Infection with antibiotic-resistant bacteria, such as vancomycin-resistant Enterococcus (VRE), is a dangerous and costly complication of broad-spectrum antibiotic therapy 1,2 . How antibioticmediated elimination of commensal bacteria promotes infection by antibiotic-resistant bacteria is a fertile area for speculation with few defined mechanisms. Here we demonstrate that antibiotic treatment of mice notably downregulates intestinal expression of RegIIIγ (also known as Reg3g), a secreted C-type lectin that kills Gram-positive bacteria, including VRE. Downregulation of RegIIIγ markedly decreases in vivo killing of VRE in the intestine of antibiotic-treated mice. Stimulation of intestinal Toll-like receptor 4 by oral administration of lipopolysaccharide re-induces RegIIIγ, thereby boosting innate immune resistance of antibiotic-treated mice against VRE. Compromised mucosal innate immune defence, as induced by broad-spectrum antibiotic therapy, can be corrected by selectively stimulating mucosal epithelial Toll-like receptors, providing a potential therapeutic approach to reduce colonization and infection by antibiotic-resistant microbes.Infections caused by highly antibiotic-resistant bacteria, such as methicillin-resistant Staphylococcus aureus (MRSA) and VRE, are an increasing menace in hospitalized patients 3,4 . Treatment of serious VRE infections is limited by the paucity of effective antibiotics 5 . VRE colonizes the gastrointestinal tract and it is likely that systemic bloodstream infections are the result of dissemination from the intestine 6 . It has been widely assumed that antibiotic treatment, by eliminating commensal flora, opens intestinal niches and provides increased access to nutrients, thereby enhancing VRE survival and proliferation. Recent studies, however, have demonstrated that commensal microbes in the intestine induce expression of proteins that restrict bacterial survival and growth 7,8 . Thus, whereas commensal microbes may directly restrict VRE proliferation, an alternative hypothesis is that commensal microbes inhibit VRE indirectly by activating mucosal innate immune defenses.Correspondence and requests for materials should be addressed to E.G.P. (Fig. 1b). RegIIIγ is a secreted lectin with potent bactericidal activity against Gram-positive bacteria that is expressed by intestinal epithelial and Paneth cells 7 . Expression of RegIIIγ is dependent on TLR-MyD88-mediated signals in intestinal epithelial cells and is induced by commensal microbes 7,9 . To determine whether RegIIIγ mediates in vivo killing of VRE in the intestine, we injected a blocking polyclonal antiserum 10 against RegIIIγ into ileal loops of wild-type mice before inoculation of VRE. The number of surviving VRE bacteria was increased by over 400% in intestines treated with RegIIIγ-specific antiserum (Fig. 1c), indicating that RegIIIγ mediates in vivo VRE killing.Administration of the broad-spectrum antibiotic combination metronidazole, neomycin and vancomycin (MNV), to which VRE is resistant, markedly increases ...

BACKGROUND:In vitro and in vivo studies suggested that combination of lipid formulation of amphotericin B (L‐AMB) and echinocandins may have a synergistic or additive effect against Aspergillus. Furthermore, clinical studies suggested that this combination may improve response of invasive aspergillosis (IA).METHODS:Between August 1993 and June 2008, the authors identified a total of 159 patients with hematological malignancies who received salvage therapy for IA, with L‐AMB alone, echinocandins alone, or a combination of L‐AMB and echinocandins. Clinical characteristics, response to salvage therapy, and death up to 12 weeks after initiation of salvage therapy were retrospectively determined for all patients.RESULTS:Seventy patients received salvage therapy with L‐AMB, 18 patients received echinocandins alone (89% of whom received caspofungin), and 71 patients received the combination therapy of amphotericin B and echinocandins (90% of who received caspofungin). The 3 salvage treatment groups were comparable in regard to clinical characteristics; graft versus host disease was more frequently encountered in the echinocandin group, whereas more patients in the L‐AMB and combination groups had neutropenia and received immunotherapy. The response to salvage therapy was better in the echinocandin group (9% L‐AMB, 28% echinocandins, and 21% for combination therapy). The 3 groups had a comparable rate of Aspergillus‐related death (58%‐64%) and overall mortality (61%‐67%).CONCLUSIONS:The combination of L‐AMB and echinocandins offered no advantage in terms of improving response or reducing mortality over either drug alone. Hence, this combination will only add to the cost of therapy without any improvement in outcome in patients with hematological malignancies. Cancer 2010. © 2010 American Cancer Society.