Journal of Gastrointestinal Surgery

https://doi.org/10.1007/s11605-019-04241-w

ORIGINAL ARTICLE

A Multicenter, Randomized, Open-Label Study to Compare

Micafungin with Fluconazole in the Prophylaxis of Invasive Fungal
Infections in Living-Donor Liver Transplant Recipients
Woo-Hyoung Kang 1 & Gi-Won Song 1 & Sung-Gyu Lee 1 & Kyung-Suk Suh 2 & Kwang-Woong Lee 2 & Nam-Joon Yi 2 &
Jae Won Joh 3 & Choon Hyuck David Kwon 4 & Jong Man Kim 3 & Dong Lak Choi 5 & Joo Dong Kim 5 & Myoung Soo Kim 6

Received: 28 December 2018 / Accepted: 21 April 2019

# 2019 The Society for Surgery of the Alimentary Tract

Abstract
Background Although invasive fungal infections (IFIs) contribute to substantial morbidity and mortality in liver transplant
recipients, only a few randomized studies analyzed the results of antifungal prophylaxis with echinocandins. The aim of this
open-label, non-inferiority study was to evaluate the efficacy and safety of micafungin in the prophylaxis of IFIs in living-donor
liver transplantation recipients (LDLTRs), with fluconazole as the comparator.
Methods LDLTRs (N = 172) from five centers were randomized 1:1 to receive intravenous micafungin 100 mg/day or flucon-
azole 100~200 mg/day (intravenous or oral). A non-inferiority of micafungin was tested against fluconazole.
Results The per-protocol set included 144 patients without major clinical trial protocol violations: 69 from the micafungin group
and 75 from the fluconazole group. Mean age of the study patients was 54.2 years and mean model for end-stage liver disease
(MELD) score amounted to 16.5. Clinical success rates in the micafungin and fluconazole groups were 95.65% and 96.10%,
respectively (difference: − 0.45%; 90% confidence interval [CI]: − 6.93%, 5.59%), which demonstrated micafungin’s non-
inferiority (the lower bound for the 90% CI exceeded − 10%). The study groups did not differ significantly in terms of the
secondary efficacy endpoints: absence of IFIs at the end of the prophylaxis and the end of the study, time to proven IFI, fungal-
free survival, and adverse reactions. A total of 17 drug-related adverse events were observed in both groups; none of them was
serious and all resolved.
Conclusion Micafungin can be used as an alternative to fluconazole in the prevention of IFIs in LDLTRs.
Clinical Trials Registration NCT01974375.

Keywords Micafungin . Fluconazole . Prophylaxis of invasive fungal infection . Living donor liver transplantation

* Gi-Won Song Abbreviations

drsong71@amc.seoul.kr
ADR Adverse drug reaction
AE Adverse event
1
Division of Liver Transplantation and Hepatobiliary Surgery, CI Confidence interval
Department of Surgery, Asan Medical Center, College of Medicine,
University of Ulsan, Seoul, South Korea
CMH Cochran-Mantel-Haenszel
2
CMV Cytomegalovirus
Department of Surgery, College of Medicine, Seoul National
University, Seoul, South Korea
EBV Epstein–Barr virus
3
EOP End of the prophylaxis
Department of Surgery, Samsung Medical Center, School of
Medicine, Sungkyunkwan University, Seoul, South Korea
EORTC/MSG European Organization for Research and
4
Treatment of Cancer/Invasive Fungal
Department of Surgery and Digestive Disease Institute, Cleveland
Clinic, Cleveland Clinic Lerner College of Medicine, Cleveland, OH,
Infections Cooperative Group and the
USA National Institute of Allergy and Infectious
5
Department of Surgery, College of Medicine, Catholic University of
Diseases Mycoses Study Group
Daegu, Daegu, South Korea EOS End of the study
6
Department of Surgery, College of Medicine, Yonsei University,
FAS Full analysis set
Seoul, South Korea HBV Hepatitis B virus

HCV Hepatitis C virus
HIV Human immunodeficiency virus
IDSA Infectious Diseases Society of America
IFI Invasive fungal infection
LB Lower bound
LDLTRs Living-donor liver transplantation recipients
LTR Liver transplant recipients
MELD Model for end-stage liver disease
NC Not calculated
PPS Per protocol set
SAE Serious adverse event
SD Standard deviation
TEAE Treatment-emergent adverse event
Introduction
Invasive fungal infections (IFIs) occur in 7–42% of liver trans-
plant recipients (LTRs). The most common etiological factors
of IFIs are Candida spp. and Aspergillus spp.1 Despite prog-
ress in antifungal agent design and prophylactic strategy de-
velopment, IFIs are still associated with poor outcomes in
posttransplant patients, with mortality rates for invasive can-
didiasis and invasive aspergillosis amounting to 30–50% and
65–90%, respectively.2, 3
An optimal antifungal prophylactic strategy for LTRs is yet
to be established.4 After weighing potential clinical benefits
against relative costs and toxicity risk, most centers do not
routinely implement antifungal prophylaxis in LTRs other
than those at high risk of IFIs.1, 5 Risk factors for IFIs include
retransplantation, renal impairment requiring dialysis, preop-
erative colonization with Candida spp., preoperative antibiot-
ic therapy lasting more than 10 days, excessive intraoperative
b l o o d l o s s , p r o l o n g e d d u r a t i o n o f s u rg e r y, a n d
choledochojejunostomy anastomosis.1, 4–9 Fluconazole and
amphotericin B, both recommended by the Infectious
Diseases Society of America (IDSA) for the prevention of
candidiasis, are commonly used in the prophylaxis of IFIs in
LTRs.10
Echinocandins are known to be safer, more effective, and
to produce fewer drug-drug interactions than other classes of
antifungals used for IFI treatment in LTRs.11–14 Micafungin is
an echinocandin antifungal agent with activity against
Candida spp. and Aspergillus spp.15–17 Given their broader
antimicrobial spectrum than that of fluconazole, lower toxic-
ity, and lesser occurrence of drug-drug interactions in humans,
echinocandins might constitute an attractive alternative in the
primary prophylaxis of IFIs in LTRs.4, 18, 19 However, pub-
lished evidence regarding the safety and efficacy of
micafungin in IFI prevention is still sparse. To the best our
knowledge, no published randomized clinical trial analyzed
the results of micafungin prophylaxis in living-donor LTRs
(LDLTRs).
J Gastrointest Surg
The aim of KOPIN (KOrean Prevention of INvasive
Fungal Disease in Liver Transplant Recipients) study was to
assess the efficacy and safety of micafungin in the prophylaxis
of IFIs in LDLTRs, with fluconazole, as the comparator.
Materials and Methods
Patients and Study Design
This was a multicenter, randomized, open-label study to com-
pare micafungin and fluconazole as prophylactic antifungal
agents in LDLTRs (ClinicalTrials.gov identifier:
NCT01974375). The patients were eligible for the study if
they were primary LDLTRs with ≥ 20 years of age, and in
the case of fertile women, had the negative result of
pregnancy test at the time of enrollment and consented to
use contraception. The patients were not enrolled if they
received systemic antifungal therapy within 14 days before
randomization, had a proven or probable IFI, had a history
of adverse events (AEs) with echinocandins, and received
retransplant or deceased-donor whole liver transplant.
Eligible patients were randomized 1:1 to either the
micafungin group or the fluconazole group within 48 h of
satisfying the criteria or within 48 h after receiving a living-
donor liver transplant, whichever occurred later. Antifungal
prophylaxis was started within 24 h post-randomization and
was continued for 21 days or until hospital discharge, which-
ever occurred first. All patients randomized to the micafungin
group received intravenous micafungin at a dose of 100 mg/
day, whereas those randomized to the fluconazole group were
given 100~200 mg of intravenous or oral fluconazole at a
single daily dose of 100~200 mg. The duration of the antifun-
gal prophylaxis could be extended over 21 days if, in the
clinician’s opinion, the patient presented with persistent risk
factors for IFI. Hence, some patients received the antifungal
prophylaxis for 35 days (micafungin) or even up to 49 days
(fluconazole). Mean duration of the antifungal prophylaxis in
the micafungin and fluconazole group was 20 and 21 days,
respectively. In recipients who developed a proven or proba-
ble IFI while receiving study medication, the treatment was
discontinued and replaced with an appropriate antifungal ther-
apy; however, the patients remained in the study to complete
all assessments.
The patients were tested for IFI at randomization, during
the prophylaxis period, at the end of the prophylaxis (EOP, the
last dosing day of the study medication), at the end of the
study (EOS, 3 months post-randomization) and at the end of
the long-term follow-up (6 months post-randomization)
(Fig. 1). During the prophylaxis period, IFI status was verified
at least once a week, or more often if clinically justified. The
baseline results of radiographic studies, bronchoscopy, blood
culture or aseptic biospecimen culture, surveillance culture of
J Gastrointest Surg
Fig. 1 Study flow chart
urine, microbiological examination of pharyngolaryngeal or
bronchial aspirate, bronchoalveolar lavage fluid (if necessary),
abdominal drainage or rectal swabs, deep-seated organ biopsy,
histology, and clinical signs or symptoms were documented.
A proven or probable IFI was diagnosed according to 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) criteria.20
Outcomes
Efficacy
The primary efficacy endpoint was clinical success defined as
the lack of a proven or probable IFI, defined according to the
EORTC/MSG criteria,20 and no additional antifungal therapy
including an increase in the study medication dosage till the
EOP. The secondary efficacy endpoints included the absence
of IFI at the EOP and EOS, time to a proven or probable IFI,
fungal-free survival at the EOS and the end of the long-term
follow-up, and change in the incidence of superficial IFI and
colonization from baseline to the EOP. Additional analyses
included determination of survival status at the EOS and at
the end of the long-term follow-up, as well as the time to
death.
Safety
AEs were coded according to the Medical Dictionary for
Regulatory Activities (MedDRA®, Version 18.0) and sum-
marized by preferred term and system organ class. The per-
centages of patients with AEs in both groups were determined
with 95% confidence intervals (CIs). All AEs were catego-
rized by their severity; AEs related to study medication (ad-
verse drug reactions, ADRs) and serious AEs (SAEs) were
recorded separately. The occurrence of AEs was recorded
since the moment the patient signed the informed consent until
the end of the study. AEs occurring after initiating a study
medication were presented as treatment-emergent adverse
events (TEAEs). Vital sign assessments and physical exami-
nations were performed at each visit; any abnormal findings
were assessed for clinical significance and potential causal
relationship with study medication. During the prophylaxis
period, hematologic and biochemical tests and urinalysis were
performed at least once a week or more often if clinically
justified.
Statistical Analysis
The efficacy was analyzed in both the full analysis set (FAS),
which included all patients who received at least one dose of
study medication after randomization, and the per-protocol set
(PPS), which consisted of a subset of FAS patients who were
assessed for clinical success at the EOP. While the primary
and secondary efficacy endpoints were analyzed for both the
FAS and PPS, the ultimate conclusion regarding the study
medication efficacy was based on the PPS analysis.
For the primary endpoint, two-sided 90% CI for the differ-
ence in the clinical success rate was calculated using the
Newcombe-Wilson method without continuity correction. If
the lower bound of the two-sided 90% CI was greater than −
10%, the non-inferiority of micafungin to the comparator
would be demonstrated. The significance of differences in
the secondary endpoints for the study groups was verified
with the Cochran-Mantel-Haenszel (CMH) test. For time-to-

event variables, Kaplan-Meier curves were presented and
compared with the stratified log-rank test. The significance
of intergroup differences in statistical characteristics of quan-
titative variables was verified with t test or Wilcoxon rank sum
test, whereas the distributions of discrete variables were com-
pared with the Chi-square test or Fisher’s exact test. Unless
specified otherwise, two-sided tests were carried out at a sig-
nificance level of 95%. All statistical analyses were done with
SAS package (SAS Institute Inc., Cary, NC, United States).
This manuscript was prepared in accordance with the
CONSORT (Consolidated Standards for Reporting Trials)
statement for reporting randomized controlled trials.21
Results
Patients
Between August 2012 and August 2015, 175 patients who
underwent LDLT at five centers in South Korea consented to
participate in this study. Three patients who did not satisfy the
screening criteria were excluded from the study, and hence,
172 patients were eventually randomized (86 per group).
Among those, 144 completed the study (69 from the
micafungin group and 75 from the fluconazole group), and
28 were withdrawn prematurely. The reasons for the with-
drawal were ‘protocol violation’ (n = 8), ‘withdrawal of con-
sent’ (n = 6), ‘adverse effect’ (n = 5), ‘lack of efficacy’ (n = 5),
Fig. 2 Disposition of patients
J Gastrointest Surg
‘violation of the exclusion criteria’ (n = 3), and ‘long-term
follow-up failure’ (n = 1) (Fig. 2).
Demographic and clinical characteristics of patients
from both groups are presented in Table 1. Mean age ±
standard deviation (SD) of the study patients was 54.2 ±
7.95 years. The study included 131 men (76.2%) and 41
women (23.8%), with mean body mass index (BMI) of
23.5 ± 3.47 kg/m2 and mean model for end-stage liver dis-
ease (MELD) score of 16.5 ± 5.28 points. A total of 101
patients (58.7%) tested positively for hepatitis B virus
(HBV), 20 (11.6%) for hepatitis C virus (HCV), 169
(98.3%) for cytomegalovirus (CMV), and 158 (91.9%)
for Epstein–Barr virus (EBV). None of the patients tested
positively for human immunodeficiency virus (HIV).
Mean age of the donors was 29.5 ± 9.67 years; the numbers
of male and female donors were 126 (73.3%) and 46
(26.7%), respectively. More than 90% of the donors were
the recipients’ offspring. No statistically significant inter-
group differences were found in the demographic charac-
teristics of the recipients and donors.
Efficacy
Primary Efficacy Endpoint
Micafungin was non-inferior to fluconazole when clinical
success rates were assessed with the PPS as the primary
analysis set (Table 2). Clinical success rates at the EOP
were 95.65% (66/69) and 96.10% (74/77) for the
J Gastrointest Surg

Table 1 Demographic and baseline characteristics (full analysis set)

Demographics Micafungin Fluconazole Total

(N = 86) (N = 86) (N = 172)

Mean ± SD age, year 54.0 ± 7.66 54.4 ± 8.28 54.2 ± 7.95

Male sex, n (%) 66 (76.7) 65 (75.6) 131(76.2)
Mean ± SD BMI, kg/m2 23.9 ± 3.45 23.1 ± 3.48 23.5 ± 3.47
Mean ± SD MELD score 16.2 ± 5.46 16.8 ± 5.11 16.5 ± 5.28
Pregnancy test, n (%)
Negative/positive 2/0 (100/0) 5/0 (100/0) 7/0 (100/0)
HIV, n (%)
Negative/positive 0/0 (0/0) 0/0 (0/0) 0/0(0/0)
HBV [HBsAg], n (%)
Negative/positive 38/48 (44.2/55.8) 33/53 (38.4/61.6) 71/101 (41.3/58.7)
HCV [anti-HCV-IgG], n (%)
Negative/positive 78/8 (90.7/9.3) 74/12 (86.1/13.9) 152/20 (88.4/11.6)
CMV [anti-CMV-IgG], n (%)
Negative/positive/not done 0/85/1 (0/98.8/1.2) 2/84/0 (2.3/97.7/0) 2/169/1 (1.2/98.3/0.6)
EBV [anti-EBV-IgG], n (%)
Negative/positive/not done 4/80/1 (4.7/93.0/1.2) 6/78/1 (7.0/90.7/1.2) 10/158/2 (5.8/91.9/1.2)

micafungin and fluconazole group, respectively (differ-
ence: − 0.45%; 90% confidence interval [CI]: − 6.93%,
5.59%). The lower bound for the 90% CI determined with
the Newcombe-Wilson method (− 6.93%) was greater than
the non-inferiority margin (− 10%), thereby demonstrating
non-inferiority of micafungin to fluconazole. After exclud-
ing prematurely withdrawn patients from FAS analysis, the
inter-group difference was − 0.40%, with the lower bound
for the 90% CI of − 7.37%; this result also corresponded to
micafungin’s non-inferiority to fluconazole. However,
when the prematurely withdrawn patients were considered
as treatment failures, the lower bound for the 90% CI was
− 14.50% (intergroup difference of − 5.81%), which did
not confirm the non-inferiority of micafungin to
fluconazole.
Secondary Efficacy Endpoints in the Per-Protocol Set
The micafungin group did not differ significantly from the
fluconazole group in terms of the proportion of patients who
lacked a proven or probable IFI at the EOP and EOS. At the
EOP, the absence of a proven or probable IFI was confirmed in
68 out of 69 patients (98.55%) from the micafungin group and
in all 77 patients (100%) from the fluconazole group (CMH
test, P = 0.30), and at the EOS, in 68 out of 69 patients
(98.55%) from the micafungin group, and in 76 out of 77
patients (98.70%) from the fluconazole group (CMH test,
P = 0.97). The study groups did not differ significantly in
terms of the time to a proven or probable IFI, as well as in
terms of fungal-free survival at the EOS and the end of the
long-term follow-up. While a statistically significant

Table 2 Clinical success rate for micafungin and fluconazole at the end of the prophylaxis period (per-protocol sets)

Per-protocol set Micafungin, n (%) Fluconazole, n (%) Difference, % (90% CI)

(N = 69) (N = 77) Fluconazole–micafungin

Clinical success rate, n (%)

Response 66 (95.65) 74 (96.10) − 0.45 (− 6.93, 5.59)
Non-response 3 (4.35) 3 (3.90)
Invasive fungal infection 1 (1.45) 0 (0.00)
Antifungal treatment 3 (4.35) 1 (1.30)
Increase of dose of clinical drug 0 (0.00) 2 (2.60)
Difference at the end of prophylaxis period
Difference rate (90% CI) − 0.45 (− 6.93, 5.59)
Non-inferior: LB > − 10% yes

CI confidence interval, LB lower bound

 J Gastrointest Surg

Table 3 Summary of secondary efficacy endpoints (per-protocol sets)

Micafungin (N = 69) Fluconazole (N = 77) P value

Invasive fungal infection At EOP, yes/no, n (%) 1/68 (1.45/98.55) 0/77 (0/100) 0.2980a
At EOS, yes/no, n (%) 1/68 (1.45/98.55) 1/76 (1.3/98.7) 0.9668a
Time to Invasive fungal result (week) Number of subjects with an event 3 (4.35) 2 (2.60)
Time to invasive fungal infection, median (week) NC NC 0.5536b
Fungal-free survival (week) Fungal infection, n (%)
EOS 3 (4.35) 2 (2.60) 0.2610b
End of follow-up 3 (4.35) 2 (2.60) 0.5536b
Percentage of participants with Baseline 1 (1.45) 0 (0.00) 0.3173a
superficial fungal infections, n (%) Prophylaxis period 2 (2.90) 4 (5.19) 0.4015a
EOP 0 (0.00) 1 (1.30) 0.3173a
EOS 1 (1.45) 0 (0.00) 0.2888a
Long term follow-up 3 (4.35) 0 (0.00) 0.0458a
Percentage of participants with Baseline 0 (0.00) 0 (0.00) NC
fungal colonization, n (%) Prophylaxis period 1 (1.45) 0 (0.00) 0.2980a
EOP 0 (0.00) 0 (0.00) NC
EOS 1 (1.45) 0 (0.00) 0.2888a
Long term follow-up 3 (4.35) 0 (0.00) 0.0458a

EOP the end of prophylaxis period, EOS the end of study, NC not calculated
a
P value from Cochran-Mantel-Haenszel test with treatment group as a factor and site as a covariate
b
P value from stratified log rank test with treatment group as a factor and site as strata

intergroup difference was found in the incidence of superficial
fungal infections (P = 0.046), it turned out to be clinically
irrelevant, as shown by the application of non-response impu-
tation to the micafungin group findings (three non-responders)
(Table 3).
Safety
Treatment-emergent adverse events (TEAEs) were identified
in 172 patients who received at least one dose of study med-
ication (85 patients from the micafungin group and 87 from
the fluconazole group). This group included 143 patients who
experienced a total of 925 AEs, among them 70 patients
(82.35%) from the micafungin group (a total of 404 AEs)
and 73 patients (83.91%) from the fluconazole group (a total
of 521 AEs). The inter-group difference in the incidence of
TEAEs was statistically insignificant (P = 0.79). Table 4
shows the TEAEs reported in > 10% of patients from either
treatment group. Among these, there were 26 ADRs related to
the study medications (in 16 patients [9.30%]): 17 ADRs in 9
patients (10.59%) from the micafungin group and 9 ADRs in
7 patients (8.05%) from the fluconazole group. A total of 15
ADRs (57.69%) were classified as mild, 9 (34.62%) as mod-
erate, and 2 (7.69%) as severe. All ADRs have resolved

Table 4 Treatment-emergent adverse events in > 10% patients in the micafungin or fluconazole prophylaxis care group (safety analysis set)

TEAEs Micafungin Fluconazole

(N = 85 (%)) [number of events] (N = 87 (%)) [number of events]

Hyperglycemia 24 (28.24) [25] 26 (29.89) [26]

Hyperkalemia 15 (17.65) [16] 16 (18.39) [18]
Insomnia 25 (29.41) [29] 31 (35.63) [33]
Delirium 9 (10.59) [10] 13 (14.94) [13]
Constipation 8 (9.41) [8] 12 (13.79) [12]
Diarrhea 9 (10.59) [9] 8 (9.20) [9]
Nausea 5 (5.88) [5] 10 (11.49) [12]
Pyrexia 16 (18.82) [17] 11 (12.64) [13]
Pleural effusion 9 (10.59) [9] 11 (12.64) [12]

TEAEs treatment-emergent adverse events

J Gastrointest Surg

Table 5 Incidence of adverse drug reactions (safety set) set, the primary efficacy endpoint, clinical success at the EOP,
System organ class preferred term Micafungin Fluconazole Total was reached by 95.65% and 96.10% of patients from the
(n = 85) (n = 87) (n = 172) micafungin and fluconazole groups, respectively. This
corresponded to a − 0.45% inter-group difference, confirming
Hepatic enzyme increased, n (%) 2 (2.35) 2(2.30) 4 that micafungin was non-inferior to fluconazole. In a previous
Aspergillus test, n (%) 1 (1.18) 1(1.15) 2 study,22 clinical success rate for fluconazole prophylaxis in
Hypokalemia, n (%) 1 (1.18) 1(1.15) 2 LTRs was approximately 92%, and hence, resembled the suc-
Hypertension, n (%) 1 (1.18) 1(1.15) 2 cess rates in both groups of patients participating in our pres-
Hyperkalemia, n (%) 2 (2.35) 0 (0.00) 2 ent study.
Diarrhea, n (%) 2 (2.35) 0 (0.00) 2 Conventional prophylactic regimens for IFI in LTRs are
Decreased appetite, n (%) 1 (1.18) 0 (0.00) 1 based on fluconazole and amphotericin B in various formula-
Hypernatremia, n (%) 1 (1.18) 0 (0.00) 1 tions; these drugs are also recommended by the IDSA in their
Hypophagia, n (%) 1 (1.18) 0 (0.00) 1 guidelines on the management of candidiasis.10 While flucon-
Lower abdominal pain, n (%) 1 (1.18) 0 (0.00) 1 azole is widely used in both general and targeted prophylaxis
Esophageal candidiasis, n (%) 1 (1.18) 0 (0.00) 1 of invasive candidiasis, the emergence of fluconazole-
Pyrexia, n (%) 1 (1.18) 0 (0.00) 1 resistant strains of some fungal species, such as Candida
Insomnia, n (%) 1 (1.18) 0 (0.00) 1 krusei and Candida glabrata, raises growing concerns.23, 24
Urticaria, n (%) 1 (1.18) 0 (0.00) 1 Furthermore, azoles are known to interact with the metabo-
Constipation, n (%) 0 (0.00) 1(1.15) 1 lism of some immunosuppressants that are commonly pre-
Candida infection, n (%) 0 (0.00) 1(1.15) 1 scribed to post-transplant patients, such as cyclosporine, tacro-
Headache, n (%) 0 (0.00) 1(1.15) 1 limus, and sirolimus.25 While amphotericin B has been widely
Syncope, n (%) 0 (0.00) 1(1.15) 1 used because of its broad spectrum of antifungal activity, now-
Total ADRs 17 9 26 * adays its application is limited due to renal toxicity concerns.7
The lipid formulation of amphotericin B has a better safety
ADRs adverse drug reactions profile than conventional amphotericin B, with lesser renal
*P = 0.5660 toxicity; therefore, it is used increasingly, especially in patients
who showed poor tolerance to conventional amphotericin B or
eventually. The intergroup difference in the number of patients presented with underlying renal impairment.26 Nevertheless,
with ADRs was not statistically significant (P = 0.57). Table 5 existing concerns with regard to the use of polyenes and
shows specific symptoms and incidences thereof. A total of 73 azoles in the prevention of IFIs in LTRs, including those men-
SAEs were reported in 48 patients (27.91%): 32 SAEs in 24 tioned above, justify development of novel antifungal thera-
(28.24%) patients from the micafungin group and 41 SAEs in pies, safer and more effective in opportunistic infections
24 (27.59%) patients from the fluconazole group. None of the caused by Candida spp.
AEs resulted in death. The inter-group difference in the inci- Echinocandins, such as micafungin, caspofungin, and
dence of SAEs was not statistically significant (P = 0.92). No anidulafungin, relatively new agents targeting fungal cell wall,
serious adverse drug reactions (SADRs) were documented. are increasingly used in clinical practice. As echinocandins do
One patient from the fluconazole group died due to mas- not interact with the P450 cytochrome or P-glycoprotein
sive bleeding after liver retransplant surgery performed after systems,27, 28 they are more effective and produce less drug-
discontinuation of the study medication; the death was con- drug interactions than other agents used for IFI prevention in
sidered to be unrelated to the study medication. While some LTRs.11–14 There are a few reasons for which micafungin
clinically relevant abnormalities in the results of laboratory deserves particular attention among other echinocandins.
tests and physical examination were reported as AEs, most First, the efficacy and safety of this agent in a prophylactic
of them were mild to moderate AEs classified as unrelated setting have already been verified empirically. Second, unlike
to the study medication. No notable observations were report- caspofungin, micafungin does not seem to interact with tacro-
ed with regard to the vital signs. limus and cyclosporine. Third, contrary to anidulafungin
which needs to be dissolved in 20% ethanol which is poten-
tially hazardous to LTRs, micafungin is soluble in water.4, 18,
19, 29
Discussion
The results of a few studies using echinocandins in the
The aims of this trial were to verify whether micafungin is prevention of IFIs in high-risk LTRs have been published
non-inferior to fluconazole in the prevention of post-LDLT recently. Winston et al.30 conducted a randomized controlled
IFIs in adult patients ≥ 20 years of age and to assess the effi- trial of another echinocandin, anidulafungin. The study dem-
cacy and safety of micafungin prophylaxis. In the per-protocol onstrated that the efficacy of anidulafungin in IFI prevention

was similar to that of fluconazole, and virtually, no fungal
strains showed resistance against this agent. Anidulafungin
had excellent efficacy in patients who had received
pretransplant fluconazole. Fortun et al.31 conducted a propen-
sity score analysis of caspofungin and fluconazole as two
alternatives of IFI prevention and found no intergroup differ-
ences in the efficacy. Furthermore, caspofungin turned out to
be significantly more effective than fluconazole in dialyzed
patients. Finally, a European trial, TENPIN, demonstrated that
micafungin was non-inferior to fluconazole in high-risk
LTRs.32
However, still little is known with regard to echinocandin
administration as a preventive option in LDLTRs, and no pro-
spective randomized studies analyzing the outcomes of anti-
fungal prophylaxis in this specific group of transplant patients
have been published to date. Whereas echinocandins and oth-
er agents show similar activity against Candida, their safety
and drug-drug interaction profiles differ, which might be im-
portant in the context of their use in antifungal prophylaxis in
LDLTRs.
Unlike in transplantation from a deceased donor, LDLTRs
receive a partial liver graft, and hence, its adequate regenera-
tion is of utmost importance. This emphasizes the vital role of
appropriate antimicrobial prophylaxis during the period when
the liver undergoes active regeneration. In addition, transplan-
tation of liver graft from a living donor is more technically
demanding as it requires reconstruction of the hepatic vein,
creating anastomoses between small or disproportionate bile
ducts and connecting minute blood vessels.33 All these factors
might contribute to graft ischemia or biliary leakage that are
both associated with increased risk of IFI. Under such circum-
stances, antifungal prophylaxis seems to be an inevitable op-
tion in LDLTRs.34
Conclusion
In conclusion, this study demonstrated that micafungin, used
in the prevention of IFIs in LDLTRs, was non-inferior to flu-
conazole in terms of clinical success rate and safety profile.
Based on these findings, micafungin can be considered an
alternative to fluconazole in a post-transplant setting.
Authors’ Contributions G-W S, S-G L, and W-H K: Substantial contri-
butions to the conception or design of the work; G-W S, N-J Y, J W J, D L
C, and M S K: Data acquisition; G-W S, S-G L, K-S S, K-W L, C H D K,
J M K, J D K, and M S K: Analysis, or interpretation of data; W-H K and
G-W S: Drafting the work or revising it critically for important intellec-
tual content; All 12 authors: Final approval of the version to be published
and agreement to be accountable for all aspects of the work in ensuring
that questions related to the accuracy or integrity of any part of the work
are appropriately investigated and resolved.
Funding Information This study was funded by Astellas Pharma Korea,
Inc. (AKR-MYC-2011-04).
J Gastrointest Surg
Compliance with Ethical Standards
The protocol of the study was approved by the institutional review board
of each study site.
Conflict of Interest The authors declare that they have no competing
interests.
The authors of this manuscript have no conflicts of interest to disclose
as described by the Journal of Gastrointestinal Surgery.
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