|ZHANG, GUODONG - US Department Of Health And Human Services (HHS)|
Submitted to: Antimicrobial Agents and Chemotherapy
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 6/16/2015
Publication Date: 6/22/2015
Publication URL: http://handle.nal.usda.gov/10113/61383
Citation: Skinner, C.B., Patfield, S.A., He, X., Zhang, G. 2015. An in vitro combined antibiotic/antibody treatment eliminates toxicity from Shiga toxin-producing E. coli. Antimicrobial Agents and Chemotherapy. 59(9):5435-5444.
Interpretive Summary: Shiga toxins (Stx) are an important virulence factor for Escherichia coli, a common and potentially deadly bacterial food contaminant. An estimated 100,000 gastrointestinal infections per year can be attributed to E. coli the United States alone. There is currently no widely accepted treatment for Shiga toxin-producting E. coli (STEC) infections due to a combination of antibiotic resistance and antibiotic-induced toxin expression. In this study, we analyzed the efficacy of 22 antibiotics on 40 diverse strains of STEC. Tigecycline was the only antibiotic tested that both inhibited the growth of all STEC strains and reduced the amount of Stx that these strains produced. The combination of tigecycline with monoclonal antibodies that detoxify Stx fully protected a mammalian (green monkey kidney) cell line from STEC. A combined therapy, one that kills the bacteria (tigecycline) and detoxifies the Stx (neutralizing antibodies) could hold great promise as an effective, universal STEC treatment.
Technical Abstract: Background: Treating Shiga toxin-producing Escherichia coli (STEC) gastrointestinal infections is a difficult endeavor. The utility of antibiotics as an STEC treatment is controversial since antibiotic resistance among STEC isolates is widespread and certain antibiotics dramatically increase expression of Shiga toxin (Stx). An important virulence factor, Stx contributes to life-threatening hemolytic uremic syndrome (HUS), which develops in a considerable portion of patients with STEC infections. Understanding the antibiotic resistance profiles of STEC isolates and the Stx induction potential of promising antibiotics are essential in evaluating any antibiotic treatment of STEC. Method and findings: A collection of 40 O157:H7 and non-O157 STEC (including the “big six”) isolates was evaluated for their resistance against 24 antibiotics using an antibiotic array. Tigecycline was effective in inhibiting all the tested STEC isolates, and also modestly inhibited production of Stx. In combination with neutralizing antibodies to Stx1 and Stx2, the tigecycline/antibody treatment fully protected Vero cells from Stx toxicity, even when the STEC bacteria and Vero cells were co-cultured together. Conclusions: Antibiotics and antibodies have shown promise in the treatment of STEC infections but different strains of STEC have exhibited different antibiotic resistances. Tigecycline appears to be an effective antibiotic against all STEC isolates tested, and the combination of an antibiotic like tigecycline with neutralizing antibodies presents a promising strategy for future STEC treatments.