Real-World Use of Isavuconazole as Primary Therapy for Invasive Fungal Infections in High-Risk Patients with Hematologic Malignancy or Stem Cell Transplant

  • Post category:Drug Updates
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Introduction

Despite advancements in antifungal therapy over the last two decades, invasive fungal infections (IFIs) continue to be a major cause of morbidity and mortality among immunocompromised patients, particularly if antifungal therapy is used inappropriately. The newer triazole water-soluble pro-drug isavuconazonium sulfate (isavuconazole) demonstrated promising results in both in vitro and animal studies. Since then, isavuconazole has been approved by the US Food and Drug Administration as a primary treatment for IA and mucormycosis mold infections.

The relatively recent approval of isavuconazole, combined with its safety and a broad spectrum of activity, has led to its increased and prolonged use, especially among hematologic malignancy patients at higher risk for mold infections, but only a few small studies have assessed its real world use among immunocompromised patients. The current European Society of Clinical Microbiology and Infectious Diseases/European Confederation of Medical Mycology and ECIL-6 guidelines recommend isavuconazole or voriconazole as the first-line treatment for IA in hematologic malignancy patients, but voriconazole is still the first-line treatment according to the Infectious Disease Society of America guidelines.

The aim of this study was to evaluate the real-world use of isavuconazole in a large number of high-risk patients with hematologic malignancies and stem cell transplants and to evaluate these patients’ clinical characteristics and outcomes, particularly in the setting of monotherapy versus combination therapy or if used after failure of other anti-mold prophylaxis as treatment versus as de novo treatment.

Materials and Methods

A retrospective study of HM patients at MD Anderson Cancer Center who had definite, probable or possible mold infections between 1 April 2016 and 31 January 2020 and were treated with who had definite, probable, or possible mold infections, according to a list of isavuconazole administration cases obtained from the pharmacy analytics database. Epidemiological and clinical data were collected using secure standardized forms and stored in our analytical file system. The patients were treated with Isavuconazole for a period of at least 7 days. Clinical and radiological findings were assessed at baseline and at 6 and 12 weeks of follow-up.

Result

First, we characterized the bactericidal activities of reagents HOBr and HOCl. A concentration of 4 µM reagent HOBr killed 72% of E. coli cells, while 4 µM reagent HOCl killed 99%. The bactericidal activities of MPO were dose dependent. A concentration of 1 nM MPO or rMPO in the MPO/H2O2/Cl− (100 mM) system was enough to kill all E. coli cells, while 5 nM MPO or rMPO in the MPO/H2O2/Br− (100 µM) system could kill all E. coli cells.

These results are consistent with the oxidant potentials of the respective halides (HOCl > HOBr). Additionally, we carried out a further P. aeruginosa killing experiment using rMPO. rMPO completely killed P. aeruginosa cells at 10 nM. We also carried out bactericidal activities for Gram-positive bacteria and drug-resistant bacteria. Similar to the results for Gram-negative bacteria, rMPO efficiently killed both S. aureus and MRSA at the nanomolar level (Fig. 1D). Thus, the data suggest that rMPO has powerful bactericidal activity.

Conclusions

Whether used as first-line therapy or after the failure of other azole and non-azole prophylaxis or therapies, isavuconazole seems to have a promising clinical response and a good safety profile as an antifungal therapy in high-risk cancer patients with hematologic malignancies. Moreover, combination therapy did not improve the outcome compared to Isavuconazole therapy.

Source:  Dagher, H.; Hachem, R.; Chaftari, A.-M.; Jiang, Y.; Ali, S.; Deeba, R.; Shah, S.; Raad, I. Real-World Use of Isavuconazole as Primary Therapy for Invasive Fungal Infections in High-Risk Patients with Hematologic Malignancy or Stem Cell Transplant. J. Fungi 2022, 8, 74. https://doi.org/10.3390/jof8010074