Activity of Tedizolid in Methicillin-Resistant Staphylococcus aureus Experimental Foreign Body-Associated Osteomyelitis

Abstract

dWe compared tedizolid alone and tedizolid with rifampin to rifampin and vancomycin plus rifampin in a rat model of methicillin-resistant Staphylococcus aureus (MRSA) foreign body-associated osteomyelitis. The study strain was a prosthetic joint infection-associated isolate. Steady-state pharmacokinetics for intraperitoneal administration of tedizolid, vancomycin, and rifampin were determined in uninfected rats. MRSA was inoculated into the proximal tibia, and a wire was implanted. Four weeks later, the rats were treated intraperitoneally for 21 days with tedizolid (n ‫؍‬ 14), tedizolid plus rifampin (n ‫؍‬ 11), rifampin (n ‫؍‬ 16), or vancomycin plus rifampin (n ‫؍‬ 13). Seventeen rats received no treatment. After treatment, quantitative bone cultures were performed. Blood was obtained for determination of drug trough concentrations in the tedizolid and tedizolid plus rifampin groups. The mean peak plasma concentration and mean area under the concentration-time curve from time zero to 24 h for tedizolid were 12 g/ml and 60 g · h/ml, respectively. The bacterial loads in all treatment groups were significantly lower than those in the control group; those in the tedizolid-plus rifampin-treated animals were not significantly different from those in the vancomycin-plus rifampin-treated animals. The range of mean plasma trough concentrations in the tedizolid group was 0.44 to 0.73 g/ml. Although neither tedizolid nor vancomycin resistance was detected in isolates recovered from bones, rifampin resistance was detected in 10 animals (63%) in the rifampin group, 8 animals (73%) in the tedizolid plus rifampin group, and a single animal (8%) in the vancomycin plus rifampin group. Tedizolid alone or tedizolid combined with rifampin was active in a rat model of MRSA foreign body-associated osteomyelitis. The emergence of rifampin resistance was noted in animals receiving tedizolid plus rifampin.

Activity of Tedizolid in Methicillin-Resistant Staphylococcus epidermidis Experimental Foreign Body-Associated Osteomyelitis

“…Recently, Bayer et al reported that tedizolid had better efficacy in reducing MRSA densities than did linezolid and vancomycin in a murine model of subcutaneous catheter-related biofilm infection (18). We recently performed a study of tedizolid activity in MRSA experimental foreign body-associated osteomyelitis in which tedizolid monotherapy as well as tedizolid-plusrifampin combination therapy were active (27). The in vitro potency of tedizolid is 2-to 8-fold higher than that of vancomycin against staphylococci, and its prolonged subinhibitory MIC and postantibiotic effect against staphylococci are greater than those of linezolid (28).…”

Role of Rifampin against Staphylococcal Biofilm Infections In Vitro , in Animal Models, and in Orthopedic-Device-Related Infections

“…In this rat model, a 3-week treatment course was started 4 weeks after infection. Park et al (48) used the same model and found that wires were sterile in 13 of 13 animals treated with vancomycin plus rifampin but in only 45% of animals treated with tedizolid plus rifampin. Tedizolid could not protect from the emergence of rifampin resistance.…”

“…In several experimental models, the role of rifampin has been tested in implantassociated osteomyelitis (44)(45)(46)(47)(48)(49)(50)(51). Again, the superiority of rifampin combinations could be shown if adequate experimental conditions were chosen.…”

Tedizolid-Rifampicin Combination Prevents Rifampicin-Resistance on in vitro Model of Staphylococcus aureus Mature Biofilm

“…To date there are limited and conflicting data about its activity on biofilms ( Bayer et al, 2016 ; Delpech et al, 2018 ; Abad et al, 2019 ), and there are no data available about its activity in combination with rifampicin on S. aureus biofilm. Indeed, to our knowledge, only Werth (2017) evaluated the in vitro pharmacodynamic interactions between tedizolid and rifampicin, and Park et al, 2016 evaluated the effect of this combination on an in vivo model of methicillin-resistant S. aureus foreign body-associated osteomyelitis. The first study focused the effect on S. aureus planktonic cells and among the combinations tested tedizolid/rifampicin seemed the most likely one to improve activity, but synergy was not found in every strain.…”