Evaluation of the Activity of Triazoles Against Non-fumigatus Aspergillus and Cryptic Aspergillus Species Causing Invasive Infections Tested in the SENTRY Program.

The activity of isavuconazole and other triazoles against non-fumigatus (non-AFM) Aspergillus causing invasive aspergillosis was evaluated. A total of 390 non-AFM isolates were collected (1/patient) in 2017-2021 from 41 hospitals. Isolates were identified by matrix-assisted laser desorption ionization-time of flight mass spectrometry and/or internal spacer region/ß-tubulin sequencing and tested by Clinical and Laboratory Standards Institute (CLSI) broth microdilution. CLSI epidemiological cutoff values were applied, where available. Isavuconazole showed activity against Aspergillus sections Flavi (n = 122; minimum inhibitory concentration [MIC]50/90, 0.5/1 mg/L), Terrei (n = 57; MIC50/90, 0.5/0.5 mg/L), Nidulantes (n = 34; MIC50/90, 0.12/0.25 mg/L), Versicolores (n = 7; MIC50, 1 mg/L), and Circumdati (n = 2; MIC range, 0.12-2 mg/L). Similar activity was displayed by other triazoles against those Aspergillus sections. Most of the isolates from Aspergillus sections Fumigati (n = 9), Nigri (n = 146), and Usti (n = 12) exhibited elevated MIC values to isavuconazole (MIC50/90, 2/-, 2/4, and 2/8 mg/L), voriconazole (MIC50/90, 2/-, 1/2, and 4/8 mg/L), itraconazole (MIC50/90, 2/-, 2/4, and 8/>8 mg/L), and posaconazole (MIC50/90, 0.5/-, 0.5/1, and >8/>8 mg/L), respectively. Isavuconazole was active (MIC values, ≤1 mg/L) against Aspergillus parasiticus, Aspergillus tamarii, Aspergillus nomius, Aspergillus nidulans, Aspergillus unguis, Aspergillus terreus, Aspergillus alabamensis, and Aspergillus hortai, while isavuconazole MIC values between 2 and 8 mg/L were observed against cryptic isolates from Aspergillus section Fumigati. Isavuconazole inhibited 96.1% of Aspergillus niger and 80.0% of Aspergillus tubingensis at ≤4 mg/L, the CLSI wild-type cutoff value for A niger. Voriconazole, itraconazole, and posaconazole showed similar activity to isavuconazole against most cryptic species. Isavuconazole exhibited potent in vitro activity against non-AFM; however, the activity of triazoles varies among and within cryptic species.

In vitro activity of manogepix and comparators against infrequently encountered yeast and mold isolates from the SENTRY Surveillance Program (2017-2022).

Manogepix is a potent new antifungal agent targeting the fungal Gwt1 enzyme. Manogepix has previously demonstrated potent in vitro activity against clinical isolates of both Candida (except Candida krusei) and Aspergillus species. This study determined the in vitro activity of manogepix and comparators against a large collection of infrequently encountered yeast and molds. Manogepix demonstrated potent in vitro activity against infrequently encountered yeasts exhibiting elevated MIC values to other drug classes, including Candida spp. (MIC50/90, 0.008/0.12 mg/L), Saprochaete clavata (Magnusiomyces clavatus) (MIC50/90, 0.03/0.06 mg/L), Magnusiomyces capitatus (MICrange, 0.016-0.06 mg/L), Rhodotorula minuta (MIC, 0.016 mg/L), and Rhodotorula mucilaginosa (MIC50/90, 0.03/0.12 mg/L). Similarly, manogepix was active against infrequently encountered mold isolates and strains exhibiting elevated MIC/MEC values to echinocandins, azoles, and amphotericin B, including Coprinopsis cinerea (MEC, 0.004 mg/L), Fusarium spp. (MEC50/90, 0.016/0.06 mg/L), Fusarium (Gibberella) fujikuroi species complex (MEC50/90, 0.016/0.03 mg/L), Lomentospora prolificans (MEC50/90, 0.03/0.06 mg/L), Microascus cirrosus (MEC, 0.008 mg/L), Paecilomyces spp. (MEC50/90, ≤0.008/0.016 mg/L), Pleurostomophora richardsiae (MEC, 0.06 mg/L), Sarocladium kiliense (MEC range, 0.016-0.12 mg/L), and Scedosporium spp. (MEC50/90, 0.03/0.06 mg/L). Manogepix demonstrated potent activity against a majority of the infrequently encountered yeast and mold isolates tested including strains with elevated MIC/MEC values to other drug classes. Additional clinical development of manogepix (fosmanogepix) in difficult-to-treat, resistant fungal infections is warranted.

Plain language summary: Did the COVID-19 pandemic change the resistance to current antifungal medicines?

WHAT IS THIS SUMMARY ABOUT?: Previous research shows that patients with COVID-19 have a high chance of getting fungal infections. Medicines called antifungals are used to treat fungal infections. However, some fungi are resistant, which means the fungi are not killed by the antifungals and they keep growing, which can make the patients sicker and even die. This is a summary of a study that looked at whether different types of fungi and their resistance to antifungals changed from before COVID-19 to during the pandemic. WHAT WERE THE RESULTS?: We found that some fungi were more common before while others were more common during the pandemic. We also observed that resistance to antifungals did not change much either between fungi collected before and during the COVID-19 pandemic. WHAT DO THE RESULTS OF THE STUDY MEAN?: Knowing which fungal species are resistant to each antifungal can help doctors choose the best treatment. The results from this study may help scientists understand the effect of the COVID-19 pandemic on antifungal resistance.

Use of isavuconazole antifungal medicine to treat mold infections in Asia and the Western Pacific region: a plain language summary.

WHAT IS THIS SUMMARY ABOUT?: Molds are types of fungus that can invade humans. It can cause a disease called invasive mold infection (IMI) and make people sick or cause death. This is a summary of a study that looked at mold samples collected from people in Asia and the Western Pacific region to check if an antifungal medicine called isavuconazole (ISC) can stop the growth of or kill these molds. WHAT WERE THE RESULTS?: One type of mold known as Aspergillus or type 1 molds, was more common than other molds. Antifungal medicines including ISC, posaconazole, voriconazole, and itraconazole slowed or stopped the growth of the type 1 molds. ISC was very active in slowing or stopping the growth of this mold. Other molds, known as non-Aspergillus or type 2 mold, were less common. The antifungals medicines mentioned above were able to slow or stop the growth of some but not all of the type 2 molds. WHAT DO THE RESULTS OF THE STUDY MEAN?: ISC stopped the growth of most type 1 molds and was as good as the other antifungal medicines against type 2 molds. WHAT IS THE PURPOSE OF THIS PLAIN LANGUAGE SUMMARY?: The purpose of this plain language summary is to help you to understand the findings from recent research. The results of this study may differ from those of other studies. Health professionals should make treatment decisions based on all available evidence not on the results of a single study.

A plain language summary of how some fungi samples that show resistance to antifungal medicines have changes in their genes.

WHAT IS THIS SUMMARY ABOUT?: Aspergillus fumigatus (shortened to A. fumigatus) is a fungus (plural: fungi) that can cause a serious infection in some people. A. fumigatus can become resistant to medicines known as azoles (isavuconazole, itraconazole, posaconazole, and voriconazole). This means they stop working and are not able to kill the fungus. Fungi can become resistant through changes in their genes, which are called mutations. Scientists looked at previously collected samples from people infected with A. fumigatus and found that 36 of the samples showed resistance to an azole. In 35 of these samples, scientists looked for mutations in 50 genes. These 50 genes are known to play a role in azole resistance and/or are important for fungal survival. WHAT WERE THE RESULTS?: In total, 18 out of 36 samples (50%) showed resistance to isavuconazole only. Of these, 12 had mutations in 4 genes important for fungal survival (called erg3C, erg2, erg7B and erg4B). Mutations were found in 2 genes that are the most common causes of azole resistance (called cyp51A and cyp51B). The most common mutation, called cyp51A TR34/L98H, was found in 9 samples. Of these, 8 samples showed resistance to all 4 of the azoles tested. WHAT DO THE RESULTS OF THE STUDY MEAN?: Studying mutations that make fungi resistant to medicines helps to make sure that people with fungal infections get treated with medicines that will work for them.

Trends in the susceptibility of U.S. Acinetobacter baumannii-calcoaceticus species complex and Stenotrophomonas maltophilia isolates to minocycline, 2014-2021.

IMPORTANCE: Acinetobacter baumannii-calcoaceticus species complex and Stenotrophomonas maltophilia are opportunistic, non-fermentative Gram-negative organisms that can cause serious hospital-acquired infections in immunocompromised patients. These pathogens are inherently resistant to several common drug classes and often acquire other resistance mechanisms, making them difficult to treat. In this study, we analyzed the trends of susceptibility of over 2,500 U.S. bacterial isolates collected from hospitalized patients over an 8-year period to minocycline, which is used to treat infections caused by these pathogens. These in vitro data suggest that minocycline is a useful treatment option for infections caused by Acinetobacter baumannii-calcoaceticus species complex or Stenotrophomonas maltophilia.

Susceptibility patterns of amphotericin B, itraconazole, posaconazole, voriconazole and caspofungin for isolates causing invasive mould infections from the SENTRY Antifungal Surveillance Program (2018-2021) and application of single-site epidemiological cutoff values to evaluate amphotericin B activity.

We evaluated the activity of amphotericin B, itraconazole, posaconazole, voriconazole and caspofungin against 1468 invasive moulds collected worldwide from 2018 to 2021. Most (>92%) of the Aspergillus spp. isolates were wildtype (WT) to amphotericin B, caspofungin and the azoles. Azole-non-wildtype A. fumigatus rates were higher in Europe (9.5%) and North America (9.1%) than Latin America (0.0%; only 12 isolates) and the Asia-Pacific region (5.3%). Amphotericin B and caspofungin were active against azole-non-wildtype A. fumigatus isolates. Posaconazole and amphotericin B were the most active agents against the Mucorales. Among the less common moulds, several expressed a pan-azole-resistant phenotype; many of these species also showed elevated MIC values (MIC, >2 mg/L) for amphotericin B and caspofungin. Although most isolates of Aspergillus spp. remain WT to the azoles, azole resistance is increasing in both North America and Europe. Amphotericin B and caspofungin exhibit potentially useful activity against azole-resistant A. fumigatus.

In Vitro Activity of Isavuconazole and Other Mould-Active Azoles against Aspergillus fumigatus with and without CYP51 Alterations.

Azole resistance in Aspergillus fumigatus (AFM) is mainly associated with mutations in CYP51A and its promoter region or its homologue CYP51B. We evaluated the in vitro activity of isavuconazole, itraconazole, posaconazole, and voriconazole against 660 AFM collected during 2017-2020. Isolates were tested via CLSI broth microdilution. CLSI epidemiological cutoff values were applied. Non-wildtype (NWT) isolates to azoles were screened for alterations in the CYP51 sequences using whole genome sequencing. Azoles had similar activities against 660 AFM isolates. Overall, AFM displayed WT MIC values to isavuconazole (92.7%), itraconazole (92.9%), posaconazole (97.3%), and voriconazole (96.7%). Only 66 isolates (10.0%) were NWT to 1 or more of the azoles, and 32 harbored one or more alterations in the CYP51 sequences. Of these, 29/32 (90.1%) were NWT to itraconazole, 25/32 (78.1%) were NWT to isavuconazole, 17/32 (53.1%) were NWT to voriconazole, and 11/32 (34.4%) were NWT to posaconazole. The most frequent alteration was CYP51A TR34/L98H, carried by 14 isolates. Four isolates carried the alteration I242V in CYP51A, and G448S; A9T, or G138C was carried by one isolate each. Multiple alterations in CYP51A were detected in five isolates. Alterations in CYP51B were noted in seven isolates. Among 34 NWT isolates without -CYP51 alterations, WT rates to isavuconazole, itraconazole, voriconazole, and posaconazole were 32.4%, 47.1%, 85.3%, and 82.4%, respectively. Ten different CYP51 alterations were detected in 32/66 NWT isolates. Alterations in AFM CYP51 sequences can have variable effects on the in vitro activity of the azoles that are best delineated by testing all triazoles.

Antifungal Activity of Isavuconazole and Comparator Agents against Contemporaneous Mucorales Isolates from USA, Europe, and Asia-Pacific.

Isavuconazole is the only US FDA-approved antifungal for treating invasive mucormycosis. We evaluated isavuconazole activity against a global collection of Mucorales isolates. Fifty-two isolates were collected during 2017-2020 from hospitals located in the USA, Europe, and the Asia-Pacific. Isolates were identified by MALDI-TOF MS and/or DNA sequencing and susceptibility tested by the broth microdilution method following CLSI guidelines. Isavuconazole (MIC50/90, 2/>8 mg/L) inhibited 59.6% and 71.2% of all Mucorales isolates at ≤2 mg/L and ≤4 mg/L, respectively. Among comparators, amphotericin B (MIC50/90, 0.5/1 mg/L) displayed the highest activity, followed by posaconazole (MIC50/90, 0.5/8 mg/L). Voriconazole (MIC50/90, >8/>8 mg/L) and the echinocandins (MIC50/90, >4/>4 mg/L) had limited activity against Mucorales isolates. Isavuconazole activity varied by species and this agent inhibited at ≤4 mg/L 85.2%, 72.7%, and 25% of Rhizopus spp. (n = 27; MIC50/90, 1/>8 mg/L), Lichtheimia spp. (n = 11; MIC50/90, 4/8 mg/L), and Mucor spp. (n = 8; MIC50, >8 mg/L) isolates, respectively. Posaconazole MIC50/90 values against Rhizopus, Lichtheimia, and Mucor species were 0.5/8 mg/L, 0.5/1 mg/L, and 2/- mg/L, respectively; amphotericin B MIC50/90 values were 1/1 mg/L, 0.5/1 mg/L, and 0.5/- mg/L, respectively. As susceptibility profiles varied among Mucorales genera, species identification and antifungal susceptibility testing are advised whenever possible to manage and monitor mucormycosis.

Ceftolozane/Tazobactam Activity Against Drug-Resistant Pseudomonas aeruginosa and Enterobacterales Causing Healthcare-Associated Infections in Eight Asian Countries: Report from an Antimicrobial Surveillance Program (2016-2018).

Purpose: To evaluate the in vitro activity of ceftolozane/tazobactam and comparator agents tested against Pseudomonas aeruginosa and Enterobacterales isolates from hospitalised patients in Asia. Ceftolozane/tazobactam is an antipseudomonal cephalosporin combined with a well-established ß-lactamase inhibitor. Methods: A total of 2038 Gram-negative organisms (376 P. aeruginosa and 1662 Enterobacterales) were collected consecutively using a prevalence-based approach from 11 medical centres. Organisms were susceptibility tested by broth microdilution according to CLSI guidelines. CLSI and EUCAST breakpoint criteria were used. Results: Ceftolozane/tazobactam was the most potent (MIC50/90, 0.5/4 mg/L) ß-lactam agent tested against P. aeruginosa isolates, inhibiting 91.0% of the isolates at an MIC of ≤4 mg/L. P. aeruginosa exhibited high rates of susceptibility to amikacin (92.0/92.0% [CLSI/EUCAST]) and colistin by EUCAST criteria only (99.2% intermediate [CLSI]/99.2% susceptible [EUCAST]). Ceftolozane/tazobactam (MIC50/90, 0.25/16 mg/L; 86.8/86.8% susceptible [CLSI/EUCAST]) and meropenem (MIC50/90, 0.03/0.12 mg/L; 93.0/93.3% susceptible [CLSI/EUCAST]) were the most active compounds tested against Enterobacterales. Isolates displayed susceptibility rates to other ß-lactam agents, ranging from 81.5/77.7% for piperacillin/tazobactam, 66.0/64.5% for cefepime, and 65.3/60.9% for ceftazidime using CLSI/EUCAST breakpoints. Among the Enterobacterales isolates, 6.8% were carbapenem-resistant Enterobacterales (CRE) and 29.6% exhibited an extended-spectrum ß-lactamase (ESBL) non-CRE phenotype. Ceftolozane/tazobactam showed good activity against ESBL non-CRE phenotype strains of Enterobacterales (MIC50/90, 0.5/8 mg/L; 84.8/84.8% susceptible), but not against isolates with a CRE phenotype (MIC50/90, >32/>32 mg/L). Conclusion: Ceftolozane/tazobactam was the most active ß-lactam agent tested against P. aeruginosa and demonstrated higher in vitro activity than the available cephalosporins when tested against Enterobacterales from Asian countries.

Multicenter Collaborative Study of the Interaction of Antifungal Combinations against Candida Spp. by Loewe Additivity and Bliss Independence-Based Response Surface Analysis.

Combination antifungal therapy is widely used but not well understood. We analyzed the spectrophotometric readings from a multicenter study conducted by the New York State Department of Health to further characterize the in vitro interactions of the major classes of antifungal agents against Candida spp. Loewe additivity-based fractional inhibitory concentration index (FICi) analysis and Bliss independence-based response surface (BIRS) analysis were used to analyze two-drug inter- and intraclass combinations of triazoles (AZO) (voriconazole, posaconazole), echinocandins (ECH) (caspofungin, micafungin, anidulafungin), and a polyene (amphotericin B) against Candida albicans, C. parapsilosis, and C. glabrata. Although mean FIC indices did not differ statistically significantly from the additivity range of 0.5−4, indicating no significant pharmacodynamic interactions for all of the strain−combinations tested, BIRS analysis showed that significant pharmacodynamic interactions with the sum of percentages of interactions determined with this analysis were strongly associated with the FIC indices (Χ2 646, p < 0.0001). Using a narrower additivity range of 1−2 FIC index analysis, statistically significant pharmacodynamic interactions were also found with FICi and were in agreement with those found with BIRS analysis. All ECH+AB combinations were found to be synergistic against all Candida strains except C. glabrata. For the AZO+AB combinations, synergy was found mostly with the POS+AB combination. All AZO+ECH combinations except POS+CAS were synergistic against all Candida strains although with variable magnitude; significant antagonism was found for the POS+MIF combination against C. albicans. The AZO+AZO combination was additive for all strains except for a C. parapsilosis strain for which antagonism was also observed. The ECH+ECH combinations were synergistic for all Candida strains except C. glabrata for which they were additive; no antagonism was found.

Tedizolid in vitro activity against Gram-positive clinical isolates causing bone and joint infections in hospitals in the USA, Europe, Latin America, and the Asia-Pacific region (2015-2019).

As bone and joint infections (BJIs) frequently require prolonged, systemic antibiotic use, tedizolid is an attractive candidate for BJI therapy in adults and children. Tedizolid activity was evaluated against 1,193 Gram-positive isolates causing BJI in American (USA), European (EUR), Latin American (LATAM), and Asian-Pacific (APAC) medical centers. Isolates consecutively collected from 2015 to 2019 were susceptibility tested by CLSI broth microdilution. Staphylococcus aureus (69.2%) was the most common pathogen with a 25.9% MRSA rate and tedizolid MIC50/90 of 0.12/0.25 mg/L (100% susceptible). Tedizolid exhibited MIC50/90 values of 0.12/0.12 mg/L (98.9% susceptible) for CoNS (7.5% of BJI), 0.12/0.25 mg/L for streptococci, and 0.25/0.25 mg/L for enterococci. Overall, high susceptibility rates (100.0%) for linezolid, daptomycin, and vancomycin were observed. In summary, tedizolid had potent in vitro activity against contemporary Gram-positive cocci causing BJI in adults and children in USA, EUR, LATAM, and APAC hospitals.

Activity of Ceftolozane-Tazobactam Against Gram-Negative Isolates from Australia and New Zealand as part of the PACTS Surveillance 2016-2018.

OBJECTIVES: Ceftolozane-tazobactam (C-T) is an anti-pseudomonal cephalosporin combined with a well-described ß-lactamase inhibitor. Ceftolozane-tazobactam has enhanced activity against Pseudomonas aeruginosa, and activity against Enterobacterales isolates that produce extended-spectrum ß-lactamases (ESBLs) or AmpC cephalosporinases. In this study, we analysed the susceptibility of Gram-negative isolates to C-T and comparators collected in Australia and New Zealand from 2016 to 2018 as part of the Program to Assess Ceftolozane-Tazobactam Susceptibility (PACTS) surveillance. METHODS: A total of 1693 nonduplicate Enterobacterales and 435 P. aeruginosa isolates were collected prospectively from hospitalized patients in six medical centres in Australia and two in New Zealand. Susceptibilities (S) to C-T and comparators were determined using broth microdilution. EUCAST breakpoints were used. Isolates with multi-drug resistant (MDR), extensively drug resistant (XDR), extended-spectrum ß-lactamase non-carbapenem resistant (ESBL, non-CRE) phenotype, and CRE were analysed. RESULTS: For P. aeruginosa, 97.5% were S to C-T while 89.9% were S to meropenem. According to EUCAST criteria, 86.4% were susceptible-increased exposure to piperacillin-tazobactam. MDR and XDR P. aeruginosa isolates had 76.7% and 65.4% S to C-T, respectively; 34.9% and 19.2% S to meropenem, respectively; and 23.3% and 15.4% were susceptible-increased exposure to piperacillin-tazobactam, respectively. Meropenem (99.8% S), amikacin (99.1% S), and C-T (96.5% S) were the most active against Enterobacterales. Susceptibilities to C-T were 94.3% for ESBL, non-CRE phenotype, and 78.4% for MDR isolates. Only three CRE and five XDR isolates were identified. CONCLUSIONS: These in vitro data indicate that C-T is a potent antimicrobial with activity against MDR and XDR P. aeruginosa, as well as ESBL, non-CRE phenotype isolates and MDR Enterobacterales.

Evaluation of the Post-Antifungal Effect of Rezafungin and Micafungin against Candida albicans, Candida parapsilosis and Candida glabrata.

Rezafungin, a new echinocandin with an extended half-life, exhibits potent activity against Candida spp. Aside from the MIC, specific interactions between antifungal and isolate, including the duration of anti-infective activity, may impact dose interval choices and infection outcome. We evaluated rezafungin and micafungin post-antifungal effect (PAFE) against C. albicans, C. parapsilosis and C. glabrata. Six Candida spp. isolates were tested, including two of each species, C. albicans, C. parapsilosis and C. glabrata. Antifungal susceptibility testing was performed using the CLSI reference broth microdilution method. Antifungal concentrations of 1x, 4x and 16x the baseline MIC were used for PAFE determinations. Colony counts were performed at T0 (pre-exposure), after the 1-h drug exposure, after the cell wash (T1), and at T2, T4, T8, T12, T24 and T48 h. Rezafungin PAFE results were equivalent to micafungin PAFE values for one C. albicans (>14.9 h) and both C. glabrata (>40 h) isolates for all concentrations tested. The rezafungin and micafungin PAFEs could not be determined against one C. albicans isolate. Prolonged PAFE results were also noted for rezafungin (range, 18.4 to >40 h) against both C. parapsilosis isolates at all concentrations, while no micafungin PAFE or a short PAFE (range, 1.8 to 7.4 h) was observed against these organisms, except at 16x bMIC. Rezafungin showed sustained growth inhibition following drug removal and displayed equivalent or longer PAFE values than micafungin against all tested Candida spp.

Ceftobiprole activity against Gram-positive and Gram-negative pathogens causing bone and joint infections in the United States from 2016 to 2020.

Bone and joint infections (BJIs) present significant treatment challenges. Ceftobiprole, a broad-spectrum cephalosporin with activity against methicillin-resistant Staphylococcus aureus, is approved in many European and other countries for the treatment of adults with community- and hospital-acquired pneumonia, excluding ventilator-associated pneumonia. In this study, the in vitro activity of ceftobiprole and comparators was evaluated against clinical isolates collected from BJIs in the USA from 2016 to 2020. Gram-positive pathogens made up 70.6% of all BJI isolates and included S. aureus (47.4% of all isolates), ß-hemolytic streptococci, coagulase-negative staphylococci, and Enterococcus faecalis. Ceftobiprole was highly active against S. aureus (MIC50/90 values, 0.5/1 mg/L; 99.6% susceptible using the European Committee on Antimicrobial Susceptibility Testing susceptibility breakpoint of ≤2 mg/L for the treatment of pneumonia patients) and exhibited potent activity against the other Gram-positive cocci and the predominant BJI Gram-negative groups. These results support the further evaluation of ceftobiprole for this potential indication.

Plain language summary: Does a person's age affect how common fungal infections are and how well drugs can kill the infections?

WHAT IS THIS SUMMARY ABOUT?: Fungi are types of microbes that include molds and yeasts. Fungal infections can make people ill and can even cause death, especially in older people. They can be treated using antifungal drugs, but some fungi are drug resistant. This means the drug cannot kill the fungi. This is a summary based on a study that looked at fungal samples to find out more about antifungal drug resistance in adults younger than 65 compared with adults aged 65 and older. WHAT WERE THE RESULTS?: The study found that one type of drug-resistant fungus, called Candida parapsilosis, was more common in older people than in younger people. Another type, called Aspergillus fumigatus, was more common in younger people than in older people. We also found genetic changes in drug-resistant fungi. These changes could explain why the drugs did not work. WHAT DO THE RESULTS MEAN?: We hope that the findings from this study can help scientists create new treatments for drug-resistant fungal infections.

Azole resistance in Candida glabrata clinical isolates from global surveillance is associated with efflux overexpression.

OBJECTIVES: We evaluated the azole resistance mechanisms and epidemiology of fluconazole-resistant Candida glabrata from a global survey. METHODS: A total of 2992 Candida spp. isolates collected during 2018-2019 were susceptibility tested by the broth microdilution reference method following CLSI guidelines. Fluconazole-resistant C. glabrata isolates were submitted to whole genome sequencing and gene expression assays using qRT-PCR. RESULTS: Among 561 CGLA isolates tested, 34 (6.1%) were fluconazole resistant. These isolates were collected from 11 countries and mainly recovered from bloodstream infections (79.4%). All fluconazole-resistant C. glabrata isolates were non-wild type for voriconazole, 24/34 were non-wild type for posaconazole, but only 2/34 were non-wild type for itraconazole. Isavuconazole MIC values ranged from 0.25 to >4 mg/L. Fluconazole-resistant C. glabrata isolates belonged to 14 different sequence types (ST). None of the isolates exhibited alterations in ERG3 or ERG11, the target of azoles. All but two fluconazole-resistant isolates displayed overexpression of CgCDR1 (22/34; 64.7%) and/or CgCDR2 (26/34; 76.5%), while 16 isolates had both genes overexpressed. Overexpression of CgSNQ2 or ERG11 was not observed. Gain of function (GoF) alterations in the transcription factor CgPDR1 were noted in 14 isolates. Four (11.8%) isolates that were nonsusceptible to one or more echinocandins had FKS2 HS1 alterations (2 S663P and 2 F659Y/deletion). CONCLUSION: Fluconazole-resistant C. glabrata was driven by overexpression of CgCDR1 and/or CgCDR2. GoF alterations in PDR1 that have been associated with increased virulence were observed. Susceptibility results and surveillance data are needed to guide treatment for these isolates.

Impact of COVID-19 on the antifungal susceptibility profiles of isolates collected in a global surveillance program that monitors invasive fungal infections.

Studies demonstrated the impact of the COVID-19 pandemic in the prevalence and susceptibility profiles of bacterial and fungal organisms. We analyzed 4821 invasive fungal isolates collected during 2018, 2019, and 2020 in 48 hospitals worldwide to evaluate the impact of this event in the occurrence and susceptibility rates of common fungal species. Isolates were tested using the CLSI broth microdilution method. While the percentage of total isolates that were C. glabrata (n = 710 isolates) or C. krusei (n = 112) slightly increased in 2020, the percentage for C. parapsilosis (n = 542), A. fumigatus (n = 416), and C. lusitaniae (n = 84) significantly decreased (P < .05). Fluconazole resistance in C. glabrata decreased from 5.8% in 2018-2019 to 2.0% in 2020, mainly due to fewer hospitals in the US having these isolates (5 vs. 1 hospital). Conversely, higher fluconazole-resistance rates were noted for C. parapsilosis (13.9 vs. 9.8%) and C. tropicalis (3.5 vs. 0.7%; P < .05) during 2020. Voriconazole resistance also increased for these species. Echinocandin resistance was unchanged among Candida spp. Voriconazole susceptibility rates in A. fumigatus were similar in these two periods (91.7% in 2018 and 2019 vs. 93.0% in 2020). Changes were also noticed in the organisms with smaller numbers of collected isolates. We observed variations in the occurrence of organisms submitted to a global surveillance and the susceptibility patterns for some organism-antifungal combinations. As the COVID-19 pandemic is still ongoing, the impact of this event must continue to be monitored to guide treatment of patients affected by bacterial and fungal infections. LAY SUMMARY: Secondary infections were documented in COVID-19 patients. We compared the prevalence of invasive fungal isolates consecutively collected in 48 worldwide hospitals and their susceptibility patterns between 2020, the year of the global COVID-19 pandemic, and the two prior years.

Evaluation of Rezafungin Provisional CLSI Clinical Breakpoints and Epidemiological Cutoff Values Tested against a Worldwide Collection of Contemporaneous Invasive Fungal Isolates (2019 to 2020).

Rezafungin is a new echinocandin under development for the treatment of candidemia and invasive candidiasis. CLSI recently approved provisional susceptible-only breakpoints and epidemiological cutoff values for Candida spp. and rezafungin. The activities of rezafungin and comparators against 2019 to 2020 invasive fungal isolates was evaluated by applying the new CLSI breakpoints. Rezafungin demonstrated potent activity against Candida albicans (MIC50/MIC90, 0.03/0.06 mg/L; 100.0% susceptible), Candida tropicalis (MIC50/MIC90, 0.03/0.06 mg/L; 100% susceptible), Candida glabrata (MIC50/MIC90, 0.06/0.06 mg/L; 98.3% susceptible), Candida krusei (MIC50/MIC90, 0.03/0.03 mg/L; 100% susceptible), and Candida dubliniensis (MIC50/MIC90, 0.06/0.12 mg/L; 100% susceptible) when tested by the CLSI broth microdilution method. Rezafungin inhibited 99.6% of Candida parapsilosis isolates (MIC50/MIC90, 1/2 mg/L) at the susceptible breakpoint of ≤2 mg/L. All C. albicans, C. tropicalis, and C. krusei isolates, as well as most C. glabrata (96.2% to 97.9%) and C. parapsilosis (86.2% to 100%) isolates, were susceptible to comparator echinocandins. Fluconazole resistance was detected among 0.5%, 4.5%, 10.5%, and 1.2% of C. albicans, C. glabrata, C. parapsilosis, and C. tropicalis isolates, respectively. All echinocandins displayed limited activity against Cryptococcus neoformans. Rezafungin and other echinocandins were active against Aspergillus fumigatus (minimum effective concentration for 90% of isolates tested [MEC90] range, 0.015 to 0.06 mg/L) and Aspergillus section Flavi (MEC90 range, 0.015 to 0.03 mg/L). All but 16 (8.6%) A. fumigatus isolates were susceptible to voriconazole, and 100% of Aspergillus section Flavi isolates were WT to mold-active azoles. When applying the CLSI clinical breakpoints, rezafungin displayed high susceptibility rates (>98.0%) against Candida isolates from invasive fungal infections and showed potent activity against Aspergillus isolates.

Elderly versus nonelderly patients with invasive fungal infections: species distribution and antifungal resistance, SENTRY antifungal surveillance program 2017-2019.

We utilized the SENTRY surveillance database from 2017 through 2019 to address pathogen frequency and antifungal resistance among 4,497 clinical isolates of fungi from patients who were either ≥ 65 years (2,170 isolates) or between 18 and 64 years of age (2,327 isolates). The younger population was more frequently infected with non-Candida yeasts and non-Aspergillus moulds. Candida glabrata was more common in the older age group (P value = 0.02). Resistance to the triazole and echinocandin classes was less common in the elderly population (4.3% and 2.7%, respectively) compared to the younger age group (11.4% and 4.4%, respectively). Resistance to fluconazole in C. parapsilosis (11.4%) was elevated in the older patient group. Decreased susceptibility to the mould-active triazoles among A. fumigatus isolates was greater in the younger age group (7.8%) than the older age group (4.4%). These data emphasize the importance of species identification and antifungal susceptibility testing to guide the treatment of individual patients.