Antibodies against β-lactamase can improve ceftazidime treatment of lung infection with β-lactam-resistant Pseudomonas aeruginosa in a rat model of chronic lung infection
Abstract:Ciofu O, Bagge N, Høiby N. Antibodies against β-lactamase can improve ceftazidime treatment of lung infection with β-lactam-resistant Pseudomonas aeruginosa in a rat model of chronic lung infection. APMIS 2002;110:881–91.
To test the hypothesis that antibodies against the chromosomal β-lactamase of Pseudomonas aeruginosa (aβab) might act as β-lactamase inhibitors in patients with cystic fibrosis and chronic lung infection with P. aeruginosa, we compared in a rat model of chronic lung infection the efficacy of treatment with ceftazidime in β-lactamase-immunized (group I) and non-immunized (group II) rats. Chronic lung infection was established with alginate-embedded P. aeruginosa producing high amounts of β-lactamase in 133 Lewis rats. Prior to infection, group I (66 rats) was immunized three times at 2-week intervals with purified β-lactamase in incomplete Freund's adjuvant (IFA) and group II (67 rats) received IFA. Ceftazidime treatment was initiated after challenge and continued for 10 days, after which the rats were sacrificed and the lung bacteriology and pathology were analysed. Rat serum was analysed for the β-lactamase inhibitory activity and aβab-specific IgG and IgG subclasses titres. β-lactamase inhibitory activity was found only in sera of rats belonging to group I and it was used to divide these rats into two subgroups: rats whose sera inhibited ≥75% of β-lactamase activity (responders) and rats whose sera inhibited ≤25% of β-lactamase activity (non-responders). The responder subgroup had significantly smaller pathological areas in the lungs and lower cfu/ml lung homogenate compared to the non-immunized group (p=0.02 and p=0.01, respectively) and compared to the non-responder subgroup (p=0.008 and p=0.0001, respectively). On the day of challenge, significantly higher titres of aβab-specific IgG and IgG subclasses antibodies were found in the responders compared to the non-responders (p < 0.0001). In the responder subgroup the avidity of IgG aβab was significantly higher than in the non-responder subgroup (p=0.0003). Our study showed that aβab with β-lactamase inhibitory activity raised by immunization with β-lactamase can improve the outcome of treatment with ceftazidime of resistant P. aeruginosa in a rat model of chronic lung infection.
Document Type: Research Article
Affiliations: Institute for Medical Microbiology and Immunology, University of Copenhagen, Copenhagen, Denmark
Publication date: 2002-12-01