{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T11:36:51Z","timestamp":1787312211796,"version":"build-2736575974"},"reference-count":51,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2025,3,15]],"date-time":"2025-03-15T00:00:00Z","timestamp":1741996800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antibiotics"],"abstract":"<jats:p>Background\/Objectives: Data about the relationship between COVID-19 and healthcare-associated Clostridioides difficile infection (HA-CDI) occurrence are still controversial. This study examines antibiotics associated with CDI in patients with and without COVID-19 infection. Methods: A prospective cohort study was conducted at the University Clinical Center Belgrade, Serbia, from January 2019 to December 2021. Patients with the first episode of HA-CDI without and with COVID-19 were included. Results of bacteriology analyses, demographic and clinical data, and data on antibiotic usage and daily defined doses (DDD) were collected by the hospital Infection Control Team. Results: Out of 547 HA-CDI cases, 341 (62.3%) had COVID-19 infection. HA-CDI patients with COVID-19 were significantly younger (p = 0.017) with fewer comorbidities (&lt;0.001). Two or more antibiotics in therapy were more frequently used by those patients (p = 0.03). COVID-19 patients were treated significantly more by third- and fourth-generation cephalosporins, fluoroquinolones (p &lt; 0.001) and macrolides (p = 0.01). Ceftriaxone had a higher median DDD in COVID-19 patients (6.00, range 1.00\u201320.00) compared to non-COVID-19 patients (4.00, range 1.00\u201314.00), (p = 0.007). Conversely, meropenem showed a lower median DDD in COVID-19 patients. Multivariate analysis identified the use of fourth-generation cephalosporins and fluoroquinolones as independent risk factors for HA-CDI in COVID-19 patients. Conclusions: Patients with HA-CDI and COVID-19 more frequently received two or more antibiotics before the onset of HAI-CDI. The third and fourth generations of cephalosporins, fluoroquinolones and macrolides were administered significantly more often in these patients. More frequent administration of ceftriaxone was observed, but the lower DDD associated with meropenem needed additional analysis.<\/jats:p>","DOI":"10.3390\/antibiotics14030303","type":"journal-article","created":{"date-parts":[[2025,3,17]],"date-time":"2025-03-17T07:49:57Z","timestamp":1742197797000},"page":"303","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Antibiotic Usage and Healthcare-Associated Clostridioides difficile in Patients with and Without COVID-19: A Tertiary Hospital Experience"],"prefix":"10.3390","volume":"14","author":[{"given":"Darko","family":"Zdravkovic","sequence":"first","affiliation":[{"name":"University Clinical Hospital Center Bezanijska Kosa, 11000 Belgrade, Serbia"},{"name":"Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7540-9829","authenticated-orcid":false,"given":"Ljiljana","family":"Markovic-Denic","sequence":"additional","affiliation":[{"name":"University Clinical Hospital Center Bezanijska Kosa, 11000 Belgrade, Serbia"},{"name":"Faculty of Medicine, Institute of Epidemiology, University of Belgrade, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0216-6392","authenticated-orcid":false,"given":"Vladimir","family":"Nikolic","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Institute of Epidemiology, University of Belgrade, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8869-9976","authenticated-orcid":false,"given":"Zoran","family":"Todorovic","sequence":"additional","affiliation":[{"name":"University Clinical Hospital Center Bezanijska Kosa, 11000 Belgrade, Serbia"},{"name":"Faculty of Medicine, Institute of Pharmacology, University of Belgrade, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9676-7198","authenticated-orcid":false,"given":"Marija","family":"Brankovic","sequence":"additional","affiliation":[{"name":"University Clinical Hospital Center Bezanijska Kosa, 11000 Belgrade, Serbia"},{"name":"Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aleksandra","family":"Radojevic","sequence":"additional","affiliation":[{"name":"University Clinical Hospital Center Bezanijska Kosa, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dusan","family":"Radovanovic","sequence":"additional","affiliation":[{"name":"University Clinical Hospital Center Bezanijska Kosa, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Borislav","family":"Toskovic","sequence":"additional","affiliation":[{"name":"University Clinical Hospital Center Bezanijska Kosa, 11000 Belgrade, Serbia"},{"name":"Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,3,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1721","DOI":"10.1016\/j.jamda.2022.01.075","article-title":"Mortality, health care use, and costs of Clostridioides difficile infections in older adults","volume":"23","author":"Feuerstadt","year":"2022","journal-title":"J. Am. Med. Dir. Assoc."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"825","DOI":"10.1056\/NEJMoa1408913","article-title":"Burden of Clostridium difficile infection in the United States","volume":"372","author":"Lessa","year":"2015","journal-title":"N. Engl. J. Med."},{"key":"ref_3","unstructured":"European Centre for Disease Prevention and Control (2024, August 12). Clostridioides difficile Infections\u2014Annual Epidemiological Report for 2018\u20132020, Available online: https:\/\/www.ecdc.europa.eu\/en\/publications-data\/clostridioides-difficile-infections-annual-epidemiological-report-2018-2020."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1223","DOI":"10.1111\/tmi.12937","article-title":"Clostridium difficile infection in low- and middle-human development index countries: A systematic review","volume":"22","author":"Forrester","year":"2017","journal-title":"Trop. Med. Int. Health"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"542","DOI":"10.1016\/S0140-6736(20)30374-3","article-title":"COVID-19: What is next for public health?","volume":"395","author":"Heymann","year":"2020","journal-title":"Lancet"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Abubakar, U., Awaisu, A., Khan, A.H., and Alam, K. (2023). Impact of COVID-19 Pandemic on Healthcare-Associated Infections: A Systematic Review and Meta-Analysis. Antibiotics, 12.","DOI":"10.3390\/antibiotics12111600"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"e34","DOI":"10.1093\/cid\/ciac684","article-title":"The Disproportionate Impact of Coronavirus Disease 2019 (COVID-19) Pandemic on Healthcare-Associated Infections in Community Hospitals: Need for Expanding the Infectious Disease Workforce","volume":"76","author":"Advani","year":"2023","journal-title":"Clin. Infect. Dis. Off. Publ. Infect. Dis. Soc. Am."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"102484","DOI":"10.1016\/j.anaerobe.2021.102484","article-title":"The burden of Clostridioides difficile infection in COVID-19 patients: A systematic review and meta-analysis","volume":"74","author":"Granata","year":"2022","journal-title":"Anaerobe"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"749","DOI":"10.1080\/14787210.2022.2011719","article-title":"Antimicrobial consumption in patients with COVID-19: A systematic review and meta-analysis","volume":"20","author":"Khan","year":"2022","journal-title":"Expert Rev. Anti-Infect. Ther."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1080\/20477724.2022.2160892","article-title":"Prevalence of antibiotics prescription amongst patients with and without COVID-19 in low- and middle-income countries: A systematic review and meta-analysis","volume":"117","author":"Satria","year":"2023","journal-title":"Pathog. Glob. Health"},{"key":"ref_11","first-page":"214","article-title":"Antibiotic Use in UK\u2019s COVID-19 Patients Often Unnecessary","volume":"326","author":"Kuehn","year":"2021","journal-title":"JAMA"},{"key":"ref_12","first-page":"520","article-title":"Antibiotic prescribing in patients with COVID-19: Rapid review and meta-analysis","volume":"27","author":"Langford","year":"2021","journal-title":"Clin. Microbiol. Infect. Off. Publ. Eur. Soc. Clin. Microbiol. Infect. Dis."},{"key":"ref_13","first-page":"e37576","article-title":"Clostridium difficile Infection Rates During the Pandemic in New York Capital Area: A Single-Center Study","volume":"15","author":"Zouridis","year":"2023","journal-title":"Cureus"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Karampatakis, T., Tsergouli, K., Kandilioti, E., Nikopoulou, A., Katsifa, H., and Kachrimanidou, M. (2023). Implication of COVID-19 pandemic on the incidence of Clostridioides difficile infection in a Greek tertiary hospital. J. Med. Microbiol., 72.","DOI":"10.1099\/jmm.0.001689"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Markovic-Denic, L., Nikolic, V., Toskovic, B., Brankovic, M., Crnokrak, B., Popadic, V., Radojevic, A., Radovanovic, D., and Zdravkovic, M. (2023). Incidence and Risk Factors for Clostridioides difficile Infections in Non-COVID and COVID-19 Patients: Experience from a Tertiary Care Hospital. Microorganisms, 11.","DOI":"10.3390\/microorganisms11020435"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"881","DOI":"10.1093\/jac\/dkt477","article-title":"Antibiotics and hospital-acquired Clostridium difficile infection: Update of systematic review and meta-analysis","volume":"69","author":"Slimings","year":"2014","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1676","DOI":"10.1093\/jac\/dkab091","article-title":"Antibiotics and healthcare facility-associated Clostridioides difficile infection: Systematic review and meta-analysis 2020 update","volume":"76","author":"Slimings","year":"2021","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_18","unstructured":"World Health Organization (2024). WHO Reports Widespread Overuse of Antibiotics in Patients Hospitalized with COVID-19, WHO. Available online: https:\/\/www.who.int\/news\/item\/26-04-2024-who-reports-widespread-overuse-of-antibiotics-in-patients--hospitalized-with-covid-19."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S0195-6701(98)90019-6","article-title":"Risk factors for Clostridium difficile infection","volume":"40","author":"Bignardi","year":"1998","journal-title":"J. Hosp. Infect."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1229","DOI":"10.1017\/ice.2019.236","article-title":"Hospital-level high-risk antibiotic use in relation to hospital-associated Clostridioides difficile infections: Retrospective analysis of 2016\u20132017 data from US hospitals","volume":"40","author":"Tabak","year":"2019","journal-title":"Infect. Control Hosp. Epidemiol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1047","DOI":"10.2147\/IDR.S194715","article-title":"Combined administration of antibiotics increases the incidence of antibiotic-associated diarrhea in critically ill patients","volume":"12","author":"Ma","year":"2019","journal-title":"Infect. Drug Resist."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Czepiel, J., Dr\u00f3\u017cd\u017c, M., and Pituch, H. (2019). Clostridium difficile infection: Review. Eur. J. Clin. Microbiol. Infect. Dis., 38.","DOI":"10.1007\/s10096-019-03539-6"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/j.anaerobe.2014.08.015","article-title":"Risk factors of Clostridium difficile infections among patients in a university hospital in Shanghai, China","volume":"30","author":"Huang","year":"2014","journal-title":"Anaerobe"},{"key":"ref_24","unstructured":"European Center for Disease Prevention and Control (2024). Antimicrobial Consumption in the EU\/EEA (ESAC-Net). Annual Epidemiological Report for 2023."},{"key":"ref_25","unstructured":"European Center for Disease Prevention and Control (2023). Antimicrobial Consumption in the EU\/EEA (ESAC-Net). Annual Epidemiological Report for 2022."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Morris, D.E., Cleary, D.W., and Clarke, S.C. (2017). Secondary bacterial infections associated with influenza pandemics. Front. Microbiol., 8.","DOI":"10.3389\/fmicb.2017.01041"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"808","DOI":"10.1016\/j.cmi.2020.04.024","article-title":"COVID-19: Don\u2019t neglect antimicrobial stewardship principles!","volume":"26","author":"Huttner","year":"2020","journal-title":"Clin. Microbiol. Infect."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"38","DOI":"10.4103\/picr.PICR_29_20","article-title":"Drug use evaluation of cephalosporins in a tertiary care hospital","volume":"13","author":"Shetty","year":"2022","journal-title":"Perspect. Clin. Res."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Peri\u0107, A., Ran\u010di\u0107, N., Dragojevi\u0107-Simi\u0107, V., Milenkovi\u0107, B., Ljubenovi\u0107, N., Rakonjac, B., Begovi\u0107-Kupre\u0161anin, V., and \u0160uljagi\u0107, V. (2022). Association between antibiotic use and hospital-onset Clostridioides difficile infection in university tertiary hospital in Serbia, 2011\u20132021: An ecological analysis. Antibiotics, 11.","DOI":"10.3390\/antibiotics11091178"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"AAC.02169-19","DOI":"10.1128\/AAC.02169-19","article-title":"Antibiotic exposure and risk for hospital-associated Clostridioides difficile infection","volume":"64","author":"Webb","year":"2020","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Kova\u010devi\u0107, N., Petri\u0107, V., Pete, M., Popovi\u0107, M., Ple\u0107a\u0161-\u0110uri\u0107, A., Pejakovi\u0107, S., Tomi\u0107, S., Damjanov, D., Kosijer, D., and Lekin, M. (2022). Clostridioides difficile infection before and during Coronavirus Disease 2019 pandemic\u2014Similarities and differences. Microorganisms, 10.","DOI":"10.3390\/microorganisms10112284"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Marinescu, A.R., Laza, R., Musta, V.F., Cut, T.G., Dumache, R., Tudor, A., Porosnicu, M., Lazureanu, V.E., and Licker, M. (2021). Clostridium difficile and COVID-19: General data, ribotype, clinical form, treatment\u2014Our experience from the largest infectious diseases hospital in Western Romania. Medicina, 57.","DOI":"10.3390\/medicina57101099"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"04135","DOI":"10.7189\/jogh.14.04135","article-title":"The global burden and trend of Clostridioides difficile and its association with world antibiotic consumption, 1990\u20132019","volume":"14","author":"Chen","year":"2024","journal-title":"J. Glob. Health"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2089","DOI":"10.1093\/jac\/dkad213","article-title":"Carrier prevalence of Clostridioides difficile in emergency departments and the association of prior antibiotic consumption: A combined cross-sectional and nested case-control study","volume":"78","author":"Chen","year":"2023","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"102579","DOI":"10.1016\/j.anaerobe.2022.102579","article-title":"Impact of COVID19 pandemic on the incidence of health-care associated Clostridioides difficile infection","volume":"75","author":"Merchante","year":"2022","journal-title":"Anaerobe"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"406","DOI":"10.1017\/ice.2020.454","article-title":"Impact of the coronavirus disease 2019 (COVID-19) pandemic on nosocomial Clostridioides difficile infection","volume":"42","author":"Pintor","year":"2021","journal-title":"Infect. Control. Hosp. Epidemiol."},{"key":"ref_37","first-page":"121","article-title":"Clostridioides difficile infection in coronavirus disease 2019 (COVID-19): An underestimated problem?","volume":"13","author":"Lewandowski","year":"2021","journal-title":"Pol. Arch. Intern. Med."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"102836","DOI":"10.1016\/j.anaerobe.2024.102836","article-title":"Increase of healthcare-onset Clostridioides difficile infection in adult population since SARS-CoV-2 pandemic: A retrospective cohort study in a tertiary care hospital from 2019 to 2022","volume":"86","year":"2024","journal-title":"Anaerobe"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1017\/ice.2022.69","article-title":"Trends in facility-level rates of Clostridioides difficile infections in US hospitals, 2019\u20132020","volume":"44","author":"Rose","year":"2023","journal-title":"Infect. Control. Hosp. Epidemiol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"102864","DOI":"10.1016\/j.anaerobe.2024.102864","article-title":"Clostridioides difficile infection in patients with and without COVID-19 during the pandemic: A retrospective cohort study from a tertiary referral hospital","volume":"88","author":"Tsankof","year":"2024","journal-title":"Anaerobe"},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Courjon, J., Contenti, J., Demonchy, E., Levraut, J., Barbry, P., Rios, G., Dellamonica, J., Chirio, D., Bonnefoy, C., and Giordanengo, V. (2021). COVID-19 patients age, comorbidity profiles and clinical presentation related to the SARS-CoV-2 UK-variant spread in the Southeast of France. Sci. Rep., 11.","DOI":"10.1038\/s41598-021-95067-7"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1017\/ice.2023.171","article-title":"Describing the monthly variability of hospital-onset Clostridioides difficile during early coronavirus disease 2019 (COVID-19) using electronic health record data","volume":"45","author":"Lang","year":"2024","journal-title":"Infect. Control. Hosp. Epidemiol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1","DOI":"10.5937\/gp27-40621","article-title":"Excess mortality and COVID-19 deaths: Preliminary data from Serbia and comparison with European experience","volume":"27","author":"Arsenovic","year":"2023","journal-title":"Geogr. Pannonica"},{"key":"ref_44","first-page":"S63","article-title":"European Society of Clinical Microbiology and Infectious Diseases: Update of the diagnostic guidance document for Clostridium difficile infection","volume":"22","author":"Crobach","year":"2016","journal-title":"Clin. Microbiol. Infect. Off. Publ. Eur. Soc. Clin. Microbiol. Infect. Dis."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"e45","DOI":"10.1093\/cid\/cix669","article-title":"2017 Infectious Diseases Society of America Clinical Practice Guidelines for the Diagnosis and Management of Infectious Diarrhea","volume":"65","author":"Shane","year":"2017","journal-title":"Clin. Infect. Dis. Off. Publ. Infect. Dis. Soc. Am."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1124","DOI":"10.14309\/ajg.0000000000001278","article-title":"ACG clinical guidelines: Prevention, diagnosis, and treatment of Clostridioides difficile infections","volume":"116","author":"Kelly","year":"2021","journal-title":"Am. J. Gastroenterol."},{"key":"ref_47","unstructured":"European Centre for Disease Prevention and Control (ECDC) (2025, January 10). COVID-19: ECDC Updates Case Definition for EU Surveillance, Available online: https:\/\/www.ecdc.europa.eu\/en\/news-events\/covid-19-ecdc-updates-case-definition-eu-surveillance."},{"key":"ref_48","unstructured":"World Health Organization (WHO) (2025, January 10). Laboratory Testing for 2019 Novel Coronavirus (2019-nCoV) in Suspected Human Cases: Interim Guidance, 17 January 2020. Available online: https:\/\/iris.who.int\/bitstream\/handle\/10665\/330676\/9789240000971-eng.pdf?sequence=1."},{"key":"ref_49","unstructured":"Institute of Public Health of Serbia (2017). Healthcare-Associated Infections Definitions, Institute of Public Health of Serbia. (In Serbian)."},{"key":"ref_50","unstructured":"World Health Organization (WHO) Defined Daily Dose (DDD): Definition and General Considerations, WHO. Available online: https:\/\/www.who.int\/tools\/atc-ddd-toolkit\/about-ddd."},{"key":"ref_51","unstructured":"Ministry of Health (2025, January 09). National Guide to Good Clinical Practice. Rational Use of Antibiotics. Belgrade, 2018, Available online: https:\/\/www.zdravlje.gov.rs\/view_file.php?file_id=527&cache=sr."}],"container-title":["Antibiotics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2079-6382\/14\/3\/303\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T16:54:22Z","timestamp":1760028862000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2079-6382\/14\/3\/303"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,3,15]]},"references-count":51,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2025,3]]}},"alternative-id":["antibiotics14030303"],"URL":"https:\/\/doi.org\/10.3390\/antibiotics14030303","relation":{},"ISSN":["2079-6382"],"issn-type":[{"value":"2079-6382","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,3,15]]}}}