Gastrointestinal Colonization with a Cephalosporinase-Producing Bacteroides Species Preserves Colonization Resistance against Vancomycin-Resistant Enterococcus and Clostridium difficile in Cephalosporin-Treated Mice

Abstract

Antibiotics that are excreted into the intestinal tract may disrupt the indigenous intestinal microbiota and promote colonization by health care-associated pathogens. ␤-Lactam, or penicillin-type, antibiotics are among the most widely utilized antibiotics worldwide and may also adversely affect the microbiota. Many bacteria are capable, however, of producing ␤-lactamase enzymes that inactivate ␤-lactam antibiotics. We hypothesized that prior establishment of intestinal colonization with a ␤-lactamaseproducing anaerobe might prevent these adverse effects of ␤-lactam antibiotics, by inactivating the portion of antibiotic that is excreted into the intestinal tract. Here, mice with a previously abolished microbiota received either oral normal saline or an oral cephalosporinase-producing strain of Bacteroides thetaiotaomicron for 3 days. Mice then received 3 days of subcutaneous ceftriaxone, followed by either oral administration of vancomycin-resistant Enterococcus (VRE) or sacrifice and assessment of in vitro growth of epidemic and nonepidemic strains of Clostridium difficile in murine cecal contents. Stool concentrations of VRE and ceftriaxone were measured, cecal levels of C. difficile 24 h after incubation were quantified, and denaturing gradient gel electrophoresis (DGGE) of microbial 16S rRNA genes was performed to evaluate the antibiotic effect on the microbiota. The results demonstrated that establishment of prior colonization with a ␤-lactamase-producing intestinal anaerobe inactivated intraintestinal ceftriaxone during treatment with this antibiotic, allowed recovery of the normal microbiota despite systemic ceftriaxone, and prevented overgrowth with VRE and epidemic and nonepidemic strains of C. difficile in mice. These findings describe a novel probiotic strategy to potentially prevent pathogen colonization in hospitalized patients.

Metallo-β-Lactamase-Producing Bacteroides Species Can Shield Other Members of the Gut Microbiota from Antibiotics

“…In a previous series of animal experiments, we showed that ␤-lactamase production by a B. thetaiotaomicron isolate could protect susceptible organisms within the same microbiota from ␤-lactam antibiotics (8). In the present study, we demonstrated that the magnitude of this effect is correlated with the genetic and phenotypic characteristics of the ␤-lactamase background in the protecting anaerobes.…”

“…This strategy holds promise for the prevention of pathogen colonization in patients treated with parenteral antibiotics, as antibiotic degradation within the colonic lumen does not impact systemic concentrations (7). We also demonstrated that, despite their receipt of parenteral ␤-lactams, mice intestinally colonized with a ␤-lactamase-producing member of the commensal microbiota (Bacteroides thetaiotaomicron) preserved colonization resistance against VRE and C. difficile (8). However, the genetics of ␤-lactam resistance in the protective Bacteroides species in this study were not known, and a comparator anaerobe was not studied.…”

Resistance Mechanisms, Epidemiology, and Approaches to Screening for Vancomycin-Resistant Enterococcus in the Health Care Setting

“…Elimination of normal gut flora by commonly used broadspectrum antibiotics (vancomycin, cephalosporins, and metronidazole) encourages the selective proliferation of VRE (9). This increases the likelihood of resulting infections with these bacteria or leaves patients more susceptible to colonization by resistant strains encountered in the environment or health care setting.…”

Can Fecal Microbiota Transplantation (FMT) Eradicate Fecal Colonization With Vancomycin-Resistant Enterococci (VRE)?

“…Specifically, the presence of Barnesiella species in the intestinal tract was able to confer resistance to VRE in patients undergoing allogeneic hematopoietic stem cell transplantation. 4 Stielfel et al 5 reported that cephalosporinase-producing Bacteroides thetaiotaomicron prevented overgrowth of VRE and C. difficile in cephalosporintreated mice. Defined microbiota transplant instead of whole stool may lead to more successful outcomes.…”