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Bacterial membrane vesicles from Acinetobacter baumannii induced by ceftazidime are more virulent than those induced
Chun-Hsiang Chiu1,2, Yi-Tzu Lee3,4, Yu-Chun Lin5,6
1Division of Infectious Diseases and Tropical Medicine, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.
Abstract:
Patients with Acinetobacter baumannii bacteremia treated with antipseudomonal cephalosporins showed higher 14-day mortality than patients treated with antipseudomonal carbapenems. We hypothesized that the bacterial membrane vesicles (BMVs) induced by antipseudomonal cephalosporins are more virulent than BMVs induced by antipseudomonal carbapenems.To simulate the clinical condition with inadequate antimicrobial treatment, carbapenem-resistant A. baumannii was treated with ceftazidime (an antipseudomonal cephalosporin) or imipenem (an antipseudomonal carbapenem) at 1/2 the minimum inhibitory concentration. BMVs and BMV-carried lipopolysaccharide were measured by nanoparticle tracking analysis and western blotting, respectively. Cytokine expression in RAW264.7 macrophages or mice serum induced by the BMVs was determined by ELISA, fluorescent bead-based immunoassay or western blotting. The virulence of the BMVs was assessed in mice. Liquid chromatography tandem-mass spectrometry was used to determine the protein contents of the BMVs.We found that ceftazidime induced a higher number of BMVs (CAZ-BMV), which carried more LPS, and induced higher expression levels of iNOS, IL-1β, and IL-6 in macrophages, higher expression of many cytokines in mice, more neutrophil infiltration in lung interstitium, and higher mortality in mice than imipenem-induced BMVs (IMP-BMV). When adjusted to same amount of LPS, CAZ-BMV still led to higher mortality than IMP-BMV. Proteomic analysis revealed different protein contents in CAZ-BMV and IMP-BMV. In conclusion, A. baumannii BMVs induced by ceftazidime are more virulent than BMVs induced by imipenem.
Insights
Antipseudomonal cephalosporins, unlike carbapenems, induce more virulent bacterial membrane vesicles (BMVs) in Acinetobacter baumannii. These ceftazidime-induced BMVs increase mortality, highlighting potential risks of certain antibiotic treatments.
Area of Science:
- Microbiology
- Immunology
- Pharmacology
Background:
- Acinetobacter baumannii bacteremia patients treated with antipseudomonal cephalosporins exhibit higher mortality than those on carbapenems.
- Bacterial membrane vesicles (BMVs) may contribute to virulence, but their induction by different antibiotic classes is not well understood.
Purpose of the Study:
- To investigate whether antipseudomonal cephalosporins induce more virulent bacterial membrane vesicles (BMVs) than antipseudomonal carbapenems in Acinetobacter baumannii.
- To compare the characteristics and virulence of BMVs induced by ceftazidime and imipenem.
Main Methods:
- Carbapenem-resistant Acinetobacter baumannii was treated with ceftazidime or imipenem at sub-inhibitory concentrations.
- BMV production, lipopolysaccharide (LPS) content, cytokine expression in macrophages and mice, and murine mortality were assessed.
- Proteomic analysis identified protein differences in BMVs.
Main Results:
- Ceftazidime induced significantly more BMVs (CAZ-BMVs) with higher LPS content compared to imipenem-induced BMVs (IMP-BMVs).
- CAZ-BMVs elicited greater pro-inflammatory cytokine (iNOS, IL-1β, IL-6) expression in macrophages and systemic cytokines in mice.
- CAZ-BMVs caused increased neutrophil infiltration and higher mortality in mice, even when normalized for LPS content.
Conclusions:
- BMVs induced by ceftazidime are more virulent than those induced by imipenem in Acinetobacter baumannii.
- The differential virulence is likely due to variations in BMV protein cargo and LPS content, impacting host immune responses.
- These findings suggest that the choice of antibiotic can influence bacterial virulence factor production, potentially affecting patient outcomes.
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