Daptomycin and Tigecycline Have Broader Effective Dose Ranges than Vancomycin as Prophylaxis against a Staphylococcus aureus Surgical Implant Infection in Mice

Abstract

Vancomycin is widely used for intravenous prophylaxis against surgical implant infections. However, it is unclear whether alternative antibiotics used to treat methicillin-resistant Staphylococcus aureus (MRSA) infections are effective as prophylactic agents. The aim of this study was to compare the efficacies of vancomycin, daptomycin, and tigecycline as prophylactic therapy against a methicillin-sensitive S. aureus (MSSA) or MRSA surgical implant infection in mice. MSSA or MRSA was inoculated into the knee joints of mice in the presence of a surgically placed medical-grade metallic implant. The efficacies of low-versus high-dose vancomycin (10 versus 110 mg/kg), daptomycin (1 versus 10 mg/kg), and tigecycline (1 versus 10 mg/kg) intravenous prophylaxis were compared using in vivo bioluminescence imaging, ex vivo bacterial counts, and biofilm formation. High-dose vancomycin, daptomycin, and tigecycline resulted in similar reductions in bacterial burden and biofilm formation. In contrast, low-dose daptomycin and tigecycline were more effective than low-dose vancomycin against the implant infection. In this mouse model of surgical implant MSSA or MRSA infection, daptomycin and tigecycline prophylaxis were effective over a broader dosage range than vancomycin. Future studies in humans will be required to determine whether these broader effective dose ranges for daptomycin and tigecycline in mice translate to improved efficacy in preventing surgical implant infections in clinical practice.

Combined <em>In vivo</em> Optical and &#181;CT Imaging to Monitor Infection, Inflammation, and Bone Anatomy in an Orthopaedic Implant Infection in Mice

“…The bioluminescent signals of Xen29-infected mice remained above background signals of sham-infected mice for the duration of the experiment ( Figure 1A,C) 16 . Our previous work demonstrated that the in vivo bioluminescent signals closely approximated the numbers of ex vivo CFU isolated from the joint/bone tissue and adherent to the implants 17,18 . In addition, the EGFP fluorescent signals were higher than sham-infected mice at early time points but approached background levels during the course of infection (Figure 2B,C) 16 .…”

“…In addition, these techniques have permitted the evaluation of the consequences of the infection and inflammation on the bone and joint tissue. Future work could take advantage of multimodality imaging to evaluate the efficacy of antimicrobial therapies, immune responses, pathogenesis of disease and the reactive changes in the bone as we have begun to investigate [14][15][16][17][18] . In addition, multimodality imaging could evaluate probes and tracers to diagnose the presence of an infection as previously described in animal models a thigh infection, endocarditis, pulmonary infections and biomaterial infections…”

“…In the present study, the protocol is described for this previously published model of an orthopaedic prosthetic joint infection in mice [14][15][16][17][18][19] , which involves the surgical placement of a titanium K-wire implant that extends from an intramedullary canal in the femur into the joint space [14][15][16][17][18][19] . S. aureus bioluminescent strain Xen29 (1 x 10 3 CFU in 2 μl PBS) was pipetted directly on top of the end titanium implant in the knee joint prior to closing the surgical site 16 .…”

“…This model involved placing a titanium Kirschner-wire (K-wire) in such a manner that the cut end of the implant extended in the knee joint from the femurs of mice [14][15][16][17][18][19] . An inoculum of Staphylococcus aureus (bioluminescent strain Xen29 or Xen36) was then pipetted onto the surface of the implant in the knee joint before the surgical site was closed [14][15][16][17][18][19] . In vivo optical imaging was used to detect and quantify the bioluminescent signals, which corresponded to the number of bacteria in the infected joint and bone tissue…”

Establishment of a new methicillin resistant staphylococcus aureus animal model of osteomyelitis

“…As for periprosthetic infections, recent studies have included an assessment of the efficacy of teicoplanin in experimental Staphylococcus aureus infections of joint prostheses [25], a rabbit model of knee joint infection [26], a rat experimental foreign-body infection by MRSA [27], and more recently an assessment of the efficacy of salvage antibiotic daptomycin [28]. A comprehensive clinical follow-up examination has also been done by Lucke et al in a peri-implant rat model of tibial osteomyelitis by inoculation of Staphylococcus aureus into the tibial cavity in combination with Kirschner wires [29].…”