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BackgroundVancomycin-resistant Enterococcus bloodstream infections (VRE-BSIs) are becoming increasingly common. Linezolid and daptomycin are the primary treatment options for VRE-BSI, but optimal treatment is unclear.MethodsThis was a national retrospective cohort study comparing linezolid and daptomycin for the treatment of VRE-BSI among Veterans Affairs Medical Center patients admitted during 2004-2013. The primary outcome was treatment failure, defined as a composite of (1) 30-day all-cause mortality; (2) microbiologic failure; and (3) 60-day VRE-BSI recurrence. Poisson regression was conducted to determine if antimicrobial treatment was independently associated with clinical outcomes.ResultsA total of 644 patients were included (linezolid, n = 319; daptomycin, n = 325). Overall, treatment failure was 60.9% (n = 392/644), and 30-day all-cause mortality was 38.2% (n = 246/644). Linezolid was associated with a significantly higher risk of treatment failure compared with daptomycin (risk ratio [RR], 1.37; 95% confidence interval [CI], 1.13-1.67; P = .001). After adjusting for confounding factors in Poisson regression, the relationship between linezolid use and treatment failure persisted (adjusted RR, 1.15; 95% CI, 1.02-1.30; P = .026). Linezolid was also associated with higher 30-day mortality (42.9% vs 33.5%; RR, 1.17; 95% CI, 1.04-1.32; P = .014) and microbiologic failure rates (RR, 1.10; 95% CI, 1.02-1.18; P = .011). No difference in 60-day VRE-BSI recurrence was observed between treatment groups.ConclusionsTreatment with linezolid for VRE-BSI resulted in significantly higher treatment failure in comparison to daptomycin. Linezolid treatment was also associated with greater 30-day all-cause mortality and microbiologic failure in this cohort.

The authors present a cohort of 661 young adult glioblastomas diagnosed using 2016 WHO World Health Organization Classification of Tumors of the Central Nervous System , utilizing comprehensive genomic profiling (CGP) to explore their genomic landscape and assess their relationship to currently defined disease entities. This analysis explored variants with evidence of pathogenic function, common copy number variants (CNVs), and several novel fusion events not described in literature. Tumor mutational burden (TMB) mutational signatures, anatomic location, and tumor recurrence are further explored. Using data collected from CGP, unsupervised machine-learning techniques were leveraged to identify 10 genomic classes in previously assigned young adult glioblastomas. The authors relate these molecular classes to current World Health Organization guidelines and reference current literature to give therapeutic and prognostic descriptions where possible. [ABSTRACT FROM AUTHOR]

Study Objective: Bloodstream infections (BSIs) are a significant cause of mortality. Use of a rapid multiplex polymerase chain reaction‐based blood culture identification panel (BCID) may improve antimicrobial utilization and clinical outcomes by shortening the time to appropriate therapy and de‐escalating antibiotics among patients on overly broad‐spectrum empiric therapy. The effect of BCID on clinical outcomes across varying institutional antimicrobial stewardship program (ASP) practices is unclear. This study evaluated clinical outcomes associated with the "real‐world" implementation of BCID in a national health system with varying ASP practices. Design: National, multicenter, retrospective, pre–post quasi‐experimental study of hospitalized patients admitted from 2015 to 2020 to VHA facilities, which introduced the BCID for ≥1 year. Setting: United States Veterans Health Administration (VHA) hospitals with BCID. Patients Hospitalized VHA patients with ≥1 blood culture positive for bacteria featured on the BCID panel. Intervention: Comparison of outcomes between the pre‐ and post‐BCID implementation groups. Measurements Outcomes evaluated included early antimicrobial de‐escalation within 48 h, defined as reduction in antimicrobial spectrum scores, time to appropriate therapy, and 30‐day mortality. Main Results A total of 4138 patients (pre‐BCID, n = 2100; post‐BCID, n = 2038) met the study criteria. Implementation of BCID was associated with significant improvements in early antimicrobial de‐escalation (34.6%: pre‐BCID vs. 38.1%: post‐BCID; p = 0.022), which persisted after adjusting for other covariates (adjusted risk ratio [aRR], 1.11; 95% confidence interval [CI], 1.02–1.20; p = 0.011). Median time to appropriate therapy was shorter in the post‐BCID implementation group relative to the pre‐BCID group (9 h: pre‐BCID vs. 8 h: post‐BCID, respectively, p = 0.005), and a greater percentage of patients received early appropriate antimicrobial therapy within 48 h in the post‐BCID implementation group (91.7%: pre‐BCID vs. 93.8%: post‐BCID; p = 0.008). In the multivariable regression analysis, BCID implementation was significantly associated with a higher likelihood of appropriate therapy within 48 h (aRR, 1.02; 95% CI, 1.01–1.08; p = 0.020). There was no difference in 30‐day mortality between groups overall (12.6% pre‐BCID vs. 11.2% post‐BCID; p = 0.211). Conclusions: In a "real‐world" clinical setting, the implementation of BCID was associated with clinical improvements in antimicrobial utilization. The BCID platform may serve as a useful adjunct for BSI management in facilities with ASP. [ABSTRACT FROM AUTHOR]

RAF family protein kinases signal through the MAPK pathway to orchestrate cellular proliferation, survival, and transformation. Identifying BRAF alterations in pediatric cancers is critically important as therapeutic agents targeting BRAF or MEK may be incorporated into the clinical management of these patients. In this study, we performed comprehensive genomic profiling on 3,633 pediatric cancer samples and identified a cohort of 221 (6.1%) cases with known or novel alterations in BRAF or RAF1 detected in extracranial solid tumors, brain tumors, or hematological malignancies. Eighty percent (176/221) of these tumors had a known‐activating short variant (98, 55.7%), fusion (72, 40.9%), or insertion/deletion (6, 3.4%). Among BRAF altered cancers, the most common tumor types were brain tumors (74.4%), solid tumors (10.8%), hematological malignancies (9.1%), sarcomas (3.4%), and extracranial embryonal tumors (2.3%). RAF1 fusions containing intact RAF1 kinase domain (encoded by exons 10–17) were identified in seven tumors, including two novel fusions TMF1‐RAF1 and SOX6‐RAF1. Additionally, we highlight a subset of patients with brain tumor with positive clinical response to BRAF inhibitors, demonstrating the rationale for incorporating precision medicine into pediatric oncology. Implications for Practice: Precision medicine has not yet gained a strong foothold in pediatric cancers. This study describes the landscape of BRAF and RAF1 genomic alterations across a diverse spectrum of pediatric cancers, primarily brain tumors, but also encompassing melanoma, sarcoma, several types of hematologic malignancy, and others. Given the availability of multiple U.S. Food and Drug Administration‐approved BRAF inhibitors, identification of these alterations may assist with treatment decision making, as described here in three cases of pediatric cancer. Despite gains in clinical success of biomarker‐informed targeted therapy in children with cancer, access to relevant targeted therapy is limited. This article describes the landscape of genomic alterations across a range of pediatric cancers, highlighting a subset of patients with brain tumors with positive clinical response to BRAF inhibitors. [ABSTRACT FROM AUTHOR]

For pediatric patients with high‐grade gliomas, standard‐of‐care treatment includes surgery, chemotherapy, and radiation therapy; however, most patients ultimately succumb to their disease. With advances in genomic characterization of pediatric high‐grade gliomas, the use of targeted therapies in combination with current treatment modalities offer the potential to improve survival in this patient population. In this report, we present the case of a 3‐year‐old girl with glioblastoma who continues to experience an exceptional and durable response (>2 years) to the poly (ADP‐ribose) polymerase (PARP) inhibitor olaparib. Our patient presented with persistent and progressive seizure activity that upon workup was the result of a large heterogeneously enhancing, mixed cystic and solid mass in the left frontal‐parietal‐temporal region. Histopathologic analysis of resected tumor tissue confirmed the diagnosis of glioblastoma, and comprehensive genomic profiling demonstrated absence of any BRAF or H3F3A mutations. Genomic profiling, however, did reveal a probable germline heterozygous BRCA2 Lys3326Ter (K3226*) nonsense variant. After debulking surgery, the patient received standard‐of‐care treatment with radiation and temozolomide. Nine months later the PARP inhibitor olaparib was administered in combination with temozolomide for 16 cycles. This regimen was well tolerated by the patient and serial imaging showed reduction in tumor size. Since completion of the regimen, the patient remains neurologically intact with no evidence of tumor recurrence. To our knowledge, this represents the first case of a pediatric glioblastoma that maintains a durable response to a therapeutic strategy that included the PARP inhibitor olaparib and more generally highlights the potential clinical utility of incorporating these agents into the treatment of pediatric high‐grade gliomas. Key Points: Germline mutations detected in pediatric gliomas may represent a cancer predisposition syndrome.Integrating molecular testing into routine clinical care for pediatric patients with glioma is critical to identify therapeutic targets and patients with a cancer predisposition syndrome.Patients with glioma with defects in DNA repair pathway components (e.g., BRCA1/2) may show increased responsiveness to poly (ADP‐ribose) polymerase (PARP) inhibitors.Combining PARP inhibitors with temozolomide (standard‐of‐care treatment) revealed no adverse events or toxicities over the course of 18 months. This article reports the first case of a pediatric glioblastoma that maintained a durable response to a therapeutic strategy that included the PARP inhibitor olaparib, highlighting the potential clinical utility of incorporating these agents into the treatment of pediatric high‐grade gliomas. [ABSTRACT FROM AUTHOR]

Background Currently, there is debate over whether the daptomycin susceptibility breakpoint for enterococci (ie, minimum inhibitory concentration [MIC] ≤4 mg/L) is appropriate. In bacteremia, observational data support prescription of high doses (>8 mg/kg). However, pharmacodynamic targets associated with positive patient outcomes are undefined. Methods Data were pooled from observational studies that assessed outcomes in daptomycin-treated enterococcal bacteremia. Patients who received an additional antienterococcal antibiotic and/or a β-lactam antibiotic at any time during treatment were excluded. Daptomycin exposures were calculated using a published population pharmacokinetic model. The free drug area under the concentration-time curve to MIC ratio (fAUC/MIC) threshold predictive of survival at 30 days was identified by classification and regression tree analysis and confirmed with multivariable logistic regression. Monte Carlo simulations determined the probability of target attainment (PTA) at clinically relevant MICs. Results Of 114 patients who received daptomycin monotherapy, 67 (58.8%) were alive at 30 days. A fAUC/MIC >27.43 was associated with survival in low-acuity (n = 77) patients (68.9 vs 37.5%, P =.006), which remained significant after adjusting for infection source and immunosuppression (P =.026). The PTA for a 6-mg/kg/day (every 24 hours) dose was 1.5%–5.5% when the MIC was 4 mg/L (ie, daptomycin-susceptible) and 91.0%–97.9% when the MIC was 1 mg/L. Conclusions For enterococcal bacteremia, a daptomycin fAUC/MIC >27.43 was associated with 30-day survival among low-acuity patients. As pharmacodynamics for the approved dose are optimized only when MIC ≤1 mg/L, these data continue to stress the importance of reevaluation of the susceptibility breakpoint. [ABSTRACT FROM AUTHOR]

Background: Patients with end-stage renal disease (ESRD) requiring intermittent haemodialysis (IHD) are at high risk of MRSA bacteraemia (MRSA-B) and often fail first-line therapy. The safety, effectiveness and optimal dosing of telavancin for MRSA-B in this patient population are unclear.Objectives: We aimed to describe clinical outcomes of telavancin in the treatment of refractory MRSA-B in patients with ESRD requiring IHD.Patients and methods: This was a retrospective study of hospitalized patients at two tertiary care academic medical centres with recurrent or persistent (≥3 days) MRSA-B treated with telavancin monotherapy. Outcomes included duration of MRSA-B (pre-telavancin versus post-telavancin) and microbiological failure (duration of MRSA-B ≥3 days after initiation of telavancin).Results: Telavancin dosed 10 mg/kg three times weekly post-IHD or 10 mg/kg every 48 h resulted in microbiological cure in 7/8 (87.5%) refractory MRSA-B cases. Telavancin monotherapy was associated with a significant reduction in median duration of bacteraemia [16 days pre-telavancin (IQR 8-19 days) versus 1 day post-telavancin (IQR 0-2 days); P = 0.018]. Telavancin was well tolerated by all patients and no adverse events were reported.Conclusions: Telavancin was very safe and highly effective in the treatment of refractory MRSA-B in a cohort of patients with ESRD requiring IHD. These data support the utility of telavancin in the armamentarium against refractory MRSA-B, particularly in the high-risk IHD-dependent population. [ABSTRACT FROM AUTHOR]