We examined the frequency of acquisition of bacterial pathogens on investigators' hands after contacting environmental surfaces near hospitalized patients. Hand imprint cultures were positive for one or more pathogens after contacting surfaces near 34 (53%) of 64 study patients, with Staphylococcus aureus and vancomycin-resistant Enterococcus being the most common isolates.

Normal prostatic epithelium depends on androgens for growth, development, secretory function, and survival (1-4). Most remarkably, androgen ablation induces massive apoptosis of prostatic epithelium (2, 5-8). Loss of androgen dependence occurs invariably during prostate carcinogenesis, accounting for poor long term success of androgen ablation therapy (9). Recent studies (10) show that acquisition of androgen autonomy occurs despite retention or elevated expression of the androgen receptor (AR) 1 in the majority of prostate tumors. AR, a 110-kDa zinc finger transcription factor belonging to the nuclear receptor superfamily, is activated by phosphorylation (11) and dimerization upon ligand binding. This promotes nuclear localization and binding of AR to androgenresponsive elements in the promoters of androgen-regulated genes. AR-mediated transcription is regulated by many ARinteracting proteins such as ARA 70 (AR-associated proteins) (12) and ARA 160 (13), along with cAMP-response element-binding protein (14), AP-1 (9, 15), and Ets (16). The growing list of recently discovered AR transcriptional co-regulators supports the notion that complex networks of signals tightly regulate transcription by androgens. Understanding how these signals promote growth and maintain cell viability will certainly impact on the therapeutic strategies for the prevention and cure of prostate cancer.TGF-␤, a potent regulator of cell growth, differentiation, apoptosis, and carcinogenesis in the prostate (17)(18)(19)(20), is under androgenic control. TGF-␤ signals through a cooperative interaction with two cell surface serine/threonine kinase receptors, . TGF-␤ first associates with constitutively active dimeric T␤RII, which then recruits and activates T␤RI kinase by transphosphorylation at a juxtamembrane glycine-serine repeat (21,26). With the help of Smad anchor for receptor activation (27), phosphorylated T␤RI is able to activate Smads 2 and 3 by phosphorylating their carboxyl-terminal serine-serine-Xaa-serine motifs (28). Active Smads 2 and 3 can form heteromeric complexes with co-Smad4, and either directly or through interactions with transcription factors and co-regulators bind to Smad-binding elements (SBEs) in TGF-␤-regulated genes (29 -31). Further activation of Smads 2 and 3 is blocked by Smad7, whose expression is induced upon TGF-␤ stimulation (32).Androgens negatively regulate TGF-␤1 ligand (17, 33) and receptor expression (34,35), along with Smad expression and activation (36) in the prostate. Recent reports show AR associates with Smad3 and that this association may either enhance

We examined the effect of subcutaneous fluoroquinolone antibiotic administration on persistence and density of vancomycin-resistant Enterococcus faecium stool colonization in mice. Levofloxacin and ciprofloxacin did not promote colonization in comparison to saline controls, whereas moxifloxacin and gatifloxacin promoted persistent overgrowth in a dose-dependent fashion.In a mouse model and in colonized patients, we have demonstrated that antibiotics with potent in vitro activity against intestinal anaerobes promote persistent high-density colonization with vancomycin-resistant Enterococcus faecium (VRE), whereas antibiotics with minimal antianaerobe activity (including ciprofloxacin) do not (4, 5). Although some fluoroquinolone antibiotics have enhanced in vitro activity against anaerobes (e.g., moxifloxacin and gatifloxacin) (1, 13), studies with human volunteers have demonstrated that none of the currently available agents in this class cause a significant reduction in the density of intestinal anaerobes (2,(6)(7)(8)(9)14). Therefore, we examined the effect of fluoroquinolone antibiotics with various levels of antianaerobe activity on the persistence of VRE stool colonization in mice.The mouse model that we have previously utilized to study the effect of antibiotics on persistence of VRE stool colonization was used (4). Male CF1 mice (Harlan Sprague-Dawley, Indianapolis, Ind.) weighing 25 to 30 g were housed in individual cages and fed rodent chow and water ad libitum. VRE colonization with Enterococcus faecium strain C68 was established in all mice by administering oral vancomcyin (250 g/ liter) in drinking water for 2 days before and 5 days after esophageal instillation of 10 8 CFU of VRE in 0.5 ml (4). After discontinuation of oral vancomycin, mice were begun on twice-daily subcutaneous injections of saline (negative controls) or antibiotics for 15 days. Three different doses of the fluoroquinolone antibiotics were studied: a low dose equal to the usual human dose administered over a 24-h period (milligrams of antibiotic per gram of body weight); a medium dose of 5 times the low dose, and a human-equivalent dose of 12 times the usual human dose calculated by the technique of Freireich et al. (11). The dose of levofloxacin was based on the 750-mg-per-day human dose. Gatifloxacin and moxifloxacin were administered only at the lower two dosages because the highest dosage of these agents resulted in significant subcutaneous tissue irritation. The dosages included ciprofloxacin at 0.4, 2, and 4.8 mg/day; levofloxacin at 0.375, 1.875, and 4.7 mg/day; gatifloxacin at 0.2 and 1 mg/day; and moxifloxacin at 0.2 and 1 mg/day. Clindamycin at 1.4 mg/day promoted persistent high-density colonization in previous experiments and was included as a positive control (4).Four mice were included in each experimental group, and the experiments were performed twice (eight mice per group). Stool samples were collected prior to starting subcutaneous antibiotics and then on days 5, 10, and 15 of antibiotic therapy. To measure the de...

In mice, subcutaneous administration of antibiotics that disrupt the anaerobic microflora (i.e., clindamycin, piperacillin-tazobactam, and ceftriaxone) facilitated in vitro growth of and toxin production by Clostridium difficile in cecal contents, whereas antibiotics that cause minimal disruption of the anaerobic microflora (i.e., levofloxacin, cefepime, and aztreonam) did not

No abstract

The potential for transfer of vancomycin-resistance genes from enterococci to Staphylococcus aureus exists when these organisms share an ecologic niche. We performed an 8-month prospective study to determine the frequency at which S. aureus and vancomycin-resistant enterococci (VRE) coexist in the intestinal tracts of VRE-colonized patients and evaluated whether antianaerobic antibiotic therapy promoted increased density of S. aureus colonization. Of 37 patients colonized with vancomycin-resistant Enterococcus faecium, 23 (62%) had S. aureus recovered from stool specimens and 20 (87%) had methicillin-resistant strains. There was no significant difference in the mean density (+/- standard deviation) of S. aureus during versus > or =1 month after discontinuation of antianaerobic antibiotic therapy (5.1+/-1.5 vs. 4.7+/-1.6 log10 colony-forming units per gram of stool; P=.34). No S. aureus isolates were resistant to vancomycin. S. aureus and VRE often coexist in the intestinal tract, providing a potential reservoir for the emergence of vancomycin-resistant S. aureus isolates.

We used a mouse model to test the hypothesis that anaerobic microbiota in the colon inhibit the establishment of vancomycin-resistant enterococci (VRE) colonization by depleting nutrients within cecal contents and limiting the association of VRE with the mucus layer. Anaerobic growth of VRE was assessed in cecal contents and cecal mucus of mice that had received treatment with subcutaneous clindamycin or saline. VRE grew to high concentrations in cecal contents of clindamycin-treated mice and in cecal mucus of both groups but not in cecal contents of saline-treated mice, unless the cecal contents were autoclaved or converted into sterile filtrates. After orogastric inoculation of VRE, clindamycin-treated mice acquired high concentrations of VRE within the mucus layer, whereas saline-treated mice did not. These results suggest that colonic microbiota inhibit VRE by producing inhibitory substances or conditions rather than by depleting nutrients. The colonic mucus layer provides a potential niche for growth of VRE.

Limiting the use of antianaerobic antibiotics in VRE-colonized patients may reduce the density of colonization with coexisting antibiotic-resistant, gram-negative bacilli.