A Retrospective Study of Invasive Fungal Disease Treated by High Dosage Micafungin Therapy VS Standard Micafungin Therapy Among Patients with Hematologic Diseases.

Background: The standard (150mg/day) micafungin treatment regimen, is an effective and well tolerated empirical therapy for invasive fungal disease (IFD) among hematologic patients; however, experience with high dosage (200-300mg/day) micafungin treatment is limited. We retrospectively evaluated both safety and effectiveness of micafungin as an empirical antifungal therapy via standard and high dosage treatments for IFD. Methods: Patients were considered to be qualied for this analysis if they were proven, probable, or possible diagnosed as IFD. Patients without any previous exposure to an echinocandin were included; for those who changed treatment dosages and had previously received another systemic therapy except uconazole for prevention were excluded. Safety and effectiveness were evaluated in all participated patients. IFD was diagnosed and classied according to standards dened by both 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 Consensus Group. Results: Totally 72 hematologic patients participated this study. 45 patients were received a standard (150mg/day)micafungin treatment, and 27 patients were received a high dosage (200-300mg/day)micafungin treatment. Neutropenia status were similar between two groups (37.78% and 33.33%), so were other underlying risk factors. The mean duration of therapy were 15.27 days (Range: 7-47 days) in standard micafungin group, and 14.96 days (Range: 7-51 days) in high dosagemicafungin group. Drug related adverse events (AEs) occurred in 11.11% of patients received the standard regimen, and 14.81% of patients received the high dosage regimen (difference, 3.70%; 95% condence interval [CI], -5.75% to 10.89%; statistically insignicant). The most common drug related AEs in the standard and high dosage treatment groups were liver dysfunction. Only 1 patient discontinued standard micafungin treatment, because liver function test value is 5 times greater than the upper limit of normal value. 86.67% of patients from standard treatment group, and

Results: Totally 72 hematologic patients participated this study. 45 patients were received a standard (150mg/day)micafungin treatment, and 27 patients were received a high dosage (200-300mg/day)micafungin treatment. Neutropenia status were similar between two groups (37.78% and 33.33%), so were other underlying risk factors. The mean duration of therapy were 15.27 days (Range: 7-47 days) in standard micafungin group, and 14.96 days (Range: 7-51 days) in high dosagemicafungin group. Drug related adverse events (AEs) occurred in 11.11% of patients received the standard regimen, and 14.81% of patients received the high dosage regimen (difference, 3.70%; 95% con dence interval [CI], -5.75% to 10.89%; statistically insigni cant). The most common drug related AEs in the standard and high dosage treatment groups were liver dysfunction. Only 1 patient discontinued standard micafungin treatment, because liver function test value is 5 times greater than the upper limit of normal value. 86.67% of patients from standard treatment group, and 88.89% of patients from high dosage treatment group had favorable overall responses (difference, 2.22%; 95% CI, -4.94% to 8.64%; statistically insigni cant).
Conclusion: Both micafungin dosing treatments were effective, and well tolerated among hematologic patients with invasive fungal infection. Therefore, there hasn't arisen any safety concern of high dosage(200-300mg/day) micafungin treatment.

Background
Invasive fungal disease (IFD), such as Candida and Aspergillus species, has caused signi cant morbidity and mortality among hematologic patients in the recent years [1,2]. Empirical antifungal treatments are used to reduce its consequences. Micafungin is an echinocandin antifungal agent with potent activity against most species of Candida and Aspergillus [3,4]. Prior studies had demonstrated that micafungin at a dosage of 100mg/day was as effective as liposomal amphotericin B [5] and voriconazole[6], and superior toitraconazole [7] for the treatment of invasive candidiasis. For persistent febrile neutropenia, micafungin as an empirical antifungal therapy did not appear to differ signi cantly from caspofungin, in terms of safety pro le and e cacy among adult patients [8]. Micafungin at a dosage of 150mg/day has been effective and well tolerated as an empirical therapy among hematologic patients with IFD [4].
Although some studies show that micafungin dosages exceeding 150mg/day are safe and well tolerated [9], the e cacy and safety of micafungin at higher dosage have not been fully investigated. Therefore, a retrospective study, mainly focused on the comparison of standard (150mg/day) with high dosage (200-300mg/day) treatment in hematologic patients with IFD, had been conducted from January 2013 until December 2017 in Shengjing Hospital of China Medical University, in order to evaluate the safety, tolerability, and e cacy of micafungin among hematologic patients with IFD.

Patient selection
For hematologic patients above age of 14, who also received micafungin therapy were considered as eligible candidates. The decisive factors for patients to be eventually included for this analysis were: they were proven, probable, or possible diagnosed as IFD. Proven IFD is de ned as demonstration of fungal elements in infected tissue for most conditions irrespective of host factors or clinical features. Probable IFD requires a host factor, clinical features, and mycological evidence. Possible IFD includes cases with appropriate host factors and su cient clinical evidence but no mycological support [10]. Patients without previous exposure to an echinocandin were included. Those who had changed treatment dosages, or previously received other systemic antifungal therapies for IFD (except uconazole for prevention) were Safety and e cacy evaluation Medical records of all participated patients were reviewed from both clinical and microbiologic perspectives. Micafungin dosages, length of therapy, and drug-related AEs were also documented.
Baseline IFD was de ned as a case diagnosed within 2 days of echinocandin initiation; breakthrough IFD occurred more than 3 days after initiation of treatment.
Patients were closely monitored on daily basis for potential AEs during micafungin therapy. All the drug related AEs which could potentially led to discontinuation of micafungin treatment, such as vital signs, blood routine, liver function and renal function, were documented and monitored for safety purposes. E cacy analyses were conducted for following cases: treatment of any baseline IFD successfully treated by micafungin therapy, absence of any breakthrough IFD during/within 7 days after completion of therapy, and discontinuation of therapy due to drug-related AEs.

Statistical methods
The primary hypothesis was that the high dosage micafungin treatment would be non-inferior to the standard treatment with respect to the development of signi cant drug-related AEs and e cacy. Noninferiority was de ned by such that the upper limit of the 2-sided 95% con dence interval (CI) for the treatment group difference, in term of percentage of patients with signi cant drug-related AEs or e cacy must be less than 15%.

Baseline characteristics
Among total of 72 quali ed hematologic patients participated this study, 45 patients were in the standard (150mg/day) treatment group, and 27 patients in the high dosage (200-300mg/day) treatment group.
The two treatment groups were similar at study entry (Table 1). Such as, median age was 47 and 48 years old in the standard and high dosage micafungin treatment group; 28 out of 45 (62.22%) and 17 out of 27 (62.96%) patients in each group were males. Furthermore, the disease (leukemia) were same for both groups, neutropenia status were similar (37.78% and 33.33%), and the main underlying risk factors were same between these two groups.

Safety and tolerability
Severe drug-related AEs were reported in 2 out of 45 patients (4.44%) in the standard (150mg/day) treatment group, and 1 out of 27 patients (3.70%) in the high dosage (200-300mg/day) treatment group.
The observed difference between the treatment groups was − 0.74%, with a 95% CI of -4.78-4.12%, which ful lled the prede ned criterion for non-inferiority. The incidences of discontinuations of micafungin therapy because of drug-related clinical AEs (2.22% VS 0%) were similar between the standard (150mg/day) and high dosage (200-300mg/day) treatment groups. The most common drug-related laboratory AEs in both treatment groups were increased alanine aminotransferase (ALT), and aspartate aminotransferase (AST). None of the drug-related laboratory events were serious or led to discontinuation of micafungin treatment. The overall rates of clinical and laboratory AEs, regardless of causality, were also similar (11.11% VS 14.81%) between the standard and high dosage treatment groups (difference, 3.70%; 95% CI, -5.75-10.89%), respectively ( Table 2). Furthermore, there were no differences in terms of parameters such as blood pressure, pulse rate, body weight, routine blood count, and renal function before and after micafungin therapy, in both standard (150mg/day) and high dosages (200-300mg/day) treatments, respectively (Table 3).  showed that 159 patients who received allogeneic hematopoietic stem cell transplantation,also received 50mg/day of micafungin to prevent fungal infection, with an effective rate of 94.9% [17]. Another retrospective study showed that the application of micafungin in the prevention of fungal infection, in patients with hematological diseases receiving chemotherapy or immunosuppressive therapy, also has good e cacy and safety [18].At present, theindications of micafunginusage have been expanded to include candidemia, acute disseminated candidiasis, Candida abscesses, and peritonitis. Similar to other echinocandins, it is fungicidal against Candida species, including those that are polyene and azole resistant and fungistatic against Aspergillus species [3].
Prior studies had demonstrated that micafungin at standard dosage (150mg/day) in adults was effective, and well tolerated as an empirical therapy for IFD patients with hematologic diseases [4]. The dosage can be increased up to 300mg/day in the case of severe fungal infections;however, the e cacy and safety of micafungin at high dosage have not been fully investigated. Therefore, we compared the standard (150mg/day) micafungin treatment with high dosage (200-300mg/day) treatment among hematologic patients with IFD.
In our study, the baseline characteristics of standard and high dosage micafungin treatment groups were comparable. The status of safety and tolerability were similar between two groups, as well as the number of AEs occurrences. Severe AEs and discontinuation of therapy due to AEs were rare cases. It suggested that the high dosage micafungin therapy was a safe and well tolerated treatment for hematologic patients. These ndings were consistent with the results from the previous studies that also led to the safety pro le of high dosage micafungin [9]. Furthermore, the e cacy of two treatment groups were also similar, the standard treatment group was not inferior to the high dosage treatment group. This conclusion should be noticeable. Several studies have indicated that the standard dosage is su cient to treat Candida infections [5,19]; however, a pharmacokinetic pharmacodynamic analysis showed that a 200-300mg daily dosage micafungin treatment for Aspergillus infections is associated with favorable outcomes [20]. In our study, only 3 out of 45 patients (6.67%) in standard treatment group were diagnosed as candidiasis, and 1 out of 27 (3.70%) patient in high dosage treatment group was diagnosed as Aspergillus. Most patients from both treatment groups weren't able to be diagnosed (55.56% for standard group, and 44.44% for high dosage group). There wasn't any mycological evidence shown the type of IFD. Standard micafungin therapy is likely suitable as an empirical treatment for IFD, especially  G and GM Test of 150mg/d and 200-300mg/d Treatments