Early-Stage IM Treatment with the Host-Derived Immunostimulant CPDI-02 Increases Curative Protection of Healthy Outbred Mice Against Subcutaneous Infection with Community-Acquired Methicillin-Resistant <i>Staphylococcus aureus</i> USA300
Jason P. Stewart,
Caleb M. Sandall,
Jacob E. Parriott,
Stephen M. Curran,
Russell J. McCulloh,
Donald R. Ronning,
Joy A. Phillips,
Robin Schroeder,
Christy Neel,
Kelly F. Lechtenberg,
Samuel M. Cohen,
Yazen Alnouti,
Sohel Daria,
D. David Smith,
Joseph A. Vetro
Affiliations
Jason P. Stewart
Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE 68198, USA
Caleb M. Sandall
Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE 68198, USA
Jacob E. Parriott
Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE 68198, USA
Stephen M. Curran
Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE 68198, USA
Russell J. McCulloh
Department of Pediatrics, University of Nebraska Medical Center, Omaha, NE 68198, USA
Donald R. Ronning
Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE 68198, USA
Joy A. Phillips
Biology Department, San Diego State University, San Diego, CA 92182, USA
Robin Schroeder
Midwest Veterinary Services, Inc., Oakland, NE 68045, USA
Christy Neel
Midwest Veterinary Services, Inc., Oakland, NE 68045, USA
Kelly F. Lechtenberg
Midwest Veterinary Services, Inc., Oakland, NE 68045, USA
Samuel M. Cohen
Department of Pathology, Microbiology, and Immunology and the Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA
Yazen Alnouti
Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE 68198, USA
Sohel Daria
Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE 68198, USA
D. David Smith
Department of Biomedical Sciences, Creighton University, Omaha, NE 68178, USA
Joseph A. Vetro
Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE 68198, USA
Background/Objectives: Community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) greatly complicates the treatment of skin and soft tissue infections (SSTI). It was previously found that subcutaneous (SQ) treatment with the mononuclear phagocyte (MP)-selective activator complements peptide-derived immunostimulant-02 (CPDI-02; formerly EP67) and increases prophylaxis of outbred CD-1 mice against SQ infection with CA-MRSA. Here, we determined if treatment with CPDI-02 also increases curative protection. Methods: Female CD-1 mice were challenged SQ with CA-MRSA USA300 LAC, then CPDI-02 or inactive scCPDI-02 was administered by a topical, SQ, IM, or IV route at 6 or 24 h post-challenge. Abscess sizes were compared over 10 days and CA-MRSA burden, neutrophils, MP, and pro-inflammatory cytokines were compared in subcutaneous abscesses. CPDI-02 PK and distribution in female CD-1 mice were compared after IM or IV dosing and CPDI-02 toxicity in male and female CD-1 mice was determined by IM dose escalation and repeat IM dosing. Results: Repeat IM treatment starting at 6 h post-challenge decreased maximum abscess surface area, CA-MRSA burden, and time to resolution, whereas repeat treatment by a topical, SQ, or IV route had no effect. Repeat treatment starting at 24 h post-challenge was ineffective by the current routes. Single IM treatment starting at 6 h post-challenge was as effective as repeat IM treatment, increased systemic exposure to CPDI-02, and, in subcutaneous abscesses, initially decreased IL-1β and increased MP. CPDI-02 was tolerated between 130 and 170 mg/kg after IM dose escalation and between 65 and 130 mg/kg after repeat IM dosing with males being more tolerant. Conclusions: Single early-stage IM treatment with CPDI-02 may increase curative protection against SSTI caused by CA-MRSA and/or other pathogens controlled by activated MP.
