Mechanism of therapeutic effectiveness of cefixime against typhoid fever

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.

FIG. 1

Therapeutic effect of cefixime on a mouse oral infection model. Male 4-week-old BALB/c mice (10/group) were infected orally with 4.4 × 10⁷ CFU of serovar Typhimurium C5 per mouse and were treated orally with cefixime twice a day for 5 days, beginning 3 days after infection.

FIG. 2

Cefixime-induced morphological changes of serovar Typhimurium FP39 inside THP-1 cells. (A) Control; (B) infected THP-1 cells after treatment for 4 h with 0.5 μg of cefixime/ml.

FIG. 3

Cefixime-induced morphological changes of serovar Typhimurium FP39 inside THP-1 cells (transmission electron microscopy). (A) Control; (B) infected THP-1 cells after treatment for 4 h with 0.5 μg of cefixime/ml. →, serovar Typhimurium inside THP-1 cells.

FIG. 4

Bactericidal activity of cefixime for serovar Typhimurium inside THP-1 cells. ——, control; , 1 μg/ml; , 10 μg/ml; , 100 μg/ml.