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Background. Staphylococcus aureus is among the most important pathogens in today's hospital setting. Methods. The effects of sneezing on the airborne dispersal of S. aureus and other bacteria were assessed in 11 healthy nasal S. aureus carriers with experimentally induced rhinovirus colds. Airborne dispersal was studied by volumetric air sampling in 2 chamber sessions with and without histamine-induced sneezing. After 2 days of preexposure measurements, volunteers were inoculated with a rhinovirus and monitored for 14 days. Daily quantitative nasal- and skin-culture samples for bacteria and nasal-culture samples for rhinovirus were obtained, cold symptoms were assessed, and volunteer activities were recorded during sessions. Results. All participants developed a cold. Sneezing caused a 4.7-fold increase in the airborne dispersal of S. aureus, a 1.4-fold increase in coagulase-negative staphylococci (CoNS), and a 3.9-fold increase in other bacteria (P<.001). An additional 2.83 colony forming units (cfu) of S. aureus/m(3)/min, 3.24 cfu of CoNS/m(3)/min, and 474.61 cfu of other bacteria/m(3)/min were released per sneeze. Rhinovirus exposure did not change the frequency of sneezing or airborne dispersal. Having respiratory allergies increased the spread of S. aureus by 3.8-fold during sneezing sessions (P<.001). Conclusion. Nasal S. aureus carriers disperse a significant amount of S. aureus into the air by sneezing. Experimental colds do not alter bacterial dispersal, but respiratory allergies multiply the effect of dispersing S. aureus. Copyright © 2006 Infectious Diseases Society of America [ABSTRACT FROM AUTHOR]

Background: Central venous catheter-related infections are a significant medical problem. Improved preventive measures are needed.Objective: To ascertain 1) effectiveness of a second-generation antiseptic-coated catheter in the prevention of microbial colonization and infection; 2) safety and tolerability of this device; 3) microbiology of infected catheters; and 4) propensity for the development of antiseptic resistance.Design: Multicenter, randomized, double-blind, controlled trial.Setting: 9 university-affiliated medical centers.Patients: 780 patients in intensive care units who required central venous catheterization.Intervention: Patients received either a standard catheter or a catheter coated with chlorhexidine and silver sulfadiazine.Measurements: The authors assessed catheter colonization and catheter-related infection, characterized microbes by molecular typing, and determined their susceptibility to antiseptics. Patient tolerance of the catheter was monitored.Results: Patients with the 2 types of catheters had similar demographic features, clinical interventions, laboratory values, and risk factors for infection. Antiseptic catheters were less likely to be colonized at the time of removal compared with control catheters (13.3 vs. 24.1 colonized catheters per 1000 catheter-days; P < 0.01). The center-stratified Cox regression hazard ratio for colonization controlling for sampling design and potentially confounding variables was 0.45 (95% CI, 0.25 to 0.78). The rate of definitive catheter-related bloodstream infection was 1.24 per 1000 catheter-days (CI, 0.26 to 3.62 per 1000 catheter-days) for the control group versus 0.42 per 1000 catheter-days (CI, 0.01 to 2.34 per 1000 catheter-days) for the antiseptic catheter group (P = 0.6). Coagulase-negative staphylococci and other gram-positive organisms were the most frequent microbes to colonize catheters. Noninfectious adverse events were similar in both groups. Antiseptic susceptibility was similar for microbes recovered from either group.Limitations: The antiseptic catheter was not compared with an antibiotic-coated catheter, and no conclusion can be made regarding its effect on bloodstream infection.Conclusions: The second-generation chlorhexidine-silver sulfadiazine catheter is well tolerated. Antiseptic coating appears to reduce microbial colonization of the catheter compared with an uncoated catheter. [ABSTRACT FROM AUTHOR]

The activity of fluconazole and amphotericin B against three isolates of Crytococcus neoformans was evaluated, with fluconazole and amphotericin B MICs of 2.0-4.0 mg/L and 1.0 mg/L respectively, using time-kill curve methods. Fluconazole was fungistatic against all isolates tested (<99.9% decrease in cfu from initial inoculum). The fungistatic activity of fluconazole was not enhanced by increasing the concentration of antifungal in solution. In contrast, amphotericin B was markedly fungicidal ( 99.9% decrease in cfu from initial inoculum). Both the rate and the extent of amphotericin B activity were enhanced when drug concentration was increased. [ABSTRACT FROM PUBLISHER]

The activity of isavuconazole and other triazoles against non- fumigatus (non-AFM) Aspergillus causing invasive aspergillosis was evaluated. A total of 390 non-AFM isolates were collected (1/patient) in 2017-2021 from 41 hospitals. Isolates were identified by matrix-assisted laser desorption ionization-time of flight mass spectrometry and/or internal spacer region/β-tubulin sequencing and tested by Clinical and Laboratory Standards Institute (CLSI) broth microdilution. CLSI epidemiological cutoff values were applied, where available. Isavuconazole showed activity against Aspergillus sections Flavi (n = 122; minimum inhibitory concentration [MIC] 50/90 , 0.5/1 mg/L), Terrei (n = 57; MIC 50/90 , 0.5/0.5 mg/L), Nidulantes (n = 34; MIC 50/90 , 0.12/0.25 mg/L), Versicolores (n = 7; MIC 50 , 1 mg/L), and Circumdati (n = 2; MIC range, 0.12-2 mg/L). Similar activity was displayed by other triazoles against those Aspergillus sections. Most of the isolates from Aspergillus sections Fumigati (n = 9), Nigri (n = 146), and Usti (n = 12) exhibited elevated MIC values to isavuconazole (MIC 50/90 , 2/-, 2/4, and 2/8 mg/L), voriconazole (MIC 50/90 , 2/-, 1/2, and 4/8 mg/L), itraconazole (MIC 50/90 , 2/-, 2/4, and 8/>8 mg/L), and posaconazole (MIC 50/90 , 0.5/-, 0.5/1, and >8/>8 mg/L), respectively. Isavuconazole was active (MIC values, ≤1 mg/L) against Aspergillus parasiticus , Aspergillus tamarii , Aspergillus nomius , Aspergillus nidulans , Aspergillus unguis , Aspergillus terreus , Aspergillus alabamensis , and Aspergillus hortai , while isavuconazole MIC values between 2 and 8 mg/L were observed against cryptic isolates from Aspergillus section Fumigati . Isavuconazole inhibited 96.1% of Aspergillus niger and 80.0% of Aspergillus tubingensis at ≤4 mg/L, the CLSI wild-type cutoff value for A niger . Voriconazole, itraconazole, and posaconazole showed similar activity to isavuconazole against most cryptic species. Isavuconazole exhibited potent in vitro activity against non-AFM; however, the activity of triazoles varies among and within cryptic species., Competing Interests: Potential conflicts of interest. JMI Laboratories was contracted to perform services in 2023 for AbbVie, Inc, Adamed Pharma S.A., AimMax Therapeutics, Allecra Therapeutics, Amicrobe, Inc, AN2 Therapeutics, Inc, Apnimed, Astellas Pharma, Inc, Basilea Pharmaceutica AG, Baxis Pharmaceuticals, Inc, Beckman Coulter, Inc, bioMérieux, Biosergen AB, Blacksmith Medicines, Bugworks, Carnegie Mellon University, Center for Discovery and Innovation, Cerba Research NV, Cidara Therapeutics, Cipla USA Inc, ContraFect Corporation, CorMedix Inc, Crestone, Inc, Discoveric Bio Beta Ltd, Dr. Falk Pharma GmbH, Entasis Therapeutics, Evopoint Biosciences, Fedora Pharmaceuticals, Forge Therapeutics, GARDP Foundation, Genentech, Gilead Sciences, Inc, GlaxoSmithKline plc, Harvard University, Institute for Clinical Pharmacodynamics, Iterum Therapeutics plc, Janssen Biopharma, Johnson & Johnson, Kbio, Inc, Lakewood-Amedex Inc, Locus Biosciences, Inc, McGill University, Medpace, Inc, Meiji Seika Pharma, Melinta Therapeutics, Menarini Group, Merck & Co, MetCura Pharmaceuticals, Inc, MicuRx Pharmaceutical Inc, Mundipharma International Ltd., Nabriva Therapeutics, National Cancer Institute, National Institutes of Health, NovoBiotic Pharmaceuticals, LLC, Ohio State University, Omnix Medical Ltd, Paratek Pharmaceuticals, Pfizer, Inc, PPD Global Central Labs, LLC, Pulmocide Ltd, Qpex Biopharma, Inc, Revagenix, Inc, Roche Holding AG, Scynexis, Inc, Seed Health, SeLux Diagnostics, Shionogi & Co, Ltd, Spero Therapeutics, Sumitovant Biopharma, Inc, Swedish National Reference Laboratory, TenNor Therapeutics, ThermoFisher Scientific, US Food and Drug Administration, University of Wisconsin, VenatoRx Pharmaceuticals, Wockhardt, and Zoetis, Inc. The authors report no individual conflicts of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Azole resistance in Aspergillus fumigatus (AFM) is increasing and often associated with cyp51 alterations. We evaluated the activity of isavuconazole and other mold-active azoles against 731 AFM isolates causing invasive aspergillosis collected in Europe (EU; n = 449) and North America (NA; n = 282). Isolates were submitted to CLSI susceptibility testing and epidemiological cutoff value (ECV) criteria. A posaconazole ECV of 0.5 mg/L was used as no CLSI ECV was determined. Azole non-wild-type (NWT) isolates were submitted for cyp51 sequencing by whole genome sequencing. Overall, isavuconazole activity (92.7%/94.0% WT in EU/NA) was comparable to other azoles (WT rate range, 90.9%-96.4%/91.8%-98.6%, respectively), regardless of the region. A total of 79 (10.8%) azole NWT isolates were detected, and similar rates of these isolates were noted in EU (10.7%) and NA (11.0%). Although most AFM were WT to azoles, increasing azole NWT rates were observed in NA (from 6.0% in 2017 to 29.3% in 2021). Azole NWT rates varied from 4.9% (2019) to 20.6% (2018) in EU without an observed trend. cyp51 alterations occurred in 56.3%/54.8% of azole NWT from EU/NA, respectively. The cyp51A TR 34 /L98H alteration was observed only in EU isolates (72.0% of EU isolates), while cyp51A I242V occurred only in NA isolates (58.3%). Isavuconazole remained active (MIC, ≤1 mg/L) against 18.5/47.1% of azole NWT AFM exhibiting cyp51 alterations in EU/NA, along with voriconazole (29.6/82.4%; MIC, ≤1 mg/L) and posaconazole (48.1/88.2%; MIC, ≤0.5 mg/L). Fourteen different cyp51 alterations were detected in 44 of 79 NWT isolates. The in vitro activity of the azoles varied in AFM that displayed cyp51 alterations. IMPORTANCE A few microbiology laboratories perform antifungal susceptibility testing locally for systemically active antifungal agents. The identification of emerging azole-resistant Aspergillus fumigatus is worrisome. As such, there is a critical role for antifungal surveillance in tracking emerging resistance among both common and uncommon opportunistic fungi. Differences in the regional prevalence and antifungal resistance of these fungi render local epidemiological knowledge essential for the care of patients with a suspected invasive fungal infection., Competing Interests: The authors declare no conflict of interest.

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.

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.

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 ., Competing Interests: This study was performed by JMI Laboratories and supported by Melinta Therapeutics, which included funding for services related to preparing the manuscript.

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

To assess oritavancin in vitro activity against clinically relevant Gram-positive pathogens in European (EU) hospitals, a total of 51,531 consecutive and unique clinical isolates collected in 2010-2019 were evaluated. All isolates were tested by CLSI broth microdilution methods. The key resistance phenotypes differed considerably between Eastern Europe (E-EU) and Western Europe (W-EU), respectively: methicillin-resistant (MR) Staphylococcus aureus 27.7%/22.9%; multidrug resistant (MDR) S. aureus , 19.7%/15.2%; MR coagulase-negative staphylococci, 77.3%/61.9%; vancomycin-resistant enterococci ( E. faecium ), 44.2%/20.9%; and MDR E. faecium , 63.8%/55.4%. There were no substantive differences in oritavancin minimum inhibitory concentration (MIC) values for the different species/organism groups over time or by EU region. Oritavancin inhibited 99.9% and 99.1% of all S. aureus and coagulase-negative staphylococci at 0.12 mg/L, respectively, and all isolates of E. faecalis and E. faecium at ≤0.5 mg/L. Oritavancin susceptibility rates against β-hemolytic and Viridans group streptococci isolates were 98.1% and 99.4%, respectively. Oritavancin had potent activity in vitro against this contemporary collection of European Gram-positive isolates from 2010 to 2019.

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., (© 2023 Wiley-VCH GmbH. Published by John Wiley & Sons Ltd.)

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.

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 (MIC 50/90 , 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 (MIC 50/90 , 0.5/1 mg/L) displayed the highest activity, followed by posaconazole (MIC 50/90 , 0.5/8 mg/L). Voriconazole (MIC 50/90 , >8/>8 mg/L) and the echinocandins (MIC 50/90 , >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; MIC 50/90 , 1/>8 mg/L), Lichtheimia spp. ( n = 11; MIC 50/90 , 4/8 mg/L), and Mucor spp. ( n = 8; MIC 50 , >8 mg/L) isolates, respectively. Posaconazole MIC 50/90 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 MIC 50/90 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.

We evaluated the in vitro activity of manogepix and comparator agents against 1,435 contemporary fungal isolates collected worldwide from 73 medical centers in North America, Europe, the Asia-Pacific region, and Latin America during 2020. Of the isolates tested, 74.7% were Candida spp.; 3.7% were non- Candida yeasts, including 27 Cryptococcus neoformans var. grubii (1.9%); 17.1% were Aspergillus spp.; and 4.5% were other molds. All fungal isolates were tested by reference broth microdilution according to CLSI methods. Based on MIC 90 values, manogepix (MIC 50 /MIC 90 , 0.008/0.06 mg/liter) was 16- to 64-fold more active than anidulafungin, micafungin, and fluconazole against Candida spp. isolates and the most active agent tested. Similarly, manogepix (MIC 50 /MIC 90 , 0.5/1 mg/liter) was ≥8-fold more active than anidulafungin, micafungin, and fluconazole against C. neoformans var. grubii . Based on minimum effective concentration for 90% of the isolates tested (MEC 90 ) and MIC 90 values, manogepix (MEC 90 , 0.03 mg/liter) was 16- to 64-fold more potent than itraconazole, posaconazole, and voriconazole (MIC 90 s, 0.5 to 2 mg/liter) against 246 Aspergillus spp. isolates. Aspergillus fumigatus isolates exhibited a wild-type (WT) phenotype for the mold-active triazoles, including itraconazole (87.0% WT) and voriconazole (96.4% WT). Manogepix was highly active against uncommon species of Candida , non- Candida yeasts, and rare molds, including 11 isolates of Candida auris (MIC 50 /MIC 90 , 0.004/0.015 mg/liter) and 12 isolates of Scedosporium spp. (MEC 50 /MEC 90 , 0.06/0.12 mg/liter). Additional studies are in progress to evaluate the clinical utility of the manogepix prodrug fosmanogepix in difficult-to-treat resistant fungal infections.

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., (© 2022 Wiley-VCH GmbH.)

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.

Bone and joint infections (BJIs) present significant treatment challenges. Ceftobiprole, a broad-spectrum cephalosporin with activity against methicillin-resistant Staphylococcus aureus, is approved in many European and other countries for the treatment of adults with community- and hospital-acquired pneumonia, excluding ventilator-associated pneumonia. In this study, the in vitro activity of ceftobiprole and comparators was evaluated against clinical isolates collected from BJIs in the USA from 2016 to 2020. Gram-positive pathogens made up 70.6% of all BJI isolates and included S. aureus (47.4% of all isolates), β-hemolytic streptococci, coagulase-negative staphylococci, and Enterococcus faecalis. Ceftobiprole was highly active against S. aureus (MIC 50/90 values, 0.5/1 mg/L; 99.6% susceptible using the European Committee on Antimicrobial Susceptibility Testing susceptibility breakpoint of ≤2 mg/L for the treatment of pneumonia patients) and exhibited potent activity against the other Gram-positive cocci and the predominant BJI Gram-negative groups. These results support the further evaluation of ceftobiprole for this potential indication., Competing Interests: Declaration of competing interest JIS is an employee of Basilea Pharmaceutica International Ltd. KAH was an employee of Basilea Pharmaceutica International Ltd. while this work was conducted. LRD, MAP, RKF, and REM have no conflicts to disclose. This study was funded in part by Basilea Pharmaceutica International Ltd., which was involved in the design and decision to present these results, and JMI Laboratories received compensation fees for services in relation to preparing the manuscript. JMI Laboratories contracted to perform services in 2021 for AbbVie Inc., Affinity Biosensors, AimMax Therapeutics, Inc., Alterity Therapeutics, Amicrobe, Inc., Arietis Pharma, Armata Pharmaceuticals, Inc., Astellas Pharma Inc., Basilea Pharmaceutica AG, Becton, Dickinson and Company (BD), bioMérieux, Inc., Boost Biomes, Brass Dome Ventures Ltd., Bravos Biosciences, Bugworks Research Inc., Centers for Disease Control and Prevention, Cerba Research, Cidara Therapeutics, Cipla Ltd., ContraFect Corp., CXC7, Diamond V, Enveda Biosciences, Fedora Pharmaceuticals, Inc., Fimbrion Therapeutics, First Light Diagnostics, Forge Therapeutics, Inc., Fox Chase Cancer Center, GlaxoSmithKline plc (GSK), Harvard University, Institute for Clinical Pharmacodynamics (ICPD), International Health Management Associates (IHMA), Inc., Iterum Therapeutics plc, Janssen Research & Development, Johnson & Johnson, Kaleido Biosciences, Inc., Laboratory Specialists, Inc. (LSI), Meiji Seika Pharma Co., Ltd., Melinta Therapeutics, Menarini Group, Merck & Co., Inc., MicuRx Pharmaceuticals Inc., Mutabilis, Nabriva Therapeutics, National Institutes of Health, Novome Biotechnologies, Omnix Medical Ltd., Paratek Pharma, Pattern Bioscience, Pfizer Inc., Prokaryotics Inc., Pulmocide Ltd., QPEX Biopharma, Inc., Roche Holding AG, Roivant Sciences, SeLux Diagnostics, Inc., Shionogi Inc., Sinovent Pharmaceuticals, Inc., SNIPR Biome ApS, Spero Therapeutics, Summit Therapeutics, Inc., T2 Biosystems, TenNor Therapeutics, Thermo Fisher Scientific, University of Southern California, University of Wisconsin, USCAST, U.S. Food and Drug Administration, Venatorx Pharmaceuticals, Inc., Weill Cornell Medicine, and Wockhardt Ltd., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

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

Objectives: We evaluated the azole resistance mechanisms and epidemiology of fluconazole-resistant Candida glabrata from a global survey., Methods: A total of 2992 Candida spp. isolates collected during 2018-2019 were susceptibility tested by the broth microdilution reference method following CLSI guidelines. Fluconazole-resistant C. glabrata isolates were submitted to whole genome sequencing and gene expression assays using qRT-PCR., Results: Among 561 CGLA isolates tested, 34 (6.1%) were fluconazole resistant. These isolates were collected from 11 countries and mainly recovered from bloodstream infections (79.4%). All fluconazole-resistant C. glabrata isolates were non-wild type for voriconazole, 24/34 were non-wild type for posaconazole, but only 2/34 were non-wild type for itraconazole. Isavuconazole MIC values ranged from 0.25 to >4 mg/L. Fluconazole-resistant C. glabrata isolates belonged to 14 different sequence types (ST). None of the isolates exhibited alterations in ERG3 or ERG11, the target of azoles. All but two fluconazole-resistant isolates displayed overexpression of CgCDR1 (22/34; 64.7%) and/or CgCDR2 (26/34; 76.5%), while 16 isolates had both genes overexpressed. Overexpression of CgSNQ2 or ERG11 was not observed. Gain of function (GoF) alterations in the transcription factor CgPDR1 were noted in 14 isolates. Four (11.8%) isolates that were nonsusceptible to one or more echinocandins had FKS2 HS1 alterations (2 S663P and 2 F659Y/deletion)., Conclusion: Fluconazole-resistant C. glabrata was driven by overexpression of CgCDR1 and/or CgCDR2. GoF alterations in PDR1 that have been associated with increased virulence were observed. Susceptibility results and surveillance data are needed to guide treatment for these isolates., Competing Interests: Declaration of Competing Interests JMI Laboratories was contracted to perform services in 2018–2021 for Achaogen, Inc., Affinity Biosensors, Albany College of Pharmacy and Health Sciences, Allecra Therapeutics, Allergan, Amicrobe Advanced Biomaterials, Inc., American Proficiency Institute, AmpliPhi Biosciences Corp., Amplyx Pharma, Antabio, Arietis Corp., Arixa Pharmaceuticals, Inc., Artugen Therapeutics USA, Inc., Astellas Pharma Inc., Athelas, Becton, Basilea Pharmaceutica Ltd., Bayer AG, Becton, Beth Israel Deaconess Medical Center, BIDMC, bioMerieux, Inc., bioMerieux SA, BioVersys Ag, Boston Pharmaceuticals, Bugworks Research Inc., CEM-102 Pharmaceuticals, Cepheid, Cidara Therapeutics, Inc., Cipla, Contrafect, Cormedix, Inc., Crestone, Inc., Curza, CXC7, DePuy Synthes, Destiny Pharma, Dickinson and Company, Discuva Ltd., Dr. Falk Pharma GmbH, Emery Pharma, Entasis Therapeutics, Eurofarma Laboratorios SA, Fedora Pharmaceutical, F. Hoffmann-La Roche Ltd., Fimbrion Therapeutics, US Food and Drug Administration, Fox Chase Chemical Diversity Center, Inc., Gateway Pharmaceutical LLC, GenePOC Inc., Geom Therapeutics, Inc., GlaxoSmithKline plc, Guardian Therapeutics, Hardy Diagnostics, Harvard University, Helperby, HiMedia Laboratories, ICON plc, Idorsia Pharmaceuticals Ltd., IHMA, Iterum Therapeutics plc, Janssen Research & Development, Johnson & Johnson, Kaleido Biosciences, KBP Biosciences, Laboratory Specialists, Inc., Luminex, Matrivax, Mayo Clinic, Medpace, Meiji Seika Pharma Co., Ltd., Melinta Therapeutics, Inc., Menarini, Merck & Co., Inc., Meridian Bioscience Inc., Micromyx, Microchem Laboratory, MicuRx Pharmaceutics, Inc., Mutabilis Co., N8 Medical, Nabriva Therapeutics plc, National Institutes of Health, NAEJA-RGM, National University of Singapore, North Bristol NHS Trust, Novartis AG, Novome Biotechnologies, Oxoid Ltd., Paratek Pharmaceuticals, Inc., Pfizer, Inc., Pharmaceutical Product Development, LLC, Polyphor Ltd., Prokaryotics, Inc., QPEX Biopharma, Inc., Ra Pharmaceuticals, Inc., Rhode Island Hospital, RIHML, Roche, Roivant Sciences, Ltd., Safeguard Biosystems, Salvat, Scynexis, Inc., SeLux Diagnostics, Inc., Shionogi and Co., Ltd., SinSa Labs, Specific Diagnostics, Spero Therapeutics, Summit Pharmaceuticals International Corp., SuperTrans Medical LT, Synlogic, T2 Biosystems, Taisho Pharmaceutical Co., Ltd., TenNor Therapeutics Ltd., Tetraphase Pharmaceuticals, The Medicines Company, The University of Queensland, Theravance Biopharma, Thermo Fisher Scientific, Tufts Medical Center, Universite de Sherbrooke, University of Colorado, University of Southern California-San Diego, University of Iowa, University of Iowa Hospitals and Clinics, University of North Texas Health Science Center, University of Wisconsin, UNT System College of Pharmacy, URMC, UT Southwestern, VenatoRx, Viosera Therapeutics, Vyome Therapeutics, Inc., Wayne State University, Wockhardt, Yukon Pharmaceuticals, Inc., Zai Lab, and Zavante Therapeutics, Inc. There are no speakers’ bureaus or stock options to declare., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Studies demonstrated the impact of the COVID-19 pandemic in the prevalence and susceptibility profiles of bacterial and fungal organisms. We analyzed 4821 invasive fungal isolates collected during 2018, 2019, and 2020 in 48 hospitals worldwide to evaluate the impact of this event in the occurrence and susceptibility rates of common fungal species. Isolates were tested using the CLSI broth microdilution method. While the percentage of total isolates that were C. glabrata (n = 710 isolates) or C. krusei (n = 112) slightly increased in 2020, the percentage for C. parapsilosis (n = 542), A. fumigatus (n = 416), and C. lusitaniae (n = 84) significantly decreased (P < .05). Fluconazole resistance in C. glabrata decreased from 5.8% in 2018-2019 to 2.0% in 2020, mainly due to fewer hospitals in the US having these isolates (5 vs. 1 hospital). Conversely, higher fluconazole-resistance rates were noted for C. parapsilosis (13.9 vs. 9.8%) and C. tropicalis (3.5 vs. 0.7%; P < .05) during 2020. Voriconazole resistance also increased for these species. Echinocandin resistance was unchanged among Candida spp. Voriconazole susceptibility rates in A. fumigatus were similar in these two periods (91.7% in 2018 and 2019 vs. 93.0% in 2020). Changes were also noticed in the organisms with smaller numbers of collected isolates. We observed variations in the occurrence of organisms submitted to a global surveillance and the susceptibility patterns for some organism-antifungal combinations. As the COVID-19 pandemic is still ongoing, the impact of this event must continue to be monitored to guide treatment of patients affected by bacterial and fungal infections., Lay Summary: Secondary infections were documented in COVID-19 patients. We compared the prevalence of invasive fungal isolates consecutively collected in 48 worldwide hospitals and their susceptibility patterns between 2020, the year of the global COVID-19 pandemic, and the two prior years., (© The Author(s) 2022. Published by Oxford University Press on behalf of The International Society for Human and Animal Mycology.)

Rezafungin is a new echinocandin under development for the treatment of candidemia and invasive candidiasis. CLSI recently approved provisional susceptible-only breakpoints and epidemiological cutoff values for Candida spp. and rezafungin. The activities of rezafungin and comparators against 2019 to 2020 invasive fungal isolates was evaluated by applying the new CLSI breakpoints. Rezafungin demonstrated potent activity against Candida albicans (MIC 50 /MIC 90 , 0.03/0.06 mg/L; 100.0% susceptible), Candida tropicalis (MIC 50 /MIC 90 , 0.03/0.06 mg/L; 100% susceptible), Candida glabrata (MIC 50 /MIC 90 , 0.06/0.06 mg/L; 98.3% susceptible), Candida krusei (MIC 50 /MIC 90 , 0.03/0.03 mg/L; 100% susceptible), and Candida dubliniensis (MIC 50 /MIC 90 , 0.06/0.12 mg/L; 100% susceptible) when tested by the CLSI broth microdilution method. Rezafungin inhibited 99.6% of Candida parapsilosis isolates (MIC 50 /MIC 90 , 1/2 mg/L) at the susceptible breakpoint of ≤2 mg/L. All C. albicans, C. tropicalis, and C. krusei isolates, as well as most C. glabrata (96.2% to 97.9%) and C. parapsilosis (86.2% to 100%) isolates, were susceptible to comparator echinocandins. Fluconazole resistance was detected among 0.5%, 4.5%, 10.5%, and 1.2% of C. albicans, C. glabrata, C. parapsilosis, and C. tropicalis isolates, respectively. All echinocandins displayed limited activity against Cryptococcus neoformans. Rezafungin and other echinocandins were active against Aspergillus fumigatus (minimum effective concentration for 90% of isolates tested [MEC 90 ] range, 0.015 to 0.06 mg/L) and Aspergillus section Flavi (MEC 90 range, 0.015 to 0.03 mg/L). All but 16 (8.6%) A. fumigatus isolates were susceptible to voriconazole, and 100% of Aspergillus section Flavi isolates were WT to mold-active azoles. When applying the CLSI clinical breakpoints, rezafungin displayed high susceptibility rates (>98.0%) against Candida isolates from invasive fungal infections and showed potent activity against Aspergillus isolates.

We utilized the SENTRY surveillance database from 2017 through 2019 to address pathogen frequency and antifungal resistance among 4,497 clinical isolates of fungi from patients who were either ≥ 65 years (2,170 isolates) or between 18 and 64 years of age (2,327 isolates). The younger population was more frequently infected with non-Candida yeasts and non-Aspergillus moulds. Candida glabrata was more common in the older age group (P value = 0.02). Resistance to the triazole and echinocandin classes was less common in the elderly population (4.3% and 2.7%, respectively) compared to the younger age group (11.4% and 4.4%, respectively). Resistance to fluconazole in C. parapsilosis (11.4%) was elevated in the older patient group. Decreased susceptibility to the mould-active triazoles among A. fumigatus isolates was greater in the younger age group (7.8%) than the older age group (4.4%). These data emphasize the importance of species identification and antifungal susceptibility testing to guide the treatment of individual patients., (Copyright © 2021. Published by Elsevier Inc.)

Objectives: This study evaluated the in vitro activity of KBP-7072 against 413 contemporary surveillance isolates, including subsets with known tetracycline resistance genes., Materials: In total, 105 Klebsiella pneumoniae (51 tetracycline resistant), 103 Escherichia coli (52 tetracycline resistant), 103 Staphylococcus aureus (51 tetracycline resistant) and 102 Streptococcus pneumoniae (51 tetracycline resistant) isolates were included. These isolates were tested by broth microdilution using fresh media. CLSI/EUCAST breakpoints were applied, except for tigecycline and omadacycline, which used FDA criteria., Results: KBP-7072 (MIC 50 , 0.06 mg/L), tigecycline (MIC 50 , 0.12 and 0.25 mg/L) and omadacycline (MIC 50 , 0.12 and 0.5 mg/L) showed similar MIC 50 s for tetracycline-susceptible and -resistant S. aureus . Other tetracycline comparators had their MIC 50 increased 64- to 256-fold by tet . For S. pneumoniae , KBP-7072 (MIC 50/90 , ≤0.015/0.03 mg/L) showed the lowest MICs, which remained unchanged for tetracycline-susceptible or -resistant isolates [mostly tet (M)]. Similar MICs were observed for omadacycline (MIC 50/90 , 0.03-0.06/0.06 mg/L) and tigecycline (MIC 50/90 , 0.03/0.03 mg/L) in the S. pneumoniae population. Tetracycline-susceptible and -resistant E. coli [94.2% tet (A)/ tet (B)], KBP-7072 (MIC 90 , 0.25 and 1 mg/L, respectively) and tigecycline (MIC 90 , 0.25 and 0.5 mg/L) showed similar MIC 90 s. KBP-7072 (MIC 50/90 , 0.25/0.5 mg/L) and tigecycline (MIC 50/90 , 0.5/0.5 mg/L) had the lowest MIC for tetracycline-susceptible K. pneumoniae . The MIC for KBP-7072 (MIC 50/90 , 1/4 mg/L) and tigecycline (MIC 50/90 , 1/2 mg/L) increased 2- to 8-fold for tetracycline-resistant K. pneumoniae , which mostly produced Tet(A)., Conclusions: KBP-7072 activity was minimally affected by the presence of acquired tetracycline genes., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy.)

Objectives: Omadacycline was tested against 7000 bacterial isolates collected prospectively from medical centres in the USA during 2019., Methods: Antimicrobial susceptibility testing was performed according to Clinical and Laboratory Standards Institute (CLSI) guidelines., Results: Omadacycline was active against: Staphylococcus aureus (MIC 50/90 , 0.12/0.25 mg/L; 98.3% susceptible), including methicillin-resistant S. aureus (MRSA); Enterococcus faecalis (MIC 50/90 , 0.06/0.25 mg/L; 100.0% susceptible), including vancomycin-resistant enterococci (VRE); Streptococcus pneumoniae (MIC 50/90 , 0.06/0.06 mg/L; 99.8% susceptible); viridans group streptococci, including Streptococcus anginosus group (MIC 50/90 , 0.03/0.06 mg/L; 100.0% susceptible); β-haemolytic streptococci, including Streptococcus pyogenes (MIC 50/90 , 0.06/0.12 mg/L; 99.2% susceptible); Enterobacterales (MIC 50/90 , 1/8 mg/L; 86.9% inhibited at ≤4 mg/L), including Escherichia coli (MIC 50/90 , 0.5/2 mg/L; 99.6% inhibited at ≤4 mg/L); Enterobacter cloacae (MIC 50/90 , 2/4 mg/L; 98.5% susceptible); Klebsiella pneumoniae (MIC 50/90 , 1/4 mg/L; 93.2% susceptible); Acinetobacter baumannii (MIC 50/90 , 0.5/4 mg/L; 90.8% inhibited at ≤4 mg/L); Haemophilus influenzae (MIC 50/90 , 0.5/1 mg/L; 100.0% susceptible); and Moraxella catarrhalis (MIC 50/90 , ≤0.12/0.25 mg/L)., Conclusion: The 2019 in vitro activity of omadacycline against key Gram-positive and Gram-negative pathogens has not changed compared with the prior 3 years of surveillance in the SENTRY Antimicrobial Surveillance Program. Omadacycline merits further study in serious infections where resistant pathogens may be encountered., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objectives: To report on the activity of ceftolozane-tazobactam and comparators against Pseudomonas aeruginosa isolates collected from hospitalized patients with pneumonia in US intensive care units (ICUs) between 2015 and 2018. Activity against all P. aeruginosa and common resistant phenotypes are described to better inform decision-making and support antimicrobial stewardship efforts., Methods: In total, 781 P. aeruginosa isolates were collected from 28 US hospitals. These isolates were tested for susceptibility to ceftolozane-tazobactam and comparators by Clinical and Laboratory Standards Institute (CLSI) broth microdilution methodology using CLSI (2020) breakpoints. Phenotypes analysed included piperacillin-tazobactam-non-susceptible (NS), cefepime-NS, ceftazidime-NS, meropenem-NS and difficult-to-treat resistance (DTR)., Results: Ceftolozane-tazobactam was the most potent agent tested (minimum inhibitory concentration to inhibit 50% and 90% of isolates of 0.5 and 2 mg/L, respectively, inhibiting 97.2% at the susceptible breakpoint of ≤4 mg/L). Traditional first-line antipseudomonal β-lactam antibiotics (piperacillin-tazobactam, cefepime and ceftazidime) demonstrated <33% susceptibility when P. aeruginosa was NS to one or more agent. Although escalation of therapy to meropenem is commonly employed clinically, meropenem susceptibility ranged from 33.6% to 44.9% if P. aeruginosa was NS to any traditional first-line antipseudomonal β-lactam agent. Conversely, ceftolozane-tazobactam remained active against isolates that were NS to other agents, inhibiting 88.4% of isolates NS to piperacillin-tazobactam, 85.0% of isolates NS to cefepime and ceftazidime, and 90.3% of isolates NS to meropenem. Ceftolozane-tazobactam also maintained activity against 73.0% of DTR isolates., Conclusions: Ceftolozane-tazobactam maintained high activity against P. aeruginosa isolated from hospitalized patients with pneumonia in US ICUs, and had the greatest activity against isolates NS to one or more antipseudomonal β-lactams and DTR isolates., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The epidemiology of invasive filamentous fungal diseases requires monitoring due to changes in susceptibility patterns of new and established antifungal agents that may affect clinical practices. We evaluated the activity of posaconazole against 2,157 invasive moulds collected worldwide from 2010-2017. The isolates included 1,775 Aspergillus spp. and 382 non-Aspergillus moulds, including 81 Fusarium spp., 62 Mucorales group, and 57 Scedosporium spp. Isolates were tested using the CLSI reference broth microdilution method. Posaconazole showed similar activity to itraconazole and voriconazole against A. fumigatus. Applying published ECV, 98.0% of the A. fumigatus and 97.7% to 100.0% of other common Aspergillus species were wildtype to posaconazole. Categorical agreement between posaconazole and the other azoles tested against A. fumigatus was 98.7%. Notably, most of the Aspergillus spp. isolates recovered from this large collection were wildtype to echinocandins and all azoles. Posaconazole non-wildtype rates of A. fumigatus varied across the different geographic regions, with 2.1% in Europe, 2.2% in North America, 1.8% in Latin America, and 0.7% in the Asia-Pacific region. The frequency of azole non-wildtype A. fumigatus isolates from Europe increased steadily from 2010-2017 for all 3 triazoles (0.0%-5.0%). The azole non-wildtype A. fumigatus rates from the other geographic areas were stable over time. Fusarium and/or Scedosporium spp. isolates were highly resistant to azoles and echinocandins. Posaconazole and amphotericin B were the most active agents against the Mucorales. Posaconazole was very active against most species of Aspergillus and was comparable to itraconazole and voriconazole against the less common moulds. Posaconazole should provide a useful addition to the anti-mould grouping of antifungal agents., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objectives: We evaluated 35 azole nonwildtype Aspergillus fumigatus isolates that were collected during 2017-2018 using whole genome sequencing (WGS) to detect alterations in the genes involved in the ergosterol biosynthesis pathway as well as other genes associated with azole resistance., Methods: Among 297 A fumigatus isolates collected worldwide, 36 isolates displayed nonwildtype MIC values to isavuconazole, itraconazole, or voriconazole when tested by the CLSI reference broth microdilution method. Isolates were submitted to WGS and results were compared to 2 azolewildtype isolates., Results: Among the 35 sequenced isolates (1 failed to produce quality sequences), 29 were nonwildtype to isavuconazole, 16 were nonwildtype to itraconazole, and 9 were nonwildtype to voriconazole (CLSI M59Ed2 criteria). A total of 9 isolates carried Cyp51A TR34/L98H alterations (8 from Italy and 1 from Belgium) and had nonwildtype MIC values for ≥2 azoles. A Cyp51B Q42L mutation was detected in 3 isolates, 1 nonwildtype voriconazole and 2 nonwildtype isavuconazole isolates. Three isolates harboured multiple mutations in Cyp51A (F46Y, M172V, E427K ± N248T, and D255E), including 1 isolate with the Cyp51B Q42L mutation. Mutations causing frameshifts, early termination, and duplications were observed among several genes and were more prevalent in isavuconazole nonwildtype isolates (66.7%) than in the isolates that were nonwildtype to 1 or 2 other azoles (22.2%). Nine isolates harboured frameshift mutations in a ERG25 homologue that is usually associated with changes in other genes and should be further evaluated., Conclusions: Cyp51A L98H/TR34 was the most common alteration observed among the azole nonwildtype A fumigatus isolates from a large surveillance study; however, only isolates that were nonwildtype to isavuconazole had alterations in multiple analysed genes. These isolates deserve further evaluation., (© 2021 Wiley-VCH GmbH.)

Objectives: Manogepix, the active moiety of the prodrug fosmanogepix, is a novel antifungal with activity against major fungal pathogens including Candida (except Candida krusei), Aspergillus and difficult-to-treat/rare moulds. We tested manogepix and comparators against 2669 contemporary (2018-2019) fungal isolates collected from 82 medical centres in North America (42.3%), Europe (37.9%), Asia-Pacific (12.3%) and Latin America (7.6%). Of these, 70.7% were Candida spp., 3.6% were non-Candida yeasts including 49 Cryptococcus neoformans var. grubii, 21.7% were Aspergillus spp. and 4.1% were other moulds., Methods: Isolates were tested for antifungal susceptibility by the CLSI reference broth microdilution method., Results: Manogepix (MIC 50/90 , 0.008/0.06 mg/L) was the most active agent tested against Candida spp. isolates; corresponding anidulafungin, micafungin and fluconazole MIC 90 values were 16- to 64-fold higher. Similarly, manogepix (MIC 50/90 , 0.5/2 mg/L) was ≥4-fold more active than anidulafungin, micafungin and fluconazole against C. neoformans var. grubii. Against Aspergillus spp., manogepix (MEC 50/90 , 0.015/0.03 mg/L) had comparable activity to anidulafungin and micafungin. Low manogepix concentrations inhibited uncommon species of Candida, non-Candida yeasts, and rare moulds including Scedosporium spp. and Lomentospora (Scedosporium) prolificans., Conclusion: Manogepix exhibited potent activity against contemporary fungal isolates, including echinocandin- and azole-resistant strains of Candida and Aspergillus spp., respectively. Although rare, Candida strains that were non-wild type for manogepix demonstrated resistance to fluconazole. However, the clinical relevance of this finding is unknown. The extended spectrum of manogepix is noteworthy for its activity against many less-common yet antifungal-resistant strains. Clinical studies are underway to evaluate the utility of fosmanogepix against difficult-to-treat resistant fungal infections., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Outbreaks of fungal bloodstream infection (BSI) are uncommon among hemodialysis patients. We investigated an outbreak of Candida tropicalis BSIs involving patients at 3 of 4 affiliated hemodialysis units., Methods: An investigation included a review of records of patients with C tropicalis BSI, a case-control study, and cultures of medications, hands of personnel, dialysis equipment, and water samples., Results: Eight patients developed C tropicalis BSIs in a 3-month period. Compared to controls, cases had a higher proportion of preceding dialyses performed on a machine with a contaminated saline prime bucket (SPB) (P= .02). Observations revealed that SPBs at units A-C were rinsed with tap water, were not routinely disinfected, and that priming tubing was allowed to contact fluid in SPBs. C tropicalis was recovered from the main compartment and hollow handle of SPBs and from other environmental samples. C tropicalis isolates from patients, SPBs and other environmental samples had indistinguishable pulsed-field gel electrophoresis patterns. Following routine disinfection of SPBs, the outbreak terminated., Conclusions: This outbreak was likely due to inadequate disinfection of SPBs. The findings emphasize the importance of disinfection of SPBs. Current use of identical SPBs warrants further evaluation of hollow SPB handles as a potential infection risk., (Copyright © 2021 Association for Professionals in Infection Control and Epidemiology, Inc. Published by Elsevier Inc. All rights reserved.)

Antifungal surveillance is an important tool to monitor the prevalence of uncommon fungal species and increasing antifungal resistance throughout the world, but data comparing results across several different Asian countries are scarce. In this study, 372 invasive molds collected in the Asia-Western Pacific region in 2011-2019 were susceptibility tested for mold-active triazoles (isavuconazole, posaconazole, voriconazole, and itraconazole). The collection includes 318 Aspergillus spp. isolates and 53 non-Aspergillus molds. The MIC values using CLSI methods for isavuconazole versus Aspergillus fumigatus ranged from 0.25 to 2 mg l -1 . Isavuconazole, itraconazole, posaconazole, and voriconazole acted similarly against A. fumigatus. The mold-active triazoles exhibited a wildtype phenotype to most of the Aspergillus spp. isolates tested (>94%), but poor activity against Fusarium solani species complex and Lomentospora prolificans. Voriconazole was most active against the Scedosporium spp. and posaconazole was most active against the Mucorales. In summary, isavuconazole displayed excellent activity against most species of Aspergillus and was comparable to other mold-active triazoles against non-Aspergillus molds., (© 2021. The Author(s), under exclusive licence to the Japan Antibiotics Research Association.)