ABSTRACT
Background and Aims
Antibiotics are sometimes prescribed as concurrent therapy in the management of acute severe ulcerative colitis (ASUC) with a rationale of treating any presumed concurrent infections. It is unclear if there are data indicating any benefit of this clinical practice. We sought to evaluate the concurrent use of antibiotics with infliximab in patients hospitalized for the treatment of ASUC.
Methods
We performed a retrospective cohort study on hospitalized patients with ASUC, comparing the outcomes of patients who received both rescue infliximab and antibiotics to patients who received rescue infliximab without antibiotics. The comparative cohorts were derived from the TriNetX US Collaborative Network. Propensity score matching was used to balance cohorts on baseline demographic and clinical characteristics. Kaplan Meier analyses and hazard ratios with 95% confidence intervals were calculated.
Results
Concurrent administration of antibiotics and antimicrobials with rescue infliximab in ASUC does not result in any benefit in IBD related surgery (HR: 1.18; 95% CI: 0.82–1.70), colectomy (HR: 1.08; 95% CI: 0.54–2.13), sepsis (HR: 1.36; 95% CI: 0.84–2.20) and mortality (HR: 0.81; 95% CI: 0.32–2.05). Furthermore, the antibiotic cohort was more likely to utilize emergency department services (HR: 1.29; 95% CI: 1.02–1.64) and critical care services (HR: 2.36; 95% CI: 1.31–4.24) in the studied outcome time period.
Conclusion
Empiric administration of antibiotics or antimicrobials with infliximab rescue therapy in ASUC does not improve outcomes and may be associated with higher health care utilization.
Keywords: concurrent treatment, health care utilization, hospitalization, infliximab
1. Introduction
Inflammatory bowel diseases (IBD) (ulcerative colitis, crohn's disease and undifferentiated IBD) affects approximately 3.1 million individuals in the United States [1]. Ulcerative colitis (UC) is characterized by immune mediated colonic inflammation of varying severity, activity and extent. The incidence rate of UC is reported to be 9–20 cases per 100,000 people [2, 3, 4], with an estimated prevalence of 1.5 million in the United States (US). The incidence of UC has stabilized in the US but continues to rise in newly industrialized countries [4]. Furthermore, there is a geographic variation in the prevalence of UC with the highest disease burden noted in Northern Europe and North America [4].
UC typically runs a relapsing and remitting clinical course with both gastrointestinal and or extraintestinal manifestations [2]. Intestinal manifestations are predominant in about 90% of patients, who present with diarrhea which may be bloody, and abdominal pain [5]. UC patients often have increased healthcare utilization with risk of increased length of hospital stay, surgical procedures and mortality which rises with the worsening clinical activity and severity of disease [6, 7, 8]. There are several validated tools for objectively assessing severity of disease. These include the Truelove‐Witts criteria and the Mayo Score which help inform treatment decisions [8].
Acute severe UC (ASUC) is a life‐threatening severe form of UC defined as > 6 bloody stools per day with 1 or more of the following: CRP > 30 mg/L, Fever > 37.8 C, erythrocyte sedimentation rate of > 30 mm/h, heart rate > 90 and hemoglobin < 10.5 [8, 9]. Hospitalization and multidisciplinary management are recommended in ASUC to avert poor outcomes [2, 10].
Intravenous steroid is the first line treatment for ASUC, however, 30% and 50% of patients fail to respond, with increased risk of colectomy without escalated therapy [8, 11, 12]. The Active UC Trials (ACT) 1 and 2, demonstrated efficacy of infliximab, an IgG1 monoclonal antibody, with activity against TNF‐a receptor in the induction and maintenance of clinical remission in patients with ASUC and thus it is widely used as a rescue therapy [13, 14]. There are recent promising reports on the use of small molecules and other biologics as rescue therapy in ASUC. These include tofacitinib, ustekinumab and upadacitinib and they have been predominantly used in patients not responding to infliximab rescue therapy [15, 16, 17]. However, the reported numbers are small, and we will learn more as they are increasingly incorporated into clinical practice. This is encouraging in that it offers additional treatment options for this severely sick cohort of patients who are at an increased risk of colectomy.
While previous studies have outlined some benefits in the use of antibiotics for Crohn's disease [18], benefits of antibiotic use in UC remain unclear except in fulminant UC, where antibiotics are used to mitigate sepsis [19, 20]. A retrospective study demonstrated that UC patients who received concomitant antibiotics with IV steroids were less likely to have increased rates of admission for hospital rescue therapy; however, there was no difference in length of stay, surgery, or rehospitalization rates [21]. Additionally, three randomized controlled trials showed no benefit of adjunctive metronidazole, metronidazole and tobramycin or ciprofloxacin in ASUC [22, 23, 24]. A study by Dickinson et al. showed decreased rates of operative intervention in patients with UC flare treated with oral vancomycin [25]. It is worth noting that all these studies were in ASUC patients receiving corticosteroids. There is also limited data on the use of vancomycin in a subset of UC patients with primary sclerosing cholangitis in an outpatient setting [26].
Concomitant antibiotics have been used with rescue infliximab in clinical settings. However, there are no reported data indicating improved outcomes or otherwise. Gorelick et al. in their recent study reported that fluoroquinolones and macrolides are associated with a decreased risk of anti‐drug antibodies in IBD patients treated with infliximab but did not evaluate the impact on patient outcomes [27].
We sought to evaluate the benefits or otherwise of administration of antibiotics simultaneously with rescue infliximab in patients with ASUC compared to rescue infliximab alone.
2. Methods
2.1. Design, Data Source and Study Population
We performed a retrospective cohort study comparing the outcomes of patients aged 18 years and older with ASUC who were admitted for rescue infliximab and received antibiotics to patients who did not receive antibiotics. The TriNetX platform, a worldwide federated health research network with access to deidentified electronic medical records of large healthcare organizations (HCOs) was the database used in this study. Because data shared through TriNetX is fully deidentified, excludes personal health information and complies with the HIPAA privacy rule, ethical approval and consent is not required for its use.
We queried the TriNetX US Collaborative Network, which consisted of 59 HCOs, using ICD‐10 codes, procedure codes, visit codes and/or keywords such as antibiotics and infliximab to identify all patients with ASUC hospitalized from January 1, 2013, through December 31, 2022 (Table 1). Cohort 1 was defined as inpatients with UC who received infliximab on or within 1 day after admission and received antibiotics on or within 1 day after infliximab administration. Cohort 2 was defined as inpatients with UC who received infliximab on or within 1 day after admission but did not receive antibiotics in the 3 days after administration of infliximab following admission.
Table 1.
Diagnosis, procedure, visit and medication terms and codes used in the TriNetX query and analysis.
| Variable type | Search term | Code type | Code (Description) |
|---|---|---|---|
| Query term | Ulcerative colitis | ICD‐10 | K51 |
| Inpatient visit | CPT | 1,013,659 (Hospital Inpatient Services) | |
| 1,013,699 (Inpatient Consultations) | |||
| 1,013,729 (Critical Care Services) | |||
| HL7V3 Visit |
IMP (Inpatient Encounter) SS (Short Stay) |
||
| Infliximab | RXNorm | 191,831(infliximab) | |
| CPT | 80,230 (infliximab) | ||
| HCPCS | Q5103 (Injection, infliximab‐dyyb, biosimilar, (inflectra), 10 mg) | ||
| Q5104 (Injection, infliximab‐abda, biosimilar, (renflexis), 10 mg) | |||
| Q5121 (Injection, infliximab‐axxq, biosimilar, (avsola), 10 mg) | |||
| Antibiotics | ATC | S01AA (Antibiotics) | |
| VA drug code | AM114 (Penicillins and Beta‐Lactam Antimicrobials) | ||
| AM150 (Chloramphenicol) | |||
| AM200 (Erythromycins/Macrolides) | |||
| AM250 (Tetracyclines) | |||
| AM300 (Aminoglycosides) | |||
| AM350 (Lincomycins) | |||
| AM400 (Quinolones) | |||
| AM500 (Antituberculars) | |||
| AM550 (Methenamine Salts) | |||
| AM600 (Nitrofurans) | |||
| AM650 (Sulfonamide/Related) | |||
| AM900 (Anti‐infectives, Other) | |||
| Propensity Score Matching |
Age Female |
TriNetX term TriNetX term |
Age at index Female |
| Heart failure | ICD‐10 | I50 | |
| Diabetes mellitus | E08‐E13 | ||
| COPD | J44 | ||
| C. difficile | A04.7 (Enterocolitis due to Clostridium difficile) | ||
| Antimicrobials | VA Drug code | AM000 | |
| Antibiotics | ATC | S01AA | |
| Outcome | IBD related surgery | CPT | 1007422 (Surgical Procedures on the Intestines [Except Rectum]) |
| Colectomy | CPT | 1007455 (Colectomy, partial) | |
| 1007463 (Colectomy, total, abdominal, without proctectomy) | |||
| 1007468 (Colectomy, total, abdominal, with proctectomy) | |||
| Sepsis | ICD‐10 | A40 (Streptococcal sepsis) | |
| A41 (Other sepsis) | |||
| Emergency department services |
CPT HL7V3 Visit |
1013711 EMER |
|
| Critical care | CPT | 1013729 (Critical Care Services) | |
| 1014309 (Critical care, evaluation and management of the critically ill or critically injured patient) | |||
| 99291 (Critical care, evaluation and management of the critically ill or critically injured patient; first 30–74 min) | |||
| Mortality | TriNetX term | Deceased |
For the purposes of a subgroup analysis, additional cohorts were formed. The same query criteria were used for each cohort but this time patients who had documentation of sepsis in the 3 months after an inpatient visit were excluded.
2.2. Baseline Characteristics
To reduce confounding, propensity score matching (PSM) was performed for baseline characteristics of both cohorts including sex, age, diagnosis of diabetes mellitus, heart failure, chronic obstructive pulmonary disease, enterocolitis due to Clostridioides difficile and use of antibiotics/antimicrobials.
2.3. Outcomes
Primary outcome was all‐cause mortality. Secondary outcomes were IBD related surgery, colectomy, use of emergency department services and use of critical care critical care services post discharge. Outcomes were measured between one and 6 weeks after the index event. The index event was defined as the time at which all query criteria were met (inpatient admission, infliximab administration and antibiotic administration [cohort 1 only]).
2.4. Statistical Analysis
All statistical analyses were performed via the TriNetX built‐in analytics function on October 18, 2023. To create balanced groups, cohorts were propensity score matched 1:1 for demographic and baseline clinical characteristics, as previously mentioned. Propensity scores were obtained from logistic regression using scikit‐learn in Python and matching was performed using a greedy, nearest‐neighbor algorithm with a 0.1 pooled standard deviation caliper. Survival analysis assessed for the probability of outcomes using the Kaplan Meier method. Differences between cohort survival curves were tested for statistical significance using the log‐rank test. Hazard ratios (HR) with 95% confidence intervals (CI) and tests for proportionality were calculated using R's Survival package v3.2‐3. The proportional hazard assumption was tested with the generalized Schoenfeld approach, with no evidence of violation. A two‐tailed p value of < 0.05 was considered as significant.
3. Results
A total of 1028 patients were included in each cohort after PSM. As illustrated in Figure 1, the differences between cohort 1 and 2 were reduced after PSM, thereby reducing the potential impact of confounders on the analysis and results. Table 2 summarizes the baseline characteristics of the study population before and after PSM. Majority of the patients were male; 52% and 53% in cohorts 1 and 2 respectively. Cohort 1 had a mean age of 40.8 years and in cohort 2 the mean age was 41.2 years. Enterocolitis was the most prevalent co‐morbid condition amongst the study participants. This was followed by diabetes mellitus, heart failure and all other chronic conditions respectively. Antimicrobials/antibiotics use was seen in approximately 90% of the study participants.
Figure 1.
Propensity score matching graph.
Table 2.
Baseline characteristics.
| Before matching | After matching | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|
|
Cohort 1 n = 1341 |
% cohort |
Cohort 2 n = 1447 |
% cohort | P‐value |
Cohort 1 n = 1028 |
% cohort |
Cohort 2 n = 1028 |
% cohort | P‐value | |
| Demographics | ||||||||||
|
Age at Index Mean ± SD |
40.6 ± 17.9 | 100 | 40.6 ± 17.8 | 100 | 0.97 | 40.8 ± 17.9 | 100 | 41.2 ± 17.9 | 100 | 0.61 |
| Female | 673 | 50.2 | 680 | 47.0 | 0.09 | 499 | 48.5 | 480 | 46.7 | 0.40 |
| Diagnosis | ||||||||||
| Enterocolitis (Clostridium difficile) | 318 | 23.7 | 155 | 10.7 | < 0.001 | 161 | 15.7 | 152 | 14.8 | 0.58 |
| Diabetes | 170 | 12.7 | 141 | 9.7 | 0.01 | 122 | 11.9 | 121 | 11.8 | 0.95 |
| Heart failure | 81 | 6.0 | 51 | 3.5 | 0.002 | 50 | 4.9 | 49 | 4.8 | 0.92 |
| Chronic obstructive pulmonary disease | 63 | 4.70 | 56 | 3.9 | 0.28 | 46 | 4.5 | 51 | 5.0 | 0.60 |
| Medications | ||||||||||
| Antimicrobials | 1235 | 92.1 | 1008 | 69.7 | < 0.001 | 924 | 89.9 | 924 | 89.9 | > 0.99 |
| Antibiotics | 767 | 57.2 | 497 | 34.3 | < 0.001 | 478 | 46.5 | 497 | 48.3 | 0.40 |
Concurrent administration of antibiotics and antimicrobials with rescue infliximab in ASUC does not appear to confer added benefit. After PSM, the cohorts did not differ with respect to the rate of IBD related surgery (HR: 1.18; 95% CI: 0.82–1.70), colectomy (HR: 1.08; 95% CI: 0.54–2.13), sepsis (HR: 1.36; 95% CI: 0.84–2.20) and mortality (HR: 0.81; 95% CI: 0.32–2.05). However, cohort 1 was more likely to utilize emergency department services (HR: 1.29; 95% CI: 1.02–1.64) and critical care services (HR: 2.36; 95% CI: 1.31–4.24) in the studied outcome time period (Table 3, Figure 2).
Table 3.
Comparison of study outcomes between cohorts.
| Patients with outcome (n) | |||||
|---|---|---|---|---|---|
| Outcome | Cohort 1 | Cohort 2 | Hazard ratio | 95% Confidence interval | Log rank p value |
| IBD related surgery | 63 | 54 | 1.18 | 0.82–1.70 | 0.37 |
| Colectomy | 17 | 16 | 1.08 | 0.54–2.13 | 0.84 |
| Sepsis | 39 | 29 | 1.36 | 0.84–2.20 | 0.21 |
| Emergency department services | 151 | 120 | 1.29 | 1.02–1.64 | 0.037 |
| Critical care | 37 | 16 | 2.36 | 1.31–4.24 | 0.003 |
| Mortality | 10* | 10 | 0.81 | 0.32–2.05 | 0.65 |
Figure 2.
Kaplan‐Meier curves for all outcomes. (a) IBD Related Surgery (log‐rank test, p = 0.37); (b) Colectomy (log‐rank test p = 0.84); (c) Sepsis (log‐rank test, p = 0.21); (d) Emergency Department Services (log‐rank test, p = 0.04); (e) Critical care services (log‐rank test, p = 0.003); (f) Mortality (log‐rank test, p = 0.65).
Results from the sub‐group analysis that excluded patients who had documentation of sepsis in the 3 months after an inpatient visit showed Cohort 1 was significantly more likely to experience use of critical care services (HR: 3.40; 95% CI: 0.94–12.35; Log Rank p = 0.048) and the use of emergency department services (HR: 1.52; 95% CI: 1.14–2.02; Log Rank p = 0.0041).
4. Discussion
ASUC is a serious complication of UC and can result in poor outcomes if appropriate and timely treatment is not instituted. Hospitalization is required for rescue therapy when corticosteroids are not effective at inducing remission. Concurrent antibiotics are often administered to patients receiving rescue infliximab therapy but the evidence supporting this practice is sparse. Mucosal inflammation and epithelial barrier damage in ASUC may lead to bacteria translocation which increases the risk of sepsis. Based on this, the screening for an underlying infectious etiology in ASUC and addition of antibiotics to the treatment regimen is often seen in clinical practice [19, 28].
Gorelik and colleagues in their 2022 study showed an immunogenic response in patients on anti‐TNF inhibitors who receive antibiotics [27]. Specific antibiotic classes such as fluoroquinolones and macrolides can alter the gut microbiome and decrease anti‐drug antibodies (ADA) development. This eventually impacts the effectiveness of the anti‐TNF inhibitor. The study, however, did not look at clinical outcomes such as remission rates and the complications of ASUC in patients who received both infliximab and antibiotics compared to infliximab alone. With the rising healthcare cost, risk of adverse effects and antibiotic resistance that come with increased antibiotic use, there is the need for large studies to further investigate this topic.
In this comprehensive large retrospective cohort study, we examined and compared the outcomes of rescue infliximab with antibiotics in ASUC to rescue infliximab without antibiotics. Patient characteristics in our study are similar to earlier studies which showed UC is more common in males and has a bimodal distribution with a second peak in the 5th decade of life [3]. Our study showed there is no difference in the outcomes of patients who received rescue infliximab simultaneously with antibiotics compared to infliximab without antibiotics with regard to risk of IBD related surgery, colectomy, sepsis and mortality. There was, however, a significant difference observed in utilization of emergency department services and critical care services; with the antibiotic group being more likely to utilize these services.
Sepsis is a known complication in patients with IBD and may impact study outcomes, specifically critical care and emergency department utilization. We performed a sub‐group analysis that excluded patients who had documentation of sepsis in the 3 months after an inpatient visit. This was to help mitigate any effect that sepsis may have had on the observed differences. Analysis of this patient subset resulted in a significant difference between cohorts in the use of critical care and the use of emergency department services, with both being more likely in Cohort 1.
Overall, patients with ASUC and UC typically have increased length of stay and the associated increased healthcare expenditure. The provision of empiric antibiotics adds to healthcare costs and increases risk of drug resistance. Prior studies have shown mixed results on the benefits of antibiotics administration with steroids in ASUC treatment [22, 23, 24, 25]. Our findings are particularly important and show no additional benefits to the use of empiric antibiotics in the absence of proven infection in ASUC patients admitted for rescue infliximab. More importantly, it may lead to worse outcomes and increased healthcare utilization. Further robust studies are required to explore the role of antibiotics on ADA development and infliximab efficacy.
There are early encouraging reports on the use of small molecules and other biologics specifically tofacitinib, ustekinumab and upadacitinib as rescue therapy predominantly in patients not responding to infliximab rescue therapy [15, 16, 17]. Larger studies are needed to improve our understanding on the use and positioning of these therapies.
A major strength of our study is our large sample size. Additionally, we extracted follow up data on patients for up to 40 days post index event, to detect differences in in other outcomes and survival. To the best of our knowledge this is the first study that addresses the subject of clinical outcomes of concurrent antibiotic administration with rescue infliximab.
We recognize the limitations associated with our study. First, it is from a retrospective data set and some relevant data may have been lost in the process of data collection. In addition, the decision to administer antibiotics was solely at the discretion of the healthcare providers and this may have resulted in selection bias. We performed PSM of the sample to mitigate this effect. Data on the exact antibiotic type administered was unavailable and identification may have provided further information on the common antibiotics administered in ASUC.
Our study adds credence to the American Gastroenterology Association technical review recommendation on management of ASUC, which indicates adjunctive antibiotics may not be effective at decreasing complications of ASUC. It also highlights the need for continued provider education to decrease the rate of empiric antibiotic use in ASUC. Further large prospective studies are needed to address this further.
Author Contributions
Kofi Clarke: conceptualization, investigation, supervision, writing – review and editing. Dominic Amakye: investigation, writing – original draft. Jiqing Shi: investigation, writing – original draft. Shannon Dalessio: data curation, writing – review and editing. Kara DiJoseph: investigation, writing – review and editing. Matthew D. Coates: investigation, writing – review and editing.
Ethics Statement
The data reviewed in this study is a secondary analysis of existing data, does not involve intervention or interaction with human subjects, and is deidentified per the de‐identification standard defined in Section §164.514(a) of the HIPAA Privacy Rule. The process by which the data is deidentified is attested to through a formal determination by a qualified expert as defined in Section §164.514(b)(1) of the HIPAA Privacy Rule. Therefore, the data analyzed within the TriNetX platform does not require ethical approval or consent for its use. https://trinetx.com/real-world-resources/case-studies-publications/trinetx-publication-guidelines/
Conflicts of Interest
The authors declare that no funding sources or financial relationships had any involvement in the study design, data collection, analysis, or interpretation, the writing of the report, or the decision to submit the report for publication.
Transparency Statement
The lead author Kofi Clarke affirms that this manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained.
Acknowledgments
Access to TriNetX is provided by Penn State Clinical and Translational Science Institute and is supported by the National Center for Advancing Translational Sciences, National Institutes of Health, through Grant UL1 TR002014. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.
Kofi Clarke and Dominic Amakye are considered as co‐first authors.
Data Availability Statement
All data generated or analyzed during this study are included in this article. Data that support the findings of this study are available from TriNetX LLC (https://trinetx.com/), access to which may require a data sharing agreement. Further enquiries can be directed to the corresponding author.
References
- 1. Dahlhamer J. M., Zammitti E. P., Ward B. W., Wheaton A. G., and Croft J. B., “Prevalence of Inflammatory Bowel Disease Among Adults Aged ≥18 Years ‐ United States, 2015,” Morbidity and Mortality Weekly Report 65 (2016): 1166–1169. [DOI] [PubMed] [Google Scholar]
- 2. Gros B. and Kaplan G. G., “Ulcerative Colitis in Adults: A Review,” Journal of the American Medical Association 330 (2023): 951–965. [DOI] [PubMed] [Google Scholar]
- 3. E. V. Loftus, Jr. , “Clinical Epidemiology of Inflammatory Bowel Disease: Incidence, Prevalence, and Environmental Influences,” Gastroenterology 126 (2004): 1504–1517. [DOI] [PubMed] [Google Scholar]
- 4. Ng S. C., Shi H. Y., Hamidi N., et al., “Worldwide Incidence and Prevalence of Inflammatory Bowel Disease in the 21st Century: A Systematic Review of Population‐Based Studies,” Lancet 390 (2017): 2769–2778. [DOI] [PubMed] [Google Scholar]
- 5. Dignass A., Eliakim R., Magro F., et al., “Second European Evidence‐Based Consensus on the Diagnosis and Management of Ulcerative Colitis Part 1: Definitions and Diagnosis,” Journal of Crohn's and Colitis 6 (2012): 965–990. [DOI] [PubMed] [Google Scholar]
- 6. Park K. T., Ehrlich O. G., Allen J. I., et al., “The Cost of Inflammatory Bowel Disease: An Initiative From the Crohn's & Colitis Foundation,” Inflammatory Bowel Diseases 26 (2020): 1–10. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7. Amakye D., Kesiena O., Ademiluyi A., Gavor M., and Rabeeah Z., “Venous Thromboembolism Prophylaxis in Inflammatory Bowel Disease: A Two‐Year Retrospective Study of Patients Presenting With Inflammatory Bowel Disease to a Community Hospital,” Cureus 14 (2022): e29178. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8. Singh S., Allegretti J. R., Siddique S. M., and Terdiman J. P., “AGA Technical Review on the Management of Moderate to Severe Ulcerative Colitis,” Gastroenterology 158 (2020): 1465–1496.e17. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9. Burri E., Maillard M. H., Schoepfer A. M., et al., “Treatment Algorithm for Mild and Moderate‐to‐Severe Ulcerative Colitis: An Update,” supplement, Digestion 101, no. Suppl 1 (2020): 2–15. [DOI] [PubMed] [Google Scholar]
- 10. Feuerstein J., “Hospital Management of Acute Severe Ulcerative Colitis,” Gastroenterology & Hepatology 17 (2021): 128–131. [PMC free article] [PubMed] [Google Scholar]
- 11. Järnerot G., Rolny P., and Sandberg‐Gertzén H., “Intensive Intravenous Treatment of Ulcerative Colitis,” Gastroenterology 89 (1985): 1005–1013. [DOI] [PubMed] [Google Scholar]
- 12. Chao C. Y., Al Khoury A., Aruljothy A., et al., “High‐Dose Infliximab Rescue Therapy for Hospitalized Acute Severe Ulcerative Colitis Does Not Improve Colectomy‐Free Survival,” Digestive Diseases and Sciences 64 (2019): 518–523. [DOI] [PubMed] [Google Scholar]
- 13. Rutgeerts P., Sandborn W. J., Feagan B. G., et al., “Infliximab for Induction and Maintenance Therapy for Ulcerative Colitis,” New England Journal of Medicine 353 (2005): 2462–2476. [DOI] [PubMed] [Google Scholar]
- 14. Sandborn W. J., Rutgeerts P., Feagan B. G., et al., “Colectomy Rate Comparison After Treatment of Ulcerative Colitis With Placebo or Infliximab,” Gastroenterology 137 (2009): 1250–1260; quiz 520. [DOI] [PubMed] [Google Scholar]
- 15. Clinton J., Motwani K. K., Schwartz S., et al., “Upadacitinib as Rescue Therapy for the Treatment of Acute Severe Colitis in an Acute Care Setting,” Digestive Diseases and Sciences 69 (2024): 1105–1109. [DOI] [PubMed] [Google Scholar]
- 16. Huang C. W., Yen H. H., and Chen Y. Y., “Rescue Therapies for Steroid‐Refractory Acute Severe Ulcerative Colitis: A Systemic Review and Network Meta‐Analysis,” Journal of Crohn's & Colitis (2024): jjae111, 10.1093/ecco-jcc/jjae111. [DOI] [PubMed] [Google Scholar]
- 17. Ranjan M. K., Neupane P., and Maharjan B., “Utility of Tofacitinib in Steroid‐Refractory Acute Severe Ulcerative Colitis,” Cureus 16 (2024): e71485. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18. Martinez‐Medina M. and Garcia‐Gil L. J., “ Escherichia coli in Chronic Inflammatory Bowel Diseases: An Update on Adherent Invasive Escherichia coli Pathogenicity,” World Journal of Gastrointestinal Pathophysiology 5 (2014): 213–227. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19. Wong C. K. W. and Yacyshyn B. R., “Fulminant Ulcerative Colitis,” Current Treatment Options in Gastroenterology 3 (2000): 217–226. [DOI] [PubMed] [Google Scholar]
- 20. Nitzan O., “Role of Antibiotics for Treatment of Inflammatory Bowel Disease,” World Journal of Gastroenterology 22 (2016): 1078–1087. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21. Gupta V., Rodrigues R., Nguyen D., et al., “Adjuvant Use of Antibiotics With Corticosteroids in Inflammatory Bowel Disease Exacerbations Requiring Hospitalisation: A Retrospective Cohort Study and Meta‐Analysis,” Alimentary Pharmacology & Therapeutics 43 (2016): 52–60. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22. Mantzaris G. J., Petraki K., Archavlis E., et al., “A Prospective Randomized Controlled Trial of Intravenous Ciprofloxacin as an Adjunct to Corticosteroids in Acute, Severe Ulcerative Colitis,” Scandinavian Journal of Gastroenterology 36 (2001): 971–974. [DOI] [PubMed] [Google Scholar]
- 23. Mantzaris G. J., Hatzis A., Kontogiannis P., and Triadaphyllou G., “Intravenous Tobramycin and Metronidazole as an Adjunct to Corticosteroids in Acute, Severe Ulcerative Colitis,” American Journal of Gastroenterology 89 (1994): 43–46. [PubMed] [Google Scholar]
- 24. Chapman R. W., Selby W. S., and Jewell D. P., “Controlled Trial of Intravenous Metronidazole as an Adjunct to Corticosteroids in Severe Ulcerative Colitis,” Gut 27 (1986): 1210–1212. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25. Dickinson R. J., O'Connor H. J., Pinder I., Hamilton I., Johnston D., and Axon A. T., “Double Blind Controlled Trial of Oral Vancomycin as Adjunctive Treatment in Acute Exacerbations of Idiopathic Colitis,” Gut 26 (1985): 1380–1384. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26. Dao A., Abidian M., Lestrange A., Mattar M., Rangnekar A., and Charabaty A., “Oral Vancomycin Induces and Maintains Remission of Ulcerative Colitis in the Subset of Patients With Associated Primary Sclerosing Cholangitis,” Inflammatory Bowel Diseases 25 (2019): e90–e91. [DOI] [PubMed] [Google Scholar]
- 27. Gorelik Y., Freilich S., Gerassy‐Vainberg S., et al., “Antibiotic Use Differentially Affects the Risk of Anti‐Drug Antibody Formation During anti‐TNFα Therapy in Inflammatory Bowel Disease Patients: A Report From the epi‐IIRN,” Gut 71 (2022): 287–295. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28. Tamir‐Degabli N., Maharshak N., and Cohen N. A., “Salvage Therapy in Acute Severe Ulcerative Colitis: Current Practice and a Look to the Future,” Turkish Journal of Gastroenterology 34 (2023): 576–583. [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
All data generated or analyzed during this study are included in this article. Data that support the findings of this study are available from TriNetX LLC (https://trinetx.com/), access to which may require a data sharing agreement. Further enquiries can be directed to the corresponding author.