Treatment of recurrent Clostridium difficile infection: a systematic review

Abstract

Background

Clostridium difficile infection (CDI) recurs in nearly one-third of patients who develop an initial infection. Recurrent CDI (RCDI) is associated with considerable morbidity, mortality, and cost. Treatment for RCDI has not been not well examined.

Methods

A systematic review.

Results

Sixty-four articles were identified evaluating eight different treatment approaches: metronidazole, vancomycin, fidaxomicin, nitazoxanide, rifampin, immunoglobulins, probiotics, and fecal bacteriotherapy. The meta-analysis found vancomycin to have a similar efficacy to metronidazole, although studies used varying doses and durations of therapy. Fidaxomicin was slightly more efficacious than vancomycin, though the number of studies was small. Good evidence for probiotics was limited. Fecal bacteriotherapy was found to be highly efficacious in a single randomized trial.

Conclusion

Metronidazole and vancomycin have good evidence for use in RCDI but heterogeneity in treatment duration and dose precludes robust conclusions. Fidaxomicin may have a role in treatment, but evidence is limited to subgroup analyses. Fecal bacteriotherapy was the most efficacious. Saccharomyces boulardii may have a role as adjunctive treatment.

Introduction

Clostridium difficile infection (CDI) is the leading cause of healthcare-associated infectious diarrhea in hospitalized patients and is on the rise in the outpatient setting [1]. Recent years have seen the emergence of a hyper-virulent strain, BI/NAP/27 [2], associated with increased toxin production and adverse clinical outcomes [1, 3–6]. Recurrent or relapsing CDI (RCDI) occurs in approximately 20–30 % of patients following initial CDI, and up to 45 % of patients will have subsequent recurrences [7]. The economic costs associated with RCDI are estimated to exceed $13,000 per relapse [8].

Current Infectious Diseases Society of America (IDSA) guidelines [9] recommend discontinuation of the offending antibiotic and treatment with metronidazole (or vancomycin for severe CDI) for the first episode of CDI. The same options are recommended for the first recurrence. Subsequent episodes of RCDI are recommended to be treated by tapering or pulse-dosed vancomycin.

Effective treatments for RCDI are urgently needed; yet, few therapeutic options have been well studied. We undertook a systematic review to critically evaluate the efficacy of therapeutic interventions in RCDI.

Methods

Search strategy and data abstraction

With the aid of an expert librarian, MEDLINE, CINAHL, EMBASE, and the Cochrane Review Database were searched in September of 2012 for articles on RCDI treatment without publication date restrictions. The full search strategy is available in Supplemental Table 1. Inclusion criteria for the review were human trials or reports that provided outcome data on a specific intervention for RCDI. No language restrictions were applied; abstracts and articles were translated as needed. The references of all relevant articles, including reviews and editorials, were manually inspected for potentially relevant studies. The search strategy was in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement [10].

Data abstracted from each study included the specifics of the treatment regimen, the definition of RCDI used, concomitant or adjunctive therapies, study design, inclusion and exclusion criteria, duration of surveillance, and study endpoint. Study endpoints that included clinical cure were considered stronger methodologically than those that used solely surrogates, such as the clearance of toxin from stool. Outcomes were measured as both clinical cure and recurrence. Clinical cure was defined as an initial positive response to therapy in a patient with RCDI. Recurrence was defined as a patient who, after initial response to RCDI therapy, had a subsequent relapse following clinical cure. When provided, side effect data and mortality data were abstracted as well.

When appropriate, quantitative analysis was performed with DerSimonian and Laird random effects modeling in RevMan software [11].

Assessment of risk of bias

Two authors independently assessed the risk of study bias. Because retrospective, prospective, and interventional studies met the inclusion criteria, the risk of bias was assessed according to the instrument developed by Downs and Black [12]. This tool encompasses six sections which assess reporting, external validity, internal validity/bias, internal validity/confounding, and power. Inter-rater agreement was excellent (Cohen's κ coefficient = 0.86). Disagreements were resolved by a third author. Studies with scores ≥12 were considered to be high-quality studies.

Results

Literature review

A total of 4,242 articles were retrieved with the search strategy described above. 173 additional studies were identified via manual chart review. Of these, 105 studies analyzing eight major treatments strategies for RCDI were identified and included in this review (see PRISMA diagram, Fig. 1).

Fig. 1.

PRISMA diagram

Vancomycin

Ten studies evaluated the efficacy of vancomycin in RCDI, with four case series [13–16] and six randomized controlled trials (RCTs) [17–22] including 615 patients with 376 sustained responses to therapy (61 %). Initial cure rates ranged from 20 to 100 %, with sustained cure rates ranging between 49 and 100 %. Six studies were of high quality. Study endpoints were histologic resolution of pseudomembranous colitis (PMC) in one study [13], resolution of toxin positive assay in one study [18], and clinical resolution in the remaining studies.

One study was exclusively among inpatients [14]; the remainder included both in- and outpatients. All studies were among adults. Variable dosing and administration methods were used; this is summarized in Table 1.

Table 1.

Vancomycin in recurrent Clostridium difficile infection (RCDI)

Study	Design	Inclusion criteria	Definition of CDI	Duration of follow up	Mean age	Adjunctive/preparatory treatments	No. treated with vancomycin	Initial response rate	Sustained response rate	Comparator	Comparator initial response	Comparator sustained response rate	Study qualitya
Tedesco et al. [13]	Case series	Patients with recurrent PMC treated with vancomycin taper and pulse	Histologic evidence of PMC	60 days	59	None	21	100 %	100 %	None	N/A	N/A	Low
Surawicz et al. [17]	RCT	Symptomatic RCDI	3 or more loose stools/day for at least 2 days with positive EIA, culture, or toxin assay	8 weeks		None	14b 38c	NR	50 %b 55 %c	Metro	NR	50 %	High
						S. boulardii	18b 45c	NR	83 %b 49 %c	Metro		52 %
Shetler et al. [14]	Case series	Recurrent PMC treated with colonic decompression and intracolonic vancomycin	Histologic evidence of PMC	NR	70	Rectal tube	7	57 %	NR	None	N/A	N/A	Low
McFarland et al. [15]	Case series	Active diarrhea with positive toxin assay	Positive EIA, at least 3 loose stools in 24 h, and one of the following findings: abdominal pain, fever, and/or leukocytosis	1 year	NR	None	125	NR	54 %	Metro	NR	58 %	High
Pépin et al. [16]	Case series	Positive toxin assay or clinical diagnosis of PMC	Positive cytotoxin assay or endoscopic evidence of PMC	60 days	NR	None	171	NR	60 %	Metro	NR	79 %	High
Musher et al. [21]	RCT	Two recurrences after 14-day treatment with metronidazole or vancomycin recurrences	Positive EIA, at least 3 loose stools in 24 h, and one of the following findings: abdominal pain, fever, and/or leukocytosis	60 days	66	None	27	74 %	66 %	Nita	77 %	72 %	Low
Basu et al. [18]	RCT	Failure of vancomycin and/or metronidazole	Positive PCR assay with 5–10 stools/day while not meeting sepsis criteria	28 days	NR	None	15	73 %	73 %	Nita	67 %	67 %	Low
Louie et al. [19]	RCT	Lack of response to metronidazole	Positive toxin assay with at least 3 loose stools in preceding 24 h	90 days	63	None	43	94 %	72 %	Fidax	95 %	88 %	High
Cornely et al. [20]	RCT	First time RCDI occurring within 90 days of index case	Positive toxin assay with at least 3 loose stools in preceding 24 h	28 days	65	None	62	73 %	65 %	Fidax	92 %	80 %	High
van Nood et al. [22]	RCT	Adults with RCDI refractory to metronidazole and/or vancomycin	Positive PCR assay with >8 stools/48 h or >3 stools in 24 h for 2 days	10 weeks	66	None	13	NR	30.8 %	Fecal transplant	NR	81.3 %	Low
					69	Bowel lavage	13	NR	23.1 %

PMC pseudomembranous colitis, NR not reported, Metro metronidazole, RCT randomized controlled trial, Nita nitazoxanide, Fidax fidaxomicin, PCR polymerase chain reaction

^aHigh quality indicates a Downs and Black score greater than or equal to 12

^bHigh dose subgroup

^cLow dose subgroup

Examining high-quality trials using vancomycin, three studied a metronidazole comparator [15–17] and two fidaxomicin [19, 20]. The metronidazole comparator studies included 179 patients given metronidazole compared to 310 receiving vancomycin. Using sustained response (e.g., no recurrence), vancomycin was as efficacious as metronidazole [relative risk (RR) 1.08, 95 % confidence interval (CI) 0.85–1.35, I² = 0 %, p = 0.53). Studies comparing fidaxomicin to vancomycin, discussed further below, included a total of 79 patients in each arm, and appeared slightly more efficacious than vancomycin (RR 1.86, 95 % CI 1.04–3.31, I² = 0 %, p = 0.04) (Fig. 2).

Fig. 2.

Forest plot of vancomycin versus metronidazole and fidaxomicin. Risk ratio of not having further relapses with vancomycin versus comparators in listed studies

Pulsing or tapering doses of vancomycin has demonstrated efficacy in small studies and subgroups [13, 15], and has been adopted as part of the current guidelines but has not yet been evaluated in large RCTs [7, 23]. Tapering vancomycin involves a prolonged regimen where the dose is slowly reduced over several weeks. Pulsing involves a dose of vancomycin every 3 days following the completion of a full 10–14-day course for several weeks [24].

Evidence supporting the use of vancomycin is moderate. There is considerable variability in dosing and duration for RCDI, but it is currently the standard of care in treating RCDI.

Metronidazole

Two case series [15, 16] and three RCTs [17, 25, 26] evaluated metronidazole in RCDI. A total of 283 patients were treated with metronidazole-containing regimens, with a second recurrence in 86 patients (29 %). Rates of initial response were between 77 and 100 %. One study concluded that metronidazole was non-inferior to vancomycin in a first relapse [16], while two favored vancomycin regimens [15, 17]. Two studies used metronidazole plus placebo as part of a control group to evaluate either C. difficile immune whey or probiotic regimens [25, 26], discussed further below.

The dosing regimens and duration of metronidazole are summarized in Table 2. The patient populations were exclusively adults. All studies included both inpatients and outpatients. Primary endpoints were resolution of symptoms without recurrence for 1 or 2 months [17, 26] or 1 year [15].

Table 2.

Metronidazole in RCDI

Study	Design	Inclusion criteria	Definition of CDI	Duration of follow up	Mean age	Adjunctive/preparatory treatments	No. treated with metronidazole	Initial response rate	Sustained response rate (%)	Comparator	Comparator initial response rate	Comparator sustained response rate	Study qualitya
Surawicz et al. [17]	RCT	Adults with symptomatic RCDI	3 or more loose stools/day for at least 2 days with positive EIA, culture or toxin assay	8 weeks	66b	None	26	87.5 %b	50	Vancoc	NR	84 %	High
						S. boulardii	27		52	Vancoc		50 %	High
McFarland et al. [15]	Case series	Adults with symptomatic RCDI	Active diarrhea with positive toxin assay	1 year	NR		38	NR	58	Vanco	NR	54 %	High
Wullt et al. [26]	RCT	Adults with toxin-positive CDI with recurrence	3 or more loose stools/day for at least 2 days with positive EIA	70 days	65	Lactobacillus plantarum 299v	12	92 %	66	None	N/A	N/A	High
					63	Placebo	9	77 %	56	NR	N/A	N/A	High
Pépin et al. [16]	Case series	RCDI with positive toxin assay or clinical diagnosis of pseudomembranous colitis	Positive cytotoxin assay or endoscopic evidence of PMC	2 months	NR	None	115	NR	79	Vanco	NR	60 %	High
Mattila et al. [25]a	RCT	Adult patients with at least two episodes of toxin-positive symptomatic CDI within 3 months	Active diarrhea with positive toxin assay	28 days	66	Clostridium difficile immune whey	20	100 %	60	CDIW	83 %	61 %	High

NR not reported, RCT randomized controlled trial, Vanco vancomycin, CDIW Clostridium difficile immune whey, EIA enzyme immunoassay, PMC pseudomembranous colitis

^aHigh quality indicates a Downs and Black score greater than or equal to 12

^bCombined for with adjunctive S. boulardii and without

^cFrom “High dose vancomycin” comparator arm

Current IDSA guidelines endorse one repeat course of metronidazole as the standard of care for the first recurrence [9]. A temporal correlation of treatment failure has been noted since the emergence of the BI/NAP1/027 strain [7, 27]. It is not recommended beyond a first recurrence because of the risk of accumulation of neurotoxic metabolites [9]. All of the identified studies were of high quality, and found a fairly consistent efficacy, similar to vancomycin (see Fig. 2).

Other antibiotics

Several other antibiotics have been examined, particularly nitazoxanide [18, 28], rifaximin [29–35], and fidaxomicin [19, 20]. Nitazoxanide is a thiazoline-class antibiotic developed primarily as an anti-parasitic agent. Early studies in primary CDI indicated it to be relatively safe and well tolerated, with a response rate similar to metronidazole [36]. Two prospective studies [18, 28] on 47 patients found an initial response in 27 patients, with one second recurrence (55 % sustained response). Both studies were in adults, used a mix of in -and outpatients, and dosed the nitazoxanide at 500 mg twice daily for 10 [21] or 14 days [18]. One study used clinical resolution as an endpoint [21], while the other used toxin assay negativity as the endpoint [18]. In each study, the authors noted efficacy rates that were similar to vancomycin in treating RCDI (see Supplemental Table 1).

Seven publications report the use of rifaximin in treating RCDI, including two case reports [29, 30], three case series [31–34], and one prospective trial [35]. These total 49 patients, and report an aggregate of 12 failures. One study used toxin clearance as the primary endpoint [35], while the rest used clinical resolution. Three used rifaximin in combination with vancomycin regimens [30, 31, 33] (see Supplemental Table 2).

Fidaxomicin is a poorly absorbed, orally administered narrow-spectrum macrolide [37]. Both studies of fidaxomicin were prospective trials in a mixed inpatient–out-patient population [19, 20], totaling 116 patients. Clinical resolution was the endpoint of both studies. Initial response rates were high at 93 %, with sustained response occurring in 82 % of patients. One study indicated a clear reduction in recurrence after treating primary CDI, and evaluated RCDI as a subset. In that secondary analysis, fidaxomicin was superior to vancomycin in preventing a second recurrence in 28 days [19]. Fidaxomicin is the only drug other than vancomycin approved by the U.S. Food and Drug Administration (FDA) for CDI [38]. Both of the existing studies on fidaxomicin compared the drug to vancomycin and found non-inferiority [19, 20], with pooled results showing the slight superiority of vancomycin (see Fig. 2). However, it is worth noting that this medication is considerably more expensive than oral vancomycin, and may have decreased activity against the NAP1-027 strain [19] (see Table 3).

Table 3.

Fidaxomicin in RCDI

Study	Design	Inclusion criteria	Definition of recurrence	Duration of follow up	Mean age	Adjunctive/preparatory treatments	No. treated with fidaxomicin	Initial response rate (%)	Sustained response rate (%)	Comparator	Comparator initial response rate (%)	Comparator sustained response rate (%)	Study qualitya
Louie et al. [19]	RCT	Lack of response to metronidazole	Positive toxin assay with at least 3 loose stools in preceding 24 h	90 days	63	None	48	95	88	Vanco	95	72	High
Cornely et al. [20]	RCT	First time RCDI occurring within 90 days of index case	Positive toxin assay with at least 3 loose stools in preceding 24 h	28 days	65	None	66	92	80	Vanco	92	65	High

RCT randomized controlled trial, vanco vancomycin

^aHigh quality indicates a Downs and Black score more than 12

Alternative antibiotic regimens deserve study, but lack the records of vancomycin and metronidazole. Evidence for fidaxomicin is moderate in light of two positive, high-quality studies. The current evidence for nitazoxanide and rifaximin is weak.

Immunoglobulins

Ten studies were found evaluating immunoglobulin treatments, with one evaluating oral immunoglobulins [25], one monoclonal antibodies [39], and the remainder polyclonal IVIG [40–44]. These articles included 77 patients, and had 21 relapses (26 %). No study reported an initial response rate lower than 80 %. One study used toxin clearance as the primary endpoint [39], with the rest reporting clinical resolution. Two studies were determined to have a low risk of bias [25, 39], while the remainder had a high risk of bias (see Table 4).

Table 4.

Studies of immunoglobulin therapy

Study	Design	Inclusion criteria	Definition of CDI	Duration of follow up	Mean age	Adjunctive/preparatory treatments	Treatment	No. treated	Initial response rate	Sustained response rate (%)	Comparator	Comparator initial response rate	Comparator sustained response rate	Study quality
Leung et al. [40]	Case series	Hypogammaglobulinemia	Active diarrhea with positive toxin assay	4–6 months	2	None	IVIG	5	100 %	80	N/A	N/A	N/A	Low
Hassett et al. [103]	Case report	Selective IgG1 antibody deficiency	NR	24 months	49	S. boulardii	IVIG	1	100 %	100	N/A	N/A	N/A	Low
Salcedo et al. [41]	Case series	Lack of response to metronidazole and vancomycin	Diarrhea, abdominal pain, fever, and positive cytotoxin assay	1 month	64	None	IVIG	2	100 %	50	N/A	N/A	N/A	Low
Beales [42]	Case series	CDI refractory to metronidazole/vancomycin	NR	5 months	76	Tapering vancomycin	IVIG	4	100 %	100	N/A	N/A	N/A	Low
Wilcox [43]	Retrospective study	RCDI refractory to metronidazole/vancomycin	At least 3 loose stools/day for 2 days with positive cytotoxin assay	3 months	79	None	IVIG	5	80 %	80	N/A	N/A	N/A	Low
McPherson et al. [44]	Retrospective study	Two or more discrete episodes of CDI occurring within 1 month	At least 3 loose stools/day for 2 days with positive cytotoxin assay	1 month	76	None	IVIG	14	NR	64	N/A	N/A	N/A	Low
Murphy et al. [104]	Case report	6-month history of RCDI refractory to metronidazole and vancomycin	Active diarrhea with positive toxin assay	4 months	57	None	IVIG	1	100 %	100	N/A	N/A	N/A	Low
Hassoun and Ibrahaim [105]	Case report	Merkel cell carcinoma and RCDI after metronidazole and vancomycin	Active diarrhea with positive toxin assay	6 weeks	72	None	IVIG	1	100 %	100	N/A	N/A	N/A	Low
Mattila et al. [25]	RCT	Adult patients with at least two episodes of CDI within 3 months and toxin-positive CDI	Active diarrhea with positive toxin assay	28 days	56	Metronidazole	OIG	18	83 %	61	Metronidazole	100 %	60 %	High
Lowy et al. [39]a	RCT	Toxin-confirmed CDI with active symptoms at time of enrollment	At least 3 loose stools in 24 h with positive toxin assay	84 days	63	Metronidazole or vancomycin	IVIGa	101	NR	93	Placebo		75 %	High

RCT randomized controlled trial, CDI Clostridium difficile infection, IVIG intravenous immunoglobulin, OIG oral immune globulin, NR not reported

^aUsed a monoclonal preparation

Depressed levels of IgG generally, and anti-C. difficile toxin A deficiency specifically, have been demonstrated as a risk factor for developing severe or recurrent CDI [45, 46]. In a previous systematic review, the greatest benefit was observed in studies restricted to known hypogamma-globulinemia patients [47], but the overall study quality was low. A more recent, high-quality RCT evaluating a monoclonal antibody against C. difficile toxins demonstrated benefits in preventing recurrence in 29 patients with active RCDI refractory to vancomycin and/or metronidazole [39].

The use of polyclonal IVIG in the treatment of recurrent or severe CDI has equivocal evidence. Evidence for using monoclonal IVIG is stronger, with a single RCT showing benefit [39]. While oral immune globulin (OIG) appears promising and has a good biological rationale for its efficacy, the solitary high-quality study to date did not demonstrate a benefit over metronidazole, which is considerably more cost-effective than the expensive immunoglobulin preparations.

Probiotics

Intestinal microbiota in a typical human outnumber host cells by 10:1, and are involved in a plethora of metabolic and biochemical interactions vital to immunologic function [48]. The complexity and activity of the flora has been likened to an organ [49], and recent advances have found a limited number of “enterotypes”, balanced microbiota, which are consistent with a state of health [50]. Antibiotic-associated diarrhea (AAD), a condition in which the microbiota is severely disrupted, allows overgrowth by virulent bacteria such as C. difficile. Probiotics attempt to remedy this by providing normal host microbes to recolonize the colon and prevent invasion by pathogens. The majority of studies of probiotics in AAD have been preventive and have indicated some benefit [51], while a growing number of studies have evaluated its utility in the treatment of CDI. Common probiotic formulations are derived from Lactobacillus spp., Enterococcus faecium, Bifidobacteria spp., and Saccharomyces boulardii.

Eight studies evaluated probiotics in RCDI, four using S. boulardii [17, 52–54], three Lactobacillus spp. [26, 55, 56], and one a non-toxigenic strain of C. difficile [57] (see Table 5). All studies used clinical symptoms as a primary endpoint. Three were considered to be high-quality studies [17, 26, 54].

Table 5.

Studies of probiotics

Study	Design	Inclusion criteria	Definition of CDI	Duration of follow up	Mean age	Adjunctive/preparatory treatments	Organisms used	No. treated with probiotics	Initial response rate	Sustained response rate (%)	Comparator	Comparator initial response rate	Comparator sustained response rate	Study qualitya
Gorbach et al. [55]	Case series	2–5 relapses over preceding 10 months	Diarrhea, abdominal pain, weight loss, and positive cytotoxin assay	NR	NR	None	Lactobacillus GG	5	80 %	80	N/A	N/A	N/A	Low
Seal et al. [57]	Case series	RCDI	Active diarrhea with positive cytotoxin assay	45 days	77	None	C. difficile (non-toxigenic)	2	100 %	100	N/A	N/A	N/A	Low
Surawicz et al. [54]	Prospective trial	Recurrent PMC	Symptomatic RCDI	30 days	56	Vancomycin	S. boulardii	13	85 %	85	N/A	N/A	N/A	Low
McFarland et al. [52]	RCT	RCDI with prior treatment with vancomycin and metronidazole	Active diarrhea with laboratory confirmation	8 weeks	57	Vancomycin or metronidazole	S. boulardii	26	NR	77	Placebo	NR	35 %	High
Elmer et al. [53]	RCT	Adult patients with active RCDI	Toxin-confirmed RCDI	4 Weeks	NR	Vancomycin, metronidazole, or both	S. boulardii	50	NR	33	Placebo	NRb	NRb	Low
Biller et al. [56]	Case series	Children with 3–5 relapses of CDI	Active diarrhea with positive toxin assay	8 months	3	Either metronidazole or vancomycin	Lactobacillus GG	5	100 %	60	N/A	N/A	N/A	Low
Surawicz et al. [17]	RCT	Toxin-confirmed RCDI with index case in last year	3 or more loose stools/day for at least 2 days with positive EIA, culture, or toxin assay	8 Weeks	61c	High-dose vancomycin	S. boulardii	41	NR	83	Placebo	NR	50 %	High
					62c	Low-dose vancomycin	S. boulardii	27	NR	49	Placebo	NR	55 %	High
					66c	Metronidazole	S. boulardii	11	NR	51	Placebo	NR	50 %	High
Wullt et al. [26]	RCT	Adults with RCDI	3 or more loose stools/day for at least 2 days with positive EIA	70 days	65	Metronidazole	L. plantarum 299v	11	72 %	54	Placebo	89 %	67 %	High

RCT randomized controlled trial, NR not reported, CDI Clostridium difficile infection

^aHigh quality indicates a Downs and Black score greater than or equal to 12

^bStudy endpoint was excretion of S. boulardii, not clinical cure

^cMean age of combined placebo/S. boulardii arms

In RCDI, S. boulardii has the strongest evidence, with two placebo-controlled RCTs finding benefit [17, 52], though the first did not control for prior antibiotic regimens, and the second found benefit only when used as an adjunct to high-dose vancomycin [58]. A third trial noted a high relapse rate (66 %), though this study found higher concentrations of S. boulardii in stool correlated with a decreased risk of recurrence [53].

Lactobacillus spp. have not been well evaluated, with two case series supporting the use of Lactobacillus GG and one randomized underpowered trial failing to show significant benefit from L. plantarum 299v [26]. Evidence for the use of other organisms is limited to case reports.

Overall, the evidence for the adjunctive use of S. boulardii in treating RCDI is moderate. Other probiotic formulations need to be studied for efficacy.

Fecal bacteriotherapy

Fecal bacteriotherapy (FBT) delivers a complete complement of intestinal microbiota and its milieu to restore normal ecology. FBT has been a reported treatment of PMC since 1958 [59]. Since then, dozens of retrospective studies have been published supporting its use. The major adverse effects associated with FBT in the published studies have been complications of the delivery mechanism, e.g., gastrointestinal bleeding from nasogastric tube placement [60].

There is variability among published protocols, but all are largely consistent with a highly detailed FBT protocol published by Bakken et al. [60]. Potential donors are screened for bloodborne viruses and gastrointestinal illness. A stool sample from a donor is collected and mixed with milk, water, or saline, filtered, and diluted to a target volume which is delivered by nasogastric tube or enema, rectal tube, or colonoscope [60]. Success rates appear to be higher with lower gastrointestinal delivery, repeated treatments, and greater volume of infusate [61], though a recent meta-analysis found no difference in upper versus lower gastrointestinal delivery [62].

Thirty-three publications addressing FBT for RCDI were identified. There were two prospective trials [63, 64], seven case reports [65–71], 23 case series [72–94], and one RCT [22]. These included 609 patients and reported 63 failures (10.3 %). Except for one study using toxin clearance as a primary endpoint [77], all used clinical criteria to define success (see Table 6).

Table 6.

Publications reporting on the effectiveness of fecal bacteriotherapy (FBT)

Study	Type	Study population	Definition of recurrence/follow up interval	Follow up interval	Method of delivery	Adjunctive/preparatory treatments	No. receiving treatment	Success rate	Study qualitya
Schwan et al. [65]	Case report	65 YOF failing several courses oral vancomycin	Toxin-positive diarrhea	2 years	Enema	Vancomycin	1	100 %	Low
Tvede and Rask-Madsen [72]	Case series	Chronic relapsing diarrhea	Toxin-positive, symptomatic diarrhea	2 years	Enema	Not reported	6	100 %	Low
Fløtterød and Hopen [70]	Case report	Patient with seven relapses of CDI	Symptomatic recurrence	NR	Duodenal tube	Bacitracin	1	100 %	Low
Paterson et al. [73]	Case series	Patients aged 30–80 years with multiple comorbidities and at least one relapse	Diarrhea, abdominal pain, toxin-positive stools	2–4 years	Enema	None reported	7	100 %	Low
Härkönen [71]	Case report	71 YO with RCDI	Symptomatic recurrence	8 months	Colonoscopy	None reported	1	100 %	Low
Lund-Tønnesen et al. [94]	Case series	Patients with RCDI	Symptomatic recurrence with toxin-positive stool	NR	Colonoscopy (one via gastrostomy)	None reported	18	100 %	Low
Persky and Brandt [66]	Case report	60 YOF with RCDI refractory to metronidazole	Persistent watery stools and toxin positivity	3 years	Colonoscopy	Not reported	1	100 %	Low
Faust et al. [74]	Case series	Patients age 34–74 years with 2–6 relapses refractory to either metronidazole or vancomycin	Symptomatic recurrence with toxin-positive stool	9–50 months	Not specified	Not specified	6	100 %	Low
Aas et al. [75]	Retrospective review	Adult patients with at least one relapse	Symptomatic recurrence with laboratory confirmation	90 days	Nasogastric tube	Oral vancomycin	16	94 %	Low
Jorup-Rönström et al. [76]	Case series	Patients aged 79–88 years with at least one recurrence of CDI	Symptomatic recurrence with toxin-positive stool	2.5–21 months	Rectal tube	Not specified	5	100 %	Low
Wettstein et al. [77]	Retrospective review	Patients aged 11–87 years with treatment failure of either metronidazole or vancomycin	Toxin-positive stool	4–6 weeks	Colonoscopy	Rifampin, metronidazole, or vancomycin	16	94 %	Low
Louie et al. [78]	Retrospective review	>6 months relapsing diarrhea	Symptomatic recurrence	1 year	Rectal catheter	None	45	96 %	Low
Hellemans et al. [67]	Case report	59 YOF with CRF and RCDI refractory to vancomycin taper and metronidazole	Symptomatic recurrence with toxin positivity	4 months	Colonoscopy	Vancomycin	1	100 %	Low
MacConnachie et al. [79]	Case series	RCDI refractory to both metronidazole and vancomycin	Symptomatic recurrence with toxin positivity	4–24 weeks	Nasogastric tube	Oral vancomycin	15	73 %	Low
Garborg et al. [80]	Retrospective review	Suspected recurrent CDI refractory to metronidazole and vancomycin	NR	NR	38 via nasogastric tube, 2 via colonoscopy	Vancomycin or metronidazole	40	70 %	Low
Kelly and de Leon [81]	Case series	At least three recurrences despite adequate treatment with standard therapy	Symptomatic recurrence with toxin-positive stool	2 months	Colonoscopy	None	12	92 %	Low
Khoruts et al. [68]	Case report	61 YOF with RCDI for over 8 months refractory to metronidazole and vancomycin	Symptomatic recurrences	6 months	Colonoscopy	None	1	100 %	Low
Mellow and Kanatzar [82]	Case series	Sequential cases of RCDI treated with FBT	Symptomatic recurrence	>7 months	Colonoscopy	Not reported	13	93 %	Low
Miller et al. [83]	Case series	Patients aged 34 and 50 years with recurrence following metronidazole and vancomycin	Symptomatic recurrence with toxin-positive stool	1–9 months	Colonoscopy	Not reported	2	100 %	Low
Rohlke et al. [84]	Case series	At least two recurrences despite adequate treatment with standard therapy including vancomycin taper	Symptomatic recurrence with toxin-positive stool	6 months	Colonoscopy	None reported	19	95 %	Low
Russell et al. [69]	Case report	2-year-old with CDI refractory to metronidazole, vancomycin, and Lactobacillus treatment	Toxin-positive stool	6 months	Nasogastric tube	Vancomycin	1	100 %	Low
Silverman et al. [85]	Case series	Adults with 6–23 months of CDI symptoms	Symptomatic recurrence	4–14 months	Self-administered enema	Saccharomyces boulardii and either vancomycin or metronidazole	7	100 %	Low
Yoon and Brandt [86]	Case series	Toxin-confirmed RCDI	Symptomatic recurrence with toxin-positive stool	3 weeks to 8 years	Colonoscopy	None reported	12	100 %	Low
Mellow and Kanatzar [93]	Case series	Recurrent or refractory CDI	Symptomatic recurrence, with follow up in the range 1–10 months	1–10 months	Colonoscopy	None reported	13	85 %	Low
Polák et al. [64]	Prospective trial	Microbiologically and endoscopically confirmed relapsing PMC	Symptomatic recurrence	6 months	Colonoscopy	Vancomycin	15	67 %	Low
Brandt et al. [87]	Retrospective review	Clinically diagnosed RCDI	Symptomatic recurrence	90 days	Colonoscopy	Not reported	77	91 %	Low
Hamilton et al. [88]	Case series	At least two recurrences despite adequate treatment with standard therapy	Toxin-positive stool	2 months	Colonoscopy	Vancomycin	43	88 %	Low
Jorup-Rönström et al. [89]	Retrospective review	At least three recurrences despite adequate treatment with standard therapy	Symptomatic recurrence	1–68 months	Either via rectal tube or colonoscopy	Loperamide and codeine	32	88 %	Low
Kassam et al. [90]	Case series	Adult patients with RCDI	Symptomatic recurrence with toxin-positive stool	51–682 days	Enema	None reported	27	93 %	Low
Kelly et al. [91]	Case series	At least three recurrences despite adequate treatment with standard therapy	Symptomatic recurrence	5–30 months	Colonoscopy	None reported	26	93 %	Low
Mattila et al. [92]	Retrospective review	Laboratory-confirmed RCDI with failure of standard therapy	Symptomatic recurrence with toxin-positive stool	12 weeks	Colonoscopy	Metronidazole or vancomycin	70	94 %b	Low
Maire [63]	Prospective trial	Laboratory-confirmed RCDI	Symptomatic recurrence with toxin-positive stool	1 year	Colonoscopy	Metronidazole or vancomycin	34	100 %	Low
van Nood et al. [22]	Prospective RCT	Adult patients with RCDI refractory to metronidazole and/or vancomycin	PCR assay-positive stool with >3 stools/day for 2 days or >8 stools in 48 h	10 weeks	Duodenal infusion	Vancomycin	73	81 %	High

YOF year old female, RCDI recurrent Clostridium difficile infection, FBT fecal bacteriotherapy, NR not reported, CRF chronic renal failur

^aHigh quality indicates a Downs and Black score greater than or equal to 12

^bOf note, all four failures had the 027 strain; in this subgroup, the overall success rate was 89 % (32/36)

An RCT undertaken in the Netherlands, the FECAL trial, demonstrated the superiority of fecal transplant delivered into the duodenum over vancomycin (RR 3.05, 95 % CI 1.09–290.05). Initial treatment cured 81 % of RCDI patients, and subsequent retreatment reached 94 % efficacy. However, it is worth noting that the treatment failure rate for vancomycin is considerably higher in this study than in any other study. This may be, in part, due to the long follow up interval of 10 weeks capturing more treatment failures. Although the total number in this trial was small (n = 16 in FBT treatment group), and the study excluded both critically ill and immunocompromised patients, this represents the strongest evidence to date in support of this practice [22].

Discussion

The treatment options of RCDI are limited; yet, the impact on patients and healthcare costs is considerable [7–9]. In our systematic review, we found that most therapeutic options currently available for treatment of RCDI have, at best, moderate evidence to support their use.

We found moderate-strength evidence that treatment with either oral vancomycin or oral metronidazole has consistent efficacy for clinical cure. One is not clearly more efficacious than the other. There is insufficient data regarding optimal dosing regimens, especially in critically ill patients. Pulsing or tapering doses of oral vancomycin have weak evidence, as does intracolonic vancomycin. No study evaluated intravenous metronidazole therapy for RCDI.

Among novel antibiotic approaches, fidaxomicin has been the most rigorously examined, mainly in primary CDI to evaluate recurrence. It is an option for RCDI, but parameters should be developed in order to guide appropriate use. Few studies have evaluated nitazoxanide, and evidence supporting the use of either is of low quality.

Non-antimicrobial options for the treatment of RCDI should be examined further. We found only one high-quality study suggesting that S. boulardii could be useful as an adjunctive therapy with high-dose vancomycin.

Evidence for polyclonal intravenous immunoglobulins is weak in RCDI, though novel approaches with monoclonal immunoglobulins and oral immunoglobulins appear promising, and merit further study in the RCDI population.

FBT has a large body of non-comparative literature supporting its use, but, to date, has only been studied in one RCT. However, this does appear to be a promising option, and a recent review of 27 papers found an 89 % overall success rate, similar to our findings [61].

The available data would suggest that a reasonable clinical approach for a patient with RCDI would be the removal, if possible, of triggering antibiotics, followed by: (1) second treatment with either metronidazole or vancomycin with consideration of adjuvant probiotics, (2) consideration of either fidaxomicin or alternative dosing regimens of vancomycin (pulse or taper) depending on cost factors, and then (3) FBT. Data supporting each measure in this algorithm become sequentially weaker, but all of these measures have reasonable evidence for efficacy, and could be attempted in a patient with RCDI.

Our analyses have several limitations, most stemming from the design of the included studies. Except for subgroups, we were not able to perform a rigorous meta-analysis of the efficacy of therapeutic options for RCDI because of the non-comparative nature of the studies and the clinical heterogeneity. Each treatment approach had a very limited number of studies, thus, even after pooling, the study populations remained quite small. Also, publication bias is a concern for interventions where case series predominate, as positive results are more likely to be published. Finally, we did not examine all possible reported interventions for RCDI treatment, mainly because of the very limited data. For example, two other interventions, colonic irrigation [95] and tigecycline [96] have been reported as being successful in single-case series, but there are inadequate data to evaluate these interventions. Other interventions that have shown some success in primary CDI, like tolevamer [97] and cholestyramine [98], have not been evaluated specifically in RCDI.

The lack of data for the effective treatment of RCDI underscores the importance of prevention of primary CDI. Antimicrobial stewardship programs are important for the prevention of CDI [99, 100] and prompt discontinuation of offending antibiotics when CDI is detected may hasten recovery and reduce the risk of RCDI [101, 102]. Future studies should examine therapies specifically for RCDI using multisite, adequately powered, methodologically rigorous study designs.