Comparative In Vivo Efficacies of Tedizolid in Neutropenic versus Immunocompetent Murine Streptococcus pneumoniae Lung Infection Models

Abstract

Given that tedizolid exhibits substantial lung penetration, we hypothesize that it could achieve good efficacy against Streptococcus pneumoniae lung infections. We evaluated the pharmacodynamics of tedizolid for treatment of S. pneumoniae lung infections and compared the efficacies of tedizolid human-simulated epithelial lining fluid (ELF) exposures in immunocompetent and neutropenic murine lung infection models. ICR mice were rendered neutropenic via intraperitoneal cyclophosphamide injections and then inoculated intranasally with S. pneumoniae suspensions. Immunocompetent CBA/J mice were inoculated similarly. Single daily tedizolid doses were administered 4 h postinoculation (termed 0 h). Changes in log 10 CFU at 24 h compared with 0-h controls were estimated. Ratios of area under the free-drug concentration-time curve to MIC (fAUC 0 -24 /MIC) required to achieve various efficacy endpoints against each isolate were estimated using the Hill equation. Tedizolid doses in neutropenic and immunocompetent mice that mimic the human-simulated ELF exposure were examined. Stasis, 1-log reduction, and 2-log reduction were achieved at fAUC 0 -24 /MIC of 8.96, 24.62, and 48.34, respectively, in immunocompetent mice and 19.21, 48.29, and 103.95, respectively, in neutropenic mice. Tedizolid at 40 mg/kg of body weight/day and 55 mg/kg/day in immunocompetent and neutropenic mice, respectively, resulted in ELF AUC 0 -24 comparable to that achieved in humans following a 200-mg once-daily clinical dose. These human-simulated ELF exposures were adequate to attain Ͼ2-log reduction in bacterial burden at 24 h in 3 out of 4 isolates in both models and 1.58-and 0.74-log reductions with the fourth isolate in immunocompetent and neutropenic mice, respectively. Tedizolid showed potent in vivo efficacy against S. pneumoniae in both immunocompetent and neutropenic lung infection models, which support its consideration for S. pneumoniae lung infections.KEYWORDS oxazolidinedione, pharmacodynamics, pneumonia S treptococcus pneumoniae represents a challenging pathogen for clinicians, as this organism has been responsible for a wide range of potentially life-threatening infections in both the community and nosocomial settings, including communityacquired pneumonia, sepsis, and meningitis (1). Pneumococcal pneumonia is a serious public health problem resulting in approximately 600,000 hospital admissions or visits to health care providers among adults annually (2). In 30% of severe S. pneumoniae infections, the bacteria are found to be resistant to at least one class of antibiotics, such as ß-lactams and macrolides, which complicates treatment and can result in as many as 7,000 deaths annually (2-4). Resistant pneumococcal pneumonia cases result in additional visits to health care providers and account for approximately $96 million in extra medical costs (2). Vancomycin tolerance, a precursor phenotype to resistance, has

Pharmacokinetics of Tedizolid in Plasma and Sputum of Adults with Cystic Fibrosis

“…In vitro studies in THP-1 macrophages demonstrated intracellular concentrations 10-to 15-fold higher than extracellular concentrations (22). However, a comparative study of tedizolid lung penetration in neutropenic and immunocompetent murine Streptococcus pneumoniae lung infection models demonstrated that the ELF penetration ratios were not significantly different between the two models (23). Therefore, the mechanism for the high ELF exposure is unclear.…”

Comparative in vitro potency and kill curve activity of tedizolid and linezolid against Gram-positive bacteria isolated from Chinese hospitalized patients in 2013–2016

“…12 The currently approved oxazolidinones (linezolid, tedizolid) exhibit in vitro bacteriostatic activities against staphylococci and enterococci, and bactericidal activities against streptococcal species. 11,[12][13][14][15][16][17] Of note, a greater intracellular accumulation 18 and at least 4-times greater in vitro potency of tedizolid compared with linezolid have been demonstrated in previous studies. 19,20 Furthermore, tedizolid has been described with a more favourable pharmacokinetic profile than linezolid in both Caucasian 21,22 and Asian healthy subjects.…”

“…10,11 The previous murine models of thigh infection or pneumonia established that both tedizolid and linezolid exhibit bacteriostatic activities against S. aureus regardless of methicillin resistance status [13][14][15]17 and bactericidal activities against S. pneumoniae, regardless of its penicillin susceptibility. 16 Although some discrepancy in the magnitude of the reduction of log CFU exists between studies which may be due to variation in the bacterial and/or mouse strains used or the initial bacterial load. 11,13,17 Additionally, a time-dependence in the time-kill activity has been shown in the study by Keel et al (2012) and by Xiao et al (2018), which suggest that tedizolid might have a greater anti-staphylococcal activity after exposure at 72 h than at 24 h. 13,17 The concentrations applied in this in vitro study represent those achieved with 200 mg once daily administration of tedizolid phosphate taking into account a protein binding of $87-90% for tedizolid.…”

Efficacy of Human-Simulated Epithelial Lining Fluid Exposure of Meropenem-Nacubactam Combination against Class A Serine β-Lactamase-Producing Enterobacteriaceae in the Neutropenic Murine Lung Infection Model

“…In vivo, antimicrobial activity requires the achievement of sufficient drug levels at the site of infection. For pulmonary infections, assessment of ELF drug concentrations enables more robust predictions of the exposure-response relationships, compared with plasma concentrations (19)(20)(21)(22)(23)(24), but oftentimes data on the drug exposures at these critical sites are limited. In the present study, the availability of data on the meropenem-nacubactam bronchopulmonary pharmacokinetics in healthy adults provided the ability to evaluate the efficacy of the combination using the human-simulated ELF exposures in a murine lung infection model, which improves the translation application of the outcomes from this study to the clinic.…”

“…Previously reported in vitro experiments demonstrated the activity of nacubactam in combination with either piperacillin, cefepime, or meropenem against a variety of ␤-lactamases, including CTX-M-15-and KPC-expressing Enterobacteriaceae strains (24,25). Additionally, the activity of nacubactam (previously OP0595) in combination with cefepime, as the ␤-lactam backbone, against CTX-M-15-positive E. coli (n ϭ 2) and KPC-positive K. pneumonia (n ϭ 2) isolates was evaluated by Morinaka et al in a thigh infection model (25).…”