[go: up one dir, main page]
More Web Proxy on the site http://driver.im/
Next Article in Journal
Tissue Biomarkers in Gastric Cancer Treatment: Present and Future
Previous Article in Journal
Role of Circulating X-Chromosome Inactivation and Xist as Biomarkers in Female Carriers of Fabry Disease
You seem to have javascript disabled. Please note that many of the page functionalities won't work as expected without javascript enabled.
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
IJTM
Volume 4
Issue 4
10.3390/ijtm4040044
ijtm-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Case Report

The Successful and Safe Real-Time TDM-Guided Treatment of Invasive Pulmonary Aspergillosis Using Isavuconazole Administered by Enteral Tube

by
Álvaro Corral Alaejos
1,*,
Jose Jiménez Casaus
1,
Ángel López Delgado
1 and
Aranzazu Zarzuelo Castañeda
2,*
1
Pharmacy. Complejo Asistencial de Zamora, Hospital Virgen de la Concha, Avda Requejo 35, 49022 Zamora, Spain
2
Department of Pharmaceutical Sciences, Faculty of Pharmacy, University of Salamanca, Campus Miguel de Unamuno, C. Lic. Méndez Nieto, s/n, 37007 Salamanca, Spain
*
Authors to whom correspondence should be addressed.
Int. J. Transl. Med. 2024, 4(4), 631-639; https://doi.org/10.3390/ijtm4040044
Submission received: 30 October 2024 / Revised: 19 November 2024 / Accepted: 20 November 2024 / Published: 22 November 2024
Browse Figure
Figure 1
<p>Chest X-ray at the time of the patient’s admission.</p> ">
Versions Notes

Abstract

:
Background: Invasive aspergillosis (IA) is an opportunistic infection that affects immunocompromised patients. While voriconazole is commonly used for IA treatment, it presents the risk of drug interactions, particularly in patients on polytherapy. Isavuconazole may serve as a safer alternative with fewer interactions. However, the use of isavuconazole is typically limited to the parenteral route for patients without access to the enteral route, due to recommendations against tablet handling for enteral administration. The objective of this study was to evaluate the suitability of isavuconazole administration via an enteral tube, by therapeutic drug monitoring of isavuconazole plasma concentrations. Methods: This case study examines a patient with diffuse large B-cell lymphoma who was diagnosed with IA and treated with isavuconazole via an enteral tube. Therapeutic pharmacokinetic monitoring of isavuconazole plasma concentrations was performed to assess the feasibility and safety of enteral administration. Results: The results show that isavuconazole concentrations were maintained within the therapeutic range when administered via an enteral tube. No significant deviations in plasma concentration were noted during the monitoring period. Conclusions: Administering isavuconazole through an enteral tube is a safe and viable alternative for patients that are unable to receive the drug via the oral route. Therapeutic monitoring of plasma concentrations is recommended to ensure proper dosing and efficacy.

1. Introduction

Nowadays, patients with hematological malignancies are at an increased risk of developing invasive fungal infections (IFIs) [1,2], presenting high morbidity and mortality despite advances in therapy [2,3]. Knowing the possible risk factors allows early implementation of prevention, diagnosis, and treatment strategies [2]. The clinical complexity of these patients often requires a multidisciplinary approach involving hematologists, infectious disease specialists, and clinical pharmacist to ensure optimal outcomes [1,2].
Most IFIs are due to Aspergillus spp. with Fumigatus species being the majority. Invasive aspergillosis (IA) is a life-threatening, opportunistic infection affecting immunocompromised patients, with an incidence of 0.8–2.3%, with variability depending on the underlying hematologic disease [4], and a mortality of 58% at 12 weeks [5,6]. The increasing resistance of fungal pathogens, including rare non-fumigatus Aspergillus species, has further complicated disease management, underscoring the importance of early, accurate diagnosis [5]. The diagnosis of IA is based on the criteria established by the EORTC/MSGERC (European Organization for Research and Treatment of Cancer/Mycoses Study Group) consensus [7].
In the updated EORTC/MSGERC [7] consensus, the definitions of invasive fungal disease, and the diagnostic criteria for probable and possible IA were defined. These definitions were established using the following major and minor criteria: Major criteria are based on the presence of risk factors (prolonged febrile neutropenia or hematologic malignancy), documented microbiological evidence (galactomannan antigen in bronchoalveolar lavage fluid (BAL) > 0.5 or serum > 0.7), and radiological findings consistent with AI. Minor criteria are based on the presence of compatible clinical manifestations (fever lasting more than 4 days, unresponsive to broad-spectrum antibiotics, and progressive dyspnea), non-specific radiological evidence for IPA, and less specific microbiological evidence. Integrating these criteria into clinical workflows improves the sensitivity and specificity of IA diagnosis, particularly in patients with overlapping symptoms of bacterial or viral infections.
With this information, probable pulmonary aspergillosis is defined as patients who meet at least one major criterion, have compatible radiological evidence, and present clinical manifestations. Possible pulmonary aspergillosis is defined as patients with risk factors, suggestive clinical manifestations, and inconclusive microbiological or radiological evidence [7,8,9,10].
However, distinguishing probable IA from other conditions, such as bacterial pneumonias or COVID-19-associated pulmonary aspergillosis (CAPA), remains a significant diagnostic challenge in real-world clinical practices [10].
The available data do not support the prophylactic use of antifungals to prevent IA; however, it could be considered if deep and long-lasting immunosuppression is expected [11]. At present, clinical guidelines recommend fist-line voriconazole therapy for IA [12,13,14] with a treatment duration of 6–12 weeks, depending on the degree and duration of immunosuppression [13,14].
In patients with hematological malignancies, polytherapy can lead to possible interactions, which can affect the success or failure of the therapy. In this case, isavuconazole may be an alternative, particularly in the context of severe immunosuppression [13]. Clinical trials have demonstrated non-inferiority of isavuconazole to voriconazole, with a better safety profile and a lower risk of interactions [15].
Isavuconazole is administered as a prodrug, at a loading dose of 200 mg every 8 h (six doses), followed by a maintenance dose of 200 mg once daily, both intravenously and orally, due to its high bioavailability [16,17]. Oral absorption is not affected by food or gastric pH, allowing it to be administered without regard to meals [14]. It has high plasma–protein binding affinity, a large volume of distribution, and a high elimination half-life, so that equilibrium concentrations will not be reached until at least 14 days after administration. It is metabolized mainly by the hepatic route [16].
The oral route is commonly preferred to the parenteral route because it reduces the risk of complications such as infections or extravasations. The problem arises in patients who do not have access to the oral route, limiting the use of isavuconazole only to the parenteral route since the technical information sheet does not support the handling of the tablets for administration via an enteral tube, stating that the capsules should not be chewed, crushed, dissolved, or opened [18].
Regardless of the route of administration, it is essential to strictly control treatment with azoles in AI, with therapeutic drug monitoring (TDM) being an effective tool to optimize both the efficacy and safety of plasma levels [19].
A recent cost-effectiveness study compared treatment of IA with isavuconazole and voriconazole, concluding that isavuconazole is more cost-effective with a willingness-to-pay threshold of €25,000 per additional QALY [20]. This study does not refer to the TDM of voriconazole, a strategy that seems to be highly endorsed in routine clinical practice for treatment optimization, with a therapeutic range of 1–4 mcg/mL [16]. However, there is still discrepancy in the usefulness of isavuconazole TDM [14,15,19,21,22]. What is clear is the marked increase in the cost of treatment of isavuconazole versus voriconazole, particularly when comparing between the intravenous and oral routes.

2. Case Presentation

A 74-year-old male diagnosed in January 2023 with diffuse large cell non-Hodgkin’s B lymphoma. The patient received first-line treatment with R-CHOP (Rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone). After the second cycle of R-CHOP, the patient presented with mucositis and grade 4 neutropenia, which was treated with G-CSF.
On day +11 of the second cycle of R-CHOP, the patient went to the emergency department for thermometric fever of 38.6 °C, poor general condition with tachycardia, and tachypnea. When laboratory test was performed again in the emergency department, the patient presented with grade 4 neutropenia, with elevated acute phase reactants (C-reactive protein, procalcitonin) and hyperlacticaemia, along with hypotension and tachycardia. After an evaluation by the hematology department, it was decided to admit him to the Intensive Care Unit (ICU) for septic shock with probable respiratory focus (condensation in the left lung base).
The radiological image at the time of admission is shown in Figure 1.

Treatment

After admission to the ICU, he required noradrenaline to maintain blood pressure and antibiotic treatment. On day +2 of admission, the patient was intubated and connected to mechanical ventilation due to respiratory failure. That same day, BAL galactomannan tested positive for Aspergillus, with and index of 0.482. The analytical technique used to perform the analysis of galactomannan in BAL was Virclia Lotus® (Vircell microbiologist, Granada, Spain). Virclia LOTUS is an analyzer, with integrated “Lotus” application software, designed for the automation of medical diagnostic techniques performed with in vitro chemiluminescence immunoassays (CLIA), in special devices called VirClia® Monotest (VirClia strips). https://www.vircell.com/soporte-tecnico/preguntas-frecuentes/10-virclia-lotus (accessed on 13 November 2024).
IV voriconazole was started with a loading dose of 6 mg/kg c/12 h (two doses), with a maintenance of 4 mg/kg c/12 h. In addition, ceftriaxone was started according to the antibiogram due to the presence of Klebsiella oxytoca in a bronchoaspirate sample (BAS). That same day, nutritional support was started with individualized parenteral nutrition. On day +4 of voriconazole treatment, TDM was performed. Voriconazole plasma concentrations were quantified by automated enzyme immunoassay. The follow-up levels and dose adjustments are shown in Table 1.
Three days later, the patient was assessed by the surgery service for percutaneous endoscopic gastrostomy (PEG) placement, which was rejected until the patient was stabilized; it was placed 7 days later. On the same day, tolerance to enteral nutrition was started, with individualized parenteral nutrition being suspended a few days later, and during this period, the dose of voriconazole was adjusted according to the TDM values.
The patient’s respiratory condition improved, and a percutaneous tracheostomy was performed. On day +20 of voriconazole treatment, a new TDM was performed, obtaining an undetectable value, so the dose was increased, and a new TDM was performed 5 days later, in which the concentration was again undetectable. Given the instability of the patient’s concentrations, it was decided to start treatment with isavuconazole 200 mg IV that same day. After the first week of treatment, isavuconazole TDM was performed, in which an infratherapeutic level was obtained. Given the long half-life of the drug, the same dose was maintained, since equilibrium had not yet been reached. Isavuconazole plasma concentrations were quantified by an ultra-performance liquid chromatography system associated with an ultraviolet detector (UV/UPLC).
The patient progressed adequately and was discharged after 36 days with isavuconazole treatment while breathing manually with oxygen through nasal goggles. Finally, three days later, the patient was discharged from the ICU and admitted to the hematology department. That same day, a new TDM of isavuconazole was performed, finding the levels within the range.
During the admission to the hematology unit, a multidrug-resistant Pseudomonas aeruginosa was isolated in his sputum, so treatment with ceftazidime/avibactam was established for 10 days. Subsequently, for 2 more week, ceftazidime was started again due to the new isolation of sensitive Pseudomonas aeruginosa,. During all this time, periodic isavuconazole TDM was performed, where the concentration was observed to progressively increase.
Considering the clinical stability of the patient, and after a review of the available literature, on day +59 of isavuconazole treatment, it was decided to begin administering isavuconazole via an enteral tube, at the same dosage, while performing periodic isavuconazole TDM.

3. Results

3.1. Outcome and Follow up

Finally, the patient was discharged on day +72 of isavuconazole treatment, with better general condition, administering medication through the PEG, and with enteral nutrition. Given the degree of immunosuppression of the patient, it was decided to maintain isavuconazole treatment for 16–20 weeks. During the entire admission no positive galactomannan was detected in any of his blood sample.
At the TDM on day +98 of isavuconazole treatment, it was observed that the isavuconazole concentration was beginning to accumulate, so it was decided to reduce the dose; the suitability of the new regimen was checked with a new isavuconazole TDM on day +145. The patient completed treatment in mid-August 2023.

3.2. Investigation

The main investigation of this work is based on the evaluation of the evolution of the isavuconazole concentrations administered intravenously and subsequent administration via an enteral tube, and finally the clinical response of the patient.

4. Discussion

The increased incidence of IA in patients with hematological malignancies, has led to a progressive increase in the use of isavuconazole, and the potential interactions risk with voriconazole, in a group of patients who are usually treated with polytherapy [23].
Techniques like high-resolution computed tomography, serum and BAL galactomannan assays, and polymerase chain reaction (PCR)-based fungal detection have greatly improved diagnostic accuracy, yet their availability and accessibility remain inconsistent across healthcare settings [23].
The updated EORTC/MSGERC [7] definitions have provided a clearer framework for defining probable and possible IA, but real-world application often reveals limitations. For example, obtaining BAL samples may not be feasible in critically ill patients due to procedural risks. In these cases, reliance on serum markers alone may reduce diagnostic sensitivity, leading to delayed or suboptimal treatment. This highlights the urgent need for non-invasive biomarkers with higher specificity and sensitivity to improve early detection and prognosis. Emerging technologies, such as metabolomic profiling or advanced imaging techniques, may address some of these gaps in the future.
In this case, taking into account that the galactomannan value in the BAL was 0.482, it did not reach the established cutoff of >0.5 defined by the EORTC/MSGERC [7] consensus for the diagnosis of probable invasive aspergillosis. However, considering that the patient presented several major criteria (febrile neutropenia upon admission, diagnosis of non-Hodgkin lymphoma) of IA, compatible radiological findings, and suggestive clinical manifestations, the patient was diagnosed with probable IPA.
The consensus itself acknowledges that there is no single established cutoff for galactomannan levels in BAL, particularly in high-risk patients, such as the case described. Variability in cutoff values is influenced by factors such as patient population, clinical context, and the diagnostic setting.
Several studies highlight that while galactomannan levels of ≥0.5 are commonly used, values as low as ≥0.2 have been suggested for specific high-risk groups to increase sensitivity in diagnosing invasive aspergillosis [24].
Moreover, considering that galactomannan levels in BAL typically appear earlier than in serum, and given the rapid diagnosis made in this patient, it is likely that the obtained value would have increased if treatment had not been initiated [25].
The interindividual variability of isavuconazole concentrations exists, mainly due to the patient’s creatinine clearance and body weight, which justifies TDM for the purpose of optimizing therapy [26]. Therefore, TDM is an essential tool to balance the drug’s efficacy with its potential toxicities, particularly in patients with altered pharmacokinetics due to organ dysfunction or concurrent medications. Isavuconazole has emerged as a valuable alternative, offering comparable efficacy with a more favourable safety profile, particularly in patients with hepatic impairment or significant drug–drug interactions. At present, an optimal therapeutic range has not been established; however, it appears that achieving minimal concentrations (Cmin > 1 mcg/mL) has been associated with a higher likelihood of treatment success [19,27,28].
There is little evidence of administration of isavuconazole via enteral tube in adult patients with hematological malignancies. Table 2 gathers all the published evidence of isavuconazole administration via enteral tube.
Some isolated clinical cases have been published in which isavuconazole concentrations like the IV route were observed when administered by gastrostomy or jejunostomy [29], even in the pediatric population [32]. Dieringer et al. found no negative impact on isavuconazole concentrations associated with the administration via enteral tube in a group of 24 patients [33]. Previously, Spivey et al. had found higher isavuconazole concentrations when administered by gavage than by IV in critically ill and non-critically ill patients [31].
McCreary et al. published the only work that refers to any patient on isavuconazole treatment with hematologic malignancies. They included a cohort of 19 patients (18 with solid organ transplantation and 1 patient with hematopoietic progenitor transplantation for myelofibrosis). This patient received isavuconazole for the treatment of A. calidoustus [30].
All in all, isavuconazole TDM appears to be a key strategy to optimize long-term IA treatment in most patients, especially in those with high body weight and critically ill patients [34]. Moreover, in patients with an enteral tube, the use of TDM is a safe strategy that supports the maintenance of isavuconazole concentrations via enteral tube, since TDM entails a lower cost than the treatment itself [19]. Another reason for the need of TDM is that it appears that the standard dose of isavuconazole is adequate for the treatment of IA caused by A. fumigatus with MICs < 0.5 mcg/mL, but the likelihood of treatment success decreases as the MIC increases [22.35]. This is even more prominent in Candida albicans and glabrata infections [35].
The case presented describes the first patient with a hematological malignancy where isavuconazole is administered via an enteral tube, due to the presence of IA in BAL. It demonstrates the stability of isavuconazole concentrations when administered through a PEG, which was monitored by performing periodic TDMs, detecting even the slightest accumulation of concentrations, as already pointed out by Spivey et al. beforehand [31]. This practice led to a significant decrease in the economic impact compared to IV administration.
In view of the above, the integration of clinical pharmacist in multidisciplinary management is increasingly considered as part of patient care, with the aim of ensuring the achievement of the therapeutic objective in this scenario of uncertainty and ensuring the efficiency of an increasingly frequent treatment.
Future research should prioritize the development of rapid diagnostic tools, personalized antifungal therapies, and preventive strategies to address these challenges. Multidisciplinary collaboration involving infectious disease specialists, hematologists, clinical pharmacist, and microbiologists is essential to optimize patient outcomes and advance our understanding of IA.

5. Conclusions

The administration of isavuconazole through an enteral tube supplemented with periodic controls of its plasma concentrations through TDM proved to be a safe and adequate practice.

Author Contributions

Conceptualization, Á.C.A., J.J.C., Á.L.D. and A.Z.C.; methodology, Á.C.A.; software, Á.C.A. and J.J.C.; formal analysis, A.Z.C.; investigation, Á.C.A., J.J.C., Á.L.D. and A.Z.C.; resources, Á.C.A., J.J.C., Á.L.D. and A.Z.C.; data curation, Á.C.A., J.J.C., Á.L.D. and A.Z.C.; writing—original draft preparation, Á.C.A. and J.J.C.; writing—review and editing, Á.L.D. and A.Z.C.; visualization, Á.C.A.; supervision, Á.C.A.; project administration, Á.C.A.; funding acquisition, Á.C.A. and A.Z.C. All authors have read and agreed to the published version of the manuscript.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Written informed consent has been obtained from the patient to publish this paper.

Data Availability Statement

The original contributions presented in this study are included in the article. Further inquiries can be directed to the corresponding authors.

Conflicts of Interest

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

References

  1. Tacke, D.; Buchheidt, D.; Karthaus, M.; Krause, S.W.; Maschmeyer, G.; Neumann, S.; Ostermann, H.; Penack, O.; Rieger, C.; Ruhnke, M.; et al. Primary Prophylaxis of Invasive Fungal Infections in Patients with Haematologic Malignancies. 2014 Update of the Recommendations of the Infectious Diseases Working Party of the German Society for Haematology and Oncology. Ann. Hematol. 2014, 93, 1449–1456. [Google Scholar] [CrossRef] [PubMed]
  2. Vargas-Espíndola, L.A.; Cuervo-Maldonado, S.I.; Enciso-Olivera, J.L.; Gómez-Rincón, J.C.; Jiménez-Cetina, L.; Sánchez-Pedraza, R.; García-Guzmán, K.; López-Mora, M.J.; Álvarez-Moreno, C.A.; Cortés, J.A.; et al. Fungemia in Hospitalized Adult Patients with Hematological Malignancies: Epidemiology and Risk Factors. J. Fungi 2023, 9, 400. [Google Scholar] [CrossRef] [PubMed]
  3. Bays, D.J.; Thompson, G.R. Fungal Infections of the Stem Cell Transplant Recipient and Hematologic Malignancy Patients. Infect. Dis. Clin. North. Am. 2019, 33, 545–566. [Google Scholar] [CrossRef] [PubMed]
  4. Enoch, D.A.; Yang, H.; Aliyu, S.H.; Micallef, C. The Changing Epidemiology of Invasive Fungal Infections. Methods Mol. Biol. 2017, 1508, 17–65. [Google Scholar] [CrossRef]
  5. Racil, Z.; Weinbergerova, B.; Kocmanova, I.; Muzik, J.; Kouba, M.; Drgona, L.; Masarova, L.; Guman, T.; Tothova, E.; Forsterova, K.; et al. Invasive Aspergillosis in Patients with Hematological Malignancies in the Czech and Slovak Republics: Fungal InfectioN Database (FIND) Analysis, 2005–2009. Int. J. Infect. Dis. 2013, 17, e101–e109. [Google Scholar] [CrossRef]
  6. Pagano, L.; Caira, M.; Candoni, A.; Offidani, M.; Fianchi, L.; Martino, B.; Pastore, D.; Picardi, M.; Bonini, A.; Chierichini, A.; et al. The Epidemiology of Fungal Infections in Patients with Hematologic Malignancies: The SEIFEM-2004 Study. Haematologica 2006, 91, 1068–1075. [Google Scholar]
  7. Mercier, T.; Castagnola, E.; Marr, K.A.; Wheat, L.J.; Verweij, P.E.; Maertens, J.A. Defining Galactomannan Positivity in the Updated EORTC/MSGERC Consensus Definitions of Invasive Fungal Diseases. Clin. Infect. Dis. 2021, 72 (Suppl. 2), S89–S94. [Google Scholar] [CrossRef]
  8. De Pauw, B.; Walsh, T.J.; Donnelly, J.P.; Stevens, D.A.; Edwards, J.E.; Calandra, T.; Pappas, P.G.; Maertens, J.; Lortholary, O.; Kauffman, C.A.; et al. Revised Definitions of Invasive Fungal Disease from the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group. Clin. Infect. Dis. 2008, 46, 1813–1821. [Google Scholar] [CrossRef]
  9. Ascioglu, S.; Rex, J.H.; de Pauw, B.; Bennett, J.E.; Bille, J.; Crokaert, F.; Denning, D.W.; Donnelly, J.P.; Edwards, J.E.; Erjavec, Z.; et al. Invasive Fungal Infections Cooperative Group of the European Organization for Research and Treatment of Cancer; Mycoses Study Group of the National Institute of Allergy and Infectious Diseases. Defining Opportunistic Invasive Fungal Infections in Immunocompromised Patients with Cancer and Hematopoietic Stem Cell Transplants: An International Consensus. Clin. Infect. Dis. 2002, 34, 7–14. [Google Scholar] [CrossRef]
  10. Pappas, P.G.; Chen, S.C.-A.; Donnelly, J.P. The Evidence Supporting the Revised EORTC/MSGERC Definitions for Invasive Fungal Infections. Clin. Infect. Dis. 2021, 72 (Suppl. 2), S77–S78. [Google Scholar] [CrossRef]
  11. Christopeit, M.; Schmidt-Hieber, M.; Sprute, R.; Buchheidt, D.; Hentrich, M.; Karthaus, M.; Penack, O.; Ruhnke, M.; Weissinger, F.; Cornely, O.A.; et al. Prophylaxis, Diagnosis and Therapy of Infections in Patients Undergoing High-Dose Chemotherapy and Autologous Haematopoietic Stem Cell Transplantation. 2020 Update of the Recommendations of the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Medical Oncology (DGHO). Ann. Hematol. 2021, 100, 321–336. [Google Scholar] [CrossRef] [PubMed]
  12. Patterson, T.F.; Thompson, G.R., III; Denning, D.W.; Fishman, J.A.; Hadley, S.; Herbrecht, R.; Kontoyiannis, D.P.; Marr, K.A.; Morrison, V.A.; Nguyen, M.H.; et al. Executive Summary: Practice Guidelines for the Diagnosis and Management of Aspergillosis: 2016 Update by the Infectious Diseases Society of America. Clin. Infect. Dis. 2016, 63, 433–442. [Google Scholar] [CrossRef] [PubMed]
  13. Douglas, A.P.; Smibert, O.C.; Bajel, A.; Halliday, C.L.; Lavee, O.; McMullan, B.; Yong, M.K.; van Hal, S.J.; Chen, S.C.-A. Australasian Antifungal Guidelines Steering Committee. Consensus Guidelines for the Diagnosis and Management of Invasive Aspergillosis, 2021. Intern. Med. J. 2021, 51 (Suppl. 7), 143–176. [Google Scholar] [CrossRef]
  14. Garcia-Vidal, C.; Alastruey-Izquierdo, A.; Aguilar-Guisado, M.; Carratalà, J.; Castro, C.; Fernández-Ruiz, M.; Aguado, J.M.; Fernández, J.M.; Fortún, J.; Garnacho-Montero, J.; et al. Executive Summary of Clinical Practice Guideline for the Management of Invasive Diseases Caused by Aspergillus: 2018 Update by the GEMICOMED-SEIMC/REIPI. Enferm. Infecc. Microbiol. Clin. 2019, 37, 535–541. [Google Scholar] [CrossRef]
  15. Maertens, J.A.; Raad, I.I.; Marr, K.A.; Patterson, T.F.; Kontoyiannis, D.P.; Cornely, O.A.; Bow, E.J.; Rahav, G.; Neofytos, D.; Aoun, M.; et al. Isavuconazole versus Voriconazole for Primary Treatment of Invasive Mould Disease Caused by Aspergillus and Other Filamentous Fungi (SECURE): A Phase 3, Randomised-Controlled, Non-Inferiority Trial. Lancet 2016, 387, 760–769. [Google Scholar] [CrossRef]
  16. Wilson, D.T.; Dimondi, V.P.; Johnson, S.W.; Jones, T.M.; Drew, R.H. Role of Isavuconazole in the Treatment of Invasive Fungal Infections. Ther. Clin. Risk Manag. 2016, 12, 1197–1206. [Google Scholar] [CrossRef]
  17. Schmitt-Hoffmann, A.; Desai, A.; Kowalski, D.; Pearlman, H.; Yamazaki, T.; Townsend, R. Isavuconazole Absorption Following Oral Administration in Healthy Subjects Is Comparable to Intravenous Dosing, and Is Not Affected by Food, or Drugs That Alter Stomach PH. Int. J. Clin. Pharmacol. Ther. 2016, 54, 572–580. [Google Scholar] [CrossRef]
  18. Agencia Española Del Medicamento Y Productos Sanitarios. Ficha Tecnica Cresemba 200 MG Polvo Para Concentrado Para Solucion Para Perfusion. Available online: https://cima.aemps.es/cima/dochtml/ft/1151036001/FT_1151036001.html (accessed on 25 June 2023).
  19. Kably, B.; Launay, M.; Derobertmasure, A.; Lefeuvre, S.; Dannaoui, E.; Billaud, E.M. Antifungal Drugs TDM: Trends and Update. Ther. Drug Monit. 2022, 44, 166–197. [Google Scholar] [CrossRef]
  20. Azanza, J.R.; Grau, S.; Vázquez, L.; Rebollo, P.; Peral, C.; López-Ibáñez de Aldecoa, A.; López-Gómez, V. The Cost-Effectiveness of Isavuconazole Compared to Voriconazole, the Standard of Care in the Treatment of Patients with Invasive Mould Diseases, Prior to Differential Pathogen Diagnosis in Spain. Mycoses 2021, 64, 66–77. [Google Scholar] [CrossRef]
  21. Gatti, M.; Campoli, C.; Belotti, T.; Cojutti, P.G.; Masetti, R.; Pession, A.; Viale, P.; Pea, F. Real-World Comparison of Isavuconazole and Voriconazole in Terms of the Need for Dosage Adjustments Guided by Clinical Pharmacological Advice During Primary Prophylaxis of Invasive Fungal Infections in Pediatric Patients with Hemato-Oncological Malignancies. Ther. Drug Monit. 2022, 44, 641–650. [Google Scholar] [CrossRef]
  22. Wilby, K.J. A Review of the Clinical Pharmacokinetics and Pharmacodynamics of Isavuconazole. Eur. J. Drug Metab. Pharmacokinet. 2018, 43, 281–290. [Google Scholar] [CrossRef] [PubMed]
  23. Fontana, L.; Perlin, D.S.; Zhao, Y.; Noble, B.N.; Lewis, J.S.; Strasfeld, L.; Hakki, M. Isavuconazole Prophylaxis in Patients With Hematologic Malignancies and Hematopoietic Cell Transplant Recipients. Clin. Infect. Dis. 2020, 70, 723–730. [Google Scholar] [CrossRef] [PubMed]
  24. Troncoso, C.R.; Sepúlveda, F.C.; Sepúlveda, P.E.; Guzmán, U.C.; Morales, G.M.; Tapia, C. Evaluation of the Aspergillus Galactomannan ag VircliaR Monotest test as an alternative to PlateliaTM Aspergillus EIA kit. Rev. Chil. Infectol. 2022, 39, 248–253. [Google Scholar] [CrossRef] [PubMed]
  25. Avcu, G.; Karapinar, D.Y. A Review of a Diagnostic Tool: Galactomannan. J. Immunol. Sci. 2018, 2, 38–42. [Google Scholar]
  26. Shirae, S.; Tsuruya, Y.; Kozaki, T.; Mizuhata, J.; Ose, A. Population Pharmacokinetics, Exposure–Safety, and Probability of Target Attainment Analyses for Isavuconazole in Japanese Patients With Deep-Seated Mycoses. J. Clin. Pharmacol. 2023, 63, 704–714. [Google Scholar] [CrossRef]
  27. Andes, D.; Kovanda, L.; Desai, A.; Kitt, T.; Zhao, M.; Walsh, T.J. Isavuconazole Concentration in Real-World Practice: Consistency with Results from Clinical Trials. Antimicrob. Agents Chemother. 2018, 62, e00585-18. [Google Scholar] [CrossRef]
  28. Desai, A.; Kovanda, L.; Kowalski, D.; Lu, Q.; Townsend, R.; Bonate, P.L. Population Pharmacokinetics of Isavuconazole from Phase 1 and Phase 3 (SECURE) Trials in Adults and Target Attainment in Patients with Invasive Infections Due to Aspergillus and Other Filamentous Fungi. Antimicrob. Agents Chemother. 2016, 60, 5483–5491. [Google Scholar] [CrossRef]
  29. Adamsick, M.L.; Elshaboury, R.H.; Gift, T.; Mansour, M.K.; Kotton, C.N.; Gandhi, R.G. Therapeutic Drug Concentrations of Isavuconazole Following the Administration of Isavuconazonium Sulfate Capsules via Gastro-Jejunum Tube: A Case Report. Transplant. Infect. Dis. 2019, 21, e13048. [Google Scholar] [CrossRef]
  30. McCreary, E.K.; Hong Nguyen, M.; Davis, M.R.; Borlagdan, J.; Shields, R.K.; Anderson, A.D.; Rivosecchi, R.M.; Marini, R.V.; Sacha, L.M.; Silveira, F.P.; et al. Achievement of Clinical Isavuconazole Blood Concentrations in Transplant Recipients with Isavuconazonium Sulphate Capsules Administered via Enteral Feeding Tube. J. Antimicrob. Chemother. 2020, 75, 3023–3028. [Google Scholar] [CrossRef]
  31. Spivey, J.; Wrenn, R.; Liu, B.; Maziarz, E.; Kram, B. Characterization of Isavuconazole Serum Concentrations after Enteral Feeding Tube Administration in a Hospitalized Cohort: A Case Series. J. Clin. Pharm. Ther. 2021, 46, 528–531. [Google Scholar] [CrossRef]
  32. Garner, L.M.; Echols, C.D.; Wilson, W.S. Enteral Tube Administration of Isavuconazole in a Pediatric Patient. Pediatr. Blood Cancer 2021, 68, e29108. [Google Scholar] [CrossRef]
  33. Dieringer, T.D.; Schaenman, J.M.; Davis, M.R. Enteral Feeding Tube Administration with Therapeutic Drug Monitoring of Crushed Posaconazole Tablets and Opened Isavuconazonium Sulfate Capsules. J. Antimicrob. Chemother. 2022, 77, 1417–1423. [Google Scholar] [CrossRef] [PubMed]
  34. Höhl, R.; Bertram, R.; Kinzig, M.; Haarmeyer, G.-S.; Baumgärtel, M.; Geise, A.; Muschner, D.; Prosch, D.; Reger, M.; Naumann, H.-T.; et al. Isavuconazole Therapeutic Drug Monitoring in Critically Ill ICU Patients: A Monocentric Retrospective Analysis. Mycoses 2022, 65, 747–752. [Google Scholar] [CrossRef] [PubMed]
  35. Wu, X.; Venkataramanan, R.; Rivosecchi, R.M.; Tang, C.; Marini, R.V.; Shields, R.K.; Clancy, C.J.; Nguyen, M.H. Population Pharmacokinetics of Intravenous Isavuconazole in Solid-Organ Transplant Recipients. Antimicrob. Agents Chemother. 2020, 64, e01728-19. [Google Scholar] [CrossRef] [PubMed]
Ijtm 04 00044 g001
Figure 1. Chest X-ray at the time of the patient’s admission.
Figure 1. Chest X-ray at the time of the patient’s admission.
Ijtm 04 00044 g001
Table 1. Voriconazole and isavuconazole TDM records.
Table 1. Voriconazole and isavuconazole TDM records.
DayDosageCminRecommendation
VORICONAZOLE
16/03/23 (0)400 mg c/12 (x2) IV--
17/03/23 (+1)300 mg c/12 h IV--
20/03/23 (+5)300 mg c/12 h IV10.1 mcg/mL200 mg c/12 h IV
23/03/23 (+8)200 mg c/12 h IV6.8 mcg/mL150 mg c/12 h IV
29/03/23 (+14)150 mg c/12 h IV2.9 mcg/mL150 mg c/12 h IV
05/04/23 (+21)150 mg c/12 h IVundetectable200 mg c/12 h IV
10/04/23 (+26)200 mg c/12 h IVundetectableChange to isavuconazole
ISAVUCONAZOLE
17/04/23 (+33)200 mg c/24 h IV0.8 mcg/mL200 mg c/24 h IV
24/04/23 (+39)200 mg c/24 h IV1.2 mcg/mL200 mg c/24 h IV
03/05/23 (+49)200 mg c/24 h IV2.4 mcg/mL200 mg c/24 h IV
10/05/23 (+56)200 mg c/24 h IV2.6 mcg/mL200 mg c/24 h PEG
18/05/23 (+64)200 mg c/24 h PEG2.8 mcg/mL200 mg c/24 h PEG
26/05/23 (+72)200 mg c/24 h PEG3.5 mcg/mL200 mg c/24 h PEG
21/06/23 (+98)200 mg c/24 h PEG4.1 mcg/mL200 mg and 100 mg PEG every other day
07/08/23 (+145)200 mg and 100 mgPEG every other day3.1 mcg/mL200 mg and 100 mg PEG every other day
Table 2. Evidence of isavuconazole administration via enteral tube.
Table 2. Evidence of isavuconazole administration via enteral tube.
YearAuthorNº PatientsTypeReference
2019Adamsick1Lung transplant[29]
2020McCreary19Solid organ transplant (18) and hematopoietic progenitors (1)[30]
2021Spivey14Critical and non-critical[31]
2021Garner1Pediatric, LMA[32]
2022Dieringer24Solid organ transplant prophylaxis[33]
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Corral Alaejos, Á.; Jiménez Casaus, J.; López Delgado, Á.; Zarzuelo Castañeda, A. The Successful and Safe Real-Time TDM-Guided Treatment of Invasive Pulmonary Aspergillosis Using Isavuconazole Administered by Enteral Tube. Int. J. Transl. Med. 2024, 4, 631-639. https://doi.org/10.3390/ijtm4040044

AMA Style

Corral Alaejos Á, Jiménez Casaus J, López Delgado Á, Zarzuelo Castañeda A. The Successful and Safe Real-Time TDM-Guided Treatment of Invasive Pulmonary Aspergillosis Using Isavuconazole Administered by Enteral Tube. International Journal of Translational Medicine. 2024; 4(4):631-639. https://doi.org/10.3390/ijtm4040044

Chicago/Turabian Style

Corral Alaejos, Álvaro, Jose Jiménez Casaus, Ángel López Delgado, and Aranzazu Zarzuelo Castañeda. 2024. "The Successful and Safe Real-Time TDM-Guided Treatment of Invasive Pulmonary Aspergillosis Using Isavuconazole Administered by Enteral Tube" International Journal of Translational Medicine 4, no. 4: 631-639. https://doi.org/10.3390/ijtm4040044

APA Style

Corral Alaejos, Á., Jiménez Casaus, J., López Delgado, Á., & Zarzuelo Castañeda, A. (2024). The Successful and Safe Real-Time TDM-Guided Treatment of Invasive Pulmonary Aspergillosis Using Isavuconazole Administered by Enteral Tube. International Journal of Translational Medicine, 4(4), 631-639. https://doi.org/10.3390/ijtm4040044

Article Metrics

Back to TopTop