Abstract
Pseudomonas aeruginosa (P. aeruginosa) infections are associated with considerable morbidity and mortality in immunocompromised patients due to antibiotic resistance. Therefore, we investigated the efficacy of the anti-P. aeruginosa serotype O11 lipopolysaccharide monoclonal antibody Panobacumab in a clinically relevant murine model of neutropenia induced by cyclophosphamide and in combination with meropenem in susceptible and meropenem resistant P. aeruginosa induced pneumonia. We observed that P. aeruginosa induced pneumonia was dramatically increased in neutropenic mice compared to immunocompetent mice. First, Panobacumab significantly reduced lung inflammation and enhanced bacterial clearance from the lung of neutropenic host. Secondly, combination of Panobacumab and meropenem had an additive effect. Third, Panobacumab retained activity on a meropenem resistant P. aeruginosa strain. In conclusion, the present data established that Panobacumab contributes to the clearance of P. aeruginosa in neutropenic hosts as well as in combination with antibiotics in immunocompetent hosts. This suggests beneficial effects of co-treatment even in immunocompromised individuals, suffering most of the morbidity and mortality of P. aeruginosa infections.
Highlights
P. aeruginosa is a virulent pathogen leading to a broad range of acute and chronic infections
We observed that upon CP treatment and after infection, inflammatory cell recruitment in Broncho-alveolar lavage fluid (BALF) was greatly reduced (Figure 3A), reaching 90% diminution for neutrophils (Figure 3B), which is consistent with the systemic leucopenia we described in Figure 1; in which we do not observe any effect of Panobacumab on the recruited cell number
We established in immunocompetent animals a clear benefit for the treatment of P. aeruginosa pneumonia with Panobacumab leading to a reduction in bacterial load in the lungs and enhanced survival benefit [18]
Summary
P. aeruginosa is a virulent pathogen leading to a broad range of acute and chronic infections. In addition to the reduction of therapeutic options, antibiotic resistance to P. aeruginosa has an increasing impact on patient mortality and hospitalization cost. Panobacumab is an IgM/κ monoclonal antibody directed against the LPS O-polysaccharide moiety of P. aeruginosa serotype IATS O11 It has been recently characterized in vitro [17] and its safety and efficacy has been demonstrated in mice [18] and humans [19]. We investigate the efficacy of Panobacumab treatment in various experimental models of P. aeruginosa that mimic clinical settings encountered among P. aeruginosa-infected patients. We studied the effect of Panobacumab in the presence of Meropenem, a prototypal antibiotic primarily administered after detection of a P. aeruginosa infection in a clinical situation. Panobacumab-induced reduction of acute pneumonia is still effective in Meropenem-resistant P. aeruginosa pneumonia
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