In Vitro Susceptibilities of Worldwide Isolates of Intrapulmonary Aspergillus Species and Important Candida Species in Sterile Body Sites against Important Antifungals: Data from the Antimicrobial Testing Leadership and Surveillance Program, 2017–2020

Shio-Shin Jean; Hung-Jen Yang; Po-Chuen Hsieh; Yu-Tsung Huang; Wen-Chien Ko; Po-Ren Hsueh

doi:10.1128/spectrum.02965-22

. 2022 Oct 31;10(6):e02965-22. doi: 10.1128/spectrum.02965-22

In Vitro Susceptibilities of Worldwide Isolates of Intrapulmonary Aspergillus Species and Important Candida Species in Sterile Body Sites against Important Antifungals: Data from the Antimicrobial Testing Leadership and Surveillance Program, 2017–2020

Shio-Shin Jean ^a,^b,ⁱ, Hung-Jen Yang ^c, Po-Chuen Hsieh ^b, Yu-Tsung Huang ^d,^j, Wen-Chien Ko ^e, Po-Ren Hsueh ^d,^f,^g,^h,^j,^k,^✉

Editor: Joshua J Obar^l

PMCID: PMC9769544 PMID: 36314941

ABSTRACT

To understand the changes of resistance in clinically commonly encountered fungi, we used the Antimicrobial Testing Leadership and Surveillance (ATLAS) database to explore in vitro antifungal susceptibilities against clinically important isolates of Aspergillus and Candida species (collected from intrapulmonary and sterile body areas, respectively). We applied the CLSI antifungal 2020 and the EUCAST antifungal 2020 guidelines. From 2017 to 2020, isolates of intrapulmonary Aspergillus fumigatus (n = 660), Aspergillus niger (n = 107), Aspergillus flavus (n = 96), Aspergillus terreus (n = 40), and Aspergillus nidulans species complex (n = 26) and sterile site-originated isolates of Candida albicans (n = 1,810), Candida glabrata (n = 894), Candida krusei (n = 120), Candida dubliniensis (n = 107), Candida lusitaniae (n = 82), Candida guilliermondii (n = 28), and Candida auris (n = 7) were enrolled in this study. Using the EUCAST 2020 breakpoints, it was demonstrated that amphotericin B and posaconazole displayed poor in vitro susceptibility rates against A. fumigatus isolates (<50% and 18.9%, respectively). In contrast, isavuconazole and itraconazole showed high in vitro potency against most Aspergillus isolates (>92%). Most intrapulmonary Aspergillus isolates exhibited MICs of ≤0.06 μg/mL to anidulafungin. Furthermore, intrapulmonary A. fumigatus isolates collected from Italy and the United Kingdom exhibited lower in vitro susceptibility to isavuconazole (72.2% and 69%, respectively) than those in the remaining ATLAS participant countries (>85%). Higher isavuconazole MIC₉₀s against C. auris and C. guilliermondii (1 and 4 μg/mL, respectively) were observed compared to the other five Candida species. Despite the aforementioned MICs and susceptibilities against fungi, research needs to consider the pharmacokinetic (PK) profiles, pharmacodynamic (PD) parameters, and clinical treatment experience with antifungals against specific Aspergillus species.

IMPORTANCE In addition to monitoring the antifungal susceptibilities of clinically important fungi, reviewing the PK/PD indices and the clinical therapy experience of antifungals under evaluation are important to guide an appropriate antifungal prescription. The efficacies of liposomal amphotericin B complex and anidulafungin for the treatment of pulmonary aspergillosis caused by different Aspergillus species need to be periodically evaluated in the future.

KEYWORDS: intrapulmonary Aspergillus species, Candida species, sterile body sites, isavuconazole, amphotericin B, anidulafungin, ATLAS

INTRODUCTION

Fungal infections can cause life-threatening complications. Among the various kinds of fungal infections, invasive candidiasis and candidemia were ranked among the top 10 nosocomial infections in the last decade (1) and are notable invasive fungal diseases (IFD) that frequently cause high mortality rates ranging from 30% to 50% (2, 3). Similarly, invasive pulmonary aspergillosis (IPA) has been reported to result in morbidities; particularly, 27.4% to 90% of IPA cases result in fatality, depending on the IPA severity and immune condition of patients (4 –6). The incidence of IPA is increasing with the growing number of immunocompromised hosts, prescription of broad-spectrum antibacterial antibiotic(s) for prolonged durations in intensive care units, and patients with severe viral infections, such as influenza and COVID-19 (6 –8). A multicenter study (predominantly in many member states of the European Union [EU]) revealed that triazole-resistant Aspergillus fumigatus isolates collected from 2009 to 2011 were more frequent (prevalence of 3.2%) than previously acknowledged (9). Periodic monitoring of fungal species-specific susceptibility is beneficial for understanding changes in antifungal resistance and recommending appropriate antifungal agents against clinically important fungi. However, substantially fewer surveys on antifungal resistance have been performed than those aimed at the resistance of bacteria of interest.

Antifungal armamentaria against clinically important fungi have been developing over the past 2 decades. According to the latest European Society for Clinical Microbiology and Infectious Diseases (ESCMID), the European Confederation of Medical Mycology (ECMM), and the European Respiratory Society (ERS) joint clinical guidelines, voriconazole (VRC) and isavuconazole (ISA) are currently the first-line treatment against IPA. In addition, posaconazole (POS) is recommended for antifungal prophylaxis during prolonged neutropenia in high-risk populations or as salvage therapy for nonresponsive patients. In contrast, liposomal amphotericin B (AMB) is recommended as salvage therapy against antimold triazole-resistant Aspergillus isolates (10). Using the antifungal database in the Antimicrobial Testing Leadership and Surveillance (ATLAS), guidelines of the Clinical and Laboratory Standards Institute (CLSI) recommended in 2020 (regarding Candida species and VRC against A. fumigatus) (11), and European Committee on Antimicrobial Susceptibility Testing (EUCAST) 2020 guidelines (12), we investigated the distributions of MICs of important antifungals, and the evolutionary trend of antifungal susceptibility results against clinically important fungi worldwide (intrapulmonary IPA and some important Candida species [13] cultured from sterile body sites) collected from 2017 through 2020. Moreover, pharmacokinetic (PK) and pharmacodynamic (PD) investigations of each antibiotic are crucial for defining the optimal antimicrobial exposure to determine its in vitro potency against the organisms under evaluation (7, 14). Therefore, we also assessed the clinical feasibility of POS, anidulafungin (AFG), and other antifungals for treating IPA isolates using the MIC distributions in this survey, PK profiles, and PD parameters of the antifungal agents.

RESULTS

Number of isolates of Aspergillus and Candida species.

In the 2017 to 2020 ATLAS antifungal program, 929 intrapulmonary isolates of various important Aspergillus species were collected from the following four regions: Europe (many EU member states, the United Kingdom, and Turkey; 443 isolates), North America (the United States and Canada; 328 isolates), Asia-Pacific (five countries; 143 isolates), and Latin America (Brazil only; 15 isolates). Furthermore, susceptibility data of 3,048 isolates of potentially high-resistance Candida species were collected from the following four regions: Europe (some EU member states, Switzerland, Turkey, Israel, and the United Kingdom; 1,432 isolates), North America (two countries; 951 isolates), Asia-Pacific (six countries; 401 isolates), and Latin America (five countries; 264 isolates).

Susceptibility data of isolates of intrapulmonary Aspergillus spp. against antifungals.

Figure 1 illustrates the changes in the annual in vitro susceptibility rates of AMB, ISA, and POS against 660 intrapulmonary A. fumigatus isolates collected from 2017 to 2020 in the ATLAS antifungal database using the EUCAST 2020 guidelines. During the 4-year study period, as assessed by the EUCAST 2020 guidelines, a wider fluctuation in the annual susceptibility rates of AMB against isolates of A. fumigatus than those of ISA and POS was observed in terms of gross variance.

FIG 1 — Trend of annual *in vitro* susceptibility rates of amphotericin B, isavuconazole, and posaconazole against 660 intrapulmonary *Aspergillus fumigatus* isolates collected from 2017 through 2020 in the ATLAS antifungal database using the EUCAST 2020 guidelines.

Table 1 illustrates the distributions of MIC and susceptibility data for some antifungal agents (AMB and four antimold triazoles) against worldwide intrapulmonary isolates of various important Aspergillus species (including A. fumigatus [n = 660], Aspergillus flavus species complex [n = 96], Aspergillus nidulans species complex [n = 26], Aspergillus niger species complex [n = 107], and Aspergillus terreus species complex [n = 40]) in the 2017 to 2020 ATLAS antifungal database. The susceptibility rates and MIC_50/90 values of AMB against 660 A. fumigatus isolates were 49.5% as evaluated by the EUCAST 2020 guidelines and 2 and 2 μg/mL, respectively. Among 22 (3.3%) VRC-resistant A. fumigatus isolates (MICs of VRC, ≥2 μg/mL), 12 (54.5%) and 19 (86.4%) isolates exhibited notable resistance in vitro to AMB and ISA, respectively. In striking contrast with A. fumigatus isolates, the in vitro susceptibility of AMB against isolates of A. niger species complex (96.3%, assessed by the EUCAST 2020 guidelines) was higher than that against A. fumigatus (P < 0.001; MIC_50/90 of AMB, 0.5 and 1 μg/mL, respectively). The MIC_50/90 values of AMB against isolates of A. flavus, A. nidulans, and A. terreus species complex enrolled in this survey were 2 and 2, 2 and 2, and 2 and 4 μg/mL, respectively.

TABLE 1.

Distributions of MICs and susceptibility profiles of various antifungal agents (polyene, four antimold triazoles) against intrapulmonary isolates of Aspergillus fumigatus, Aspergillus nidulans, Aspergillus terreus, Aspergillus niger, and Aspergillus flavus species complex cultured from 2017 through 2020 in the Antimicrobial Testing Leadership and Surveillance project according to the guidelines of the Clinical and Laboratory Standards Institute 2020 (12) and the European Committee on Antimicrobial Susceptibility Testing 2020 (13)^c

Species (no. of isolates) and antifungal agent	No. of isolates (cumulative percentage) according to MIC (μg/mL)										MIC₅₀ (μg/mL)	MIC₉₀ (μg/mL)	S (%)	I (%)	R (%)
Species (no. of isolates) and antifungal agent	0.03	0.06	0.12	0.25	0.5	1	2	4	8	16	MIC₅₀ (μg/mL)	MIC₉₀ (μg/mL)	S (%)	I (%)	R (%)
A. fumigatus (660)
Amphotericin B				1 (0.2)	11 (1.8)	315 (49.5)	331 (99.7)	2 (100)			2	2	49.5^b	N/A	50.5^b
Amphotericin B, if MICs of voriconazole >2 μg/mL (22)						10 (45.5)	12 (100)				2	2	45.5^b	N/A	54.5^b
Isavuconazole			3 (0.5)	49 (7.9)	422 (71.8)	138 (92.7)	26 (96.7)	13 (98.6)	5 (99.4)	4 (100)	0.5	1	92.7^b	N/A	3.3^b
Isavuconazole, if MICs of voriconazole >2 μg/mL (22)						1 (4.5)	2 (13.6)	10 (59.1)	5 (81.8)	4 (100)	4	16	4.5^b	N/A	86.4^b
Voriconazole		1 (0.2)	13 (2.1)	311 (49.2)	284 (92.3)	29 (96.7)	16 (99.1)	3 (99.5)	1 (99.7)	2 (100)	0.5	0.5	92.3^a/96.7^b	4.4^a	3.3^a^,^b
Posaconazole		7 (1.1)	118 (18.9)	331 (69.1)	186 (97.3)	16 (99.7)	0 (99.7)	1 (99.8)	1 (100)		0.25	0.5	18.9^b	N/A	30.9^b
Itraconazole				36 (5.5)	295 (50.2)	282 (92.9)	27 (97)	10 (98.5)	4 (99.1)	6 (100)	0.5	1	92.9^b	N/A	7.1^b
Aspergillus nidulans spp. complex (26)
Amphotericin B					2 (7.7)	5 (26.9)	18 (96.2)	0 (96.2)	1 (100)		2	2	N/A	N/A	N/A
Isavuconazole	2 (7.7)	4 (23.1)	13 (73.1)	7 (100)							0.25	0.25	100^b	N/A	0^b
Voriconazole	3 (11.5)	4 (26.9)	11 (69.2)	6 (92.3)	2 (100)						0.12	0.25	100^b	N/A	0^b
Posaconazole		1 (3.8)	6 (26.9)	11 (69.2)	8 (100)						0.25	0.5	N/A	N/A	N/A
Itraconazole			2 (7.7)	4 (23.1)	15 (80.8)	5 (100)					0.5	1	100^b	N/A	0^b
Aspergillus terreus spp. complex (40)
Amphotericin B						9 (22.5)	25 (85)	6 (100)			2	4	N/A	N/A	N/A
Isavuconazole		1 (2.5)	7 (20)	10 (45)	20 (95)	1 (97.5)	1 (100)				0.5	0.5	97.5^b	N/A	0^b
Voriconazole		1 (2.5)	7 (20)	12 (50)	19 (97.5)	1 (100)					0.25	0.5	N/A	N/A	N/A
Posaconazole			5 (12.5)	27 (80)	8 (100)						0.25	0.5	12.5^b	N/A	20^b
Itraconazole			1 (2.5)	8 (22.5)	26 (87.5)	5 (100)					0.5	1	100^b	N/A	0^b
Aspergillus niger spp. complex (107)
Amphotericin B			1 (0.9)	4 (4.7)	62 (62.6)	36 (96.3)	4 (100)				0.5	1	96.3^b	N/A	2.7^b
Isavuconazole					9 (8.4)	45 (50.5)	29 (77.6)	19 (95.3)	3 (98.1)	2 (100)	1	4	N/A	N/A	N/A
Voriconazole			2 (1.9)	3 (4.7)	47 (48.6)	39 (85)	15 (99.1)	1 (100)			1	2	N/A	N/A	N/A
Posaconazole			2 (1.9)	9 (10.3)	76 (81.3)	20 (100)					0.5	1	N/A	N/A	N/A
Itraconazole			1 (0.9)	2 (2.8)	5 (7.5)	34 (39.3)	51 (86.9)	10 (96.3)	4 (100)		2	4	N/A	N/A	N/A
Aspergillus flavus spp. complex (96)
Amphotericin B						23 (24)	67 (93.8)	5 (99)	1 (100)		2	2	N/A	N/A	N/A
Isavuconazole			1 (1)	13 (14.6)	50 (66.7)	31 (99)	1 (100)				0.5	1	99^b	N/A	0^b
Voriconazole				22 (22.9)	52 (77.1)	21 (99)	1 (100)				0.5	1	N/A	N/A	N/A
Posaconazole			7 (7.3)	39 (47.9)	49 (99)	1 (100)					0.5	0.5	N/A	N/A	N/A
Itraconazole			1 (1)	12 (13.5)	54 (69.8)	29 (100)					0.5	1	100^b	N/A	0^b

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According to the clinical breakpoints recommended by the Clinical and Laboratory Standards Institute 2020.

According to the clinical breakpoints recommended by the European Committee on Antimicrobial Susceptibility Testing 2020.

Bold values in parentheses indicate the numerals of cumulative percentage above 90% of isolates for given subsets. S, susceptible; I, intermediate; R, resistant; N/A, not applicable.

ISA was shown to exhibit >92% rates of in vitro susceptibility against isolates of A. fumigatus, A. flavus, A. nidulans, and A. terreus species complex according to the EUCAST 2020 guidelines. Similar to ISA, isolates of most Aspergillus species exhibited 93 to 100% susceptibilities to itraconazole (ITC) using the EUCAST 2020 guidelines, except for A. niger species complex, which was due to the lack of clinical breakpoints. Furthermore, the susceptibility rates of VRC against isolates of A. fumigatus were 92.3% and 96.7%, respectively, when assessed using the CLSI 2020 and EUCAST 2020 guidelines. An excellent in vitro susceptibility to VRC was also observed in isolates of A. nidulans species complex when applying the EUCAST 2020 guidelines. Despite the lack of susceptibility breakpoints, we observed that the distributions of MIC values of VRC against A. terreus and A. flavus species complex were significantly lower than those of A. niger species complex (P < 0.001, between different Aspergillus species as assessed using the Mann-Whitney U test). The MIC_50/90 values of VRC against A. terreus, A. flavus, and A. niger species complex were 0.25 and 0.5, 0.5 and 1, and 1 and 2 μg/mL, respectively. In addition, POS was demonstrated to be active in vitro against only 18.9% and 12.5% of intrapulmonary isolates of A. fumigatus and A. terreus species complex, respectively, when applying the EUCAST 2020 guidelines.

The MIC distributions of AFG against isolates of various Aspergillus species.

Table 2 illustrates the MIC distributions and MIC_50/90 values of AFG against worldwide intrapulmonary isolates of different Aspergillus species in the 2017 to 2020 ATLAS antifungal database. The MIC₉₀s of AFG against all Aspergillus species ranged from 0.016 to 0.03 μg/mL. In addition, regardless of VRC resistance, similar MIC distributions of AFG against A. fumigatus isolates were observed.

TABLE 2.

Distributions of MICs and MIC₅₀ and MIC₉₀ values of anidulafungin against worldwide intrapulmonary isolates of Aspergillus fumigatus, Aspergillus nidulans, Aspergillus terreus, Aspergillus niger, and Aspergillus flavus species complex cultured from 2017 through 2020 in the Antimicrobial Testing Leadership and Surveillance project^a

Aspergillus spp. (no. of isolates)	No. of isolates (cumulative %) according to MIC (μg/mL)							MIC₅₀/MIC₉₀ (μg/mL)
Aspergillus spp. (no. of isolates)	0.002	0.004	0.008	0.016	0.03	0.06	0.12	MIC₅₀/MIC₉₀ (μg/mL)
Aspergillus fumigatus (660)	26 (3.9)	91 (17.7)	167 (43)	241 (79.5)	110 (96.2)	25 (100)		0016/0.03
Aspergillus fumigatus if MICs of VRC >2 μg/mL (22)	2 (9.1)	3 (22.7)	8 (59.1)	6 (86.4)	2 (95.5)	1 (100)		0.008/0.03
Aspergillus nidulans spp. complex (26)	2 (7.7)	4 (23.1)	5 (42.3)	11 (84.6)	3 (96.2)	0 (96.2)	1 (100)	0.016/0.03
Aspergillus terreus spp. complex (40)	3 (7.5)	4 (17.5)	10 (42.5)	15 (80)	7 (97.5)	1 (100)		0.016/0.03
Aspergillus niger spp. complex (107)	21 (19.6)	40 (57)	32 (86.9)	11 (97.2)	3 (100)			0.004/0.016
Aspergillus flavus spp. complex (96)	12 (12.5)	34 (47.9)	30 (79.2)	18 (97.9)	2 (100)			0.008/0.016

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Bold values in parentheses indicate the numerals of cumulative percentage above 90% of isolates for given subsets.

Susceptibility rates of AMB and ISA against A. fumigatus collected from different ATLAS participant countries.

Figure 2 shows the susceptibility rates of AMB and ISA against isolates of A. fumigatus among 15 ATLAS participant countries that submitted at least 10 isolates from 2017 to 2020 as evaluated using the EUCAST 2020 guidelines. In brief, except in France (76.2%), Czechia (71.4%), Turkey (68%), Australia (64.8%), and Thailand (60%), the susceptibility rates of AMB against intrapulmonary isolates of A. fumigatus collected from the remaining 10 countries were less than 60% when evaluated using the EUCAST 2020 guidelines. In contrast, with the exception of susceptibility to ISA in Italy (69%), the United Kingdom (72.2%), and Czechia (85.7%), those against A. fumigatus isolates collected from the remaining 12 participant countries were higher than 91% when evaluated using the EUCAST 2020 guidelines. The ISA MIC distribution of intrapulmonary A. fumigatus isolates collected in Italy was significantly higher than those of other countries (P < 0.05), except for the United Kingdom (Fig. 2), when evaluated using the Mann-Whitney U test.

FIG 2 — *In vitro* susceptibility rates of amphotericin B and isavuconazole against intrapulmonary *Aspergillus fumigatus* isolates collected from 2017 through 2020 in the ATLAS antifungal database using the EUCAST 2020 guidelines. Differences in the susceptibility rates of isavuconazole against *A. fumigatus* isolates cultured in some countries were analyzed using the Mann-Whitney U test. *, P value of <0.05 (the numeral in parenthesis indicates the number of isolates).

Susceptibility rates of antifungals against important Candida spp.

Table 3 presents the MIC distributions of four antimold triazoles, fluconazole (FLC), AFG, and AMB against 3,048 isolates worldwide of various important Candida species—including Candida albicans (n = 1,810 [59.4%]), Candida glabrata (n = 894 [29.3%]), Candida krusei (n = 120 [3.9%]), Candida dubliniensis (n = 107 [3.5%]), Candida lusitaniae (n = 82 [2.7%]), Candida guilliermondii (n = 28 [0.9%]), and Candida auris (n = 7 [0.23%])—cultured from sterile body sites in the 2017 to 2020 ATLAS database. Clinical breakpoints for interpreting the susceptibilities of some antifungal agents to Candida species are currently lacking. Using the EUCAST 2020 guidelines, the susceptibility rates of POS against isolates of C. albicans and C. dubliniensis were 97.6% and 97.2%, respectively. The susceptibility rates of VRC against isolates of C. albicans and C. krusei were 99.9% and 99.2%, respectively, when applying the CLSI 2020 guidelines. In addition, the MIC₉₀ values of ISA were equal to or 2-fold higher than those of VRC against the isolates of various Candida species analyzed in this study. Among different Candida species, the susceptibility rates of AMB against isolates of C. albicans, C. dubliniensis, C. glabrata, and C. krusei were 99.9%, 100%, 99.8%, and 85.8%, respectively, when applying the EUCAST 2020 criteria. Moreover, between the guidelines of CLSI 2020 and EUCAST 2020, we observed a more significant discrepancy in the susceptibility rates (P < 0.001) of AFG against isolates of C. glabrata (27.4% [95.6% versus 68.2%]) than those of C. albicans (12.1% [99.9% versus 87.8%]) and C. krusei (13.3% [100% versus 86.7%]). Figure 3 illustrates the in vitro susceptibility rates of four antifungals against isolates of important Candida species in the 2017 to 2020 ATLAS antifungal database using the EUCAST 2020 guidelines.

TABLE 3.

MIC distributions of various antimold triazoles, anidulafungin, and amphotericin B against worldwide isolates of different Candida species collected from sterile body sites from 2017 through 2020 in the Antimicrobial Testing Leadership and Surveillance project

Candida spp. and antifungal agent	No. of isolates (cumulative %) according to MIC (μg/mL)														MIC₉₀ (μg/mL)
Candida spp. and antifungal agent	0.002	0.004	0.008	0.015	0.03	0.06	0.12	0.25	0.5	1	2	4	8	>16	MIC₉₀ (μg/mL)
Candida albicans (1,810)
VRC	193 (10.7)	645 (46.3)	749 (87.7)	167 (96.9)	46 (99.4)	8 (99.9)	0 (99.9)	0 (99.9)	1 (99.9)	0 (99.9)	0 (99.9)	0 (99.9)	1 (100)		0.015
POS	2 (0.1)	20 (1.2)	55 (4.3)	365 (24.4)	882 (73.1)	443 (97.6)	40 (99.8)	1 (99.9)	1 (99.9)	0 (99.9)	0 (99.9)	0 (99.9)	1 (100)		0.06
ISA	574 (31.7)	544 (61.8)	577 (93.6)	93 (98.8)	15 (99.6)	4 (99.8)	0 (99.8)	2 (99.9)	0 (99.9)	0 (99.9)	0 (99.9)	0 (99.9)	1 (100)		0.008
FLC			2 (0.1)	11 (0.7)	11 (1.3)	160 (10.2)	1168 (74.7)	363 (94.8)	67 (98.5)	19 (99.5)	5 (99.8)	1 (99.8)	1 (99.9)	2 (100)	0.25
ITC	1 (0.06)	25 (1.4)	35 (3.4)	135 (10.8)	371 (31.3)	840 (77.7)	349 (97)	49 (99.7)	3 (99.9)	1 (99.9)	0 (99.9)	0 (99.9)	1 (100)		0.12
AFG	37 (2)	148 (10.2)	433 (34.1)	523 (63)	449 (87.8)	195 (98.6)	22 (99.8)	2 (99.9)	0 (99.9)	1 (100)					0.06
AMB						1 (0.06)	1 (0.1)	125 (7)	1435 (86.3)	246 (99.9)	2 (100)				1
Candida glabrata (894)
VRC			2 (0.2)	9 (1.2)	69 (8.9)	444 (58.6)	240 (85.5)	36 (89.5)	17 (91.4)	29 (94.6)	29 (97.9)	17 (99.8)	2 (100)		0.5
POS					1 (0.1)	4 (0.6)	75 (8.9)	334 (46.3)	365 (87.1)	68 (94.7)	39 (99.1)	3 (99.4)	4 (99.9)	1 (100)	1
ISA		1 (0.1)	8 (1)	45 (6)	100 (17.2)	300 (50.8)	290 (83.2)	56 (89.5)	21 (91.8)	24 (94.5)	34 (98.3)	13 (99.8)	2 (100)		0.5
FLC							1 (0.1)	2 (0.3)	5 (0.9)	31 (4.4)	336 (41.9)	358 (82)	62 (88.9)	99 (100)	16
AFG	4 (0.4)	3 (0.8)	15 (2.5)	66 (9.8)	152 (26.8)	370 (68.2)	245 (95.6)	13 (97.1)	3 (97.4)	12 (98.8)	7 (99.6)	4 (100)			0.12
AMB								12 (1.3)	204 (24.2)	676 (99.8)	2 (100)				1
Candida krusei (120)
VRC						2 (1.7)	29 (25.8)	77 (90)	11 (99.2)	1 (100)					0.25
POS					1 (0.8)	2 (2.5)	21 (20)	54 (65)	42 (100)						0.5
ISA					1 (0.8)	8 (7.5)	36 (37.5)	51 (80)	24 (100)						0.5
AFG			1 (0.8)	4 (4.2)	48 (44.2)	51 (86.7)	16 (100)								0.12
AMB									1 (0.8)	102 (85.8)	17 (100)				2
Candida lusitaniae (82)
VRC		8 (9.8)	60 (82.9)	11 (96.3)	2 (98.8)	0 (98.8)	0 (98.8)	0 (98.8)	1 (100)						0.015
POS			1 (1.2)	0 (1.2)	17 (22)	53 (86.6)	10 (98.8)	1 (100)							0.12
ISA	7 (8.5)	7 (17.1)	34 (58.5)	22 (85.4)	11 (98.8)	0 (98.8)	0 (98.8)	1 (100)							0.03
FLC							9 (11)	39 (58.5)	25 (89)	5 (95.1)	2 (97.6)	2 (100)			1
AFG						1 (1.2)	9 (12.1)	38 (58.5)	32 (97.6)	2 (100)					0.5
AMB								22 (26.8)	51 (89)	9 (100)					1
Candida dubliniensis (107)
VRC	6 (5.6)	34 (37.4)	53 (86.9)	12 (98.1)	1 (99.1)	0 (99.1)	1 (100)								0.015
POS				8 (7.5)	60 (63.6)	36 (97.2)	2 (99.1)	1 (100)							0.06
ISA	56 (52.3)	14 (65.4)	34 (97.2)	1 (98.1)	1 (99.1)	1 (100)									0.008
FLC					1 (0.9)	23 (22.4)	58 (76.6)	22 (97.2)	1 (98.1)	0 (98.1)	1 (99.1)	0 (99.1)	0 (99.1)	1 (100)	0.25
ITC			1 (0.9)	0 (0.9)	20 (19.6)	52 (68.2)	26 (92.5)	7 (99.1)	1 (100)						0.12
AFG		1 (0.9)	3 (3.7)	11 (14)	42 (53.3)	28 (79.4)	22 (100)								0.12
AMB						2 (1.9)	8 (9.3)	60 (65.4)	34 (97.2)	3 (100)					0.5
Candida guilliermondii (28)
VRC				1 (3.6)	4 (17.9)	14 (67.9)	4 (82.1)	0 (82.1)	0 (82.1)	1 (85.7)	0 (85.7)	2 (92.9)	2 (100)		4
POS							8 (28.6)	13 (75)	3 (85.7)	3 (96.4)	1 (100)				1
ISA				1 (3.6)	1 (7.1)	3 (17.9)	10 (53.6)	7 (78.6)	1 (82.1)	0 (82.1)	2 (89.3)	2 (96.4)	0 (96.4)	1 (100)	4
FLC											12 (42.9)	10 (78.6)	0 (78.6)	6 (100)	16
AFG									2 (7.1)	5 (25)	19 (92.9)	2 (100)			2
AMB								5 (17.9)	20 (89.3)	3 (100)					1
Candida auris (7)
VRC							3 (42.9)	2 (71.4)	0 (71.4)	2 (100)					1
POS						4 (57.1)	1 (71.4)	1 (85.7)	1 (100)						0.5
ISA			5 (71.4)	0 (71.4)	0 (71.4)	0 (71.4)	0 (71.4)	0 (71.4)	1 (85.7)	1 (100)					1
AFG						1 (14.3)	0 (14.3)	6 (100)							0.25
AMB										5 (71.4)	2 (100)				2

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FIG 3 — *In vitro* susceptibility rates of different antifungals against isolates of important *Candida* species cultured from sterile body sites from 2017 to 2020 in the ATLAS antifungal database using the EUCAST 2020 guidelines (the numeral in parenthesis indicates the number of isolates). N/A, not applicable. *, P value of <0.001 when compared using Chi-square test. ^#, If CLSI 2020 guidelines were applied, 95.6% of *Candida glabrata* isolates tested were susceptible to anidulafungin (12).

DISCUSSION

This 2017 to 2020 antifungal ATLAS study highlighted several important points. First, using the EUCAST 2020 breakpoints, AMB and POS were significantly less active in vitro against intrapulmonary A. fumigatus than other antimold triazoles. In contrast, ISA and ITC were highly active in vitro against the isolates of many Aspergillus species. Second, most intrapulmonary Aspergillus isolates exhibited AFG MICs of ≤0.06 μg/mL. Third, the intrapulmonary A. fumigatus isolates collected from Italy and the United Kingdom exhibited higher in vitro nonsusceptibility (NS) rates to ISA than those in the remaining ATLAS participant countries, which has never been addressed in the literature. Fourth, higher ISA MIC₉₀s were observed against isolates of C. auris and C. guilliermondii (1 and 4 μg/mL, respectively) than against the other five Candida species (ranging from 0.008 to 0.5 μg/mL). Table 4 summarizes the susceptible breakpoints of different antifungals against various Aspergillus and Candida species in the CLSI 2020 and EUCAST 2020 guidelines (12, 13). Additionally, Table 5 summarizes the PK/PD profiles of different antimold antifungal agents against molds. We utilized these data and mathematical calculations to estimate the suitability of respective antifungal agent against these important fungi.

TABLE 4.

Susceptible breakpoints of different antifungals against various Aspergillus and Candida species in the guidelines of the Clinical and Laboratory Standards Institute (CLSI) 2020 and the European Committee on Antimicrobial Susceptibility Testing (EUCAST) 2020^a

Species and guideline	Susceptible breakpoints (μg/mL) of different antifungal agents
Species and guideline	AMB	AFG	FLC	VRC	ISA	POS	ITC
Aspergillus fumigatus
CLSI 2020	N/A	N/A	N/A	0.5	N/A	N/A	N/A
EUCAST 2020	1	N/A	N/A	1	1	0.125	1
Aspergillus nidulans spp. complex
CLSI 2020	N/A	N/A	N/A	N/A	N/A	N/A	N/A
EUCAST 2020	N/A	N/A	N/A	1	0.25	N/A	1
Aspergillus terreus spp. complex
CLSI 2020	N/A	N/A	N/A	N/A	N/A	N/A	N/A
EUCAST 2020	N/A	N/A	N/A	N/A	1	0.125	1
Aspergillus niger spp. complex
CLSI 2020	N/A	N/A	N/A	N/A	N/A	N/A	N/A
EUCAST 2020	1	N/A	N/A	N/A	N/A	N/A	N/A
Aspergillus flavus spp. complex
CLSI 2020	N/A	N/A	N/A	N/A	N/A	N/A	N/A
EUCAST 2020	N/A	N/A	N/A	N/A	1	N/A	1
Candida albicans
CLSI 2020	N/A	0.25	2; (SDD^b) 4	0.12	N/A	N/A	N/A
EUCAST 2020	1	0.03	2	0.06	0.06	0.06	0.06
Candida glabrata
CLSI 2020	N/A	0.12	N/A	N/A	N/A	N/A	N/A
EUCAST 2020	1	0.06	0.001	N/A	N/A	N/A	N/A
Candida krusei
CLSI 2020	N/A	0.25	N/A	0.5	N/A	N/A	N/A
EUCAST 2020	1	0.06	N/A	N/A	N/A	N/A	N/A
Candida dubliniensis
CLSI 2020	N/A	N/A	N/A	N/A	N/A	N/A	N/A
EUCAST 2020	N/A	N/A	2	0.06	0.06	0.06	0.06
Candida guilliermondii
CLSI 2020	N/A	2	N/A	N/A	N/A	N/A	N/A
EUCAST 2020	N/A	N/A	N/A	N/A	N/A	N/A	N/A

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The susceptible breakpoints of antifungals against Candida lusitaniae and Candida auris are lacking in the both guidelines in 2020. N/A, not applicable.

SDD, susceptible dose dependent.

TABLE 5.

Pharmacokinetic profiles and pharmacodynamic indices of antifungal agents (antimold triazoles, anidulafungin, and liposomal amphotericin B complex) against the studied molds^a

Antibiotic and dosage (PD indices against molds)	PK profile
Antibiotic and dosage (PD indices against molds)	C_max (μg/mL), total form drug	Half-life (h)	Protein binding (%)	fAUC_0–24 (mg · h/L)	C_ELF (μg/mL)	ELF/plasma ratio
Voriconazole (%T>MIC)	7~8 (6 mg/kg bid on day 1, then 4 mg/kg bid since day 2)	6	58	Mean, 24.8 (4 mg/kg)	Mean, 19.3	Mean, 11 (±8), calculated in terms of the concentrations
Posaconazole 400 mg bid (%T>MIC)	Mean, 3.2 (multiple doses of 400 mg bid)	24~27	98	73		0.86~1.02 in terms of AUC ratio; 0.20~0.31 in terms of total concentrations
Isavuconazole 372 mg every 8 h × 6 doses, and 372 mg once daily since day 3 (%T>MIC)	245~345 (mean, 295~300)	85~117	99	97		0.36~0.73 in terms of AUC ratio
Anidulafungin 100 mg once daily following 200 mg loading (%T>MIC, C_max)	7.0~7.2	40~50	99	98	0.9~1.1	0.15~0.37
Liposomal amphotericin B complex (C_max/MIC)	5.17 (±1.89, for total form); 1.08 (±0.31, for liberated form) (multiple doses of 4.55 ± 0.23 mg/kg/day)	400	98	168 (3 mg/kg/day)	1.60 (± 0.58) (4.55 ± 0.23 mg/kg/day)	1.54 (± 0.44) for liberated form

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C_max, maximal concentration in serum; bid, twice daily; fAUC_0–24, area under the concentration-time curve from 0 to 24 h; ELF, epithelial lining fluid; C_ELF, concentration in epithelial lining fluid; %T>MIC, the percentage of a dosage interval in which the serum level exceeds the MIC of a given organism.

In agreement with a 2007 to 2008 Korean study investigating the in vitro antifungal susceptibilities of 636 bloodstream isolates of Candida species (including C. albicans and C. glabrata) (15), the present susceptibility data showed that isolates of four Candida species exhibited excellent susceptibility rates to AMB and VRC (>85% and ≥99%, respectively) using the current guidelines. In addition, the FLC MIC₉₀s against isolates of C. guilliermondii and C. lusitaniae (16 and 1 μg/mL, respectively) were the same as those of the 2011 to 2016 Taiwanese survey (16).

A 2013 Korean study of 56 A. fumigatus isolates showed that the in vitro susceptibility rate to AMB was 91.1% (17), which was similar to that of a 2018 to 2021 Iranian survey (90.5%) (18). In contrast, a high in vitro NS rate of AMB against clinical A. fumigatus isolates (80.2% of which exhibited MICs of ≥4 μg/mL) was found in Hamilton, Canada in 2015 (19). The present antifungal study also revealed significantly lower in vitro susceptibility rates of AMB against 660 pulmonary A. fumigatus isolates (49.5%; Table 1) and 22 VRC-resistant A. fumigatus isolates (45.5%; Table 1) compared to a 2019 Spanish study (98.5% against 847 clinical A. fumigatus sensu lato isolates; P < 0.001) (20) and a 2010 to 2016 Portugal study (84.7% against 190 clinical A. fumigatus isolates; P < 0.001) (21). There is a significant diversity in the susceptibilities of AMB to A. fumigatus isolates collected from different countries. Consistent with the review by Posch et al. (22), A. terreus species complex exhibited relatively high MICs for AMB (Table 1) and high susceptibility rates to triazoles in this antifungal surveillance.

Consistent with another investigation (r = 0.885) (23), the MIC₉₀ values of ISA against IPA isolates enrolled in this study were also similar to those of VRC. A high NS rate of ISA against A. fumigatus isolates (22.6%) primarily collected from the thorax was reported in a 2018 to 2020 Danish survey (24). However, the ISA MIC₅₀ values of 0.12 to 1 μg/mL against various pulmonary Aspergillus species and a 7.3% NS rate of ISA against A. fumigatus in the present survey were similar to those of a 2012 to 2014 Denmark study (<0.125 to 2 μg/mL and 5.7%, respectively) (25). Apart from the use of agricultural triazole fungicides (8), a significantly elevated frequency of resistance to antimold triazoles in A. fumigatus was observed in high-temperature environments, including composts (8), greenhouses (26), and hot-climate countries such as Vietnam (27) and Pakistan (28). Further research is required to assess whether these factors contribute to the high NS rates of ISA in intrapulmonary A. fumigatus in Italy and the United Kingdom.

Liposomal AMB complexes have been used for the treatment of IFD for more than 20 years. The frequency of resistance to AMB in fungi was considered extremely rare because it directly binds to ergosterol, which is not genetically encoded and exerts fungicidal effects that are not physiologically favorable for developing resistance (8, 29). Due to lacking information about factors impacting AMB susceptibility, we have no idea about the cause(s) resulting in significant variations in the annual NS rates to AMB against worldwide intrapulmonary A. fumigatus isolates. However, Blum et al. addressed that an increased catalase activity after AMB exposure has been found in association with AMB resistance in Aspergillus species (19, 30). Additionally, through the analyses of single nucleotide polymorphisms, Fan et al. found that mutations on six kinds of genes (ERG3, TcsB, MpkB, MpkC, CatA, Fos1) in A. fumigatus are significantly associated with decreased ergosterol biosynthesis or defective reduction-oxidation homeostasis, conferring them resistant to AMB (31). The maximal concentration (C_max)/MIC ratio of 2.5 for AMB, an important PD target of AMB against A. fumigatus, is associated with near-maximal antifungal efficacy in a murine IPA model (32). The liposomal AMB complex, which is well-localized at lung infection sites, was shown to be considerably superior in vivo to deoxycholate AMB with regard to improving survival in a murine IPA model (33). However, according to PK data on the concentration of liposomal AMB complex in blood (liberated form, 1.08 ± 0.31 μg/mL) and its concentration at epithelial lining fluid (ELF) (1.60 ± 0.58 μg/mL) following administration with a dosage of 4 to 5 mg/kg/day for 5 to 7 days (Table 5) (34), a prescription of liposomal AMB complex with a dosage of >4 mg/kg/day for the treatment of IPA isolates with MICs of >0.5 μg/mL is estimated to be likely ineffective. This result corresponded to the findings of a low susceptibility rate against all A. fumigatus isolates (<50%) as assessed using the EUCAST 2020 guidelines (Table 1). In addition, although the susceptibility MIC breakpoints of AMB against A. flavus and A. terreus species complex are currently lacking in the EUCAST 2020 guidelines (13), according to Al-Saigh et al.’s in vitro investigation (35), we estimate that the liposomal AMB complex is also less effective against A. flavus and A. terreus species complex, which requires significantly higher C_maxs for effective killing than that against A. fumigatus (35).

An analysis of POS concentration monitoring in IPA treatment showed a strong clinical concentration-efficacy relationship (36). In this survey, the susceptibility rate of POS to intrapulmonary A. fumigatus isolates (18.9%; Table 1) was significantly different from that in a Spanish investigation (94 to 94.5%; P < 0.001) (20). However, the PK characteristics of POS (Table 5) include the following: the protein affinity was 98%, the half-life was 24 to 27 h (37), the mean plasma C_max was 3.2 μg/mL following administration of multiple doses of 400 mg twice daily (38), the ratio of penetration from plasma to ELF ranged from 0.20 to 0.31 in terms of total concentrations (39), and the mean value of the area under the concentration-time curve (AUC) from 0 to 12 h (AUC_0–12) in ELF ranged from 11.2 to 18.3 mg · h/L following oral administration of multiple doses of 400 mg twice daily in humans (40, 41). Furthermore, a supplementary PD target of the AUC/MIC ratio achieving 1-log killing of A. fumigatus was 2.07 ± 1.02 (6). Through the POS’s PK and PD data, we estimate that POS administered orally at multiple doses of 400 mg twice daily is likely an effective regimen for the treatment of intrapulmonary Aspergillus isolates with MICs of <0.5 μg/mL. Markedly contrasting with a low in vitro susceptibility against A. fumigatus (18.9%; Table 1), as assessed by the EUCAST 2020 criteria (13) from the aforementioned PK/PD data and MIC distributions, POS is a reliable salvage therapy against important pulmonary Aspergillus species as recommended by the ESCMID-ECMM-ERS guidelines. Similar to POS and consistent with the favorable treatment outcomes of IPA patients receiving therapy of ISA (MICs of ≥2 μg/mL for the implicated intrapulmonary Aspergillus isolates, day 42 mortality rate, 21.4% [3/14]) in the SECURE study (42), an excellent PK profile as well as PD index and good tolerability were observed for ISA (43 –45) against intrapulmonary isolates of Aspergillus species, including ISA-resistant Aspergillus isolates (Table 5).

Noncomparative studies have shown that therapy with capsofungin achieved a 30 to 90% success rate in the clinical treatment of IPA (46). According to a report published by Li et al. (37), the percentage of dosage interval in which the serum level exceeds the MIC (i.e., %T_>MIC) and the C_max at the infection sites (including ELF and alveolar macrophages [AM]) are critical determinants of the fungistatic activity of AFG. In this survey, the MIC₉₀ values of AFG against most intrapulmonary Aspergillus isolates ranged from 0.016 to 0.03 μg/mL (Table 2). Following intravenous administration of 200 mg loading and 100 mg once daily for more than 10 days, the AFG’s PK characteristics include the following: the protein affinity was 99% (47), the half-life was 40 to 50 h, total drug C_max was 7.0 to 7.2 μg/mL (48), and the AFG concentrations at ELF and AM were 0.9 to 1.1 and ≥37 μg/mL, respectively (49). According to the AFG’s PD parameters and MIC distributions against intrapulmonary isolates of Aspergillus species enrolled in this ATLAS study, we estimate that the standard-dose AFG regimen is likely to be potent against important IPA isolates. Nevertheless, the clinical efficacy of AFG monotherapy or in combination with other antifungals (AMB or VRC) against IPA in patients with hematological cancer is debatable (50).

This in vitro antifungal study has some limitations. First, some single-point alterations (G138C, Y431C, G434C, and G448S, etc.) (23) and other mutations involving TR₃₄/L98H, TR₃₄/L98H/S297T/F495I, and TR₄₆/Y121F/T298A, among others, in the CYP51A gene (encoding 14-α-demethylase, the main target of triazoles) sequence (8, 24, 25) were shown to be responsible for VRC resistance in A. fumigatus isolates; however, these VRC-resistant A. fumigatus isolates are not available for the resistance gene analyses. Second, the number of intrapulmonary A. fumigatus isolates collected from some ATLAS participant countries might be too low to perform susceptibility analysis. Third, the clonality of the VRC-resistant A. fumigatus isolates in this survey was not analyzed.

In conclusion, this in vitro 2017 to 2020 ATLAS investigation regarding the susceptibility profile of clinically important fungi showed high NS rates for AMB and POS against isolates of important IPA species. In contrast, ITC, ISA, and VRC were highly active in vitro against most IPA isolates worldwide, except in Italy and the United Kingdom. From the PK/PD profile of AFG and the relevant MIC distributions of AFG against IPA, we consider that this antifungal agent may have good potency against important IPA species, although its clinical anti-IPA efficacy needs further deliberative evaluation. These data highlight the need for continued surveillance of the in vitro activities of the available antifungals.

MATERIALS AND METHODS

ATLAS protocol.

In 2006, Pfizer Pharmaceutical (New York City, NY, USA) conducted the ATLAS project to investigate the global in vitro susceptibility data of important microorganisms implicated in clinical infections. The National Taiwan University Hospital (NTUH) (Taipei, Taiwan), a 2,500-bed tertiary care center in northern Taiwan, has participated in the ATLAS program since 2012. The ATLAS program was approved by the institutional review board of each participating center, including NTUH (NTUH 201211047RSC).

Enrolled fungal isolates.

Most Candida parapsilosis and Candida tropicalis isolates show excellent in vitro susceptibility to FLC (16). Other than C. parapsilosis and C. tropicalis, in the ATLAS antifungal survey, we enrolled isolates of some clinically important Candida species (including C. albicans, C. auris, C. dubliniensis, C. glabrata, C. guilliermondii, C. krusei, and C. lusitaniae [13, 16]) that were collected from sterile body sites, including bone tissue, other biopsied tissue, blood, and fluid aspirated from the intra-articular, cerebrospinal, peritoneal, or pleural space. In addition, all enrolled Aspergillus isolates were collected from secretions of the lower respiratory tract (expectorated sputum, tracheal aspirate, and bronchoalveolar lavage or wash fluid) or the biopsied tissue of the lung parenchyma. Because the MIC data of ISA against fungi (including important Candida and Aspergillus species) collected from the ATLAS database have been available since 2017, the 2017 to 2020 antifungal MIC results in the ATLAS database were extracted for analysis in this study.

Species identification.

Sabouraud dextrose agar (SDA) was used for the culture of Aspergillus species. In addition, SDA, Sabouraud brain heart infusion agar, or both were used for culture of Candida species. Species were first identified using macro- and micromorphology at each participating center. The species were further confirmed using thermotolerance (incubation at 37°C and 43°C) and matrix-assisted laser desorption ionization–time of flight mass spectrometry (Bruker, Bremen, Germany) for Candida species and using thermotolerance (incubation at 50°C) for A. fumigatus isolates, respectively, at the International Health Management Associates (Schaumburg, IL, USA) prior to susceptibility testing. In this study, the term “species complex” for some Aspergillus species other than A. fumigatus in the absence of detailed molecular characterization was used as stated elsewhere (25). According to the ATLAS protocol, only the first isolate from a single patient was included in the ATLAS program.

Criteria for susceptibility interpretation.

Broth microdilution susceptibility testing was used for Aspergillus and Candida species in accordance with the CLSI M38 and CLSI M51 standards, respectively (51, 52). As antimold triazole-resistant A. fumigatus isolates have been detected in many regions worldwide (7), we also explored the susceptibility of antifungals against VRC-resistant A. fumigatus isolates in this survey. The concentration range tested for antifungals was 0.002 to 16 μg/mL.

Statistical analysis.

Categorical variables are expressed as percentages of the total number of isolates. The differences in susceptibility rates between antifungals against Aspergillus and Candida species were analyzed using the chi-square test as appropriate. When the susceptibility MIC breakpoints against specific Aspergillus species were lacking, the MIC distributions of a given antifungal against different isolates of Aspergillus species were compared using the Mann-Whitney U test as appropriate. Pearson’s correlation analysis and calculation of variance (standard deviation) were used to analyze the trend and degree of deviation, respectively, regarding the annual susceptibility rates of the three antifungals against intrapulmonary A. fumigatus isolates collected between 2017 and 2020. All statistical calculations were two-tailed, and a P value of <0.05 was considered statistically significant. All statistical analyses were performed using SPSS version 17.0 (Chicago, Armonk, NY, USA).

Ethical approval.

The institutional review board of each participating center, including the National Taiwan University Hospital (Taipei, Taiwan) [NTUH 201211047RSC], approved the ATLAS study.

Supplementary Material

Reviewer comments

reviewer-comments.pdf^{(215.3KB, pdf)}

ACKNOWLEDGMENTS

This study was supported by Pfizer Pharmaceutical (New York, NY).

We declare no competing interests.

Contributor Information

Po-Ren Hsueh, Email: hsporen@gmail.com.

Joshua J. Obar, Geisel School of Medicine at Dartmouth

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[B19] 19.Ashu EE, Korfanty GA, Samarasinghe H, Pum N, You M, Yamamura D, Xu J. 2018. Widespread amphotericin B-resistant strains of Aspergillus fumigatus in Hamilton. Infect Drug Resist 11:1549–1555. doi: 10.2147/IDR.S170952. [DOI] [PMC free article] [PubMed] [Google Scholar]

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[B28] 28.Saleem S, Naz SA, Shafique M, Jabeen N, Ahsan SW. 2018. Fungal contamination in smokeless tobacco products traditionally consumed in Pakistan. J Pak Med Assoc 68:1471–1477. [PubMed] [Google Scholar]

[B29] 29.Robbins N, Caplan T, Cowen LE. 2017. Molecular evolution of antifungal drug resistance. Annu Rev Microbiol 71:753–775. doi: 10.1146/annurev-micro-030117-020345. [DOI] [PubMed] [Google Scholar]

[B30] 30.Blum G, Perkhofer S, Haas H, Schrettl M, Würzner R, Dierich MP, Lass-Flörl C. 2008. Potential basis for amphotericin B resistance in Aspergillus terreus. Antimicrob Agents Chemother 52:1553–1555. doi: 10.1128/AAC.01280-07. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B31] 31.Fan Y, Wang Y, Xu J. 2020. Comparative genome sequence analyses of geographic samples of Aspergillus fumigatus-relevance for amphotericin B resistance. Microorganisms 8:1673. doi: 10.3390/microorganisms8111673. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B32] 32.Al-Nakeeb Z, Petraitis V, Goodwin J, Petraitiene R, Walsh TJ, Hope WW. 2015. Pharmacodynamics of amphotericin B deoxycholate, amphotericin B lipid complex, and liposomal amphotericin B against Aspergillus fumigatus. Antimicrob Agents Chemother 59:2735–2745. doi: 10.1128/AAC.04723-14. [DOI] [PMC free article] [PubMed] [Google Scholar]

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PERMALINK

In Vitro Susceptibilities of Worldwide Isolates of Intrapulmonary Aspergillus Species and Important Candida Species in Sterile Body Sites against Important Antifungals: Data from the Antimicrobial Testing Leadership and Surveillance Program, 2017–2020

Shio-Shin Jean

Hung-Jen Yang

Po-Chuen Hsieh

Yu-Tsung Huang

Wen-Chien Ko

Po-Ren Hsueh

Roles

ABSTRACT

INTRODUCTION

RESULTS

Number of isolates of Aspergillus and Candida species.

Susceptibility data of isolates of intrapulmonary Aspergillus spp. against antifungals.

FIG 1.

TABLE 1.

The MIC distributions of AFG against isolates of various Aspergillus species.

TABLE 2.

Susceptibility rates of AMB and ISA against A. fumigatus collected from different ATLAS participant countries.

FIG 2.

Susceptibility rates of antifungals against important Candida spp.

TABLE 3.

FIG 3.

DISCUSSION

TABLE 4.

TABLE 5.

MATERIALS AND METHODS

ATLAS protocol.

Enrolled fungal isolates.

Species identification.

Criteria for susceptibility interpretation.

Statistical analysis.

Ethical approval.

Supplementary Material

ACKNOWLEDGMENTS

Contributor Information

REFERENCES

Associated Data

Supplementary Materials

ACTIONS

PERMALINK

RESOURCES

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