Treatment and prevention of recurrent Clostridium difficile infection with functionalized bovine antibody-enriched whey in a hamster primary infection model

Hans Jürgen Heidebrecht, William J. Weiss, Mark Pulse, Anton Lange, Karina Gisch, Heike Kliem, Sacha Mann, Michael W. Pfaffl, Ulrich Kulozik, Christoph von Eichel-Streiber

Research output: Contribution to journalArticle

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Abstract

Toxin-induced Clostridium difficile infection (CDI) is a major disease characterized by severe diarrhea and high morbidity rates. The aim with this study was to develop an alternative drug for the treatment of CDI. Cows were repeatedly immunized to establish specific immunoglobulin G and A titers against toxins A (TcdA) and B (TcdB) and against C. difficile cells in mature milk or colostrum. The effect of three different concentrations of anti-C. difficile whey protein isolates (anti-CD-WPI) and the standard of care antibiotic vancomycin were investigated in an animal model of CD infected hamsters (6 groups, with 10 hamsters each). WPI obtained from the milk of exactly the same cows pre-immunization and a vehicle group served as negative controls. The survival of hamsters receiving anti-CD-WPI was 50, 80 and 100% compared to 10 and 0% for the control groups, respectively. Vancomycin suppressed the growth of C. difficile and thus protected the hamsters at the time of administration, but 90% of these hamsters nevertheless died shortly after discontinuation of treatment. In contrast, the surviving hamsters of the anti-CD-WPI groups survived the entire study period, although they were treated for only 75 h. The specific antibodies not only inactivated the toxins for initial suppression of CDI, but also provoked the inhibition of C. difficile growth after discontinuation, thus preventing recurrence. Oral administration of anti-CD-WPI is a functional therapy of CDI in infected hamsters for both primary treatment and prevention of recurrence. Thus, anti-CD-WPI could address the urgent unmet medical need for treating and preventing recurrent CDI in humans.

Original languageEnglish
Article number98
JournalToxins
Volume11
Issue number2
DOIs
StatePublished - Feb 2019

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Clostridium Infections
Clostridium
Clostridium difficile
Cricetinae
Antibodies
Infection
Vancomycin
Proteins
Immunization
Therapeutics
Immunoglobulin A
Animals
Immunoglobulin G
Whey
Anti-Bacterial Agents
Milk
Recurrence
Pharmaceutical Preparations
Colostrum
Primary Prevention

Keywords

  • Bovine milk
  • Clostridium difficile infection
  • Hamster model of CDI
  • Prevention of recurrence
  • sIgA

Cite this

Heidebrecht, Hans Jürgen ; Weiss, William J. ; Pulse, Mark ; Lange, Anton ; Gisch, Karina ; Kliem, Heike ; Mann, Sacha ; Pfaffl, Michael W. ; Kulozik, Ulrich ; von Eichel-Streiber, Christoph. / Treatment and prevention of recurrent Clostridium difficile infection with functionalized bovine antibody-enriched whey in a hamster primary infection model. In: Toxins. 2019 ; Vol. 11, No. 2.
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abstract = "Toxin-induced Clostridium difficile infection (CDI) is a major disease characterized by severe diarrhea and high morbidity rates. The aim with this study was to develop an alternative drug for the treatment of CDI. Cows were repeatedly immunized to establish specific immunoglobulin G and A titers against toxins A (TcdA) and B (TcdB) and against C. difficile cells in mature milk or colostrum. The effect of three different concentrations of anti-C. difficile whey protein isolates (anti-CD-WPI) and the standard of care antibiotic vancomycin were investigated in an animal model of CD infected hamsters (6 groups, with 10 hamsters each). WPI obtained from the milk of exactly the same cows pre-immunization and a vehicle group served as negative controls. The survival of hamsters receiving anti-CD-WPI was 50, 80 and 100{\%} compared to 10 and 0{\%} for the control groups, respectively. Vancomycin suppressed the growth of C. difficile and thus protected the hamsters at the time of administration, but 90{\%} of these hamsters nevertheless died shortly after discontinuation of treatment. In contrast, the surviving hamsters of the anti-CD-WPI groups survived the entire study period, although they were treated for only 75 h. The specific antibodies not only inactivated the toxins for initial suppression of CDI, but also provoked the inhibition of C. difficile growth after discontinuation, thus preventing recurrence. Oral administration of anti-CD-WPI is a functional therapy of CDI in infected hamsters for both primary treatment and prevention of recurrence. Thus, anti-CD-WPI could address the urgent unmet medical need for treating and preventing recurrent CDI in humans.",
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Heidebrecht, HJ, Weiss, WJ, Pulse, M, Lange, A, Gisch, K, Kliem, H, Mann, S, Pfaffl, MW, Kulozik, U & von Eichel-Streiber, C 2019, 'Treatment and prevention of recurrent Clostridium difficile infection with functionalized bovine antibody-enriched whey in a hamster primary infection model', Toxins, vol. 11, no. 2, 98. https://doi.org/10.3390/toxins11020098

Treatment and prevention of recurrent Clostridium difficile infection with functionalized bovine antibody-enriched whey in a hamster primary infection model. / Heidebrecht, Hans Jürgen; Weiss, William J.; Pulse, Mark; Lange, Anton; Gisch, Karina; Kliem, Heike; Mann, Sacha; Pfaffl, Michael W.; Kulozik, Ulrich; von Eichel-Streiber, Christoph.

In: Toxins, Vol. 11, No. 2, 98, 02.2019.

Research output: Contribution to journalArticle

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T1 - Treatment and prevention of recurrent Clostridium difficile infection with functionalized bovine antibody-enriched whey in a hamster primary infection model

AU - Heidebrecht, Hans Jürgen

AU - Weiss, William J.

AU - Pulse, Mark

AU - Lange, Anton

AU - Gisch, Karina

AU - Kliem, Heike

AU - Mann, Sacha

AU - Pfaffl, Michael W.

AU - Kulozik, Ulrich

AU - von Eichel-Streiber, Christoph

PY - 2019/2

Y1 - 2019/2

N2 - Toxin-induced Clostridium difficile infection (CDI) is a major disease characterized by severe diarrhea and high morbidity rates. The aim with this study was to develop an alternative drug for the treatment of CDI. Cows were repeatedly immunized to establish specific immunoglobulin G and A titers against toxins A (TcdA) and B (TcdB) and against C. difficile cells in mature milk or colostrum. The effect of three different concentrations of anti-C. difficile whey protein isolates (anti-CD-WPI) and the standard of care antibiotic vancomycin were investigated in an animal model of CD infected hamsters (6 groups, with 10 hamsters each). WPI obtained from the milk of exactly the same cows pre-immunization and a vehicle group served as negative controls. The survival of hamsters receiving anti-CD-WPI was 50, 80 and 100% compared to 10 and 0% for the control groups, respectively. Vancomycin suppressed the growth of C. difficile and thus protected the hamsters at the time of administration, but 90% of these hamsters nevertheless died shortly after discontinuation of treatment. In contrast, the surviving hamsters of the anti-CD-WPI groups survived the entire study period, although they were treated for only 75 h. The specific antibodies not only inactivated the toxins for initial suppression of CDI, but also provoked the inhibition of C. difficile growth after discontinuation, thus preventing recurrence. Oral administration of anti-CD-WPI is a functional therapy of CDI in infected hamsters for both primary treatment and prevention of recurrence. Thus, anti-CD-WPI could address the urgent unmet medical need for treating and preventing recurrent CDI in humans.

AB - Toxin-induced Clostridium difficile infection (CDI) is a major disease characterized by severe diarrhea and high morbidity rates. The aim with this study was to develop an alternative drug for the treatment of CDI. Cows were repeatedly immunized to establish specific immunoglobulin G and A titers against toxins A (TcdA) and B (TcdB) and against C. difficile cells in mature milk or colostrum. The effect of three different concentrations of anti-C. difficile whey protein isolates (anti-CD-WPI) and the standard of care antibiotic vancomycin were investigated in an animal model of CD infected hamsters (6 groups, with 10 hamsters each). WPI obtained from the milk of exactly the same cows pre-immunization and a vehicle group served as negative controls. The survival of hamsters receiving anti-CD-WPI was 50, 80 and 100% compared to 10 and 0% for the control groups, respectively. Vancomycin suppressed the growth of C. difficile and thus protected the hamsters at the time of administration, but 90% of these hamsters nevertheless died shortly after discontinuation of treatment. In contrast, the surviving hamsters of the anti-CD-WPI groups survived the entire study period, although they were treated for only 75 h. The specific antibodies not only inactivated the toxins for initial suppression of CDI, but also provoked the inhibition of C. difficile growth after discontinuation, thus preventing recurrence. Oral administration of anti-CD-WPI is a functional therapy of CDI in infected hamsters for both primary treatment and prevention of recurrence. Thus, anti-CD-WPI could address the urgent unmet medical need for treating and preventing recurrent CDI in humans.

KW - Bovine milk

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