Effect of Surotomycin, a Novel Cyclic Lipopeptide Antibiotic, on Intestinal Colonization with Vancomycin-Resistant Enterococci and Klebsiella pneumoniae in Mice

Abstract

Surotomycin (formerly called CB-183,315) is a novel, orally administered cyclic lipopeptide antibacterial in development for the treatment of Clostridium difficile infection (CDI) that has potent activity against vancomycin-resistant enterococci (VRE) but limited activity against Gram-negative bacilli, including Bacteroides spp. We used a mouse model to investigate the impact of surotomycin exposure on the microbiome, and to test the consequences of the disruption on colonization by vancomycin-resistant enterococci (VRE) and extended-spectrum β-lactamase-producing Klebsiella pneumoniae (ESBL-KP), in comparison with the effects of oral vancomycin and metronidazole. Mice (8 per group) received saline, vancomycin, metronidazole, or surotomycin through an orogastric tube daily for 5 days and were challenged with 10(5) CFU of VRE or ESBL-KP administered through an orogastric tube on day 2 of treatment. The concentrations of the pathogens in stool were determined during and after treatment by plating on selective media. A second experiment was conducted to determine if the antibiotics would inhibit established VRE colonization. In comparison to controls, oral vancomycin promoted VRE and ESBL-KP overgrowth in stool (8 log10 to 10 log10 CFU/g; P < 0.001), whereas metronidazole did not (<4 log10 CFU/g; P > 0.5). Surotomycin promoted ESBL-KP overgrowth (>8 log10 CFU/g; P, <0.001 for comparison with saline controls) but not VRE overgrowth. Surotomycin suppressed preexisting VRE colonization, whereas metronidazole and vancomycin did not. These results suggest that treatment of CDI with surotomycin could reduce levels of VRE acquisition and overgrowth from those with agents such as vancomycin and metronidazole. However, surotomycin and vancomycin may promote colonization by antibiotic-resistant Gram-negative bacilli.

FIG 1

Effects of antibiotic treatment on the concentrations of enterococci (A) and aerobic and facultative Gram-negative bacilli (B) in stool by culture. Mice received daily subcutaneous antibiotic treatment for 5 days. Error bars represent standard errors. Abx, antibiotics.

FIG 2

Comparison of the stool microbiota of mice by 16S rRNA deep-sequencing analysis after 5 days of antibiotic treatment. The relative abundances of the major bacterial phyla are shown. Mean results for the total number of mice in each group (4 mice for the surotomycin group and 5 each for the metronidazole, vancomycin, and control groups) are shown. Numbers indicate data for individual mice in each group.

FIG 3

Comparison of the stool microbiota of mice by 16S rRNA deep-sequencing analysis before, during, and after treatment with oral surotomycin or vancomycin. Mice received daily oral antibiotic treatment for 5 days (day 0 to day 5). Numbers indicate the day of sample collection: day 0, prior to treatment; day 5, after 5 days of antibiotic treatment; day 10, 5 days after the last antibiotic dose; day 15, 10 days after the last antibiotic dose. The relative abundances of the major bacterial phyla are shown as a composite for 5 total mice in each group at each time point.

FIG 4

Effects of antibiotic treatment on the concentrations of Bacteroides spp. (A) and Clostridium leptum (B) in the stool specimens of mice as determined by real-time PCR. Mice (4 in the surotomycin group and 5 each in the metronidazole, vancomycin, and control groups) received daily oral antibiotic treatment for 5 days (day 0 to day 5). Error bars represent standard errors.

FIG 5

Effects of antibiotic treatment on the establishment of colonization by vancomycin-resistant enterococci (VRE) (A) and extended-spectrum β-lactamase-producing Klebsiella pneumoniae (ESBL-KP) (B) in mice. Mice (8 per group) received daily oral antibiotic treatment for 5 days (day 0 to day 5). Error bars represent standard errors.