Effect of Ceftaroline, Ceftazidime/Avibactam, Ceftolozane/Tazobactam, and Meropenem/Vaborbactam on Establishment of Colonization by Vancomycin-Resistant Enterococci and Klebsiella pneumoniae in Mice

Background: The potential for promotion of intestinal colonization with healthcare-associated pathogens by new antibiotics used to treat infections due to multidrug-resistant Gram-negative bacilli is unclear. Methods: Mice treated for 3 days with daily subcutaneous phosphate-buffered saline (control), ceftazidime/avibactam, ceftolozane/tazobactam, ceftaroline, and meropenem/vaborbactam were challenged with 10,000 colony-forming units (CFU) of vancomycin-resistant Enterococcus (VRE) resistant to each of the antibioics or carbapenemase-producing Klebsiella pneumoniae 1 day after the final treatment dose. The concentrations of VRE or K. pneumoniae in stool were measured on days 1, 3, 6, and 15 after challenge. Results: Control mice had transient low levels of VRE or K. pneumoniae (<3 log10 CFU/g) detected in stool with negative cultures on days 6 and 15 after challenge. In comparison to control mice, each of the antibiotics promoted establishment of high-density colonization with VRE (mean concentration, >8 log10 CFU/g of stool on day 1 after challenge) that persisted at >4 log10 CFU/g of stool through day 15 (P<0.01). In comparison to control mice, meropenem/vaborbactam and ceftaroline promoted high-density colonization with K. pneumoniae (peak concentration, >8 log10 CFU/g of stool) (P<0.01), ceftolozane/tazobactam promoted colonization to a lesser degree (peak concentration, >5 log10 CFU/g of stool), and ceftazidime/avibactam did not promote colonization (P>0.05). Conclusions: Our results suggest that several beta-lactam antibiotics recently developed for treatment of infections with resistant Gram-negative bacilli have the potential to promote colonization by healthcare-associated pathogens. Additional studies are needed to examine the impact of these agents in patients.