Pharmacodynamic and Protective Properties of a Murine Lipopolysaccharide‐Specific Monoclonal Antibody in Experimental <i>Pseudomonas aeruginosa</i> Pneumonia in Mice

Antimicrob Agents Chemother

et al. 1993

Human immunoglobulin G1 (IgG1) monoclonal antibodies (MAbs) reactive with type-specific Pseudomonas aeruginosa lipopolysaccharide (LPS) and flagella were compared for their protective activities against Fisher immunotype 2 P. aeruginosa pneumonia in neutropenic mice. The activity of the antiflagella MAb at a dose of 500 micrograms per mouse was comparable to that of the anti-LPS MAb at the same dose. In vivo protection was correlated with bacterial density in the lung tissue and blood of infected mice. In vitro data suggested that the protective activity of the antiflagella MAb was due more to inhibition of bacterial motility than to opsonophagocytosis of bacteria by alveolar macrophages. In contrast, the protective activity of the anti-LPS MAb was primarily related to alveolar macrophage-mediated opsonophagocytosis. Antiflagella MAb at a dose of 500 micrograms combined with oral sparfloxacin at a subtherapeutic dose of 62.5 micrograms produced a significant increase in survival (P < 0.05) compared with that produced by either agent alone or no treatment. The additive effects between the antiflagella MAb and sparfloxacin at sub-MICs on the inhibitory effects of bacterial motility supported the in vivo effect of the combination. These data suggest that human isotype-matched antiflagella and anti-LPS MAbs have similar protective activities against Pseudomonas pneumonia in neutropenic mice, despite discrete mechanisms of antibody-matched protection. In addition, in vivo synergy was demonstrated between antiflagella MAb and sparfloxacin in this model.

mentioning

confidence: 99%

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

Antimicrob Agents Chemother

et al. 1993

“…1). On day 4 after the first dose of cyclophoswith heat-inactivated mouse ascitic fluid containing MAb P. aeruginosa pneumonia was produced in the 1D3 (final concentration, 5 ,ug/ml) were resuspended in nic mice by intratracheal challenge with P. aerugiHanks' balanced salt solution containing 0.1% gelatin, 0.15 by a previously described procedure (16). Infected mM CaCl1 and 1.0 mM MgCl2 (GHBSS +) to a cell density re monitored for survival for 7 days.…”

Section: Methodsmentioning

confidence: 99%

“…Although substantial lung penetration of an IgG3 MAb with similar specificity has VOL. 36, 1992 been demonstrated (16), effective treatment of P. aeruginosa pneumonia with LPS-specific MAb alone is difficult in neutropenic hosts.…”

Section: Methodsmentioning

confidence: 99%

“…Recently, considerable interest in passive immune therapy by the use of a monoclonal antibody (MAb) against P. aeruginosa infections has developed (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.…”

mentioning

confidence: 99%

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

Antimicrob Agents Chemother

et al. 1992

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.

“…Pneumonia was produced by intratracheal challenging with P aeruginosa according to a published method (17), and the 50% lethal dose (LD50 ) for this strain was determined to be 1.9 X 107 cfu. This study demonstrated that 6 X 107 cfu was the minimum inoculum which resulted in uniformly fatal pneumonia in mouse model.…”

Section: Methodsmentioning

confidence: 99%

Endogenous Tumor Necrosis Factor (TNF) α Mediates Neutrophil Accumulation at the Mid‐Phase of a Murine Model of Pseudomonas aeruginosa Pneumonia

Microbiology and Immunology

et al. 1997

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