Effects of the combination of lipopolysaccharide-specific monoclonal antibodies and sparfloxacin against Pseudomonas aeruginosa pneumonia in neutropenic mice

Abstract

The effects of the combination of a murine monoclonal antibody (MAb) (20,26,29). Past studies have supported the possibility that MAb specific for the lipopolysaccharide (LPS) 0 side chain of P. aeruginosa, which has serotype-specific opsonic activity, is a possible candidate for the treatment of P. aeruginosa pneumonia (5,16,19,30). Although a previous investigator (18) indicated that neutropenia adversely affects the therapeutic efficacy of antibody in pseudomonal pneumonia, hyperimmune intravenous immunoglobulin used in conjunction with tobramycin was shown to be efficacious against this disease in neutropenic animals. More recently, Collins and colleagues (2) showed a beneficial effect of combination therapy with a murine immunoglobulin Gl (IgGl) LPSreactive MAb and oral ciprofloxacin in a leukopenic rat model of systemic pseudomonal infection. Therefore, combination therapy with LPS-specific MAbs and antimicrobial agents appears to be an important strategy for treating P. aeruginosa pneumonia in neutropenic patients.It has been demonstrated that several quinolone derivatives are useful in the treatment of P. aeruginosa pneumonia in normal and neutropenic guinea pigs (4, 9, 27). Sparfloxacin (AT-4140) is a newly developed quinolone for oral use that has broad and potent antibacterial activity (14). This compound is characterized by its excellent tissue penetration and long half-life in plasma and tissues (13). Furthermore, sparfloxacin is bactericidal for P. aeruginosa at a * Corresponding author. concentration near the MIC and can be used prophylactically for fatal P. aeruginosa pneumonia in mice (10, 14).Our study was designed to evaluate the efficacy of an LPS-specific IgG3 MAb in conjunction with a suboptimal dose of oral sparfloxacin in a neutropenic mouse model of P. aeruginosa pneumonia. MATERIALS AND METHODSReagents. Cyclophosphamide (Endoxan) was provided by Shionogi & Co., Ltd., Osaka, Japan. Sparfloxacin was provided in powder form by Dainippon Pharmaceutical Co., Ltd., Osaka, Japan. Prior to use, sparfloxacin was suspended in 0.5% tragacanth gum (Nacalai Tesque, Inc., Tokyo, Japan) for oral administration.Bacteria and LPS.

Therapeutic effects of a human antiflagella monoclonal antibody in a neutropenic murine model of Pseudomonas aeruginosa pneumonia

“…Administration of human and murine IgG antiflagella MAbs 1 h postchallenge also saved mice when as little as 1 to 2 ,ug per mouse was used (28,29). A similarly high dose of anti-LPS MAb was previously required for protection in the neutropenic pneumonia model (20), suggesting the relative stringency of the model as far as antibody-mediated protection is concerned.…”

“…A neutropenic murine model ofP. aeruginosa pneumonia was used as described previously (20). Five-week-old specific-pathogenfree female Slc:ICR mice were obtained from Shizuoka Agricultural Cooperation Associations for Laboratory Animals, Shizuoka, Japan.…”

“…Lungs were removed aseptically and were homogenized in 9 ml of sterile saline per g of lung tissue prior to culture. Bronchoalveolar lavage was performed as described previously (20). More than 97% of the cells in the lavage fluid from neutropenic mice 12 h after challenge were found to be alveolar macrophages (AMs).…”

“…Sparfloxacin acts synergistically with a murine LPS-specific MAb against Pseudomonas pneumonia in neutropenic mice (20). The present study was designed to compare the protective activity of a human anti-flagella MAb with that of human anti-LPS MAb in a neutropenic mouse model of P. aeruginosa pneumonia and to examine the antibacterial interaction between the antiflagella MAb and sparfloxacin in this model.…”

Airway Interleukin‐8 in Elderly Patients with Bacterial Lower Respiratory Tract Infections

“…We also demonstrated that human recombinant IL-8 at a range of 6.25 to 25 ng/ml enhanced the opsonophagocytic killing of P. aeruginosa It-1 strain by human neutrophils in a dose-dependent manner. The bactericidal action was complement-dependent, and mediated by a serotype-specific, anti-LPS MAb (13). This range of IL-8 was shown to be clinically achievable in sputum samples or BAL fluids from patients with pneumonia or CAD (14,16,17).…”