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 Table of Contents  
INVITED DRUG REVIEW
Year : 2022  |  Volume : 24  |  Issue : 1  |  Page : 1-7

Isavuconazole - The new triazole


Department of Microbiology, St. John's Medical College and Hospital, St. John's National Academy of Health Sciences, Bengaluru, Karnataka, India

Date of Submission24-Jun-2022
Date of Acceptance01-Jul-2022
Date of Web Publication11-Jul-2022

Correspondence Address:
Dr. Jayanthi Savio
Department of Microbiology, St. John's Medical College and Hospital, St. John's National Academy of Health Sciences, Sarjapur Road, Bengaluru - 560 034, Karnataka
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jacm.jacm_11_22

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  Abstract 


The increase in susceptible population to invasive fungal infections, especially candidemia and aspergillosis has resulted in the introduction of newer antifungal agents, especially in the azole group. Isavuconazole is one such agent with an extended antifungal spectrum. It is found to be useful not only in the management of candidemia and aspergillosis but also mucormycosis.

Keywords: Candidemia, Aspergillosis, Invasive fungal infections


How to cite this article:
Savio J. Isavuconazole - The new triazole. J Acad Clin Microbiol 2022;24:1-7

How to cite this URL:
Savio J. Isavuconazole - The new triazole. J Acad Clin Microbiol [serial online] 2022 [cited 2022 Aug 11];24:1-7. Available from: https://www.jacmjournal.org/text.asp?2022/24/1/1/350315




  Introduction Top


The advances in therapeutic management of critically ill and chronic health conditions have resulted in an increase in a population susceptible to invasive fungal infections (IFIs).[1] Although globally the most common IFIs include candidemia and aspergillosis, in the Indian setting, it also includes mucormycosis, especially among patients with non-classical underlying risk factors.[2] Diagnosis and treatment of these infections are a challenge. Lack of mycology specific laboratory facilities, expensive drugs, prolonged antifungal regimens, side effects of antifungal agents and inherent resistance among pathogens contribute to this challenge.[3],[4] In addition to these, invasive mycoses due to multiple pathogens are on the rise in the recent past which compounds the problem.[5],[6],[7] In this scenario, the options for medical management are limited. The antifungal arsenal in the management of IFIs includes the azoles, echinocandins, polyenes and flucytosine. Although limitations related to spectrum of activity, development of resistance, and toxicity is specific to each one of them, the azoles are best in terms of tolerability and their side effect profile.[1],[8] Azoles have been the recommended antifungals for invasive aspergillosis (IA) unless the implicated species is inherently resistant.[9],[10] Until recently amphotericin B (AmphoB), a highly nephrotoxic drug was the only drug of choice for the treatment of mucormycosis. The newer second generation triazoles both posaconazole (POSA) and isavuconazole (ISA) have a wide antifungal spectrum including mucorales, but the use of POSA is limited by its poor CSF penetration.[11] With the introduction of ISA, the scope of managing mucormycosis, especially in patients with impaired renal functions has improved.

The aim of this review is to present the available literature on this new triazole - ISA, its structure, mechanism of action, pharmacokinetics, pharmacodynamics, current recommendations for its use in clinical practice for adults and children, safety and resistance.


  Structure and Mechanism of Action Top
[Figure 1][1]

ISA inhibits fungal cytochrome P450-dependent lanosterol 14α-demethylase (Cyp51), which catalyses conversion of lanosterol to ergosterol. This results in the depletion of ergosterol, an essential component of the fungal membrane. The altered cell permeability due to the presence of methylated sterols in the membrane and resulting accumulation of toxic ergosterol precursors in the cytoplasm leads to cell lysis and death.[12] The broader antifungal activity of ISA even against pathogens resistant to other azoles such as itraconazole (ITRA), voriconazole (VORI), and POSA can be attributed to its structure. In addition to the basic triazole ring structure, it has a side arm consisting of an N-(3-acetoxypropyl)-N-methylamino-carboxymethyl group that helps in orienting the molecule to engage the triazole ring with the binding pocket of the fungal CYP51 protein with greater avidity.[13],[14]




  Pharmacokinetics Top


The prodrug isavuconazonium sulfate is a water-soluble triazole precursor which can be administered both orally and intravenously. The plasma esterases rapidly break it down to the active component, ISA, and an inactive cleavage product which is just <1% of the active ISA. Being highly water soluble, it does not require the addition of beta-cyclodextrin to its IV formulation to improve solubility thus eliminating cyclodextrin-induced nephrotoxicity.[1],[13],[15],[16]

It is available as powder for infusion (372 mg ISA sulfate equivalent to 200 mg ISA) and as oral capsules (186 mg ISA sulfate equivalent to 100 mg ISA). The loading dose is 200 mg every eight hours for six doses given over a 48-h period, followed by a maintenance dose of 200 mg daily. The bioavailability is excellent with 98% of the active drug reaching circulation. The recommended dose is the same for both oral and intravenous (IV) administration. The absorption and serum concentrations are not affected by food, gastric acidity or mucosal integrity. Timing of food intake, drugs altering gastric acid secretion and presence of mucositis do not hinder administration of this drug. IV or oral administration follows dose-dependent pharmacokinetics with minimal inter or intra subjects variability, reaching a peak plasma concentration in one and two to three hours after administration, respectively. The findings have shown that dose adjustments are not required when switching between oral and IV formulations as they are bioequivalent. The volume of distribution is large, with almost 98% bound to proteins, mostly to albumin. It is distributed in most tissues, the liver, lungs, eyes, kidneys, bone, nasal mucosa, including brain, the sanctuary site.[1],[13],[16]

Hepatic metabolism with predominant cytochrome enzymes CYP3A4 and CYP3A5 and modification by uridine diphosphate-glucuronosyltransferases (UGT) is the primary mode of elimination. Excretion in feces and urine is equal. It has a long terminal half-life elimination ranging from 100 to 115 h. Although patients with liver disease have higher exposure to ISA, dose adjustment is not recommended in mild to moderate hepatic impairment (Child–Pugh classes A and B), but there are no data for severe liver disease (Child–Pugh class C).

Its urinary concentrations with oral or IV administration is almost same with only slightly higher concentrations following IV dosing. Renal impairment does not affect the area under the curve (AUC) or the maximum serum concentration (Cmax) thus eliminating the need for dose adjustments with reduced renal function including end-stage renal disease (ESRD).[1],[13],[16]

ISA is also a pregnancy class C drug and should not be given to pregnant women unless the potential benefit to the patient outweighs the risk to the foetus. Since the drug is excreted in the milk of lactating rats, it should be avoided in women who are breastfeeding.[13],[17]


  Pharmacodynamics Top


ISA is highly active against all Candida species including less susceptible species such as C. glabrata and C. krusei. It demonstrates greater potency than fluconazole and is as active as ITRA and VORI. For Candida species including C.glabrata and C.kurusei, the minimum inhibitory concentration (MIC) values for 50% (MIC50) and 90% (MIC90) inhibitory were <0.5 and <2.0 mg/L, respectively.[13] The potency is higher than POSA. Activity against Cryptococcus gattii and C. neoformans is excellent with efficacy comparable to POSA and voriconazole and greater against isolates with reduced fluconazole susceptibilities. The MIC50 and MIC90 of C. neoformans were <0.015 and 0.6 mg/L, respectively, and those of C. gattii were 0.03 and 0.06 mg/L, respectively. It is also active against Trichosporon spp. It is highly active against most common species of Aspergillus, the A. fumigatus, A. terreus, A. flavus and A. niger, including strains resistant to ITRA, caspofungin (CASPO), or AmphoB. ISA also has a very good activity against the Mucorales. Coccidioides (MICs: 0.06–0.12 μg/mL; n = 6), Histoplasma (MICs: 0.03 μg/mL; n = 2), and Paracoccidioides (MIC: 0.001 μg/mL; n = 1) are other fungi against which ISA is active.[13],[18],[19]


  Drug – Drug Interactions Top


Most of these interactions by ISA are similar to other triazoles. It includes drugs metabolized by various enzyme systems and/or with substrates of drug transporters. ISA is a moderate inhibitor of CYP3A4/5 and can therefore increase the exposure to other CYP3A4 substrates, such as benzodiazepines (midazolam) and immunosuppressive drugs (cyclosporine, tacrolimus and sirolimus). The effect of ISA on midozolam and immunosuppressant agents has been documented in healthy subjects. Monitoring of the immunosuppressants is recommended to adjust the optimum dose. ISA is also a mild inducer of CYP2B6 but does not affect activities of CYP1A2, CYP2C8, CYP2D6 or CYP2C19. Warfarine pharmacodynamics (CYP2C9 substrates) is unaffected by ISA. Inducers of UGT may increase its metabolism. Oral rifampin, which induces both CYP3A4 and UGT (Uridine 5'-diphospho-glucuronosyltransferases and can decrease ISA AUC by 97% and Cmax by 75%). Thus, co-administration of rifampin and ISA is contraindicated. ISA increases AUC of mycophenolic acid by 35% due to its mild inhibitory action on UGT and this necessitates monitoring for mycophenolate-related toxicities. ISA is an inhibitor of P-glycoprotein (P-gp), BCRP (in vitro) and organic cation transporters 1 and 2 (OCT1 and OCT2). Atorvastatin (OATP1B1 and P-gp substrate; also a substrate for CYP3A4), digoxine (P-gp substrate) and metformin (OCT1, OCT2 and MATE1 substrate) increased by 37%, 25% and 52% when combined with ISA. Methotrexate (BCRP, OAT1 and OAT3 substrate) remains largely unaffected. With this current knowledge of drug-drug interaction of ISA, one must avoid the combinations with absolute contraindication and ensure monitoring for adverse events with the others during management of patients.[1],[13],[16],[17]


  Clinical Use Top


Prophylaxis

There is limited data on ISA as primary antifungal prophylaxis against IFIS among immunocompromised patients. A study published in 2020 by Lauren Fontana et al. is a retrospective review of breakthrough IFIs (bIFIs) among adult hematologic malignancy patients and HCT recipients who received ≥7 days of Isa. The incidence of bIFIs with ISA was compared to those receiving POSA and voriconazole (VORI) during the same time period.

There were 12 bIFIs during the periods of neutropenia (Aspergillus species [7], Mucorales [2], Fusarium species[2] and C.glabrata [1]) representing 8.3% of patients and 6.1% of courses, after a median duration of 14 days of ISA prophylaxis. Seven (58.3%) died within 42 days of onset of bIFI. IPA in particular complicated 6.8% of ISA, 1.3% of POS and zero VORI courses. The investigators observed an increased rate of bIFI, especially IPA, when using ISA for primary prophylaxis.[20] In another open-label, prospective, Phase 2 study published in 2021, ISA was found to be a safe and effective alternative for primary antifungal prophylaxis in patients with newly diagnosed hematologic malignancy who underwent remission-induction chemotherapy. Studies using ISA as primary prophylaxis in large numbers of different patient population groups are needed to resolve the safety and efficacy profile of ISA compared to other systemic antifungals.[20],[21],[22]

Invasive aspergillosis

IA is the most common IFI encountered especially among immunocompromised patients which results in significant mortality and morbidity. The overall one-year survival rate is about 25% with IA among patients HSCT. In the background of limited treatment options and significant toxicities and drug interactions with the available drugs, ISA was introduced in 2015 for treatment for IA. SECURE, a phase 3 prospective, randomised, double-blinded study helped to approve ISA for the treatment for IA. It established non-inferiority of the ISA arm in the different subgroups of the study population. Since then, studies have reported its use not only for IA in patients with classical haematological malignant conditions but also in non-neutropenic critically ill patients and in chronic pulmonary aspergillosis.[1],[23],[24]

Invasive mucormycosis

Mucormycosis occurs primarily among immunocompromised and in the Indian setting among uncontrolled diabetic patients. A high mortality of >50% warrants an early diagnosis and treatment of this condition. Management is effective when surgical debridement, antifungal therapy reversal of underlying disease are combined. The anti-fungal agents used include AmphoB and POSA. Both these are associated with significant toxicity and adverse events. The Food and Drug Administration approved the use of ISA for invasive mucormycosis based on the results of the VITAL (ISA treatment for mucormycosis: a single-arm open-label trial and case-control, analysis, Clinicaltrials.gov, number NCT01731353 study in 2015. Treatment was successful for 63% of the patients (complete or partial response at the end of therapy) along with 21% of patients achieving stable disease. There are many studies reporting ISA to be efficacious for both primary and salvage therapies. Its overall end-of-treatment response rates are comparable to L-AmphoB, with almost similar crude or all-cause mortality. It also seems to be a promising agent for long-term therapy.[1],[25],[26],[27],[28]

Candidiasis

Candidemia is one of the most common fungal infections among hospitalised patients both in developed and developing countries. Echinocandins (ECHINO) are often used as the first-line therapy for candidemia. ACTIVE (ISA versus caspofungin in the treatment of candidemia and other Invasive Candida infections: The ACTIVE Trial Clinicaltrials.gov, NCT00413218, a Phase 3 randomized double-blind clinical trial for the primary treatment of patients with candidemia or invasive candidiasis compared IV ISA to IV CASPO followed by oral ISA or VORI. The study did not demonstrate non-inferiority of ISA in comparison to CASPO. The overall response rates two weeks after the end of therapy as well as survival on days 14 and 56 were similar in both arms. The clearance rate of Candida from the bloodstream in patients with candidemia was similar. The incidence of breakthrough or recurrent infections was slightly higher in the CASPO group. Success rates in the patients who transitioned from IV to oral therapy were 82.6% in the ISA group and 77.5% in the CASPO group. This finding supports the use of ISA as a step-down therapy for candidiasis.[29]

In the recent past, the problem with candidiasis has been the emergence of MDR candida, Candida auris. The therapeutic options are limited for its treatment. Since echinocandins are recommended as the first-line option pending AFST results, emergence of resistance to this class is imminent. Use of combinations of antifungals could therefore optimize therapy. Recently in-vitro studies have reported a synergistic interaction of ISA with ECHINO against C. auris. Analysis of time-kill curves has confirmed ISA – ECHINO combinations to be more effective than monotherapy regimens. Synergism and fungistatic activity is achieved with combinations of ISA in low concentrations (≥0.125 mg/L) and ≥1 mg/L of ECHINO. ISA also displayed more activity and[29] greater synergy when tested with anidulafungin than VORI against the C. auris clinical isolates that displayed resistance phenotypes. These promising results could initiate use of combination of ISA with ECHINO for the treatment of C. auris infections.[29],[30],[31]


  Use in Children Top


Just as in adults, IFIs are significant complications in children, especially hematologic malignancies, as well as in allogeneic hematologic stem cells transplantation (HSCT) recipients and treating them is a challenge. Triazole and polyenes are the systemic antifungals used for aspergillosis and mucormycosis. The use of ISA is still off-label for paediatric population. Case reports and articles published have evaluated the tolerance, safety and therapeutic response. Investigators have used adult doses for children weighing 30 kg and more and half that for those under 30 kg.[32]

The most recent study published is a retrospective analysis by Philippe Zimmermann et al. They have evaluated safety of ISA in treatment or prophylaxis for IFIs in 15 immuno-compromised children. This study included a mixed patient population (B-cell acute lymphoblastic leukemia [ALL] five, T-cell ALL two, Fanconi anemia two, aplastic anaemia two, acute myeloblastic leukemia one, anaplastic large cell lymphoma one, Burkitt lymphoma one and myelodysplastic syndrome one). Ten of these patients were post-HSCT status. Nine of these patients received ISA as a curative treatment (4 proven and 5 probable) and six as prophylaxis. The median trough plasma concentration in the curative and prophylactic arms was almost similar (3.19 mg/L [0.88; 5.00], and 2.94 mg/L [2.77; 3.29]). The difference in median duration of treatment between the two groups was 14 days (81 days [15; 276] and 95 days [15; 253]). The response was satisfactory in all cases at day 90 and no side effects were reported.[32]

The study underlines the safety of 100 mg ISA in children <30 kg. Close monitoring of plasma levels is recommended 10 days after initiation therapy and especially when co-administered with drugs metabolized through cytochrome CYP 3A4 and then every two weeks during the maintenance period. A cautious dose adjustments with 20% increases or decreases are also suggested. Well-planned randomised studies including larger cohorts with specific underlying conditions are required to establish dosing regimens and their efficacy and need for therapeutic drug monitoring (TDM).[32],[33],[34]


  Data on Safety Top


The most frequent side effects reported include gastrointestinal symptoms such as nausea, vomiting and diarrhoea similar to those with VORI. Patients can rarely present with skin rash, eye disorders such as visual hallucinations and peripheral neuropathy. Hepatobiliary disorders are lower compared to VORI (please reframe this sentence – done). ISA shortens QT interval contrary to other triazoles, in a dose related manner. Although no cardiology associated risk is identified, it may be contraindicated in patients with short QT syndrome or must be used with caution when combined with other QT-shortening drugs. However, patients with other triazole-induced QT prolongation could benefit by switching to ISA. Compared to liposomal AmphoB, ISA is found to be well tolerated in patients requiring treatment even beyond six months. The adverse events are low even with long-term therapy. Given this favourable safety profile of ISA, studies have shown switching to ISA resulted in improvement in the adverse events with prior azoles used.[1],[35],[36]


  Therapeutic Drug Monitoring Top


Clinical trials have not established the need for TDM. A study by Andes et al. established that TDM may not be necessary for ISA in most instances.[37] This study evaluated plasma concentrations of 283 samples from patients receiving ISA in clinical practice and compared the values with those from clinical trials. The concentration was nearly identical between the two groups with >1 μg/ml in 90% of patients. However, TDM is recommended in patients receiving ISA and displaying therapeutic failure, unexplained hepatotoxicity, noncompliance, obesity, those receiving concomitant medications that reduce ISA concentrations, age <18 years or those suffering from moderate hepatic failure. Currently, neither the European Conference on Infections in Leukaemia (ECIL-6) guidelines nor the Infectious Disease Society of America Guidelines (IDSA) for Aspergillosis recommend routine TDM for ISA.[1],[13],[37]


  Resistance Top


ISA resistance mechanisms could be similar to those contributing to Fluconazole (FLU) resistance in Candida. Repeated exposure to the drugs within the azole class could be a contributing factor. The postulated mechanisms include overexpression of efflux pumps through the ATP-binding cassette (ABC) transporter overexpression, mutations in genes coding the target enzyme (ERG11) which reduces azole binding and mutations in ERG3 gene resulting in the inability of azoles to disrupt the cell membrane. Multiple mechanisms of resistance can be present in a single Candida strain and can lead to cross-resistance among the triazoles. The ISA MICs for C. albicans are greatly affected in the presence of ABC transporters, CDr1 and CgCDR1. The major facilitator superfamily (MFS) transporters MDR1 or FLU1 do not affect ISA MICs. Cyp51A gene alterations leading to changes in the enzyme targeted by azoles are the most well-described azole resistance mechanism in Aspergillus species. Other potential mechanisms could be efflux pumps and mutations in the promoter region of Cyp51A. Cross-resistance to ISA in Aspergillus isolates with Cyp51A mutations confers resistance to other azoles, such as VORI. Cyp51A L98H/TR34 was the most common alteration observed among the azole non-wild type Aspergillus fumigatus isolates. Since Mucorales exhibit varying degrees of sensitivity to ISA, species identification and MIC testing are recommended before initiation of therapy.[1],[38]


  Current Recommendations Top


The current European Society of Clinical Microbiology and Infectious Diseases/European Confederation of Medical Mycology and ECIL-6 guidelines recommend ISA or VORI as the first-line treatment for IA in haematologic malignancy patients, but VORI is still the first-line treatment according to the IDSA guidelines. ISA as first-line therapy or after the failure to other azoles and non-azole prophylaxis or therapies has shown promising clinical response and a good safety profile, especially patients with haematologic malignancies.[1],[13],[35]


  Cost Effectiveness Top


Using economic modelling, cost-effectiveness studies have been carried out in the US, UK, Sweden, Spain and Canada.[35],[39],[40],[41] They have found ISA to be cost-saving when compared to VORI in the treatment of IA. The cost-savings included the cost of the drug, the cost of adverse events including mortality, hospitalisations, readmissions and loss of productivity. The study from Canada concluded ISA as a cost-effective strategy for the treatment of patients with suspected IPA, regardless of their life expectancy.[35],[39],[40],[41]


  Summary Top


ISA the new triazole has the advantages of ease of administration, convenient dosing regimen, good safety and efficacy profile, requirement for TDM only in special situations. It has been in use since 2015 for treatment of both IA and mucormycosis. Its utility for the management of IA among adults with haematologic malignancies is established. However, data on its use in children are still inadequate. It has the potential for use as prophylaxis and in therapy as salvage and in combination.

In the Indian setting, it could be especially helpful in the management of mucormycosis as patients very often present with impaired renal functions secondary to diabetes the primary predisposing condition. Liposomal AmphoB may be prohibitively expensive and conventional AmphoB may be contraindicated in many of them. ISA will benefit such patients.

Interestingly, there are the reports of repurposing of ISA for infectious and non-infectious conditions because of its additional dynamics. It is found to be amoebicidal against acanthamoeba[42] antiviral against Lassa virus[43] and activity on potential Parkinson's disease targets.[44]

The current evidence for ISA as a recommended antifungal is promising. However, only studies in the future will establish its role unlike other antifungal agents in the treatment of non-fungal infections and non-infectious conditions.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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Abstract
Introduction
Structure and Me...
Pharmacokinetics
Pharmacodynamics
Drug – Dru...
Clinical Use
Use in Children
Data on Safety
Therapeutic Drug...
Resistance
Current Recommen...
Cost Effectiveness
Summary
Structure and Me...
References

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