Clinical Pharmacokinetics of Triazoles in Pediatric Patients

Triazoles represent an important class of antifungal drugs in the prophylaxis and treatment of invasive fungal disease in pediatric patients. Understanding the pharmacokinetics of triazoles in children is crucial to providing optimal care for this vulnerable population. While the pharmacokinetics is extensively studied in adult populations, knowledge on pharmacokinetics of triazoles in children is limited. New data are still emerging despite drugs already going off patent. This review aims to provide readers with the most current knowledge on the pharmacokinetics of the triazoles: fluconazole, itraconazole, voriconazole, posaconazole, and isavuconazole. In addition, factors that have to be taken into account to select the optimal dose are summarized and knowledge gaps are identified that require further research. We hope it will provide clinicians guidance to optimally deploy these drugs in the setting of a life-threatening disease in pediatric patients

ESCMID-ECMM guideline : diagnosis and management of invasive aspergillosis in neonates and children

ACKNOWLEDGEMENT Prof Warris is supported by the Wellcome Trust Strategic Award (grant 097377) and the MRC Centre for Medical Mycology (grant MR/N006364/1) at the University of Aberdeen. FUNDING European Society of Clinical Microbiology and Infectious Diseases (ESCMID) and the European Confederation of Medical Mycology (ECMM)Peer reviewedPostprintPostprin

Optimization of flucloxacillin dosing regimens in critically ill patients using population pharmacokinetic modelling of total and unbound concentrations

Background: Initial appropriate anti-infective therapy is associated with improved outcomes in patients with severe infections. In critically ill patients, altered pharmacokinetic (PK) behaviour is common and known to influence the achievement of PK/pharmacodynamic targets. Objectives: To describe population PK and optimized dosing regimens for flucloxacillin in critically ill patients. Methods: First, we developed a population PK model, estimated between-patient variability (BPV) and identified covariates that could explain BPV through non-linear mixed-effects analysis, using total and unbound concentrations obtained from 35 adult critically ill patients treated with intermittent flucloxacillin. Second, we validated the model using external datasets from two different countries. Finally, frequently prescribed dosing regimens were evaluated using Monte Carlo simulations. Results: A two-compartment model with non-linear protein binding was developed and validated. BPV of the maximum binding capacity decreased from 42.2% to 30.4% and BPV of unbound clearance decreased from 88.1% to 71.6% upon inclusion of serumalbumin concentrations and estimated glomerular filtration rate (eGFR; by CKD-EPI equation), respectively. PTA (target of 100%fT(>MIC)) was 91% for patients with eGFR of 33mL/min and 1 g q6h, 87% for patients with eGFR of 96 mL/min and 2 g q4h and 71% for patients with eGFR of 153 mL/min and 2 g q4h. Conclusions: For patients with high creatinine clearance who are infected with moderately susceptible pathogens, therapeutic drug monitoring is advised since there is a risk of underexposure to flucloxacillin. Due to the non-linear protein binding of flucloxacillin and the high prevalence of hypoalbuminaemia in critically ill patients, dose adjustments should be based on unbound concentrations

Outpatient parenteral antifungal therapy (OPAT) for invasive fungal infections with intermittent dosing of liposomal amphotericin B

Triazole resistant A. fumigatus has been documented in many parts of the world. In the Netherlands, incidence is now above 10% and results in the need for long-term parenteral therapy with liposomal amphotericin B (LAmB). The long terminal half-life of LAmB suggests that intermittent dosing could be effective, making the application of outpatient antifungal therapy (OPAT) possible. Here, we report our experience with the use of OPAT for Invasive Fungal Infections (IFI). All adult patients treated with LAmB with a 2 or 3 times weekly administration via the outpatient departments in four academic tertiary care centers in the Netherlands and Belgium since January 2010 were included in our analysis. Patient characteristics were collected, as well as information about diagnostics, therapy dose and duration, toxicity, treatment history and outcome of the IFI. In total, 18 patients were included. The most frequently used regimen (67%) was 5 mg/kg 3 times weekly. A partial response to the daily treatment prior to discharge was confirmed by CT-scan in 17 (94%) of patients. A favorable outcome was achieved in 13 (72%) patients. Decrease in renal function occurred in 10 (56%) cases but was reversible in all and was treatment limiting in one patient only. The 100-day mortality and 1-year mortality after initiation of OPAT were 0% and 6%, respectively. In a selected population, and after confirmation of initial response to treatment, our data support the use of OPAT with LAmB for treatment of IFI in an intermittent dosing regimen

still a concern in patients with haematological malignancies and stem cell transplant recipients-authors' response

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Impact of cyp51A Mutations on the Pharmacokinetic and Pharmacodynamic Properties of Voriconazole in a Murine Model of Disseminated Aspergillosis ▿

The in vivo efficacy of voriconazole against 4 clinical Aspergillus fumigatus isolates with MICs ranging from 0.125 to 2 mg/liter (CLSI document M38A) was assessed in a nonneutropenic murine model of disseminated aspergillosis. The study involved TR/L98H, M220I, and G54W mutants and a wild-type control isolate. Oral voriconazole therapy was started 24 h after intravenous infection of mice and was given once daily for 14 consecutive days, with doses ranging from 10 to 80 mg/kg of body weight, using survival as the endpoint. Survival for all isolates was dependent on the voriconazole dose level (R2 value of 0.5 to 0.6), but a better relationship existed for the area under the concentration-time curve over 24 h in the steady state divided by the MIC (AUC/MIC ratio) or the AUC for the free, unbound fraction of the drug divided by the MIC (fAUC/MIC ratio) (R2 value of 0.95 to 0.98). The 24-h fAUC/MIC ratio showed a clear relationship to effect, with an exposure index for amount of free drug required for 50% of maximum effectiveness (fEI50) of 11.17 at day 7. Maximum effect was reached at values of around 80 to 100, comparable to that observed for posaconazole and A. fumigatus. Mice infected with an isolate having a MIC of 2 mg/liter required an exposure that was inversely correlated with the increase in MIC compared to that of the wild-type control, but due to nonlinear pharmacokinetics, this required only doubling of the voriconazole dose. The efficacy of voriconazole for isolates with high MICs for other triazoles but voriconazole MICs within the wild-type population range was comparable to that for the wild-type control. Finally, we used a grapefruit juice-free murine model of aspergillosis and concluded that this model is appropriate to study pharmacokinetic/pharmacodynamic relationships of voriconazole

Caspofungin Population Pharmacokinetics in Critically Ill Patients Undergoing Continuous Veno-Venous Haemofiltration or Haemodiafiltration

Background and Objective Sepsis and continuous renal replacement therapy (CRRT) can both significantly affect antifungal pharmacokinetics. This study aimed to describe the pharmacokinetics of caspofungin in critically ill patients during different CRRT modes

Pharmacokinetic evaluation of twice-a-week micafungin for prophylaxis of invasive fungal disease in children with acute lymphoblastic leukaemia:a prospective observational cohort study

Objectives To determine the pharmacokinetics of twice-a-week micafungin prophylaxis in paediatric leukaemic patients to provide the rationale for this approach. Methods Twice-a-week micafungin at a dose of 9 mg/kg (maximum 300 mg) was given during the leukaemic induction treatment with at least one pharmacokinetic assessment. Non-linear mixed-effects modelling was used for analysis. For model building, our paediatric data were strengthened with existing adult data. Monte Carlo simulations were performed with twice-a-week dosing regimens of 5, 7 and 9 mg/kg and flat dosing per weight band. Simulated paediatric exposures were compared with the exposure in adults after a once-daily 100 mg regimen. Results Sixty-one paediatric patients were included with a median age and weight of 4.0 years (range 1.0-17) and 19.5 kg (range 8.60-182), respectively. A two-compartment model best fitted the data. CL and central V-d were lower (P < 0.01) in paediatric patients compared with adults. Predicted exposures (AUC(0-168 h)) for the 5, 7 and 9 mg/kg and flat dosing per weight band regimens exceeded the adult reference exposure. Conclusions All twice-a-week regimens appeared to result in adequate exposure for Candida therapy, with simulated exposures well above the adult reference exposure. These findings provide the rationale for the pharmacokinetic equivalence of twice-a-week and once-daily micafungin regimens. The greater micafungin exposures seem to be caused by a slower-than-anticipated CL in our paediatric leukaemic patients. The generalizability of our results for Aspergillus prophylaxis cannot be provided without assumptions on target concentrations and within-class identical efficacy