Vancomycin Enema in the Treatment of Clostridium difficile Infection

Abstract

Background:

Current guidelines for the treatment of Clostridium difficile infections (CDIs) recommend vancomycin enemas for patients with adynamic ileus. There is significant variability in guideline recommendations for vancomycin dose and enema volume and whether a retention enema should be used. The most recent (2017) guidelines from the Infectious Diseases Society of America/Society for Healthcare Epidemiology of America recommend rectal instillation of 500 mg of vancomycin in 100 mL of physiologic saline every 6 hours as a retention enema.

Methods:

Published studies regarding vancomycin enema use in CDI (1990–present) were reviewed to compare drug dose, volume, and whether a retention enema was used in order to determine the efficacy and make recommendations for optimal dosing.

Results:

Case series with higher vancomycin dose, higher enema volume, and use of retention enema demonstrated greater efficacy. Use of smaller volumes and lower doses (100 mL; 125–250 mg q 6 hours) demonstrated no efficacy of intracolonic vancomycin.

Conclusion:

We recommend revision of the current CDI guideline recommendations for patients with adynamic ileus to the following: Vancomycin per rectum (500 mg in a volume of 500 mL q 6 hours) by retention enema (18F Foley catheter with 30-cc balloon inserted into the rectum, balloon inflated, solution instilled, and catheter clamped for 60 minutes) for optimal efficacy.

Severe Clostridium difficile infection (CDI) carries a high mortality rate. Early diagnosis and aggressive medical management is imperative to improve outcomes. Although enteral vancomycin is the primary recommended treatment for CDI, the presence of adynamic ileus may prevent oral vancomycin from reaching the distal colon.

In patients with ileus, vancomycin retention enemas are recommended by national and international guidelines to treat the distal colon adequately. We reviewed the current recommendations regarding vancomycin enema for patients with CDI and ileus and the evidence available regarding the treatment's efficacy in CDI.

Variable Recommendations for Vancomycin Enema for CDI

There is significant variability in the national and international guideline recommendations for vancomycin enema for CDI regarding dose, volume, and whether retention enemas should be used (Table 1).

Table 1.

Guideline Recommendations for Vancomycin Enema for Clostridium difficile Infection

Guideline	Severe Complicated Disease
IDSA/SHEA Guidelines 2010 [5]	Vancomycin 500 mg q 6 h orally (PO) or via nasogastric tube (NGT) and metronidazole 500 mg q 8 h intravenously (IV). Consider adding vancomycin 500 mg (in 100 mL of 0.9% saline) q 6 h via enema if ileus is present
American College of Gastroenterology (ACG) Guidelines 2013 [10]	Vancomycin delivered PO (500 mg QID) and per rectum (500 mg in 500 mL QID) plus intravenous metronidazole (500 mg TID) is the treatment of choice for patients with complicated CDI with ileus or toxic colon or significant abdominal distention. (Strong recommendation; low-quality evidence) Direct instillation via colonic retention enema, colonoscopy, or long rectal tube is an effective strategy in smaller series reports. For this approach, vancomycin 500 mg in at least 500 mL QID is recommended. A higher dosing strategy is utilized, and it is given in a greater volume than previously recommended based on the hypothesis that larger volumes increase the likelihood that the drug will be delivered to the more proximal aspect of the colon; a volume of at least 500 mL is believed to ensure delivery to the ascending and transverse colon
European Society of Clinical Microbiology and Infectious Diseases (ESCMID) 2014 [7]	Intravenous metronidazole 500 mg TID for 10 days and intracolonic vancomycin retention enema 500 mg in 100 mL of 0.9% saline QID for 10 days
WSES Guidelines for Management of Clostridium difficile Infection in Surgical Patients 2015 [11]	In patients in whom oral antibiotics cannot reach the colon, vancomycin may be administered by enema, and metronidazole can be given IV (1 g of vancomycin dissolved in 500 mL of 0.9% saline given rectally q 6 h via retention enema)
Practice Parameters for the Management of Clostridium difficile Infection. American Society of Colon and Rectal Surgeons, 2015 [12]	No recommendation regarding vancomycin dose/enema volume. “In addition to the oral route, vancomycin enemas have also been used as an adjunctive treatment for primary therapy, with reported success rates up to 70% to 89%.”
Australasian Society for Infectious Diseases (ASID) 2016 [8,9]	If patient is unable to tolerate oral therapy: vancomycin 125 mg QID by NGT AND IV metronidazole 500 mg TID ± rectal tube vancomycin 500 mg in 100 mL of 0.9% saline TID–QID.
Guidelines Update by IDSA/SHEA 2017 [6]	If ileus is present, consider adding rectal instillation of vancomycin (500 mg in approximately 100 mL of 0.9% saline per rectum q 6 h as a retention enema). Intravenously administered metronidazole (500 mg q 8 h) should be administered together with oral or rectal vancomycin, particularly if ileus is present

The current (2017) Infectious Diseases Society of America (IDSA) Guidelines recommend the following: “If an ileus is present, then vancomycin can also be administered per rectum even though it is unclear whether a sufficient quantity of the drug reaches beyond the left colon. Despite the lack of data, it seems prudent to administer vancomycin by oral and/or rectal routes at higher dosages for patients with fulminant CDI (500 mg 6 hourly by mouth and 500 mg in approximately 100 mL of normal saline by retention enema)” [5,6]. Similar recommendations for vancomycin retention enema are made by the 2014 European Society of Clinical Microbiology and Infectious Diseases (ESCMID) Guidelines [7].

The 2016 Australasian Society for Infectious Diseases (ASID) recommends “rectal tube vancomycin at the same dose and volume as the IDSA and ESCMID guidelines (500 mg in 100 mL of 0.9% saline) [8,9] but states that administration every six or eight hours is acceptable. This organization does not indicate that a retention enema should be used.

In contrast to the IDSA, ESCMID, and ASID guidelines, the American College of Gastroenterology (ACG) 2013 guidelines recommend a vancomycin dose of 500 mg in a higher volume (500 mL) four times a day and does not specify whether a retention enema should be used [10]. The 2015 World Society of Emergency Surgery (WSES) guidelines recommend vancomycin retention enemas in a higher dose and volume than all other guidelines (1 g of vancomycin dissolved in 500 mL of 0.9% saline given rectally every six hours via retention enema) [11].

Although most guidelines recommend enemas of vancomycin in 100 mL for CDI treatment in patients with adynamic ileus, significant concern remains that a volume of 100 mL of 0.9% saline is not adequate to reach the distal or proximal colon. In view of this concern, it is important to review the evidence regarding the efficacy of vancomycin retention enemas in CDI.

Evidence for the Efficacy of Vancomycin Enema for CDI

There are limited published data evaluating the efficacy of vancomycin enemas in CDI. An early report described administration of vancomycin directly into the colon via a catheter placed by colonoscopy, with an initial dose of 2000 mg, followed by a 100-mg dose every six hours, combined with an additional 100 mg after every watery stool is passed for 14 days for severe CDI [1]. In 1993, a comprehensive review recommended the following CDI treatment for adynamic ileus: “Consider direct instillation of vancomycin (500 mg/Liter) by rectal perfusion or by long intestinal tube” [2]. The initial IDSA Practice Guidelines for the Management of Infectious Diarrhea recommended enteral metronidazole for CDI and made no suggestions for vancomycin enema [3].

Published case series provide additional information regarding the efficacy of vancomycin enema for CDI treatment (Table 2). In 1994, Olson et al. described a 10-year experience treating CDI [4]. Of the 908 patients in the study, eight were treated with vancomycin retention enema (clamp time minimum 60 minutes) 500 mg in 100 mL of 0.9% saline for ileus. This strategy resulted in six survivors. However, of the survivors, only three had documented pseudomembranous colitis, and the severity of the CDI was uncertain in the other three patients.

Table 2.

Studies of Vancomycin Enema Efficacy in Clostridium difficile Treatment

Reference	No. of Cases	Hospital Setting	Co-Morbidities and Outcomes	Intracolonic Vancomycin Dosing Regimens per Rectum
Akamine et al. [18]	26 with moderate/severe CDI seen over 10 years: 2003–2012 compared with 101 patients without intracolonic vancomycin	Single VA center, Loma Linda, CA	Median age 69 y; mean Severity Score Index (range 0–9) = 5.2 suggestive of “moderate” CDI; mean white blood cell count (WBC) 27K; 10 patients died	Variable doses ranging from 0.25 g q 24 h to 1 g q 6 h; most common dose 500 mg q 6 h; no data regarding enema volume
Saffouri et al. [16]	17 with “severe” CDI seen over 7 years 2005–2012	Single tertiary-care teaching hospital, Rochester, MN	Median age 70 years; “severe” CDI (WBC >15K or serum creatinine >1.5 × baseline) or “severe complicated” (i.e., shock, hypotension, ileus, toxic megacolon, or ICU admission); 1 patient died	Variable doses ranging from 0.25 g q 6 h to 1 g q 6 h; most common dose 500 mg q 6 h. Variable volumes used (100–1,000 mL)
				Table. Vancomycin Dilution in 0.9% Saline (Modified from Reference 16)
				Saline (mL)	Dose (mg)	No. Pts.	No. Not Tolerating
				1,000	1,000 q 6 h 500 q 8 h 500 q 12 h	2 1 1	0 0 0
				500	500 q 6 h	5	1
				250	250 q 6 h	1	0
				100	500 q 6 h	3	1
				Unknown	500 q 8 h 500 q 6 h 125 q 12 h 250 q 6 h	1 1 1 1	0 0 0 0
Kim et al. [15]	47 with severe CDI seen over 2.75 years: 2007–2009	Single inner-city hospital, Bronx, NY	Mean age 65 years; “severe” CDI (any of the following: WBC >15K, abdominal tenderness, acidosis); mean WBC 27K; 10 patients died. 33 (70%) responded to adjunct vancomycin with complete resolution without surgery	Standard dose was 1 g dissolved in 500 mL of 0.9% saline given rectally q 6 h via retention enema
Apiusarnthanarkak et al. [14]	9 seen over 3 years 1998–2001	Single tertiary-care teaching hospital, St. Louis, MO	Median age 65 years; mean APACHE II score 18 (range 12–26); median WBC 24K; 1 patient died	Variable doses ranging from 0.5 g q 4 h to 1 g q 12 h; most common dose 1 g q 1 2h. An intravenous solution of vancomycin (0.5–1 g dissolved in 1–2 L of 0.9% saline) was prepared and dispensed by the hospital pharmacy; dosing intervals were defined as every 4–12 h at the attending physician's discretion. The method of administration recommended by the hospital pharmacy was retention enema. An 18F Foley catheter with a 30-cc balloon was inserted into the rectum, the balloon inflated, the drug solution instilled, and the catheter clamped for 60 min. The balloon was then deflated and the catheter removed. The therapy was continued until clinical improvement was achieved
Shetler et al. [13]	8 with “severe” CDI with ileus and toxic megacolon	Single VA center, Palo Alto, CA	Mean age 70 years; median WBC 24K; 4 patients died	Decompressive colonoscopy with intracolonic perfusion of vancomycin (0.25 g q 6 h). Vancomycin 1 g was dissolved in 1 L of sterile water. After this, 250 mL of this solution was administered through the colonic tube, which then was clamped for 3 h. This procedure was repeated every 6 h. The tube was connected to low intermittent suction for decompression between drug administrations. This therapy was continued until clinical improvement was achieved
Malamood et al. [17]	24; January 2003–December 2013	Temple University, Philadelphia, PA	For combined outcome of surgery/death, 45.8% for controls and 50.0% for vancomycin group (p = 0.73); no efficacy for vancomycin enemas	Vancomycin per rectum mixed in 100 mL of tap water ranged from 125 to 250 mg q 6–8 h
Olson et al. [4]	8 with severe ileus	Minneapolis VAMC 1982–1991	Efficacy confirmed in 6 patients	Vancomycin retention enemas (500 mg of vancomycin in 100 mL of 0.9% saline). A No. 18 Foley catheter with a 30-cc balloon was inserted into the rectum, the balloon inflated, the medication instilled, and the catheter clamped for 60 min. The balloon then was deflated, the catheter removed, and the treatment repeated q 6 h. Five patients were positive for pseudomembranous colitis at sigmoidoscopy. Seven patients were treated with intravenous metronidazole in addition to the oral medication. This approach proved effective in six patients, with the response time ranging from 4 to 17 d

The Veterans Affairs Palo Alto Health Care System reported outcomes for eight patients who had received vancomycin through a fenestrated tube positioned by colonoscopy with a dose of 250 mg in 250 mL of 0.9% saline every six hours. The tube was clamped for a minimum of three hours after instillation. Only three patients survived [13].

Another single-institution report from Barnes-Jewish Hospital reviewed the outcomes of nine patients treated with vancomycin retention enemas (minimum clamp time 60 minutes) for CDI over a three-year period [14]. Doses and volumes of vancomycin were variable, with ranges from 0.5–1 g dissolved in 1–2 L of 0.9% saline given every 4–12 hours. Complete resolution of CDI was noted in eight patients, with one death from progressive multi-organ failure.

Kim et al. reported the largest case series of patients receiving vancomycin retention enema for CDI [15]. Patients with severe infections (n = 47) were treated with 1 g of vancomycin dissolved in 500 mL of 0.9% saline administered as a retention enema (clamp time not reported). Complete CDI resolution with surgery was reported in 33 patients (70%). Of the 14 patients who had incomplete resolution, nine underwent surgery, with survival in seven patients.

In a report from the Mayo Clinic of 17 patients with severe CDI treated with vancomycin enemas, variable vancomycin doses (most commonly 500 mg) and saline volumes (9 of 17 had 500–1,000 mL) were used [16]. No information was provided on whether there were retention enemas. A complete response was reported in 12 patients. Of the five who did not respond, three underwent colectomy, one had a fecal transplant, and one died.

In a cohort-matched study from Temple University, 24 patients with CDI who were treated with vancomycin retention enemas (125 or 250 mg instilled in 100 mL of tap water every six hours, clamped for a minimum of 30 minutes) were compared with 48 matched controls [17]. No difference in the mortality rate was identified (41.7% in the control patients vs. 45.5% in the vancomycin-treated patients; p = 0.74). In both groups, 16.4% of the patients required surgical intervention.

A retrospective review from Loma Linda University compared 26 patients who received intra-colonic vancomycin (variable doses [from 250 mg q 24 hours to 1 gram q 6 hours; most common dose 500 mg q 6 hours]; no data regarding enema volume or whether they were retention enemas) for severe CDI with 101 patients who did not. The patients who received intracolonic vancomycin had higher rates of toxic megacolon, intensive care unit admission, and colectomy, yet maintained a mortality rate similar to that in the group who received standard treatment, suggesting a protective effect to intra-colonic vancomycin [18].

Discussion

This review has documented that higher vancomycin enema volume, higher vancomycin dose, and the use of retention enema is associated with greater efficacy in CDI treatment. Potential underlying reasons for this are: (1) 100 mL is not adequate to reach the proximal colon; (2) a large enema volume may have a lavage effect on intra-colonic toxin; and (3) the larger volume can introduce oxygen into the colonic lumen, which may perturb the anaerobic C. difficile, which is sensitive to even low levels of oxygen in the environment. However, a smaller volume (100 mL) may suffice for vancomycin instillation into a rectal stump after total abdominal colectomy for CDI [19].

As a reference, for a single-contrast barium enema study, a radiology department commonly dilutes 400 mL of 100% barium in 1,600 mL of water (2,000 mL total) and allows the rectal contrast to flow by gravity (https://radiopaedia.org/articles/single-contrast-barium-enema) until the right side of the colon is opacified. Gastrografin enemas are used for the treatment of distal intestinal obstruction syndrome in patients with cystic fibrosis, and most patients require a volume of 20–50 mL/kg to fill the colon and attempt reflux of the contrast into the distal small bowel [20].

With the use of retention vancomycin enemas in CDI, it is important that the 30-cc Foley catheter balloon be deflated at all times except during the 60-minute interval for the instillation of the vancomycin volume every six hours. Prolonged balloon inflation in the rectum has been associated with mucosal necrosis and rectal bleeding. We do not recommend use of a rectal Malecot instead of a Foley catheter, as this tube does not have a balloon to occlude the rectal lumen, and therefore will not result in a true retention enema. Similarly, vancomycin should not be instilled via the irrigation port of fecal management systems, as this approach fails to deliver the drug to the proximal colon and will not result in a retention enema [21].

For patients who undergo diverting loop ileostomy for severe CDI, intra-operative high-volume colonic lavage is performed with 8 L of warmed polyethylene glycol 3350/electrolyte solution (GoLytely; Braintree Laboratories, Braintree, MA) infused into the colon via the ileostomy and collected via a rectal drainage tube. Post-operatively, antegrade vancomycin flushes (500 mg in 500 mL of lactated Ringer's solution q 8 hours for 10 days) are administered via a 24F Malecot catheter left in the efferent limb of the loop ileostomy. In addition, patients were continued on IV metronidazole (500 mg q 8 hours) for 10 days [22].

The diluent for vancomycin retention enemas is commonly 0.9% saline, and clinicians should monitor for hyperchloremia as a possible complication. As described above for loop ileostomy administration, vancomycin retention enemas also may be diluted in lactated Ringer's solution instead of saline.

Summary Recommendation

Given the published evidence reviewed here for the treatment of CDI with adynamic ileus, we confirmed that the case series with higher vancomycin dose and higher enema volume demonstrated greater efficacy. The 2015 case series by Malamood et al. with use of smaller volumes and lower dose (100 mL of enema volume; 125–250 mg q 6 hours) confirmed the absence of efficacy of intra-colonic vancomycin.

Based on this evidence, we recommend revision of the current CDI guidelines for patients with adynamic ileus to the following: Vancomycin per rectum (500 mg in a volume of 500 mL q 6 hours) by retention enema (18F Foley catheter with 30-cc balloon inserted into the rectum, balloon inflated, solution instilled, and catheter clamped for 60 minutes).

Footnotes

Author Disclosure Statement

No funding was received for this manuscript. The authors have no conflicts of interest to declare.

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