Dosing of IV posaconazole to treat critically ill patients with invasive pulmonary aspergillosis: a population pharmacokinetics modelling and simulation study.

BACKGROUND: Posaconazole is used for the prophylaxis and treatment of invasive fungal infections in critically ill patients. Standard dosing was shown to result in adequate attainment of the prophylaxis Cmin target (0.7 mg/L) but not of the treatment Cmin target (1.0 mg/L). OBJECTIVES: To provide an optimized posaconazole dosing regimen for IV treatment of patients with invasive pulmonary aspergillosis in the ICU. METHODS: A population pharmacokinetics (popPK) model was developed using data from the POSA-FLU PK substudy (NCT03378479). Monte Carlo simulations were performed to assess treatment Cmin and AUC0-24 PTA. PTA ≥90% was deemed clinically acceptable. PopPK modelling and simulation were performed using NONMEM 7.5. RESULTS: Thirty-one patients with intensive PK sampling were included in the PK substudy, contributing 532 posaconazole plasma concentrations. The popPK of IV posaconazole was best described by a two-compartment model with linear elimination. Interindividual variability was estimated on clearance and volume of distribution in central and peripheral compartments. Posaconazole peripheral volume of distribution increased with bodyweight. An optimized loading regimen of 300 mg q12h and 300 mg q8h in the first two treatment days achieved acceptable PTA by Day 3 in patients <100 kg and ≥100 kg, respectively. A maintenance regimen of 400 mg q24h ensured ≥90% Cmin PTA, whereas the standard 300 mg q24h was sufficient to achieve the AUC0-24 target throughout 14 days, irrespective of bodyweight. CONCLUSIONS: We have defined a convenient, optimized IV posaconazole dosing regimen that was predicted to attain the treatment target in critically ill patients with invasive aspergillosis.

Population Pharmacokinetics of Total and Unbound Isavuconazole in Critically Ill Patients: Implications for Adaptive Dosing Strategies.

BACKGROUND AND OBJECTIVES: Isavuconazole is a broad-spectrum antifungal agent for the management of invasive fungal disease. Optimised drug exposure is critical for patient outcomes, specifically in the critically ill population. Solid information on isavuconazole pharmacokinetics including protein binding in patients in the intensive care unit is scarce. We aimed to describe the total and unbound isavuconazole pharmacokinetics and subsequently propose a dosage optimisation strategy. METHODS: A prospective multi-centre study in adult intensive care unit patients receiving isavuconazole was performed. Blood samples were collected on eight timepoints over one dosing interval between days 3-7 of treatment and optionally on one timepoint after discontinuation. Total and unbound isavuconazole pharmacokinetics were analysed by means of population pharmacokinetic modelling using NONMEM. The final model was used to perform simulations to assess exposure described by the area under the concentration-time curve and propose an adaptive dosing approach. RESULTS: Population pharmacokinetics of total and unbound isavuconazole were best described by an allometrically scaled two-compartment model with a saturable protein-binding model and interindividual variability on clearance and the maximum binding capacity. The median (range) isavuconazole unbound fraction was 1.65% (0.83-3.25%). After standard dosing, only 35.8% of simulated patients reached a total isavuconazole area under the concentration-time curve > 60 mg·h/L at day 14. The proposed adaptive dosing strategy resulted in an increase to 62.3% of patients at adequate steady-state exposure. CONCLUSIONS: In critically ill patients, total isavuconazole exposure is reduced and protein binding is highly variable. We proposed an adaptive dosing approach to enhance early treatment optimisation in this high-risk population. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT04777058.

Isavuconazole Exposure in Critically Ill Patients Treated with Extracorporeal Membrane Oxygenation: Two Case Reports and a Narrative Literature Review.

Effective dosing of isavuconazole in patients supported by extracorporeal membrane oxygenation (ECMO) is important due to the role of isavuconazole as a first-line treatment in patients with influenza- and COVID-19-associated pulmonary aspergillosis. To date, robust pharmacokinetic data in patients supported by ECMO are limited. Therefore, it is unknown whether ECMO independently impacts isavuconazole exposure. We measured isavuconazole plasma concentrations in two patients supported by ECMO and estimated individual pharmacokinetic parameters using non-compartmental analysis and two previously published population pharmacokinetic models. Furthermore, a narrative literature review on isavuconazole exposure in adult patients receiving ECMO was performed. The 24 h areas under the concentration-time curve and trough concentrations of isavuconazole were lower in both patients compared with exposure values published before. In the literature, highly variable isavuconazole concentrations have been documented in patients with ECMO support. The independent effect of ECMO versus critical illness itself on isavuconazole exposure cannot be deduced from our and previously published (case) reports. Pending additional data, therapeutic drug monitoring is recommended in critically ill patients, regardless of ECMO support.

Age is just a number: the concept of time to benefit in older adults.

A female nursing home resident aged >70 years was admitted to the geriatric ward with de novo dysphagia 6 days after being discharged from the stroke unit. Metformin and ezetimibe had been added to her treatment regimen which already consisted of clopidogrel, atorvastatin, denosumab, calcium and vitamin D. At the geriatric ward a multidisciplinary team involving clinical pharmacists reviewed all treatments and appraised the time to benefit, ascertaining whether there was sufficient time left to experience therapeutic benefits. As a result, metformin, ezetimibe, denosumab, calcium and vitamin D were discontinued. This case report illustrates that both mortality risk assessment and evaluation of the time to benefit should be part of any medication review in frail older adults. Conversely, with limited available data pertaining to the concept of time to benefit, we advocate a broader awareness among pharmacists and a systematic assessment in future clinical trials.

Drug-related hospital admissions in older adults: comparison of the Naranjo algorithm and an adjusted version of the Kramer algorithm.

PURPOSE: Drug-related admissions (DRAs) are an important cause of preventable harm in older adults. Multiple algorithms exist to assess causality of adverse drug reactions, including the Naranjo algorithm and an adjusted version of the Kramer algorithm. The performance of these tools in assessing DRA causality has not been robustly shown. This study aimed to evaluate the ability of the adjusted Kramer algorithm to adjudicate DRA causality in geriatric inpatients. METHODS: DRAs were assessed in a convenience sample of patients admitted to the acute geriatric wards of an academic hospital. DRAs were identified by expert consensus and causality was evaluated using the Naranjo and the adjusted Kramer algorithms. Positive agreement with expert consensus was calculated for both algorithms. A multivariable logistic regression analysis was performed to explore determinants for a DRA. RESULTS: A total of 218 geriatric inpatients was included of whom 65 (29.8%) experienced a DRA. Positive agreement was 72.3% (95% confidence interval (CI), 59.6-82.3%) and 100% (95% CI, 93.0-100%) for the Naranjo and the adjusted Kramer algorithm, respectively. Diuretics were the main culprits and most DRAs were attributed to a fall (n = 18; 27.7%). A fall-related principal diagnosis was independently associated with a DRA (odds ratio 20.11; 95% CI, 5.60-72.24). CONCLUSION: The adjusted Kramer algorithm demonstrated a higher positive agreement with expert consensus in assessing DRA causality in geriatric inpatients compared to the Naranjo algorithm. Our results further support implementation of the adjusted Kramer algorithm as part of a standardized DRA assessment in older adults.

Isavuconazole in the Treatment of Aspergillus fumigatus Fracture-Related Infection: Case Report and Literature Review.

Aspergillus fracture-related infection (FRI) is a rare, but severe complication in trauma surgery. The optimal antifungal treatment for Aspergillus osteomyelitis, including FRI, has not been established yet, as only cases have been documented and data on bone penetration of antifungal drugs are scarce. We describe a patient with Aspergillus fumigatus FRI of the tibia who was treated with isavuconazole after developing liver function disturbances during voriconazole therapy. Isavuconazole, the active moiety formed after hydrolysis of the prodrug isavuconazonium sulfate by plasma esterases, was administered in a maintenance dose of 200 mg q24 h, followed by 150 mg q24 h. The patient completed a six-month antifungal treatment course. Although fracture union was not achieved during six months of follow-up after therapy cessation, no confirmatory signs of FRI were observed. Additionally, two literature searches were conducted to review available data on antifungal treatment of Aspergillus osteomyelitis and bone penetration of antifungals. One hundred and eight cases of Aspergillus osteomyelitis, including six (5.6%) FRI cases, were identified. Voriconazole and (lipid formulations of) amphotericin B were the most commonly used antifungals. In three (2.8%) cases isavuconazole was prescribed as salvage therapy. Data on antifungal bone penetration were reported for itraconazole, voriconazole, amphotericin B, anidulafungin and 5-fluorocytosin. Isavuconazole might be a promising alternative for the treatment of Aspergillus osteomyelitis. However, standardized case documentation is needed to evaluate the efficacy of isavuconazole and other antifungals in the treatment of Aspergillus osteomyelitis, including FRI.

Impact of duration of perioperative antibiotic prophylaxis on development of fracture-related infection in open fractures.

INTRODUCTION: Infection is a common complication of open fractures potentially leading to nonunion, functional loss, and even amputation. Perioperative antibiotic prophylaxis (PAP) is standard practice for infection prevention in the management of open fractures. However, optimal duration of PAP remains controversial. The objectives were to assess whether PAP duration is independently associated with infection in open fractures and if administration of PAP beyond the commonly-recommended limit of 72 h has any effect on the infection rate. MATERIALS AND METHODS: Over a 14-year period from 2003 to 2017, 530 skeletally-mature patients with operatively-treated, non-pathologic, long-bone open fractures were treated at one institution. Twenty-eight patients were excluded because of death or loss to follow-up and the remaining 502 patients (with 559 open fractures) who completed a 24-month follow-up were included in this retrospective study. The outcome was fracture-related infection (FRI), defined by the criteria of a recent consensus definition. A logistic generalized estimating equations regression model was conducted, including PAP duration and variables selected by a least absolute shrinkage and selection operator (LASSO) method, to assess the association between PAP duration and FRI. Propensity score analysis using a 72-h cut-off was performed to further cope with confounding. RESULTS: PAP duration, adjusted for the LASSO selected predictors, was independently associated with FRI (OR: 1.11 [95%CI, 1.04-1.19] for every one-day increase in PAP duration, p = 0.003). PAP duration longer than 72 h did not significantly increase the odds for FRI compared to shorter durations (p = 0.06, analysis adjusted for propensity score). CONCLUSIONS: This study found no evidence that administration of prophylactic antibiotics beyond 72 h in patients with long-bone open fractures is warranted. Analyses adjusted for known confounders even revealed a higher risk for FRI for longer PAP. However, this effect cannot necessarily be considered as causal and further research is needed.