key: cord-0993900-29e4rm5k
authors: Jing, Ran; Morrissey, Ian; Xiao, Meng; Sun, Tian-Shu; Zhang, Ge; Kang, Wei; Guo, Da-Wen; Aram, Jalal A; Wang, Jeffrey; Utt, Eric A; Wang, Yao; Xu, Ying-Chun
title: In vitro Activity of Isavuconazole and Comparators Against Clinical Isolates of Molds from a Multicenter Study in China
date: 2022-04-22
journal: Infect Drug Resist
DOI: 10.2147/idr.s360191
sha: 0fae07a114ad56fa455a641baff2b4c5236599fb
doc_id: 993900
cord_uid: 29e4rm5k

PURPOSE: Monitoring antifungal susceptibility patterns for new or established antifungals is imperative. Antifungal resistance is frequent in molds, frequently leading to invasive mold infections (IMIs) in immunocompromised patients with high morbidity and mortality. Limited availability of effective antifungals for treatment of IMIs in China is an enormous challenge. The purpose of this study was to monitor in vitro antifungal resistance profiles of mold isolates from China, with a particular focus on evaluating in vitro isavuconazole (ISA) activity against these isolates, contributing to the treatment guidance in clinics. METHODS: We evaluated the in vitro activity of ISA and its comparators (voriconazole [VOR] and amphotericin B [AMB]) against 131 clinical isolates of Aspergillus spp. (n = 105) and Mucorales order (n = 26) collected between 2017 and 2020 from China. RESULTS: ISA and VOR exhibited similar in vitro activity against Aspergillus spp., with minimum inhibitory concentration (MIC)(50) of 1 µg/mL and MIC(90) of 2 µg/mL, respectively. Overall, AMB was less active than azoles against Aspergillus spp. (MIC(50): 4 µg/mL, MIC(90): 8 µg/mL). Against the Mucorales order, ISA demonstrated MIC(50) of 0.5 µg/mL and MIC(90) of 1 µg/mL; however, one strain each of Mucor circinelloides and Syncephalastrum racemosum were resistant to ISA (MICs: >8 µg/mL). VOR exhibited little or no activity (MIC(50): 8 µg/mL, MIC(90): >8 µg/mL) against the Mucorales order, whereas AMB had MIC(50) and MIC(90) of 1 µg/mL. CONCLUSION: This was the first multicenter, in vitro study conducted in China and demonstrated the excellent activities of ISA against most species of the Mucorales order. MIC indicated an advantage over currently available azole antifungals, positioning ISA as a potential alternative to VOR for clinical management of IMIs. As with other antimicrobials, clinicians should employ stewardship and best practices in relation to potential resistance to new azole antifungals.

Invasive mold infections (IMIs), including invasive aspergillosis (IA) and mucormycosis, cause considerable morbidity, mortality, and economic burden predominantly among immunocompromised individuals worldwide. [1] [2] [3] IMIs mainly affect immunocompromised patients such as those with hematological malignancies, organ transplants, and those prescribed long-term steroid therapy. [4] [5] [6] Besides, mucormycosis is also involved in angio-invasion with higher mortality than IA; and infection is increasingly reported in patients with uncontrolled diabetes mellitus. 3, [6] [7] [8] Like other countries, China is also facing an increase in the incidence of IMIs due to rapid economic development and an aging population. This increases the burden on public health and socio-economic systems, and raises health-care costs. 3, 8 Azoles, mainly voriconazole (VOR), are recommended as primary antifungals for IA treatment. 9 However, the emergence of azole-resistant Aspergillus fumigatus is gradually being reported worldwide and is associated with point mutations, particularly in the cyp51 gene. 10, 11 Amphotericin B (AMB) formulations are used as the mainstay of treatment for mucormycosis, 12 despite being associated with a high frequency of treatment-related adverse effects such as nephrotoxicity. 13 Therefore, the treatment of IMIs remains a huge challenge worldwide.

The extended-spectrum triazole antifungal, isavuconazole (ISA), was approved in 2015 by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for the treatment of IA and mucormycosis. 14, 15 Previous studies have reported the excellent activity of ISA against a broad range of yeasts and molds, with lower toxicity than VOR and fewer drug-drug interactions than other azoles. 16, 17 Considering that ISA is currently unavailable in China, studies on in vitro antifungal activity of ISA against yeast and mold isolates from the region are lacking. We participated in the 2020 Analysis of Resistance in Antifungals (ARIA) Study conducted by IHMA, Europe Sarl. This was the first multicenter study conducted in China to evaluate the in vitro antifungal activity of ISA and its comparators (VOR and AMB) against molds including those belonging to Aspergillus spp. and the Mucorales order. The purpose of the current study was to monitor in vitro antifungal resistance profiles of mold isolates from China between 2017 and 2020, with a particular focus on evaluating in vitro ISA activity against these isolates to contribute to the treatment guidance in the clinics. In those species from which resistant isolates were identified, genetic sequencing along with an alignment for known genetic determinants of resistance (CYP 51s) with reference strains was performed to identify potential associations with ISA resistance.

This study was approved by the Human Research Ethics Committee of Peking Union Medical College Hospital (HS-2468). An informed consent waiver was granted by Peking Union Medical College Hospital prior to ethics approval, since only invitro susceptibility testing of strains isolated from patients was conducted, and no patient-specific information was collected. The results were only used for evaluation of antifungal agents, and no clinical diagnoses were made.

A total of 131 clinical filamentous isolates were collected from 2017-2020 under the China Hospital Invasive Fungal Surveillance Net -North China Program (CHIF-NET). These strains were originally isolated from a total of 8 participating regions of northern China, including Beijing, Tianjin, Inner Mongolia, Hebei, Heilongjiang, Jilin, Liaoning, and Shanxi Provinces. All strains were sub-cultured on Sabouraud dextrose agar (SDA) (Thermo Fisher Scientific) and incubated at 28°C for 3-7 days.

All isolates were identified by combining conventional morphological methods and matrix-assisted laser desorption/ ionization time of flight mass spectrometry (MALDI-TOF MS), using VITEK ® MS (bioMérieux, Marcy-l'Étoile, France) and M-Discover 100 MALDI-TOF MS (Zhuhai Meihua Medical Technology Co., Ltd). One unidentified isolate and two Mucor spp. strains were subsequently identified using molecular sequencing of the internal transcribed spacer (ITS) and/ or D1/D2 regions of ribosomal DNA. Nucleotide sequences were then homologically aligned with reliable sequences in the GenBank database (https://www.blast.ncbi.nlm.nih.gov/Blast.cgi) using two reference sequences of M. circinelloides 1006PhL (CYP51F1 and CYP51F5 genes). 2102 broth microdilution method (BMD) as described in the CLSI standard M38-A3. 18 Frozen 96-well panels provided by IHMA containing three antifungal agents: ISA (0.008-8 μg/mL), VOR (0.008-8 μg/mL) and AMB (0.06-8 μg/mL) were used. After these strains were cultured on SDA and incubated at 28°C for 3-7 days, an adequate amount of conidia was collected using 1 mL of sterile saline with 0.1% Tween-20 (Sigma: P1379). Subsequently, the turbidity of the stock suspension was adjusted to an A 530 of between 0.09 and 0.13 for Aspergillus spp. or 0.15 and 0.17 for Mucorales order. 18 Thereafter, the suspension was diluted 50-fold in Roswell Park Memorial Institute (RPMI) 1640 (+MOPS) culture medium, after which 100 µL of inoculum was added to the wells of the antifungal panels to give a final inoculum between approximately 2×10 3 to 2.5×10 4 colony forming unit (CFU)/mL and the desired test concentrations of antifungal agents in a total volume of 200 µL. 18 The minimum inhibitory concentration (MIC), 50% MIC (MIC 50 ) and 90% MIC (MIC 90 ) were determined as defined in the CLSI M38-A3 document. 18 For Aspergillus spp., the MICs for ISA and its comparators were observed after 46-50 h of incubation at 35°C. Due to the rapid growth of Mucorales isolates, the incubation time was shorter, and MICs for ISA and its comparators were recorded between 21 h and 26 h. 18 Candida parapsilosis ATCC 22019, Candida krusei ATCC 6258, Aspergillus flavus ATCC ® 204304™ and A. fumigatus ATCC ® MYA-3627™ were used as quality control and reference strains. 19 Analysis of Mucor circinelloides CYP51s (Sterol 14-Demethylase) Amino Acid Sequences

The homologous sequences of Mucor circinelloides CYP51s (Gene ID: HMPREF1544_03888.1 and HMPREF1544_08704.1) were obtained from FungiDB database (http://FungiDB.org). The paralogs of CYP51s were named CYP51F5 or CYP51F1 according to Nelson's database nomenclature. 20 Using the BLAST program (tblastn), M. circinelloides 1006PhL was identified as the reference strain from Mucor species (GenBank No. AOCY00000000.1); and the amino acid sequences of A. fumigatus CYP51A (GenBank protein ID: AAK73659.1) and CYP51B (GenBank protein ID: AAK73660.1) were used as query sequences. Species-specific primer sequences are presented in Table 1 . The sequences of CYP51F5 and CYP51F1 were amplified by Beijing Ruibio BioTech Co., Ltd (Beijing, China). Subsequently, CYP51s amino acids sequences of M. circinelloides strains (M35 and M49) were translated using CLC Sequence Viewer software (version 8.0).

To find potential substitutions of CYP51s amino acids likely affecting azole resistance in M. circinelloides, alignment using Saccharomyces cerevisiae S288C Erg11 (reference strain; CYP51 sterol 14-demethylase) was compared with the CYP51s amino acids sequences of M. circinelloides strains (M35 and M49).

Although several studies have evaluated epidemiological cut-off values (ECVs) for AMB, posaconazole, and itraconazole against a limited number of isolates of Mucorales order, 21 ECV values have not been formally established for ISA and VOR against isolates of Mucorales order or may be inapplicable to the interpretation of drug susceptibilities in China due to lack of clinical data in the population from China. Therefore, the MIC 50 and MIC 90 were calculated for evaluating in vitro activities of these antifungal agents against isolates of Mucorales order. However, ECVs are formally established for VOR, ISA, and AMB against some major Aspergillus spp., such as A. fumigatus, A. flavus, A. niger, and A. terreus 22 and were used for susceptibility testing of these organisms.

common genera were Rhizomucor spp. and Lichtheimia spp. (15.4%, 4/26 each). For Rhizomucor spp., R. pusillus isolates were the most prevalent (n = 3), followed by R. miehei (n = 1), which were identified by using molecular sequencing. For Lichtheimia spp., all isolates were identified as Lichtheimia ramosa (n = 4). Syncephalastrum spp. 

The lower respiratory tract (LRT, i.e., sputum, bronchoalveolar lavage fluid, tracheal aspirate) (75.6%, 99/131) was the primary culture source, followed by secretions (9.2%, 12/131), swabs (i.e., ear, nasopharyngeal, cornea, and skin 6.9%, 9/ 131), bodily fluids (i.e., blood, pleural fluid, cerebrospinal fluid, and abdominal dialysate; 3.8%, 5/131), pus (n = 3), tissue (n = 2), and stool (n = 1). Of note, more than half (61.5%, 16/26) of the isolates of Mucorales order originated from LRT, with sputum (n = 13) as the most frequent culture source. Of all the isolates of R. arrhizus, one was cultured from blood.

Isavuconazole Activity Against Aspergillus spp. and Mucorales Order MIC distributions for ISA against Aspergillus spp. and species of Mucorales order are shown ( Table 2 ). Among the Aspergillus isolates, MICs for ISA ranged from 0.06-4 μg/mL ( Table 3 ). The median MIC (mMIC) for ISA among all Aspergillus spp. was 1 μg/mL, with a low mMIC of 0.12 μg/mL for A. terreus complexes, a high mMIC of 2 μg/mL for A. niger complexes, and the same mMIC value of 1 μg/mL for A. fumigatus complexes (constituted the majority of the isolates identified) and A. flavus complexes (Table 3 ). Based on the ECVs available, a large proportion of Aspergillus strains in this study were wild-type (WT; MIC ≤ECV; range, 80.0-100.0%) ( Table 3) .

In this study, the activity of ISA against isolates of Mucorales order was slightly higher than observed for Aspergillus spp. (MIC 50 : 1 μg/mL), with a lower MIC 50 at 0.5 μg/mL (Table 3) . Compared with Aspergillus spp., a lower mMIC value of 0.5-0.75 μg/mL was observed for Rhizopus spp., Rhizomucor spp., Syncephalastrum spp., and Lichtheimia spp. (Table 3 ). Higher mMIC values of 1 μg/mL were observed for R. oryzae/R. arrhizus and R. pusillus ( Table 3) .

All MICs of quality control (QC; Candida parapsilosis ATCC 22019, Candida krusei ATCC 6258) and reference strains (A. flavus, A. fumigatus) were within expected limits (Supplementary Table 1 ). MIC distributions for VOR and AMB against Aspergillus spp. and species of Mucorales order are shown (Tables 4 and 5 ). The overall MIC 50 and MIC 90 for both azoles against Aspergillus spp. (n = 105) were 1 μg/mL and 2 μg/mL, respectively (Table 3) . WT susceptibility to ISAwas 80% and to VOR was 100% among A. flavus, A. niger, and A. terreus complexes. MIC 90 for both azoles was lower (1 μg/mL) against A. fumigatus complexes (n = 75) with a WT susceptibility of 90%. Of all Aspergillus spp. studied, A. terreus complex (n = 9) was the most susceptible to ISA and VOR with an MIC 50 of 0.12 μg/mL and MIC 90 of 0.5 μg/mL. AMB was less active than both azoles against Aspergillus spp., with an MIC 50 of 4 μg/mL and MIC 90 of 8 μg/mL, particularly against A. fumigatus complexes (89.3% of non-WT were less susceptible).

Compared with Aspergillus spp., ISA demonstrated better activity against the isolates of Mucorales order (n = 26) and Rhizopus spp. with an MIC 50 of 0.5 μg/mL (Table 3) . However, VOR lacked any meaningful activity against the Mucorales order with both MIC 50 and MIC 90 values of >8 μg/mL across all species (Table 3) .

Overall, from in vitro data, AMB was the most active fungistatic-agent against the Mucorales order with an MIC range of 0.12-2 μg/mL, compared with an MIC range of 0.25->8 μg/mL for Aspergillus spp. (Table 3) (Table 3) . Notably, among three strains of S. racemosum included, ISA demonstrated an MIC of 0.5 μg/mL for two strains; and no in vitro activity against one of strain with an MIC of >8 μg/mL (Table 3) . Consensus sequences for CYP51F1 and CYP51F5 were aligned against each other. The CYP51s of M. circinelloides-M35, M. circinelloides-M49, and Erg11 of S. cerevisiae S288C were screened for amino acid substitutions previously and confirmed as correlation to resistance to short-tailed azoles (e.g. VOR) in different fungal species (analogous to Y140F in S. cerevisiae). 23, 24 As depicted in Figure 1 

Rhizomucor miehei (1) 1

Syncephalastrum racemosum ( 

Isavuconazole has been indicated for the treatment of IFIs in the USA and Europe since 2015. However, due to limited data from studies in China, it is currently unavailable for the treatment of IFIs in China. This was the first multicenter study to evaluate the in vitro activity of ISA and its comparators (VOR and AMB) against clinical isolates of Aspergillus spp. and Mucorales order in China. Both azoles exhibited a low MIC 50 and MIC 90 against combined Aspergillus spp. However, AMB was less active than the azoles against Aspergillus spp. with high MICs. In this study, AMB was less active against Aspergillus species, including A. flavus complexes, A. terreus complexes, and A. fumigatus complexes. It is well-documented that the majority of strains from A. terreus and A. flavus complexes are intrinsically resistant to AMB, and VOR is recommended as the first line of treatment. 25 Additionally, A. fumigatus isolates were less susceptible to AMB, with 89.3% of non-WT isolates susceptible to AMB. There are several possibilities for this observation. First, the CLSI range of MICs of AMB to the reference strain (A. fumigatus ATCC ® MYA-3627™) was from 0.5-4 µg/mL, 19 thus the MIC of AMB against A. fumigatus in our study was in the upper limit of CLSI MIC range. Notably, a study from Canada indicated that 96.4% (188/195) of A. fumigatus isolates were less susceptible to AMB, 26 which was higher than our study (89.3%). This suggested that widespread AMB resistance might be gradually trending in many parts of the world including Canada and northern areas of China. Since AMB has been the recommended drug of choice for IA treatment, a large-scale and longterm use might result in an increasing trend of resistance to A. fumigatus. Given that the AMB susceptibility patterns could vary among geographic/ecological populations, Ashu et al. indicated that local clinicians should understand the limitations of the aforementioned recommendations, 26 and apply stewardship in the management of AMB. However, whether AMB resistance is also common in other parts of China remains to be investigated in a study with a larger sample size from various regions. Azoles demonstrated contrasting activity against isolates from the Mucorales order, with an MIC 50 of 0.5 µg/mL and MIC 90 of 1 µg/mL for ISA and an MIC 50 of 8 µg/mL and MIC 90 of >8 µg/mL for VOR. An MIC 50 and MIC 90 of 1 µg/mL was reported for AMB.

Rhizopus spp. has been reported as the most frequent cause of mucormycosis worldwide (~48-66%), followed by Mucor spp. (14%) and Lichtheimia spp. (13%) [27] [28] [29] with R. arrhizus being identified as the most common (33%) subspecies. 29 The present study corroborates earlier reports, in that Rhizopus spp. was the most predominant cause of mucormycosis, with fewer Mucor spp. isolated. Moreover, the sites from which isolates were cultured in the current study (i.e., LRT) were also more frequent in the prior study, 29 as also reported in an epidemiology and susceptibility study conducted in USA. 30 In addition to an increase in the incidence of IMIs globally and in China, [1] [2] [3] 8, 31 a gradual increase in patients with COVID-19 co-infected with IA or mucormycosis has also been reported. [32] [33] [34] [35] [36] The incidence of invasive pulmonary aspergillosis in patients with COVID-19 ranged from 19.4-33.3%. 33 Considering the possibility of combined infections as well as limited availability of antifungal agents in China, development of new antifungal drugs is critical for effective treatment. Many isolates of the Mucorales order are resistant to the echinocandin and azole classes of antifungals. 37, 38 Besides, due to the disadvantages of the currently recommended VOR and available AMB, 9, 39 there is a need for drugs such as ISA which has been developed as a more effective and safer antifungal azole that may be used to treat a wide range of IMIs. 16, 17 In the current study, both ISA and AMB demonstrated considerable activity against most species of the Mucorales order and exhibited better activity than VOR. However, similar activities were observed between ISA and VOR against Aspergillus spp., with MICs ranging between 0.06-4 μg/mL. Overall, our findings in clinical isolates of molds from China were consistent with studies conducted in the Netherlands/India and Denmark (Table 6) in that ISA (MIC ranges: 0.125-≥8 μg/mL) and AMB (MIC ranges: ≤0.03-1 μg/mL) exhibited notably increased activity compared with VOR (MIC ranges: 1-≥16 μg/mL) against isolates from the Mucorales order. Notably, Rhizopus spp. strains in China were more susceptible to ISA with MICs between 0.06-2 μg/mL compared with those tested in the Netherlands/India and Denmark with MICs between 0.125-8 μg/mL (Table 6) . Strains from the Mucorales order such as M. circinelloides, isolated from the US demonstrated higher MICs for ISA (2->16 μg/mL) and AMB (≤0.03-8 μg/mL) compared with those from China (ISA: 0.5-8 μg/mL; AMB: 0.5-1 μg/mL) ( Table 6 ). 

Of the two M. circinelloides strains identified, M35 was resistant and M49 was sensitive to ISA. These results do not corroborate the results reported by Arendrup et al., in which ISA exhibited in vitro activity against isolates of Mucorales order except for M. circinelloides (13 isolates evaluated). 40 Another possible contribution to VOR resistance (short-tailed azoles) by V293A (M. circinelloides) substitution (V311A, S. cerevisiae) was reported in two different functional analysis and structure-based studies. 41 There was a V (valine) to A (alanine) substitution (V311 for S. cerevisiae) observed in CYP51F5s (293A for both M. circinelloides). Therefore, results observed in the current study are consistent with a previous study in which the Y129F substitution in M. circinelloides CYP51F5 possibly affected its intrinsic resistance to VOR, with the V293A substitution also potentially playing a role. As ISA belongs to mid-tailed azoles, 41 the substitutions on Y129F and V293A in M. circinelloides CYP51F5 found in both M35 and M49 did not appear to be associated with ISA resistance in M. circinelloides-M35. Despite Syncephalastrum spp. rarely causing mucormycosis and fewer cases reported, 29 ISA resistance in one S. racemosum strain was observed in this study. The occurrence of ISA resistance in M. circinelloides and S. racemosum suggested that there may be species-specific differences in susceptibility patterns of several species of Mucorales order. Therefore, rapid identification of infection causing species and improved surveillance is critical to ensure optimal treatment.

ISA exhibited in vitro activity against most clinical isolates from the Mucorales order. Among clinical isolates of Aspergillus spp., similar MICs were reported for ISA and other azoles (VOR). However, as with all antimicrobial agents, clinicians should employ appropriate stewardship to minimize potential resistance to antifungals, and rationally deploy new antifungals in the treatment of IA and mucormycosis. 

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Infection and Drug Resistance is an international, peer-reviewed open-access journal that focuses on the optimal treatment of infection (bacterial, fungal and viral) and the development and institution of preventive strategies to minimize the development and spread of resistance. The journal is specifically concerned with the epidemiology of antibiotic resistance and the mechanisms of resistance development and diffusion in both hospitals and the community. The manuscript management system is completely online and includes a very quick and fair peer-review system, which is all easy to use

The study was performed by the Department of Clinical Laboratory, Peking Union Medical College Hospital, China, and supported by Pfizer Inc. We thank IHMA Europe Sarl, Switzerland for providing technical guidance. Editorial support was provided by Varkha Agrawal (Ph.D., CMPP™) an employee of Pfizer.