Delafloxacin: a novel fluoroquinolone with activity against methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa

Introduction: The resistance to current antimicrobial agents, including fluoroquinolones, has continued to grow among various pathogens indicating a need for new antimicrobials to combat multi-drug resistant (MDR) organisms. In June 2017, delafloxacin received approval by the US Food and Drug Administration for the treatment of acute bacterial skin and skin-structure infections (ABSSSIs) in adults caused by designated susceptible bacteria.

Areas covered: This review describes the pharmacology, pharmacodynamics, pharmacokinetics, product information, efficacy, and safety of delafloxacin.

Expert commentary: Delafloxacin is a novel oral and intravenous fluoroquinolone with activity against methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa, offering a new option for the treatment of ABSSSI and potentially for complicated urinary tract infections and severe community-acquired bacterial pneumonia.     

3′-Deoxy-3′-[<Superscript>18</Superscript>F]Fluorothymidine Uptake Is Related to Thymidine Phosphorylase Expression in Various Experimental Tumor Models

Purpose

We recently reported that high thymidine phosphorylase (TP) expression is accompanied by low tumor thymidine concentration and high 3′-deoxy-3′-[¹⁸F]fluorothymidine ([¹⁸F]FLT) uptake in four untreated lung cancer xenografts. Here, we investigated whether this relationship also holds true for a broader range of tumor models.

Procedures

Lysates from n = 15 different tumor models originating from n = 6 institutions were tested for TP and thymidylate synthase (TS) expression using western blots. Results were correlated to [¹⁸F]FLT accumulation in the tumors as determined by positron emission tomography (PET) measurements in the different institutions and to previously published thymidine concentrations.

Results

Expression of TP correlated positively with [¹⁸F]FLT SUV_max (ρ = 0.549, P < 0.05). Furthermore, tumors with high TP levels possessed lower levels of thymidine (ρ = ??0.939, P < 0.001).

Conclusions

In a broad range of tumors, [¹⁸F]FLT uptake as measured by PET is substantially influenced by TP expression and tumor thymidine concentrations. These data strengthen the role of TP as factor confounding [¹⁸F]FLT uptake.

     

Phage Display Selection, <Emphasis Type="Italic">In Vitro</Emphasis> Characterization,and Correlative PET Imaging of a Novel HER3 Peptide

Purpose

HER3 (ERBB3) is a receptor tyrosine kinase that is implicated in treatment resistance across multiple cancers, including those of the breast, lung, and prostate. Overexpression of HER3 following targeted therapy can occur rapidly and heterogeneously both within a single lesion and across sites of metastasis, making protein quantification by biopsy highly challenging. A global, non-invasive methodology such as positron emission tomography (PET) imaging can permit serial quantification of HER3, providing a useful approach to monitor HER3 expression across the entire tumor burden both prior to and following treatment. PET imaging of HER3 expression may permit a more personalized approach to targeted therapy by allowing for detection of HER3-mediated resistance, in addition to informing clinical trial patient selection for novel therapies targeting HER3.

Procedures

Phage display selection targeting the HER3 extracellular domain was performed in order to develop a peptide with optimal blood clearance and highly accurate HER3 quantification.

Results

The selection converged to a consensus peptide sequence that was subsequently found to bind HER3 with an affinity of 270 ± 151 nM. The peptide, termed HER3P1, was bound with high selectivity to HER3 over other similar receptor tyrosine kinases such as EGFR and HER2. Furthermore, HER3P1 was able to distinguish between high and low HER3-expressing cells in vitro. The peptide was radiolabeled with Ga-68 and demonstrated to specifically bind HER3 by in vivo PET imaging. Uptake of [⁶⁸Ga]HER3P1 was highly specific for HER3-positive tumors, with tumor-to-background ratios ranging from 1.59–3.32, compared to those of HER3-negative tumors, ranging from 0.84–0.93. The uptake of [⁶⁸Ga]HER3P1 also demonstrated high (P < 0.001) correlation with protein expression as quantified by Western blot and confirmed by biodistribution.

Conclusions

HER3P1 accurately quantifies expression of HER3 by PET imaging and has potential utility as a clinical imaging agent.

     

The public health implications of HIV criminalization: past,current, and future research directions

While public health remains the primary site of authority for preventing HIV transmission, recent shifts in the biopolitics of HIV have heightened tensions in the institutional and discursive relations through which the sexual lives of people living with HIV and broader HIV epidemics are regulated. Most notably, over the past decade, criminal justice responses to HIV have gained considerable traction. The growing use of the criminal law to regulate perceived HIV transmission risks has occasioned considerable controversy among people living with HIV, community-based AIDS organizations, health-care providers, public health authorities, prosecutors, judges, and the legal community. This article introduces a special section of Critical Public Health focused on the public health implications of HIV criminalization. The article reviews past and current work on the topic, situates the contributions made by the articles published in the special section, and outlines directions for future inquiry.