A murine model of diarrhea, growth impairment and metabolic disturbances with Shigella flexneri infection and the role of zinc deficiency.

Shigella is one of the major enteric pathogens worldwide. We present a murine model of S. flexneri infection and investigate the role of zinc deficiency (ZD). C57BL/6 mice fed either standard chow (HC) or ZD diets were pretreated with an antibiotic cocktail and received S. flexneri strain 2457T orally. Antibiotic pre-treated ZD mice showed higher S. flexneri colonization than non-treated mice. ZD mice showed persistent colonization for at least 50 days post-infection (pi). S. flexneri-infected mice showed significant weight loss, diarrhea and increased levels of fecal MPO and LCN in both HC and ZD fed mice. S. flexneri preferentially colonized the colon, caused epithelial disruption and inflammatory cell infiltrate, and promoted cytokine production which correlated with weight loss and histopathological changes. Infection with S. flexneri ΔmxiG (critical for type 3 secretion system) did not cause weight loss or diarrhea, and had decreased stool shedding duration and tissue burden. Several biochemical changes related to energy, inflammation and gut-microbial metabolism were observed. Zinc supplementation increased weight gains and reduced intestinal inflammation and stool shedding in ZD infected mice. In conclusion, young antibiotic-treated mice provide a new model of oral S. flexneri infection, with ZD promoting prolonged infection outcomes.

A multi-center randomized trial to assess the efficacy of gatifloxacin versus ciprofloxacin for the treatment of shigellosis in Vietnamese children.

BACKGROUND: The bacterial genus Shigella is the leading cause of dysentery. There have been significant increases in the proportion of Shigella isolated that demonstrate resistance to nalidixic acid. While nalidixic acid is no longer considered as a therapeutic agent for shigellosis, the fluoroquinolone ciprofloxacin is the current recommendation of the World Health Organization. Resistance to nalidixic acid is a marker of reduced susceptibility to older generation fluoroquinolones, such as ciprofloxacin. We aimed to assess the efficacy of gatifloxacin versus ciprofloxacin in the treatment of uncomplicated shigellosis in children. METHODOLOGY/PRINCIPAL FINDINGS: We conducted a randomized, open-label, controlled trial with two parallel arms at two hospitals in southern Vietnam. The study was designed as a superiority trial and children with dysentery meeting the inclusion criteria were invited to participate. Participants received either gatifloxacin (10 mg/kg/day) in a single daily dose for 3 days or ciprofloxacin (30 mg/kg/day) in two divided doses for 3 days. The primary outcome measure was treatment failure; secondary outcome measures were time to the cessation of individual symptoms. Four hundred and ninety four patients were randomized to receive either gatifloxacin (n=249) or ciprofloxacin (n=245), of which 107 had a positive Shigella stool culture. We could not demonstrate superiority of gatifloxacin and observed similar clinical failure rate in both groups (gatifloxacin; 12.0% and ciprofloxacin; 11.0%, p=0.72). The median (inter-quartile range) time from illness onset to cessation of all symptoms was 95 (66-126) hours for gatifloxacin recipients and 93 (68-120) hours for the ciprofloxacin recipients (Hazard Ratio [95%CI]=0.98 [0.82-1.17], p=0.83). CONCLUSIONS: We conclude that in Vietnam, where nalidixic acid resistant Shigellae are highly prevalent, ciprofloxacin and gatifloxacin are similarly effective for the treatment of acute shigellosis.

[Effects of Huoxiang Zhengqi liquid on enteric mucosal immune responses in mice with Bacillus dysenteriae and Salmonella typhimurium induced diarrhea].

OBJECTIVE: To explore the effects of Huoxiang Zhengqi liquid (HXZQ) on enteric mucosal immune responses in mice with Bacillus dysenteriae and Salmonella typhimurium induced diarrhea (BSD). METHOD: Mice were randomly divided into four groups with 10 mice in each group: control group (control), BSD group, Huoxiang Zhengqi liquid treated BSD groups at high dosage and low dosage (HXZQ high, HXZQ low). HXZQ was administrated from the day of diarrhea induction at dosage of 5.21 g kg(-1) and 0.52 g kg (-1) respectively. Peyer's patch and periphery lymphocytes were prepared for flow cytometry, and level of TNF-alpha in periphery and enteric tissue homogenate were determined with ELISA. Student's t-test was used for statistics. RESULT: Mice in BSD group started showing continuous diarrhea at the day of induction till the fourth day when the mice were sacrificed. Diarrhea in the mice of HXZQ high and low groups lasted for 36 and 54 h respectively. There were more CD4+ and CD8+ cells in periphery, less CD4+ cells in peyer's patch in BSD mice comparing to normal mice. In peyer's patch, there were more CD8+ cells in mice in HXZQ high and low groups and more CD4+ in mice in HXZQ high group. Higher level TNF-alpha in periphery and intestinal tissue homogenate in BSD group were observed. Mice in HXZQ high group showed the decreased level TNF-alpha in periphery and enteric tissue homogenate. CONCLUSION: The immune regulation on peyer's patch CD4+ and CD8+ cells and suppression on TNF-alpha level in enteric homogenate might partially explain the effect of HXZQ on improvement of BSD.

Enteric protein loss and intestinal permeability changes in children during acute shigellosis and after recovery: effect of zinc supplementation.

The effect of zinc supplementation on intestinal permeability changes and protein loss was studied in 32 children aged between 1 and 12 years during bouts of acute shigellosis and after recovery. An intestinal permeability test and then a 48 hour balance study were performed on all patients. They were then blindly assigned to receive vitamin B syrup either with or without zinc acetate (15 mg/kg per day) for a month. All patients received a five day course of nalidixic acid. The balance study was repeated during convalescence and follow up, but a permeability test was done only at follow up after one month. Intestinal permeability, expressed as a urinary lactulose:mannitol excretion ratio, improved significantly (p = 0.001) along with a significant increase (p = 0.005) in mannitol excretion in the zinc supplemented children, suggesting a resolution of small bowel mucosal damage. The latter was associated with a higher coefficient of nitrogen absorption (p = 0.03), suggesting a possible role of zinc in the treatment of shigellosis. Enteric protein loss, as assessed by faecal alpha 1 antitrypsin clearance, was not influenced by zinc supplementation.

Effect of antibiotics on food intake and absorption of nutrients for children with diarrhea due to Shigella.

The effect of antibiotic therapy on intake of food and absorption of nutrients for 19 male children aged 1-5 years with suspected shigella infection was studied. The children were admitted to the hospital with acute diarrhea, high fever, abdominal pain, and greater than or equal to 25 red blood cells and white blood cells per high-power field in the stool. Microbiologic diagnosis was made within 48 hours of admission. On the basis of clinical and microbiologic criteria, children were classified as having mild or severe infection. Ten children with mild infection did not receive antibiotics, whereas nine children with severe infection were treated with ampicillin. After the children were rehydrated, a 72-hour balance study was carried out during the acute stage of infection with Shigella and was repeated 2 weeks after recovery. The levels of consumption of food and absorption of nutrients were estimated. During the acute stage of infection, such levels were higher for the children treated with antibiotics than for the untreated group. During the recovery phase, the levels of intake of food and absorption of nutrients were equal for both groups. Thus, children who are treated with appropriate antibiotics not only may recover from infection with Shigella more rapidly, but they also may be able to absorb nutrients more efficiently.