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

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

<b>Background/Objectives</b>: Community-acquired methicillin-resistant <i>Staphylococcus aureus</i> (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 (...

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Main Authors: 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
Format: Article
Language:English
Published: MDPI AG 2024-12-01
Series:Pharmaceutics
Subjects:
antimicrobial resistance
AMR
antibiotic resistance
ABR
drug-resistant bacteria
antibiotic-resistant bacteria
Online Access:https://www.mdpi.com/1999-4923/16/12/1621
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Summary:<b>Background/Objectives</b>: Community-acquired methicillin-resistant <i>Staphylococcus aureus</i> (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. <b>Methods</b>: 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. <b>Results</b>: 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. <b>Conclusions</b>: 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.
ISSN:1999-4923

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