Effect of Linezolid on the 50% Lethal Dose and 50% Protective Dose in Treatment of Infections by Gram-Negative Pathogens in Naive and Immunosuppressed Mice and on the Efficacy of Ciprofloxacin in an Acute Murine Model of Septicemia

Abstract

cMurine models of infection were used to study the effect of linezolid on the virulence of Gram-negative bacteria and to assess potential pharmacodynamic interactions with ciprofloxacin in the treatment of these infections, prompted by observations from a recent clinical trial. Naive and immunosuppressed mice were challenged with Klebsiella pneumoniae 53A1109, K. pneumoniae GC6658, and Pseudomonas aeruginosa UC12120 in acute sepsis and pulmonary infection models, using different serial dilutions of these pathogens (groups of 8 animals each). Linezolid (100 mg/kg/dose) was administered orally at 0.5 and 4.0 h postchallenge in the sepsis model and at 4 h postchallenge followed by 2 days of twice-daily treatment in the pulmonary model. Further, ciprofloxacin alone and in combination with oral linezolid was investigated in the sepsis model. Survival was assessed for 4 and 10 days postchallenge in the systemic and respiratory models, respectively. The data were fitted to a nonlinear regression analysis to determine 50% lethal doses (LD 50 s) and 50% protective doses (PD 50 s). A clinically relevant, high-dose regimen of linezolid had no significant effect on LD 50 in these models. This lack of effect was independent of immune status. A combination of oral ciprofloxacin with linezolid yielded lower PD 50 s than oral ciprofloxacin alone (ciprofloxacin in combination, 8.4 to 32.7 mg/kg; oral ciprofloxacin, 39.4 to 88.3 mg/kg). Linezolid did not improve the efficacy of subcutaneous ciprofloxacin (ciprofloxacin in combination, 2.0 to 2.4 mg/kg; subcutaneous ciprofloxacin, 2.0 to 2.8 mg/kg). In conclusion, linezolid does not seem to potentiate infections caused by Gram-negative pathogens or to interact antagonistically with ciprofloxacin.

Neuroprotective potential of Linezolid: a quantitative and distribution study via mass spectrometry

“…The higher ratios are suggestive of non-specific binding to the hydrophobic brain tissue, with repeated dosing. The lowest values were reached after week 4 (23.58 ± 6.1 lg/ml), these values were still significantly higher than the MIC's for a number of bacterial agents which cause central nervous system infections (Ager and Gould 2012;Marra et al 2012). This is demonstrated by studies which have showed the drug's efficacy against a large number of resistant CNS infections.…”

“…For the short term study, the animals received a single dose of LIN (100 mg/kg) which was prepared in 10 % DMSO, this was based on a previous study in which this amount was well tolerated in rodents and showed excellent kill characteristics in a murine model of septicaemia (Marra et al 2012). In the short term study, female Sprague-Dawley rats (with ad libitum access to food and water throughout the study) were given a single dose of LIN via oral gavage thereafter they were periodically sacrificed (0, 0.25, 0.5, 1, 2, 4, 6, 8 and 24 h; n = 3 per time-point) post-dose to determine the short term plasma and brain pK profile of LIN.…”

The inverse autotransporters of Yersinia ruckeri, YrInv and YrIlm, contribute to biofilm formation and virulence

“…Larvae were considered dead if they repeatedly did not respond to touch. The median lethal dose (LD 50 ) was calculated by nonlinear regression analysis using GraphPad Prism 5 (GraphPad, La Jolla) as (Marra et al ., 2012; Tietgen et al ., 2018).…”

Nafamostat mesilate inhibits linezolid metabolism via its antioxidant effects

“…The method of LZD administration was based on a previous report. 12 Mice were administered 1 mL of LZD suspension (100 mg kg −1 , subcutaneous injection), 0.2 mL of NM suspension (30 mg kg −1 , intraperitoneal injection), or 0.2 mL of saline. Intraperitoneal injection of NM or saline was performed at 1 hour, 2 hours, 3 hours, and 4 hours after administration of LZD.…”