Peroral Ciprofloxacin Therapy Impairs the Generation of a Protective Immune Response in a Mouse Model for Salmonella enterica Serovar Typhimurium Diarrhea, while Parenteral Ceftriaxone Therapy Does Not

Abstract

bNontyphoidal Salmonella (NTS) species cause self-limiting diarrhea and sometimes severe disease. Antibiotic treatment is considered only in severe cases and immune-compromised patients. The beneficial effects of antibiotic therapy and the consequences for adaptive immune responses are not well understood. We used a mouse model for Salmonella diarrhea to assess the effects of per os treatment with ciprofloxacin (15 mg/kg of body weight intragastrically 2 times/day, 5 days) or parenteral ceftriaxone (50 mg/kg intraperitoneally, 5 days), two common drugs used in human patients. The therapeutic and adverse effects were assessed with respect to generation of a protective adaptive immune response, fecal pathogen excretion, and the emergence of nonsymptomatic excreters. In the mouse model, both therapies reduced disease severity and reduced the level of fecal shedding. In line with clinical data, in most animals, a rebound of pathogen gut colonization/fecal shedding was observed 2 to 12 days after the end of the treatment. Yet, levels of pathogen shedding and frequency of appearance of nonsymptomatic excreters did not differ from those for untreated controls. Moreover, mice treated intraperitoneally with ceftriaxone developed an adaptive immunity protecting the mice from enteropathy in wild-type Salmonella enterica serovar Typhimurium challenge infections. In contrast, the mice treated intragastrically with ciprofloxacin were not protected. Thus, antibiotic treatment regimens can disrupt the adaptive immune response, but treatment regimens may be optimized in order to preserve the generation of protective immunity. It might be of interest to determine whether this also pertains to human patients. In this case, the mouse model might be a tool for further mechanistic studies.

Efficacy of Cryptdin-2 as an Adjunct to Antibiotics from Various Generations Against Salmonella

“…However, reports of increasing MIC values and subsequent increase in the occurrence of typhoidal salmonellae resistant to ciprofloxacin suggest that it will not remain effective for much longer [20,21]. Furthermore, extended-spectrum cephalosporins such as ceftriaxone are now being used specially for treating children [22,23]. These therapeutic failures have prompted lively research on possible synergism of 27 mm f cefo (20 lg/ml): 20 mm g cryptdin-2 (10 lg/ml) ?…”

Evaluation of Salmonella enterica Serovar Typhimurium TTSS-2 Deficient fur Mutant as Safe Live-Attenuated Vaccine Candidate for Immunocompromised Mice

“…The SPI2-TTSS deficient Salmonella Typhimurium strain has already been established as safe vaccine [13], [14]. Though it gives protective mucosal immunity in C57BL/6 mice but it causes lethal infections in various isogenic immunocompromised mice in our experiments.…”

“…Typhimurium ssaV mutant, showed O-antigen specific responses and were protected from subsequent S . Typhimurium challenge infections [13], [14]. However, in this study, introduction of S. Typhimurium SPI2-T3SS mutant to immune-compromised mice (IL10 −/− , CD40L −/− , iNos −/− ) indicated that the mutant deficient in T3SS-II is not safe enough and caused lethal infections.…”

“…As a measure of mucosal immune response, serum IgG and luminal secretory IgA responses were qualitatively assessed by Western blotting and FACS analysis as described previously [13], [14]. Serum and gut washes from MT12 and MT13 immunized mice groups were collected at 30 days p.v.…”

What Makes A Bacterial Oral Vaccine a Strong Inducer of High-Affinity IgA Responses?

“…Moon et al [97] demonstrated that certain species in the intestinal microbiota can degrade the secretory component of sIgA and thereby reduce the levels of total intestinal sIgA. Further, there are numerous studies suggesting that antibiotic treatment either enhances or inhibits the response to oral vaccines [98][99][100]. The variation observed may be due to a highly complex interplay between live-attenuated strains that are differentially susceptible to antibiotics, differential depletion of microbiota constituents, and direct side-effects of certain antibiotics on mammalian cells.…”