Vitamin A supplementation boosts control of antibiotic-resistant Salmonella infection in malnourished mice.

Disseminated disease from non-typhoidalSalmonella entericastrains results in >20% mortality globally. Barriers to effective treatment include emerging multidrug resistance, antibiotic treatment failure, and risk factors such as malnutrition and related micronutrient deficiencies. Individuals in sub-Saharan Africa are disproportionately affected by non-typhoidalS.entericabloodstream infections. To inform a clinical trial in people, we investigated vitamin A as a treatment in the context of antibiotic treatment failure in a mouse model of vitamin A deficiency. Vitamin A-deficient (VAD) mice exhibited higher systemic bacterial levels with a multidrug-resistant clinical isolate in comparison to mice on a control diet. Sex-specific differences in vitamin A deficiency and disseminated infection withS.entericaserotype Typhimurium (S. Typhimurium) were observed. VAD male mice had decreased weight gain compared to control male mice. Further, infected VAD male mice had significant weight loss and decreased survival during the course of infection. These differences were not apparent in female mice. In a model of disseminatedS. Typhimurium infection and antibiotic treatment failure, we assessed the potential of two consecutive doses of vitamin A in alleviating infection in male and female mice on a VAD or control diet. We found that subtherapeutic antibiotic treatment synergized with vitamin A treatment in infected VAD male mice, significantly decreasing systemic bacterial levels, mitigating weight loss and improving survival. These results suggest that assessing vitamin A as a therapy during bacteremia in malnourished patients may lead to improved health outcomes in a subset of patients, especially in the context of antibiotic treatment failure. Author summary Non-typhoidalSalmonellaserotypes generally cause diarrhea in people. However, there are certain factors that make people at risk of developing a more severe infection where the bacteria can enter the blood and cause fever and whole-body symptoms. Patients with this infection are usually hospitalized, and about one in five patients do not survive. The factors that make this bloodstream infection possible include pathogen features like resistance to antibiotics and patient factors like a malnourished state. Better treatments are needed. In this study, the authors assess vitamin A as a treatment during antibiotic treatment failure in a mouse model. Vitamin A-deficient male mice have better outcomes with vitamin A and antibiotic co-therapy, whereas female mice do not benefit. Despite similar levels of bacteria causing infection systemically, female mice show better outcomes in terms of weight loss and survival than male mice overall. This research provides evidence that a clinical study assessing vitamin A as a treatment in people could lead to improved survival for malnourished patients presenting with severe bloodstream infection.