Isavuconazole therapeutic drug monitoring in critically ill ICU patients: A monocentric retrospective analysis

Höhl, Rainer; Bertram, Ralph; Kinzig, Martina; Haarmeyer, Golo‐Sung; Baumgärtel, Matthias; Geise, Arnim; Muschner, Dorothea; Prosch, Doris; Reger, Mira; Naumann, Hans‐Theodor; Ficker, Joachim H.; Kubitz, Jens C.; Steinmann, Joerg; Sörgel, Fritz

doi:10.1111/myc.13469

Cited by 30 publications

(25 citation statements)

References 26 publications

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“…In a recent study in the ICU, in which CAPA was excluded, the median Cmin was 1.74 mg/L (0.24–4.96) in 82 trough concentrations and 31.7% of samples were below 1 mg/L. BMI and SOFA score (>12) were associated with lower plasma concentrations [ 62 ]. Furthermore, in the study by Wu et al, peripheral volume of distribution was positively correlated with BMI and clearance was higher in women [ 58 ].…”

Section: Discussionmentioning

confidence: 99%

Population Pharmacokinetics of Isavuconazole in Critical Care Patients with COVID-19-Associated Pulmonary Aspergillosis and Monte Carlo Simulations of High Off-Label Doses

Perez

Corne²,

Pasquier

et al. 2023

JoF

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Isavuconazole is a triazole antifungal agent recently recommended as first-line therapy for invasive pulmonary aspergillosis. With the COVID-19 pandemic, cases of COVID-19-associated pulmonary aspergillosis (CAPA) have been described with a prevalence ranging from 5 to 30%. We developed and validated a population pharmacokinetic (PKpop) model of isavuconazole plasma concentrations in intensive care unit patients with CAPA. Nonlinear mixed-effect modeling Monolix software were used for PK analysis of 65 plasma trough concentrations from 18 patients. PK parameters were best estimated with a one-compartment model. The mean of ISA plasma concentrations was 1.87 [1.29–2.25] mg/L despite prolonged loading dose (72 h for one-third) and a mean maintenance dose of 300 mg per day. Pharmacokinetics (PK) modeling showed that renal replacement therapy (RRT) was significantly associated with under exposure, explaining a part of clearance variability. The Monte Carlo simulations suggested that the recommended dosing regimen did not achieve the trough target of 2 mg/L in a timely manner (72 h). This is the first isavuconazole PKpop model developed for CAPA critical care patients underlying the need of therapeutic drug monitoring, especially for patients under RRT.

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Section: Discussionmentioning

confidence: 99%

Population Pharmacokinetics of Isavuconazole in Critical Care Patients with COVID-19-Associated Pulmonary Aspergillosis and Monte Carlo Simulations of High Off-Label Doses

Perez

Corne²,

Pasquier

et al. 2023

JoF

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“…The remaining 105 values included were from samples of 32 patients without COVID‐19 taken between October 2017 and January 2021. The latter set of data had in part been included in our previous study 8 . Initial plasma concentrations were analysed 1–5 days after first administration to optimise therapy regarding efficacy, adverse events and resistance development.…”

Section: Methodsmentioning

confidence: 99%

“…Therapeutic drug monitoring (TDM) ensures precision dosing to achieve consistent plasma levels 7 . Based upon routine TDM, we have previously shown that isavuconazole levels in critically ill patients are significantly affected by clinical characteristics such as body mass index (BMI) or sepsis‐related organ failure assessment (SOFA) score 8 . The present study includes intensive care patients with or without coronavirus disease 2019 (COVID‐19).…”

Section: Introductionmentioning

confidence: 99%

Clinical and demographic factors affecting trough levels of isavuconazole in critically ill patients with or without COVID‐19

Bertram,

Naumann,

Bartsch

et al. 2023

Mycoses

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BackgroundThe broad‐spectrum antifungal isavuconazole is administered to treat invasive aspergillosis and mucormycosis.ObjectivesIsavuconazole plasma concentrations in critically ill ICU patients with or without COVID‐19 and invasive fungal infection were determined, and factors for sub‐therapeutic drug levels (<1 μg/mL) were evaluated.Patients and MethodsIsavuconazole plasma levels were measured as part of therapeutic drug monitoring (TDM) in ICUs of a tertiary hospital. Concentrations determined 20–28 h after previous dosing were defined as trough (Cmin) levels. A total of 160 Cmin levels from 62 patients with invasive fungal infections were analysed, 30 of which suffering from COVID‐19. Patient characteristics included into univariable and multivariable analyses were gender, age, COVID‐19 status, body mass index (BMI), sepsis‐related organ failure (SOFA) score, renal replacement therapy (RRT) and extracorporeal membrane oxygenation (ECMO) requirement.ResultsThe mean Cmin of isavuconazole in all patients was 1.64 μg/mL (interquartile range 0.83–2.24 μg/mL, total range 0.24–5.67 μg/mL). In total, 34.4% of the Cmin values (corresponding to 46.8% of patients) were below a threshold concentration of 1 μg/mL. Drug concentrations between patients with or without COVID‐19 did not differ (p = .43). In contrast, levels were significantly lower in patients with female sex (p = .0007), age ≤ 65 years (p = .002), BMI > 25 (p = .006), SOFA score > 12 (p = .026), RRT (p = .017) and ECMO requirement (p = .001).ConclusionsIsavuconazole plasma levels can be negatively affected by patients' risk factors, supportive renal replacement and ECMO therapy. Future prospective studies analysing the relevance of isavuconazole drug levels in ICU patient outcome are urgently needed.

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“…However, suboptimal isavuconazole concentrations have been reported in critically ill patients, and are more frequent in obese patients and those undergoing renal replacement techniques [ 19 ]. Höhl et al determined isavuconazole levels in 41 critical patients, and found that up to 31.7% of measurements taken in the trough period were below the limit of 1 µg/mL (EUCAST breakpoint), and 12.1% of peak levels did not reach 1 μg/mL [ 39 ]. Significantly lower levels were associated with a higher BMI and a higher SOFA score, which may suggest the need to monitor levels in this specific population.…”

Section: Question 6: In What Situations Should We Monitor Whether Tre...mentioning

confidence: 99%

Managing the Next Wave of Influenza and/or SARS-CoV-2 in the ICU—Practical Recommendations from an Expert Group for CAPA/IAPA Patients

José

Estella

Nuvials

et al. 2023

JoF

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The aim of this study was to establish practical recommendations for the diagnosis and treatment of influenza-associated invasive aspergillosis (IAPA) based on the available evidence and experience acquired in the management of patients with COVID-19-associated pulmonary aspergillosis (CAPA). The CAPA/IAPA expert group defined 14 areas in which recommendations would be made. To search for evidence, the PICO strategy was used for both CAPA and IAPA in PubMed, using MeSH terms in combination with free text. Based on the results, each expert developed recommendations for two to three areas that they presented to the rest of the group in various meetings in order to reach consensus. As results, the practical recommendations for the management of CAPA/IAPA patients have been grouped into 12 sections. These recommendations are presented for both entities in the following situations: when to suspect fungal infection; what diagnostic methods are useful to diagnose these two entities; what treatment is recommended; what to do in case of resistance; drug interactions or determination of antifungal levels; how to monitor treatment effectiveness; what action to take in the event of treatment failure; the implications of concomitant corticosteroid administration; indications for the combined use of antifungals; when to withdraw treatment; what to do in case of positive cultures for Aspergillus spp. in a patient with severe viral pneumonia or Aspergillus colonization; and how to position antifungal prophylaxis in these patients. Available evidence to support the practical management of CAPA/IAPA patients is very scarce. Accumulated experience acquired in the management of CAPA patients can be very useful for the management of IAPA patients. The expert group presents eminently practical recommendations for the management of CAPA/IAPA patients.

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Isavuconazole therapeutic drug monitoring in critically ill ICU patients: A monocentric retrospective analysis

Cited by 30 publications

References 26 publications

Population Pharmacokinetics of Isavuconazole in Critical Care Patients with COVID-19-Associated Pulmonary Aspergillosis and Monte Carlo Simulations of High Off-Label Doses

Population Pharmacokinetics of Isavuconazole in Critical Care Patients with COVID-19-Associated Pulmonary Aspergillosis and Monte Carlo Simulations of High Off-Label Doses

Clinical and demographic factors affecting trough levels of isavuconazole in critically ill patients with or without COVID‐19

Managing the Next Wave of Influenza and/or SARS-CoV-2 in the ICU—Practical Recommendations from an Expert Group for CAPA/IAPA Patients

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