Bovine antibodies targeting primary and recurrent Clostridium difficile disease are a potent antibiotic alternative

Melanie L Hutton,Bliss A Cunningham,Kate E Mackin,Julian I Rood,Shelley A Lyon,Dena Lyras,Meagan L James

doi:10.1038/s41598-017-03982-5

Melanie L Hutton, Bliss A Cunningham + Show 5 more

Open Access

https://doi.org/10.1038/s41598-017-03982-5

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Abstract

The increased incidence of antibiotic resistant ‘superbugs’ has amplified the use of broad spectrum antibiotics worldwide. An unintended consequence of antimicrobial treatment is disruption of the gastrointestinal microbiota, resulting in susceptibility to opportunistic pathogens, such as Clostridium difficile. Paradoxically, treatment of C. difficile infections (CDI) also involves antibiotic use, leaving patients susceptible to re-infection. This serious health threat has led to an urgent call for the development of new therapeutics to reduce or replace the use of antibiotics to treat bacterial infections. To address this need, we have developed colostrum-derived antibodies for the prevention and treatment of CDI. Pregnant cows were immunised to generate hyperimmune bovine colostrum (HBC) containing antibodies that target essential C. difficile virulence components, specifically, spores, vegetative cells and toxin B (TcdB). Mouse infection and relapse models were used to compare the capacity of HBC to prevent or treat primary CDI as well as prevent recurrence. Administration of TcdB-specific colostrum alone, or in combination with spore or vegetative cell-targeted colostrum, prevents and treats C. difficile disease in mice and reduces disease recurrence by 67%. C. difficile-specific colostrum should be re-considered as an immunotherapeutic for the prevention or treatment of primary or recurrent CDI.

Highlights

There is a desperate worldwide need to minimise the use of antibiotics
As colostrum has the potential to be used as a prevention or treatment of primary disease or recurrence, we examined the use of spore, vegetative cell- or TcdB-specific colostrum for the prevention and treatment of C. difficile infections (CDI) in a mouse model of infection
C. difficile-specific antibody titres in colostrum were determined by enzyme-linked immunosorbent assay (ELISA) and in all cases were elevated compared to non-immune bovine colostrum (NI-BC) from unvaccinated cows (Fig. 1)

Summary

Introduction

There is a desperate worldwide need to minimise the use of antibiotics. the treatment of most bacterial infections relies on antibiotic use, resistance has emerged and is one of our most serious global health threats. In support of the approach of targeting TcdB, antibodies against TcdB, but not TcdA, protected piglets from gastrointestinal and systemic signs of CDI when administered intraperitoneally[13] Delivery of both anti-TcdA and anti-TcdB neutralising antibodies to either piglets or humans via systemic routes was not beneficial compared to anti-TcdB antibodies alone[12, 13] and administration of anti-TcdA antibodies alone may return adverse clinical outcomes[13]. Colostrum is resistant to gastrointestinal degradation[20] and, unlike antibiotics, does not adversely disrupt the resident microbiota[17] This concept is relevant for managing the increasing incidence, severity and recurrence of CDI. As colostrum has the potential to be used as a prevention or treatment of primary disease or recurrence, we examined the use of spore-, vegetative cell- or TcdB-specific colostrum for the prevention and treatment of CDI in a mouse model of infection

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Conclusion