Impact of the Timing of Antibiotic Administration on Digestive Colonization with Carbapenemase-Producing Enterobacteriaceae in a Murine Model

Abstract

While antibiotic use is a risk factor of carbapenemase-producing Enterobacteriaceae (CPE) acquisition, the importance of timing of antibiotic administration relative to CPE exposure remains unclear. In a murine model of gut colonization by New Delhi metallo-beta-lactamase-1 (NDM-1)-producing Klebsiella pneumoniae, a single injection of clindamycin within at most 1 week before or after CPE exposure induced colonization persisting up to 100 days. The timing of antibiotic administration relative to CPE exposure may be relevant to infection control and antimicrobial stewardship approaches. KEYWORDS Klebsiella pneumoniae, NDM-1, carbapenemase, gut microbiota, murine model C arbapenemase-producing Enterobacteriaceae (CPE) are an emerging public health issue, considered a critical priority by the World Health Organization (1). Among CPE, New Delhi metallo-beta-lactamase-1 (NDM-1)-producing Enterobacteriaceae are particularly preoccupying. Indeed, NDM-1 confers resistance to most ␤-lactams, including carbapenems, and has spread worldwide (2), raising fears of severe infections without therapeutic options (3).In the hospital setting, contact with a CPE-colonized patient or prior antibiotic use are major risk factors for CPE acquisition (4, 5). Among antibiotics, antianaerobes (e.g., piperacillin-tazobactam or clindamycin) seem particularly at risk (6, 7).While antibiotics are a known risk factor, the role of the timing of CPE exposure relative to antibiotic administration is unclear. We describe here a murine model of gut colonization with NDM-1-producing Klebsiella pneumoniae following a single administration of clindamycin and assess the effects of timing of clindamycin administration relative to CPE exposure on effective CPE colonization.The French Ethical Committee for Animal Experimentation approved this study (APAFIS #7166). Seven-week-old C57BL/6 male mice housed under specific-pathogen-free conditions and a clinical isolate of Klebsiella pneumoniae-producing NDM-1-carbapenemase were used (8).First, we validated the murine model of CPE gut colonization. Mice were divided into four groups with or without 24-h CPE exposure in drinking water (10 7 CFU/ml at day 0) and/or intraperitoneal clindamycin (200 g) (Fig. 1). The CPE load was evaluated by plating stool samples onto selective medium (lysogeny broth agar with 32 mg/liter cefotaxime and 6 mg/liter vancomycin). In mice exposed to both CPE and clindamycin,

Gut colonisation with multidrug-resistant Klebsiella pneumoniae worsens Pseudomonas aeruginosa lung infection

“…As previously reported 10 , antibiotic administration (clindamycin) was required to maintain stable gut colonisation by CPE up to day 14 (Fig. 1b).…”

A comprehensive evaluation of risk factors for mortality, infection and colonization associated with CRGNB in adult solid organ transplant recipients: a systematic review and meta-analysis

“…Prior use of piperacillin/tazobactam [ 13 ] and ciprofloxacin use [ 12 ] were considered independent risk factors, with antibiotic exposure occurring within the preceding 3 months. In a murine model of intestinal colonization, the timing of antibiotic use was critical for the effective colonization of CPE [ 43 ]. Therefore, avoiding antibiotic misuse is significant for the management of CRGNB epidemic spread, while further research is required to elucidate the optimal timing of antibiotic administration.…”

Animal models of Klebsiella pneumoniae mucosal infections

“…The authors propose a protocol for the use of the antimicrobial where, based on the timing of the colonization process, clindamycin treatment a week before the inoculation showed the best results in the colonization model. When clindamycin was given 2 or 3 weeks before or after the inoculation, gut colonization was not as successful (Le Guern et al, 2019).…”

“…Another technique employed to colonize the gut microbiota of mice is through "contamination" of the drinking water with the intended bacteria. In the works describing the method, the animals received preventive antibiotic treatment (also in the water) with either clindamycin or streptomycin, followed by administration of water containing the bacteria (Favre-Bonté et al, 1999;Le Guern et al, 2019). Aiming to demonstrate the dynamics between GI infection and antibiotic administration, male C57BL/6 mice received 10 7 /mL of a New Delhi metallo-beta-lactamase-1 (NDM-1) positive strain in the water, after antibiotic treatment.…”