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Orthopaedic Proceedings
Vol. 105-B, Issue SUPP_17 | Pages 24 - 24
24 Nov 2023
ANTIBODY-DRUG CONJUGATE THERAPY AGAINST S. AUREUS IMPLANT-ASSOCIATED INFECTION IN A MURINE MODEL
Tvilum A Johansen MI Glud L Malskær D Khamas A Carmali S Mhatre S Søgaard A Faddy E de Vor L Rooijakkers S Østergaard L Meyer R Zelikin A Jørgensen N
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Aim

Infections represent a serious threat to the successful utilization of implants in modern medicine. Implant-associated infections are difficult to treat, because they involve biofilms that protect bacteria from the immune system and harbour antibiotic-tolerant persister cells.

In this work, we developed an antibody-drug conjugate (ADC) containing the anti-neoplastic drug mitomycin C (MMC) as a novel treatment paradigm for implant-associated infections. MMC was chosen as it is a potent antimicrobial against biofilms and its synthesis into an ADC was chosen to alleviate toxicity. Following development and synthesis of the ADC, stability and release of MMC was measured. We then used the ADC to kill bacteria in suspension and in biofilms, in vitro and in vivo.

Method

Mitomycin C was conjugated to a commercially available antibody against S. aureus via a disulfide linkage, with a drug release occurred via thiol-disulfide exchange.

ADC as tested against S. aureus under various growth conditions (planktonic, persisters and biofilm). In vitro toxicity of ADC vs MMC was measured using a human cell line (MOLT-4).

Finally, two independent in vivo experiments were performed in a murine implant-associated osteomyelitis model. In experiment one ADC treatment was compared NaCl, vancomycin and vancomycin + ADC (n=10 for all groups). Subsequently, ADC was compared to NaCl, the antibody used in the ADC construction, MMC and a novel ADC constructed with a non-S. aureus antibody (n=10 for all groups). All treatments were started day 7 post inoculation and were administered for 3 days. CFU enumeration was done following sonication to quantify bacterial load.

Orthopaedic Proceedings
Vol. 104-B, Issue SUPP_10 | Pages 27 - 27
1 Oct 2022
RIFAMPICIN DOES NOT REDUCE MOXIFLOXACIN TISSUE CONCENTRATIONS FOLLOWING ONE-STAGE REVISION IN A PORCINE MODEL OF IMPLANT-ASSOCIATED OSTEOMYELITIS
Vittrup S Jensen LK Hanberg P Slater J Hvistendahl MA Stilling M Jørgensen N Bue M
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Aim

This study investigated if co-administration of rifampicin with moxifloxacin led to a decrease in moxifloxacin concentrations in relevant tissues in a porcine model of implant-associated osteomyelitis caused S. aureus. Pharmacokinetics were measured using microdialysis and treatment effect was measured by quantifying bacterial load from implant and periprosthetic bone following a 1-stage revision and antibiotics.

Method

15 female pigs received a stainless-steel implant in the right proximal tibia and were randomized into two groups. Infection was introduced by inoculating the implant with Staphylococcus aureus as previously described1. On day 7 post surgery, all pigs were revised with implant removal, debridement of implant cavity and insertion of a sterile implant. 7 days of treatment was then initiated with either moxifloxacin 400 mg iv q.d. (M) or moxifloxacin and rifampicin 450 mg iv b.i.d. (RM). At day 14, animals were sedated and microdialysis was applied for continuous sampling of moxifloxacin concentrations during 8 h in five compartments: the implant cavity, cancellous bone in both the infected and non-infected proximal tibia, and adjacent subcutaneous tissue on both the infected and non-infected side using a previously described setup2. Venous blood samples were collected. Implant and adjacent bone were removed for analysis.