JMI Laboratories

Abstract Background Manogepix (MGX) is a novel agent targeting the fungal Gwt1 enzyme. This agent is undergoing phase 3 clinical trials for invasive candidiasis and mould infections. Here, we assessed the in vitro activity of MGX against US mould isolates from invasive infections. Methods A total of 94 mould isolates from 12 hospitals in 2023 were tested. Confirmatory identification was performed by MALDI-TOF or 28S sequencing. Isolates were tested by reference broth microdilution method according to CLSI guidelines against MGX, voriconazole (VRC), posaconazole (POS), isavuconazole (ISA), and amphotericin B (AMB). Susceptible, nonsusceptible (NS), wildtype (WT), or nonwildtype (NWT) isolates were identified applying CLSI breakpoints or epidemiological cutoff values (ECV). No breakpoints or ECVs are available for MGX. Results 27 mould species and 11 genera were represented (Figure 1). Source of infection was varied (Figure 2). For 44 Aspergillus fumigatus (AFUM), MGX MEC90 was 0.03 mg/L, 16 to 32-fold lower than MIC90 for azoles (Table 1). 6.8% of AFUM were NS to ISA and 11.4% NS to VRC. For VRC-NS AFUM (n = 5), MGX MECs were 0.008 – 0.03 mg/L. For 9 Aspergillus niger species complex (ANSC), MGX MECs were 0.004-0.015 mg/L, 64 to 500-fold lower than MIC for azoles. All ANSC isolates were WT to VRC and ISA. For 9 Fusarium spp., MGX MECs were 0.004 – 0.03 mg/L while all azoles had limited activity (MICs ≥ 4 mg/L). For 5 Scedosporium/Lomentospora, MGX MECs were 0.008 to 0.03 mg/L, comparator agent MICs were >500-fold higher. For the 8 Zygomycota (5 Rhizopus spp., 2 Mucor spp., and 1 Lichtheimia), MGX MECs ranged from 0.25 to 4 mg/L, which was similar to other comparators. Conclusion MGX has potent in vitro activity against mould isolates collected from invasive infections as part of a worldwide surveillance program. MGX has low MECs for challenging moulds including azole-R or azole-NWT Aspergillus spp. and Fusarium spp. and Scedosporium/Lomentospora spp. with elevated MICs to other agents. MGX is a promising novel antifungal agent for the treatment of invasive mould infections, including those caused by resistant isolates and warrants further development for clinical use. Disclosures Marisa Winkler, MD, PhD, Basilea: Advisor/Consultant|Basilea: Grant/Research Support|GSK: Advisor/Consultant|GSK: Grant/Research Support|Melinta Therapeutics: Advisor/Consultant|Melinta Therapeutics: Grant/Research Support|Mundipharma: Advisor/Consultant|Mundipharma: Grant/Research Support|Pfizer: Advisor/Consultant|Pfizer: Grant/Research Support|Pulmocide: Advisor/Consultant|Pulmocide: Grant/Research Support Mariana Castanheira, PhD, Melinta Therapeutics: Advisor/Consultant|Melinta Therapeutics: Grant/Research Support

BackgroundAmpicillin and vancomycin are used for the treatment of patients with enterococcal infections. In vitro STIC for these agents against Enterococcus species were established decades ago based on limited clinical and pharmacokinetic-pharmacodynamic (PK-PD) data. Using non-clinical PK-PD targets for efficacy, population PK models, simulation, and in vitro surveillance data, PK-PD target attainment analyses were performed to identify STIC for these agents against E. faecalis and E. faecium.MethodsPopulation PK models for each agent were identified from the literature. PK-PD targets for efficacy were based on data from a neutropenic murine invasive enterococcal infection model. Using replication, simulated patients with demographic variables resembling a clinical trial population were generated. These variables with population PK models were used to generate ampicillin and vancomycin exposures after administration of ampicillin 2 g IV q4h adjusted for creatinine clearance (CLcr) and vancomycin weight-based loading doses followed by dosing regimens based on weight and CLcr. On Days 5 to 6, vancomycin AUC values were assigned from distributions assuming administration of dosing regimens adjusted using therapeutic drug monitoring. Percent probabilities of PK-PD target attainment by MIC based on median and randomly assigned ampicillin and vancomycin PK-PD targets associated with a 1-log10 CFU reduction from baseline for each pathogen were assessed in the context of in vitro surveillance data and any available clinical PK-PD and outcome by MIC data from the literature.ResultsPercent probabilities of PK-PD target attainment by MIC on Days 1 to 2 and 5 to 6 for ampicillin and vancomycin are shown in Figure 1 and Figure 2, respectively. Table 1 shows candidate susceptible breakpoints for E. faecalis and E. faecium based on these data, with recommended and existing STIC shown in Table 2. These data suggest ampicillin and vancomycin susceptible breakpoints of ≤ 8 and ≤ 4 mg/L for both species, respectively, consistent with CLSI STIC. In totality, the results from the literature search for clinical data did not provide meaningful information.ConclusionThe results of these analyses provide support for recommendations for ampicillin and vancomycin STIC for E. faecalis and E. faecalis.DisclosuresAll Authors: No reported disclosures

BackgroundAztreonam-avibactam (ATM-AVI) has recently been approved for clinical use in the European Union and United States to treat Gram-negative infections, including those caused by metallo-β-lactamase (MBL) producers. We evaluated the activity of ATM-AVI against Enterobacterales (ENT) isolated from patients with intra-abdominal infections (IAI).Activity of β-lactamase inhibitor combinations and ceftriaxone against Enterobacterales from intra-abdominal infectionsAbbreviations: ATM-AVI, aztreonam-avibactam; CAZ-AVI, ceftazidime-avibactam; MEM-VAB, meropenem-vaborbactam; IMI-REL, imipenem-relebactam; PIP-TAZ, piperacillin-tazobactam; CRO, ceftriaxone; MDR, multidrug-resistant.Activity of selected β-lactamase inhibitor combinations against carbapenem-resistant Enterobacterales (CRE) stratified by carbapenemase (CBase) type* Exclude MBL co-producers.Methods3,565 isolates (1/patient) were consecutively collected from patients with IAI in 52 medical centers from 28 countries located in Europe, Asia-Pacific region, and Latin America in 2020-2024. Isolates were susceptibility tested by broth microdilution. Carbapenem-resistant ENT (CRE) were screened for carbapenemases (CBase) by whole genome sequencing.Distribution of carbapenemase (CBase) types by region* Exclude MBL co-producers.ResultsThe most common ENT species were E. coli (50.4%), K. pneumoniae (18.0%), and E. cloacae species complex (8.0%). Susceptibility by species is shown in Table 1. Only 2 ENT exhibited ATM-AVI MIC > 4 mg/L (MIC50/90, ≤0.03/0.12 mg/L), 2 E. coli with ATM-AVI MIC of 8 mg/L. A multidrug-resistant (MDR) phenotype (not susceptible [S] to ≥ 3 classes per EUCAST) was observed in 14.6% of ENT (n=522) and the most active β-lactamase inhibitor combination (BLIC) against MDR isolates were ATM-AVI (99.6% S), CAZ-AVI (91.9% S), and MEM-VAB (91.6% S). Piperacillin-tazobactam (PIP-TAZ) was active against 82.2% of ENT and 38.1% of MDR, and meropenem was active against 97.4% of ENT and 82.2% of MDR. Only ATM-AVI showed good activity against CRE (MIC50/90, 0.25/1 mg/L, 100.0% S); CAZ-AVI, MEM-VAB, and IMI-REL were active against 59.2%, 57.3%, and 43.4% of CRE, respectively (Figure 1). A CBase was identified in 92 isolates (89.3% of CREs), and included KPCs (44.7% of CREs), MBLs (40.8%), and OXA-48 type (15.5%); 11.7% of CRE had 2 CBase types. All CBase producers were ATM-AVI-S whereas susceptibility to CAZ-AVI, MEM-VAB, and IMI-REL were 55.4%, 54.3%, and 42.9%, respectively. The frequencies of CBases varied markedly by region (Figure 2).ConclusionATM-AVI exhibited almost complete activity against ENT causing IAI in EU, Asia, and LA hospitals. The activities of other BLICs against CRE were compromised by the high occurrence of MBL and OXA-48-like producers.DisclosuresHelio Sader, United States Food and Drug Administration: FDA Contract Number: 75F40123C00140 Rodrigo E. Mendes, PhD, GSK: Grant/Research Support|Shionogi & Co., Ltd.: Grant/Research Support|United States Food and Drug Administration: FDA Contract Number: 75F40123C00140 Katherine Perez, PhD, Pfizer: Stocks/Bonds (Public Company) Marisa Winkler, MD, PhD, Basilea: Advisor/Consultant|Basilea: Grant/Research Support|GSK: Advisor/Consultant|GSK: Grant/Research Support|Melinta Therapeutics: Advisor/Consultant|Melinta Therapeutics: Grant/Research Support|Mundipharma: Advisor/Consultant|Mundipharma: Grant/Research Support|Pfizer: Advisor/Consultant|Pfizer: Grant/Research Support|Pulmocide: Advisor/Consultant|Pulmocide: Grant/Research Support Mariana Castanheira, PhD, Melinta Therapeutics: Advisor/Consultant|Melinta Therapeutics: Grant/Research Support

BackgroundMultidrug-resistant (MDR) Acinetobacter baumannii-calcoaceticus complex (ACB) have gained attention as an important clinical challenge in the last decades, due to its ability to develop resistance to front-line agents. Cefiderocol (FDC), a siderophore cephalosporin, uses the iron transport systems of Gram-negative bacteria to enhance cell entry. The activity of FDC and comparators was evaluated against ACB from US hospitals, including resistant subsets, collected as part of the SENTRY Antimicrobial Surveillance Program.Methods1,999 ACB isolates were collected from 76 US sites (2020–2024). Susceptibility (S) testing was performed by broth microdilution with cation-adjusted Mueller-Hinton broth (CAMHB) for comparators and iron-depleted CAMHB for FDC. CLSI/FDA criteria were applied. Isolates with imipenem or meropenem MIC ≥4 mg/L (nonS by CLSI) were screened for β-lactamase genes.Results29.4% (587/1,999) of isolates included were carbapenem-nonS, where carbapenemase genes were detected in 86.4% (507/587) of isolates (Table 1). blaOXA-23 (59.4%; 301/507) prevailed, followed by blaOXA-24 (35.1%; 178/507). A small number of isolates (5.5%; 28/507) carried mostly blaNDM or double carbapenemases. FDC (92.9–97.7%S) had MIC50 of 0.12 mg/L and MIC90 of 1 mg/L against all ACB. β-lactam comparators had limited activity against these isolates (66.8–72.0%S). FDC (94.4–97.8%S by CLSI) had an MIC90 of 2 mg/L against carbapenem-nonS ACB carrying OXA-23- and OXA-24-like. A FDC MIC90 of 64 mg/L was obtained against the small subset carrying blaNDM or double carbapenemases, with only ACB carying blaNDM showing FDC MIC ≥2 mg/L. 13.6% (80/587) of carbapenem-nonS ACB did not carry acquired carbapenemases, and FDC (91.2%S; CLSI) was active against this subset.ConclusionThis study demonstrates the resistant nature of ACB causing infections in US hospitals, and FDC as an active agent against these isolates, regardless of carbapenem resistance phenotype or genotype. Other β-lactam agents, including newer and older β-lactam- β-lactamase-inhibitor combinations were inactive against this collection. These in vitro data suggest FDC as an important option for the treatment of infections caused by carbapenem-nonS ACB.DisclosuresRodrigo E. Mendes, PhD, GSK: Grant/Research Support|Shionogi & Co., Ltd.: Grant/Research Support|United States Food and Drug Administration: FDA Contract Number: 75F40123C00140 Mariana Castanheira, PhD, Melinta Therapeutics: Advisor/Consultant|Melinta Therapeutics: Grant/Research Support

Abstract Background Candida auris (CARS) is an emerging infectious threat due to rising infection rates, eradication difficulty, and multidrug resistance. The US Centers for Disease Control (CDC) has tentative resistant (R)-only breakpoints (BP) against CARS for fluconazole (FLC), amphotericin B (AmB), anidulafungin (AND), caspofungin (CAS), and micafungin (MCF) with the caveat that the correlation between the values and clinical outcomes is unknown. Susceptible (S)-only BP for CARS from the Clinical and Laboratory Standards Institute (CLSI) exist for rezafungin (RZF). The CLSI S-only BP for RZF is several dilutions lower than the R CDC BPs for other echinocandins (ECH). It is imperative to understand the geographic distribution of CARS and MIC patterns to RZF and other agents. Methods CARS clinical isolates were collected from invasive candidal infections between 2014 – 2024 in 12 hospitals in 5 US Census divisions. Antifungal susceptibility testing was performed by reference broth microdilution with interpretation for AND, CAS, MCF, FLC, and AmB by CDC criteria (R ≥4, ≥2, ≥4, ≥32, and ≥2 mg/L) and RZF by CLSI criteria (NS≥1 mg/L). Isolates R/NS to any ECH were submitted to whole genome sequencing and analyzed for alterations in FKS1. Results 79 isolates were tested. Exponential increase in numbers is seen since 2021 (Figure 1). 86.1% were S to RZF; 97.5% and 44.3% were R to FLC and AmB, respectively. 77 isolates were R to FLC, within this group, 85.7% were S to RZF (Table 1). 35 isolates were R to AmB, these were all R to FLC and 88.6% were S to RZF. No RZF NS isolates were collected prior to 2022, there were 2 isolates in 2022, 4 in 2023, and 5 in 2024 (11 total). Isolates that were only NS to RZF were wildtype (WT) for FKS1 whereas those R/NS to ≥ 1 ECH had FKS1 alterations (Table 1). Conclusion CARS isolates have been rapidly increasing in prevalence-based surveillance. For ECH, molecular analysis indicates that isolates with an in vitro susceptibility profile showing NS to RZF but not-R to other ECH are WT for FKS1. RZF is an empiric treatment of choice for CARS given high R rates to FLC and AmB, minimal cross-resistance, and lack of S breakpoints for other ECH. Disclosures Marisa Winkler, MD, PhD, Basilea: Advisor/Consultant|Basilea: Grant/Research Support|GSK: Advisor/Consultant|GSK: Grant/Research Support|Melinta Therapeutics: Advisor/Consultant|Melinta Therapeutics: Grant/Research Support|Mundipharma: Advisor/Consultant|Mundipharma: Grant/Research Support|Pfizer: Advisor/Consultant|Pfizer: Grant/Research Support|Pulmocide: Advisor/Consultant|Pulmocide: Grant/Research Support Kelley A. Fedler, BS, Melinta Therapeutics: Grant/Research Support Mariana Castanheira, PhD, Melinta Therapeutics: Advisor/Consultant|Melinta Therapeutics: Grant/Research Support

Abstract Background Gepotidacin (GEP) is a recently approved, bactericidal, first-in-class triazaacenaphthylene antibiotic that inhibits bacterial DNA replication by a distinct binding site, unique mechanism of action and provides well-balanced inhibition (for most pathogens) of two different type II topoisomerase enzymes. This study reports on the in vitro activity of GEP and other oral antibiotics tested against contemporary E. coli (EC) and K. pneumoniae (KPN) clinical isolates collected from patients with urinary tract infections (UTI) in the United States (US). Methods 1,011 EC and 398 KPN isolates were collected in 2023 from 58 medical centers in the US. Isolates were tested for susceptibility by CLSI methods. MIC results for comparator agents were interpreted per CLSI guidelines. Multidrug-resistant (MDR) and extended-spectrum β-lactamase (ESBL) subsets were categorized per CLSI criteria. Results GEP (MIC50/90, 2/4 µg/mL) displayed activity against EC isolates, with all (100%) isolates having GEP MICs ≤16 µg/mL. Other oral agents demonstrated the following rates of susceptibility: amoxicillin-clavulanate (AMC, 88%), ampicillin (AM, 52%), ciprofloxacin (CIP, 80%), fosfomycin (FOS, 99%), mecillinam (MEC, 95%), nitrofurantoin (FM, 97%), and trimethoprim-sulfamethoxazole (SXT, 72%). GEP maintained similar MIC50 values (1–2 µg/mL) and MIC90 values (4 µg/mL) against drug not susceptible (NS) subsets of EC. GEP (MIC50/90, 4/16 µg/mL) was also active against KPN isolates tested, with 92% of isolates having GEP MICs ≤16 µg/mL. Other oral agents demonstrated the following rates of susceptibility: AMC (90%), CIP (82%), FM (28%), and SXT (81%). The majority of GEP MIC50/90 values were within 1- to 2-dilutions (MIC50/90 values 4-16/16-64 µg/mL) against drug-NS subsets of KPN. Conclusion GEP demonstrated in vitro activity against contemporary EC and KPN, including ESBL-producing and MDR isolates. This activity remained unaffected for EC isolates NS to other oral standard-of-care antibiotics and was within 1- to 2- dilutions of the value for the total population for drug-NS subsets of KPN. Susceptibility to other oral agents was ≥80% except for AM and SXT against EC isolates, and was between 80-90% except for FM against KPN isolates. Disclosures Renuka Kapoor, PhD, GSK: Employee|GSK: Stocks/Bonds (Public Company) Nicole E. Scangarella-Oman, MS, GSK: Employee|GSK: Stocks/Bonds (Public Company) Rodrigo E. Mendes, PhD, GSK: Grant/Research Support|Shionogi & Co., Ltd.: Grant/Research Support|United States Food and Drug Administration: FDA Contract Number: 75F40123C00140

The increasing prevalence of candidemia and invasive candidiasis infections caused by Candida auris represents a global health risk. Such infections are difficult to treat as they are often multidrug-resistant and are linked to high rates of mortality. Rezafungin is a second-generation echinocandin with antifungal activity against a range of Candida species, including wild type, and azole- and some echinocandin-resistant isolates. Its stability and prolonged half-life permit less frequent dosing compared with other echinocandins, leading to high front-loaded exposures and potential earlier mycological clearance from infection sites. These properties make rezafungin a candidate for the treatment of candidemia and invasive candidiasis infections due to C. auris. Accordingly, this narrative review article describes available evidence for the activity and effectiveness of rezafungin against C. auris isolates and infections. To date, the activity of rezafungin against C. auris isolates and infections has been demonstrated in in vitro and in vivo non-clinical experiments, and in pharmacokinetic/pharmacodynamic target attainment estimations utilizing clinical data. With similar potency to other echinocandins, rezafungin demonstrates in vitro and in vivo activity that is comparable to or better than that seen with other echinocandins, and similar to that for rezafungin in other Candida species. Like other echinocandins, its activity is reduced in fks-mutant isolates. Although there is currently a dearth of data on the therapeutic activity of rezafungin against C. auris, it is reasonable that rezafungin may be a viable choice for treating candidemia and invasive candidiasis caused by C. auris. Further clinical investigations are necessary.

BackgroundPseudomonas aeruginosa (PSA) possess various intrinsic treatment-limiting resistance mechanisms, leading to decreased antibiotic permeability, and also the ability to acquire resistance. Cefiderocol (FDC) is a siderophore cephalosporin that uses the iron transport systems of Gram-negative bacteria to optimize cell entry. The activity of FDC and comparator agents were evaluated against PSA causing infections in US hospitals, including resistant subsets, as part of the SENTRY Antimicrobial Surveillance Program.Methods4,400 PSA were collected from 36 sites in the US in 2020–2023. Susceptibility (S) testing was performed by broth microdilution with cation-adjusted Mueller-Hinton broth (CAMHB) for comparators and iron-depleted CAMHB for FDC. CLSI/FDA criteria were applied. Isolates with imipenem (IMI) or meropenem MIC ≥4 mg/L (nonS by CLSI) were screened for β-lactamase genes. Multidrug resistance (MDR) was defined as nonS to ≥3 drug classes by CLSI; whereas, extensively drug resistance (XDR) was defined as nonS to all but 2 or fewer drug classes.Results14.6% (643/4,400) and 4.7% (206/4,400) PSA isolates were MDR and XDR, respectively. 22.3% (980/4,400) PSA were carbapenem-nonS, with only 9 (0.9%) strains carrying carbapenemases. FDC and β-lactam/β-lactamase inhibitor (BL/BLI) combinations showed S of > 95% against all PSA, except for piperacilin-tazobactam (79.9%S) (Table). FDC (90.8–99.4%) showed MIC50 of 0.12 mg/L and MIC90 of 0.5–1 mg/L against MDR, XDR and carbapenem-nonS isolates, whereas BL/BLI showed S of 2.9–90.2%. FDC (100%S) inhibited all PSA carrying carbapenemases at the CLSI S breakpoint of ≤2 mg/L. Other comparators showed S of < 35% against the latter subset. FDC (MIC50/90, 0.12/0.5 mg/L; 96.8–99.4%S) had MIC 4- to 8-fold lower than IMI-relebactam (MIC50/90, 1/2 mg/L; 90.0%S) and cetolozane-tazobactam (MIC50/90, 1/4 mg/L; 90.9%S), which were also active against carbapenem-nonS PSA absent of carbapenemase genes.ConclusionFDC showed potent and cosistent activity against PSA clinical isolates from US hospitals, including resistant subsets and those with or without carbapenemase genes. These data demonstrate FDC activity against PSA resistant subsets, for which antibiotic treatment options are limited.DisclosuresRodrigo E. Mendes, PhD, GSK: Grant/Research Support

Abstract Background Aztreonam-avibactam (ATM-AVI) is under clinical development for treatment of Gram-negative infections, including those caused by metallo-β-lactamase (MBL) producers. We evaluated the activity of ATM-AVI and comparators against cephalosporin non-susceptible (S) E. cloacae (ECLC) and C. freundii species complex (CFC) from patients hospitalized in United States (US) medical centers. Antimicrobial susceptibility of cephalosporin-non-susceptible E. cloacae and C. freundii species complex Methods A total of 43,235 Enterobacterales (1/patient) were collected via the INFORM Surveillance Program and susceptibility tested by broth microdilution in 2019-2023; among those, 5,106 (11.8%) were ECLC (n=3,732) or CFC (n=1,374). We evaluated the antimicrobial susceptibility and β-lactamase production of isolates ceftazidime-resistant (MIC ≥ 16 mg/L) or cefepime-non-S (MIC ≥ 2 mg/L). The collection includes 1,065 ECLC and 379 CFC. ATM-AVI was tested with AVI at fixed 4 mg/L and a PK/PD S breakpoint of ≤ 8 mg/L was applied for comparison. Comparator included ceftazidime-avibactam (CAZ-AVI), meropenem-vaborbactam (MEM-VAB), and cefiderocol (carbapenem-resistant [CB-R] isolates only), among others. All isolates (n=1,444) were characterized by whole genome sequencing. Results Isolates were mainly from urinary tract (35.5%), pneumonia (23.6%), and bloodstream infection (BSI; 16.1%). The most common ESBLs were CTX-M type (99; 49.0% of ESBL producers), SHV type (95; 47.0%), and OXA type (80; 39.6%); ≥ 2 ESBLs were identified in 67 isolates (33.1%), mainly OXA-1/30 plus a CTX-M (64 isolates; 31.7%). A carbapenemase was identified in 55 of 64 (85.9%) CB-R isolates; including KPC type (40 isolates; 62.5% of CB-R) and NDM-1 (15; 23.4% of CB-R). ATM-AVI inhibited 99.9% of isolates at ≤ 8 mg/L and showed complete activity (100.0% inhibited at ≤ 8 mg/L) against ESBL producers and CB-R isolates, including NDM producers (Table). CAZ-AVI and MEM-VAB were active against 92.1-92.6% of ESBL producers and 70.3-71.9% of CB-R isolates. Cefiderocol was active against 83.9% of CB-R isolates but only 46.7% of NDM producers. Conclusion ATM-AVI was highly active against cephalosporin-non-S ECLC and CFC, including MBL producers. The activities of CAZ-AVI, MEM-VAB, and cefiderocol were compromised against CB-R isolates due to the high frequency of NDM producers. Disclosures All Authors: No reported disclosures