Dupilumab Safety and Efficacy up to 1 Year in Children Aged 6 Months to 5 Years with Atopic Dermatitis: Results from a Phase 3 Open-Label Extension Study.

BACKGROUND: Pediatric patients with moderate-to-severe atopic dermatitis (AD) often experience a high disease burden and have a high risk of persistent disease. Standard-of-care immunosuppressive systemic treatments have been used off-label for AD in pediatric patients despite concerns for suboptimal safety with continuous use and risk of relapse upon discontinuation. The biologic agent dupilumab is the first systemic treatment approved for moderate-to-severe AD in children as young as 6 months. Long-term safety and efficacy data in this patient population are needed to inform continuous AD management. OBJECTIVES: The purpose of this work was to determine the long-term safety and efficacy of dupilumab treatment up to 1 year in an open-label extension (OLE) study [LIBERTY AD PED-OLE (NCT02612454)] in children aged 6 months to 5 years with moderate-to-severe AD who previously participated in the 16-week, double-blind, phase 3 LIBERTY AD PRESCHOOL trial (NCT03346434 part B; parent study) and were subsequently enrolled in PED-OLE. METHODS: In PED-OLE, patients received dupilumab every 4 weeks according to a weight-tiered regimen (body weight ≥ 5 kg to < 15 kg: 200 mg; ≥ 15 kg to < 30 kg: 300 mg). RESULTS: Data for 142 patients were analyzed, 60 of whom had completed the 52-week visit at time of database lock. Mean age at baseline was 4.1 y [SD, 1.13; range, 1.0-5.9 years]. A majority (78.2%) of patients reported ≥ 1 treatment-emergent adverse event (TEAE), most of which were mild or moderate and transient. The most frequently reported TEAEs were nasopharyngitis (19.7%), cough (15.5%), and pyrexia (14.1%). One TEAE led to treatment discontinuation (severe urticaria, which resolved in 1 day). By week 52, 36.2% of patients had achieved an Investigator's Global Assessment score of 0/1 (clear/almost clear skin), and 96.6%, 79.3%, and 58.6% had at least 50%, 75%, or 90% improvement, respectively, in Eczema Area and Severity Index scores. CONCLUSIONS: Consistent with results seen in adults, adolescents, and older children (aged 6-11 years), treatment with dupilumab for up to 1 year in children aged 6 months to 5 years with inadequately controlled moderate-to-severe AD demonstrated an acceptable long-term safety profile and sustained efficacy. These results support the long-term continuous use of dupilumab in this patient population. TRIAL REGISTRATION: ClinicalTrials.gov Identifiers: NCT02612454 and NCT03346434 (part B).

Atopic dermatitis (AD) is a chronic inflammatory skin disease that often results in a high disease burden in young children and their families. Patients often need long-term treatment to control their disease symptoms, including itch and rash. Dupilumab treatment for 16 weeks has shown benefits in children aged 6 months to 5 years with moderate-to-severe AD, with an acceptable safety profile. As AD is likely to continue from childhood into adolescence and adulthood, there is a need for data supporting long-term use of dupilumab in young children. In this study, children who completed the 16-week study continued dupilumab treatment for up to 1 year, receiving 200 mg or 300 mg of dupilumab (depending on the child's bodyweight) every 4 weeks. Through the year of treatment, 78.2% of patients reported at least one side effect, most of which were mild or moderate. Only one patient interrupted treatment because of severe skin rash (hives), which was resolved in 1 day. At the end of the year, 36.2% of patients had clear or almost clear skin, and almost all (96.6%) achieved at least 50% improvement in their extent and severity of disease. Additionally, 79.3%, and 58.6% had at least 75% or 90% improvement in their extent and severity of disease. In summary, consistent with results seen in adults, adolescents, and older children, this study showed that 1-year dupilumab treatment provides continued benefits with an acceptable safety profile. These results support long-term continuous use of dupilumab in children aged 6 months to 5 years with moderate-to-severe AD. What is the long-term safety and efficacy profile in young children with moderate-to-severeatopic dermatitis treated with dupilumab?

Perfusion Collateral Index versus Hypoperfusion Intensity Ratio in Assessment of Collaterals in Patients with Acute Ischemic Stroke.

BACKGROUND AND PURPOSE: Perfusion-based collateral indices such as the perfusion collateral index and the hypoperfusion intensity ratio have shown promise in the assessment of collaterals in patients with acute ischemic stroke. We aimed to compare the diagnostic performance of the perfusion collateral index and the hypoperfusion intensity ratio in collateral assessment compared with angiographic collaterals and outcome measures, including final infarct volume, infarct growth, and functional independence. MATERIALS AND METHODS: Consecutive patients with acute ischemic stroke with anterior circulation proximal arterial occlusion who underwent endovascular thrombectomy and had pre- and posttreatment MRI were included. Using pretreatment MR perfusion, we calculated the perfusion collateral index and the hypoperfusion intensity ratio for each patient. The angiographic collaterals obtained from DSA were dichotomized to sufficient (American Society of Interventional and Therapeutic Neuroradiology [ASITN] scale 3-4) versus insufficient (ASITN scale 0-2). The association of collateral status determined by the perfusion collateral index and the hypoperfusion intensity ratio was assessed against angiographic collaterals and outcome measures. RESULTS: A total of 98 patients met the inclusion criteria. Perfusion collateral index values were significantly higher in patients with sufficient angiographic collaterals (P < .001), while there was no significant (P = .46) difference in hypoperfusion intensity ratio values. Among patients with good (mRS 0-2) versus poor (mRS 3-6) functional outcome, the perfusion collateral index of ≥ 62 was present in 72% versus 31% (P = .003), while the hypoperfusion intensity ratio of ≤0.4 was present in 69% versus 56% (P = .52). The perfusion collateral index and the hypoperfusion intensity ratio were both significantly predictive of final infarct volume, but only the perfusion collateral index was significantly (P = .03) associated with infarct growth. CONCLUSIONS: Results show that the perfusion collateral index outperforms the hypoperfusion intensity ratio in the assessment of collateral status, infarct growth, and determination of functional outcomes.

To scan or not to scan: effect of scanning the axilla of all patients undergoing diagnostic breast ultrasound.

BACKGROUND: Breast ultrasonography is a useful modality in patients undergoing diagnostic and screening breast imaging. However, breast ultrasound has a high false positive rate and can be time-consuming to perform. PURPOSE: The purpose of this study was to evaluate the clinical impact of incidental axillary findings found on diagnostic breast ultrasounds at a single multi-site institution that has a standard protocol of scanning the axilla for all breast ultrasound exams. METHODS: All diagnostic breast ultrasounds were retrospectively reviewed from January 2017 to September 2019. Follow-up imaging, relevant clinical history, and pathology results were also reviewed. All positive axillary findings were divided into incidental or non-incidental findings depending on whether there was a direct clinical indication to scan the axilla. Descriptive statistics were performed with a 5% level of significance. RESULTS: Of the 19,695 diagnostic ultrasounds performed during this timeframe, there were 91 (0.5%) incidental axillary findings given a BIRADS category 3 or 4, and none of these findings resulted in the diagnosis of an occult breast cancer. One biopsy-proven SLL/CLL lymphoma was diagnosed that was otherwise clinically occult. CONCLUSION: Routine axillary scanning in all patients undergoing a diagnostic breast ultrasound at a large multi-site institution yields a low rate of incidental findings and has minimal impact on detection of cancer.

Automated estimation of ischemic core volume on noncontrast-enhanced CT via machine learning.

BACKGROUND: Accurate estimation of ischemic core on baseline imaging has treatment implications in patients with acute ischemic stroke (AIS). Machine learning (ML) algorithms have shown promising results in estimating ischemic core using routine noncontrast computed tomography (NCCT). OBJECTIVE: We used an ML-trained algorithm to quantify ischemic core volume on NCCT in a comparative analysis to pretreatment magnetic resonance imaging (MRI) diffusion-weighted imaging (DWI) in patients with AIS. METHODS: Patients with AIS who had both pretreatment NCCT and MRI were enrolled. An automatic segmentation ML approach was applied using Brainomix software (Oxford, UK) to segment the ischemic voxels and calculate ischemic core volume on NCCT. Ischemic core volume was also calculated on baseline MRI DWI. Comparative analysis was performed using Bland-Altman plots and Pearson correlation. RESULTS: A total of 72 patients were included. The time-to-stroke onset time was 134.2/89.5 minutes (mean/median). The time difference between NCCT and MRI was 64.8/44.5 minutes (mean/median). In patients who presented within 1 hour from stroke onset, the ischemic core volumes were significantly (p = 0.005) underestimated by ML-NCCT. In patients presented beyond 1 hour, the ML-NCCT estimated ischemic core volumes approximated those obtained by MRI-DWI and with significant correlation (r = 0.56, p < 0.001). CONCLUSION: The ischemic core volumes calculated by the described ML approach on NCCT approximate those obtained by MRI in patients with AIS who present beyond 1 hour from stroke onset.

MR Angiography in Assessment of Collaterals in Patients with Acute Ischemic Stroke: A Comparative Analysis with Digital Subtraction Angiography.

Collateral status has prognostic and treatment implications in acute ischemic stroke (AIS) patients. Unlike CTA, grading collaterals on MRA is not well studied. We aimed to evaluate the accuracy of assessing collaterals on pretreatment MRA in AIS patients against DSA. AIS patients with anterior circulation proximal arterial occlusion with baseline MRA and subsequent endovascular treatment were included. MRA collaterals were evaluated by two neuroradiologists independently using the Tan and Maas scoring systems. DSA collaterals were evaluated by using the American Society of Interventional and Therapeutic Neuroradiology grading system and were used as the reference for comparative analysis against MRA. A total of 104 patients met the inclusion criteria (59 female, age (mean ± SD): 70.8 ± 18.1). The inter-rater agreement (k) for collateral scoring was 0.49, 95% CI 0.37-0.61 for the Tan score and 0.44, 95% CI 0.26-0.62 for the Maas score. Total number (%) of sufficient vs. insufficient collaterals based on DSA was 49 (47%) and 55 (53%) respectively. Using the Tan score, 45% of patients with sufficient collaterals and 64% with insufficient collaterals were correctly identified in comparison to DSA, resulting in a poor agreement (0.09, 95% CI 0.1-0.28). Using the Maas score, only 4% of patients with sufficient collaterals and 93% with insufficient collaterals were correctly identified against DSA, resulting in poor agreement (0.03, 95% CI 0.06-0.13). Pretreatment MRA in AIS patients has limited concordance with DSA when grading collaterals using the Tan and Maas scoring systems.

Exome Sequencing Identified Molecular Determinants of Retinal Dystrophies in Nine Consanguineous Pakistani Families.

Inherited retinal dystrophies (IRDs) are a heterogeneous group of degenerative disorders of the retina. Retinitis Pigmentosa (RP) is a common type of IRD that causes night blindness and loss of peripheral vision and may progress to blindness. Mutations in more than 300 genes have been associated with syndromic and non-syndromic IRDs. Recessive forms are more frequent in populations where endogamy is a social preference, such as Pakistan. The aim of this study was to identify molecular determinants of IRDs with the common presentation of night blindness in consanguineous Pakistani families. This study included nine consanguineous IRD-affected families that presented autosomal recessive inheritance of the night blindness phenotype. DNA was extracted from blood samples. Targeted exome sequencing of 344 known genes for retinal dystrophies was performed. Screening of nine affected families revealed two novel (c.5571_5576delinsCTAGATand c.471dup in EYS and SPATA7 genes, respectively) and six reported pathogenic mutations (c.304C>A, c.187C>T, c.1560C>A, c.547C>T, c.109del and c.9911_11550del in PDE6A, USH2A, USH2A, NMNAT1, PAX6 and ALMS1 genes, respectively) segregating with disease phenotype in each respective family. Molecular determinants of hereditary retinal dystrophies were identified in all screened families. Identification of novel variants aid future diagnosis of retinal dystrophies and help to provide genetic counseling to affected families.

In vivo efficacy of WCK 6777 (ertapenem/zidebactam) against carbapenemase-producing Klebsiella pneumoniae in the neutropenic murine pneumonia model.

OBJECTIVES: Ertapenem has proven to be an effective antimicrobial; however, increasing enzyme-mediated resistance has been noted. Combination with zidebactam, a ß-lactam enhancer, is restorative. Human-simulated regimens (HSRs) of ertapenem and zidebactam alone and in combination (WCK 6777; 2 g/2 g q24h) were assessed for efficacy against carbapenemase-producing Klebsiella pneumoniae (CP-KP) in the pneumonia model. METHODS: Infected ICR mice were rendered neutropenic and exposed to various doses of ertapenem and zidebactam alone and in combination to develop the HSRs that were subsequently confirmed in additional pharmacokinetic studies. Twenty-one CP-KP (KPC or OXA-48-like producers) with WCK 6777 MICs of 1-8 mg/L were utilized. Mice were treated for 24 h with saline or HSRs of ertapenem, zidebactam and WCK 6777. Efficacy was defined as change in mean lung bacterial density relative to 0 h. RESULTS: Confirmatory pharmacokinetic analysis showed agreement between predicted human exposures (%fT>MIC) and those achieved in vivo for all three HSRs. The 0 h bacterial density across all isolates was 6.69 ±â€Š0.31 log10 cfu/lungs. At 24 h, densities increased by 2.57 ±â€Š0.50, 2.2 ±â€Š0.60 and 2.05 ±â€Š0.71 log10 cfu/lungs in the 24 h control, ertapenem HSR and zidebactam HSR groups, respectively. Overall, 18/21 of the isolates exposed to the WCK 6777 HSR displayed a killing profile that exceeded the translational benchmark for efficacy of a 1 log10 cfu reduction. Among the remaining three isolates, two displayed ∼0.5 log10 kill and stasis was observed in the third. CONCLUSIONS: Human-simulated exposures of WCK 6777 demonstrated potent in vivo activity against CP-KP, including those with WCK 6777 MICs up to 8 mg/L.

Utilization and evolving prescribing practice of opioid and non-opioid analgesics in patients undergoing lymphadenectomy for cutaneous malignancy.

BACKGROUND AND OBJECTIVES: Opioids are commonly prescribed following surgery and can lead to persistent opioid use. We assessed changes in prescribing practices following an opioid education initiative for patients undergoing lymphadenectomy for cutaneous malignancy. METHODS: A single-institution retrospective study of all eligible patients (3/2016-3/2020) was performed. RESULTS: Indications for lymphadenectomy in 328 patients were metastatic melanoma (84%), squamous cell carcinoma (10%), and Merkel cell carcinoma (5%). At discharge, non-opioid analgesics were increasingly utilized over the 4-year study period, with dramatic increases after education initiatives (32%, 42%, 59%, and 79% of pts, respectively each year; p < 0.001). Median oral morphine equivalents (OMEs) prescribed also decreased dramatically starting in year 3 (250, 238, 150, and 100 mg, respectively; p < 0.001). Patients discharged with 200 mg OMEs were less likely to also be discharged with non-opioid analgesics (40% vs. 64%. respectively, p < 0.001). CONCLUSIONS: Analgesic prescribing practices following lymphadenectomy for cutaneous malignancy improved significantly over a 4-year period, with use of non-opioids more than doubling and a 60% reduction in median OME. Opportunities exist to further increase non-opioid use and decrease opioid dissemination after lymphadenectomy for cutaneous malignancy.

Guided tour of hidden tracts in the pelvis: exploring pelvic fistulas.

BACKGROUND: Fistulas are an abnormal connection between two or more epithelial surfaces. When fistulization between adjacent structures occurs in the pelvis, there is almost invariably significant associated morbidity and impact on a patient's quality of life. Imaging may aid in the diagnosis of pelvic fistulas and is essential to identify any associated pathology, define the course of the fistula, and aid in pre-surgical planning. PURPOSE: This article aims to review the wide array of clinical and imaging presentations of fistulas in the pelvis, with a focus on the radiologists' role in managing this challenging entity. METHODS: This article will review each classification type of fistula. RESULTS: Pelvic fistula is a devastating condition that causes significant morbidity and evaluation can be challenging. CONCLUSIONS: Imaging, and particularly MRI, plays a vital role in the diagnosis, characterizing the course of a fistula and demonstrating associated complications, which are essential to guide treatment decisions.

A functional genomics screen identifying blood cell development genes in Drosophila by undergraduates participating in a course-based research experience.

Undergraduate students participating in the UCLA Undergraduate Research Consortium for Functional Genomics (URCFG) have conducted a two-phased screen using RNA interference (RNAi) in combination with fluorescent reporter proteins to identify genes important for hematopoiesis in Drosophila. This screen disrupted the function of approximately 3500 genes and identified 137 candidate genes for which loss of function leads to observable changes in the hematopoietic development. Targeting RNAi to maturing, progenitor, and regulatory cell types identified key subsets that either limit or promote blood cell maturation. Bioinformatic analysis reveals gene enrichment in several previously uncharacterized areas, including RNA processing and export and vesicular trafficking. Lastly, the participation of students in this course-based undergraduate research experience (CURE) correlated with increased learning gains across several areas, as well as increased STEM retention, indicating that authentic, student-driven research in the form of a CURE represents an impactful and enriching pedagogical approach.

Bactericidal In Vitro Activity of a Tissue-Achievable Concentration of Cefazolin against Methicillin-Resistant Staphylococcus aureus.

Background: Methicillin-resistant Staphylococcus aureus (MRSA) is a major cause of skin and soft tissue infections and their recurrences. Although traditionally not considered for use against MRSA, cefazolin presents a possible option when administered using ultrasonic drug dispersion (UD2). This novel technique localizes delivery of drug into the subcutaneous tissue and achieves concentrations that exceed the minimum inhibitory concentrations (MICs) of most clinical MRSA isolates. The purpose of this study was to evaluate the impact of achievable cefazolin concentrations on the rate and extent of bactericidal activity using time-kill methodologies Materials and Methods: The cefazolin MICs of the four MRSA isolates selected for this in vitro time-kill study were 64, 128, 256, and 512 mg/L. Duplicates of drug-free control and cefazolin experiments were carried out using the average UD2-achievable cefazolin concentration (1,300 mg/L). Experiments were incubated at 37°C throughout each run. Samples were plated and incubated for 18 to 24 hours. The lower limit of detection of colony forming units per milliliter (CFU/mL) was 1.7 log10 CFU/mL. Cefazolin was considered bactericidal when it decreased bacterial density by ≥3 log10 CFU/mL from the initial inoculum after 24 hours of incubation. Results: Cefazolin produced mean 24-hour CFU changes of -4.39 to -4.89 log10 CFU/mL against MRSA isolates with MICs from 64 to 512 mg/L. Cefazolin demonstrated bactericidal activity against all studied MRSA isolates and no regrowth was observed at 24 hours. Conclusions: The mean cefazolin tissue concentration achieved by UD2 was bactericidal against four MRSA isolates. Further investigation is warranted to assess the utility of UD2-administered cefazolin against MRSA skin and soft tissue infections.

Imipenem/Cilastatin/Relebactam Alone and in Combination against Pseudomonas aeruginosa in the In Vitro Pharmacodynamic Model.

Combination therapy may enhance imipenem/cilastatin/relebactam's (I/R) activity against Pseudomonas aeruginosa and suppress resistance development. Human-simulated unbound plasma concentrations of I/R at 1.25 g every 6 h (h), colistin at 360 mg daily, and amikacin at 25 mg/kg daily were reproduced alone and in combination against six imipenem-nonsusceptible P. aeruginosa isolates in an in vitro pharmacodynamic model over 24 h. For I/R alone, the mean reductions in CFU ± the standard errors by 24 h were -2.52 ± 0.49, -1.49 ± 0.49, -1.15 ± 0.67, and -0.61 ± 0.10 log10 CFU/ml against isolates with MICs of 1/4, 2/4, 4/4, and 8/4 µg/ml, respectively. Amikacin alone also resulted in 24 h CFU reductions consistent with its MIC, while colistin CFU reductions did not differ. Resistant subpopulations were observed after 24 h in 1, 4, and 3 I/R-, colistin-, and amikacin-exposed isolates, respectively. The combination of I/R and colistin resulted in synergistic (n = 1) or additive (n = 2) interactions against three isolates with 24-h CFU reductions ranging from -2.62 to -4.67 log10 CFU/ml. The combination of I/R and amikacin exhibited indifferent interactions against all isolates, with combined drugs achieving -0.51- to -3.33-log10 CFU/ml reductions. No resistant subpopulations were observed during I/R and colistin combination studies, and when added to amikacin, I/R prevented the emergence of amikacin resistance. Against these six multidrug-resistant P. aeruginosa, I/R alone achieved significant CFU reductions against I/R-susceptible isolates. Combinations of I/R plus colistin resulted in additivity or synergy against some P. aeruginosa, whereas the addition of amikacin did not provide further antibacterial efficacy against these isolates.

Augmented Renal Clearance and How to Augment Antibiotic Dosing.

Augmented renal clearance (ARC) refers to the state of heightened renal filtration commonly observed in the critically ill. Its prevalence in this patient population is a consequence of the body's natural response to serious disease, as well as the administration of fluids and pharmacologic therapies necessary to maintain sufficient blood pressure. ARC is objectively defined as a creatinine clearance of more than 130 mL/min/1.73 m2 and is thus a crucial condition to consider when administering antibiotics, many of which are cleared renally. Using conventional dosing regimens risks the possibility of subtherapeutic concentrations or clinical failure. Over the past decade, research has been conducted in patients with ARC who received a number of antibacterials frequently used in the critically ill, such as piperacillin-tazobactam or vancomycin. Strategies to contend with this condition have also been explored, though further investigations remain necessary.

Assessment of Meropenem and Vaborbactam Room Temperature and Refrigerated Stability in Polyvinyl Chloride Bags and Elastomeric Devices.

PURPOSE: Meropenem and vaborbactam is an intravenous beta-lactam/beta-lactamase inhibitor combination antibiotic active against multidrug resistant gram-negative bacteria. It may be a suitable treatment for inpatient and outpatient management of infections, and the intravenous admixture stability is therefore important for optimal utilization. The purpose of this study was to determine the stability of meropenem and vaborbactam in polyvinyl chloride (PVC) infusion bags and elastomeric pumps at room and refrigerated temperatures. METHODS: Meropenem and vaborbactam vials were reconstituted according to manufacturer instructions and diluted in PVC infusion bags to final concentrations of 4, 8, and 16 mg/mL and in elastomeric pumps to 11.4 mg/mL (n = 5 replicates per concentration and per temperature). PVC bags and elastomeric pumps were stored at room temperature (~24 °C) or in the refrigerator (~4 °C) and sampled over 12 and 144 h, respectively. Stability was defined as the duration that meropenem and vaborbactam concentrations remained ≥90% of the original concentrations. FINDINGS: All room temperature replicates across the tested concentrations retained meropenem and vaborbactam stability over 12 h and displayed concentration-dependent degradation. Refrigerated studies resulted in meropenem and vaborbactam stability at all tested concentrations up to 120 h. IMPLICATIONS: Meropenem and vaborbactam in PVC bags (4, 8, and 16 mg/mL) and elastomeric pumps (11.4 mg/mL) were stable for 12 h at room temperature and 120 h when refrigerated. These stability data allow for enhanced flexibility in the preparation, storage, wastage, and administration of meropenem and vaborbactam in the hospital and outpatient setting.

Machine-driven parameter screen of biochemical reactions.

The development of complex methods in molecular biology is a laborious, costly, iterative and often intuition-bound process where optima are sought in a multidimensional parameter space through step-by-step optimizations. The difficulty of miniaturizing reactions under the microliter volumes usually handled in multiwell plates by robots, plus the cost of the experiments, limit the number of parameters and the dynamic ranges that can be explored. Nevertheless, because of non-linearities of the response of biochemical systems to their reagent concentrations, broad dynamic ranges are necessary. Here we use a high-performance nanoliter handling platform and computer generation of liquid transfer programs to explore in quadruplicates 648 combinations of 4 parameters of a biochemical reaction, the reverse-transcription, which lead us to uncover non-linear responses, parameter interactions and novel mechanistic insights. With the increased availability of computer-driven laboratory platforms for biotechnology, our results demonstrate the feasibility and advantage of methods development based on reproducible, computer-aided exhaustive characterization of biochemical systems.

Comparative In Vivo Antibacterial Activity of Human-Simulated Exposures of Cefiderocol and Ceftazidime against Stenotrophomonas maltophilia in the Murine Thigh Model.

Cefiderocol is a novel siderophore cephalosporin that utilizes bacterial ferric iron transports to cross the outer membrane. Cefiderocol shows high stability against all classes of ß-lactamases, rendering it extremely potent against carbapenem- and multidrug-resistant Gram-negative organisms. Using a neutropenic murine thigh model, we compared the efficacies of human-simulated exposures of cefiderocol (2 g Q8H 3 h infusion) and ceftazidime (2 g Q8H 2 h infusion) against Stenotrophomonas maltophilia, an emerging opportunistic Gram-negative organism associated with serious and often fatal nosocomial infections. Twenty-four S. maltophilia isolates were studied, including isolates resistant to ceftazidime, trimethoprim-sulfate, and/or levofloxacin. The thighs were inoculated with bacterial suspensions of 108 CFU/mL and the human-simulated regimens were administered over 24 h. Efficacy was measured as the change in log10CFU/thigh at 24 h compared with 0 h controls. Cefiderocol human-simulated exposure demonstrated potent bacterial killing; mean bacterial reduction at 24 h was -2.67 ± 0.68 log10CFU/thigh with ≥ 2 log-reduction achieved in 21 isolates (87.5%) and ≥ 1 log-reduction achieved in the remaining three isolates (12.5%). In comparison, ceftazidime human-simulated exposure produced mean bacterial reduction of -1.38 ± 1.49 log10CFU/thigh among 10 ceftazidime-susceptible isolates and mean bacterial growth of 0.64 ± 0.79 log10CFU/thigh among 14 ceftazidime-non-susceptible isolates. While ceftazidime showed modest efficacy against most susceptible isolates, humanized cefiderocol exposures resulted in remarkable in vivo activity against all S. maltophilia isolates examined, inclusive of ceftazidime-non-susceptible isolates. The potent in vitro and in vivo activity of cefiderocol supports the development of this novel compound for managing S. maltophilia infections.

Effect of Clinically Meaningful Antibiotic Concentrations on Recovery of Escherichia coli and Klebsiella pneumoniae Isolates from Anaerobic Blood Culture Bottles with and without Antibiotic Binding Resins.

Blood cultures are routinely collected in pairs of aerobic and anaerobic bottles. Artificial sterilization of Gram-negative bacteria in aerobic bottles containing clinically meaningful antibiotic concentrations has previously been observed. This study assessed recovery from anaerobic bottles with and without antibiotic binding resins. We studied the recovery of Escherichia coli and Klebsiella pneumoniae when exposed to meropenem, imipenem, cefepime, cefazolin, levofloxacin, and piperacillin-tazobactam in resin-containing BacT/Alert FN Plus and BD Bactec Plus anaerobic/F bottles as well as resin-free BacT/Alert SN and BD Bactec standard anaerobic bottles. Bottles were inoculated with bacteria and whole blood containing peak, midpoint, or trough concentrations and incubated for up to 120 hours in their respective detection systems. In E. coli resin-containing bottles, recovery was observed in 10/24 (42%), 17/24 (71%), and 18/24 (75%) (P = 0.034) of those exposed to peak, midpoint, and trough concentrations, respectively. In K. pneumoniae resin-containing bottles, recovery was observed in 8/16 (50%), 10/16 (63%), and 10/16 (63%) (P = 0.710), respectively. No growth was detected in bottles containing cefepime regardless of concentration, while recovery was observed in the presence of all concentrations of cefazolin and piperacillin-tazobactam. Recovery in bottles with meropenem and imipenem was more frequently observed in BacT/Alert FN Plus bottles compared with Bactec Plus bottles. Resin-free bottles demonstrated significantly lower recovery than bottles containing binding resin. Clinical concentrations of certain antibiotics can adversely affect detection of E. coli and K. pneumoniae in anaerobic blood culture bottles. Obtaining blood cultures immediately before a dose and utilizing resin-containing anaerobic bottles will maximize the likelihood of recovery.

Assessment of the Physical Compatibility of Eravacycline and Common Parenteral Drugs During Simulated Y-site Administration.

PURPOSE: Eravacycline is a broad-spectrum, intravenous fluorocycline antibiotic approved for the treatment of complicated intra-abdominal infections in adults. A 60-minute infusion is recommended for each infused dose. Compatibility data that may allow convenient Y-site administration of eravacycline with other parenteral medications are unavailable. We aimed to determine the physical compatibility of eravacycline with other intravenous medications by simulated Y-site administration. METHODS: Eravacycline was reconstituted according to published prescribing information and diluted with 0.9% sodium chloride to a concentration of 0.6 mg/mL. Simulated Y-site administration was performed by mixing 5 mL of eravacycline with an equal volume of 51 other intravenous medications, including crystalloid and carbohydrate hydration fluids and 20 antimicrobials. Secondary medications were assessed at the upper range of concentrations considered standard for intravenous infusion. Mixtures underwent visual inspection and turbidity measurement immediately on mixture and at 3 subsequent time points (30, 60, and 120 minutes after admixture), and pH was measured at 60 minutes for comparison with the baseline value of the secondary medication. FINDINGS: Eravacycline was physically compatible with 41 parenteral drugs (80%) by simulated Y-site administration. Incompatibility was observed with albumin, amiodarone hydrochloride, ceftaroline fosamil, colistimethate sodium, furosemide, meropenem, meropenem/vaborbactam, micafungin sodium, propofol, and sodium bicarbonate. IMPLICATIONS: Eravacycline for injection was physically compatible with most parenteral medications assessed. Pharmacists and nurses should be knowledgeable of the observed incompatibilities with eravacycline to prevent the unintentional mixing of incompatible intravenous medications.

Machine learning for semi-automated classification of glioblastoma, brain metastasis and central nervous system lymphoma using magnetic resonance advanced imaging.

BACKGROUND: Differentiating glioblastoma, brain metastasis, and central nervous system lymphoma (CNSL) on conventional magnetic resonance imaging (MRI) can present a diagnostic dilemma due to the potential for overlapping imaging features. We investigate whether machine learning evaluation of multimodal MRI can reliably differentiate these entities. METHODS: Preoperative brain MRI including diffusion weighted imaging (DWI), dynamic contrast enhanced (DCE), and dynamic susceptibility contrast (DSC) perfusion in patients with glioblastoma, lymphoma, or metastasis were retrospectively reviewed. Perfusion maps (rCBV, rCBF), permeability maps (K-trans, Kep, Vp, Ve), ADC, T1C+ and T2/FLAIR images were coregistered and two separate volumes of interest (VOIs) were obtained from the enhancing tumor and non-enhancing T2 hyperintense (NET2) regions. The tumor volumes obtained from these VOIs were utilized for supervised training of support vector classifier (SVC) and multilayer perceptron (MLP) models. Validation of the trained models was performed on unlabeled cases using the leave-one-subject-out method. Head-to-head and multiclass models were created. Accuracies of the multiclass models were compared against two human interpreters reviewing conventional and diffusion-weighted MR images. RESULTS: Twenty-six patients enrolled with histopathologically-proven glioblastoma (n=9), metastasis (n=9), and CNS lymphoma (n=8) were included. The trained multiclass ML models discriminated the three pathologic classes with a maximum accuracy of 69.2% accuracy (18 out of 26; kappa 0.540, P=0.01) using an MLP trained with the VpNET2 tumor volumes. Human readers achieved 65.4% (17 out of 26) and 80.8% (21 out of 26) accuracies, respectively. Using the MLP VpNET2 model as a computer-aided diagnosis (CADx) for cases in which the human reviewers disagreed with each other on the diagnosis resulted in correct diagnoses in 5 (19.2%) additional cases. CONCLUSIONS: Our trained multiclass MLP using VpNET2 can differentiate glioblastoma, brain metastasis, and CNS lymphoma with modest diagnostic accuracy and provides approximately 19% increase in diagnostic yield when added to routine human interpretation.