Please summarize evidence for using rectal administration of vancomycin for Clostridoides difficile infections including dose and compounding instructions.

Comment by InpharmD Researcher

The evidence is mixed regarding the use of a prepared vancomycin enema for rectal treatment of Clostridoides difficile infection (CDI). Guidelines appear to support regular and high-dose vancomycin enema for severely complicated CDI, but robust data is lacking, and treatment failures remain evident throughout the literature. The enema is typically prepared by mixing vancomycin 100-500 mg in 100-500 mL of tap water or normal saline and dosed most frequently at Q6H. Yet details for compounding the enema are lacking, and the optimal preparation and dosing method has not been identified.

Background

A 2019 review provides updates on current guidelines for the treatment of Clostridium difficile infections (CDIs) and the role of vancomycin enemas in therapy, particularly for patients with ileus involvement (see Table 1). Generally, Data are retrieved from published case series, which detail the use of higher vancomycin dose, enema volume, and enema retention, with vancomycin doses typically distilled in 0.9% saline. Conversely, using lower doses (125-250 mg q6h) and volumes (e.g., 100 mL) did not result in significance when assessing clinical outcomes. Based on the evidence identified, the authors recommend using vancomycin 500 mg q6h, in a volume of 500 mL, per rectum via retention enema for patients with adynamic ileus for optimal efficacy. Notably, compounding instructions were not identified for the recommended vancomycin enemas. [1]

A 2020 narrative review summarized the evidence on the efficacy and adverse effects of high-dose vancomycin (> 500 mg/day) for the treatment of CDIs, which includes vancomycin retention enemas. Overall, key findings revealed little evidence supporting the superior efficacy of high-dose oral vancomycin over the standard 125 mg dose for non-severe or severe cases. In fulminant CDI, some weak observational evidence suggested potential benefits of high-dose oral vancomycin when combined with intravenous (IV) metronidazole and retention enemas, particularly in cases of ileus, though robust RCT data is lacking. It also highlighted the variable recommendations by major guidelines such as the Infectious Diseases Society of America (IDSA) and the European Society of Clinical Microbiology and Infectious Diseases (ESCMID). These guidelines generally support the use of high-dose oral vancomycin in fulminant disease, particularly when ileus or toxic megacolon is present, with or without the addition of vancomycin retention enemas, while evidence remains insufficient for the routine use of high doses in non-fulminant CDI. In conclusion, larger studies are needed to clarify the role of high-dose vancomycin, particularly in fulminant CDI, and emphasize the need for better-defined dosing schedules to optimize treatment outcomes. [2]

A 2015 case report discussed the treatment of a 33-year-old man with refractory CDI resistant to vancomycin that ultimately required transplantation with fecal microbiota. In the case report, the authors prepared the vancomycin enema by instilling 500 mg of vancomycin in 100 mL of normal saline and administering 4 times per day. However, the patient returned 8 days later with complaints of pain and persistent diarrhea, necessitating the use of fecal microbiota, which eventually led to symptom resolution. [3]

A 2014 letter to the editor summarized the author’s institutional experience with the use of per rectum (PR) vancomycin in the treatment of CDI. The management guidelines for CDI recommend stratifying treatment based on disease severity, with the presence of ileus, megacolon, and hypotension/shock considered severe-complicated CDI. In these cases, guidelines suggest adding PR vancomycin to the standard treatment of oral vancomycin and IV metronidazole. The authors identified 17 patients who received PR vancomycin between 2005 and 2012, with the majority having severe-complicated CDI. The most common dosing regimen was 500 mg of PR vancomycin every 6 hours, and most patients (88%) also received concomitant oral vancomycin. However, there was a wide variety of vancomycin doses administered. The authors also observed a high failure rate (29%) among these patients, with three requiring colectomy, one receiving fecal transplantation, and one dying of CDI. [4]

References:

[1] Fawley J, Napolitano LM. Vancomycin Enema in the Treatment of Clostridium difficile Infection. Surg Infect (Larchmt). 2019;20(4):311-316. doi:10.1089/sur.2018.238.
[2] Bader MS, Hawboldt J, Main C, Mertz D, Loeb M, Farrell A, Joyce J. Review of high dose vancomycin in the treatment of Clostridioides difficile infection. Infect Dis (Lond). 2020 Nov-Dec;52(12):847-857. doi: 10.1080/23744235.2020.1800080. Epub 2020 Aug 3. PMID: 32744879.
[3] Jang MO, An JH, Jung SI, Park KH. Refractory Clostridium difficile Infection Cured With Fecal Microbiota Transplantation in Vancomycin-Resistant Enterococcus Colonized Patient. Intest Res. 2015 Jan;13(1):80-4. doi: 10.5217/ir.2015.13.1.80. Epub 2015 Jan 29. PMID: 25691847; PMCID: PMC4316227.
[4] Saffouri G, Khanna S, Estes L, Pardi D. Outcomes from rectal vancomycin therapy in patients with Clostridium difficile infection. Am J Gastroenterol. 2014 Jun;109(6):924-5. doi: 10.1038/ajg.2014.80. PMID: 24896763.

Literature Review

A search of the published medical literature revealed 3 studies investigating the researchable question:

Please summarize evidence for using rectal administration of vancomycin for Clostridoides difficile infections including dose and compounding instructions.

Level of evidence

C - Multiple studies with limitations or conflicting results  Read more→



Please see Tables 1-3 for your response.


 

Guideline Recommendations for Vancomycin Enema for Clostridium difficile Infection (CDI)

Guideline Severe Complicated Disease

Australasian Society for Infectious Diseases (ASID) Guidelines 2016

If patient is unable to tolerate oral therapy: vancomycin 125 mg QID by nasogastric (NGT) AND IV metronidazole 500 mg TID ± rectal tube vancomycin 500 mg in 100 mL of 0.9% saline TID-QID.

Infectious Diseases Society of America (IDSA)/Society for Healthcare Epidemiology of America (SHEA) Guidelines 2017

If ileus is present, consider adding rectal instillation of vancomycin (500 mg in ~100 mL of 0.9% saline per rectum q6h as a retention enema). IV administered metronidazole (500 mg q8h) should be administered together with oral or rectal vancomycin, particularly if ileus is present.

World Society of Emergency Surgery (WSES) Guidelines 2019

In patients in whom oral antibiotics cannot reach the colon, vancomycin may be administered as retention enema via a large rectal tube or catheter (Recommendation 1B).

Patients with fulminant colitis should be treated with high dose vancomycin (500 mg q6h), oral and/or by enema, in combination with intravenous metronidazole (500 mg q8h) (Recommendation 1 C).

American College of Gastroenterology (ACG) Guidelines 2021

For patients with an ileus, the addition of vancomycin enemas (500 mg in 100 mL saline q6h) may be beneficial (conditional recommendation, very low quality of evidence)

Clinical benefit is questionable, however, based on a retrospective study failing to show decreased mortality with adjunctive vancomycin enemas; theoretically, drug delivery by enema in the setting of ileus may be beneficial, as medications may not pass beyond the upper gastrointestinal (GI) tract when orally administered in this setting. 

American Society of Colon and Rectal Surgeons (ASCRS) Guidelines 2021

Vancomycin 500 mg QID orally and metronidazole 500 mg IV TID; for patients with ileus, consider adding vancomycin per rectum.

Vancomycin enema therapy may be dose- and volume-dependent.

European Society of Clinical Microbiology and Infectious Diseases (ESCMID) Guidelines 2021

When oral therapy is not possible, attempt intraluminal (gastroduodenal or coloscopic) delivery of vancomycin or fidaxomicin (Good practice statement)

Evidence for intraluminal vancomycin is limited to case series (dosages 250 mg QD to 1 g QID; most common 500 mg q6h for a median of 7 days)

References:

[1] Fawley J, Napolitano LM. Vancomycin Enema in the Treatment of Clostridium difficile Infection. Surg Infect (Larchmt). 2019;20(4):311-316. doi:10.1089/sur.2018.238
[2] Johnson S, Lavergne V, Skinner AM, et al. Clinical Practice Guideline by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA): 2021 Focused Update Guidelines on Management of Clostridioides difficile Infection in Adults. Clin Infect Dis. 2021;73(5):e1029-e1044. doi:10.1093/cid/ciab549
[3] McDonald LC, Gerding DN, Johnson S, et al. Clinical Practice Guidelines for Clostridium difficile Infection in Adults and Children: 2017 Update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA). Clin Infect Dis. 2018;66(7):e1-e48. doi:10.1093/cid/cix1085
[4] Kelly CR, Fischer M, Allegretti JR, et al. ACG Clinical Guidelines: Prevention, Diagnosis, and Treatment of Clostridioides difficile Infections [published correction appears in Am J Gastroenterol. 2022 Feb 1;117(2):358. doi: 10.14309/ajg.0000000000001529]. Am J Gastroenterol. 2021;116(6):1124-1147. doi:10.14309/ajg.0000000000001278
[5] van Prehn J, Reigadas E, Vogelzang EH, et al. European Society of Clinical Microbiology and Infectious Diseases: 2021 update on the treatment guidance document for Clostridioides difficile infection in adults. Clin Microbiol Infect. 2021;27 Suppl 2:S1-S21. doi:10.1016/j.cmi.2021.09.038
[6] Sartelli M, Di Bella S, McFarland LV, et al. 2019 update of the WSES guidelines for management of Clostridioides (Clostridium) difficile infection in surgical patients. World J Emerg Surg. 2019;14:8. Published 2019 Feb 28. doi:10.1186/s13017-019-0228-3
[7] Poylin V, Hawkins AT, Bhama AR, et al. The American Society of Colon and Rectal Surgeons Clinical Practice Guidelines for the Management of Clostridioides difficile Infection. Dis Colon Rectum. 2021;64(6):650-668. doi:10.1097/DCR.0000000000002047

 

Intracolonic use of vancomycin for treatment of clostridium difficile colitis in a patient with a diverted colon: report of a case

Design

Case report

Case presentation

A 59-year-old Hispanic male, presented with abdominal pain, distention, and diarrhea, and was found to have perforated cecal diverticulitis. Stool samples before antibiotic therapy were positive for C. difficile toxin. The patient underwent a right hemicolectomy with end ileostomy, and was started on ciprofloxacin and metronidazole.

On postoperative day 8, the patient developed profuse diarrhea via the ileostomy, with a high white blood cell count. Stool samples were negative for C. difficile toxin. The ciprofloxacin was discontinued, and intravenous metronidazole was continued.

On postoperative day 10, the diarrhea persisted, and a flexible sigmoidoscopy revealed diffuse pseudomembranes. A course of vancomycin enemas was initiated prepared by mixing 500 mg vancomycin in 500 mL normal saline per rectum twice daily, which led to a gradual improvement in the patient's condition. By the eighth day of this therapy, the diarrhea had resolved, and a follow-up sigmoidoscopy showed complete resolution of the colitis.

Study Author Conclusions

In view of the reports of failure of intravenous metronidazole to effectively treat pseudomembranous colitis, consideration should be given to the early administration of intracolonic vancomycin when the oral route is not available.

References:

Nathanson DR, Sheahan M, Chao L, Wallack MK. Intracolonic use of vancomycin for treatment of clostridium difficile colitis in a patient with a diverted colon: report of a case. Dis Colon Rectum. 2001 Dec;44(12):1871-2. doi: 10.1007/BF02234471. PMID: 11742178.

 

Vancomycin Enemas as Adjunctive Therapy for Clostridium difficile Infection

Design

Retrospective case-control study

N= 24

Objective

To examine clinical outcomes of patients with clostridium difficile infection (CDI) treated with vancomycin per rectal (VPR) and compare results to a matched control group.

Study Groups

Rectal vancomycin (n= 24)

No rectal vancomycin (n= 48)

Inclusion Criteria

Patients with diarrhea and positive stool test for C. difficile toxin and/or pseudomembranes, received 4 or more doses of VPR

Exclusion Criteria

Alternative causes for symptoms

Methods

Data were collected from a single tertiary-care intensive care unit (ICU). All patients with diarrhea and positive stool test or pseudomembranes were included for analysis. VPR was prepared by mixing 100 mL of tap water with vancomycin to create a dose that ranged from 125 to 250 mg, and was administered every 6-8 hours.

Duration

Data collection period: January 2003 to December 2013

Outcome Measures

Primary: Combined endpoint of colon surgery or death

Baseline Characteristics

 

Rectal vancomycin (n= 24)

No rectal vancomycin (n= 48)

 

Age, years

61.8 61.1  

Male

45.8% 52.1%  

Immunosuppression

17.4% 16.7%  

Albumin, g/dL

2.01 1.91  

APACHE II

20.0 20.0  

Overall LOS

25.0 28.0  

ICU LOS

12.0 14.0  

Episode severity

Mild-moderate

Severe

Severe complicated

 

4.2%

25%

70.8%

 

6.3%

45.8%

47.9%

 

Results

Endpoint

Rectal vancomycin (n= 24)

No rectal vancomycin (n= 48)

p-Value

Combined endpoint

Colon surgery

Death

Survived

50%

4 (16.7)

11 (45.8%)

3

45.8%

8 (16.7%)

20 (41.7%)

2

0.73

1.00

0.74

--

Adverse Events

N/A

Study Author Conclusions

In a case-control study, the use of VPR was not demonstrated to reduce the need for colectomy or decrease mortality. Based on our modest sample size and failure to show efficacy, we cannot strongly advocate for the use of VPR

InpharmD Researcher Critique

As noted by the authors, the study has several weaknesses, including a small sample size that may lead to type II errors, lack of control over antibiotic regimens and timing of treatment, and the unavailability of C. difficile strain data during the study period.

References:

Malamood M, Nellis E, Ehrlich AC, Friedenberg FK. Vancomycin Enemas as Adjunctive Therapy for Clostridium difficile Infection. J Clin Med Res. 2015 Jun;7(6):422-7. doi: 10.14740/jocmr2117w. Epub 2015 Apr 8. PMID: 25883704; PMCID: PMC4394914.