Mechanism of Therapeutic Effectiveness of Cefixime against Typhoid Fever

Abstract

␤-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 monocytederived 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.

Studies on the therapeutic effect of propolis along with standard antibacterial drug in Salmonella enterica serovar Typhimurium infected BALB/c mice

“…It was proved that a single component of propolis was not as effective as the total extract, which further supported that synergism existed in various compounds of propolis to make effective biological impact [23]. On the other hand, the effectiveness of cefixime was due to its reasonable penetration into the monocytes thus inhibiting the growth of bacteria [24]. …”

An Open Randomized Comparison of Gatifloxacin versus Cefixime for the Treatment of Uncomplicated Enteric Fever

“…The fact that we saw a high overall failure rate associated with cefixime despite all of the strains being fully sensitive in vitro to the drug shows that the mechanism of action of cefixime [21], [22] may not be suited to the eradication of S. Typhi or Paratyphi A from the body or blood, and the poor intracellular penetration into macrophages and reticulo endothelial tissues where the typhoid organisms colonize [16] may be the cause of high failure rates.…”

Pharmacodynamic Evaluation of the Intracellular Activities of Antibiotics against Staphylococcus aureus in a Model of THP-1 Macrophages

“…Macrolides may also suffer from the same effects, but their bacteriostatic character is probably the most critical determinant in their lack of an intracellular killing effect. Conversely, the bactericidal effects of ␤-lactams against intracellular S. aureus when these compounds are used at large extracellular concentrations, as seen here for oxacillin and in previous studies with ampicillin and meropenem (36), not only could be due to the fact that these drugs may reach intracellular concentrations that eventually reach far above their MICs but could also be due to the production of cellular factors that enhance their activities (37,45,67). Our results with linezolid and rifampin require attention, a By use of all data points from antibiotic concentrations of 0.01 to 1,000 times the MIC.…”