GBT1118, a voxelotor analog, protects red blood cells from damage during severe hypoxia.

A lack of objective metrics in Sickle Cell Disease (SCD) makes it difficult to assess individual patient therapy options or assess the effects of therapy. This is further complicated by mechanisms of action involving multiple interconnected effects, that combine to relieve SCD symptoms. In 2019, based on the increase in hemoglobin concentration observed in the HOPE trial, the Food and Drug Administration approved voxelotor (Oxbryta®, Global Blood Therapeutics) for SCD patients 12 years and older. The main mechanism of action for voxelotor was increased hemoglobin-oxygen affinity, but other mechanisms may apply. In this study, we assessed the effect of GBT1118, an Oxbryta analog, on hypoxia-induced lethal and sub-hemolytic red blood cell (RBC) membrane damage using RBC Mechanical Fragility (MF), a metric of existing membrane damage and prospective hemolysis. RBC MF was measured non-invasively using a proprietary system comprising an electromagnetic bead mill and fiberoptic spectrophotometry detection. Three cycles of severe hypoxia (<5% oxygenated hemoglobin) with follow-up reoxygenation resulted in a significant increase in RBC MF for all SCD (Hb-S >60%) samples. Supplementation with GBT1118 caused no significant changes in pre-hypoxia RBC MF. However, following GBT1118 treatment, cell stability showed significantly less degradation, as evidenced by a significantly smaller RBC MF increase after three cycles of hypoxia-reoxygenation. These findings indicate that GBT1118 prevents hypoxia-induced membrane damage in sickled RBC, in part by alternative mechanisms not associated with induced changes in hemoglobin-oxygen affinity.

Carbapenemase-producing Enterobacteriaceae isolates resistant to last-line antibiotics in an Italian general hospital.

The global dissemination of carbapenemase-producing Enterobacteriaceae (CPE) is of great concern for public health. These bacteria have the potential for rapid dissemination in healthcare settings and cause infections associated with high rates of morbidity and mortality. A total of 221 carbapenem non-susceptible Enterobacteriaceae isolates were collected from patients admitted to an Italian general hospital from January 2016 to March 2017. Among these isolates, 78.3% were carbapenemase producers: 96% were positive for the blaKPC gene and the remainder for the blaVIM gene (allelic variant VIM-1). CPE isolates were mainly Klebsiella pneumoniae, but we also detected carbapenemase enzymes in Citrobacter freundii, Enterobacter cloacae and Escherichia coli. Among CPE isolates, 79.2% exhibited co-resistance to two or more non-b-lactam agents and 38% of these isolates (all KPC-positive) were resistant to colistin. This percentage reached 55% among CPE isolated from the bloodstream. All patients with colistin-resistant CPE isolates recovered from blood samples showed an unfavorable outcome within 7 days from the first positive blood culture. Our data show the dissemination of a high percentage of CPE isolates co-resistant to last-line antibiotics. In addition, we report the first identification in our hospital of CPE isolates harboring the blaVIM gene and Escherichia coli harboring the blaKPC gene. These results underline the need to implement antibiotic stewardship and infection control programs, and emphasize the need for novel antimicrobial agents active against CPE.

Diagnostic accuracy of presepsin (sCD14-ST) and procalcitonin for prediction of bacteraemia and bacterial DNAaemia in patients with suspected sepsis.

Early diagnosis and prompt targeted therapy are essential for septic patients' outcome. Procalcitonin (PCT) has been shown to predict bacteraemia and bacterial DNAaemia. Presepsin, the circulating soluble form of CD14 subtype, increases in response to bacterial infections, and is considered a new, emerging, early marker for sepsis. We evaluated the diagnostic accuracy of presepsin in predicting bacteraemia and bacterial DNAaemia in 92 patients with suspected sepsis, and we compared it with that of PCT and C-reactive protein (CRP). Presepsin median values were significantly higher in bacteraemic vs non-bacteraemic patients [1290 pg ml-1, interquartile range (IQR) 1005-2041 vs 659 pg ml-1, IQR 381-979; P<0.001] and in patients with vs patients without bacterial DNAaemia (1297 pg ml-1, IQR 1001-2046 vs 665 pg ml-1, IQR 381-940; P<0.001). Receiver operating characteristics analysis showed an area under the curve (AUC) for presepsin of 0.788 [95 % confidence interval (CI): 0.687-0.889; P<0.001] in predicting bacteraemia and of 0.777 (95 % CI: 0.676-0.878; P<0.001) in predicting bacterial DNAaemia, lower, but not significantly different, than those of PCT (0.876, P=0.12 and 0.880, P=0.07, respectively). Both biomarkers performed significantly better than CRP, which had an AUC for bacteraemia of 0.602 and for DNAaemia of 0.632 (all P values <0.05). In conclusion, in patients with suspected sepsis, presepsin and PCT showed a good diagnostic accuracy in predicting both bacteraemia and bacterial DNAaemia, superior to CRP.

Procalcitonin levels in gram-positive, gram-negative, and fungal bloodstream infections.

Procalcitonin (PCT) can discriminate bacterial from viral systemic infections and true bacteremia from contaminated blood cultures. The aim of this study was to evaluate PCT diagnostic accuracy in discriminating Gram-positive, Gram-negative, and fungal bloodstream infections. A total of 1,949 samples from patients with suspected bloodstream infections were included in the study. Median PCT value in Gram-negative (13.8 ng/mL, interquartile range (IQR) 3.4-44.1) bacteremias was significantly higher than in Gram-positive (2.1 ng/mL, IQR 0.6-7.6) or fungal (0.5 ng/mL, IQR 0.4-1) infections (P < 0.0001). Receiver operating characteristic analysis showed an area under the curve (AUC) for PCT of 0.765 (95% CI 0.725-0.805, P < 0.0001) in discriminating Gram-negatives from Gram-positives at the best cut-off value of 10.8 ng/mL and an AUC of 0.944 (95% CI 0.919-0.969, P < 0.0001) in discriminating Gram-negatives from fungi at the best cut-off of 1.6 ng/mL. Additional results showed a significant difference in median PCT values between Enterobacteriaceae and nonfermentative Gram-negative bacteria (17.1 ng/mL, IQR 5.9-48.5 versus 3.5 ng/mL, IQR 0.8-21.5; P < 0.0001). This study suggests that PCT may be of value to distinguish Gram-negative from Gram-positive and fungal bloodstream infections. Nevertheless, its utility to predict different microorganisms needs to be assessed in further studies.

Procalcitonin better than C-reactive protein, erythrocyte sedimentation rate, and white blood cell count in predicting DNAemia in patients with sepsis.

BACKGROUND: Procalcitonin (PCT) levels can be used to predict bacteremia and DNAemia in patients with sepsis. In this study, the diagnostic accuracy of PCT in predicting blood culture (BC) results and DNAemia, as detected by real-time PCR (RT-PCR), was compared with that of other markers of inflammation commonly evaluated in patients with suspected sepsis, such as C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and white blood cell (WBC) count. METHODS: A total of 571 patients for whom BC, blood RT-PCR, PCT, CRP, ESR, and WBC count were requested for laboratory diagnosis of sepsis were included in the study. Receiver operating characteristic curve analysis was performed to compare the ability of the above biomarkers to predict BC and blood RT-PCR results. RESULTS: A total of 108 pathogens were identified by BC (79 pathogens, 14.5% positive rate) and/or RT-PCR (90 pathogens, 16.5% positive rate), after exclusion of 26 contaminated samples. The PCT areas under the curve (AUCs) in predicting BC (0.843; 95% CI 0.796-0.890; p < 0.0001) and RT-PCR (0.916; 95% CI 0.888-0.945; p < 0.0001) results were significantly greater than AUCs found for CRP, ESR, and WBC count. CONCLUSIONS: PCT showed a better diagnostic accuracy than CRP, ESR, and WBC count in predicting DNAemia and bacteremia in patients with suspected sepsis.