PII-039 - PLERIXAFOR AS PATHOGEN AGNOSTIC PROPHYLAXIS OR ADVUVANT TREATMENT

M. Evans¹, D. Caridha², A. Kress², D. Selig², R. Racharaks², M. Demeese², J. DeMeese², T. Langowski², R. Nadeau², J. DeLuca²; ¹Walter Reed Army Institute of Research, Silver Spring, MD, USA, ²Walter Reed Army Institute of Research.

Background: Plerixafor is an (2008) FDA-approved CXCR4 antagonist; an immune stimulant used for stem cell collection that has been well tolerated by hundreds in the general population. Investigator-led studies show plerixafor resolved ongoing viral and bacterial infections and decreased the incidence of new infections in patients with immunodeficiency. We investigated whether plerixafor’s potential could be expanded in mice without aberrant CXCR4 signaling.

Methods: The murine neutropenic thigh infection model is an industry standard. We compared plerixafor as a prophylaxis, sole treatment and treatment adjuvant with antibiotics to a negative control group. A highly virulent and multi-drug resistant strain of Acinetobacter baumannii (AB5075) was inoculated, 24 hours later thigh biopsy was performed. The primary endpoint was colony forming units (CFUs) per mg of tissue.
Ten mice were in the following groups: vehicle control (1), plerixafor 5 mg/kg 3 days prior to inoculation (2), plerixafor 1 day prior to inoculation (3), plerixafor at inoculation (4), rifampin 2.5 mg/kg alone (5), rifampin 2.5 mg/kg with plerixafor prophylaxis (6), rifampin 2.5 mg/kg with plerixafor adjuvant (7), rifampin 10 mg/kg alone (8), rifampin 10 mg/kg with plerixafor prophylaxis (9) and rifampin 10 mg/kg with plerixafor adjuvant (10).

Results: Groups 1-10 average CFU/gm log averages: 9.86; 8.96; 9.30; 8.98; 8.58; 9.63; 8.29; 8.08; 7.64; 7.84 respectively. Standard deviations were 0.87; 0.41; 0.59; 0.43; 0.57; 0.88; 0.36; 0.67; 0.52; 0.44. ANOVA was performed followed by Dunnett's method. Groups 8, 9 and 10 had significantly less colony forming units. P < 0.01

Conclusion: Despite the trend of decreased bacterial units in the plerixafor groups, high-dose plerixafor does not appear effective in treating or preventing infection of Acinetobacter baumannii.

Our dosing is near that allometrically scaled from the FDA dose and commonly used. The dose for prevention of infection in humans (with WHIM syndrome) is more than 10-fold less. A dose 100 times lower has been shown effective for mice in other infectious diseases. Therefore, our dose may have been excessive.

Recent studies show CXCR4 has a role in T cell activity. T cell activation occurs at 30 hours therefore our model could not assess these effects.

The current study suggests longer studies with likely lower dosing are needed.