Mechanism of therapeutic effectiveness of cefixime against typhoid fever

beta -Lactams have been considered ineffective against organisms growing in side 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 typ hoid fever was investigated using Salmonella enterica serovar Typhimurium i nstead of S. enterica serovar Typhi both in a cellular and in a mouse infec tion 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 change s of serovar Typhimurium in THP-1 cells were also observed by electron micr oscopy. The concentration of cefixime inside THP-1 cells was almost half (4 6 to 48%) of the concentration outside the cells when serovar Typhimurium c oexisted in the solution. The length of time after oral dosing (8 mg/kg) th at cefixime was present-calculated from levels in serum-at a concentration above the MIC at which 90% of the serovar Typhi organisms inside human cell s were inhibited was presumed to be more than 12 h. Cefixime also showed ex cellent activity in the mouse systemic and oral infection models based on i nfections caused by serovar Typhimurium. It is concluded that a fair amount of cefixime can enter mammalian cells and inhibit the growth of bacteria i nside cells when the bacteria are sensitive enough to cefixime, as are sero vars Typhimurium and Typhi.