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.

Vaborbactam increases meropenem susceptibility in Pseudomonas aeruginosa clinical isolates displaying MexXY and AmpC upregulation.

To evaluate the resistance mechanisms among Pseudomonas aeruginosa clinical isolates exhibiting meropenem (MEM) MIC values higher than meropenem-vaborbactam (MEV). P. aeruginosa clinical isolates collected in US hospitals from 2014 to 2019 were susceptibility tested. Whole-genome and transcriptome sequencing were performed. Results were analyzed for strain typing, acquired ß-lactamases, and mutations in chromosomal genes; gene expression was measured for known ß-lactam resistance contributors. Results were compared to a control group of 10 P. aeruginosa isolates displaying MIC values at 8 mg/L for meropenem ± vaborbactam (MEM = MEV). Out of 88 isolates displaying MEM > MEV, 33 (37.5%) isolates had reproducibly lower MIC values for meropenem-vaborbactam compared to meropenem when retested. The expression of mexX, mexY, mexZ, and ampC was significantly greater among a higher percentage of the MEM > MEV isolates. Furthermore, the association of mexXY and ampC overexpression was detected in 17/33 MEM > MEV isolates and only 1/10 MEM = MEV isolate. In addition, the Pseudomonas-derived cephalosporinase amino acid substitution R79Q was detected among 33.3% of the isolates displaying MEM > MEV, and none of the isolates displayed MEM = MEV. Other resistance mechanisms were not observed or were equally observed in both groups. In rare cases, vaborbactam plays a role in lowering the meropenem MIC values in P. aeruginosa clinical isolates likely due to the inhibition of the AmpC gene that was overexpressed in the presence of upregulation of MexXY with or without alterations in the AmpC gene. IMPORTANCE Pseudomonas aeruginosa isolates are intrinsically resistant to multiple antimicrobial agents and meropenem is an important therapeutic option to treat infections caused by this organism. Meropenem-vaborbactam activity is similar to that of meropenem alone against P. aeruginosa isolates. Isolates belonging to this species that display lower meropenem-vaborbactam compared to meropenem are rare. We initiated this study to understand the resistance mechanisms that could lead to lower meropenem-vaborbactam MIC values when compared to meropenem alone. We documented that isolates displaying lower meropenem-vaborbactam exhibited overexpression of MexXY and AmpC. In addition, isolates displaying the R79Q PDC (AmpC) mutation were more likely to display lower meropenem-vaborbactam when compared to isolates displaying the same MIC values for these agents.

Screen for New Antimicrobial Natural Products from the NCI Program for Natural Product Discovery Prefractionated Extract Library.

The continuing emergence of antibiotic-resistant microbes highlights the need for the identification of new chemotypes with antimicrobial activity. One of the most prolific sources of antimicrobial molecules has been the systematic screening of natural product samples. The National Institute of Allergy and Infectious Diseases and the National Cancer Institute here report a large screen of 326,656 partially purified natural product fractions against a panel of four microbial pathogens, resulting in the identification of >3000 fractions with antifungal and/or antibacterial activity. A small sample of these active fractions was further purified and the chemical structures responsible for the antimicrobial activity were elucidated. The proof-of-concept study identified many different chemotypes, several of which have not previously been reported to have antimicrobial activity. The results show that there remain many unidentified antibiotic compounds from nature.

Trends of ß-Lactamase Occurrence Among Escherichia coli and Klebsiella pneumoniae in United States Hospitals During a 5-Year Period and Activity of Antimicrobial Agents Against Isolates Stratified by ß-Lactamase Type.

Background: The temporal and longitudinal trends of ß-lactamases and their associated susceptibility patterns were analyzed for Escherichia coli and Klebsiella pneumoniae isolates consecutively collected in 56 United States hospitals during 2016-2020. Methods: Isolates (n = 19 453) were susceptibility tested by reference broth microdilution methods. Isolates that displayed minimum inhibitory concentration (MIC) values ≥2 mg/L for at least 2 of the following compounds-ceftazidime, ceftriaxone, aztreonam, or cefepime-or resistance to the carbapenems were submitted to whole genome sequencing for identification of ß-lactamases. Longitudinal and temporal trends were determined by slope coefficient. New CTX-M and OXA-1 variants were characterized. Results: Extended-spectrum ß-lactamases (ESBLs) were detected among 88.0% of the isolates that displayed elevated cephalosporin/aztreonam MICs without carbapenem resistance. bla CTX-M-15 was detected among 55.5% of the ESBL producers. ESBL rates were stable over time, but significant increases were noted among bloodstream infection and K pneumoniae isolates, mainly driven by an increase in bla CTX-M. Carbapenem resistance and carbapenemase genes were noted among 166 and 145 isolates, respectively, including 137 bla KPC, 6 bla SME, 3 bla OXA-48-like, and 3 bla NDM. Ceftazidime-avibactam and carbapenems were very active (>99% susceptibility) against ESBL producers without carbapenem resistance. Ceftazidime-avibactam inhibited 97.0% of the carbapenem-resistant isolates. This agent and meropenem-vaborbactam inhibited 96.4% and 85.0% of the 2020 isolates, respectively. Conclusions: Overall, ESBL-producing isolates were stable, but an increase was noted for K pneumoniae isolates driven by CTX-M production. Carbapenem-resistant Enterobacterales rates decreased in the study period. The prevalence of metallo-ß-lactamases and OXA-48-like remains low. Continuous surveillance of ß-lactamase-producing isolates is prudent.

The plethora of resistance mechanisms in Pseudomonas aeruginosa: transcriptome analysis reveals a potential role of lipopolysaccharide pathway proteins to novel ß-lactam/ß-lactamase inhibitor combinations.

OBJECTIVES: Whole genome and transcriptome analysis of 213 Pseudomonas aeruginosa isolates resistant to antipseudomonal ß-lactams collected in 30 countries was performed to evaluate resistance mechanisms against these agents. METHODS: Isolates were susceptibility tested by reference broth microdilution. Whole genome and transcriptome sequencing were performed, and data were analysed using open-source tools. A statistical analysis of changes in the expression of >5500 genes was compared to the expression of PAO1. RESULTS: The high-risk clones ST235 and ST111 were the most prevalent among >90 sequence types (STs). Metallo-ß-lactamase (MBLs) genes were detected in 40 isolates. AmpC and MexXY were the most common genes overexpressed in approximately 50% of the 173 isolates that did not carry MBLs. Isolates overexpressing pmrA and pmrB, the norspermidine production genes speD2 and speE2, and the operon arnBCADTEF-ugd were noted among strains resistant to ceftolozane-tazobactam and ceftazidime-avibactam, despite the lack of polymyxin resistance often associated to increased expression of these genes. Overexpression of MuxABC-OpmB, OprG, and OprE proteins were associated with resistance to ceftolozane-tazobactam in addition to the usual genes involved in cephalosporin, monobactam, and carbapenem resistance. Statistical analysis identified discrete mutations in ArmZ, OprD, and AmpC that correlated to antipseudomonal ß-lactam resistance. CONCLUSIONS: P. aeruginosa resistance mechanisms are complex. This analysis suggests the role of multiple genes in resistance to antipseudomonal ß-lactams, including some not commonly described.

Activity of Tedizolid and Comparator Agents Against Gram-positive Isolates Causing Skin and Skin Structure Infections in Pediatric Patients in United States Hospitals (2015-2019).

BACKGROUND: Tedizolid was approved by the United States Food and Drug Administration to treat acute bacterial skin and skin structure infections in adults in 2014, and in 2020, United States Food and Drug Administration expanded the approval of tedizolid to treat pediatric patients 12 years of age and older. This study assessed the activity of tedizolid and comparator agents against clinical surveillance isolates collected from pediatric patients with skin and skin structure infection in the United States. METHODS: A total of 2747 gram-positive organisms (1 per patient) were collected in 2015 to 2019 from pediatric (≤17 years old) patients with skin and skin structure infections. The isolates were collected from 33 US medical centers and susceptibility tested against tedizolid and comparators by reference broth microdilution methods. Susceptibility results for main pathogens were stratified by patient age: ≤1 years old (851 isolates), 2 to 5 years old (623), 6 to 12 years old (754) and 13 to 17 years old (519). RESULTS: Staphylococcus aureus (n = 2163) was the main pathogen recovered from all age groups, followed by ß-hemolytic streptococci (n = 460). Tedizolid inhibited all S. aureus , including methicillin-resistant S. aureus (MRSA) isolates (41.0%), regardless of the age group. MRSA rates varied by age group; MRSA was highest among ≤1 years old (45.0%) and lowest in the 13 to 17 years old (32.7%) groups. Linezolid, daptomycin and vancomycin also displayed susceptibility rates of 100% against S. aureus isolates. Clindamycin (81.3%-98.5%), tetracycline (91.6%-97.1%) and trimethoprim-sulfamethoxazole (97.0%-100%) susceptibility rates varied among age groups and methicillin resistance profiles. Overall, tedizolid, linezolid, daptomycin and vancomycin inhibited all gram-positive pathogens in this collection. CONCLUSIONS: Tedizolid was very active against a large collection of gram-positive pathogens causing skin and skin structure infection in pediatric patients, including MRSA isolates.

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

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

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

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

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

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

Comparison of T1Rho MRI, Glucose Metabolism, and Amyloid Burden Across the Cognitive Spectrum: A Pilot Study.

OBJECTIVE: The pathological cascades associated with the development of Alzheimer's disease (AD) have a common element: acidosis. T1rho MRI is a pH-sensitive measure, with higher values associated with greater neuropathological burden. The authors investigated the relationship between T1rho imaging and AD-associated pathologies as determined by available diagnostic imaging techniques. METHODS: Twenty-seven participants (men, N=13, women, N=14; ages 55-90) across the cognitive spectrum (healthy control subjects [HCs] with normal cognition, N=17; participants with mild cognitive impairment [MCI], N=7; participants with mild AD, N=3) underwent neuropsychological testing, MRI (T1-weighted and T1rho [spin-lattice relaxation time in the rotating frame]), and positron emission tomography imaging ([11C]Pittsburg compound B for amyloid burden [N=26] and [18F]fluorodeoxyglucose for cerebral glucose metabolism [N=12]). The relationships between global T1rho values and neuropsychological, demographic, and imaging measures were explored. RESULTS: Global mean and median T1rho were positively associated with age. After controlling for age, higher global T1rho was associated with poorer cognitive function, poorer memory function (immediate and delayed memory scores), higher amyloid burden, and more abnormal cerebral glucose metabolism. Regional T1rho values, when controlling for age, significantly differed between HCs and participants with MCI or AD in select frontal, cingulate, and parietal regions. CONCLUSIONS: Higher T1rho values were associated with greater cognitive impairment and pathological burden. T1rho, a biomarker that varies according to a feature common to each cascade rather than one that is unique to a particular pathology, has the potential to serve as a metric of neuropathology, theoretically providing a measure for assessing pathological status and for monitoring the neurodegeneration trajectory.

Efficacy and Effectiveness of Advanced Hearing Aid Directional and Noise Reduction Technologies for Older Adults With Mild to Moderate Hearing Loss.

OBJECTIVES: The purpose of the present study was to investigate the laboratory efficacy and real-world effectiveness of advanced directional microphones (DM) and digital noise reduction (NR) algorithms (i.e., premium DM/NR features) relative to basic-level DM/NR features of contemporary hearing aids (HAs). The study also examined the effect of premium HAs relative to basic HAs and the effect of DM/NR features relative to no features. DESIGN: Fifty-four older adults with mild-to-moderate hearing loss completed a single-blinded crossover trial. Two HA models, one a less-expensive, basic-level device (basic HA) and the other a more-expensive, advanced-level device (premium HA), were used. The DM/NR features of the basic HAs (i.e., basic features) were adaptive DMs and gain-reduction NR with fewer channels. In contrast, the DM/NR features of the premium HAs (i.e., premium features) included adaptive DMs and gain-reduction NR with more channels, bilateral beamformers, speech-seeking DMs, pinna-simulation directivity, reverberation reduction, impulse NR, wind NR, and spatial NR. The trial consisted of four conditions, which were factorial combinations of HA model (premium versus basic) and DM/NR feature status (on versus off). To blind participants regarding the HA technology, no technology details were disclosed and minimal training on how to use the features was provided. In each condition, participants wore bilateral HAs for 5 weeks. Outcomes regarding speech understanding, listening effort, sound quality, localization, and HA satisfaction were measured using laboratory tests, retrospective self-reports (i.e., standardized questionnaires), and in-situ self-reports (i.e., self-reports completed in the real world in real time). A smartphone-based ecological momentary assessment system was used to collect in-situ self-reports. RESULTS: Laboratory efficacy data generally supported the benefit of premium DM/NR features relative to basic DM/NR, premium HAs relative to basic HAs, and DM/NR features relative to no DM/NR in improving speech understanding and localization performance. Laboratory data also indicated that DM/NR features could improve listening effort and sound quality compared with no features for both basic- and premium-level HAs. For real-world effectiveness, in-situ self-reports first indicated that noisy or very noisy situations did not occur very often in participants' daily lives (10.9% of the time). Although both retrospective and in-situ self-reports indicated that participants were more satisfied with HAs equipped with DM/NR features than without, there was no strong evidence to support the benefit of premium DM/NR features and premium HAs over basic DM/NR features and basic HAs, respectively. CONCLUSIONS: Although premium DM/NR features and premium HAs outperformed their basic-level counterparts in well-controlled laboratory test conditions, the benefits were not observed in the real world. In contrast, the effect of DM/NR features relative to no features was robust both in the laboratory and in the real world. Therefore, the present study suggests that although both premium and basic DM/NR technologies evaluated in the study have the potential to improve HA outcomes, older adults with mild-to-moderate hearing loss are unlikely to perceive the additional benefits provided by the premium DM/NR features in their daily lives. Limitations concerning the study's generalizability (e.g., participant's lifestyle) are discussed.

Early Phase PIB-PET as a Surrogate for Global and Regional Cerebral Blood Flow Measures.

BACKGROUND AND PURPOSE: To explore the potential for simplified measures of [11 C]PIB uptake to serve as a surrogate for cerebral blood flow (CBF) measures, thereby, providing both pathological and functional information in the same scan. METHODS: Participants (N = 24, 16 M, 8 F, 57-87 years) underwent quantitative [15 O]water imaging and dynamic [11 C]PIB imaging. Time-activity curves were created for each participant's regional [11 C]PIB data scaled in standardized uptake values (SUVs). The frame in which maximal uptake occurred was defined for each subject (ie, "peak"). The concentration (SUV) for each region at the individual's peak, during the 3.5-4 minute time interval and for the initial 6 minute sum, was determined. R1 (ie, relative delivery using cerebellum as reference tissue) from the simplified reference tissue model 2 was determined for each region. PIB SUVs were compared to the absolute CBF global and regional values (in mL/minute/100 mL) and the R1 values were compared to the cerebellar-normalized rCBF. RESULTS: Significant linear relationships were found for all SUV measures with measures of absolute global and regional CBF that were comparable to the relationship between normalized CBF and R1. The individual SUVpeak exhibited the strongest relationship both regionally and globally. All individuals and all regions had highly significant regression slopes. Age, gender, or amyloid burden did not influence the relationship. CONCLUSION: Early PIB uptake has the potential to effectively serve as a surrogate for global and regional CBF measures. The simple and readily obtainable individual's SUVpeak value was the strongest predictor regionally and globally of CBF.