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Published on: October 29, 2020
Mechanism of therapeutic effectiveness of cefixime against typhoid fever
Y Matsumoto1, A Ikemoto, Y Wakai
1Medicinal Biology Research Laboratories, Fujisawa Pharmaceutical Co., Ltd., Osaka, Japan. yoshimi_matsumoto@po.fujisawa.co.jp
Abstract:
beta-Lactams have been considered ineffective against organisms growing inside mammalian cells because of their poor penetration into cells. However, cefixime has been shown to be clinically effective against typhoid fever. The probable mechanism of therapeutic effectiveness of cefixime against typhoid fever was investigated using Salmonella enterica serovar Typhimurium instead of S. enterica serovar Typhi both in a cellular and in a mouse infection model. Cefixime was able to inhibit the growth of serovar Typhimurium inhabiting monocyte-derived THP-1 cells. Elongation of serovar Typhimurium in THP-1 cells was observed microscopically. Apparent morphological changes of serovar Typhimurium in THP-1 cells were also observed by electron microscopy. The concentration of cefixime inside THP-1 cells was almost half (46 to 48%) of the concentration outside the cells when serovar Typhimurium coexisted in the solution. The length of time after oral dosing (8 mg/kg) that cefixime was present-calculated from levels in serum-at a concentration above the MIC at which 90% of the serovar Typhi organisms inside human cells were inhibited was presumed to be more than 12 h. Cefixime also showed excellent activity in the mouse systemic and oral infection models based on infections caused by serovar Typhimurium. It is concluded that a fair amount of cefixime can enter mammalian cells and inhibit the growth of bacteria inside cells when the bacteria are sensitive enough to cefixime, as are serovars Typhimurium and Typhi.
Insights
Cefixime effectively inhibits intracellular Salmonella growth within mammalian cells, challenging the notion that beta-lactams are ineffective against intracellular bacteria. This study demonstrates cefixime
Area of Science:
- Pharmacology
- Microbiology
- Cell Biology
Background:
- Beta-lactam antibiotics are generally considered ineffective against intracellular bacteria due to poor cell penetration.
- Cefixime has demonstrated clinical efficacy against typhoid fever, suggesting intracellular activity.
- The mechanism of cefixime's effectiveness against intracellular Salmonella enterica serovar Typhi remains unclear.
Purpose of the Study:
- To investigate the probable mechanism of cefixime's therapeutic effectiveness against intracellular Salmonella.
- To evaluate cefixime's ability to penetrate mammalian cells and inhibit intracellular bacterial growth.
Main Methods:
- Utilized Salmonella enterica serovar Typhimurium in a cellular infection model with THP-1 cells.
- Employed microscopy and electron microscopy to observe bacterial morphology and growth within cells.
- Quantified intracellular cefixime concentrations and assessed its presence in serum over time.
Main Results:
- Cefixime successfully inhibited the growth of Salmonella Typhimurium within THP-1 cells.
- Microscopic analysis revealed bacterial elongation and morphological changes inside cells.
- Intracellular cefixime concentration reached 46-48% of extracellular levels, with sustained therapeutic levels in serum.
Conclusions:
- Cefixime can effectively penetrate mammalian cells and inhibit intracellular bacterial growth.
- The findings support cefixime's utility against intracellular Salmonella infections, including typhoid fever.
- Bacterial sensitivity to cefixime is crucial for its intracellular efficacy.
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