Mechanism of therapeutic effectiveness of cefixime against typhoid fever
Mechanism of therapeutic effectiveness of cefixime against typhoid fever
复制标题
DOI：
10.1128/aac.45.9.2450-2454.2001
复制
发表时间：
2001-09-01
影响因子：
4.9
通讯作者：
Matsumo, K
中科院分区：
文献类型：
--
作者：
Matsumoto, Y;Ikemoto, A;Matsumo, K
β-内酰胺类药物被认为对在哺乳动物细胞内生长的生物无效，因为它们对细胞的渗透性很差。然而，头孢克新已被证明在临床上对伤寒有效。用伤寒沙门氏菌代替伤寒沙门氏菌，在细胞模型和小鼠感染模型上研究了头孢克肟治疗伤寒的可能机制。头孢克新能抑制单核细胞来源的THP-1细胞中的鼠伤寒沙门氏菌的生长。显微镜下观察THP-1细胞中鼠伤寒沙门氏菌的伸长。在电子显微镜下观察到THP-1细胞中鼠伤寒沙门氏菌的明显形态变化。当鼠伤寒沙门氏菌共存时，THP-1细胞内的头孢克肟浓度几乎是细胞外浓度的一半(46%~48%)。口服头孢克新(8 mg/kg)后，根据血清中的浓度计算，在高于MIC的浓度下，人体细胞内90%的伤寒杆菌被抑制的时间长度被推定为超过12h。在基于鼠伤寒杆菌感染的小鼠全身和口腔感染模型中，头孢克肟也显示出良好的活性。结论是，当细菌对头孢克肟足够敏感时，相当数量的头孢克肟可以进入哺乳动物细胞并抑制细胞内细菌的生长，小鼠伤寒杆菌和伤寒杆菌也是如此。
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.