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Introduction

Healthcare-associated infections (HAIs) have been problematic for healthcare institutions for decades. Although significant progress has been made in preventing some infection types, about 1 in 31 hospital patients has at least one episode of an HAI.¹ The annual National and State Healthcare-Associated Infections Progress Report (HAI Progress Report), published in 2017 by the Centers for Disease Control and Prevention (CDC), found a decreasing trend in the incidence of central line-associated bloodstream infections, surgical site infections, hospital-onset methicillin-resistant Staphylococcus aureus (MRSA) bacteremia, and infections caused by Clostridioides difficile. This is good news; however, these infections are still a persistent problem.²

In 2012, the CDC reported that C. difficile infections (CDIs) have emerged as a major problem in healthcare settings, causing 337,000 infections and 14,000 deaths annually with more than 90% occurring in patients 65 years of age or older.3^,4 CDIs primarily occurred in the inpatient setting; however, due to an increase in performing medical procedures in the outpatient setting, this trend has changed; 75% of patients with symptoms of CDI present in long-term care or ambulatory settings.⁴ According to the CDC, regardless of the setting in which those with symptoms present, the high prevalence of CDIs can be attributed to a single factor — overuse of antibiotics.

What is a C. difficileInfection?

C. difficile is a gram-positive bacterium that is ubiquitous in the environment in which people live, even in the human digestive tract. It produces spores that are difficult to remove from health care facilities and people’s homes. It is typically harmless unless conditions are optimal to allow it to proliferate within the body and produce toxins A and B, which can cause C. difficile colitis and infectious diarrhea. Symptoms of CDIs can range from mild diarrhea to severe colon inflammation that can be fatal. These infections usually occur when a patient takes antibiotics that change the normal flora of the colon and allows the C. difficile to proliferate and produce toxins.

Diarrhea is the most common symptom of CDIs.^5,6 Patients with mild cases may also exhibit these symptoms:

• Watery diarrhea, 3 or more times daily for several days
• Crampy abdominal pain or tenderness
• Nonspecific findings such as feeling poorly, fever, nausea, and vomiting

Symptoms of more severe CDIs include the following:

• Watery diarrhea up to 15 times per day
• Severe abdominal pain
• Loss of appetite
• Fever
• Blood or pus in the stool
• Weight loss
• Abdominal distention

In some cases, CDIs can perforate the intestines; this complication is a medical emergency can be fatal if not managed immediately, usually with emergency laparotomy.

C. difficile can be diagnosed using several assays (Table 1). The polymerase chain reaction (PCR), a type of nucleic acid amplification test (NAAT), is a sensitive method used for testing liquid or unformed stool samples for presence of the gene that produces toxin B. It cannot be used to test formed stools; people are frequently colonized with C. difficile and their formed stools will test positive. An enzyme immunoassay test for toxin A and B is also available but is less sensitive.

Current Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology (SHEA) guidelines7 recommend using a stool toxin test in combination with a glutamate dehydrogenate (GDH) test or NAAT in adult patients as part of a multistep algorithm rather than NAAT alone when there is no standard institutional criteria for stool submission samples. The NAAT does not differentiate C. difficile colonization versus C. difficile infection and can lead to a potential misdiagnosis of a patient with colonization as actually having CDI. The NAAT can, however, be used alone if there are institutional standards for patient stool submission samples. Testing should not be repeated within 7 days of the same episode of diarrhea.

Once diagnosed, CDI can be categorized as nonsevere if the white blood cell count is less than 15,000 cells/mL and serum creatinine is less than 1.5 mg/dL.⁷ If either laboratory value is above these cutoffs, the infection is categorized as severe. Fulminant CDI is determined by the presence of hypotension, shock, ileus, or megacolon.

Infants and neonates have a high prevalence of being asymptomatic carriers of toxigenic C. difficile and should not be routinely tested.⁷ Toddlers ages 1–2 years old who have diarrhea are not routinely tested unless other potentially infectious or noninfectious causes have been excluded. In children older than 2 years of age with prolonged or worsening diarrhea and risk factors for or exposures to C. difficile, testing is recommended.

Risk Factors for C. difficile

Although C. difficile can occasionally cause problems in healthy people in the ambulatory setting, the pathogen most often affects patients in institutional settings. Most of these patients have been treated with a broad-spectrum antibiotic for a sustained time period or with multiple antibiotics that kill a wide variety of bacteria, including the normal gut flora. High-risk antibiotics include clindamycin, cephalosporins, and quinolones such as ciprofloxacin and levofloxacin. Other risk factors for CDI include the following^4-6:

• Surgery of the gastrointestinal tract
• Diseases of the colon such as inflammatory bowel diseases (Crohn’s disease or ulcerative colitis) or colorectal cancer
• Weakened immune system
• Use of chemotherapy agents
• Previous CDI
• Advanced age – 65 years or older
• Kidney disease
• Use of acid-suppressive medications such as proton pump inhibitors (PPIs)

Individuals may be exposed to C. difficile by ingesting spores from the environment, especially in health care settings where infected patients excrete the spores. The C. difficile spores can live on dry surfaces for extended periods.

Drug Treatment Options for CDIs

Treatment of patients with CDIs begins with discontinuation of prior antibiotic therapy, when possible. Unfortunately, this may not be feasible if the patient is being treated long-term for a severe bone or heart infection. To reduce or minimize the risk of CDIs, an antibiotic stewardship program should be implemented in health care facilities to minimize the frequency and duration of high-risk antibiotic therapy and the number of antibiotics prescribed.⁷

For patients with CDI, a 10- to 14-day course of one of the following oral antibiotics is typically prescribed for treatment: vancomycin, fidaxomicin, metronidazole, or rifaximin.⁷ A second course of antibiotics is needed in about 25% of patients with CDI.

Before the 2017 guidelines were published, PPIs were stopped immediately after diagnosis of CDI based on an epidemiologic association between the use of PPIs and CDIs; however, PPIs no longer need to be discontinued as a measure to prevent CDIs. There is not enough clinical evidence to support the discontinuation of PPIs.^7,8

The previous guidelines recommended metronidazole as the first-line therapy for initial cases of mild-to-moderate CDIs and vancomycin for more severe cases; however, the 2017 guidelines recommend either vancomycin or fidaxomicin as the drug of choice for all initial CDI episodes (Table 2).^7,8 In pediatric patients with an initial episode or first recurrence of nonsevere CDIs, oral metronidazole or vancomycin is still recommended. Oral vancomycin is recommended over metronidazole for severe CDIs in children.

Fidaxomicin

Fidaxomicin is a macrolide antibiotic approved by the Food and Drug Administration (FDA) for treatment of C. difficile–associated diarrhea (CDAD) in adult patients. The recommended adult dose is 200 mg twice daily for 10 days.⁹ It is one of the first-line treatments for a nonsevere initial CDI episode, a severe initial episode, first recurrence if vancomycin used initially, and second or subsequent recurrence.

In a meta-analysis comparing fidaxomicin with vancomycin and metronidazole, the cure rate was essentially the same between fidaxomicn and vancomycin, but the cure rate was significantly higher than with metronidazole. Fidaxomicin, however, was significantly better than vancomycin and metronidazole in preventing recurrence of the CDI, especially in higher risk patients.^10,11

Fidaxomicin is available only as a 200 mg tablet. There are no pediatric dosing guidelines or recommendations and no compounded fidaxomicin oral suspension information available at the time of this program’s publication.

Vancomycin

Vancomycin is a glycopeptide antibiotic that has a broad spectrum of gram-positive antimicrobial activity, including coverage of MRSA infections. Vancomycin is administered parenterally to treat most infections because it is not absorbed in the gastrointestinal tract; however, it must be given orally to treat CDIs to treat the infection locally. It has an FDA-approved indication for the treatment of CDAD.^7,12

Dosing of oral vancomycin was simplified in the 2017 guidelines (Table 2). The recommended treatment for initial nonsevere or severe episodes and first recurrence if metronidazole was used initially is vancomycin 125 mg 4 times daily by mouth or nasogastric (NG) tube.

For an initial fulminant episode, vancomycin 500 mg is given 4 times daily by mouth or NG tube. If ileus is involved, rectal instillation of vancomycin may be added. According to the new treatment guidelines, a retention enema can be compounded by adding vancomycin 500 mg to 100 mL of 0.9% sodium chloride solution. It can be given a beyond-use date of 14 days if refrigerated or 63 days if frozen at –10°C.¹³

Retention vancomycin enemas, used off-label, are supported by published clinical evidence if an ileus is present and blocking or partially blocking the oral administration of the vancomycin reaching the colon.^7,14 Retention enemas help to provided better coverage of the infected areas of the gastrointestinal tract. Although this recommendation is also in the European Society of Clinical Microbiology and Infectious Disease (ESCMID) guidelines¹⁵ and mentioned in the American Society of Colon and Rectal Surgeons¹⁶ and the Australasian Society for Infectious Diseases (ASID)¹⁷ practice parameters, there is stronger clinical evidence supporting a higher volume colonic retention enema (500 mg vancomycin in 500 mL of 0.9% saline) to ensure better coverage of the colon and improved outcomes.^18-20 The ESCMID also recommends high-volume retention enemas in patients when the oral dose of vancomycin cannot reach the colon.

For second or subsequent recurrence of CDI, vancomycin can be administered in a tapered-and-pulsed regimen. This regimen consists of vancomycin 125 mg 4 times daily for 10–14 days followed by 2 times daily for a week, then once daily for a week, and finally once every 2–3 days for 2–8 weeks. This tapered-and-pulsed regimen is used in an effort to keep the C. difficile vegetative forms in check while allowing the restoration of the normal gut floral; however, it could potentially become a patient adherence issue. Another treatment option is vancomycin 125 mg 4 times daily by mouth for 10 days followed by rifaximin 400 mg 3 times daily for 20 days. The use of rifaximin was shown in a small study to reduce the recurrence rate by 50% as compared with placebo (15% versus 31%).²¹

Recommendations for the treatment of CDIs in pediatric patients with vancomycin were also simplified in the current guidelines. The dose of oral vancomycin is 10 mg/kg/dose (up to a maximum dose of 125 mg) 4 times daily for 10 days in initial nonsevere or severe/fulminant episodes. Parenteral metronidazole may be added for an initial severe/fulminant episode. Recommendations for second or subsequent CDI recurrence follow the simpler adult recommendation: 10 days of oral vancomycin followed by 20 days of rifaximin.

Vancomycin is commercially available as 125 mg and 250 mg oral capsules; 3.75 g, 7.5 g, 10.5 g or 15 g powder for oral solution; and 500 mg, 750 mg, or 1 g lyophilized vials. Premixed parenteral formulations are also commercially available. Beginning in 2018, vancomycin was marketed commercially as an oral solution, Firvanq, for easier administration in pediatric patients and for adults who cannot swallow solid dosage forms.²²

If the commercial oral solution is on manufacturer backorder, it may be compounded using active pharmaceutical ingredient (API) Vancomycin Hydrochloride Powder, USP, or other commercial products (Boxes 1 and 2).^23,24 The compounded liquid formulations of vancomycin are often more affordable for patients than the capsules. Some gastroenterologists prefer a compounded oral solution formulation to have a low osmolality, especially when they are used in treating pediatric patients with short gut syndrome. If there is a documented medical need for a vancomycin solution with a low osmolality, it can be compounded with SyrSpend, as its osmolality is less than 50 mOsm/L,²⁵ whereas most commercial oral liquids have osmolalities exceeding 300 mOsm/L.

Rifaximin

Rifaximin is a miscellaneous, nonabsorbed antibiotic that is approved by FDA for treatment of hepatic encephalopathy, irritable bowel syndrome with diarrhea (IBS-D), and traveler’s diarrhea. It is not approved for CDAD.²⁶

Rifaximin is recommended in the 2017 guidelines for second or subsequent CDI recurrences following a 10-day course of vancomycin. Rifaximin is dosed at 400 mg 3 times daily for 20 days.⁷ In a prospective pilot trial by Basu et al., rifaximin was shown to be a possible treatment alternative for mild-to-moderate CDI cases that are resistant to metronidazole.²⁷ Twenty-two patients whose CDIs were resistant to metronidazole were switched to the rifaximin regimen. Sixteen (73%) patients had complete eradication (stool sample negative for C. difficile) both immediately following treatment and at 56 days post-treatment. Rifaximin was also well tolerated.

There are no rifaximin pediatric dosing guidelines for patients younger than 12 years of age, but limited studies of younger patients are available. In a small study of pediatric patients ages 3–15 years with IBS-D, rifaximin was given in doses of 200 mg orally 3 times daily.²⁸ Another study of pediatric patients 12–18 years of age with inflammatory bowel disease suggested dosing rifaximin 10–30 mg/kg/day up to a maximum of 1200 mg per day divided into 3 doses.²⁹

Rifaximin is commercially available as a 200 mg or 550 mg tablet. If a patient, including those in the pediatric age group, cannot swallow these large tablets, rifaximin can be compounded into an oral suspension (Box 3).³⁰

Metronidazole

Metronidazole is pharmacologically categorized as an amebicide, antiprotozoal, nitroimidazole, and miscellaneous antibiotic, and it is used to treat a variety of different infections in both adult and pediatric patients (Table 3).^31,32 It is Pregnancy Risk Factor B and is contraindicated for use during the first trimester of pregnancy. Oral metronidazole was considered first-line therapy for treatment of mild CDIs in the previous guidelines; this was (and is) an off-label use in both adult and pediatric patients (Table 3).⁸

For adults with an initial, non-severe CDI, oral immediate-release metronidazole 500 mg 3 times daily for 10 days may be used as an alternative if vancomycin or fidaxomicin is unavailable.⁷ For an initial fulminant CDI episode with ileus, intravenous (IV) metronidazole 500 mg should be administered every 8 hours with oral or rectal vancomycin.

Pediatric treatment of CDIs includes oral vancomycin or metronidazole 7.5 mg/kg/dose (up to a maximum of 2 g/day) 3 or 4 times daily for 10 days (Table 3). For an initial severe/fulminant episode, IV metronidazole 10 mg/kg/dose may be added 4 times daily with the oral or rectal vancomycin regimen.

Since metronidazole is commercially available only in parenteral and tablet forms, an oral suspension may be compounded to accommodate smaller doses or if the patient cannot take a large tablet. The metronidazole tablets are made with the metronidazole base. When crushed and used in a compounded suspension, the tablet-based compounded product is not palatable because metronidazole base has a very bitter taste. It is better for the patient and improves adherence if the compounded metronidazole oral suspension is prepared with API metronidazole benzoate; this salt form does not have a bad taste. The metronidazole benzoate is much heavier than the metronidazole base, so the amount of benzoate salt will be more than the base. One gram of metronidazole benzoate is equivalent to 625 mg of metronidazole base.³³ The compounded oral suspension is stable for 90 days refrigerated or stored at room temperature (Box 4). The metronidazole benzoate can be mixed in Ora-Blend, Ora-Blend SF, or a 1:1 mixture of Ora-Plus and Ora-Sweet or Ora-Sweet SF.³⁴ It can also be compounded using cherry syrup.

If the commercial metronidazole tablets need to be used to prepare the compounded oral metronidazole suspension, the concentration of the preparation can be decreased to 15 mg/mL and mixed in chocolate-cherry syrup to improve palatability.³⁵

Fecal Microbiota for Transplantation

The recurrence rate for CDAD is about 5% to 35%.³⁶ Even though retreatment with a second course of antibiotics is recommended, a chronic cycle of relapse and treatment can occur, especially in patients with the previously listed risk factors. Fecal microbiota for transplantation (FMT) or bacteriotherapy has successfully broken this relapse cycle in patients with recurrent CDIs (RCDI). Bakken stated in 2003 that a review of 100 published case reports collectively demonstrated a 94% success or cure rate in patients treated with fecal bacteriotherapy.³⁶

The fecal donor is usually a relative of the patient chosen based on diet similarities and the flora present on testing of the donor’s stool. The actual procedure is relatively easy and affordable; however, in May 2013, the FDA implemented regulations on fecal transplants that classified fecal microbiota as a biologic product.^37,38 The FDA requirements for an investigational new drug (IND) were modified later in 2013 to allow enforcement discretion as long as donors are known to the family and the recipient signs consent.³⁹

Following this regulatory change, some physicians began advising patients to self-administer FMT using an at-home enema kit. Patients were provided with instructions to blend a stool sample in saline and administer the slurry via an enema bag. However, there are serious problems with this “do-it-yourself” (DIY) approach, and the FDA issued a safety alert in June 2019 regarding the use of FMT.⁴⁰ FDA said that two immunocompromised adults who received FMT developed invasive infections caused by extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli, resulting in the death of one of the recipients. The same donor stool was used in both individuals and was not tested for ESBL-producing gram-negative organisms before use.

In an emergency, a physician may be granted authorization to administer FMT over the telephone by the FDA in the form of an emergency investigational new drug (IND) application. This allows treatment to begin before the FDA receives the written IND application. However, because of the incidents reported in the June 2019 safety alert, FDA has determined that the following must be completed before the investigational use of FMT⁴⁰:

• Donor screening with questions that specifically address risk factors for colonization with multidrug resistant organisms (MDROs)
• MDRO testing of donor stool and exclusion of stool that tests positive for MDRO

In 2012, OpenBiome (The Microbiome Health Research Institute), a 501(c)(3) nonprofit organization, was founded to help clinicians administer and treat their patients with FMT promptly without applying for an emergency IND.⁴¹ The organization operates similar to a blood bank. Donors undergo a rigorous screening process that includes a 200-question clinical evaluation with an internal medicine specialist and a battery of serological and stool-based assays to screen for infectious pathogens including antibiotic-resistant bacteria. Fewer than 3% of the potential donors pass the screening. Once donors are approved, donations can be made for up to 60 days. The donor must then requalify and continue to repeat this screening process every 60 days.

OpenBiome offers three products to clinicians for FMT:

• FMT Lower Delivery Microbiota Preparation for administration via colonoscopy, sigmoidoscopy, or enema
• FMT Upper Delivery Microbiota Preparation for administration via nasoenteric/gastric tube or esophagogastroduodenoscopy, or EGD
• FMT Capsule DE Microbiota Preparation for oral administration

These products are kept frozen at OpenBiome and shipped overnight when ordered to the healthcare facility or clinician. The suspensions are kept frozen until administration. They can remain thawed for up to 4 hours at room temperature or 8 hours refrigerated. They must be discarded if not used within this time frame as hazardous waste material. The capsule is also kept frozen and administered to the patient frozen. If thawed, the capsule must be used within 10 minutes or refrozen if not used.

Bezlotoxumab

Bezlotoxumab is a human monoclonal antibody that binds to C. difficile toxin B and neutralizes its effects.⁴² In early 2017, FDA approved bezlotoxumab to reduce the recurrence of CDIs in patients 18 years or older who are receiving an antibacterial treatment of CDI and are at high risk for RCDI. It is not used alone for treatment for CDI but rather is used in conjunction with metronidazole, vancomycin, or fidaxomicin. Bezlotoxumab is administered as a single dose of 10 mg/kg IV infusion over 60 minutes.⁴²

The MODIFY I and II trials were double-blind, randomized, placebo-controlled, phase 3 trials involving 2,655 adults receiving standard oral therapy for primary or recurrent Clostridium difficile infections.⁴³ Participants received an infusion of bezlotoxumab, actoxumab plus bezlotoxumab, or placebo. Actoxumab was given alone in the MODIFY I trial, but the trial was discontinued after a planned interim analysis. The primary endpoint — recurrent infection within 12 weeks after infusion — was 64% for those on bezlotoxumab alone, 58% for actoxumab plus bezlotoxumab, and 54% for placebo.

Probiotics

Although it is logical to assume that probiotics would be beneficial to restore the normal gut flora and possibly prevent RCDI, limited data support their benefit and there is a potential risk for septicemia.⁷ Use of Saccharomyces boulardii and Lactobacillus species has shown mixed results; however, S. boulardii may be studied in the future for the treatment of CDIs because it may inhibit the effects of toxins A and B on the human colonic mucosa.⁴⁴ At this time, the use of probiotics to treat or prevent CDIs is not recommended.

Hygienic Measures for Prevention of CDIs

Since C. difficile spores can live on dry surfaces for a long time, all healthcare facilities need to have a good cleaning protocol that uses chlorinated bleach products or another Environmental Protection Agency–approved sporicidal disinfectant.⁷ Good hand hygiene should be practiced by all staff using soap and water; C. difficile spores are not killed by alcohol-based gels or sanitizers are not effective.

For patients with suspected or known CDIs, isolation and hygiene procedures should be in place and carefully adhered to by all patients, staff (including housekeeping), and visitors. Everyone entering the room of a patient with known or suspected CDI should wear a gown and gloves and use disposable equipment. Visitors and patients should be instructed in and encouraged to follow good hand hygiene. For staff and visitors, this includes handwashing before and after visits to the patient’s room, and thorough handwashing after using the restroom.

Resources

The CDC has excellent information about CDIs for patients, clinicians, facilities, and state health departments including guidelines for clinicians plus evaluation and assessment tools for facilities and health departments.⁴⁵ This information can be accessed at https://www.cdc.gov/cdiff/.

Conclusion

As patients seek medical care for different problems, they are at risk for acquiring serious HAIs. CDIs can cause significant diarrhea and other serious gastrointestinal problems, even death. Although the CDI rate is decreasing, it is important to identify those patients who are at risk for developing a CDI and properly treat them if a diagnosis is confirmed. Healthcare facilities also need to be proactive and take the measures necessary to prevent and/or reduce this risk of infection.

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