Maintaining Fluoroquinolone Class Efficacy: Review of Influencing Factors

Previous experience with antimicrobial resistance has emphasized the importance of appropriate stewardship of these pharmacotherapeutic agents. The introduction of fluoroquinolones provided potent new drugs directed primarily against gram-negative pathogens, while the newer members of this class demonstrate more activity against gram-positive species, including Streptococcus pneumoniae. Although these agents are clinically effective against a broad range of infectious agents, emergence of resistance and associated clinical failures have prompted reexamination of their use. Appropriate use revolves around two key objectives: 1) only prescribing antimicrobial therapy when it is beneficial and 2) using the agents(s) with optimal activity against the expected pathogens(s). Pharmacodynamic principles and properties can be applied to achieve the latter objective when prescribing agents belonging to the fluoroquinolone class. A focused approach emphasizing “correct-spectrum” coverage may reduce development of antimicrobial resistance and maintain class efficacy

Contact-Dependent Activation of Macrophages by Naive CD4\u3csup\u3e+\u3c/sup\u3e T cells.

Naive T cells are positioned at the origin of adaptive immune responses. The activation of naive T cells is usually viewed from the perspective of IL-2 production and entry into the cell cycle. This activation is antigen specific and MHC restricted via TCR ligation/CD3 signaling but also demands the simultaneous ligation of and signaling via CD28. Naive T cell TCR ligation without appropriate co-stimulus produces an anergic state, in which the naive T cell fails to produce IL-2 or expand clonally. It is implied that cells that might present self-destructive antigens would be incapable of delivering required costimulus thus avoiding initiation of inappropriate immune responses. However, CD45RBhi expressing THP cells express high levels of CD40L that is sustained following extended periods of TCR/CD3 stimulation. CD40L is the major T cell molecule involved in contact-dependent signaling of both B-cell and macrophage effector functions. This suggests that naive CD4+ T cells are capable of participating in and contributing to on-going immune responses following signaling via TCR/CD3 alone. This dissertation represents efforts to analyze the contact signaling capability of naive CD4+ T cells and their ability to trigger macrophage cytocidal/tumoricidal functions. The data generated by this research demonstrate that: Naive T cell purification by endothelial panning was superior to the standard method of CD44 panning for studies on T cell mediated macrophage activation. The activation requirements for contact signaling of macrophages by naive T cells are less stringent than the requirements for activation of naive T cell proliferation. Viable naive THP and antigen presenting splenic macrophages are capable of delivering reciprocal activating signals. Viable naive THP responding to presented antigen were able to trigger IFNg-primed macrophages to produce nitric oxide by both CD40L-dependent and CD40L-independent signaling pathways

Panning T Cells on Vascular Endothelial Cell Monolayers: A Rapid Method for Enriching Naive T Cells

A key functional/phenotypic difference between naive and memory T cells is the ability of memory and activated T cells to home to sites of inflammation by adhering to vascular endothelial cells. To determine if this trait could be used to separate naive T cells from memory T cells. CD4+ T cells were incubated with monolayers of IFN-γ-primed vascular endothelial cells after which the phenotypic and functional characteristics of the nonadherent population were assayed. The nonadherent population 1) contained a five-fold decrease in the frequency of cells displaying the CD44high/CD45RBlow memory phenotype and 2) responded well to allostimulation but displayed a reduced ability to respond to immobilized anti-CD3 antibody and, when isolated from ovalbumin-immunized mice, displayed a reduced recall response to ovalbumin in vitro. These studies demonstrate that two brief incubations of T cells with monolayers of IFN-γ-primed endothelial cells can significantly enrich for naive T cells as determined by both phenotypic and functional analyses

Antistaphylococcal Activity of CB-181963 (CAB-175), an Experimental Parenteral Cephalosporin

Among 265 methicillin-susceptible and -resistant staphylococci, CB-181963 (CAB-175) had a 50% minimum inhibitory concentration of 2 μg/ml and a 90% minimum inhibitory concentration of 4 μg/ml. All strains except two vancomycin-resistant S. aureus and 5 vancomycin-intermediate S. aureus strains were also susceptible to vancomycin and teicoplanin, and all were susceptible to linezolid, ranbezolid, tigecycline, and quinupristin-dalfopristin. Most methicillin-resistant strains were levofloxacin resistant. CB-181963 was bactericidal against all six methicillin-resistant strains at four times the MIC after 24 h