RISK FACTORS AND INCIDENCE FOR CLOSTRIDIOIDES DIFFICILE INFECTION IN COVID-19 AND NON-COVID-19 PATIENTS – OUR EXPERIENCES
Keywords:
CDI, risk factors, COVID 19, treatment regimensAbstract
Introduction: Clostridioides difficile infection (CDI) is a major cause of healthcare-associated diarrhea. Identifying risk factors and evaluating treatment regimens are critical to reducing morbidity and mortality.
Aim: This study aimed to compare epidemiological and demographic features, risk factors, and treatment experiences in CDI patients with and without COVID-19 coinfection.
Material and methods: Data were collected from patients admitted at the University Clinic for Infectious Diseases, Skopje, North Macedonia (October 2020-June 2025). COVID-19 diagnosis was based on clinical criteria and PCR confirmation, while CDI was confirmed by culture and toxin detection, supplemented with molecular stool testing when available.
Results: Among 847 hospitalized patients, CDI was confirmed in 56(6.7%) cases: 24 (44.6%) with COVID-19 and 32(55.4%) without, with no significant statistical difference. The median age was 67 years with no significant differences in age, gender, or comorbidity distribution between groups. Proton pump inhibitor use was high in both groups (73.2%). Antibiotic and corticosteroid exposure prior to CDI onset was significantly more frequent in COVID-19 patients (p<0.005). Hospitalization was longer in the COVID-19 group (p=0.005), and mortality was higher (p=0.03). Treatment included oral metronidazole (31%), oral vancomycin (54%), combined parenteral metronidazole and oral vancomycin (10%), and vancomycin with rifaximin (5%).
Conclusion: CDI incidence appeared unchanged across periods, likely due to strict infection control measures. Age, comorbidities, hospitalization, and antimicrobial or steroid exposure remain key risk factors. Metronidazole and vancomycin remain effective first line treatments in our settings.
References
Finn E, Andersson FL, Madin‑Warburton M. Burden of Clostridioides difficile infection (CDI)‑a systematic review of the epidemiology of primary and recurrent CDI. BMC Infect Dis 2021; 21(1): 456. doi: 10.1186/s12879-021-06147-y.
Azimirad M, Noori M, Raeisi H, Yadegar A, Shahrokh S, Asadzadeh Aghdaei H, et al. How does COVID‑19 pandemic impact on incidence of Clostridioides difficile infection and exacerbation of its gastrointestinal symptoms? Front Med (Lausanne) 2021; 8: 775063. doi: 10.3389/fmed.2021.775063.
Król Z, Szymański P, Bochnia A, Abramowicz E, Płachta A, Rzepliński R, et al. Transformation of a large multi‑speciality hospital into a dedicated COVID‑19 centre during the coronavirus pandemic. Ann Agric Environ Med 2020; 27(2): 201-206. doi: 10.26444/aaem/123801.
Tosoni A, Rizzatti G, Nicolotti N, Di Giambenedetto S, Addolorato G, Franceschi F, et al. Hospital reengineering against COVID‑19 outbreak: 1‑month experience of an Italian tertiary care center. Eur Rev Med Pharmacol Sci 2020; 24(15): 8187-8191. doi:10.26355/eurrev_202008_22509.
Ndayishimiye C, Sowada C, Dyjach P, Stasiak A, Middleton J, Lopes H, et al. Associations between the COVID‑19 pandemic and hospital infrastructure adaptation and planning-a scoping review. Int J Environ Res Public Health 2022; 19(13): 8195. doi: 10.3390/ijerph19138195.
World Health Organization (WHO). Living guidance for clinical management of COVID-19: living guidance [Internet]. Geneva (CH): World Health Organization; 2020 May 27 [cited 2025 Oct 28]. https://apps.who.int/iris/bitstream/handle/10665/332196/ WHO-2019-nCoV-clinical-2020.5-eng.pdf.
European Centre for Disease Prevention and Control (ECDC). Case definition for coronavirus disease 2019 (COVID-19), as of 3 December 2020 [Internet]. Stockholm (SE): ECDC; 2020 Dec 3 [cited 2025 Oct 28]. https://www.ecdc.europa.eu/en/covid- 19/surveillance/case-definition.
Randel A. Infectious diarrhea: IDSA updates guidelines for diagnosis and management. Am Fam Physician 2018; 97(10): 676-677. PMID: 29763277.
Kelly CR, Fischer M, Allegretti JR, LaPlante K, Stewart DB, Limketkai BN, et al. NH. ACG clinical guidelines: Prevention, diagnosis, and treatment of Clostridioides difficile infections. Am J Gastroenterol 2021; 116(6): 1124-1147. doi: 10.14309/ajg. 0000000000001278.
Kong LY, Davies K, Wilcox MH. The perils of PCR‑based diagnosis of Clostridioides difficile infections: Painful lessons from clinical trials. Anaerobe 2019; 60: 102048. doi: 10.1016/j.anaerobe.2019.06.001.
Schäffler H, Breitrück A. Clostridium difficile-From colonization to infection. Front Microbiol 2018; 9: 646. doi: 10.3389/fmicb.2018.00646.
Coia JE, Kuijper EJ. The ESCMID study group for Clostridium difficile: History, role and perspectives. Adv Exp Med Biol 2018; 1050: 245-254. doi: 10.1007/978-3-319-72799-8_14.
Mihajlov K, Andreska A, Ristovska N, Grdanoska T, Trajkovska‑Dokic E. Distribution of Clostridium difficile ribotypes in Macedonian patients and their antimicrobial susceptibility. Open Access Maced J Med Sci 2019; 7(12): 1896-1901. doi: 10.3889/oamjms.2019.456.
European Centre for Disease Prevention and Control (ECDC). European surveillance of Clostridioides (Clostridium) difficile infections. Surveillance protocol version 2.4 [Internet]. Stockholm (SE): ECDC; 2022 [cited 2025 Oct 28]. Available from: https://www.ecdc.europa.eu/sites/default/files/documents/clostridium-difficile-infections-EU-surveillance-protocol-vers2.4.pdf.
Mu Y, Dudeck MA, Jones K, Li Q, Soe MM, Nkwata A, et al. Trends in hospital onset Clostridioides difficile infection incidence, National Healthcare Safety Network, 2010–2018. Infect Control Hosp Epidemiol 2020; 41(S1): 53-54. doi: 10.1017/ice.2020.537.
Guh AY, Mu Y, Winston LG, Johnston H, Olson D, Farley MM, et al. Trends in US burden of Clostridioides difficile infection and outcomes. N Engl J Med 2020; 382(14): 1320-1330. doi: 10.1056/NEJMoa1910215.
Rizzo KR, Yi SH, Garcia EP, Zahn M, Epson E. Reduction in Clostridium difficile infection rates following a multifacility prevention initiative in Orange County, California: A controlled interrupted time series evaluation. Infect Control Hosp Epidemiol 2019; 40(8): 872-879. doi: 10.1017/ice.2019.135.
Redmond SN, Silva SY, Wilson BM, Cadnum JL, Donskey CJ. Impact of reduced fluoroquinolone use on Clostridioides difficile infections resulting from the fluoroquinolone-resistant ribotype 027 strain in a Veterans Affairs medical center. Pathog Immun 2019; 4(2): 251-259. doi: 10.20411/pai.v4i2.327.
Karas JA, Enoch DA, Aliyu SH. A review of mortality due to Clostridium difficile infection. J Infect 2010; 61(1): 1-8. doi: 10.1016/j.jinf.2010.04.010.
Abad CL, Safdar N. A review of Clostridioides difficile infection and antibiotic‑associated diarrhea. Gastroenterol Clin North Am 2021; 50(2): 323-340. doi: 10.1016/j.gtc.2021.02.010.
Langford BJ, So M, Raybardhan S, Leung V, Soucy JP, Westwood D, et al. Antibiotic prescribing in patients with COVID‑19: Rapid review and meta‑analysis. Clin Microbiol Infect 2021; 27(4): 520-531. doi: 10.1016/j.cmi.2020.12.018.
Kovačević N, Lendak D, Popović M, Plećaš Đuric A, Pete M, Petrić V, et al. Clinical presentations, predictive factors, and outcomes of Clostridioides difficile infection among COVID‑19 hospitalized patients-A single center experience from the COVID hospital of the University Clinical Center of Vojvodina, Serbia. Medicina (Kaunas) 2022; 58(9): 1262. doi: 10.3390/medicina58091262.
Despotović A, Barać A, Cucanić T, Cucanić K, Stevanović G. Antibiotic (mis)use in COVID‑19 patients before and after admission to a tertiary hospital in Serbia. Antibiotics (Basel) 2022; 11(7): 847. doi: 10.3390/antibiotics11070847.
Sahu AK, Mathew R, Bhat R, Malhotra C, Nayer J, Aggarwal P, et al. Steroids use in non‑oxygen requiring COVID‑19 patients: A systematic review and meta‑analysis. QJM 2021; 114(7): 455-463. doi: 10.1093/qjmed/hcab212.
Cruciani M, Pati I, Masiello F, Pupella S, De Angelis V. Corticosteroids use for COVID‑19: An overview of systematic reviews. Le Infez Med 2022; 30(4): 469-479. doi: 10.53854/liim-3004-1.
Tawam D, Baladi M, Jungsuwadee P, Earl G, Han J. The positive association between proton pump inhibitors and Clostridium difficile infection. Innov Pharm 2021; 12(1): 10.24926/iip.v12i1.3439. doi: 10.24926/iip. v12i1.24926.
Trifan A, Stanciu C, Girleanu I, Stoica OC, Singeap AM, Maxim R, et al. Proton pump inhibitors therapy and risk of Clostridium difficile infection: Systematic review and meta‑analysis. World J Gastroenterol 2017; 23(35): 6500-6515. doi: 10.3748/wjg. v23.i35.6500.
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Copyright (c) 2026 Arlinda Lloga Osmani, Ivan Vidinikj , Dajana Georgievska , Ilir Demiri , Marija Dimzova , Mesut Hasipi , Milenkovikj Zvonko
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