We have developed a murine model of the Hematopoietic Syndrome of the Acute Radiation Syndrome (H-ARS) for efficacy testing of medical countermeasures (MCM) against radiation according to the FDA Animal Rule. Ten to 12 week old male and female C57BL/6 mice were exposed to the LD50/30-LD70/30 dose of total body irradiation (TBI, 137Cs, 0.62-0.67 Gy min-1) in the morning hours when mice were determined to be most radiosensitive, and assessed for 30 day survival and mean survival time (MST). Antibiotics were delivered in the drinking water on days 4-30 post-TBI at a concentration based on the amount of water that lethally-irradiated mice were found to consume. The fluoroquinolones, ciprofloxacin and levofloxacin, and the tetracycline doxycycline and aminoglycoside neomycin, all significantly increased MST of decedent mice, while ciprofloxacin (p=0.061) and doxycycline + neomycin (p=0.005) showed at least some efficacy to increase 30 day survival. Blood sampling (30uL/mouse every 5th day) was found to negatively impact 30 day survival. Histopathology of tissues harvested from non-moribund mice showed expected effects of lethal irradiation, while moribund mice were largely septicemic with a preponderance of enteric organisms. Kinetics of loss and recovery of peripheral blood cells in untreated mice and those treated with two MCM, granulocyte-colony stimulating factor and Amifostine, further characterized and validated our model for use in screening studies and pivotal efficacy studies of candidate MCM for licensure to treat irradiated individuals suffering from H-ARS.

Abstract. An epizootic of subclinical lymphoplasmacytic gastritis occurred in cynomolgus monkeys maintained at our research facility. Gastric pathology data and histologic sections of 63 adolescent monkeys (2.5-3.5 years old) sacrificed during the epizootic were reviewed. Localized to multifocal reddening of the gastric mucosa was noted grossly in 7 of 44 (16%) monkeys harboring Helicobacter pylori, but not in any of 19 monkeys in which these bacteria were not seen. Gastritis, characterized by accentuation of lymphoplasmacytic infiltrates in antral and to a lesser degree cardiac mucosa, occurred in 42 of 63 (67%) monkeys evaluated and in 42 of 44 (93%) monkeys in which H. pylori was observed microscopically. Two monkeys with H. pylori infection had infiltrate scores that overlapped with the upper limit of scores of H. pylori-negative animals. Coincident with accentuated infiltrates were gastric gland epithelial hyperplasia, reduction in mucin content of surface and gland epithelia, and comparatively minor infiltrates of neutrophils in superficial lamina propria and gastric glands. Antral mucosa thickness often exceeded 1.5 to 2 times normal. Antral mucosal erosions occurred in 7 of 44 (16%) monkeys with H. pylori. Argyrophilic bacteria morphologically consistent with H. pylori were present in antral and less commonly cardiac mucosal glands. Intensity of bacterial colonization correlated with lymphoplasmacytic infiltrates (r ϭ 0.754) and hyperplasia (r ϭ 0.700), although responses were quite variable. These bacteria were not detected in fundic mucosa except in instances where parietal cells were substantially depleted in glands coincident with localized increases in lamina propria inflammatory cell infiltrates. Helicobacter heilmannii-like organisms (HHLOs) were present in fundic glands of all 63 monkeys; colonization was often pronounced. Scores for fundic mucosal inflammation did not correlate with presence or intensity of colonization with HHLOs (r ϭ 0.005). Rather, fundic inflammation scores positively correlated with the antral inflammation scores (r ϭ 0.548). Bacteria morphologically, biochemically, and genetically consistent with H. pylori were cultured from gastric mucosal specimens confirming bacterial identification. These findings demonstrate that adolescent cynomolgus monkeys are susceptible to natural infection with H. pylori and develop many morphologic hallmarks of H. pylori-related gastritis in humans.Key words: Animal model; bacteria; gastritis; Gastrospirillum hominis; Helicobacter; Helicobacter heilmannii; Helicobacter pylori; monkey; nonhuman primate; spirochetes; stomach.Spirochetes or spiral-shaped bacteria have long been recognized as constituents of gastric microflora in various mammalian species. 8,29,36,48,55,61,62 38 Most Helicobacter species do not have strict host specificity. Rather, certain species have been isolated from multiple host species and experimental transmission among animal species has been shown. 19,22,31,37,41,52 Suspected zoonotic transmission has also been reported. ...

A class effect of quinolone antibacterial agents observed during animal toxicity testing is a specific arthropathy (QAP). Despite the growing list of laboratory animals susceptible to QAP and reports of arthralgia in patients treated with quinolones, the potential for QAP development in humans remains unknown. This review discusses current concepts in the biology of articular cartilage and how these concepts elucidate QAP pathogenesis. Biomechanical forces within synovial joints and toxicokinetic properties of quinolones contribute to QAP induction. Since a limited number of mechanistic pathways exist for acute articular damage, QAP may serve as a research tool to probe the pathobiology of injury to articular cartilage.

No abstract

The efficacy of telavancin, a bactericidal lipoglycopeptide, was compared to that of vancomycin and linezolid against methicillin-resistant Staphylococcus aureus (MRSA) in a murine pneumonia model. Telavancin produced greater reductions in lung bacterial titer and mortality than did vancomycin and linezolid at human doses equivalent to those described by the area under the concentration-time curve. These results suggest the potential utility of telavancin for treatment of MRSA pneumonia.Nosocomial pneumonia due to methicillin-resistant Staphylococcus aureus (MRSA) has been reported with increasing frequency over the past 2 decades (13). Vancomycin and linezolid, two drugs that are slowly bactericidal and bacteriostatic, respectively, are frequently used in the treatment of nosocomial pneumonia caused by Staphylococcus aureus, including MRSA. However, overall clinical cure rates attained with these two drugs are less than optimal (8).Telavancin is a novel lipoglycopeptide that operates through multiple mechanisms to produce potent and rapid bactericidal activity against clinically relevant gram-positive bacteria, including MRSA (4, 5, 7). We have previously shown that telavancin exhibits potent antibacterial activity against a range of gram-positive bacteria, including MRSA, in two animal models of soft-tissue infection, with the area under the concentrationtime curve (AUC)/MIC ratio being the pharmacodynamically linked parameter (3). In the studies described here, we assessed the efficacy of telavancin in an immunocompromised murine model of MRSA-induced pneumonia.Telavancin for injection (250 mg/vial) was reconstituted in 5% dextrose in water. Vancomycin (Sigma-Aldrich, St. Louis, MO) and linezolid (Pharmacia, Kalamazoo, MI) were dissolved in 5% dextrose in water and hydroxypropyl-␤-cyclodextrin, respectively. MRSA ATCC 33591 was obtained from the American Type Culture Collection (Manassas, VA). MICs were determined by the broth microdilution method according to protocol M7-A5 of the National Committee for Clinical Laboratory Standards (6). The MICs of telavancin, vancomycin, and linezolid against MRSA 33591 were 0.5, 1, and 1 g/ml, respectively. The doses used in pharmacodynamic studies were chosen to approximate human doses equivalent to those described by AUCs as opposed to other pharmacokinetic parameters since the AUC/MIC ratio is believed to be the key pharmacodynamically linked parameter for all three drugs against S. aureus (1, 3).All studies were approved by the Institutional Animal Care and Use Committee at Theravance, Inc. Female BALB/c mice (Harlan, Indianapolis, IN), weighing between 16 and 26 g, were rendered neutropenic by treatment with 250 mg/kg of cyclophosphamide intraperitoneally at 4 and 2 days prior to infection. Neutropenic animals were lightly anesthetized with isoflurane gas and then held in an upright position to be inoculated. Each animal was inoculated by placing 50 l of inoculum containing approximately 10 7 CFU of MRSA onto the tip of the nares. The animals were allowed to inhale t...