Prostate-specific membrane antigen-PET/CT may result in stage migration in prostate cancer: performances, quantitative analysis, and potential criticism in the clinical practice.

AIM: The early detection of prostate cancer (PCa) metastatic disease with PET imaging leads to stage migration and change of disease management. We aimed to assess the impact on clinical management deriving from prostate-specific membrane antigen (PSMA) imaging with a digital PET/CT during the routine application in the staging and restaging process of PCa. MATERIAL AND METHODS: Eighty consecutive PCa patients underwent 18F-PSMA-1007. Digital PET/CT were retrospectively evaluated and discussed with oncologists to evaluate the impact on clinical management. Performances analysis, correlation among variables also considering semiquantitative parameters have been conducted. RESULTS: In the whole group of 80 patients at staging (N = 31) and restaging (N = 49), the detection rate of PSMA PET was 85% for all lesions. At staging, the performance analysis resulted in sensitivity 77.6%, specificity 89.5%, negative predictive value (NPV) 77.6%, positive predictive value (PPV) 89.5%, accuracy 85.7%, and area under curve (AUC) 0.87%. The performance of restaging PET in the group of patients with PSA values <1 ng/ml resulted in the following values: sensitivity 66.7%, specificity 92.9%, NPV 85.7%, PPV 81.3%, accuracy 82.6%, and AUC 0.79. Semiquantitative analysis revealed a mean value of SUVmax, metabolic tumor volume, and total lesion PSMA expression with differences in patients with high risk compared to low intermediate. At restaging PET, semiquantitative values of patients with total prostate specific antigen (tPSA) ≤ 1 ng/ml were significantly less than those of the tPSA > 1 ng/ml. A significant impact on clinical management was reported in 46/80 patients (57.5%) based on PSMA PET findings at staging and restaging. CONCLUSION: Although PSMA-PET provides optimal performances, its current role in redefining a better staging should be translated in the current clinical scenario about potential improvement in clinical/survival outcomes.

Evaluation of the Effects of Heteroaryl Ethylene Molecules in Combination with Antibiotics: A Preliminary Study on Control Strains.

The discovery of compounds with antibacterial activity is crucial in the ongoing battle against antibiotic resistance. We developed two QSAR models to design six novel heteroaryl drug candidates and assessed their antibacterial properties against nine ATCC strains, including Enterococcus faecalis, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and also Salmonella enterica and Escherichia coli, many of which belong to the ESKAPE group. We combined PB4, a previously tested compound from published studies, with GC-VI-70, a newly discovered compound, with the best cytotoxicity/MIC profile. By testing sub-MIC concentrations of PB4 with five antibiotics (linezolid, gentamycin, ampicillin, erythromycin, rifampin, and imipenem), we evaluated the combination's efficacy against the ATCC strains. To assess the compounds' cytotoxicity, we conducted a 24 h and 48 h 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay on colorectal adenocarcinoma (CaCo-2) cells. We tested the antibiotics alone and in combination with PB4. Encouragingly, PB4 reduced the MIC values for GC-VI-70 and for the various clinically used antibiotics. However, it is essential to note that all the compounds studied in this research exhibited cytotoxic activity against cells. These findings highlight the potential of using these compounds in combination with antibiotics to enhance their effectiveness at lower concentrations while minimizing cytotoxic effects.

Acinetobacter baumannii and Cefiderocol, between Cidality and Adaptability.

Among the bacterial species included in the ESKAPE group, Acinetobacter baumannii is of great interest due to its intrinsic and acquired resistance to many antibiotics and its ability to infect different body regions. Cefiderocol (FDC) is a novel cephalosporin that is active against Gram-negative bacteria, with promising efficacy for A. baumannii infections, but some studies have reported therapeutic failures even in the presence of susceptible strains. This study aims to investigate the interactions between FDC and 10 A. baumannii strains with different susceptibilities to this drug. We confirmed diverse susceptibility profiles, with resistance values close to the EUCAST-proposed breakpoints. The minimal bactericidal concentration (MBC)/MIC ratios demonstrated bactericidal activity of the drug, with ratio values of ≤4 for all of the strains except ATCC 19606; however, bacterial regrowth was evident after exposure to FDC, as were changes in the shapes of colonies and bacterial cells. A switch to a nonsusceptible phenotype in the presence of high FDC concentrations was found in 1 strain as an adaptation mechanism implemented to overcome the cidal activity of this antibiotic, which was confirmed by the presence of heteroresistant, unstable subpopulations in 8/10 samples. Genomic analyses revealed the presence of mutations in penicillin-binding protein 3 (PBP3) and TonB3 that were shared by all of the strains regardless of their resistance phenotype. Because our isolates harbored ß-lactamase genes, ß-lactamase inhibitors showed the ability to restore the antimicrobial activity of FDC despite the different nonsusceptibility levels of the tested strains. These in vitro results support the concept of using combination therapy to eliminate drug-adapted subpopulations and regain full FDC activity in this difficult-to-treat species. IMPORTANCE This work demonstrates the underrated presence of Acinetobacter baumannii heteroresistant subpopulations after exposure of A. baumannii strains to FDC and its instability. Both A. baumannii and FDC are of great interest for the scientific community, as well as for clinicians; the former represents a major threat to public health due to its resistance to antibiotics, with related costs of prolonged hospitalization, and the latter is a novel, promising cephalosporin currently under the magnifying glass.

Heteroaryl-Ethylenes as New Effective Agents for High Priority Gram-Positive and Gram-Negative Bacterial Clinical Isolates.

The World Health Organization has identified antimicrobial resistance as a public health emergency and developed a global priority pathogens list of antibiotic-resistant bacteria that can be summarized in the acronym ESKAPE (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacterales species), reminding us of their ability to escape the effect of antibacterial drugs. We previously tested new heteroaryl-ethylene compounds in order to define their spectrum of activity and antibacterial capability. Now, we focus our attention on PB4, a compound with promising MIC and MBC values in all conditions tested. In the present study, we evaluate the activity of PB4 on selected samples of ESKAPE isolates from nosocomial infections: 14 S. aureus, 6 E. faecalis, 7 E. faecium, 12 E. coli and 14 A. baumannii. Furthermore, an ATCC control strain was selected for all species tested. The MIC tests were performed according to the standard method. The PB4 MIC values were within very low ranges regardless of bacterial species and resistance profiles: from 0.12 to 2 mg/L for S. aureus, E. faecalis, E. faecium and A. baumannii. For E. coli, the MIC values obtained were slightly higher (4-64 mg/L) but still promising. The PB4 heteroaryl-ethylenic compound was able to counteract the bacterial growth of both high-priority Gram-positive and Gram-negative clinical strains. Our study contributes to the search for new molecules that can fight bacterial infections, in particular those caused by MDR bacteria in hospitals. In the future, it would be interesting to evaluate the activity of PB4 in animal models to test for its toxicity.

Gold standard susceptibility testing of fosfomycin in Staphylococcus aureus and Enterobacterales using a new agar dilution panel®.

OBJECTIVES: Many clinical laboratories have difficulty in routinely performing in vitro fosfomycin susceptibility testing using the agar dilution (AD) method, considered to be the gold standard method. The objective of our work was to evaluate a rapid commercial fosfomycin agar dilution panel against clinical Staphylococcus aureus and Enterobacterales strains, in two different centres located in Italy and in the UK. METHODS: A total of 99 Enterobacterales (mostly Escherichia coli and Klebsiella pneumoniae) and 80 S. aureus clinical isolates was used to evaluate the commercial device, a 12-well panel containing fosfomycin incorporated into CA-MH agar supplemented with 25mg/L of glucose-6-phosphate (Liofilchem S.r.l., Roseto degli Abruzzi, Italy). Testing was performed in two centres (Italy and UK) and kit results were compared against the gold standard in-house AD MIC method. RESULTS: According to the EUCAST breakpoints, fosfomycin inhibited 61% of the S. aureus strains, and 76% of the Enterobacterales isolates tested by the AD reference method. There was a Categorical Agreement (CA) of 100% and an Essential Agreement (EA) of 91.25% for S. aureus; while the Enterobacterales strains showed a CA of 94% and an EA of 97%. No evaluation errors were observed among S. aureus, while 5% Major Error and 1% Very Major Error were observed for the Enterobacterales. CONCLUSIONS: Our results confirmed the feasibility of determining fosfomycin susceptibility using a commercial AD panel as a routine substitution for the AD test. The few differences observed were only in strains with MICs around the breakpoint used.

Somatostatin Receptor PET/CT Imaging for the Detection and Staging of Pancreatic NET: A Systematic Review and Meta-Analysis.

We investigated the diagnostic performance of Somatostatin Receptor Positron Emission Tomography/Computed Tomography (SSR-PET/CT) for the detection of primary lesion and initial staging of pancreatic neuroendocrine tumors (pNETs). A comprehensive literature search up to January 2020 was performed selecting studies in presence of: sample size ≥10 patients; index test (i.e., 68Ga-DOTATOC or 68Ga-DOTANOC or 68Ga-DOTATATE PET/CT); and outcomes (i.e., detection rate (DR), true positive, true negative, false positive, and false-negative). The methodological quality was evaluated with QUADAS-2. Pooled DR and pooled sensitivity and specificity for the identification of the primary tumor were assessed by a patient-based and a lesion-based analysis. Thirty-eight studies were selected for the qualitative analysis, while 18 papers were included in the meta-analysis. The number of pNET patients ranged from 10 to 142, for a total of 1143 subjects. At patient-based analysis, the pooled sensitivity and specificity for the assessment of primary pNET were 79.6% (95% confidence interval (95%CI): 71-87%) and 95% (95%CI: 75-100%) with a heterogeneity of 59.6% and 51.5%, respectively. Pooled DR for the primary lesion was 81% (95%CI: 65-90%) and 92% (95%CI: 80-97%), respectively, at patient-based and lesion-based analysis. In conclusion, SSR-PET/CT has high DR and diagnostic performances for primary lesion and initial staging of pNETs.