To test the hypothesis that establishing gastrointestinal colonization with multiresistant Enterococcus faecium (VRE) C68 results from expansion of the enterococcal population in the upper small bowel, we compared VRE quantities recovered from the proximal, middle, and distal segments of the small bowel from mice treated with different antimicrobial agents. Antibiotics associated with high-level VRE fecal colonization (cefotetan, ceftriaxone, clindamycin, and ticarcillin-clavulanic acid) increased VRE quantities in all small-bowel segments, whereas cefepime and piperacillin-tazobactam did not. Enterococcal expansion did not correlate with reductions in numbers of native gram-negative or anaerobic flora. Green fluorescence protein-expressing E. faecium bacteria were found adjacent to the small bowel epithelial lining in colonized mice. These data indicate that enterococcal bowel colonization begins within the proximal small bowel and does not correlate with inhibition of other cultivable flora. Host or enterococcal factors induced by exposures to certain antibiotics may play a role in facilitating E. faecium colonization of the mammalian gastrointestinal tract.Multiresistant Enterococcus faecium (VRE) continues to be an important cause of nosocomial infection, especially in severely immunocompromised patients (10). Data from clinical studies indicate that gastrointestinal colonization frequently precedes clinical infection and that exposure to antimicrobial agents increases the risk of becoming colonized or infected with multiresistant E. faecium (9, 18). Prominent implicated antibiotics include third-generation cephalosporins, agents with potent activity against anaerobic bacteria, and vancomycin (2, 13).Using a mouse model of VRE colonization designed to examine the impact of antimicrobial administration on the establishment of VRE gastrointestinal colonization, we have shown that some broad-spectrum antimicrobial agents (cefotetan and ceftriaxone) promote heavy colonization while others (aztreonam, cefazolin, cefepime, and piperacillin-tazobactam) do not (15). The tendency to promote fecal colonization appears to be related to the intrinsic activity of the agent against E. faecium and the extent to which the agent is concentrated in bile. In separate experiments designed to examine the impact of antimicrobial agents on the persistence of high-level fecal colonization, activity against anaerobic flora was the most important characteristic (4, 6).Although the associations of different antibiotic classes with colonization in our mouse model now seem relatively clear, the mechanisms by which colonization occurs remain unknown. In particular, the location within the bowel where the expansion of the enterococcal population occurs is not known. A study by Pultz and colleagues (12) suggested that one area of significant antimicrobial impact is in the proximal large bowel (cecum), where treatment with clindamycin promotes enterococcal overgrowth in the cecal contents as well as increased enterococcal numbers within the...
The DNA mismatch repair pathway is an important repair mechanism in the cell that ensures genomic stability. Mismatch repair deficiencies are shown to be associated with certain hereditary forms of cancer as well as many sporadic cancers. The loss of mismatch repair also leads to resistance to chemotherapeutic agents and other types of DNA stress including ionizing radiation. An alternative treatment strategy for mismatch repair deficient cancers is the use of iododeoxyuridine and ionizing radiation together to generate cytotoxicity that will eventually lead to cell death. There are measurable differences in the cell cycle dynamics for mismatch repair proficient and deficient cells with and without treatment using iododeoxyuridine. A finite-state probabilistic cell cycle model is developed to study the effects of iododeoxyuridine on the cell cycle dynamics. We discuss how these models can be used to maximize therapeutic gain through the design of optimal dosing strategies of iododeoxyuridine and optimal timing of the ionizing radiation treatment. We introduce a conceptual hybrid modeling framework to study the dynamics of mismatch repair pathway in order to be able to manipulate the pathway to improve therapeutic gain. We also discuss the experimental data that are required to support the modeling framework.
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