Echinocandins Research Articles

Candida albicans Genes Modulating Echinocandin Susceptibility of Caspofungin-Adapted Mutants Are Constitutively Expressed in Clinical Isolates with Intermediate or Full Resistance to Echinocandins.

The opportunistic fungus Candida albicans is the leading cause of invasive candidiasis in immune-compromised individuals. Drugs from the echinocandin (ECN) class, including caspofungin, are used as a first line of therapy against invasive candidiasis. The only known mechanism of clinical resistance to ECNs is point mutations in the FKS1 gene, which encodes the drug target. However, many clinical isolates developed decreased ECN susceptibilities in the absence of resistance-associated FKS1 mutations. We have identified 15 C. albicans genes that contribute to decreased drug susceptibility. We explored the expression of these 15 genes in clinical isolates with different levels of ECN susceptibility. We found that these 15 genes are expressed in clinical isolates with or without FKS1 mutations, including those strains that are less susceptible to ECNs. In addition, FKS1 expression was increased in such less susceptible isolates compared to highly susceptible isolates. Similarities of gene expression patterns between isolates with decreased ECN susceptibilities in the absence of FKS1 mutations and clinically resistant isolates with mutations in FKS1 suggest that clinical isolates with decreased ECN susceptibilities may be a precursor to development of resistance.

1947. Activity of Rezafungin against Echinocandin–Non-wild type C. glabrata Clinical Isolates from the Rezafungin Surveillance Program (2014–2021)

Abstract Background Fluconazole (FLC) resistance (R) is common in C. glabrata (CGLA). Echinocandins (ECHs) are often used as first-line therapy. R to ECHs has been associated with FKS1 and FKS2 gene alterations. Rezafungin (RZF), a new ECH approved by the US FDA to treat candidemia and invasive candidiasis, was evaluated against a collection of ECH–non-wild type (NWT) CGLA isolates. Methods A total of 1045 CGLA collected (1/patient) in 2014–2021 from 58 medical centers located in North America (NA; n=459; 20 centers), Europe (EU; n=396; 23 centers), Asia-Pacific (AP; n=130; 10 centers), and Latin America (LA, n=60; 5 centers) were identified by MALDI-TOF and/or sequencing and tested by CLSI broth microdilution. CLSI breakpoints (BP) and epidemiological cut-off values were applied. ECH NWT isolates were submitted to FKS analysis by whole genome sequencing. Results RZF showed similar activity to other ECHs against CGLA (Table), inhibiting 98.5% at ≤0.5 mg/L. Anidulafungin (ANF), caspofungin (CSF), and micafungin (MCF) susceptibility (S) rates were 96.2%, 97.5%, and 97.3%, respectively. ECH-NWT CGLA were detected in 42 isolates (4.0% overall): NA showed the highest rate of ECH NWT isolates (29; 6.3%), followed by EU (10; 2.5%), AP (2; 1.5%), and LA (1; 1.7%). The RZF S rate was 61.9% of ECH-NWT CGLA, while the S rate to ANF, CSF, and MCF was 21.4%, 40.5%, and 33.3%, respectively. Alteration in FKS genes were observed in 31 CGLA (73.8% of ECH NWT; 3.0% overall). RZF was active against >50% of these isolates. RFZ was also active against >90% of ECH-NWT CGLA carrying wildtype FKS genes. Equivalent activity was noted to other ECHs against ECH-NWT isolates. However, ECHs were 4 to 8-fold more active against ECH-NWT CGLA that did not display alterations in FKS genes than those with FKS alterations. FKS2 hot spot(HS)-1 alterations were observed in 22 isolates (12 displayed S663F), while FKS1-HS1 alterations were noted in 9 isolates (7 displayed S629P). FLC-R was observed in 6.9% of CGLA overall and 16.7% of the ECH-NWT isolates. Conclusion RZF demonstrated potent in vitro activity against CGLA and remained active against most isolates of CGLA displaying an ECH-NWT phenotype with or without FKS alterations. Disclosures Cecilia G. Carvalhaes, MD, PhD, AbbVie: Grant/Research Support|bioMerieux: Grant/Research Support|Cipla: Grant/Research Support|CorMedix: Grant/Research Support|Melinta: Grant/Research Support|Pfizer: Grant/Research Support Paul Rhomberg, BS, MT(ASCP), bioMerieux: Grant/Research Support|Melinta: Grant/Research Support|Pfizer: Grant/Research Support Abby Klauer, BS, Melinta: Grant/Research Support Lalitagauri M. Deshpande, PhD, Melinta: Grant/Research Support|Paratek: Grant/Research Support Mariana Castanheira, PhD, AbbVie: Grant/Research Support|Basilea: Grant/Research Support|bioMerieux: Grant/Research Support|Cipla: Grant/Research Support|CorMedix: Grant/Research Support|Entasis: Grant/Research Support|Melinta: Grant/Research Support|Paratek: Grant/Research Support|Pfizer: Grant/Research Support|Shionogi: Grant/Research Support

2115. Rezafungin Activity against Invasive Candidiasis Isolates Globally: Results from the 2022 Rezafungin Surveillance Program

Abstract Background Rezafungin (RZF) is a new echinocandin (ECH) approved by the US FDA to treat candidemia and invasive candidiasis (IC). Fluconazole (FLC) resistance (R) is a raising concern to treat IC, and ECHs are often used as first-line therapy. We evaluated the in vitro activity of RZF, caspofungin (CSF), micafungin (MCF), anidulafungin (ANF), and azoles against a global collection of 500 Candida isolates causing IC. Methods C. albicans (CA; 233 isolates; 46.6%), C. glabrata (CG; 102; 20.4%), C. parapsilosis (CP; 82; 16.4%), C. tropicalis (CT; 41; 8.2%), C. krusei (CK; 18; 3.6%), C. dubliniensis (CD; 15; 3.0%), and C. auris (CARS; 9; 1.8%) isolates were collected (1/patient) in 2022 from 52 medical centers located in Europe (EU; n=203; 19 centers), North America (NA; n=167; 14 centers), Asia-Pacific (AP; n=63; 8 centers), and Latin America (LA, n=67; 7 centers), identified by MALDI-TOF MS and/or sequencing and tested by CLSI broth microdilution. CLSI breakpoints (BP) were applied where available. CARS CDC tentative BPs were applied. Results RFZ exhibited activity against CA (Table) inhibiting 99.1% of the isolates overall, and 98.6%, 99.0%, 100%, and 100% of isolates from NA, EU, AP, and LA. Only 1 CA isolate (from US) displayed a FLC MIC value within the susceptible-dose dependent (SDD) category. CSP, ANF, and MCF showed S rates of 99.1% against CA. All but 1 CG isolate was susceptible (S) to RZF (99.0%S). CG S rates to CSP, ANF, MCF, and FLC were 98.0%, 98.0%, 97.1%, and 96.1% (SDD), respectively. All CP isolates were S to RZF, CSF, and MCF. However, only 84.1% of CP isolates were S to FLC. RZF and other ECHs inhibited all FLC-R isolates (10 total, 9 EU and 1 US). All CT and CK isolates were S to RZF and other ECHs. All CT were also S to azoles, and 94.4% of CK were S to VRC. Only RZF BPs are available by CLSI against CD (86.7%S). All CARS isolates (9 total; 4 EU, 3 NA, and 2 LA) were FLC-R; but 77.8% and 88.9% were S to RZF and other ECHs, respectively. Conclusion RZF demonstrated potent in vitro activity against invasive candidiasis isolates regardless of the region, and remained active against FLC-R CP and most of the FLC-R CARS isolates. Based on MIC50 and MIC90 results, RZF had similar activity to the other ECHs overall. Disclosures Cecilia G. Carvalhaes, MD, PhD, AbbVie: Grant/Research Support|bioMerieux: Grant/Research Support|Cipla: Grant/Research Support|CorMedix: Grant/Research Support|Melinta: Grant/Research Support|Pfizer: Grant/Research Support Paul Rhomberg, BS, MT(ASCP), bioMerieux: Grant/Research Support|Melinta: Grant/Research Support|Pfizer: Grant/Research Support Abby Klauer, BS, Melinta: Grant/Research Support Mariana Castanheira, PhD, AbbVie: Grant/Research Support|Basilea: Grant/Research Support|bioMerieux: Grant/Research Support|Cipla: Grant/Research Support|CorMedix: Grant/Research Support|Entasis: Grant/Research Support|Melinta: Grant/Research Support|Paratek: Grant/Research Support|Pfizer: Grant/Research Support|Shionogi: Grant/Research Support

Genome-Wide DNA Changes Acquired by Candida albicans Caspofungin-Adapted Mutants.

Drugs from the echinocandin (ECN) class are now recommended 'front-line' treatments of infections caused by a prevailing fungal pathogen, C. albicans. However, the increased use of ECNs is associated with a rising resistance to ECNs. As the acquisition of ECN resistance in C. albicans is viewed as a multistep evolution, determining factors that are associated with the decreased ECN susceptibility is of importance. We have recently identified two cohorts of genes that are either up- or downregulated in concert in order to control remodeling of cell wall, an organelle targeted by ECNs, in laboratory mutants with decreased ECN susceptibility. Here, we profiled the global DNA sequence of four of these adapted mutants in search of DNA changes that are associated with decreased ECN susceptibility. We find a limited number of 112 unique mutations representing two alternative mutational pathways. Approximately half of the mutations occurred as hotspots. Approximately half of mutations and hotspots were shared by ECN-adapted mutants despite the mutants arising as independent events and differing in some of their phenotypes, as well as in condition of chromosome 5. A total of 88 mutations are associated with 43 open reading frames (ORFs) and occurred inside of an ORF or within 1 kb of an ORF, predominantly as single-nucleotide substitution. Mutations occurred more often in the 5'-UTR than in the 3'-UTR by a 1.67:1 ratio. A total of 16 mutations mapped to eight genomic features that were not ORFs: Tca4-4 retrotransposon; Tca2-7 retrotransposon; lambda-4a long terminal repeat; mu-Ra long terminal repeat; MRS-7b Major Repeat Sequence; MRS-R Major Repeat Sequence; RB2-5a repeat sequence; and tL (CAA) leucine tRNA. Finally, eight mutations are not associated with any ORF or other genomic feature. Repeated occurrence of single-nucleotide substitutions in non-related drug-adapted mutants strongly indicates that these DNA changes are accompanying drug adaptation and could possibly influence ECN susceptibility, thus serving as factors facilitating evolution of ECN drug resistance due to classical mutations in FKS1.

Candida parapsilosis isolates carrying mutations outside FKS1 hotspot regions confer high echinocandin tolerance and facilitate the development of echinocandin resistance

Candida parapsilosis is a significant cause of candidemia worldwide. Echinocandin-resistant (ECR) and echinocandin-tolerant (ECT) C. parapsilosis isolates have been reported in various countries but are rare. Resistance and tolerance are predominantly caused by mutations related to the hotspot (HS) regions of the FKS1 gene. A relatively high proportion of clinical C. parapsilosis isolates carrying mutations outside the HS regions has been noted in some studies, but an association with echinocandin (EC) resistance or tolerance was not explored. Herein, CRISPR-Cas9 was used and the association between amino acid substitution in FKS1 outside HS 1/2 (V595I, S745L, M1328I, F1386S, and A1422G) with EC susceptibility profile was delineated. None of the mutations conferred EC resistance, but they resulted in a significantly higher level of EC tolerance than the parental isolate, ATCC 22019. When incubated on agar plates containing ECs, specifically caspofungin and micafungin, ECR colonies were exclusively observed among ECT isolates, particularly mutants carrying V595I, S745L, and F1386S. Additionally, mutants had significantly better growth rates in yeast extract peptone dextrose (YPD) and YPD containing agents inducing membrane and oxidative stresses. The mutants had a trivial fitness cost in the Galleria mellonella model relative to ATCC 22019. Collectively, this study supports epidemiological studies to catalog mutations occurring outside the HS regions of FKS1, even if they do not confer EC resistance. These mutations are important as they potentially confer a higher level of EC tolerance and a higher propensity to develop EC resistance, therefore unveiling a novel mechanism of EC tolerance in C. parapsilosis. The identification of EC tolerance in C. parapsilosis may have direct clinical benefit in patient management.

469. Healthcare Resource Utilization (HRU) among Hospitalized Patients (Pts) with Candidemia (C) and Invasive Candidiasis without Candidemia (IC) Who Received Definitive Treatment with an Echinocandin (EC) Across United States (US) Hospitals

Abstract Background Guidelines recommend ECs as preferred agents for C/IC. Although studies demonstrate that the ECs are safe and effective for the treatment of pts with C/IC, there are scant HRU data among hospitalized adult pts who received an EC for C/IC. This study sought to describe current EC use patterns and outcomes for C/IC across US hospitals. Methods A retrospective, multi-centered observational study was performed using the Premier Healthcare Database (1/2016-4/2019). Inclusion criteria: hospitalized; age ≥ 18 years, presence of Candida sp. on clinical culture consistent with C/IC; and received ≥3 days of an EC between -2 days of index culture to discharge. Pts were stratified by presence of C/IC. Baseline characteristics and treatment patterns (EC received, receipt of EC in relation to index culture, and EC duration) were assessed. Outcomes: discharge status (in-hospital death vs discharge location), hospital length of stay (LOS) post index culture, and hospital costs (overall and component costs) post index culture. Results 1,865 pts met study criteria. The mean (SD) age was 58.9 (19), 48% were female, mean (SD) Charlson Comorbidity Index was 3.4 (2.7) and 55% resided in the ICU at index culture. The most common Candida sp. were C. albicans (37%), C. glabrata (28%), C. parapsilosis (11%), and C. tropicalis (10%). Most pts had C (66%). Baseline characteristic and treatment patterns were largely similar between C/IC pts except for Candida sp., EC received, and EC duration (Table). Mean HRU was greater in pts with IC vs C (Table and Figure). No differences in HRU were observed in pts who died vs survived. In-hospital mortality was higher in pts with C vs IC. Most pts with C/IC received additional medical care post-discharge and pts with IC vs C were more likely to be discharged to a home health agency. Conclusion Hospital costs associated with C/IC are substantial, with most attributable to room and board costs. In-hospital mortality was considerable for pts with C/IC and many pts with C/IC required additional medical care in a long-term care facility or with a home health agency post-discharge. New treatment options are needed to mitigate the costs and outcomes associated with daily receipt of EC for pts with C/IC. Disclosures Thomas Lodise, Jr., Pharm.D., PhD, BioFire Diagnostics: Grant/Research Support|cidara: Advisor/Consultant|cidara: Honoraria|Entasis: Grant/Research Support|Merck: Advisor/Consultant|Merck: Grant/Research Support|Paratek: Advisor/Consultant|Shionogi: Advisor/Consultant|Spero: Advisor/Consultant|Venatrox: Advisor/Consultant Kevin W. Garey, PharmD, MS, Acurx: Grant/Research Support|cidara: Advisor/Consultant|cidara: Grant/Research Support|Paratek: Grant/Research Support|Seres Health: Grant/Research Support|Summit: Grant/Research Support Brian H. Nathanson, Ph.D., cidara: Grant/Research Support|Merck: Advisor/Consultant|Merck: Grant/Research Support.

1731. Rezafungin Activity against Candida spp. and Aspergillus spp. Isolates Causing Invasive Infections Worldwide in 2021

Abstract Background Rezafungin (RZF) is a once-weekly echinocandin (ECH) with a long half-life and front-loaded drug exposure. RZF is in development to treat candidemia and invasive candidiasis and prevent invasive fungal disease caused by Candida, Aspergillus, and Pneumocystis spp. We evaluated the in vitro activity of RZF, caspofungin (CSF), micafungin (MCF), and anidulafungin (ANF) against a worldwide collection of fungal isolates causing invasive infection. Methods 830 isolates were collected from Europe (EU; 40.2%), North America (NA; 31.6%), Asia-Pacific (APAC; 15.3%), and Latin America (LA; 12.9%), identified by MALDI-TOF and/or sequencing, and tested by CLSI broth microdilution. Isolates included C. albicans (CA; 316 isolates), C. glabrata (CG; 162), C. parapsilosis (CP; 148), C. tropicalis (CT; 83), C. dubliniensis (CD; 21), C. krusei (CK; 19), Cryptococcus neoformans (CN; 10) A. fumigatus (AF; 59), and A. section Flavi (ASF; 12). CLSI criteria was applied, including the recently approved rezafungin provisional breakpoints against Candida spp. Results RFZ inhibited 99.7% of CA, 98.1% of CG, 95.2% of CD, and all CP, CT, and CK (MIC50/90 in Table) at the susceptibility (S) breakpoint (BP). RZF had similar activity to the other ECHs against CA (99.7%S), CG (95.7-96.3%S), CT (100.0%S), CK (100.0%S), and CD (MIC50/90 range, 0.015-0.06/0.03-0.06 mg/L). Although CSF displayed lower MIC50/90 values (0.25/0.25 mg/L) than RZF (MIC50/90, 1/2 mg/L), MCF (MIC50/90, 1/1 mg/L), and ANF (MIC50/90, 2/4 mg/L) against CP, all ECHs but ANF (87.2%S) inhibited 100% of CP isolates at the respective BP. Only 1 CA (EU), 1 CD (EU), and 3 CG (NA) were non-S to RZF, while 1 CA (EU), 6 CG (5 NA, 1 APAC), and 19 CP (8 EU, 5 NA, 4 APAC, 2 LA) were ANF non-S. Limited activity was noted for all ECHs against CN (MIC50, > 4 mg/L). All AF isolates were inhibited by RZF at ≤ 0.06 mg/L, and ANF, MCF, and CSF at ≤ 0.12 mg/L. RZF (MIC range, 0.008-0.06 mg/L) and other ECHs (MIC range, 0.008-0.12 mg/L) were also active against 7 voriconazole non-S AF isolates (4 NA, 3 EU). RZF and other ECHs inhibited all ASF isolates at ≤ 0.06 mg/L. Conclusion RZF was very active against Candida spp., AF, and ASF isolates causing invasive infections worldwide, including voriconazole non-S AF isolates and CP displaying non-S to ANF. Disclosures Cecilia G. Carvalhaes, MD, PhD, AbbVie: Grant/Research Support|Cidara: Grant/Research Support|Melinta: Grant/Research Support|Pfizer: Grant/Research Support Paul Rhomberg, BS, MT(ASCP), Cidara: Grant/Research Support|Pfizer: Grant/Research Support Paul Rhomberg, BS, MT(ASCP), Cidara: Grant/Research Support|Pfizer: Grant/Research Support Greg Strand, MLS (ASCP)CM, Cidara: Grant/Research Support Abby L. Klauer, BS, Cidara: Grant/Research Support Mariana Castanheira, PhD, AbbVie: Grant/Research Support|Cidara: Grant/Research Support|GSK: Grant/Research Support|Melinta: Grant/Research Support|Pfizer: Grant/Research Support|Shionogi: Grant/Research Support.

468. Assessment of The Proportion of Hospitalized Patients (Pts) with Candidemia (C) and Invasive Candidiasis without Candidemia (IC) Who Received an Echinocandin (EC) and Were Potentially Eligible for an Earlier Hospital Discharge (HD)

Abstract Background The primary driver of costs for C/IC pts is hospital length of stay. Studies across multiple infections demonstrate that most clinically stable pts with modest diagnostic & therapeutic requirements can be safely discharged prior to actual HD day. Few studies have assessed if there is an opportunity to accelerate time to HD in pts with C/IC. This study sought to determine the proportion of US hospitalized adult pts with C/IC who received an EC near HD & was potentially eligible for an earlier HD. Methods Design: Retrospective, multi-centered observational study using Premier Healthcare Database (1/2016-4/2019). Study criteria: hospitalized; age ≥ 18 years; Candida sp. on a culture consistent with C/IC; ≥3 days of an EC for C/IC; discharged alive; & received an EC near HD (-2 day to HD day). Pts were considerable potentially dischargeable if they met the following 3 criteria & maintained these 3 criteria until HD: resided on a non-ICU hospital ward, taking oral medications, & had no receipt of any diagnostic/therapeutic interventions (insertion of PICC lines were permitted). The difference in hospital days between first potentially eligible HD day & actual HD day was quantified. The proportion of pts that was potentially eligible for an earlier HD was examined overall & by Charlson Comorbidity index (CCI), C/IC, & Candida sp. Results During study period, 1,599 pts received an EC ≥ 3 days for C/IC & were discharged alive. Of the 1,599 pts, 1,008 (63%) were on an EC near HD. For the 1,008 pts on an EC near HD, the mean (SD) age was 59 (16) years, 52% were male, 40% had a CCI ≥4, 35% were in the ICU on index C/IC culture day, & 64% had C vs IC. C. glabrata (31%) & C. albicans (31%) were the most frequent Candida. sp. Of the 1,008 pts on an EC near HD, 14%, 21%, 29%, & 38% were potentially dischargeable 4, 3, 2, & 1 day(s), respectively, prior to the actual HD day (Figure). The proportion of pts who were potentially eligible for HD at least 2 days prior to actual HD day did not vary by CCI score, C/IC, & Candida sp. Conclusion Our findings suggest that a high proportion of hospitalized pts with C/IC receiving an EC near the time of HD, had modest diagnostic/therapeutic requirements prior to actual HD day & were potentially eligible for an earlier HD regardless of CCI, infection type, or Candida sp. Disclosures Thomas Lodise, Jr., Pharm.D., PhD, BioFire Diagnostics: Grant/Research Support|cidara: Advisor/Consultant|cidara: Honoraria|Entasis: Grant/Research Support|Merck: Advisor/Consultant|Merck: Grant/Research Support|Paratek: Advisor/Consultant|Shionogi: Advisor/Consultant|Spero: Advisor/Consultant|Venatrox: Advisor/Consultant Kevin W. Garey, PharmD, MS, Acurx: Grant/Research Support|cidara: Advisor/Consultant|cidara: Grant/Research Support|Paratek: Grant/Research Support|Seres Health: Grant/Research Support|Summit: Grant/Research Support Brian H. Nathanson, Ph.D., cidara: Grant/Research Support|Merck: Advisor/Consultant|Merck: Grant/Research Support.

Multiple Genes of Candida albicans Influencing Echinocandin Susceptibility in Caspofungin-Adapted Mutants.

Candida albicans is an opportunistic human fungal pathogen that causes invasive infections in immunocompromised individuals. Despite the high anticandidal activity among the echinocandins (ECNs), a first-line therapy, resistance remains an issue. Furthermore, many clinical isolates display decreased ECN susceptibility, a physiological state which is thought to lead to resistance. Determining the factors that can decrease susceptibility is of high importance. We searched for such factors genome-wide by comparing the transcriptional profiles of five mutants that acquired decreased caspofungin susceptibility in vitro in the absence of canonical FKS1 resistance mutations. The mutants were derived from two genetic backgrounds and arose due to independent mutational events, some with monosomic chromosome 5 (Ch5). We found that the mutants exhibit common transcriptional changes. In particular, all mutants upregulate five genes from Ch2 in concert. Knockout experiments show that all five genes positively influence caspofungin and anidulafungin susceptibility and play a role in regulating the cell wall mannan and glucan contents. The functions of three of these genes, orf19.1766, orf19.6867, and orf19.5833, were previously unknown, and our work expands the known functions of LEU42 and PR26. Importantly, orf19.1766 and LEU42 have no human orthologues. Our results provide important clues as to basic mechanisms of survival in the presence of ECNs while identifying new genes controlling ECN susceptibility and revealing new targets for the development of novel antifungal drugs.

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.

1076. Activity of Rezafungin and Comparator Antifungal Agents Tested Against a Worldwide Collection of Contemporaneous Invasive Fungal Isolates (2019-2020)

1076. Activity of Rezafungin and Comparator Antifungal Agents Tested Against a Worldwide Collection of Contemporaneous Invasive Fungal Isolates (2019-2020)

Progress in mechanisms and immunological treatment of chronic mucocutaneous candidiasis associat-ed with congenital IL-17 pathway deficiency

Chronic mucocutaneous candidiasis (CMC) is a rare, persistent and recurrent infection affecting skin, nails, and oral and genital mucosae. It is mainly caused by Candida albicans and hard to be cured with routine antifungal therapy. Usually, CMC is a primary immunodeficiency disease and can be divided into two categories. The most common one is CMC disease (CMCD), which defined as Candida infection confined to the surface of the skin and mucous membranes and not complicated by systemic Candida albicans infection or other clinical symptoms. The other category is systemic CMC (SCMC) complicated by infections caused by other pathogens, systemic invasive fungal infections, or other clinical symptoms apart from the symptoms of CMCD. It is currently believed that both CMCD and SCMC are related to immunodeficiency caused by gene mutations related to IL-17 signal pathway. The inhibited Th17 proliferation, decreased secretion of IL-17 or IL-22 cytokine, or increased IL-17 or IL-22 neutralizing antibody induced by the mutations promoted the susceptibility to Candida or other pathogens. In the treatment of CMC, in addition to the traditional antifungal drugs such as azoles, polyenes and echinocandins, biological agents and target gene therapy offer potential new therapeutic strategies. This article reviewed the association between congenital immunodeficiency in the IL-17 signaling pathway and CMC, and the possible immunological therapeutic approaches and new therapeutic targets. Key words: Chronic mucocutaneous candidiasis; Candidia albicans; IL-17

Clinical analysis of 49 cases with invasive fungal infections in pediatric intensive care unit

Objective To investigate the clinical characteristics of invasive fungal infections(IFI) in PICU and analyze the risk factors for diagnosis and treatment earlier. Methods The clinical data of patients with IFI hospitalized in PICU from January 2013 to December 2017 were retrospectively studied. Results There were 179 cases of patients with positive fungal cultures, of which 49 cases were IFI.There were 23 males and 26 females, the mean age was(3.87±2.42) years.A total of 47 cases had underlying diseases.In positive specimen, there were 36 cases of bronchoalveolar lavage fluid or sputum cultures, 14 cases of blood cultures, 7 cases of urinary cultures, 3 cases of thoracic/ascites cultures, 2 cases of bone marrow cultures, and 1 case of cerebrospinal fluid culture.There were 12 cases who had at least two sites infection at the same time.A total of 53 strains of fungal pathogens were cultivated, among which 45 cases were candida, 5 cases were aspergillus, and 3 cases were penicillium marneffei, and 4 cases had two fungal infections.The presence of underlying diseases, blood transfusions, use of antibiotics/glucocorticoids/immunosuppressors, invasive procedures, and long hospital stays were risk factors(all P<0.05). Drug susceptibility analysis showed that all strains were sensitive to antifungal drugs of amphotericin B/liposomes, azoles and echinocandins, except 1 case of Candida utilis, 1 case of Saccharomyces cerevisiae and 1 case of Candida lusitaniae.There were 26 patients only treated with one antifungal drug and 23 had combined drugs.All patients had fever.Eleven patients developed multiple organ dysfunction syndrome and 6 died. Conclusion There are no specific clinical manifestations for children with IFI and with critical condition and high mortality.Candida is the most common fungal infection.The lung is the most common part of infection.The children of IFI with risk factors such as underlying diseases, blood transfusions, use of antibiotics/glucocorticoids/immunosuppressors, invasive procedures and long hospital stays, should be identified in combination with laboratory examination and use antifungal drugs rationally as early as possible. Key words: Pediatric intensive care unit; Invasive fungal infections; Children; Fisk factors

Differential pulse polarographic investigation of micafungin and anidulafungin using a dropping mercury electrode.

The electrochemical behavior of the echinocandin antifungals anidulafungin (AF) and micafungin (MF) has been investigated by differential pulse polarography (DPP). The measurements were carried out in a supporting electrolyte solution consisting of Britton-Robinson buffer and methanol at various substance concentrations and pH values. An amperometric cell with a three electrode system consisting of a dropping mercury electrode (DME) as working electrode, an auxiliary platinum electrode and an Ag/AgCl reference electrode was used in all experiments. AF was electrochemically reduced at potentials between -1.3 and -1.5 V. MF showed a first reduction peak (a) between -1.0 and -1.4 V and a second peak (b) between -1.5 and -1.8 V. A strong pH-dependence was observed, with optimal results at pH 2.0-3.0 for the AF peak, pH 2.0 for the MF peak (a) and pH 5.0 for the MF peak (b). A linear correlation between the concentration and the peak current has been demonstrated for all reduction peaks. MF peak (a) showed a similar behavior to the AF peak regarding shape, peak current and pH-dependence. Therefore, it can be assumed that both reductions are based on the same mechanism, a two-step reduction of the N-acyl group.

Isavuconazole vs. Caspofungin for Candidemia

Both azole and echinocandin antifungal agents can be used to treat candidemia and invasive candidiasis. Isavuconazole is a newer, triazole antifungal

We can do better: a fresh look at echinocandin dosing.

We can do better: a fresh look at echinocandin dosing.

Echinocandins: Their Role in the Management of Candida Biofilms

The importance of antifungal agents and their clinical implications has received little attention in comparison to antibiotics, particularly in the health-care setting. However, apart from bacterial infections rising in hospitals, the incidences of fungal infections are growing with the development of resistance to conventional antifungal agents. Newer antifungal agents such as echinocandins (ECs) have been extensively studied over the past decade and are recognised as a superior treatment compared with prior antifungals as a first line of therapy in tertiary institutions. Caspofungin (CAS), micafungin (MICA) and anidulafungin (ANID) are the three most widely used EC antifungal agents. The treatment of biofilm-associated fungal infections affecting patients in tertiary health-care facilities has been identified as a challenge, particularly in Indian Intensive Care Unit (ICU) settings. With the rising number of critically ill patients requiring invasive devices such as central venous catheters for treatment, especially in ICUs, these devices serve as a potential source of nosocomial infections. Candida spp. colonisation is a major precursor of these infections and further complicates and prolongs treatment procedures, adding to increasing costs both for hospitals and the patient. Analysing studies involving the use of these agents can help in making critical decisions for antifungal therapy in the event of a fungal infection in the ICU. In addition, the development of resistance to antifungal agents is a crucial factor for assessing the appropriate antifungals that can be used for treatment. This review provides an overview of ANID in biofilms, along with CAS and MICA, in terms of clinical efficacy, resistance development and potency, primarily against Candida spp.

Outcomes Comparing Initial Short vs Long Course Echinocandin Therapy in Patients with Candidemia Caused by Fluconazole Susceptible Strains

Background Guidelines for candidemia (CAND) treatment recommend initial echinocandin (ECHINO) therapy with transition to fluconazole (FLUC) after 5–7 days in patients with clinical stability, FLUC-susceptibility, and negative cultures; however, optimal timing for transition is unknown. In the era of rapid diagnostics and antimicrobial stewardship programs (ASP), studies are needed to evaluate the impact of earlier transition in CAND due to routinely FLUC-susceptible species.Methods Retrospective study of adult patients at NewYork-Presbyterian Hospital from 2012 to 2014. Inclusion criteria included ≥1 blood culture with C. albicans, C. tropicalis or C. parapsilosis, ≥1 dose ECHINO initial therapy, ≥3 days total treatment, and no prior episode of CAND within 30 days. Patients with polymicrobial bloodstream infection excluded. Patients de-escalated from ECHINO at ≤3 days (short-course; SC-ECH) were compared with those who received ≥4 days of ECHINO (long course; LC-ECH). The primary outcome was 14-day complete response (CR), defined as survival with clinical improvement and sterilization of blood cultures. Secondary outcomes included day 7 microbiological success (MicroS) and 28-day survival (SURV).Results76 patients included: 21 in SC-ECH, 55 in LC-ECH groups. C. albicans (58%) most common species. Majority were male (59%) with median age 64 years (IQR 49–74), 62% were in ICU at time of CAND, 50% had recent surgery. No significant baseline differences between SC-ECH and LC-ECH groups, including in PITT bacteremia score ≥4 (43% vs. 42%; P = 0.4) or median APACHE (20 vs. 20; P = 0.684). There was no difference between SC-ECH vs. LC-ECH in CR (52% vs. 49%; P = 1.0), early MicroS (81% vs. 87%; P = 0.484), or SURV (62% vs. 73%; P = 0.523). On multivariable analysis with duration of ECHINO therapy forced into the model, only PITT bacteremia score <4 remained an independent predictor of CR (OR 6.1, 95% CI 2.1, 17.9; P = 0.001).Conclusion In adult patients with CAND due to routinely FLUC-susceptible species, early de-escalation from ECHINO was associated with similar outcomes, including day 7 MicroS. Early de-escalation based on early species identification has the potential to be a target for ASPs to optimize antifungal therapy without compromising clinical outcomes.Disclosures All authors: No reported disclosures.

Impact of echinocandin on prognosis of proven invasive candidiasis in ICU: A post-hoc causal inference model using the AmarCAND2 study

guidelines recommend first-line systemic antifungal therapy (SAT) with echinocandins in invasive candidiasis (IC), especially in critically ill patients. This studyaimed at assessing the impact of echinocandins compared to azoles as initial SAT on the 28-day prognosis in adult ICU patients. From the prospective multicenter AmarCAND2 cohort (835 patients), we selected those with documented IC and treated with echinocandins (ECH) or azoles (AZO). The average causal effect of echinocandins on 28-day mortality was assessed using an inverse probability of treatment weight (IPTW) estimator. 397 patients were selected, treated with echinocandins (242 patients, 61%) or azoles (155 patients, 39%); septic shock: 179 patients (45%). The median SAPSII was higher in the ECH group (48 [35; 62] vs. 43 [31; 58], p=0.01). Crude mortality was 34% (ECH group) vs. 25% (AZO group). After adjustment on baseline confounders, no significant association emerged between initial SAT with echinocandins and 28-day mortality (HR: 0.95; 95% CI: [0.60; 1.49]; p = 0.82). However, echinocandin tended to benefit patients with septic shock (HR: 0.46 [0.19; 1.07]; p=0.07). Patients who received echinocandins were more severely ill. Echinocandin use was associated with a non-significant 7% decrease of 28-day mortality and a trend to a beneficial effect for patient with septic shock.

Influence of T2 Candida Testing for Rapid Diagnosis of Candida Infections on Antifungal Stewardship Efforts at a Large Academic Medical Center: A Retrospective, Single-center Study

BackgroundAntimicrobial stewardship has traditionally focused on the optimal use of antibacterial agents. Much less attention is focused on the optimal use of antifungal therapy (AFT). The high mortality and emergence of resistance in invasive infections due to Candida presents a critical opportunity for AFT stewardship. The T2Candida (T2C) panel is a rapid diagnostic test using magnetic resonance to detect 5 different species of Candida in whole blood. T2C has a sensitivity of 91%, specificity of 99%, negative predictive value of 99%, and generates results in <6 hours.MethodsWe conducted a retrospective analysis of candidemia cases at the UAB Medical Center in 2015–16. T2C testing was introduced in January 2016. We compared outcomes among patients prior to and following the implementation of routine T2C testing. The focus of the study was to gather data on AFT, time to initiation of therapy(TTT), and overall use of echinocandin patterns during the study period utilizing days of therapy (DOT) /1000 pt days as a parameter.ResultsIn 2015 and 2016, 100 patients and 138 patients with candidemia, respectively, were included in the analysis. In 2016, there were 354 T2C valid results; 36 (10.2%) were positive and 318 (89.8%) were negative. The TTT for all candidemic patients in 2015 was 2.02 days vs 1.15 days for candidemic patients in 2016, including all who were blood culture(BC)+ and/or T2C+ (P < 0.0001). For patients with candidemia in 2016, TTT in the T2C+ group vs those in whom only BC+ was 0.09 days and 1.69 days, respectively (P < 0.00001). Comparing results for 2015 and 2016, we observed echinocandin (ECH) usage of 15.1 and 17.8 DOT/1000 pt days, respectively.ConclusionWe observed a significant decrease in the TTT for candidemic patients since introduction of the T2C. These results suggest that rapid identification of candidemia may be an important tool for AFT stewardship. We hypothesize that other factors, such as the updated IDSA Treatment Guidelines for Candidiasis and increased attention to the early intervention for sepsis campaign, may have influenced the use of ECH, and is supported by the observation that along with the decrease in TTT, we observed a slight increase in the DOT/ 1000 pt days between 2015 and 2016, suggesting more liberal use of empiric ECH.Disclosures All authors: No reported disclosures.