Infect Dis Ther (2020) 9:151–163 https://doi.org/10.1007/s40121-020-00282-w ORIGINAL RESEARCH Comparison of the Safety and Tolerance Profile of Micafungin with that of Other Echinocandins and Azoles in Patients with Pre-existing Child–Pugh B or C Liver Disease: A Case–Control Retrospective Study Antonio Vena . Emilio Bouza . Matteo Bassetti . Francesco Menichetti . Maria Merelli . Santiago Grau . Jesús Fortun . Marı́a Isabel Sánchez . José Marı́a Aguado . Paloma Merino . Francisco Bonache . Patricia Muñoz Received: October 14, 2019 / Published online: February 21, 2020 Ó The Author(s) 2020 ABSTRACT hospitals. All micafungin patients were ran- domly matched with one patient who received Introduction: To assess the association between another echinocandin and with one patient who exposure to micafungin, other echinocandins, or received azole treatment. Primary outcome was azoles and the development of short-term liver development of STLI or LTLI (development of injury (STLI) or long-term liver injury (LTLI) in any type of liver tumor during the follow-up patients with Child–Pugh B or C liver disease. period). Methods: Multicenter case–control study of Results: Of 2335 patients with chronic liver patients with Child–Pugh B or C liver disease who disease admitted to the six centers, 20 (0.85%) received antifungals (AF) for C 72 h (May were found to have Child–Pugh B or C liver 2009–May 2015) in six Spanish and Italian disease and received micafungin for C 72 h. During AF treatment, the frequency of STLI was Enhanced digital features To view enhanced digital 10% in each group. Most cases of STLI were features for this article go to https://doi.org/10.6084/ asymptomatic, and AFs had to be switched to m9.figshare.11550816. another class of AF in only two patients (one micafungin and one azole). No patients devel- Electronic supplementary material The online version of this article (https://doi.org/10.1007/s40121- oped acute liver insufficiency, were admitted to 020-00282-w) contains supplementary material, which the ICU, or had to undergo transplantation. is available to authorized users. Follow-up data (median of 1.3 years) were A. Vena  E. Bouza  F. Bonache  P. Muñoz (&) A. Vena  M. Bassetti  M. Merelli Clinical Microbiology and Infectious Diseases, Infectious Diseases Clinic, Department of Medicine, Hospital General Universitario Gregorio Marañón, University of Udine and Azienda Sanitaria Madrid, Spain Universitaria Integrata, Udine, Italy e-mail: pmunoz@micro.hggm.es A. Vena  M. Bassetti A. Vena  E. Bouza  P. Muñoz Department of Health Sciences, Infectious Disease Instituto de Investigación Sanitaria Hospital Clinic, University of Genoa and Hospital Policlinico Gregorio Marañón, Madrid, Spain San Martino-IRCCS, Genoa, Italy E. Bouza  P. Muñoz F. Menichetti CIBER Enfermedades Respiratorias-CIBERES (CB06/ Infectious Diseases Clinic, Nuovo Santa Chiara 06/0058), Madrid, Spain University Hospital, Azienda Ospedaliera Universitaria Pisana, Pisa, Italy A. Vena  E. Bouza  J. M. Aguado  P. Muñoz Medicine Department, School of Medicine, Universidad Complutense de Madrid, Madrid, Spain 152 Infect Dis Ther (2020) 9:151–163 available for 30 patients. LTLI was observed in microbiota, gut permeability, and immune only one patient, who had previously received dysfunction [1, 2]. The frequency of IFI in ESLD treatment with azoles. patients ranges from 1 to 10% [3, 4], and Conclusions: Our study suggests that the development of IFI has a profound effect on the administration of micafungin to patients with outcome of ESLD [5, 6]. end-stage liver disease does not imply a higher Echinocandins are among the better toler- risk of developing STLI or LTLI. ated antifungals in patients with ESLD [7–14]. Nevertheless, micafungin is the only Keywords: End-stage liver disease; Liver injury; echinocandin not approved in patients with Micafungin; Safety ESLD because of an EMA warning on the potential development of liver tumors, as shown in preclinical studies in rats treated with Key Summary Points high micafungin doses for either 3 or 6 months. In humans, data on hepatotoxicity in Patients with end-stage liver disease patients treated with micafungin are scarce (ESLD) are at high risk of invasive fungal [15–21] and, to our knowledge, only three infections. studies have partially evaluated this issue Information on the efficacy and safety of among ESLD patients [12–14]. However, data on micafungin compared with other the incidence of long-term liver injury (LTLI) antifungals in ESLD patients is scarce. and the relative magnitude of this risk com- pared with other antifungals have not been The administration of micafungin to reported. patients with ESLD was safe and did not We performed a large, multicenter, imply a higher risk of developing short- or case–control study in order to define, in routine long-term liver injury. clinical practice, the association between expo- sure to micafungin, other echinocandins, or azoles, and the development of short-term liver INTRODUCTION injury (STLI) or LTLI in a population of patients with pre-existing Child–Pugh B or C ESLD. Patients with end-stage liver disease (ESLD) are at high risk of acquiring invasive fungal infec- tions (IFI) because of alterations in gut MATERIALS AND METHODS Study Design and Setting S. Grau Department of Pharmacy, Hospital del Mar, Universitat Autònoma de Barcelona, Barcelona, We performed a retrospective, multicenter, Spain case–control study in six large tertiary-care hos- pitals in Spain and Italy. The study cohort con- J. Fortun Infectious Diseases Department, Hospital sisted of adult patients with chronic Child–Pugh Universitario Ramón y Cajal, Madrid, Spain B or C ESLD [22] who received C 72 h of therapy with micafungin, other echinocandins ,or azoles M. I. Sánchez Clinical Microbiology and Infectious Diseases from May 2009 to May 2015. Department, Hospital Puerta de Hierro, Madrid, In order to avoid bias, cases were identified Spain in each institution based on the diagnosis and procedure codes of the International Classifica- J. M. Aguado Unit of Infectious Diseases, Hospital Universitario tion of Disease, Ninth Revision, Clinical Modifica- ‘12 de Octubre’, Madrid, Spain tion (ICD-9-CM). Patients with a primary and secondary diagnosis of chronic liver disease P. Merino Clinical Microbiology Department, Hospital (ICD-9-CM codes used for that purpose are lis- Universitario Clinico San Carlos, Madrid, Spain ted within the electronic supplementary Infect Dis Ther (2020) 9:151–163 153 material) were identified. Data were cross- defined as an increase during antifungal treat- checked with pharmacy databases consisting of ment in transaminase levels to [ 3 times the all patients who received an echinocandin or an upper limit of normal for patients who started azole during the study period. Information on antifungal therapy with normal liver function. etiology, severity of liver disease, and antifungal If patients started antifungal treatment with exposure were then re-checked using the clini- abnormal baseline transaminase levels (i.e., cal charts. [ 50% greater than the upper limit of normal), STLI was defined as a doubling of the baseline Inclusion Criteria transaminase level. LTLI was defined as the development of any type of liver tumor during To be considered cases, patients had to meet all the follow-up period. of the following criteria: (1) ESLD classified as Secondary outcomes were cumulative inci- Child–Pugh B or C [22] on the first day that dence of patients stopping treatment owing to antifungal therapy was started; (2) micafungin abnormal liver function, cumulative incidence at 100 mg daily for at least 72 h; and (3) prior of patients needing transplantation owing to and subsequent measurement of liver function. hepatotoxicity, re-admission for any cause in For each case, we selected two matched the following year, and number of episodes of controls: one receiving another class of ascitic decompensation or gastrointestinal echinocandins (caspofungin loading dose of bleeding during the following year. 70/50 mg followed by 50/35 mg once daily or anidulafungin loading dose of 200 mg then Clinical Data 100 mg once daily) and one receiving an azole (fluconazole 400 mg once daily or voriconazole Data collected included demographic data, eti- loading dose of 6 mg/kg then 4 mg/kg twice ology of liver disease, underlying disease, and daily). To be considered matched controls, clinical course. When available, laboratory data patients had to be Child–Pugh B or C ESLD and were collected at days - 7, - 3, 0, ? 1, ? 3, ? 5, fulfill the following conditions: (1) same sex; (2) ? 7, ? 14, ? 28, ? 45, ? 60, ? 120, and ? 180 antifungal therapy at about the same time as and included the international normalized the case; (3) antifungal therapy with the same ratio, aspartate aminotransferase (AST), alanine indication as the case (empirical or targeted aminotransferase (ALT), alkaline phosphatase, treatment); and (4) survival for as long as the total bilirubin, gamma glutamyl transferase, case after administration of antifungal drugs. creatinine, and albumin. Detailed data were also Patients who underwent liver transplanta- collected on concomitant drugs, type of inva- tion were eligible for the study only if the graft sive fungal infection, and pathogens. was affected by a chronic disease (i.e., patient with recurrence of HCV cirrhosis after liver Ethics transplant). For both cases and controls, the index date was defined as the date of the first The study was approved by the institutional administration of the study drug. review board of the coordinating center (Hospital General Universitario Gregorio Mar- Follow-Up and Outcomes añón, MICRO.HGUGM.2014-017) and was in accordance with the declaration of Helsinki. Outcomes were assessed during a follow-up Informed consent was deemed unnecessary due period that began on the index date and ended to the retrospective nature of the study. on the date of death or the last clinical visit until the end of June 2016. Statistical Analysis The primary outcome of the study was the incidence of short- or long-term toxicity in Patients who received micafungin were com- patients with Child–Pugh B or C ESLD. STLI was pared with those who received other 154 Infect Dis Ther (2020) 9:151–163 echinocandins or azoles. To detect significant other echinocandins had a higher MELD score differences between groups, we used the Chi and a higher Child–Pugh score. No differences square test or Fisher exact test for categorical were detected between patients who received variables and a 2-tailed t test or Mann–Whitney micafungin and other echinocandins, although test for continuous variables, when appropriate. those with micafungin were significantly older Values are expressed as mean ± standard devi- (61.2 vs. 52.8 years, P = 0.01). ation (continuous variables) or as percentages of the group from which they were derived (cate- Comparison Between STLI and LTLI gorical variable). A multivariable logistic regression analysis Exposure to antifungal treatment is reported in was performed to assess risk factors for STLI. Table 1. Antifungals were mostly administered Variables associated with the development of as targeted therapy against Candida spp. (60%). STLI in the univariate analysis (P value B 0.3) The most frequent indications for antifungal were selected for possible inclusion. Statistical treatment were bloodstream infections (33.3%) significance was set at P \ 0.05. The results were and urinary tract infections (10%), with no analyzed using SPSS, v.17.0 (SPSS, Chicago, IL, significant differences between groups. Length USA). of therapy was significantly longer among patients receiving azoles (mean duration RESULTS 19.2 days) than among those treated with micafungin (12.3 days) or other echinocandins Between May 2009 and May 2015 (6 years), (10.9 days). In contrast, compared to azoles, 2335 patients with a diagnosis of chronic liver septic shock was more frequent in patients who disease were admitted to the six study centers received micafungin (35% vs. 0%, p = 0.08) or (Hospital General Universitario Gregorio Mar- other echinocandins (50% vs. 0%, p = 0.03). añón, 537 patients; Nuovo Santa Chiara Six of 60 patients (10%) patients developed University Hospital, 520; Santa Maria Miseri- STLI: two patients with micafungin, two cordia Hospital, 450; Hospital Universitario patients with other echinocandins, and two Ramón y Cajal, 400; Hospital Puerta de Hierro, patients with azoles. The rate of STLI was 0.81 260; and Hospital del Mar, 168). Of these, 20 cases per 100 patient-days for micafungin, 0.91 patients who fulfilled the criteria of Child–Pugh cases per 100 patient-days for other echinocan- B or C liver disease received micafungin for dins, and 0.51 cases per 100 patient-days for C 72 h. Overall, patients receiving micafungin azoles. represented 0.85% of all those with a diagnosis The increase in serum aminotransferase was of chronic liver disease. asymptomatic in all patients who experienced STLI, and antifungal discontinuation was required in only two cases: one patient who was Comparison of ESLD Patients Receiving receiving micafungin and another who was Micafungin with Those Treated receiving azoles. Figure 1 shows how laboratory with Other Echinocandins or Azoles values changed over time. There were no rele- vant differences in liver function over time The demographics and baseline characteristics between the groups. Interestingly, in all evalu- of the three groups (20 patients each) selected able patients, transaminase levels returned to for the case–control study are summarized in normal after withdrawal or switching of anti- Table 1. Univariate analysis revealed no signifi- fungal therapy. No patients developed acute cant differences between cases and controls liver insufficiency requiring ICU admission or regarding etiology of liver disease, other liver transplantation. comorbidities, previous antibiotic therapy, and Overall, in-hospital mortality was 35% for rate of cirrhosis-related complications. How- cases treated with micafungin, 45% for other ever, when compared with patients who echinocandins, and 25% for azoles (p = 0.39). received azoles, those with micafungin and Infect Dis Ther (2020) 9:151–163 155 Table 1 Clinical characteristics of the study population and exposure to antifungal treatment Characteristics Total n = 60 Micafungin Other Azoles p n = 20 echinocandins n = 20 n = 20 Age (years) (mean ± SD) 58.2 ± 14.5 61.2 ± 11.2 52.8 ± 9.6 60.6 ± 20.1 0.13 Male sex 45 (75.0) 15 (75.0) 15 (75.0) 15 (75.0) 1 Race White 59 (98.3) 20 (100) 20 (100) 19 (95.0) 1 Non-white 1 (1.7) 0 0 1 (5.0) Pre-existing liver disease HCV-associated cirrhosis 26 (43.3) 7 (35.0) 12 (60.0) 7(35.0) 0.64 HBV-associated cirrhosis 7 (11.6) 3 (15.0) 1 (5.0) 3 (15.0) 0.11 Alcohol-associated cirrhosis 18 (30.0) 7 (35.0) 5 (25.0) 6 (30.0) 0.52 Cryptogenic cirrhosis 4 (6.6) 0 1 (5.0) 3 (15.0) 0.78 Hepatocellular carcinoma 8 (13.3) 2 (10.0) 4 (20.0) 2 (20.0) 0.15 a Other causes 7 (11.6) 3 (15.0) 3 (15.0) 1 (5.0) 0.56 Baseline MELD score 17.7 ± 7.3 18.6 ± 7.6 19.6 ± 5.8 14.9 ± 7.9 0.10 Baseline child–pugh class B 35 (58.3) 12 (60.0) 8 (40.0) 15 (75.0) 0.08 Baseline child–pugh class C 25 (41.6) 8 (40.0) 12 (60.0) 5 (25.0) 0.08 Baseline child–pugh score 9.1 ± 1.4 9.1 ± 1.4 9.6 ± 1.2 8.6 ± 9.1 0.07 Complications within previous year Episode of ascites 17 (28.3) 5 (25.0) 8 (40.0) 4 (20.0) 0.34 Episodes of gastrointestinal bleeding 5 (8.3) 1 (5.0) 2 (10.0) 2 (10.0) 0.80 Antibiotic exposure 46 (76.6) 14 (70.0) 18 (90.0) 14 (70.0) 0.22 Other comorbidities Heart failure 6 (10.0) 3 (15.0) 2 (10.0) 1 (5.0) 0.57 Renal chronic disease 12 (20.0) 4 (20.0) 6 (30.0) 2 (10.0) 0.28 Respiratory disease 7 (11.6) 3 (15.0) 2 (10.0) 2 (10.0) 0.85 Diabetes mellitus 16 (26.6) 8 (40.0) 6 (30.0) 2 (10.0) 0.09 Cancer 12 (20.0) 6 (30.0) 3 (15.0) 3 (15.0) 0.39 HIV infection 5 (8.3) 3 (15.0) 1 (5.0) 1 (5.0) 0.41 Reason for starting AF therapy Empirical therapy 24 (40.0) 10 (50.0) 9 (45.0) 5 (25.0) 0.23 Targeted therapy 36 (60.0) 10 (50.0) 11 (55.0) 15 (75.0) 156 Infect Dis Ther (2020) 9:151–163 Table 1 continued Characteristics Total n = 60 Micafungin Other Azoles p n = 20 echinocandins n = 20 n = 20 Length of AF treatment (median, range) 14.1 ± 8.0 12.3 ± 6.5 10.9 ± 5.6 19.2 ± 9.1 < 0.001 Invasive fungal infection Bloodstream infection 20 (33.3) 5 (50.0) 6 (54.5) 9 (60.0) 0.88 Abdominal infection 5 (8.3) 2 (20.0) 0 3 (20) 0.13 Urinary tract 6 (10.0) 2 (20.0) 2 (18.9) 2 (13.3) 0.89 Lung 2 (3.3) 0 1 (9.1) 1 (6.7) 0.64 Othera 3 (5.0) 1 (10.0) 2 (18.9) 0 0.24 b Isolated pathogens Candida spp. 34 (94.4) 10/10 (100) 10/11 (90.1) 14/15 (93.3) 0.49 Aspergillus spp. 2 (5.6) 0 1/11 (9.1) 1/15 (6.7) Septic shock 17 (28.3) 7 (35.0) 10 (50.0) 0 0.22 SOFA score (mean ± SD) 6.8 ± 3.2 6.5 ± 3.2 8.1 ± 2.8 5.8 ± 3.2 0.06 Development of short-term hepatotoxicity 6 (10.0) 2 (10.0) 2 (10.0) 2 (10.0) 1 In-hospital mortality 22 (36.6) 8 (40.0) 9 (45.0) 5 (25.0) 0.39 Bold value indicate p \ 0.05 AD ascitic decompensation a Hepatocellular carcinoma b Overall, a pathogen was isolated in 36 out of 60 patients (60.0%) No deaths were considered related to the anti- diagnosis of hepatocellular carcinoma 3 years fungal drugs. Causes of death were mostly after the index date. related to worsening of underlying disease (nine patients), invasive fungal infection (six Risk Factors for Liver Injury patients). Follow-up information was available for 30 We performed a univariate analysis in order to patients until a median of 1.3 years after dis- identify potential risk factors for STLI, including charge. During the following year, no differ- the following variables: age, other underlying ences were observed between groups with conditions, severity of liver disease, septic respect to rate of re-hospitalization [50.0% (6/ shock, baseline liver and renal function, and 12) for micafungin vs. 85.7% (6/7) for other length of antifungal treatment. The only vari- echinocandins and 81.8% (9/11) for azoles, ables associated with STLI were presence of p = 0.23)], number of episodes of ascitic septic shock at the time of antifungal therapy decompensation [(16.6% (2/12) vs. 14.3% (1/7) (66.7% vs. 24.1%, p = 0.04) and higher MELD vs. 27.3% (3/11)], gastrointestinal bleeding (0% score (24.6 ± 8.6 vs 1.6.9 ± 6.8, p = 0.01) in each group), or mortality rate [33.3% (4/12) (Table 2). However, differences were not signif- vs. 28.7% (2/7)vs 36.3% (4/11)]. Only 1 patient icant for any variables in the multivariate in the azoles group experienced LTLI with a new analysis. Infect Dis Ther (2020) 9:151–163 157 Fig. 1 Mean AST (a), ALT (b) and mean bilirubin (c) level according to specific study drug 158 Infect Dis Ther (2020) 9:151–163 Table 2 Univariate models predicting short-term liver toxicity Characteristics No liver injury Hepatotoxicity p n = 54 n=6 Age (years) (mean ± SD) 57.8 ± 14.8 61.5 ± 13.1 0.56 Male sex 42 (77.8) 3 (50.0) 0.15 Severity of liver disease Child B 32 (37.0) 3 (50) 0.68 Child C 22 (40.7) 3 (50) 0.68 Baseline child–pugh score 9.0 ± 1.4 10.0 ± 1.5 0.12 Baseline MELD score 16.9 ± 6.9 24.9 ± 8.5 0.001 Reason for starting AF therapy Empirical therapy 20 (37.0) 4 (66.7) 0.20 Targeted therapy 34 (63.0) 2 (33.3) Septic shock 13 (24.1) 4 (66.7) 0.04 Length of AF treatment 14.5 ± 8.2 10.5 ± 5.2 0.24 Micafungin treatment 18 (33.3) 2 (33.3) 1 Significant p values shown in bold SD standard deviation, ICU intensive care unit, AF antifungal Table 3 Incidence of STLI according to baseline MELD between the index date and the development of score STLI was 7 days (range 3–14 days). Meld Micafungin Other Azoles score n = 20 echinocandins n = 20 DISCUSSION n = 20 \ 10 0/1 (0) 0/0 0/4 To our knowledge, the present study is the first to show that, compared with other echinocan- 10–20 1/10 (10.0) 1/10 (10.0) 0/13 dins or azoles, exposure to micafungin in [ 20 1/9 (11.1) 1/10 (10.0) 2/3 (66.7) patients with ESLD does not increase the risk of STLI or LTLI. The incidence of IFI among patients with advanced liver disease has been reported to be Given that only one patient had LTLI, uni- as high as 10% [23, 24], with a mortality rate up variate analysis was not performed to identify to 98% [2, 5, 25–27]. In addition, liver disease risk factors for long-term liver complications. has been found to be an independent risk factor The incidence of STLI according to the for mortality [25], possibly because of abnor- baseline MELD score is reported in Table 3. malities of the immune system [6, 28–30]. This When the baseline MELD score was [ 20, the risk is proportional to the level of hepatic incidence of STLI was significantly higher in impairment [5, 31]. patients with azoles (2/3, 66.6%) than in those The choice of antifungals in patients with treated with micafungin (1/9, 11.1%) or other ESLD is limited by a number of factors, includ- ecchinocandins (1/10; 10%). The median time ing medical comorbidities, drug–drug Infect Dis Ther (2020) 9:151–163 159 interactions, and antifungal resistance [32], data show that micafungin, in comparison to although the main factor limiting treatment is other echinocandins or azole therapy, did not the hepatotoxicity of antifungal drugs [33]. incur a higher risk of hepatotoxicity in patients Liposomal amphotericin B and azoles are both with ESLD. Indeed, the groups had similar rates associated with a significant risk of hepatotoxi- of STLI and a comparable change in transami- city (27%) [21, 33–35]. Moreover, liposomal nase level during therapy. More specifically, the amphotericin B has been associated with an transaminase level remained stable or decreased increasing risk of nephrotoxicity and infusion- during micafungin therapy, and discontinua- related reactions [36], whereas azoles have a tion of micafungin due to its hepatic adverse limited spectrum of antifungal activity and can effects was required in only one patient. More- cause severe drug–drug interactions [37]. Thus, over, in our study, in comparison to flucona- the use of alternative antifungal drugs for the zole, micafungin and the other echinocandins treatment of IFIs in patients with pre-existing were more commonly prescribed among liver disease is of particular clinical relevance. patients with higher MELD score, which is by Echinocandins have an excellent safety pro- itself a risk factor for STLI. file and are promising agents for the treatment As for LTLI, we found no major safety con- of IFI in patients with ESLD. Both anidulafungin cerns relating the development of hepatic and caspofungin have been studied for this tumors during a follow-up period of more than indication, although information is mainly 1 year. Preclinical data from animal studies from patients with Child–Pugh A or B liver reported the development of foci of altered disease, while experience in Child–Pugh C dis- hepatocytes and hepatocellular tumors in rats ease is very limited [7–11]. treated with high doses of micafungin for pro- Micafungin has a broad in vitro spectrum, longed periods. Interestingly, although similar potent in vivo activity, a favorable safety profile, studies have never been performed for anidu- and excellent bioavailability, and is indicated lafungin [42] or caspofungin [43], comparable for the treatment of invasive candidiasis results were also observed in long-term studies [38, 39], esophageal candidiasis [40], and anti- performed in animals receiving voriconazole fungal prophylaxis in patients with hemato- [44] or fluconazole [45]. In the present study, we logical disease [41]. observed only one patient previously treated Micafungin is generally safe in patients who with azoles experiencing a new diagnosis of do not have chronic liver disease, with no evi- hepatocarcinoma during the follow-up period. dence of a greater risk of STLI than other anti- We did not find evidence of liver tumors in any fungal drugs [38–41]. A systematic review and of the ESLD patients treated with micafungin, meta-analysis [21] showed that abnormal liver thus pointing to potential differences in tumor function test results during treatment with development between humans and rats. Our micafungin were observed in 3% of the patients, findings are consistent with the results from a with only 2.7% discontinuing treatment for pooled safety analysis including 3028 patients hepatotoxicity. In a more recent study, no treated with micafungin [20] and support the increased risk of short-term liver injury was absence of post-marketing reports of hepatic observed in comparison to other antifungals adenoma or carcinoma related to micafungin, (fluconazole, caspofungin, voriconazole and despite more than 1,000,000 patients world- amphotericin B) in a cohort of pediatric and wide having received the drug. adult patients without chronic renal and liver There are several potential limitations of our conditions who received micafungin [15]. study. First, its retrospective design and the Evidence of hepatic toxicity in patients with relatively small number of patients included are chronic liver disease receiving micafungin is the major weakness. However, patients were very limited but also generally reassuring identified after checking more than 2000 [12–14]. Nevertheless, the relative magnitude of patients in six large Spanish and Italian hospi- short-term liver risk compared to other anti- tals. Second, channeling bias is also likely since fungals in the ESLD population is less clear. Our providers who are aware of the EMA warning 160 Infect Dis Ther (2020) 9:151–163 would be expected to avoid prescription of ‘‘A way of making Europe’’ (grant number PI13/ micafungin in patients with a higher risk of 01148). Antonio Vena is supported by a Rio developing STLI or LTLI. Third, although we Hortega grant from the Instituto de Salud Carlos used a predefined definition for hepatic injury, a III Madrid Spain, which is partially funded by direct relationship between hepatotoxicity and the European Regional Development Fund antifungals exposure could be difficult to eval- (FEDER) ‘‘A way of making Europe’’ (grant uate, especially in high-risk groups of patients number CM15/00181). No funding or sponsor- in which other variables (comorbidities, global ship was received for the publication of this degree of immunosuppression, other hepato- article. This study was supported by an inde- toxic drugs, toxins, etc.) may have played a role pendent medical grant from Astellas. The fun- leading to over- or underreporting toxicity in ders had no role in study design, data collection our analysis. Fourth, although * 70% of and analysis, decision to publish, or preparation patients received antibiotics within the previous of the manuscript. 1 year, we did not have data available regarding which antibiotics and how long they were Editorial Assistance. We would like to administered. Such aspects may have also been express our special thanks to Magdalena Salcedo confounders for liver events. Lastly, we did not for helping us with the preparation of the study count recurrent episodes of antifungal admin- design. istration in this analysis, and the risk for STLI and LTLI could be different than that for the Authorship. All named authors meet the first episode. International Committee of Medical Journal Strengths of our study include its multicen- Editors (ICMJE) criteria for authorship for this tric design and its optimal follow-up. To our article, take responsibility for the integrity of knowledge, this study is the first in-depth report the work as a whole, and have given their on short- and long-term safety of micafungin in approval for this version to be published. patients with ESLD and its comparison with other echinocandins and azoles. Disclosures. Matteo Bassetti has participated in advisory boards and/or received speaker honoraria from Achaogen, Angelini, Astellas, CONCLUSIONS AstraZeneca, Bayer, Basilea, Cidara, Gilead, Menarini, MSD, Paratek, Pfizer, Roche, The In conclusion, according to our study hypoth- Medicine Company, Shionogi, Tetraphase, esis, the administration of micafungin to VenatoRx and Vifor. Patricia Munoz is a con- patients with pre-existing Child–Pugh B or C sultant and/or speaker for Astellas, Gilead, ESLD was safe and, in routine clinical practice, Merck, Novartis and Pfizer and T2 Biosystems. did not imply a higher risk of developing short- Matteo Bassetti and Antonio Vena now belong or long-term liver injury. to ‘‘Department of Health Sciences, Infectious Disease Clinic, University of Genoa and Hospi- tal Policlinico San Martino-IRCCS, Genoa, Italy’’. Emilio Bouza, Francesco Menichetti, ACKNOWLEDGEMENTS Maria Merelli, Santiago Grau, Jesús Fortun, Marı́a Isabel Sánchez, José Marı́a Aguado, We thank the participants of the study. Paloma Merino and Francisco Bonache have nothing to declare. Funding. The present study was funded by the PROgrama MULtidisciplinar para la Gestión Compliance with Ethical Guidelines. The de Antifúngicos y la Reducción de Candidiasis study was approved by the institutional review Invasora (PROMULGA II Project), Instituto de board of the coordinating center (Hospital Salud Carlos III Madrid Spain, and by the General Universitario Gregorio Maranon European Regional Development Fund (FEDER) MICRO.HGUGM.2014-017) and was in Infect Dis Ther (2020) 9:151–163 161 accordance with the declaration of Helsinki. 7. Spriet I, Meersseman W, Annaert P, de Hoon J, Informed consent was deemed unnecessary due Willems L. Pharmacokinetics of caspofungin in a critically ill patient with liver cirrhosis. Eur J Clin to the retrospective nature of the study. Pharmacol. 2011;67(7):753–5. Data Availability. The datasets generated 8. van der Elst KC, Bruggemann RJ, Rodgers MG, Alf- during and/or analyzed during the current fenaar JW. Plasma concentrations of caspofungin at two different dosage regimens in a patient with study are available from the corresponding hepatic dysfunction. Transpl Infect Dis. 2012;14(4): author on reasonable request. 440–3. Open Access. This article is distributed 9. Mistry GC, Migoya E, Deutsch PJ, Winchell G, under the terms of the Creative Commons Hesney M, Li S, et al. Single- and multiple-dose administration of caspofungin in patients with Attribution-NonCommercial 4.0 International hepatic insufficiency: implications for safety and License (http://creativecommons.org/licenses/ dosing recommendations. J Clin Pharmacol. by-nc/4.0/), which permits any noncommer- 2007;47(8):951–61. cial use, distribution, and reproduction in any 10. Dowell JA, Stogniew M, Krause D, Damle B. medium, provided you give appropriate credit Anidulafungin does not require dosage adjustment to the original author(s) and the source, provide in subjects with varying degrees of hepatic or renal a link to the Creative Commons license, and impairment. J Clin Pharmacol. 2007;47(4):461–70. indicate if changes were made. 11. Montesinos P, Rodriguez-Veiga R, Martinez-Cua- dron D, Boluda B, Navarro I, Vera B, et al. Treat- ment of invasive fungal disease using anidulafungin alone or in combination for hema- REFERENCES tologic patients with concomitant hepatic or renal impairment. Rev Iberoam Micol. 2015;32(3):185–9. 1. Pilmis B, Puel A, Lortholary O, Lanternier F. New 12. Luque S, Campillo N, Alvarez-Lerma F, Ferrandez O, clinical phenotypes of fungal infections in special Horcajada JP, Grau S. Pharmacokinetics of mica- hosts. Clin Microbiol Infect. 2016;22(8):681–7. fungin in patients with pre-existing liver dysfunc- tion: a safe option for treating invasive fungal 2. Falcone M, Massetti AP, Russo A, Vullo V, Venditti infections. Enferm Infecc Microbiol Clin. M. Invasive aspergillosis in patients with liver dis- 2016;34(10):652–4. ease. Med Mycol. 2011;49(4):406–13. 13. Undre N, Pretorius B, Stevenson P. Pharmacoki- 3. Theocharidou E, Agarwal B, Jeffrey G, Jalan R, netics of micafungin in subjects with severe hepatic Harrison D, Burroughs AK, et al. Early invasive dysfunction. Eur J Drug Metab Pharmacokinet. fungal infections and colonization in patients with 2015;40(3):285–93. cirrhosis admitted to the intensive care unit. Clin Microbiol Infect. 2016;22(2):189 (e1–7). 14. Hebert MF, Smith HE, Marbury TC, Swan SK, Smith WB, Townsend RW, et al. Pharmacokinetics of 4. Hassan EA, Abd El-Rehim AS, Hassany SM, Ahmed micafungin in healthy volunteers, volunteers with AO, Elsherbiny NM, Mohammed MH. Fungal moderate liver disease, and volunteers with renal infection in patients with end-stage liver disease: dysfunction. J Clin Pharmacol. 2005;45(10): low frequency or low index of suspicion. Int J Infect 1145–52. Dis. 2014;23:69–74. 15. Schneeweiss S, Carver PL, Datta K, Galar A, Johnson 5. Bartoletti M, Giannella M, Caraceni P, Domenicali MD, Johnson MG, et al. Short-term risk of liver and M, Ambretti S, Tedeschi S, et al. Epidemiology and renal injury in hospitalized patients using mica- outcomes of bloodstream infection in patients with fungin: a multicentre cohort study. J Antimicrob cirrhosis. J Hepatol. 2014;61(1):51–8. Chemother. 2016;71(10):2938–44. 6. Russo A, Giuliano S, Vena A, Lucidi C, Falcone M, 16. Neofytos D, Huang YT, Cheng K, Cohen N, Perales Raponi G, et al. Predictors of mortality in non- MA, Barker J, et al. Safety and efficacy of intermit- neutropenic patients with invasive pulmonary tent intravenous administration of high-dose aspergillosis: does galactomannan have a role? micafungin. Clin Infect Dis. 2015;61(Suppl 6): Diagn Microbiol Infect Dis. 2014;80(1):83–6. S652–61. 162 Infect Dis Ther (2020) 9:151–163 17. Heimann SM, Vehreschild MJ, Meintker L, Heinz 28. Albillos A, Lario M, Alvarez-Mon M. Cirrhosis-as- W, Schroeder T, von Bergwelt-Baildon M, et al. sociated immune dysfunction: distinctive features Different doses of micafungin for prophylaxis of and clinical relevance. J Hepatol. 2014;61(6): invasive fungal diseases in hemato-oncological 1385–96. high-risk patients: a web-based non-interventional trial in four large university hospitals in Germany. 29. Ferri C, Antonelli A, Mascia MT, Sebastiani M, Fal- Transpl Infect Dis. 2014;16(6):968–74. lahi P, Ferrari D, et al. HCV-related autoimmune and neoplastic disorders: the HCV syndrome. Dig 18. Valerio M, Munoz P, Bouza E. Liver toxicity of Liver Dis. 2007;39(Suppl 1):S13–21. micafungin. Is this drug safe? Enferm Infecc Microbiol Clin. 2011;29(Suppl 2):29–32. 30. Gomez F, Ruiz P, Schreiber AD. Impaired function of macrophage Fc gamma receptors and bacterial 19. Cornely OA, Marty FM, Stucker F, Pappas PG, Ull- infection in alcoholic cirrhosis. N Engl J Med. mann AJ. Efficacy and safety of micafungin for 1994;331(17):1122–8. treatment of serious Candida infections in patients with or without malignant disease. Mycoses. 31. Theocharidou E, Pieri G, Mohammad AO, Cheung 2011;54(6):e838–47. M, Cholongitas E, Agarwal B, et al. The Royal Free Hospital score: a calibrated prognostic model for 20. Cornely OA, Pappas PG, Young JA, Maddison P, patients with cirrhosis admitted to intensive care Ullmann AJ. Accumulated safety data of mica- unit. Comparison with current models and CLIF- fungin in therapy and prophylaxis in fungal dis- SOFA score. Am J Gastroenterol. 2014;109(4): eases. Expert Opin Drug Saf. 2011;10(2):171–83. 554–62. 21. Wang JL, Chang CH, Young-Xu Y, Chan KA. Sys- 32. Pfaller MA, Messer SA, Woosley LN, Jones RN, tematic review and meta-analysis of the tolerability Castanheira M. Echinocandin and triazole anti- and hepatotoxicity of antifungals in empirical and fungal susceptibility profiles for clinical oppor- definitive therapy for invasive fungal infection. tunistic yeast and mold isolates collected from 2010 Antimicrob Agents Chemother. 2010;54(6): to 2011: application of new CLSI clinical break- 2409–19. points and epidemiological cutoff values for char- acterization of geographic and temporal trends of 22. Desmet VJ, Gerber M, Hoofnagle JH, Manns M, antifungal resistance. J Clin Microbiol. 2013;51(8): Scheuer PJ. Classification of chronic hepatitis: 2571–81. diagnosis, grading and staging. Hepatology. 1994;19(6):1513–20. 33. Tverdek FP, Kofteridis D, Kontoyiannis DP. Anti- fungal agents and liver toxicity: a complex inter- 23. Lin LN, Zhu Y, Che FB, Gu JL, Chen JH. Invasive action. Expert Rev Anti Infect Ther. 2016;14(8): fungal infections secondary to acute-on-chronic 765–76. liver failure: a retrospective study. Mycoses. 2013;56(4):429–33. 34. Denning DW, Ribaud P, Milpied N, Caillot D, Her- brecht R, Thiel E, et al. Efficacy and safety of 24. Karvellas CJ, Pink F, McPhail M, Austin M, Auzinger voriconazole in the treatment of acute invasive G, Bernal W, et al. Bacteremia, acute physiology aspergillosis. Clin Infect Dis. 2002;34(5):563–71. and chronic health evaluation II and modified end stage liver disease are independent predictors of 35. Potoski BA, Brown J. The safety of voriconazole. mortality in critically ill nontransplanted patients Clin Infect Dis. 2002;35(10):1273–5. with acute on chronic liver failure. Crit Care Med. 2010;38(1):121–6. 36. Ullmann AJ, Sanz MA, Tramarin A, Barnes RA, Wu W, Gerlach BA, et al. Prospective study of ampho- 25. Garcia-Vidal C, Peghin M, Cervera C, Gudiol C, tericin B formulations in immunocompromised Ruiz-Camps I, Moreno A, et al. Causes of death in a patients in four European countries. Clin Infect Dis. contemporary cohort of patients with invasive 2006;43(4):e29–38. aspergillosis. PLoS One. 2015;10(3):e0120370. 37. Andes D, Azie N, Yang H, Harrington R, Kelley C, 26. Chen J, Yang Q, Huang J, Li L. Clinical findings in Tan RD, et al. Drug–drug interaction associated 19 cases of invasive pulmonary aspergillosis with with mold-active triazoles among hospitalized liver cirrhosis. Multidiscip Respir Med. 2014;9(1):1. patients. Antimicrob Agents Chemother. 2016;60(6):3398–406. 27. Wu Z, Ling Z, Shao F, Sheng J, Li L. Invasive pul- monary aspergillosis in patients with acute-on- 38. Kuse ER, Chetchotisakd P, da Cunha CA, Ruhnke chronic liver failure. J Int Med Res. 2012;40(5): M, Barrios C, Raghunadharao D, et al. Micafungin 1958–65. versus liposomal amphotericin B for candidaemia and invasive candidosis: a phase III randomised Infect Dis Ther (2020) 9:151–163 163 double-blind trial. Lancet. 2007;369(9572): versus fluconazole for prophylaxis against invasive 1519–27. fungal infections during neutropenia in patients undergoing hematopoietic stem cell transplanta- 39. Pappas PG, Rotstein CM, Betts RF, Nucci M, Talwar tion. Clin Infect Dis. 2004;39(10):1407–16. D, De Waele JJ, et al. Micafungin versus caspo- fungin for treatment of candidemia and other 42. EraxisTM (anidulafungin) for injection: prescribing forms of invasive candidiasis. Clin Infect Dis. information. Pfizer Inc, 2009. 2007;45(7):883–93. 43. Cancidas (caspofungin acetate) prescribing infor- 40. de Wet NT, Bester AJ, Viljoen JJ, Filho F, Suleiman mation. Merck & co. Inc. JM, Ticona E, et al. A randomized, double blind, comparative trial of micafungin (FK463) vs flu- 44. Vfend (voriconazole): prescribing information. Pfi- conazole for the treatment of oesophageal can- zer, Inc, 2010. didiasis. Aliment Pharmacol Ther. 2005;21(7): 899–907. 45. Diflucan (fluconazole): prescribing information. Pfizer Inc, 2010. 41. van Burik JA, Ratanatharathorn V, Stepan DE, Miller CB, Lipton JH, Vesole DH, et al. Micafungin