Evaluation of intraosteoblastic activity of dalbavancin against Staphylococcus aureus in an ex vivo model of bone cell infection

Abstract

Objectives Long-acting lipoglycopeptides are promising therapeutic options in Staphylococcus aureus bone and joint infections (BJIs). This study evaluated the ability of dalbavancin to eradicate the intraosteoblastic reservoir of S. aureus, associated with BJI chronicity. Methods Osteoblastic cells were infected with a standardized inoculum of the S. aureus reference strain HG001 and incubated for 24 h with dalbavancin, vancomycin or rifampicin using the MIC, 10×MIC, 100×MIC and/or the intraosseous concentrations reached using standard therapeutic doses (i.e. vancomycin, 10 mg/L; rifampicin, 2 mg/L; and dalbavancin, 6 mg/L). The remaining intracellular bacteria were quantified by plating cell lysates. Results MICs of dalbavancin, vancomycin and rifampicin were 0.125, 1 and 0.004 mg/L, respectively. Dalbavancin significantly reduced the intracellular inoculum of S. aureus starting at a concentration equal to the MIC, with a significant dose effect, ranging from a reduction of 31.4% (95% CI = 17.6%–45.2%) at MIC to 51.6% (95% CI = 39.8%–63.4%) at 100×MIC compared with untreated cells. Of note, dalbavancin was the only molecule to significantly reduce the intraosteoblastic inoculum at low concentration (MIC). At intraosseous concentrations, dalbavancin reduced the intracellular inoculum by 49.6% (95% CI = 45.1%–54.1%) compared with untreated cells (P < 0.001), with no significant difference compared with vancomycin (38.1%; 95% CI = 19.2%–57.0%; P = 0.646), and was less efficient than rifampicin (69.0%; 95% CI = 63.2-74.8; P < 0.001). Conclusions Dalbavancin was able to decrease the intraosteoblastic S. aureus inoculum by 50% at intraosseous concentrations reached during standard human therapeutic dosing, with no difference compared with vancomycin, and remained less efficient than rifampicin. However, it was the only molecule significantly active at low concentration.

Intracellular activity and in vivo efficacy in a mouse model of septic arthritis of the novel pseudopeptide Pep16 against Staphylococcus aureus clinical isolates

“…In comparison with newer contenders like dalbavancin and rifamycins, Pep16 showcased remarkable intracellular activity. Chauvelot et al 11 showed that dalbavancin, a recently introduced extended-duration lipoglycopeptide, significantly reduced the presence of S. aureus in osteoblasts starting at its MIC (0.125 mg/L), demonstrating a dose-dependent effectiveness. However, Pep16 outperformed dalbavancin, achieving reductions of 86.6% for MRSA isolates and approximately 63% for MSSA isolates.…”

“…In contrast, the peak of reduction by dalbavancin at 100× its MIC was only 51.6%. 11 In another study, conducted by Abad et al 19 on rifamycins, a group of antibiotics that inhibit bacterial RNA polymerase, the potential intracellular activity of these drugs against S. aureus was highlighted. When examining concentrations that were 10× or 100× their respective MICs, all rifamycins exhibited significant intracellular activity.…”

Antibody-antibiotic conjugate targeted therapy for orthopedic implant-associated intracellular S. aureus infections

“…In the case of S. aureus bone tissue infection, the types of intracellular colonization mainly involved osteoblasts, chondrocytes, synovial endothelial cells, and macrophages, as has been reported in numerous studies [25][26][27]. However, in the PJI model, the dominant cell types that are colonized by S. aureus cells were not clear, and it was unknown whether the presence of antibiotics affected the types of cells that were colonized.…”

Emerging resistance inStaphylococcus epidermidisduring dalbavancin exposure: a case report andin vitroanalysis of isolates from prosthetic joint infections

“… 5 This is consistent with in vitro data, whereby dalbavancin was significantly more effective at reducing cultivable S. epidermidis from biofilms compared with vancomycin. 6 The pharmakokinetic properties with exceptionally long half-life of dalbavancin (149–250 h) 1 together with clinically relevant synovial and bone concentrations including intra-osteoblastic activity 7 , 8 and a favourable safety profile 9 , 10 render dalbavancin an attractive option for prolonged outpatient antibiotic treatment of implant-associated orthopaedic infections such as prosthetic joint infection (PJI) or fracture-related infection. 2 …”