and management of the previously mentioned rare yeasts. This guideline summarises the consensus recommendations with regards to the diagnostic and therapeutic options for patients with these rare yeast infections, with the intent of providing practical assistance in clinical decision making. Because there is less clinical experience of patients with rare yeast infections and studies on these patients were not randomised, nor were groups compared, most recommendations are not robust in their validation but represent insights by use of expert opinions and in-vitro susceptibility results. In this Review, we report the key features of the epidemiology, diagnosis, antifungal susceptibility, and treatment outcomes of patients with Geotrichum, Saprochaete, Magnusiomyces, and Trichosporon spp infections.
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http://dx.doi.org/10.1016/S1473-3099(21)00203-6DOI Listing
August 2021

Pharmacokinetics of two oral paracetamol formulations in hospitalized octogenarians.

Br J Clin Pharmacol 2021 Aug 21. Epub 2021 Aug 21.

Pharmacy Department, University Hospitals Leuven, Leuven, Belgium.

Aim: It is currently unclear how paracetamol (acetaminophen) should be dosed in order to increase its efficacy while warranting safety in very old adults. The objective was to evaluate the pharmacokinetics of two oral paracetamol formulations and its metabolites in hospitalized octogenarians.

Methods: Geriatric inpatients aged 80 years and older received a 1000mg paracetamol tablet or granulate at 8AM, 2PM and 8PM. After at least four consecutive gifts, plasma samples were collected around the 8AM dose [trough,+0.5,+1,+2,+4,+5 and +6hours]. Plasma concentrations of paracetamol and its metabolites were determined and individual pharmacokinetic parameters were derived. The Edmonton Frail Scale was used to assess frailty. An analgesic plasma target was defined as an average plasma concentration (Cavg) of 10 mg/L.

Results: The mean (±SD) age was 86.78 (±4.20) years. The majority (N=26/36, 72%) received the tablet, 10 (28%) the granulate. Thirty patients (85%) were classified with moderate to severe frailty. Seven (21%) patients had a Cavg above 10 mg/L. The median [IQR] time to reach the peak concentration (T ) was 50.5 [31.50-92.50] and 42.50 [33.75-106.75] min for the tablet and granulate, respectively. The coefficient of variation was 95% for T and 30% for Cavg of paracetamol. A correlation of Cavg of paracetamol was observed with female sex and total serum bilirubin.

Conclusion: Large interindividual differences were found for pharmacokinetic parameters of oral paracetamol in frail inpatients after multiple dosing. Female sex and higher total serum bilirubin concentrations were associated with paracetamol exposure. No significant differences were observed between the tablet and granulate.
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http://dx.doi.org/10.1111/bcp.15049DOI Listing
August 2021

A Large Retrospective Assessment of Voriconazole Exposure in Patients Treated with Extracorporeal Membrane Oxygenation.

Microorganisms 2021 Jul 20;9(7). Epub 2021 Jul 20.

Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, 3000 Leuven, Belgium.

Background: Voriconazole is one of the first-line therapies for invasive pulmonary aspergillosis. Drug concentrations might be significantly influenced by the use of extracorporeal membrane oxygenation (ECMO). We aimed to assess the effect of ECMO on voriconazole exposure in a large patient population.

Methods: Critically ill patients from eight centers in four countries treated with voriconazole during ECMO support were included in this retrospective study. Voriconazole concentrations were collected in a period on ECMO and before/after ECMO treatment. Multivariate analyses were performed to evaluate the effect of ECMO on voriconazole exposure and to assess the impact of possible saturation of the circuit's binding sites over time.

Results: Sixty-nine patients and 337 samples (190 during and 147 before/after ECMO) were analyzed. Subtherapeutic concentrations (<2 mg/L) were observed in 56% of the samples during ECMO and 39% without ECMO ( = 0.80). The median trough concentration, for a similar daily dose, was 2.4 (1.2-4.7) mg/L under ECMO and 2.5 (1.4-3.9) mg/L without ECMO ( = 0.58). Extensive inter-and intrasubject variability were observed. Neither ECMO nor squared day of ECMO (saturation) were retained as significant covariates on voriconazole exposure.

Conclusions: No significant ECMO-effect was observed on voriconazole exposure. A large proportion of patients had voriconazole subtherapeutic concentrations.
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http://dx.doi.org/10.3390/microorganisms9071543DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8303158PMC
July 2021

Quantification and Explanation of the Variability of First-Dose Amikacin Concentrations in Critically Ill Patients Admitted to the Emergency Department: A Population Pharmacokinetic Analysis.

Eur J Drug Metab Pharmacokinet 2021 Sep 23;46(5):653-663. Epub 2021 Jul 23.

Department of Pharmacy, Univesity Hospitals Leuven, Leuven, Belgium.

Background: There may be a difference between the determinants of amikacin exposure in emergency department (ED) versus intensive care (ICU) patients, and the peak amikacin concentration varies widely between patients. Moreover, when the first dose of antimicrobials is administered to septic patients admitted to the ED, fluid resuscitation and vasopressors have just been initiated. Nevertheless, population pharmacokinetic modelling data for amikacin in ED patients are unavailable.

Objective: The aim of this study was to quantify the interindividual variability (IIV) in the pharmacokinetics of amikacin in patients admitted to the ED and to identify the patient characteristics that explain this IIV.

Methods: Patients presenting at the ED with severe sepsis or septic shock were randomly assigned to receive amikacin 25 mg/kg or 15 mg/kg intravenously. Blood samples were collected at 1, 6 and 24 h after the onset of the first amikacin infusion. Data were analysed using nonlinear mixed-effects modelling.

Results: A two-compartment population pharmacokinetic model was developed based on 279 amikacin concentrations from 97 patients. The IIV in clearance (CL) and central distribution volume (V) were 71% and 26%, respectively. Body mass index (BMI), serum total protein level, serum sodium level, and fluid balance 24 h after amikacin administration explained 30% of the IIV in V, leaving 18% of the IIV unexplained. BMI and creatinine clearance according to the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation 24 h after amikacin administration explained 46% of the IIV in CL, and 39% remained unexplained.

Conclusion: The IIV of amikacin pharmacokinetics in ED patients is large. Higher doses may be considered in patients with low serum sodium levels, low total protein levels, or a high fluid balance.

Trial Registration: ClinicalTrials.gov ID: NCT02365272.
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http://dx.doi.org/10.1007/s13318-021-00698-wDOI Listing
September 2021

Reproducibility of fluid status measured by bioelectrical impedance analysis in healthy volunteers: a key requirement to monitor fluid status in the intensive care unit.

Anaesthesiol Intensive Ther 2021 ;53(3):193-199

Department of Pharmacy, Leuven University Hospital, Leuven, 3000, Belgium.

Introduction: Little is known about the use of bioelectrical impedance analysis (BIA) in critically ill patients. The objective of this study was to evaluate the reproducibility of BIA measurements by comparing non-dominant versus dominant body-side measurements at 2 separate time points in healthy volunteers in order to extrapolate key elements that may be of relevance in critically ill patients.

Material And Methods: A prospective observational validation experiment was carried out in healthy volunteers. Full-body and segmental multiple frequency BIA measurements were carried out at the non-dominant and the dominant body side, consecutively, and on 2 separate occasions within 1 week. Parameters of interest were both raw data (impedance and phase angle) at the individual frequencies (5-50-100-200 kHz) and body fluid compartment volume estimations (total body water, extracellular water volume, intracellular water volume, volume excess).

Results: A total of 42 measurements were performed in 22 volunteers. Median (interquartile range) age and time between measurements was 26 years (24; 35) and 2.07 days (1.00; 2.99), respectively. The intraclass-correlation coefficients (ICCs) for body fluid compartment volumes estimated by full-body BIA, were greatly above 90%, showing excellent agreement, except for volume excess which showed moderate agreement. Full-body raw impedance and phase angle measurements showed highly variable and much lower ICCs. For both estimated body fluid compartment volumes and raw measurements, segmental BIA showed also highly variable and low ICCs.

Conclusions: Overall this study showed that in healthy volunteers, BIA-derived fluid parameters are reproducible, and differences can be attributed to the changes in clinical status.
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http://dx.doi.org/10.5114/ait.2021.105826DOI Listing
January 2021

Meropenem Pharmacokinetics and Target Attainment in Critically Ill Patients Are Not Affected by Extracorporeal Membrane Oxygenation: A Matched Cohort Analysis.

Microorganisms 2021 Jun 16;9(6). Epub 2021 Jun 16.

Clinical Pharmacology and Pharmacotherapy, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, 3000 Leuven, Belgium.

Existing evidence is inconclusive whether meropenem dosing should be adjusted in patients receiving extracorporeal membrane oxygenation (ECMO). Therefore, the aim of this observational matched cohort study was to evaluate the effect of ECMO on pharmacokinetic (PK) variability and target attainment (TA) of meropenem. Patients admitted to the intensive care unit (ICU) simultaneously treated with meropenem and ECMO were eligible. Patients were matched 1:1, based on renal function and body weight, with non-ECMO ICU patients. Meropenem blood sampling was performed over one or two dosing intervals. Population PK modelling was performed using NONMEM7.5. TA was defined as free meropenem concentrations >2 or 8 mg/L (i.e., 1 or 4× minimal inhibitory concentration, respectively) throughout the whole dosing interval. In total, 25 patients were included, contributing 27 dosing intervals. The overall TA was 56% and 26% for the 2 mg/L and 8 mg/L target, respectively. Population PK modelling identified estimated glomerular filtration rate according to the Chronic Kidney Disease Epidemiology equation and body weight, but not ECMO, as significant predictors. In conclusion, TA of meropenem was confirmed to be poor under standard dosing in critically ill patients but was not found to be influenced by ECMO. Future studies should focus on applying dose optimisation strategies for meropenem based on renal function, regardless of ECMO.
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http://dx.doi.org/10.3390/microorganisms9061310DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8234236PMC
June 2021

The Potential Role of Bacteriophages in the Treatment of Recalcitrant Chronic Rhinosinusitis.

Antibiotics (Basel) 2021 Jun 5;10(6). Epub 2021 Jun 5.

Department of Otorhinolaryngology, UZ Leuven, 3000 Leuven, Belgium.

Chronic rhinosinusitis is a common condition affecting 5-12% of the general population worldwide. In a limited number of cases, the disease is recalcitrant to medical and surgical interventions, causing a major impact on physical, social and emotional well-being and increasing pressure on healthcare systems. Biofilm formation and dysbiosis caused by and play a role in the pathogenesis of recalcitrant chronic rhinosinusitis. In these cases, a promising treatment alternative is the application of bacteriophages, which are viruses that infect and lyse bacteria. In this review, we appraise the evidence for the use of bacteriophages in the treatment of recalcitrant chronic rhinosinusitis. Additionally, (dis)advantages of bacteriophages and considerations for implementation of phage therapy in otorhinolaryngology practice will be discussed.
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http://dx.doi.org/10.3390/antibiotics10060675DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8229554PMC
June 2021

Timeliness of administration of amoxicillin-clavulanic acid and meropenem in a large tertiary care centre.

Int J Clin Pharm 2021 Jun 17. Epub 2021 Jun 17.

Pharmacy Department, University Hospitals Leuven, Leuven, Belgium.

Background For amoxicillin-clavulanic acid and meropenem to be effective, concentrations must exceed the minimum inhibitory concentration of infecting pathogens. Objective To retrospectively evaluate time windows between both scheduled prescription and administration and reconstitution-preparation and end of administration of intravenous amoxicillin-clavulanic acid and meropenem prescriptions. Setting 37 hospital wards at a tertiary hospital, Belgium. Method All adult hospital stays with at least one amoxicillin-clavulanic acid or meropenem administration in 2018 were reviewed. Time windows were deemed acceptable if < 30 min between prescription and administration and < 90 or < 150 min between reconstitution-preparation and end of administration for amoxicillin-clavulanic acid and meropenem, respectively. Main outcome measure Time windows between prescription and administration and between reconstitution-preparation and administration. Results For 50 273 administered prescriptions, both time windows were acceptable in 53.7% of first dose and 56.4% of follow-up dose administrations. 43.7% of first doses did not respect the time window between reconstitution-preparation and administration (2.8%) or between prescription and administration (40.9%). These discrepancies equalled 11.1% and 26.3% for follow-up doses, respectively. Large variation across hospital wards was observed. After the first five consecutive administrations, 93.1% of patients had not received their antibiotics within the time windows allowed. The most striking predictor of timely administration with respect to both prescription and reconstitution-preparation time was prescription synchronisation with nursing administration rounds. Conclusion For amoxicillin-clavulanic acid and meropenem, timeliness of reconstitution-preparation and administration was appropriate in approximately half of administrations. Evaluating and safeguarding the timeliness of antibiotic administration should be considered an important aspect of antibiotic stewardship.
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http://dx.doi.org/10.1007/s11096-021-01297-0DOI Listing
June 2021

Pharmacokinetic/Pharmacodynamic Target Attainment Based on Measured versus Predicted Unbound Ceftriaxone Concentrations in Critically Ill Patients with Pneumonia: An Observational Cohort Study.

Antibiotics (Basel) 2021 May 11;10(5). Epub 2021 May 11.

Clinical Pharmacology and Pharmacotherapy, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, 3000 Leuven, Belgium.

The impact of ceftriaxone pharmacokinetic alterations on protein binding and PK/PD target attainment still remains unclear. We evaluated pharmacokinetic/pharmacodynamic (PK/PD) target attainment of unbound ceftriaxone in critically ill patients with severe community-acquired pneumonia (CAP). Besides, we evaluated the accuracy of predicted vs. measured unbound ceftriaxone concentrations, and its impact on PK/PD target attainment. A prospective observational cohort study was carried out in adult patients admitted to the intensive care unit with severe CAP. Ceftriaxone 2 g q24h intermittent infusion was administered to all patients. Successful PK/PD target attainment was defined as unbound trough concentrations above 1 or 4 mg/L throughout the whole dosing interval. Acceptable overall PK/PD target attainment was defined as successful target attainment in ≥90% of all dosing intervals. Measured unbound ceftriaxone concentrations (CEFu) were compared to unbound concentrations predicted from various protein binding models. Thirty-one patients were included. The 1 mg/L and 4 mg/L targets were reached in 26/32 (81%) and 15/32 (47%) trough samples, respectively. Increased renal function was associated with the failure to attain both PK/PD targets. Unbound ceftriaxone concentrations predicted by the protein binding model developed in the present study showed acceptable bias and precision and had no major impact on PK/PD target attainment. We showed suboptimal (i.e., <90%) unbound ceftriaxone PK/PD target attainment when using a standard 2 g q24h dosing regimen in critically ill patients with severe CAP. Renal function was the major driver for the failure to attain the predefined targets, in accordance with results found in general and septic ICU patients. Interestingly, CEFu was reliably predicted from CEFt without major impact on clinical decisions regarding PK/PD target attainment. This suggests that, when carefully selecting a protein binding model, CEFu does not need to be measured. As a result, the turn-around time and cost for ceftriaxone quantification can be substantially reduced.
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http://dx.doi.org/10.3390/antibiotics10050557DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8151456PMC
May 2021

Posaconazole for prevention of invasive pulmonary aspergillosis in critically ill influenza patients (POSA-FLU): a randomised, open-label, proof-of-concept trial.

Intensive Care Med 2021 06 29;47(6):674-686. Epub 2021 May 29.

Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium.

Purpose: Influenza-associated pulmonary aspergillosis (IAPA) is a frequent complication in critically ill influenza patients, associated with significant mortality. We investigated whether antifungal prophylaxis reduces the incidence of IAPA.

Methods: We compared 7 days of intravenous posaconazole (POS) prophylaxis with no prophylaxis (standard-of-care only, SOC) in a randomised, open-label, proof-of-concept trial in patients admitted to an intensive care unit (ICU) with respiratory failure due to influenza (ClinicalTrials.gov, NCT03378479). Adult patients with PCR-confirmed influenza were block randomised (1:1) within 10 days of symptoms onset and 48 h of ICU admission. The primary endpoint was the incidence of IAPA during ICU stay in patients who did not have IAPA within 48 h of ICU admission (modified intention-to-treat (MITT) population).

Results: Eighty-eight critically ill influenza patients were randomly allocated to POS or SOC. IAPA occurred in 21 cases (24%), the majority of which (71%, 15/21) were diagnosed within 48 h of ICU admission, excluding them from the MITT population. The incidence of IAPA was not significantly reduced in the POS arm (5.4%, 2/37) compared with SOC (11.1%, 4/36; between-group difference 5.7%; 95% CI - 10.8 to 21.7; p = 0.32). ICU mortality of early IAPA was high (53%), despite rapid antifungal treatment.

Conclusion: The higher than expected incidence of early IAPA precludes any definite conclusion on POS prophylaxis. High mortality of early IAPA, despite timely antifungal therapy, indicates that alternative management strategies are required. After 48 h, still 11% of patients developed IAPA. As these could benefit from prophylaxis, differentiated strategies are likely needed to manage IAPA in the ICU.
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http://dx.doi.org/10.1007/s00134-021-06431-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8164057PMC
June 2021

Antifungal Prophylaxis After Lung Transplantation: Where are We Now?

Transplantation 2021 Feb 22. Epub 2021 Feb 22.

1Faculty of Medicine, KU Leuven; Leuven, Belgium 2Dept. of Respiratory Diseases, University Hospitals Leuven; Leuven, Belgium 3Dept. of Microbiology, Immunology and Transplantation, KU Leuven; Leuven, Belgium and Dept. of Laboratory Medicine and National Reference Center for Mycosis, University Hospitals Leuven, Leuven, Belgium 4Dept. of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium and Dept. Pharmacy, University Hospitals Leuven, Leuven, Belgium. 5Dept. CHROMETA, Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), KU Leuven; Leuven, Belgium.

Background: Lung transplantation is an important treatment option for various end-stage lung diseases. However, survival remains limited due to graft rejection and infections. Despite that fungal infections are frequent and carry a bad prognosis, there is currently no consensus on efficacy, optimal drug, route or duration of antifungal prophylaxis. This narrative review summarizes current strategies for antifungal prophylaxis after lung transplantation.

Methods: English-language articles in Embase, Pubmed, UptoDate and bibliographies were used to assess efficacy and safety of available antifungal agents for prophylaxis in adult lung transplant recipients.

Results: Overall, there are limited high quality data. Universal prophylaxis is more widely used and may be preferable over targeted prophylaxis. Both formulations of inhaled amphotericin B and systemic azoles are effective at reducing fungal infection rates, yet with their own specific advantages and disadvantages. The benefit of combination regimens has yet to be proven. Considering the post-transplant timing of onset of fungal infections, postoperative prophylaxis during the first postoperative months seems indicated for most patients.

Conclusions: Based on existing literature, universal antifungal prophylaxis with inhaled amphotericin B and/or systemic voriconazole for at least 3 to 6 months after lung transplantation may be advisable, with a slight preference for amphotericin B because of its better safety profile.Supplemental Visual Abstract; http://links.lww.com/TP/C166.
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http://dx.doi.org/10.1097/TP.0000000000003717DOI Listing
February 2021

Concomitant use of isavuconazole and CYP3A4/5 inducers: Where pharmacogenetics meets pharmacokinetics.

Mycoses 2021 Sep 19;64(9):1111-1116. Epub 2021 May 19.

Department of Pharmaceutical and Pharmacological Sciences, KU Leuven and Pharmacy Department, University Hospitals Leuven, Leuven, Belgium.

Background: Isavuconazole is a triazole antifungal drug, approved for the treatment of invasive aspergillosis and mucormycosis. Isavuconazole is metabolised by CYP3A4 and CYP3A5, and it has been shown that the CYP3A inducer rifampin reduces isavuconazole exposure. By extrapolation, the concomitant use of isavuconazole with moderate and strong CYP450 inducers is contraindicated, although it is known that some CYP450 inducers are less potent in comparison with rifampin.

Objectives: We aim to document exposure to isavuconazole in patients concomitantly treated with a CYP450 inducer that is less potent compared to rifampin. Moreover, although it is well known that CYP3A enzymes are important for the metabolism of isavuconazole, this induction effect has never been studied in combination with the patient's CYP3A genotype.

Patients: We report three patients treated with both isavuconazole and a CYP3A inducer that is less potent compared to rifampin (rifabutin or phenobarbital), in whom we determined isavuconazole concentrations.

Results: These cases suggest that the CYP3A4/5 genotype is an important determinant for isavuconazole exposure and that it might also influence the CYP450 induction interaction.

Conclusions: CYP3A inducers that are less potent compared to rifampin, may be combined with isavuconazole in patients with loss of CYP3A5 activity (CYP3A5*3/*3). Therapeutic drug monitoring is recommended during this combination. However, low-isavuconazole exposure was observed in the extensive metaboliser with CYP3A4*1/*1 and CYP3A5*1/*3 alleles.
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http://dx.doi.org/10.1111/myc.13300DOI Listing
September 2021

Meropenem Stability in Human Plasma at -20 °C: Detailed Assessment of Degradation.

Antibiotics (Basel) 2021 Apr 16;10(4). Epub 2021 Apr 16.

Clinical Pharmacology and Pharmacotherapy, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, 3000 Leuven, Belgium.

There are concerns about the stability of meropenem in plasma samples, even when frozen at -20 °C. Previous smaller studies suggested significant degradation of meropenem at -20 °C after 3-20 days. However, in several recent clinical studies, meropenem plasma samples were still stored at -20 °C, or the storage temperature and/or time were not mentioned in the paper. The aim of this study was to describe and model meropenem degradation in human plasma at -20 °C over 1 year. Stability of meropenem in human plasma at -20 °C was investigated at seven concentrations (0.44, 4.38, 17.5, 35.1, 52.6, 70.1, and 87.6 mg/L) representative for the range of relevant concentrations encountered in clinical practice. For each concentration, samples were stored for 0, 7, 14, 21, 28, 42, 56, 70, 84, 112, 140, 168, 196, 224, 252, 280, 308, 336, and 364 days at -20 °C before being transferred to -80 °C until analysis. Degradation was modeled using polynomial regression analysis and artificial neural network (ANN). Meropenem showed significant degradation over time in human plasma when stored at -20 °C. Degradation was present over the whole concentration range and increased with higher concentrations until a concentration of 35.1 mg/L. Both models showed accurate prediction of meropenem degradation. In conclusion, this study provides detailed insights into the concentration-dependent degradation of meropenem in human plasma stored at -20 °C over 1 year. Meropenem in human plasma is shown to be stable at least up to approximately 80 days when stored at -20 °C. The polynomial model allows calculating original meropenem concentrations in samples stored for a known period of time at -20 °C.
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http://dx.doi.org/10.3390/antibiotics10040449DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8072937PMC
April 2021

Fluconazole Underexposure in Critically Ill Patients: a Matter of Using the Right Targets?

Antimicrob Agents Chemother 2021 05 18;65(6). Epub 2021 May 18.

Clinical Pharmacology and Pharmacotherapy, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium

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http://dx.doi.org/10.1128/AAC.00430-21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8316108PMC
May 2021

Letter to the Editor regarding: Ceftriaxone exposure in patients undergoing extracorporeal membrane oxygenation.

Int J Antimicrob Agents 2021 May 26;57(5):106326. Epub 2021 Mar 26.

KU Leuven Clinical Pharmacology and Pharmacotherapy, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium; Pharmacy Department, University Hospitals Leuven, Leuven, Belgium.

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http://dx.doi.org/10.1016/j.ijantimicag.2021.106326DOI Listing
May 2021

Itraconazole for COVID-19: preclinical studies and a proof-of-concept randomized clinical trial.

EBioMedicine 2021 Apr 19;66:103288. Epub 2021 Mar 19.

Department of Cardiovascular Sciences and Clinical Department of Laboratory Medicine, KU Leuven, Belgium.

Background: The antifungal drug itraconazole exerts in vitro activity against SARS-CoV-2 in Vero and human Caco-2 cells. Preclinical and clinical studies are required to investigate if itraconazole is effective for the treatment and/or prevention of COVID-19.

Methods: Due to the initial absence of preclinical models, the effect of itraconazole was explored in a clinical, proof-of-concept, open-label, single-center study, in which hospitalized COVID-19 patients were randomly assigned to standard of care with or without itraconazole. Primary outcome was the cumulative score of the clinical status until day 15 based on the 7-point ordinal scale of the World Health Organization. In parallel, itraconazole was evaluated in a newly established hamster model of acute SARS-CoV-2 infection and transmission, as soon as the model was validated.

Findings: In the hamster acute infection model, itraconazole did not reduce viral load in lungs, stools or ileum, despite adequate plasma and lung drug concentrations. In the transmission model, itraconazole failed to prevent viral transmission. The clinical trial was prematurely discontinued after evaluation of the preclinical studies and because an interim analysis showed no signal for a more favorable outcome with itraconazole: mean cumulative score of the clinical status 49 vs 47, ratio of geometric means 1.01 (95% CI 0.85 to 1.19) for itraconazole vs standard of care.

Interpretation: Despite in vitro activity, itraconazole was not effective in a preclinical COVID-19 hamster model. This prompted the premature termination of the proof-of-concept clinical study.

Funding: KU Leuven, Research Foundation - Flanders (FWO), Horizon 2020, Bill and Melinda Gates Foundation.
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http://dx.doi.org/10.1016/j.ebiom.2021.103288DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7979145PMC
April 2021

Prevalence of Antibiotic Allergy Labels in a Tertiary Referral Center in Belgium.

J Allergy Clin Immunol Pract 2021 06 16;9(6):2415-2425.e8. Epub 2021 Feb 16.

Department of Microbiology, Immunology and Transplantation, Allergy and Clinical Immunology Research Group, KU Leuven, Leuven, Belgium; Department of General Internal Medicine, Division of Allergy and Clinical Immunology, University Hospitals Leuven, Leuven, Belgium. Electronic address:

Background: Antibiotic (AB) allergies are among the most frequently occurring adverse drug reactions. In US literature, AB allergy labels (AAL) are reported in 10% to 15% of patients' charts; however, large-scale European analyses are scarce.

Objectives: To retrospectively assess the prevalence of AAL in a tertiary referral hospital in Belgium between 2010 and 2018.

Methods: Patients who consulted and/or were hospitalized during the study period, who had been labeled with an AB allergy, were selected for further analysis.

Results: Of 1,009,598 unique patients (outpatients, n = 736,469; inpatients, n = 273,129), 28,147 patients (3%) were registered with 1 or more AAL, being 1% of outpatients (n = 9562) and 7% of inpatients (n = 18,585). Women were more likely to carry an AAL (68%) compared with men (32%, P < .001). In patients with an AAL, 9% had multiple labels and 5% had labels for multiple AB classes. Most frequently, beta-lactams were involved (84% of AAL), followed by quinolones (7%) and sulfonamides and macrolides (both 3%). Moreover, 88% of the reactions were self-reported, mostly being an unspecified rash (53%), whereas only 3% were considered confirmed AAL.

Conclusion: With an overall prevalence of 3%, the burden of AAL is less in our Western European center compared with US reports. However, this prevalence most likely still represents an overestimation of genuine AB allergic patients because most labels lack confirmation and/or specifications. Our work indicates that knowledge of the local epidemiology of AAL is necessary to estimate the impact of better allergy labeling and delabeling strategies.
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http://dx.doi.org/10.1016/j.jaip.2021.01.047DOI Listing
June 2021

Guidance for Demonstrating the Societal Value of new Antibiotics.

Front Pharmacol 2020 1;11:618238. Epub 2021 Feb 1.

KU Leuven Department of Pharmaceutical and Pharmacological Sciences, Leuven, Belgium.

Given that antibiotic use is associated with externalities, standard economic evaluation which considers costs and health gains accruing to patients under-values antibiotics. Informed by a scoping review, this discussion paper aims to identify the societal value elements of antibiotics and to provide guidance on how these value elements can be incorporated in economic evaluation. With a view to appropriately quantify the societal value of antibiotics, there is a need for good practice guidelines on the methodology of economic evaluation for such products. We argue that it is important to assess antibiotics at population level to account for their transmission, diversity, insurance, spectrum, novel action and enablement values. In addition to the value of antibiotics to infected patients, economic evaluations need to use modeling approaches to explore the impact of different modes of employing new and existing antibiotics (for example, as last resort treatment) on disease transmission and resistance development in current and future patients. Hence, assessing the value of antibiotics also involves an ethical dimension. Further work is required about how the multiple value elements of antibiotics are linked to each other and how they can be aggregated.
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http://dx.doi.org/10.3389/fphar.2020.618238DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7882732PMC
February 2021

A Population Pharmacokinetic Modeling and Simulation Study of Posaconazole Oral Suspension in Immunocompromised Pediatric Patients: A Short Communication.

Ther Drug Monit 2021 08;43(4):512-518

Clinical Pharmacology and Pharmacotherapy Unit, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven.

Background: Posaconazole oral suspension emerged as a promising candidate for prophylaxis of invasive fungal infections in immunocompromised children. Its pharmacodynamic advantages include a broad-spectrum activity and a favorable safety profile; however, they are overshadowed by its large pharmacokinetic (PK) variability, which might cause subtherapeutic exposure. The aim of this study was to develop a population (pop) PK model based on rich sampling data to better understand the PK of posaconazole oral suspension in pediatric patients.

Methods: Data were obtained from a prospective interventional study involving hospitalized pediatric patients with a hematologic malignancy and prophylactically treated with posaconazole oral suspension. After constructing the popPK model, the probability of target attainment (PTA; 100% T ≥ 0.7 mg/L) for prophylaxis under fixed, body weight-based, and body surface area-based dosing was evaluated using Monte Carlo simulation.

Results: Fourteen patients contributed 112 posaconazole plasma concentrations. The PK of posaconazole was adequately described by a 1-compartment model with lag time 2.71 hours [13%]; nonlinear bioavailability ED50 99.1 mg/m2 (fixed); first-order absorption rate constant 0.325 hour-1 [27%]; apparent volume of distribution 1150 L [34%]; and apparent clearance 15.4 L/h [24%] (∼70-kg individual). The bioavailability decreased in the presence of diarrhea and co-treatment with a proton pump inhibitor (PPI). The unexplained interindividual variability in posaconazole PK remained large. The PTA was <85%, irrespective of the simulated dosing strategy. Patients without diarrhea and not administered a PPI had the highest PTA (85% under the fixed 300-mg dosing 4 times per day).

Conclusions: Therapeutic drug monitoring is recommended during prophylactic posaconazole therapy in immunocompromised pediatric patients. Large-scale comparative studies are needed to characterize the PK variability between different posaconazole formulations in this cohort.
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http://dx.doi.org/10.1097/FTD.0000000000000877DOI Listing
August 2021

Pharmacokinetics and target attainment of intravenous posaconazole in critically ill patients during extracorporeal membrane oxygenation.

J Antimicrob Chemother 2021 04;76(5):1234-1241

Department of Pharmaceutical and Pharmacological Sciences, KU Leuven and Pharmacy Department, University Hospitals Leuven, Leuven, Belgium.

Background: Posaconazole is an antifungal drug used for prophylaxis and treatment of invasive fungal infections. Severe influenza has been identified as a risk factor for invasive pulmonary aspergillosis in critically ill patients. In this population, extracorporeal membrane oxygenation (ECMO) is used as rescue therapy, although little is known about the pharmacokinetics (PK) of posaconazole during ECMO.

Objectives: To determine the PK and target attainment of six patients treated with IV posaconazole under ECMO and to develop a population PK model that can be used to simulate the PTA.

Methods: Critically ill patients treated with posaconazole and ECMO were included in this study. Plasma samples were collected at several timepoints within one dosing interval on two occasions: an early (Day 2-3) and a late (Day 4-7) sampling day. Daily trough concentrations were measured.

Results: The median (IQR) AUC0-24, CL and Vd were 34.3 (28.3-37.7) mg·h/L, 8.7 (8.0-10.6) L/h and 389 (314-740) L, if calculated with non-compartmental analysis based on the observed concentrations. All measured trough concentrations were ≥0.7 mg/L and 11/16 were ≥1 mg/L, which are the haematological thresholds for prophylaxis and treatment of invasive aspergillosis, respectively. The targeted PTA (>90%) was attained for prophylaxis but not for treatment.

Conclusions: ECMO does not appear to influence posaconazole exposure compared with haematology patients. However, some trough levels were below the lower limit for treatment. An a priori dose adjustment does not appear to be necessary but drug monitoring is recommended.
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http://dx.doi.org/10.1093/jac/dkab012DOI Listing
April 2021

Ultra-performance liquid chromatography for quantification of amphotericin B plasma concentrations after use of liposomal amphotericin B.

J Antimicrob Chemother 2021 03;76(4):961-966

Department of Pharmacy and Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.

Objectives: Liposomal amphotericin B is widely used to treat life-threatening invasive fungal infections and has replaced conventional amphotericin B deoxycholate due to its more favourable toxicity profile. Despite the fact that liposomal amphotericin B has been licensed for several decades, there is still a paucity of clinical pharmacokinetic data. An assay for the quantification of amphotericin B is necessary to allow the study of its pharmacokinetics.

Methods: A UPLC-photodiode array (PDA) analytical method was developed and validated (linearity, accuracy, precision, dilution integrity, carry-over, selectivity and stability) in accordance with EMA requirements.

Results: The analytical method was validated over a concentration range of 0.5-50.0 mg/L. Accuracy ranged from 97.6% to 112.1% and within-day repeatability and between-day reproducibility from 1.0% to 6.6% and from 0.4% to 4.6%, respectively, dependent on the concentration. Originally, the goal was to develop an analytical method to separate the liposomal and free amphotericin B fractions, but this was not achieved. Difficulties and bottlenecks encountered are presented.

Conclusions: A UPLC-PDA analytical method was developed to quantify total amphotericin B in plasma after the use of liposomal amphotericin B.
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http://dx.doi.org/10.1093/jac/dkaa515DOI Listing
March 2021

Optimizing pharmacotherapy on geriatric hospital units in Belgium - a national survey.

Acta Clin Belg 2020 Dec 21:1-8. Epub 2020 Dec 21.

Department of Geriatric Medicine, University Hospitals Leuven, Leuven, Belgium.

: Inappropriate prescribing remains highly prevalent on geriatric units. The aim of this investigation, initiated by the Belgian College for Geriatrics, was to evaluate the implementation of strategies to optimize pharmacotherapy on geriatric units in Belgium.: A literature search was performed to identify strategies to support the appropriate use of medications in very old inpatients. These strategies were subsequently validated based on Delphi consensus rounds and a national survey was developed. Experts were selected by the research team in collaboration with the Belgian College for Geriatrics. The survey was sent to the heads of the geriatric departments of all Belgian hospitals (n = 100).: After 3 months a response rate of 55% was achieved. Strategies that were implemented more frequently were the use of electronic prescribing (85%), performing a structured medication review (69%) and providing patient education (76%). In a minority (24%) of hospitals, a clinical pharmacist was directly involved in the multidisciplinary geriatric team. Implementation of clinical decisions support systems (CDSS) was reported by 36% of the hospitals. Educational strategies for healthcare professionals and strategies to optimize transitional care were variable.: Taking into account the current body of evidence, strategies that include transitional care components, CDSS or ward-based clinical pharmacy services should be further promoted on Belgian geriatric units.
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http://dx.doi.org/10.1080/17843286.2020.1864162DOI Listing
December 2020
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