Hospital Infection Control: Clostridioides difficile

Clostridioides difficile remains a leading cause of healthcare-associated infection. Efforts at C. difficile prevention have been hampered by an increasingly complex understanding of transmission patterns and a high degree of heterogeneity among existing studies. Effective prevention of C. difficile infection requires multimodal interventions, including contact precautions, hand hygiene with soap and water, effective environmental cleaning, use of sporicidal cleaning agents, and antimicrobial stewardship. Roles for probiotics, avoidance of proton pump inhibitors, and isolation of asymptomatic carriers remain poorly defined.

Clostridioides difficile (previously named Clostridium difficile ) causes nearly 500,000 infections and 29,000 associated deaths in the United States each year, making it the leading cause of healthcare-associated infection and gastroenteritis-associated mortality. 1 While C. difficile first emerged as a hospital-associated infection and remains predominantly healthcare-associated, its epidemiology continues to evolve. Nearly one-third of C. difficile cases are now acquired in the community. 2 Whether this shift of C. difficile into the community reflects an escape from the hospital environment, spread via outpatient healthcare contact, or perhaps even a community source for infection remains poorly understood. Genomic epidemiology has shown C. difficile transmission to be more complex than initially assumed, confirming acquisition from unexpectedly diverse sources. 3 As a robust, survivable, and genetically diverse pathogen, C. difficile poses a difficult challenge for infection prevention efforts. This review summarizes the current evidence base for C. difficile infection (CDI) prevention with particular attention to the inpatient, surgical, and perioperative settings.

Basic Pathophysiology

C. difficile is an anaerobic, spore-forming, gram-positive bacillus. The spores are highly durable, resistant to many disinfectants (including ethanol), and capable of long-term environmental persistence. Violating Koch's postulates, the mere acquisition of C. difficile is insufficient to cause disease. True infection results from the production of two toxins, TcdA and TcdB , which damage intestinal epithelial and cytoskeletal structure, leading to severe diarrhea, toxic megacolon, and even death. A healthy and diverse gut microbiota inhibits germination and toxin production, whereas disruption of the normal flora facilitates toxin production, resulting in disease. Antibiotic exposure is the most common trigger for disrupted flora, though other risk factors for developing CDI include advanced age, chronic disease, and gastric acid suppression. 4 In the absence of such triggers, asymptomatic C. difficile carriage has been reported in as many as 45% of neonates and 10% of hospitalized adults. 5 6

Epidemiology of Healthcare-Associated C. difficile Infection

Healthcare-associated CDI rates increased dramatically in the early 2000s, driven largely by the rapid emergence of a hypervirulent strain known as NAP1 (North American pulsed-field gel electrophoresis (PFGE) type 1)/027 (polymerase chain reaction (PCR) ribotype 027). The NAP1/027 strain's fitness has been attributed in part to high-level fluoroquinolone resistance, while virulence may stem from increased toxin production and enhanced toxin binding affinity. 7 8 9 Although still strongly associated with the healthcare setting, NAP1/027 prevalence has begun to decline in some regions. 10 11 Even as the NAP1 wave may have reached its crest, overall rates of CDI show no sign of slowing. 12 Currently, C. difficile surpasses even Staphylococcus aureus as the most prevalent healthcare-associated pathogen in the United States. 13 14 Hospital-onset CDI occurs at a rate of 2.8 to 9.3 cases per 10,000 patient days and may complicate as many as 1% of all hospitalizations.

Epidemiologic studies estimate postoperative CDI rates between 0.5 and 1.5%, though this rate has been increasing over time. 15 16 Patient-specific risk factors specifically associated with perioperative CDI include age, procedure type, and receipt of perioperative antibiotics. 17 18 19 When CDI occurs postoperatively, it is associated with significantly increased mortality rates as high as 30% for CDI complicated by sepsis. 20

Environmental contamination by patients with C. difficile infection is nearly universal. Microbiologic surveys of the homes and hospital rooms of patients with C. difficile infection recover C. difficile nearly 100% of the time, with toilets, sinks, and high-touch surfaces carrying the highest organism burden. 21 22 Additionally, shedding of spores persists for weeks after treatment. 23 Asymptomatic carriage occurs at rates thrice that of true disease, and carriers may still shed C. difficile spores. 24 Similar to symptomatic patients, high rates of skin surface and environmental contamination have been observed with carriers. 25 As the role of asymptomatic carriers in the spread of C. difficile remains an area of active study, how to appropriately manage this potentially large reservoir for C. difficile transmission remains unclear.

Methods for Prevention of C. difficile Infection

Given the multiple risk factors for developing CDI, diverse sources of acquisition, and high survivability of the organism itself, CDI prevention requires multimodal interventions.

Hand Hygiene

With its propensity for resistance to disinfectants and long-term environmental persistence, hand hygiene is fundamental for minimizing CDI transmission. C. difficile can be recovered from the hands of healthcare providers caring for patients with CDI nearly 60% of the time and from environmental surfaces 30 to 50% of the time. 23 26 27 28 Widely used alcohol based hand sanitizers are ineffective against C. difficile spores. Studies have repeatedly confirmed that washing with soap and water more effectively reduces the spore burden on hands than alcohol-based sanitizers. 28 29 30 31 Importantly, soap and water do not kill C. difficile spores, they simply facilitate removal from the hands. Although hand washing with soap and water for 15 to 30 seconds clearly reduces spore burden, the benefits of hand hygiene have been harder to demonstrate at the facility level, perhaps reflecting the difficulty of achieving sustained compliance on a large scale. Studies show mixed results; some confirm reductions in facility-wide CDI rates following improvements in usage of soap and water, while others fail to confirm the anticipated difference between soap and water versus alcohol-based hand sanitizer use. 32 33 34 35 36 Probably the largest evidence base comes from the “ Cleanyourhands ” campaign in England and Wales, where procurement rates for soap (considered a proxy for proper hand hygiene compliance) correlated with reduced CDI rates. 37 Recent guidelines emphasize the use of soap and water specifically in settings with high-CDI incidence, while permitting hand hygiene with either soap and water or alcohol-based cleansers in routine settings with low-CDI incidence. However, the majority of hospitals continue to recommend hand hygiene with soap and water for any patients with CDI, regardless of local incidence rates, given the lack of efficacy of alcohol-based sanitizers.

As the efficacy of hand hygiene depends on compliance, multiple studies have sought to identify successful techniques for improving hand washing rates among providers. Though no techniques have proven completely effective individually, several have led to modestly improved hand washing compliance. Potentially effective interventions include teaching providers a structured hand-washing technique, using an audit and feedback approach, and relocating sinks to convenient locations near the patient. 38 39

Given the convenience of alcohol-based hand sanitizers, there have been several recent attempts at chemically modifying hand sanitizers to improve efficacy against C. difficile spores. Sporicidal effect may be improved by acidification and warming of ethanol-based sanitizers; however, clinical benefit from such modifications remains to be assessed. 40 41

Contact Precautions

Contact precautions include donning of gown and gloves upon entry to the room of any patient with suspected or confirmed CDI. Whenever possible, patients with CDI should be placed in private rooms with private commodes. If private facilities are unavailable, cohorting by CDI status is a reasonable alternative. The duration of contact precautions recommended by the Infectious Diseases Society of America (IDSA) varies by local CDI incidence rates. At a minimum, isolation is recommended for 48 hours after symptom resolution, however, in high-incidence settings isolation may be extended up until discharge. The latter recommendation for prolonged isolation is based upon evidence that C. difficile shedding may continue for at least 1 to 4 weeks after treatment. 23 26

Patients with C. difficile infection typically contaminate multiple body sites (chest, abdomen, hands, and arms), environmental surfaces (bed rails, tables, telephones, and call buttons), and hospital equipments. 42 43 44 The use of contact precautions with gown and gloves is intended to reduce the transfer of C. difficile to healthcare provider's hands, clothing, and equipment through contact with these surfaces. Despite microbiologic plausibility, evidence for clinical efficacy at reducing CDI rates is less certain.

Recent genomic studies of CDI transmission demonstrate extremely diverse sources. In a landmark study from the Oxford health system, 45% of CDI cases were genetically distinct from all hospital contacts, suggesting a relatively limited role for direct transmission within the hospital. 3 At the very least, the use of private rooms or commodes reduces CDI rates. 45 The additional benefits of contact precautions have been further challenged by a recent prospective cohort study in which discontinuation of routine contact precautions for all CDI patients had no effect on overall CDI rates. 46 Notably, this study was highly selective regarding which patients could forego isolation, patients still had private commodes, had to be fully continent, and could not be infected with a hypervirulent strain (e.g., NAP1). Additionally, CDI rates were low throughout the study period. Until more definitive studies become available, IDSA recommendations continue to support contact precautions as a useful strategy for CDI prevention.

Antimicrobial Stewardship

While receipt of nearly any antibiotic increases CDI risk, two recent meta-analyses confirmed that risk varies significantly by antibiotic class ( Table 1 ). Clindamycin (odds ratio [OR] = 16.8), fluoroquinolones (OR = 5.50), cephalosporins, and carbapenems (OR = 5.68) consistently confer the highest risk of CDI. Macrolides, penicillin, and sulfonamides confer a lower but still statistically significant risk, while doxycycline is the only antimicrobial which does not appear to increase CDI risk. 48 Emerging evidence suggests that piperacillin–tazobactam may also inhibit C. difficile growth, conferring a lower risk of CDI relative to other broad-spectrum antibiotics. At least one survey-based study found lower rates of C. difficile carriage among patients receiving piperacillin–tazobactam compared with those receiving cephalosporins or fluoroquinolones. 49

Table 1

The same risks still apply to short-term perioperative antibiotic usage. Even the short-term use of ertapenem (OR = 3.13) or cefoxitin (OR = 2.7) significantly increases the risk of CDI relative to narrow-spectrum agents (e.g., cefazolin). 15 50 Efforts to minimize antibiotic exposure or select the lowest risk agent reduce subsequent risk of CDI.

Antimicrobial stewardship has proven to be one of the most effective means of reducing CDI rates. Multiple studies in the hospital setting have confirmed that implementation of an antimicrobial stewardship program can reduce CDI incidence by as much as 24 to 60%. 51 52 53 54 55 The same significant reductions in CDI rates have been observed with antimicrobial stewardship efforts targeting perioperative antibiotic prophylaxis. Although most existing studies have been retrospective, stewardship interventions targeting perioperative prophylaxis reduce CDI rates as much as 60 to 71%. 56 57 58

The goal of an effective antimicrobial stewardship program is to optimize antibiotic choice, timing of administration, and duration to maximize the intended antibiotic effect, while minimizing adverse effects (including risk of CDI or other multidrug resistance pathogens). Key interventions include (1) selection of antibiotics that are effective for the intended purpose without being unnecessarily broad-spectrum, (2) avoidance of prolonged antimicrobial prophylaxis or longer than recommended treatment courses, and (3) avoidance of unnecessary antibiotic administration (e.g., for treatment of asymptomatic bacteriuria or viral respiratory infections).

Especially relevant for the surgical setting, the IDSA provides guidelines on selection, dosing, and duration of perioperative prophylactic antibiotics. 59 While a complete discussion of recommendations is beyond the scope of this review, cefazolin is frequently the first-line choice for nonallergic patients. Options for procedures with higher risk of gram-negative or anaerobic organisms (e.g., colorectal operations) expand to include cefazolin plus metronidazole, ceftriaxone plus metronidazole, or ertapenem, though ertapenem leads to higher risk of CDI. Avoiding carbapenems, fluoroquinolones, or clindamycin wherever possible may help to reduce risk of CDI, as these agents confer the highest overall risk. Duration of prophylaxis should almost never exceed 24 hours; in fact, the most recent guidelines of Centers for Disease Control (CDC) specifically recommend avoiding additional doses for antimicrobial prophylaxis, following closure of the surgical wound.

Another important aspect of antimicrobial stewardship includes accurate allergy assessment. Nearly 10% of patients report a β-lactam allergy, and reported β-lactam allergy frequently leads to the use of alternative prophylaxis agents. Alternative agents, such as clindamycin carry a higher risk of CDI; patients receiving alternative agents due to reported penicillin allergy are up to 23% more likely to develop CDI. 60 Consequently, obtaining an accurate allergy history, coupled with penicillin allergy testing or allergy consultation where available, may reduce the risk of CDI.

Environmental Decontamination

With high rates of contamination on multiple surfaces in the patient care environment and a propensity for persistence, admission to a room in which the preceding occupant had CDI is an independent risk factor for CDI. 68 C. difficile can be recovered from environmental samples in nearly all rooms previously occupied by a patient with CDI, and has been recovered in greater than 25% of rooms even after cleaning. 22 69 Although high rates of environmental contamination are thought to increase risk of CDI, the strain causing disease is frequently different than the strain isolated from the patient's immediate surroundings. Molecular epidemiologic surveys have shown greater than expected genetic diversity among CDI isolates, suggesting that only a minority of CDI cases are attributable to direct acquisition within the hospital environment. 3 70

Beyond observational and epidemiologic data, several studies have assessed the effect of various cleaning protocols on rates of CDI with conflicting results. Some of the inconsistency in assessing the impact of environmental transmission on CDI rates may be explained by variation in study methodologies. Most studies that demonstrated significant reductions in CDI rates after changes in cleaning protocols were undertaken in high-incidence settings, whereas negative trials appear correlated with lower incidence settings where effect would be inherently more difficult to detect. 71 72 73 As such, environmental decontamination retains an important role in high-incidence settings, including the hospital environment ( Table 2 ).

Table 2

Abbreviations: CDI, Clostridioides difficile infection; IRR, incident rate ratio; MDRO, multi-drug resistant organisms; OR, odds ratio; PPI, proton pump inhibitor; RCT, randomized controlled trial; RR, risk ratio; UV, ultraviolet.

There are multiple facets to environmental decontamination, including (1) quality control of cleaning adequacy, (2) use of appropriate sporicidal cleaning agents, and (3) consideration of adjunct decontamination methods (e.g., ultraviolet (UV) light or hydrogen peroxide aerosols). First, C. difficile decontamination depends upon thoroughness of room cleaning. Cleaning methods (including chemical or UV light based) lose efficacy if gross contamination is present. 74 75 In addition, even in the absence of chemical cleaning, physical cleaning may result in as much as a three-log reduction in spore burden. 76 Various quality-improvement trials aimed to improve room cleaning methods have shown modest but sometimes statistically significant reductions in either C. difficile environmental contamination or facility-specific nosocomial CDI rates. 77 78 Successful interventions include improved training for environmental service workers, audits of cleaning adequacy (using either C. difficile environmental cultures, fluorescent, or bioluminescent markers) and use of specially trained terminal decontamination teams dedicated to cleaning the rooms of patients on contact precautions. 79 80 81

Selection of appropriate sporicidal cleaning agents is also important, as studies have shown that neutral detergents or quaternary ammonium compounds are insufficient to kill C. difficile spores. In fact, some detergents may actually promote sporulation and survival. 82 In contrast, studies assessing efficacy of sporicidal cleaning agents have shown the greatest benefit in high-incidence settings and when used in conjunction with other CDI prevention measures. 71 Glutaraldehyde, peracetyl, and peroxide based agents are effective against C. difficile ; however, direct comparisons of products using uniform microbiologic methods have demonstrated wide variability in performance. 36 83 84 85 86 In general, hypochlorite- or bleach-based solutions have the most consistent benefit across studies, including effectiveness studies measuring reductions in CDI rates following the incorporation of hypochlorite solutions into cleaning protocols. 87

More recently, several no-touch adjunct measures have shown promise, particularly those based on UV light or hydrogen peroxide vapors or aerosols. 88 89 90 91 92 While all enhanced strategies require specialized equipment and cannot be conducted with the patient in the room, hydrogen peroxide vapor and aerosol-based systems also require that the room be sealed during treatment. In contrast, UV light systems are easier to deploy and are supported by one of the largest cluster-randomized trials to assess terminal room cleaning methods, to date. The Benefits of Enhanced Terminal Room Disinfection Study (BETR-D) demonstrated a statistically significant reduction in incidence of C. difficile and multidrug resistant organisms following the addition of UV light treatment to standard cleaning procedures, with a relative risk ratio of 0.7 ( p = 0.036). 93 A recently completed secondary analysis confirmed that enhanced disinfection of high-risk rooms (e.g., those housing patients with CDI) reduces hospital-wide C. difficile incidence through an indirect impact on all hospitalized patients. 94

Prevention Measures with Uncertain Value

Screening and Isolation of Asymptomatic Carriers

Asymptomatic carriers of C. difficile pose a particular challenge. Carriers are known to shed spores even when asymptomatic, resulting in environmental contamination rates similar to those with active disease. 95 Mathematical modeling studies suggest that isolation of colonized patients upon admission has the potential to significantly reduce CDI transmission rates; however real-world studies are lacking to date. 96 Molecular epidemiologic studies have found evidence of CDI acquired by transmission from asymptomatic carriers, though these events appear to account for only a minority of actual CDI cases. 97 98 At least one large, controlled quasiexperimental study has been conducted to determine whether screening for C. difficile carriage followed by isolation precautions of carriers can reduce CDI rates. This single-center study estimated a reduction in CDI cases of roughly 7 per 10,000 patient days, which was sufficient to reach statistical significance. 99 Despite these encouraging initial findings, replication beyond a single center and assurance against confounding factors are still necessary before this potentially costly intervention can be more widely recommended. As such, current IDSA guidelines do not endorse screening or isolation of asymptomatic carriers.

Proton Pump Inhibitor Stewardship

Multiple epidemiologic studies have suggested an increased risk of CDI with proton pump inhibitor use, particularly in healthcare-associated CDI. 2 100 101 The role of proton pump inhibitors in risk of community-acquired CDI is less clear. 102 To date no studies confirm that proton pump inhibitor discontinuation reduces CDI risk. Given recent recognition of proton pump inhibitor overuse, it is prudent to assess whether the medication is still indicated and consider discontinuation when, clinically appropriate.

Probiotics

Numerous studies have sought to assess the effect of probiotics on CDI risk. Unfortunately, most are hampered by widely varying formulations and significant industry involvement in many extant trials. Multiple meta-analyses have summarized the multiple trials performed to determine the efficacy of probiotics for CDI prevention. Highlighting substantial heterogeneity in both studies and analytic methodology, effect estimates for probiotics range from OR of 0.35 to 0.61. 103 104 105 106 Studies that assessed particular formulations confirmed similarly wide heterogeneity, though combination formulations were in general slightly superior. Whether probiotics have any role in prevention of perioperative CDI prevention remains largely untested, except for a single-prospective randomized trial which found no effect. 107

CDI Prevention Bundles

With multiple methods for CDI prevention available, there have been several attempts to create C. difficile prevention bundles. Most studies of CDI prevention bundles demonstrated an associated decline in CDI rates after implementation, yet these studies are hampered by variability in methods and bundle components. Several meta-analyses have attempted to synthesize currently available data to identify particularly effective components of CDI prevention, though study heterogeneity limited conclusions to qualitative assessments only. Individual bundle components achieving at least a moderate level of support across studies include contact precautions with gloves, antimicrobial stewardship, and terminal cleaning of rooms with chlorine-based agents. 108 109

Novel Approaches for the Future

A wide range of additional strategies for minimizing the risk of C. difficile infection are in various stages of development and assessment. Though none are currently ready for clinical use, a few novel approaches that may play a role in future CDI prevention are briefly highlighted here.

Antibodies to toxin B are protective against recurrent C. difficile infection, prompting efforts to create toxoid vaccines for C. difficile . 110 There are currently several candidate vaccines in early phases of clinical trials. 111 112 113 While some studies have shown evidence of immunogenicity, assessment of clinical outcomes awaits phase-III trial data.

Colonization with a nontoxigenic strain of C. difficile (which are incapable of causing diarrhea) appears to be protective against CDI in animal models. One such strain (NTCD-M3) was found to be well-tolerated and similarly protective in a small phase-II human trial for the prevention of recurrent CDI. 114 Phase-III trials are still needed, and it remains to be seen whether the protective effect is mitigated by antibiotic receipt that may still result in significant disruption of the remainder of the gut microbiota.

Ribaxamase is an oral β-lactamase intended to minimize the effects of intravenous (IV) broad-spectrum antibiotics on the gut microbiota. By degrading any residual β-lactam antibiotics secreted into the gut after hepatobiliary clearance, ribaxamase may reduce exposure of the gut microbiota to systemically administered antibiotics. Phase-I and -IIa trials support the intended mechanism of action; however, clinical effect remains to be assessed. 115 116

Conclusion

Despite being a wide-spread and consequential healthcare-associated infection, efforts at C. difficile prevention have been hindered by complex transmission patterns, a limited number of available high-quality studies, and moderate efficacy of current measures. While ongoing research is needed to answer many of the remaining questions in CDI epidemiology and prevention, there are a few interventions that have proven particularly effective in high-incidence settings. Generally supported interventions for reducing CDI transmission include contact precautions, hand hygiene with soap and water, quality control of environmental cleaning, use of chlorine-based sporicidal agents, and adjunctive treatment with UV light or peroxide aerosols. Roles for probiotics, limitation of proton-pump inhibitor usage, and isolation of asymptomatic carriers remain to be defined. Efforts to develop an effective toxoid vaccine or to mitigate the harms of systemic antibiotics on the gut microbiota offer some promise for the more distant future.

Conflict of Interest Dr. Anderson reports grants from AHRQ, grants from CDC, personal fees from UpToDate, Online, outside the submitted work.

Support Information

Nicholas Turner was supported in part by an Antibacterial Resistance Leadership Group fellowship (National Institute of Allergy and Infectious Diseases UM1AI104681). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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