Prolonged treatment with antibiotics is a risk factor for systemic candidiasis. By affecting overall bacterial burden in the gut and depletion of antagonistic bacteria, antibiotic treatment reduces colonization resistance and thereby promotes fungal overgrowth. As the gut is an important source for translocation of Candida into the blood stream, high intestinal fungal burden increases the likelihood of translocation and subsequent dissemination. We hypothesized that antibiotic treatment might additionally affect host susceptibility by impacting tissue physiology or immune responses to infection.

To test this hypothesis, we systemically infected mice by intravenous injection of C. albicans. Pretreatment with a combination of antibiotics led to significantly reduced survival in specific-pathogen free (SPF) mice, indicating that antibiotic treatment indeed affects host susceptibility. This effect was reproducible across SPF mice that differed in their microbiome composition prior to treatment. However, antibiotics had no effect on the susceptibility of germ free mice, suggesting that changes in the microbiota, rather than a direct impact on host cell physiology, are responsible for the negative impact of antibiotics on host resistance.

Immunophenotyping revealed a profound impact of antibiotic treatment on immune cell numbers in different compartments, cytokine production after infection, and the antifungal efficacy of innate immune cells. The later is likely to explain the significantly higher renal fungal burden observed in antibiotic-treated mice two days after infection.

Importantly, intestinal colonization with C. albicans prior to infection, resembling the situation in patients, abrogates antibiotic-induces susceptibility differences, but antibiotic treatment of colonized mice leads to stronger Th17 responses and increased amounts of C. albicans-specific IgG. This could lead to increased immunopathology in hosts that are not able to clear the infection.