Agatha Borne

Novel Antiseptic Urinary Catheters for Prevention of Urinary Tract Infections: Correlation of In Vivo and In Vitro Test Results

ABSTRACT Urinary catheters are widely used for hospitalized patients and are often associated with high rates of urinary tract infection. We evaluated in vitro the antiadherence activity of a novel antiseptic Gendine-coated urinary catheter against several multidrug-resistant bacteria. Gendine-coated urinary catheters were compared to silver hydrogel-coated Foley catheters and uncoated catheters. Bacterial biofilm formation was assessed by quantitative culture and scanning electron microscopy. These data were further correlated to an in vivo rabbit model. We challenged 31 rabbits daily for 4 days by inoculating the urethral meatus with 1.0 × 109 CFU streptomycin-resistant Escherichia coli per day. In vitro, Gendine-coated urinary catheters reduced the CFU of all organisms tested for biofilm adherence compared with uncoated and silver hydrogel-coated catheters (P < 0.004). Scanning electron microscopy analysis showed that a thick biofilm overlaid the control catheter and the silver hydrogel-coated catheters but not the Gendine-coated urinary catheter. Similar results were found with the rabbit model. Bacteriuria was present in 60% of rabbits with uncoated catheters and 71% of those with silver hydrogel-coated catheters (P < 0.01) but not in those with Gendine-coated urinary catheters. No rabbits with Gendine-coated urinary catheters had invasive bladder infections. Histopathologic assessment revealed no differences in toxicity or staining. Gendine-coated urinary catheters were more efficacious in preventing catheter-associated colonization and urinary tract infections than were silver hydrogel-coated Foley catheters and uncoated catheters.

Preclinical Assessment of a 980-nm Diode Laser Ablation System in a Large Animal Tumor Model

PURPOSE To characterize the performance of a 980-nm diode laser ablation system in an in vivo tumor model. MATERIALS AND METHODS This study was approved by the institutional animal care and use committee. The ablation system consisted of a 15-W, 980-nm diode laser, flexible diffusing-tipped fiber optic, and 17-gauge internally cooled catheter. Ten immunosuppressed dogs were inoculated subcutaneously with canine-transmissible venereal tumor fragments in eight dorsal locations. Laser ablations were performed at 79 sites where inoculations were successful (99%) at powers of 10 W, 12.5 W, and 15 W, with exposure times between 60 and 180 seconds. In 20 cases, multiple overlapping ablations were performed. After the dogs were euthanized, the tumors were harvested, sectioned along the applicator tract, measured, and photographed. Measurements of ablation zone were performed on gross specimen. Histopathology and viability staining was performed with hematoxylin and eosin and nicotinamide adenine dinucleotide hydrogen staining. RESULTS Gross pathologic examination confirmed a well circumscribed ablation zone with sharp boundaries between thermally ablated tumor in the center surrounded by viable tumor tissue. When a single applicator was used, the greatest ablation diameters ranged from 12 mm at the lowest dose (10 W, 60 seconds) to 26 mm at the highest dose (15 W, 180 seconds). Multiple applicators created ablation zones as large as 42 mm in greatest diameter (with the lasers operating at 15 W for 120 seconds). CONCLUSIONS The new 980-nm diode laser and internally cooled applicator effectively create large ellipsoid thermal ablations in less than 3 minutes.

Whole-Body Biodistribution Kinetics, Metabolism, and Radiation Dosimetry Estimates of 18F-PEG6-IPQA in Nonhuman Primates

We recently developed the radiotracer 4-[(3-iodophenyl)amino]-7-(2-[2-{2-(2-[2-{2-(18F-fluoroethoxy)-ethoxy}-ethoxy]-ethoxy)-ethoxy}-ethoxy]-quinazoline-6-yl-acrylamide) (18F-PEG6-IPQA) for noninvasive detection of active mutant epidermal growth factor receptor kinase-expressing non–small cell lung cancer xenografts in rodents. In this study, we determined the pharmacokinetics, biodistribution, metabolism, and radiation dosimetry of 18F-PEG6-IPQA in nonhuman primates. Methods: Six rhesus macaques were injected intravenously with 141 ± 59.2 MBq of 18F-PEG6-IPQA, and dynamic PET/CT images covering the thoracoabdominal area were acquired for 30 min, followed by whole-body static images at 60, 90, 120, and 180 min. Blood samples were obtained from each animal at several time points after radiotracer administration. Radiolabeled metabolites in blood and urine were analyzed using high-performance liquid chromatography. The 18F-PEG6-IPQA pharmacokinetic and radiation dosimetry estimates were determined using volume-of-interest analysis of PET/CT image datasets and blood and urine time–activity data. Results: 18F-PEG6-IPQA exhibited rapid redistribution and was excreted via the hepatobiliary and urinary systems. 18F-PEG6 was the major radioactive metabolite. The critical organ was the gallbladder, with an average radiation-absorbed dose of 0.394 mSv/MBq. The other key organs with high radiation doses were the kidneys (0.0830 mSv/MBq), upper large intestine wall (0.0267 mSv/MBq), small intestine (0.0816 mSv/MBq), and liver (0.0429 mSv/MBq). Lung tissue exhibited low uptake of 18F-PEG6-IPQA due to the low affinity of this radiotracer to wild-type epidermal growth factor receptor kinase. The effective dose was 0.0165 mSv/MBq. No evidence of acute cardiotoxicity or of acute or delayed systemic toxicity was observed. On the basis of our estimates, diagnostic dosages of 18F-PEG6-IPQA up to 128 MBq (3.47 mCi) per injection should be safe for administration in the initial cohort of human patients in phase I clinical PET studies. Conclusion: The whole-body and individual organ radiation dosimetry characteristics and pharmacologic safety of diagnostic dosages of 18F-PEG6-IPQA in nonhuman primates indicate that this radiotracer should be acceptable for PET/CT studies in human patients.

A Biodistribution and Toxicity Study of Cobalt Dichloride-N-Acetyl Cysteine in an Implantable MRI Marker for Prostate Cancer Treatment

PURPOSE C4, a cobalt dichloride-N-acetyl cysteine complex, is being developed as a positive-signal magnetic resonance imaging (MRI) marker to localize implanted radioactive seeds in prostate brachytherapy. We evaluated the toxicity and biodistribution of C4 in rats with the goal of simulating the systemic effects of potential leakage from C4 MRI markers within the prostate. METHODS AND MATERIALS 9-μL doses (equivalent to leakage from 120 markers in a human) of control solution (0.9% sodium chloride), 1% (proposed for clinical use), and 10% C4 solution were injected into the prostates of male Sprague-Dawley rats via laparotomy. Organ toxicity and cobalt disposition in plasma, tissues, feces, and urine were evaluated. RESULTS No C4-related morbidity or mortality was observed in the biodistribution arm (60 rats). Biodistribution was measurable after 10% C4 injection: cobalt was cleared rapidly from periprostatic tissue; mean concentrations in prostate were 163 μg/g and 268 μg/g at 5 and 30 minutes but were undetectable by 60 minutes. Expected dual renal-hepatic elimination was observed, with percentages of injected dose recovered in tissues of 39.0 ± 5.6% (liver), >11.8 ± 6.5% (prostate), and >5.3 ± 0.9% (kidney), with low plasma concentrations detected up to 1 hour (1.40 μg/mL at 5-60 minutes). Excretion in urine was 13.1 ± 4.6%, with 3.1 ± 0.54% recovered in feces by 24 hours. In the toxicity arm, 3 animals died in the control group and 1 each in the 1% and 10% groups from surgical or anesthesia-related complications; all others survived to scheduled termination at 14 days. No C4-related adverse clinical signs or organ toxicity were observed. CONCLUSION C4-related toxicity was not observed at exposures at least 10-fold the exposure proposed for use in humans. These data demonstrating lack of systemic toxicity with dual routes of elimination in the event of in situ rupture suggest that C4 warrants further investigation as an MRI marker for prostate brachytherapy.

A Pilot Trial of Vascular Targeted Photodynamic Therapy for Renal Tissue

PURPOSE Vascular targeted photodynamic therapy represents the newest generation of photodynamic therapy and a new paradigm for minimally invasive ablative therapy. We report a pilot trial of vascular targeted photodynamic therapy to evaluate the effect on porcine renal tissue. MATERIALS AND METHODS Pigs underwent continuous infusion of WST-09 (Negma-Lerads, Toussous le Noble, France) and concurrent illumination with interstitial laser at a wavelength of 763 nm to the lower pole of the kidney. Drug doses were 0.5 to 1.0 mg/kg and light doses were 100 to 200 J. Nuclear renography was performed on postoperative day 5. On postoperative day 7 arteriography, pyelography, computerized tomography of the abdomen and necropsy were performed. RESULTS Four of 7 animals completed therapy and all evaluations. Three animals died, including 1 of surgical complications and 2 of an anaphylactoid reaction to the Cremophor solvent in the compound. All kidneys in surviving animals functioned on nuclear renography. Renal function remained unchanged. No lesions or urine leakage was visible on imaging. On necropsy lesion size was 5 x 4 x 3 to 7 x 7 x 14 mm depending on the drug/light dose. Histology showed a distinct demarcation between the treated zone and the surrounding parenchyma at higher doses. Lesions were well demarcated with necrotic tubules, glomerular fibrinoid necrosis, capillary loop thrombosis, interstitial hemorrhage and lymphocytic infiltrates. CONCLUSIONS Significant tissue effect with some necrosis was seen at these low drug/light combinations. This study provides the initial proof of principle that justifies further preclinical investigation of vascular targeted photodynamic therapy for renal tumors. A newer, water based formulation should decrease the incidence of reactions in swine. This newer formulation may allow further safe investigation of this novel treatment paradigm.

Novel endoscopic application of a new flexible-fiber CO2 laser for esophageal mucosal ablation in a porcine model

BACKGROUND AND STUDY AIMS The CO (2) laser is a surgical tool that is widely used because of its predictable penetration depth and minimal collateral damage due to efficient absorption of CO (2) laser energy by tissue water. Until recently, endoscopic use was limited by lack of an efficient, flexible delivery system. The aim of the current study was to evaluate the performance, efficacy, and safety of a novel, photonic band-gap CO (2) laser configured for esophageal mucosal ablation. MATERIALS AND METHODS This was an endoscopic experimental study in a porcine survival model. Initial evaluation was done on ex vivo tissue followed by endoscopic studies at 7-, 10-, 15-, and 20-W power and at 0-, 1-, 2-, 5-, and 10-mm distances, using continuous and pulsed currents, to determine optimal performance settings. In an IACUC-approved protocol, six pigs underwent circumferential ablation of the distal 6 cm of the esophagus at 10W continuous current. The animals were monitored for 2 or 4 weeks to evaluate delayed effects. Prior to euthanasia, the proximal esophagus was ablated to evaluate the homogeneity of ablation and depth of injury immediately after single and repeat ablation. RESULTS The animals resumed normal diets within 24 hours and experienced no dysphagia or weight loss. Pathology at 2 and 4 weeks revealed complete re-epithelialization with minimal histologic injury. A single application of the laser produced complete transepithelial ablation of a mean of 83.3 % of the surface area (range 55 % - 100 %); depth of injury was to the muscularis mucosa in five pigs and to the superficial submucosa in one pig. With ablation, sloughing, and re-ablation, a mean of 95 % transepithelial ablation was achieved (range 80 % -100 %) with similar depth of injury. CONCLUSIONS Using a novel, flexible CO (2) laser, homogeneous ablation was achieved with predictable penetration and minimal deep tissue injury. These results warrant further evaluation of the laser in Barretts esophagus, as it may overcome the limitations of current technologies including perforation, stricture, and inhomogeneity.