Outcomes by Candida spp. in the ReSTORE Phase 3 trial of rezafungin versus caspofungin for candidemia and/or invasive candidiasis.

Rezafungin is a long-acting, intravenously administered echinocandin for the treatment of candidemia and invasive candidiasis (IC). Non-inferiority of rezafungin vs caspofungin for the treatment of adults with candidemia and/or IC was demonstrated in the Phase 3 ReSTORE study based on the primary endpoints of day 14 global cure and 30-day all-cause mortality. Here, an analysis of ReSTORE data evaluating efficacy outcomes by baseline Candida species is described. Susceptibility testing was performed for Candida species using the Clinical and Laboratory Standards Institute reference broth microdilution method. There were 93 patients in the modified intent-to-treat population who received rezafungin; 94 received caspofungin. Baseline Candida species distribution was similar in the two treatment groups; C. albicans (occurring in 41.9% and 42.6% of patients in the rezafungin and caspofungin groups, respectively), C. glabrata (25.8% and 26.6%), and C. tropicalis (21.5% and 18.1%) were the most common pathogens. Rates of global cure and mycological eradication at day 14 and day 30 all-cause mortality by Candida species were comparable in the rezafungin and caspofungin treatment groups and did not appear to be impacted by minimal inhibitory concentration (MIC) values for either rezafungin or caspofungin. Two patients had baseline isolates with non-susceptible MIC values (both in the rezafungin group: one non-susceptible to rezafungin and one to caspofungin, classified as intermediate); both were candidemia-only patients in whom rezafungin treatment was successful based on the day 30 all-cause mortality endpoint. This analysis of ReSTORE demonstrated the efficacy of rezafungin for candidemia and IC in patients infected with a variety of Candida species.

Activity of aztreonam-avibactam against Enterobacterales resistant to recently approved beta-lactamase inhibitor combinations collected in Europe, Latin America, and the Asia-Pacific Region (2020-2022).

BACKGROUND: Aztreonam-avibactam is under clinical development for treatment of infections caused by carbapenem-resistant Enterobacterales (CRE), especially those resistant to recently approved ß-lactamase inhibitor combinations (BLICs). OBJECTIVES: To evaluate a large collection of CRE isolates, including those non-susceptible to ceftazidime-avibactam, meropenem-vaborbactam, and/or imipenem-relebactam. METHODS: Overall, 24 580 Enterobacterales isolates were consecutively collected (1/patient) in 2020-2022 from 64 medical centres located in Western Europe (W-EU), Eastern Europe (E-EU), Latin America (LATAM), and the Asia-Pacific region (APAC). Of those, 1016 (4.1%) were CRE. Isolates were susceptibility tested by broth microdilution. CRE isolates were screened for carbapenemase genes by whole genome sequencing. RESULTS: Aztreonam-avibactam inhibited 99.6% of CREs at ≤8 mg/L. Ceftazidime-avibactam, meropenem-vaborbactam, and imipenem-relebactam were active against 64.6%, 57.4%, and 50.7% of CRE isolates, respectively; most of the non-susceptible isolates carried metallo-beta-lactamases. Aztreonam-avibactam was active against ≥98.9% of isolates non-susceptible to these BLICs. The activity of these BLICs varied by region, with highest susceptibility rates observed in W-EU (76.9% for ceftazidime-avibactam, 72.5% for meropenem-vaborbactam, 63.8% for imipenem-relebactam) and the lowest susceptibility rates identified in the APAC region (39.9% for ceftazidime-avibactam, 37.8% for meropenem-vaborbactam, and 27.5% for imipenem-relebactam). The most common carbapenemase types overall were KPC (44.6% of CREs), NDM (29.9%), and OXA-48-like (16.0%). KPC predominated in LATAM (64.1% of CREs in the region) and W-EU (61.1%). MBL occurrence was highest in APAC (59.5% of CREs in the region), followed by LATAM (34.0%), E-EU (28.9%), and W-EU (23.6%). CONCLUSIONS: Aztreonam-avibactam demonstrated potent activity against CRE isolates resistant to ceftazidime-avibactam, meropenem-vaborbactam, and/or imipenem-relebactam independent of the carbapenemase produced.

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.

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.

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.

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.

Evaluation of XGEN Multi Sepsis Flow Chip Molecular Assay for Early Diagnosis of Bloodstream Infection.

Among healthcare-associated infections that can affect a critically ill patient, bloodstream infections are one of the most frequent causes of mortality, especially in hospitalized patients. The objective of this work is to evaluate the performance of the XGEN Multi Sepsis Flow Chip for the rapid diagnosis of bloodstream infections compared with conventional tests. In total, 101 positive blood culture samples were included, and the results obtained by the phenotypic conventional method (culture with susceptibility profile) were compared with results obtained by the XGEN Multi Sepsis Flow Chip. This molecular assay allows the simultaneous detection of the main bloodstream infection pathogens, and their most common antibiotic resistance markers in a short period of time. It was possible to observe substantial agreement between the methods for identifying the genus of pathogens. Considering species, the agreement was excellent. In relation to susceptibility, excellent agreement was noted between the detected resistance genes and susceptibility profile obtained through conventional antibiograms. The evaluated assay presented very early and satisfactory results for identification and detection of resistance genes of the main pathogens involved in bloodstream infections.

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.

Recent increase in fluconazole-nonsusceptible Candida parapsilosis in a global surveillance with the expansion of the Erg11 Y132F genotype and a rapid detection method for this alteration.

We evaluated the rates of fluconazole nonsusceptibility among 1103 Candida parapsilosis isolates collected globally from 2018 to 2021. These rates were <10.3% until 2020 but increased to 15.4% in 2021. Fluconazole-nonsusceptible C. parapsilosis rates were highest in Europe (96/466 isolates; 20.6%) followed by the US (23/386; 6.0%). As the Erg11 Y132F alteration has been a common fluconazole nonsusceptibility mechanism in C. parapsilosis, we developed a PCR assay to detect this mutation. This assay displayed 100% sensitivity and specificity when tested against 56 isolates previously submitted to whole genome sequencing. The Erg11 Y132F alteration was detected in 83.2% of the isolates (104/125) collected during 2018 to 2021 using the PCR assay. The highest rates of the Erg11 Y132F genotype were observed among fluconazole-nonsusceptible isolates from Europe (93.8%), followed by the US (60.9%). An increase in fluconazole-nonsusceptible C. parapsilosis was documented in 2021. Most isolates from Europe and the US carried the Y132F Erg11 alteration that has been reported in various countries.

Ceftazidime-avibactam, meropenem-vaborbactam, and imipenem-relebactam activities against multidrug-resistant Enterobacterales from United States Medical Centers (2018-2022).

A total of 35,360 Enterobacterales isolates were consecutively collected from 75 US medical centers in 2018-2022. Among these isolates, 2612 (7.4%) were categorized as multidrug-resistant (MDR). Isolates were susceptibility tested by reference broth microdilution methods. Carbapenem-resistant Enterobacterales (CRE) were screened for carbapenemase (CPE) genes by whole genome sequencing. The highest MDR rates was observed among Klebsiella pneumoniae (12.2%), followed by Raoultella spp. (10.9%) and Providencia stuartii (9.8%). Ceftazidime-avibactam and meropenem-vaborbactam were very active and showed identical susceptibility rates against MDR isolates (97.9%). Imipenem-relebactam (93.5% susceptible [S]) exhibited slightly lower susceptibility rates due to its limited activity against Morganellaceae family. The most active ß-lactamase inhibitor combination (BLI) against CRE isolates (n = 310) was ceftazidime-avibactam (84.2%S), followed by meropenem-vaborbactam (81.9%S) and imipenem-relebactam (74.8%S). All 3 BLIs were very active against KPC producers and none were active against MBL producers. Ceftazidime-avibactam exhibited greater activity against OXA-48-type producers than meropenem-vaborbactam and imipenem-vaborbactam.

Changing Epidemiology of Carbapenemases Among Carbapenem-Resistant Enterobacterales From United States Hospitals and the Activity of Aztreonam-Avibactam Against Contemporary Enterobacterales (2019-2021).

Background: As the frequency of metallo-ß-lactamase (MBL)-producing Enterobacterales is increasing worldwide, effective antimicrobials to treat the infections caused by these organisms are urgently needed. Methods: The activity of aztreonam-avibactam and comparators were evaluated against 27 834 Enterobacterales isolates collected from 74 US medical centers in 2019-2021. Isolates were susceptibility tested by broth microdilution. An aztreonam-avibactam pharmacokinetic/pharmacodynamic breakpoint of ≤8 mg/L was applied for comparison. Antimicrobial susceptibility and the frequency of key resistance phenotypes were assessed then stratified by year and infection type. Carbapenem-resistant Enterobacterales (CRE) were screened for carbapenemase (CPE) genes by whole genome sequencing. Results: Aztreonam-avibactam inhibited >99.9% of Enterobacterales at ≤8 mg/L. Only 3 isolates (0.01%) had an aztreonam-avibactam minimum inhibitory concentration (MIC) >8 mg/L. The CRE rates were 0.8%, 0.9%, and 1.1% in 2019, 2020, and 2021, respectively; 99.6% (260 of 261) of CRE isolates were inhibited at an aztreonam-avibactam MIC of ≤8 mg/L. The CRE susceptibility to meropenem-vaborbactam decreased from 91.7% in 2019 to 83.1% in 2020 and 76.5% in 2021 (82.1% overall). The CRE, multidrug-resistant, and extensively drug-resistant phenotypes were markedly higher among isolates from pneumonia compared with other infections. The most common carbapenemase among CRE was Klebsiella pneumoniae carbapenemase (65.5% of CRE), followed by New Delhi metallo-ß-lactamase (11.1%), oxacillinase (OXA)-48-like (4.6%), Serratia marcescens enzyme (2.3%), and imipenemase (1.5%). Among non-CPE-producing CRE isolates (n = 44; 16.9% of CRE), 97.7% were inhibited at ≤8 mg/L aztreonam-avibactam and 85.4% were meropenem-vaborbactam susceptible. Conclusions: The frequencies of MBL and OXA-48-type producers increased markedly. Aztreonam-avibactam demonstrated potent and consistent activity against Enterobacterales across infection types and over time.

Comparative activity of newer ß-lactam/ß-lactamase inhibitor combinations against Pseudomonas aeruginosa isolates from US medical centres (2020-2021).

OBJECTIVES: To evaluate the in-vitro activity of ceftazidime-avibactam, ceftolozane-tazobactam, meropenem-vaborbactam, imipenem-relebactam and comparator agents against contemporary Pseudomonas aeruginosa isolates from US hospitals. METHODS: In total, 3184 isolates were collected consecutively from 71 US medical centres in 2020-2021, and susceptibility tested by reference broth microdilution. Clinical Laboratory Standard Institute breakpoints were applied. RESULTS: Ceftazidime-avibactam [97.0% susceptible (S)], ceftolozane-tazobactam (98.0%S), imipenem-relebactam (97.3%S) and tobramycin (96.4%S) were the most active agents against the aggregate P. aeruginosa isolate collection, and retained good activity against piperacillin-tazobactam-non-susceptible, meropenem-non-susceptible and multi-drug-resistant (MDR) isolates. All other antimicrobials tested showed limited activity against piperacillin-tazobactam-non-susceptible, meropenem-non-susceptible and MDR isolates. The most common infections were pneumonia (45.9%), skin and skin structure infections (19.0%), urinary tract infections (17.0%) and bloodstream infections (11.7%); ceftazidime-avibactam, ceftolozane-tazobactam and imipenem-relebactam showed consistent activity against isolates from these infection types. Susceptibility to piperacillin-tazobactam and meropenem was lower among isolates from pneumonia compared with other infection types. CONCLUSIONS: Ceftazidime-avibactam, ceftolozane-tazobactam and imipenem-relebactam were highly active, and exhibited similar coverage against a large contemporary collection of P. aeruginosa isolates from US hospitals. Cross-resistance among the newer ß-lactams/ß-lactam inhibitors (BL/BLIs) varied markedly; ≥72.1% of isolates resistant to one of the three newer BL/BLIs approved for P. aeruginosa treatment remained susceptible to at least one of the other two BL/BLIs, indicating that all three should be tested in the clinical laboratory. These three BL/BLIs represent valuable therapeutic options for P. aeruginosa infection.

Antimicrobial activity of ceftibuten-avibactam against a global collection of Enterobacterales from patients with urinary tract infections (2021).

We evaluated the in vitro activity of ceftibuten-avibactam against Enterobacterales causing urinary tract infection (UTI). A total of 3216 isolates (1/patient) were consecutively collected from patients with UTI in 72 hospitals from 25 countries in 2021 then susceptibility tested by CLSI broth microdilution. Ceftibuten-susceptible breakpoints currently published by EUCAST (≤ 1 mg/L) and CLSI (≤ 8 mg/L) were applied to ceftibuten-avibactam for comparison. The most active agents were ceftibuten-avibactam (98.4%/99.6% inhibited at ≤ 1/ ≤ 8 mg/L), ceftazidime-avibactam (99.6% susceptible [S]), amikacin (99.1%S), and meropenem (98.2%S). Ceftibuten-avibactam (MIC50/90, 0.03/0.06 mg/L) was fourfold more potent than ceftazidime-avibactam (MIC50/90, 0.12/0.25 mg/L) based on MIC50/90 values. The most active oral agents were ceftibuten (89.3%S; 79.5% inhibited at ≤ 1 mg/L), levofloxacin (75.4%S), and trimethoprim-sulfamethoxazole (TMP-SMX; 73.4%S). Ceftibuten-avibactam inhibited 97.6% of isolates with an extended-spectrum ß-lactamase phenotype, 92.1% of multidrug-resistant isolates, and 73.7% of carbapenem-resistant Enterobacterales (CRE) at ≤ 1 mg/L. The second most active oral agent against CRE was TMP-SMX (24.6%S). Ceftazidime-avibactam was active against 77.2% of CRE isolates. In conclusion, ceftibuten-avibactam was highly active against a large collection of contemporary Enterobacterales isolated from patients with UTI and exhibited a similar spectrum to ceftazidime-avibactam. Ceftibuten-avibactam may represent a valuable option for oral treatment of UTI caused by multidrug-resistant Enterobacterales.

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.

Performance of the Vitek 2 Advanced Expert System (AES) as a Rapid Tool for Reporting Antimicrobial Susceptibility Testing (AST) in Enterobacterales from North and Latin America.

This study evaluated the performance of the Vitek 2 Advanced Expert System (AES) confidence level report as a rapid tool for reporting antimicrobial susceptibility testing (AST) results for a challenging set of Enterobacterales isolates from North and Latin America. Enterobacterales isolates (n = 513) were tested by CLSI broth microdilution (BMD) and Vitek 2 (N802 and XN15 AST cards). Wild-type isolates and isolates harboring acquired ß-lactamases by whole-genome sequencing were included. The AES assessment of confidence level (green, yellow, and red reports) was compared to BMD results and known genotypes and reviewed by a microbiologist for accuracy. Totals of 148 (28.8%) wild-type isolates and 365 (71.2%) Enterobacterales isolates harboring carbapenemase (211 [41.1%]), extended-spectrum ß-lactamase (ESBL) (122 [23.8%]), and/or transferrable AmpC (tAmpC) (32 [6.2%]) genes were evaluated. The AES confidence level was assessed for 488 isolates, and a phenotype was recognized for 447 (91.6%) isolates. Green, yellow, and red AES reports were noted for 382 (78.3%), 65 (13.3%), and 41 (8.4%) isolates, respectively. Compared to BMD, 96.3% of green AES reports could be confidently and rapidly auto-released, enabling rapid adjustments to antimicrobial therapy. In addition, 69.2% of yellow reports were acceptable, and recommendations to address current AES limitations were made. IMPORTANCE Antimicrobial susceptibility testing (AST) reports are one of the most important clinical microbiology laboratory tasks. AST reports are essential to drive antimicrobial therapy, provide information to monitor antimicrobial resistance rates, and trigger further tests to detect outbreaks or confirm new mechanisms of resistance. Commercial AST devices are frequently used to generate AST reports, and an advanced expert system (AES), such as the Vitek 2 AES, incorporates extensive knowledge to recognize certain susceptibility patterns as indicative of specific phenotypes. Moreover, the Vitek 2 AES also provides a level of confidence for auto-releasing the reports. In this study, the performance of the Vitek 2 AES was compared to state-of-the-art methodologies for AST, broth microdilution and ß-lactamase gene detection, whole-genome sequencing, against a collection of 513 Enterobacterales clinical isolates harboring various ß-lactamase genes, including carbapenemase, ESBL, and transferrable AmpC genes, from 73 medical centers in 7 countries in North and Latin America.

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.

Five-year analysis of the in vitro activity of tedizolid against a worldwide collection of indicated species causing clinical infections: results from the Surveillance of Tedizolid Activity and Resistance (STAR) programme.

Objectives: The Surveillance of Tedizolid Activity and Resistance (STAR) programme monitored the tedizolid activity against Staphylococcus aureus, Enterococcus faecalis, Streptococcus pyogenes, Streptococcus agalactiae and Streptococcus anginosus group. We evaluated the antimicrobial susceptibility of 47 400 unique Gram-positive clinical isolates from the STAR programme collected from USA (21 243), Europe (17 674), Asia-Pacific (4954) and Latin America (3529) medical centres (2015-19). Methods: All isolates were tested for susceptibility by reference broth microdilution method. WGS and in silico analysis were performed on linezolid-non-susceptible (NS) isolates. Results: Tedizolid was active against ≥99.9% of S. aureus (100.0% of MSSA and >99.9% of MRSA), E. faecalis, S. pyogenes, S. agalactiae and S. anginosus group isolates, with MIC50 values ranging from 0.12 to 0.25 mg/L and MIC90 values of 0.25 mg/L. Linezolid, vancomycin and daptomycin were also active agents against these organisms. Tedizolid inhibited all VRE and 73.1% of linezolid-NS E. faecalis isolates. Ampicillin and daptomycin retained 100.0% activity against VRE and linezolid-NS E. faecalis isolates. Linezolid-NS E. faecalis isolates carried mostly the optrA gene. G2576T alterations in the 23S rRNA were observed in one linezolid-NS S. aureus isolate and one linezolid-NS E. faecalis isolate. Conclusions: No resistance trends were observed for tedizolid during the study period.

Antimicrobial Activity of Ceftaroline and Comparator Agents Against Ceftriaxone-Nonsusceptible Streptococcus pneumoniae from the United States (2008-2020).

We evaluated the activity of ceftaroline against clinical isolates of ceftriaxone-nonsusceptible Streptococcus pneumoniae from United States medical centers. Streptococcus pneumoniae isolates (n = 21,750) were consecutively collected from 201 medical centers in 2008-2020 and tested for susceptibility by broth microdilution method. Among these isolates, 1,419 (6.5%) were ceftriaxone-nonsusceptible (ceftriaxone minimum inhibitory concentration [MIC], ≥2 mg/L). Other resistant subgroups analyzed included multidrug-resistant (MDR; nonsusceptibility to ≥3 classes of agents; n = 4,454) and extensively drug-resistant (XDR; nonsusceptibility to ≥5 classes; n = 1,708) isolates. Ceftriaxone susceptibility increased from 89.0% (2008-2011) to 98.1% (2018-2020). Ceftaroline was active against 99.9% of ceftriaxone-nonsusceptible isolates (MIC50/90, 0.25/0.25 mg/L) and retained potent activity against MDR (n = 4,454; MIC50/90, 0.12/0.25 mg/L; >99.9% susceptible) and XDR (n = 1,708; MIC50/90, 0.25/0.25 mg/L; 100.0% susceptible) isolates. Only one isolate had a ceftaroline MIC ≥0.5 mg/L. In summary, ceftaroline demonstrated potent and consistent activity over time (2008-2020) against a large collection of S. pneumoniae from U.S. medical centers, including ceftriaxone-nonsusceptible, MDR, and XDR isolates.

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.