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Available online 24 January 2023
Recurrent Clostridium difficile infection treated with bezlotoxumab
Infección recurrente por Clostridium difficile tratada con bezlotoxumab
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Beatriz Palenzuela Afonso
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bpalafo@gobiernodecanarias.org

Corresponding author.
, Ana B. Caparrós Nieto, Macarena González Cruz, Cristina Martínez Faci
Oncohematología Pediátrica, Servicio de Pediatría, Hospital Universitario de Canarias, San Cristóbal de La Laguna, Santa Cruz de Tenerife, Spain
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Dear Editor:

Infection by Clostridioides (formerly Clostridium) difficile is a disease mediated by toxins. This pathogen is a strictly anaerobic gram-positive rod. Its main virulence factors are toxins A and B, encoded by the tcdA and tcdB gene, respectively.1 Infection by C. difficile is the leading cause of nosocomial diarrhoea associated to the use of antibiotics and its incidence is increasing in the community, which constitutes a significant public health problem due to the associated morbidity and costs.2

The European Society of Clinical Microbiology and Infectious Diseases defines infection by C. difficile as a compatible clinical picture such as diarrhoea, ileus and toxic megacolon in combination with either microbiologic evidence of free toxins in stool or the presence of toxigenic C. difficile in stool without reasonable evidence for an alternative aetiology. Recurrent C. difficile infection is defined as recurrence of symptoms within 8 weeks after the onset of a previous episode, and severe infection as an episode resulting in need for intensive care unit admission, colectomy or death.3

The usual treatment of C. difficile is metronidazole or oral vancomycin, for both mild and severe cases, and rifaximin is a widely accepted alternative, in addition to faecal microbiota transplantation in recurrent cases.3 Strategies have been developed to reduce the likelihood of recurrence, including bezlotoxumab, an antitoxin B human monoclonal antibody.4

Bezlotoxumab was approved for use in humans based on the outcomes of the MODIFY I and II international multicentric, double-blind randomised placebo-controlled trials.5 These studies demonstrated that the use of bezlotoxumab (10 mg/kg as a single dose) was associated with a greater reduction in the recurrence of C. difficile infection and a similar safety profile in adults compared to placebo.

The MODIFY trials were conducted in the adult population (>18 years) treated with standard antibiotherapy (metronidazole, oral vancomycin or fidaxomicin) and showed that its effect was greater in individuals with at least 1 risk factor.6 The risk factors for recurrence were: age 65 years or greater, history of infection by C. difficile in the past 6 months, compromised immunity, severe C. difficile infection or isolation of a strain associated with poor outcomes.6 In addition, it showed that bezlotoxumab reduced the recurrence of infection by C. difficile for a period of 12 weeks.4 Bezlotoxumab has yet to be approved for use in the paediatric population.

We present the case of a female adolescent aged 12 years with non-Hodgkin lymphoma at the prepyloric level causing pyloric stenosis that precluded enteral nutrition (complete liquid diet). The patient had 3 episodes of C. difficile infection over a 3-month period. Both the initial infection and the 2 recurrences followed administration of broad-spectrum antibiotics for management of febrile neutropenia, and the first 2 episodes manifested with diarrhoea. The first episode was treated with metronidazole and the first recurrence with oral vancomycin. In the third episode, diarrhoea was associated with substantial dilation of the colon, ileus, systemic inflammatory response syndrome, disseminated intravascular coagulation and pulmonary embolism, with significant clinical worsening requiring transfer to the paediatric intensive care unit for treatment despite early initiation of antibiotherapy.

On account of the detection of infection by C. difficile and the episode being the second recurrence, the decision was made to add bezlotoxumab to the treatment regimen on a compassionate basis, with administration of a single dose of 10 mg/kg intravenously. The patient exhibited progressive improvement, with full resolution of symptoms and negative stool toxin test results and no adverse events associated with the administration of bezlotoxumab. As of this writing, 7 months after the episode, the patient has required an additional course of broad-spectrum antibiotherapy due to febrile neutropenia, but has not had additional infections by C. difficile.

In conclusion, infection by C. difficile is a public health problem that also affects the paediatric population. Many paediatric patients share the risk factors of adults, and therefore may experience the benefits of bezlotoxumab observed in the adult population. This case report concerns an immunocompromised patient with recurrent severe infection by C. difficile who benefitted from its use. Thus, we think it is necessary to study the efficacy and safety of this drug in the paediatric population.

References
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B. Rogado-Vegas, J. Sánchez-Gundín, D. Gómez-Gómez, M. Valero-Domínguez.
Bezlotoxumab en prevención de recurrencias de infección por Clostridium difficile.
Ofil-Ilaphar, 31 (2021), pp. 112-113
[2]
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Cost of Clostridium difficile associated diarrhea in Spain.
Rev Esp Salud Publica., 87 (2013), pp. 25-33
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R.E. Ooijevaar, Y.H. van Burden, E.M. Tercer, A. Goorhuis, M.P. Bauer, J.J. Keller, et al.
Update of treatment algorithms for Clostridium difficile infection.
Clin Microbiol Infect, 24 (2018), pp. 452-462
[4]
S. Johnson, D.N. Gerding.
Bezlotoxumab.
Clin Infect Dis., 68 (2019), pp. 699-704
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D.N. Gerding, S. Johnson, M. Rupnik, K. Aktories.
Clostridium difficile binary toxin CDT: mechanism, epidemiology, and potential clinical importance.
Gut Microbes, 5 (2014), pp. 15-27
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E. Bouza, O.A. Cornely, A. Ramos-Martínez, R. Plesniak, M.C. Ellison, M.E. Hanson, et al.
Analysis of C. difficile infection-related outcomes in European participants in the bezlotuxumab MODIFY I and II trials.
Eur J Clin Microbiol Infect Dis, 39 (2020), pp. 1933-1939

Previous presentation: case presented at the XIV National Congress of Paediatric Haematology and Oncology.

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