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Bacteremia versus endotoxemia in experimental mouse leukopenia--role of antibiotic chemotherapy
1Department of Microbiology, Molecular Genetics, and Immunology, University of Kansas Medical Center, Kansas City 66160-7832, USA.
Abstract:
Imipenem and ceftazidime have different specificities for penicillin-binding proteins and cause a differential release of lipopolysaccharide (LPS) from gram-negative bacteria in vitro. In studies in mice made leukopenic by the administration of cyclophosphamide, the innate relative resistance to the lethal effects of LPS was not significantly changed, but these animals became highly sensitized to bacterial infection. When leukopenic mice were challenged with graded doses of Escherichia coli O111:B4, an LD50 was achieved at a dose of approximately 10(6) cfu. Administration of either antibiotic resulted in a shift in the LD50 of approximately 500-fold, in contrast to D-galactosamine-treated LPS-sensitized mice, in which a < 10-fold increase in the LD50 was observed with antibiotic therapy. Further, if mice were made LPS-sensitive with D-galactosamine, no differences between leukopenic and normal mice were noted with antibiotic therapy.
Insights
Antibiotics like imipenem and ceftazidime significantly increase survival in leukopenic mice challenged with E. coli. This antibiotic effect is more pronounced than in D-galactosamine-sensitized mice, highlighting altered host defense mechanisms.
Area of Science:
- Microbiology
- Immunology
- Pharmacology
Background:
- Antibiotics exhibit varying specificities for penicillin-binding proteins.
- Antibiotic treatment differentially affects lipopolysaccharide (LPS) release from gram-negative bacteria.
- Cyclophosphamide-induced leukopenia in mice alters susceptibility to bacterial infections and LPS toxicity.
Purpose of the Study:
- To investigate the impact of antibiotic therapy on the survival of leukopenic mice challenged with Escherichia coli.
- To compare the efficacy of antibiotics in leukopenic mice versus D-galactosamine-sensitized mice regarding LPS-induced lethality.
Main Methods:
- Induction of leukopenia in mice using cyclophosphamide.
- Challenging leukopenic and normal mice with graded doses of Escherichia coli O111:B4.
- Administering imipenem or ceftazidime to assess survival rates.
- Comparing results with D-galactosamine-treated LPS-sensitized mice.
Main Results:
- Leukopenic mice showed increased sensitization to bacterial infection but not to LPS lethality.
- Antibiotic administration shifted the LD50 of E. coli by approximately 500-fold in leukopenic mice.
- In D-galactosamine-sensitized mice, antibiotics provided a < 10-fold increase in LD50.
- Antibiotic efficacy was similar in leukopenic and normal D-galactosamine-sensitized mice.
Conclusions:
- Antibiotics significantly enhance survival in leukopenic mice infected with E. coli.
- The protective effect of antibiotics against bacterial infection is more pronounced in leukopenic hosts than in LPS-sensitized hosts.
- Host immune status, specifically leukopenia, significantly modulates the therapeutic outcome of antibiotic treatment against gram-negative bacterial infections.