Advances in Clostridioides difficile therapeutics

KEYWORDS:

• Antibiotics
• Clostridioides difficile
• dysbiosis
• fecal microbiota transplantation
• microbiome
• microbiota
• recurrence
• therapy

1. Introduction

Clostridioides difficile is an urgent public health threat by virtue of being the most common pathogen in hospitals and an increased risk of community-acquired infection [1]. The incidence of Clostridioides difficile infection (CDI) is increasing with a disproportionate rise in recurrent CDI seen in the United States. The primary risk factors for CDI are antibiotic exposure, advanced age, presence of comorbid conditions such as immunosuppression, inflammatory bowel disease, chronic kidney disease, amongst others [1]. The pathophysiology of both primary and recurrent CDI includes a disruption of the gut microbiota, i.e. dysbiosis. The clinical features of CDI range from diarrhea, abdominal pain, fever to fulminant colitis with severe sepsis. The cornerstone of the management of initial CDI is an antibiotic therapy and multiply recurrent CDI is managed with microbiome restoration therapies to restore gut dysbiosis [1]. This article discusses recent advances in the diagnosis and therapy of primary and recurrent CDI.

1.1. Body

There are two major challenges in the management of CDI: making an accurate diagnosis of CDI and selecting the appropriate therapeutic modality upon making the diagnosis [2].

1.2. Accurate diagnosis of C difficile infection

A common fallacy in the diagnosis of CDI is the reliance on the stool assay for C difficile without an accurate symptom assessment [3]. There are different assays for C difficile which should be interpreted in the context of their sensitivity and specificity [4].

The predominant clinical feature of CDI is diarrhea. The vast majority of patients with CDI present with diarrhea with the exception being those with fulminant CDI who may have an ileus or toxic megacolon. While evaluating patients with suspected CDI, taking an accurate diarrhea history is pertinent [3]. Patients with CDI typically would have the aforementioned risk factors for CDI. Clinicians should use the Bristol stool scale defining diarrhea as three or more Bristol type 6 (unformed) or type 7 (liquid) stools in the absence of another cause and no intermittent constipation [2,5]. In the absence of typical symptoms of diarrhea, stool testing for CDI should not be obtained.

The most commonly used stool assay for detection of the C difficile bacterium is a nucleic acid amplification test such as a polymerase chain reaction (PCR) to detect the C difficile toxin-producing gene [4]. This test is highly sensitive (>95%) for the presence of the organism but does not detect toxin production. In patients with a positive PCR, the attribution of a positive PCR test to CDI should be done in the presence of symptoms [3,4]. Using PCR alone risks an overdiagnosis if not interpreted in the context of clinical symptoms. Some centers use PCR as a 2-step algorithm where PCR is followed by toxin detection by enzyme immunoassay (EIA) but this approach has not been validated in large studies.

The other test that is used less commonly as standalone is an EIA that detects the C difficile toxin in stool. An EIA assay has lower sensitivity compared to a PCR-based assay but is highly specific for CDI [3,4]. Typically, an EIA-based assay is used in conjunction with a glutamate dehydrogenase (GDH) as a two-step protocol. A GDH assay (which has similar sensitivity as a PCR assay but is not specific for C difficile) is used as an initial screen and is followed by an EIA. If both GDH and EIA are positive, the patient is considered to have CDI. If GDH is positive and EIA is negative; then this is typically followed by a PCR assay due to the low sensitivity of the EIA assay. If the PCR is negative in this situation, CDI is ruled out [3,4]. If PCR is positive and symptoms are present; CDI is diagnosed. It is extremely rare to get a negative GDH but a positive EIA for toxin assay. In this instance, a PCR assay can be utilized downstream.

An important element in making an accurate diagnosis of CDI is a response to antibiotics. The majority of patients with a true diagnosis of CDI respond to antibiotics with a typical time to respond to antibiotics for CDI being about 4–5 days [3]. The antibiotics used to treat CDI, namely, vancomycin or fidaxomicin, have a high response rate while taking them and do not treat causes of diarrhea other than CDI. Since primary non-response to antibiotics is rare, in patients who do not respond to guideline-based antibiotic therapy for CDI, an alternate diagnosis should be considered [3,6].

1.3. Antibiotic management of C difficile infection

The treatment of CDI is dependent on the severity and number of episodes, i.e. primary or recurrent CDI (Table 1). Metronidazole is no longer recommended as a first-line treatment for CDI [3,6]. A non-fulminant first episode of CDI should be treated with a 10-day course of vancomycin at 125 mg four times a day or a 10-day course of fidaxomicin at 200 mg twice a day [3,4]. Fidaxomicin has several advantages over vancomycin including twice-daily dosing and a reduced rate of recurrence compared to vancomycin. A regimen of fidaxomicin extending the same number of doses over a 25-day course (200 mg twice a day for 5 days and then 200 mg once every other day from day 7 through day 25) has shown to have very low recurrence rates in a clinical trial of elderly hospitalized patients [7]. Both vancomycin and fidaxomicin may have cost and insurance coverage challenges and may need prior authorization. There may be patient assistance programs available through drug manufacturers to offset the cost to the patient. In patients who are at a high risk of recurrence, a one-time intravenous dose of bezlotoxumab can be used as a recurrence prevention strategy [8]. Risk factors in which bezlotoxumab has been shown to be efficacious include age greater than 65, prior history of CDI, immunosuppression, presence of severe CDI or presence of the hypervirulent C difficile strain [8]. Fulminant CDI is managed with high dose oral vancomycin, intravenous metronidazole, and rectal vancomycin (in patients with an ileus) and an early surgical consult [3]. Intravenous tigecycline has been described for the management of fulminant CDI in case series and may be used as an adjunct if guideline recommended therapies are failing.

Table 1. Management of Clostridioides difficile infection

Disease classification	Recommended treatment in adults
Non-severe, initial episode	Vancomycin 125 mg by mouth QID x 10 days OR Fidaxomicin 200 mg by mouth BID x 10 daysIf above agents are unavailable: metronidazole 500 mg TID x 10 days
Severe, initial episode	Same treatment as non-severe except metronidazole is not recommended
Fulminant, initial episode,	Vancomycin 500 mg QID by mouth (and per rectum in case of ileus or megacolon) & metronidazole 500 mg intravenous TID, early surgery consult
First recurrence	Vancomycin 125 mg by mouth QID x 10 days if metronidazole used initially Taper-pulse vancomycin or fidaxomicin 200 mg BID x 10 d if vancomycin was used initially
Second or subsequent recurrence	Vancomycin 125 mg QID or Fidaxomicin 200 mg BID x 10 days followed by Fecal microbiota transplantation OR Taper-pulse vancomycin OR Fidaxomicin 200 mg BID for 10 days OR Vancomycin 125 mg orally 4 times a day for 10 days followed by rifaximin 400 mg 3 times a day for 20 days

QID = four times a day, TID = three times a day, BID = two times a day. A typical vancomycin taper-pulse regimen is 125 mg QID for 14 days, BID for 14 days, once daily for 7 days, once every other day for 8 days and once every 3 days for 15 days

The antibiotic choice for a first recurrence (defined by another episode within 8 weeks of stopping antibiotic therapy) depends on the regimen used for the initial episode [3,6]. If vancomycin was used, then a vancomycin pulse and taper regimen (e.g. 125 mg four times a day for 2 weeks, twice daily for a week, once daily for a week, every other day for 8 days, and every third day for 15 days) or a fidaxomicin regimen can be used. In case metronidazole was used for the first episode, then a standard vancomycin course may be used [3,4]. Intravenous bezlotoxumab would be beneficial in this situation [8].

A second recurrence or a third episode may be managed by a vancomycin taper and pulse, vancomycin followed by rifaximin (rifaximin chaser regimen), vancomycin followed by fidaxomicin in a chaser and taper regimen or a brief course of antibiotics followed by microbiome restoration [3,6]. The overall risk of recurrence after a second recurrence is greater than 50% with antibiotic therapy. Case series and clinical trials have demonstrated a greater than 85% success rate with microbiome restoration overall to prevent recurrent CDI in this high-risk population [1].

1.4. Microbiome restoration for C difficile infection

The predominant method of performing microbiome restoration is fecal microbiota transplantation (FMT) which is dependent on procuring stool from well-screened donors [1]. Donors undergo screening for health conditions associated with an altered microbiome and infectious screening with blood and stool assays. Donors should be screened and excluded for carriage or infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) as SARS-CoV-2 could potentially be transmitted via stool [2]. If a stool assay is not available for SARS-CoV-2, a surrogate test such as a nasopharyngeal PCR may be used [2]. The overall success rates from microbiota restoration therapies are upward of 85% compared to less than 50% success rates with antimicrobials in patients with multiply recurrent CDI [3,9]. Studies have shown that efficacy with colonoscopic instillation is higher than nasogastric or enema instillation but comparable to capsules [10]. Fresh or freeze-thawed stools have similar efficacy allowing banking of stool with anaerobic preparation. An example of such a stool bank is OpenBiome which has supplied stool all over the United States. As of the writing of this article, OpenBiome has ceased its wide-spread operations.

There are concerns and pitfalls with FMT. Meta-analyses of studies reporting FMT demonstrated significant heterogeneity in reporting of different methodological components of FMT [11–13]. This heterogeneity exists due to the lack of standardization of these different components such as donor screening, donor preparation, stool preparation, and instillation and follow-up [11]. Safety concerns from FMT such as transmission of shiga-toxin-producing E coli and extended spectrum beta-lactamase E coli with serious events including bacteremia and mortality have been reported [14,15].

This has led to the development of standardized capsule-based and enema-based products which are in clinical trials. Capsule-based products include CP101 which has been efficacious in a phase II double-blinded randomized-controlled trial (RCT) with an overall efficacy of 74.5% compared to 61.5% placebo; RBX7455 which has been efficacious in a phase I open-labeled trial (overall recurrence prevention efficacy 90%) and SER-109 which has been efficacious in a phase III double-blinded RCT (overall efficacy 88.9% compared to 59% placebo) [16–19]. An enema-based therapy, RBX2660 has been efficacious in phase II and a phase III double-blinded RCT [20]. Finally, VE303 is a capsule-based synthetically produced therapy that is undergoing a phase II double-blinded RCT, and results are awaited.

Conceivably, the best way to prevent recurrent CDI is to prevent primary CDI. Antibiotic stewardship, patient isolation practices, and hand hygiene have been the cornerstone of preventing CDI in hospital settings [3]. There is a dire need to implement antibiotic stewardship in the outpatient settings. Antibiotics are lifesaving but need to be used judiciously. In most patients, the narrowest spectrum antibiotic for the lowest effective dose and duration possible to treat an infection should be used. Antibiotics for the prevention of infections should be individualized on a case-by-case basis. Novel techniques to minimize the impact of the antibiotics on the gut microbiome are being developed. Ribaxamase is an orally administered β-lactamase that has shown a reduced incidence of CDI compared with placebo in patients receiving intravenous cephalosporins [21]. Probiotics and oral vancomycin prophylaxis have not been shown to be useful in the prevention of primary CDI [3]. Recent retrospective studies have evaluated the role of oral vancomycin prophylaxis for the prevention of CDI in patients with a history of CDI and there may be a benefit [3]. These data need to be confirmed in prospective trials. Until then, oral vancomycin prophylaxis could be considered on a case-by-case basis in patients with a history of CDI.

The next 12 months are going to be exciting for the field of C difficile therapeutics. Updated clinical guidelines for CDI management are expected from the American College of Gastroenterology, the Infectious Diseases Society of America, and the American society of Colo-rectal surgeons. Scientific publications from the CP101, RBX2660, and SER-109 trials will be available. We will be expecting results from the VE303 studies and the initiation of larger clinical trials for CP101 and RBX7455. Since standardized microbiome restoration products have shown promising data, these are likely to receive approval from the United States Food and Drug Administration (FDA) for human use and the FDA guidance on FMT is likely to be finalized. Standardized microbiome restoration products are likely to replace conventional FMT for the management of recurrent CDI.

Declaration of interest

S Khanna has received research grants from Rebiotix, Inc (A Ferring company), consulting fees from Shire Plc, Premier Inc, Facile therapeutics and ProbioTech Inc, outside of the submitted work. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.