Showing papers by "Brendan Gilmore published in 2010"

The use of lytic bacteriophages in the prevention and eradication of biofilms of Proteus mirabilis and Escherichia coli.

Abstract: Antibiotics have been the cornerstone of the clinical management of bacterial infections since their discovery in the early part of the last century. Eight decades later, their widespread, often indiscriminate use, has resulted in an overall reduction in their effectiveness, with reports of multidrug-resistant bacteria now commonplace. Increasing reliance on indwelling medical devices, which are inherently susceptible to biofilm-mediated infections, has contributed to unacceptably high rates of nosocomial infections, placing a strain on healthcare budgets. This study investigates the use of lytic bacteriophages in the treatment and prevention of biofilms of bacterial species commonly associated with infections of indwelling urological devices and catheter-associated urinary tract infections. The use of lytic bacteriophages against established biofilms of Proteus mirabilis and Escherichia coli is described, whereby biofilm populations have been reduced successfully by three to four log cycles (99.9-99.99% removal). The prevention of biofilm formation on Foley catheter biomaterials following impregnation of hydrogel-coated catheter sections with a lytic bacteriophage has also been investigated. This has revealed an approximate 90% reduction in both P. mirabilis and E. coli biofilm formation on bacteriophage-treated catheters when compared with untreated controls.

Antimicrobial Activity of Short, Synthetic Cationic Lipopeptides

Abstract: The increasing emergence of multidrug-resistant micro-organisms presents one of the greatest challenges in the clinical management of infectious diseases. Therefore, novel antimicrobial agents are urgently required to address this issue. In this report, we describe the solid phase synthesis, characterization, microbiological and toxicological evaluation of a library of ultrashort cationic antimicrobial lipopeptides based on the previously described tetrapeptide amide H-Orn-Orn-Trp-Trp-NH2 conjugated with saturated fatty acids which have inherent antimicrobial activity. The microbiological activity of these ultrashort cationic lipopeptides, which exhibit excellent, broad-spectrum antimicrobial activity against a number of clinically important pathogenic bacteria and fungi, including multidrug resistant micro-organisms in both planktonic and sessile (biofilm) cultures is reported.

Increased expression of fibroblast activation protein-alpha in keloid fibroblasts: implications for development of a novel treatment option

Abstract: Keloid scars are common benign fibroproliferative reticular dermal lesions with unknown etiology and ill-defined management with high rate of recurrence post surgery. The progression of keloids is characterized by increased deposition of extracellular matrix proteins, invasion into the surrounding healthy skin and inflammation. Fibroblasts are considered to be the key cellular mediators of fibrogenesis in keloid scars. Fibroblast activation protein alpha (FAP-α) and dipeptidyl peptidase IV (DPPIV) are proteases located at the plasma membrane promoting cell invasiveness and tumor growth and have been previously associated with keloid scars. Therefore, in this study we analyzed in further detail the expression of FAP-α in keloid fibroblasts compared to control skin fibroblasts. Dermal fibroblasts were obtained from punch-biopsies from the active margin of four keloids and four control skin samples. Flow cytometry was used to analyze FAP-α expression and the CytoSelect® 24-Well Collagen I Cell Invasion Assay was applied to study fibroblast invasion. Secretion of extracellular matrix (ECM) proteins was investigated by multiplexed particle-based flow cytometric assay and enzyme-linked immunosorbent assay. We found an increased expression of FAP-α in keloid fibroblasts compared to control skin fibroblasts (p < 0.001). Inhibition of FAP-α/DPPIV activity using the irreversible inhibitor H2N-Gly-Pro diphenylphosphonate reduced the increased invasiveness of keloid fibroblasts (p < 0.001) indicating that keloid invasion may be partly FAP-α/DPPIV mediated. FAP-α/DPPIV inhibition had no effect, (a) on the synthesis of the ECM proteins procollagen type I C-terminal peptide and fibronectin, (b) on the production of fibroblast growth factor or vascular endothelial growth factor, (c) on the expression of the proinflammatory cytokines interleukin-6 (IL-6), interleukin 8 (IL-8) or monocyte chemotactic protein-1. These results suggest a potential role for FAP-α and DPPIV in the invasive behavior of keloids. FAP-α and DPPIV may increase the invasive capacity of keloid fibroblasts rather than by modulating inflammation or ECM production. Since FAP-α expression is restricted to reactive fibroblasts in wound healing and normal adult tissues are generally FAP-α negative, inhibiting FAP-α/DPPIV activity may be a novel treatment option to prevent keloid progression.

Validation of the CDC Biofilm Reactor as a Dynamic Model for Assessment of Encrustation Formation on Urological Device Materials

Abstract: Contemporary medical science is reliant upon the rational selection and utilization of devices, and therefore, an increasing need has developed for in vitro systems aimed at replicating the conditions to which urological devices will be subjected to during their use in vivo. We report the development and validation of a novel continuous flow encrustation model based on the commercially available CDC biofilm reactor. Proteus mirabilis-induced encrustation formation on test biomaterial sections under varying experimental parameters was analyzed by X-ray diffraction, infrared- and Raman spectroscopy and by scanning electron microscopy. The model system produced encrusted deposits similar to those observed in archived clinical samples. Results obtained for the system are highly reproducible with encrustation being rapidly deposited on test biomaterial sections. This model will have utility in the rapid screening of encrustation behavior of biomaterials for use in urological applications.

Catheter-based drug-device combination products: an overview

Abstract: The use of catheters to support normal physiological function dates back more than two millennia. Catheters therefore represent the oldest, yet still the most commonly employed indwelling medical devices employed in clinical medicine. Catheters often represent simple and cost effective solutions for a plethora of clinical, surgical and diagnostic indications. However, their use is frequently beset by serious complications relating to device-associated infection and microbial biofilm formation, as well as issues of patient discomfort and acceptability. Despite this, extensive use of catheter-based interventions in a diverse range of applications has fuelled explosive growth in the medical devices market. In this chapter we examine the evolution of catheters (urological, cardiovascular and peritoneal) from early crude apparatus to technologically advanced medical devices, exploiting advances in biomaterials technology. This chapter also examines the infectious complications associated with each catheter type and development of advanced drug–device combination products designed to circumvent them.