Real-Time In Vivo Bioluminescent Imaging for Evaluating the Efficacy of Antibiotics in a Rat Staphylococcus aureus Endocarditis Model

Abstract

Therapeutic options for invasive Staphylococcus aureus infections have become limited due to rising antimicrobial resistance, making relevant animal model testing of new candidate agents more crucial than ever. In the present studies, a rat model of aortic infective endocarditis (IE) caused by a bioluminescently engineered, biofilm-positive S. aureus strain was used to evaluate real-time antibiotic efficacy directly. This strain was vancomycin and cefazolin susceptible but gentamicin resistant. Bioluminescence was detected and quantified daily in antibiotic-treated and control animals with IE, using a highly sensitive in vivo imaging system (IVIS). Persistent and increasing cardiac bioluminescent signals (BLS) were observed in untreated animals. Three days of vancomycin therapy caused significant reductions in both cardiac BLS (>10-fold versus control) and S. aureus densities in cardiac vegetations (P < 0.005 versus control). However, 3 days after discontinuation of vancomycin therapy, a greater than threefold increase in cardiac BLS was observed, indicating relapsing IE (which was confirmed by quantitative culture). Cefazolin resulted in modest decreases in cardiac BLS and bacterial densities. These microbiologic and cardiac BLS differences during therapy correlated with a longer time-above-MIC for vancomycin (>12 h) than for cefazolin (ϳ4 h). Gentamicin caused neither a reduction in cardiac S. aureus densities nor a reduction in BLS. There were significant correlations between cardiac BLS and S. aureus densities in vegetations in all treatment groups. These data suggest that bioluminescent imaging provides a substantial advance in the real-time monitoring of the efficacy of therapy of invasive S. aureus infections in live animals.

A fully functional drug-eluting joint implant

“…While similar survival rate was observed for animals treated with VPE and VTBC, VPE (but not VTBC) completely eradicated all the bacteria in the joint. This may be partly due to Xen29’s higher susceptible to vancomycin [55] than to tobramycin [56]. …”

The truncated phage lysin CHAPkeliminatesStaphylococcusaureusin the nares of mice

“…This strain is derived from the parental strain S. aureus ATCC 12600, a pleural fluid isolate which has been engineered with a stable copy of the modified Photorhabdus luminescens luxABCDE operon at a single integration site on the bacterial chromosome. 21,30,32 When metabolically active this strain emits luminescence, which can then be rapidly detected and quantified RepoRt RepoRt…”

Medical biofilms

“…Emergence of PCR techniques have shorten the time period but they also sample body fluids (blood, saliva, urine), which will not provide an accurate estimate of the actual biofilm flora colonizing an implant. Xiong et al (2005) reports a rapid, continuous method for real-time monitoring of biofilm development, both in vitro and in a mouse infection model, through non-invasive imaging of bioluminescent bacteria (Fig. 5).…”

“…The animals were imaged ventrally, with their chest area shaved, to avoid background signal from animal hair. The process of infection was monitored daily by detecting photon emission around the region of interest (heart area) over a 6-day course (Xiong et al, 2005).…”