tedizolid and Pneumonia--Staphylococcal

Few antibiotics are approved to treat Staphylococcus aureus pneumonia. Tedizolid is an oxazolidinone with potent in vitro activity against S. aureus and is currently under investigation for hospital-acquired and ventilator-associated bacterial pneumonia. Limited data exist on the comparative efficacy of tedizolid versus current first-line treatments vancomycin and linezolid in the compromised host. Our objective was to compare the efficacy of human-simulated epithelial lining fluid (ELF) exposures of tedizolid, linezolid and vancomycin against S. aureus in neutropenic and immunocompetent murine pneumonia models.. Eight S. aureus isolates (four MRSA and four MSSA) were studied. Neutropenic and immunocompetent mice were inoculated intranasally with bacterial suspensions of 107 and 109 cfu/mL, respectively, then treated for up to 72 h with model-specific regimens of tedizolid, linezolid and vancomycin simulating human ELF exposures after clinical doses. Mice were sacrificed at 24, 48 or 72 h and changes in log10 cfu/lungs were compared with 0 h controls.. Mean bacterial burdens at 0 h were 5.81 and 8.17 log10 cfu/lungs for neutropenic and immunocompetent mice, respectively, and increased at 24 h in the absence of antibiotic treatment to 7.97 and 9.00 log10 cfu/lungs, respectively. In neutropenic and immunocompetent mice, tedizolid was associated with bacterial density changes of -2.69 ± 0.62 and -3.57 ± 0.88 log10 cfu/lungs at 72 h, respectively. In both models, tedizolid treatment produced greater bacterial reductions than vancomycin and was not statistically significantly different from linezolid.. Human-simulated ELF exposures of tedizolid demonstrated sustained efficacy in compromised and competent models of pneumonia. Validation of these findings in patients is warranted.

Topics: Animals; Anti-Bacterial Agents; Colony Count, Microbial; Disease Models, Animal; Female; Linezolid; Lung; Mice, Inbred BALB C; Neutropenia; Oxazolidinones; Pneumonia, Staphylococcal; Protein Synthesis Inhibitors; Tetrazoles; Treatment Outcome; Vancomycin

The antibacterial efficacies of tedizolid phosphate (TZD), linezolid, and vancomycin regimens simulating human exposures at the infection site against methicillin-resistant Staphylococcus aureus (MRSA) were compared in an in vivo mouse pneumonia model. Immunocompetent BALB/c mice were orally inoculated with one of three strains of MRSA and subsequently administered 20 mg/kg TZD every 24 hours (q24h), 120 mg/kg linezolid q12h, or 25 mg/kg vancomycin q12h over 24 h. These regimens produced epithelial lining fluid exposures comparable to human exposures observed following intravenous regimens of 200 mg TZD q24h, 600 mg linezolid q12h, and 1 g vancomycin q12h. The differences in CFU after 24 h of treatment were compared between control and treatment groups. Vehicle-dosed control groups increased in bacterial density an average of 1.1 logs. All treatments reduced the bacterial density at 24 h with an average of 1.2, 1.6, and 0.1 logs for TZD, linezolid, and vancomycin, respectively. The efficacy of TZD versus linezolid regimens against the three MRSA isolates was not statistically different (P > 0.05), although both treatments were significantly different from controls. In contrast, the vancomycin regimen was significantly different from TZD against one MRSA isolate and from linezolid against all isolates. The vancomycin regimen was less protective than either the TZD or linezolid regimens, with overall survival of 61.1% versus 94.7% or 89.5%, respectively. At human simulated exposures to epithelial lining fluid, vancomycin resulted in minimal reductions in bacterial counts and higher mortality compared to those of either TZD or linezolid. TZD and linezolid showed similar efficacies in this MRSA pneumonia model.

Topics: Acetamides; Administration, Oral; Animals; Anti-Bacterial Agents; Colony Count, Microbial; Disease Models, Animal; Drug Administration Schedule; Female; Humans; Injections, Intravenous; Linezolid; Methicillin-Resistant Staphylococcus aureus; Mice; Mice, Inbred BALB C; Oxazolidinones; Pneumonia, Staphylococcal; Survival Rate; Tetrazoles; Vancomycin