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Prevention of Infection Due to Clostridium difficile
P re v e n t i o n o f I n f e c t i o n D u e t o C l o s t r i d i u m d i ff i c i l e Christopher C. Cooper, MDa, Robin L.P. Jump, MD, PhDb,c, Teena Chopra, MD, MPHa,* KEYWORDS Clostridium difficile Prevention Hand washing Contact precautions Environmental decontamination Bleach Antibiotic stewardship Infection control KEY POINTS Preventing Clostridium difficile infection is difficult and typically requires a multifaceted bundled approach. Whenever possible, assign infected individuals to a single-bed room. The duration of isolation/contact precautions may vary between facilities. Health care personnel should don gowns and gloves on room entry and remove before exiting the room, followed by hand washing, ideally using soap and water. Chlorine-containing disinfectants are preferred for decontaminating rooms after Clostridium difficile infection. Reducing unnecessary antibiotic use can decrease infection rates. Developing a successful antibiotic stewardship program can help to accomplish this.
INTRODUCTION
Clostridium difficile is a leading nosocomial pathogen worldwide. It is associated with tremendous morbidity, mortality, and health care expenditures. Prevention is especially difficult because of the durability of the spores and requires implementation of multipronged strategies. Useful methods to prevent C difficile spread include increased hand hygiene, use of contact precautions, and use of sporicidal decontamination agents. In addition, a focus on effective antibiotic stewardship can significantly
Disclosure Statement: None (C.C. Cooper and T. Chopra). Dr R.L.P. Jump is a Co-Principal Investigator on a grant from Pfizer to study disparities in pneumococcal vaccination rates. a Division of Infectious Diseases, Wayne State University, 3990 John R. Street, 5 Hudson, Detroit, MI 48201, USA; b Infectious Disease Section, Medical Division, Geriatric Research Education and Clinical Center (GRECC), Louis Stokes Cleveland Veterans Affairs Medical Center, 10701 East Boulevard, Cleveland, OH 44106, USA; c Division of Infectious Diseases and HIV Medicine, Department of Medicine, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106, USA * Corresponding author. E-mail address: [email protected] Infect Dis Clin N Am - (2016) -–http://dx.doi.org/10.1016/j.idc.2016.07.005 0891-5520/16/ª 2016 Elsevier Inc. All rights reserved.
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decrease the burden of disease.1 The focus of this article is on preventative strategies to reduce the C difficile infection (CDI) frequency. PATHOGENESIS
C difficile causes a spectrum of disease with symptoms ranging from diarrhea to toxic megacolon and death. The principal risk factor is antibiotic exposure, although several other factors also increase the risk for infection, including advanced age, gastric acid suppression, and low albumin/chronic disease states.1 Acquisition occurs through spore ingestion. The pathogenesis centers on the disruption of the indigenous intestinal microbiome. The most common cause of this is systemic antibiotic administration. In individuals with an intact gut microbiome, the spores are unable to find an ecological niche. However, in people with a disrupted gut microbiome, ingested spores are able to germinate and multiply.2 After germination, the bacterium begins secreting a pair of exotoxins, TcdA and TcdB, which disrupt the cell cytoskeleton and ultimately leads to a disease state.3 The spore represents a reservoir for the organism. Spores are able to resist extreme environmental conditions and are capable of persisting for months in the environment.4,5 C difficile spores are difficult to remove from environmental surfaces and from health care worker hands via routine infection control measures. People with CDI shed spores onto their skin and into the environment. Following successful treatment of an episode of symptomatic CDI, people may become asymptomatic carriers of C difficile. These individuals continue to shed C difficile spores into the environment and can serve as a source of dissemination of spores to others.6–8 The asymptomatic carriage prevalence in hospitalized individuals is close to 10%, and in long-term care facilities (LTCFs), the prevalence is approximately 50%.9,10 EPIDEMIOLOGY
CDI has developed into an enormous burden on society. It is now the most frequent cause of gastroenteritis-related deaths across the United States.11 In 2011, C difficile was responsible for 453,000 infections and 29,000 deaths.12 Although still primarily a hospital-acquired pathogen, reports are increasing throughout the community and LTCFs.13,14 CDI imposes major costs on hospital systems, insurance providers, and society as a whole.15 In the United States, the estimated attributable cost was $11,285 per case, and the total annual financial impact was approximately 1.5 billion dollars, between 2011 and 2013.16 The incidence of CDI has dramatically grown in frequency and severity over the last 15 years. This escalation was ultimately connected to an epidemic strain of C difficile, known as BI/NAP1/027. This strain exhibits enhanced toxin production and fluoroquinolone resistance. The discovery of strain BI/NAP1/027 occurred in Pittsburgh, during the year 2000. Reports of outbreaks in Canada and other regions of the United States soon followed. These outbreaks then spread throughout the United Kingdom and Europe.17,18 PREVENTION
As stated above, CDI prevention generally requires several different interventions. These strategies fall into the broad categories of infection control and prevention as well as risk factor reduction.
Prevention of Infection due to C difficile
INFECTION CONTROL AND PREVENTION
Disease transmission occurs through ingestion of C difficile spores, which are the organism’s dormant form. The degree of C difficile colonization increases at a steady rate and approaches 40% after a month of hospitalization.19 Colonization can occur either by exposure to a contaminated environment or through contact with health care workers.6 Infection control and prevention practices seek to reduce transmission of spores to uncolonized individuals. This strategy uses a combination of contact precautions, environmental disinfection, and hand decontamination. Hand Hygiene
Hand hygiene, a fundamental component of infection control, is the most important aspect of preventing C difficile transmission. Contamination of health care worker’s hands with C difficile occurs regularly when caring for a person with CDI, with rates of contamination of up to 59%.6,8,20–22 In fact, touching the patient is not even required; hand contamination can happen just as often after touching “high-touch” surfaces in the room.20,21 Unfortunately, adherence to routine hand hygiene by health care personnel is poor in many settings.23,24 In recent years, use of alcohol-based hand rubs (ABHR) has gained popularity. Hand hygiene rates are higher with the use of ABHR.25,26 Implementing ABHR decreases the frequencies of both methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus (VRE) infections in the hospital.27–29 However, C difficile spores are extremely resistant to destruction by alcohol.30 In fact, the ethanol shock method is used in laboratory settings to assist in isolating C difficile from stool samples.31 Consequently, health care workers who use ABHR to decontaminate their hands may simply be moving spores around the skin. Conversely, it is hypothesized using soap and water physically removes the spores from the skin. Several laboratory studies have compared various forms of hand hygiene. Washing with soap and water was superior to ABHR for spore removal. Soap and water use may lead to a greater than 90% decrease in spore contamination; however, alcohol-based interventions do not reduce the amount of spore contamination.32–34 Other studies have analyzed the benefit of chlorhexidine with mixed results. One study found that the efficacy of chlorhexidine antiseptic exceeded plain soap at removing C difficile.6 However, other studies failed to show any benefit to chlorhexidine washes over plain soap.32,35 Consequently, there is a hypothetical risk that widespread implementation of ABHR could increase CDI incidence. However, no clinical studies have demonstrated this. In an observational study conducted at a Veterans Administration hospital, the CDI rate remained unchanged after implementation of ABHR. However, there was a 21% reduction in health care–acquired MRSA and a 41% reduction in VRE.27 Numerous other studies have also not been able to find an increase in CDI rates with routine ABHR usage.29,36–38 The Cleanyourhands campaign was a national effort in England and Wales to improve hand hygiene rates. The study analyzed the association between hospital procurement rates of soap and ABHR with rates of nosocomial infection. They found increased hospital ordering of soap was independently associated with decreased CDI. Conversely, there was an independent correlation between obtaining elevated quantities of ABHR and decreased MRSA bacteremia. Based on this evidence, the current Society for Healthcare Epidemiology of America–Infectious Diseases Society of America guidelines recommend, “During outbreaks or in settings with hyperendemic CDI, perform hand hygiene with soap and water as the preferred method before exiting the room of a patient with CDI.”1 However, in
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lower-incidence settings, the benefits of soap and water against C difficile need to be weighed against reductions in other nosocomial infections with ABHR. Contact Precautions
Another important aspect to preventing horizontal transfer of spores is instituting isolation procedures. Isolation procedures include contact precautions, individual rooms, and dedicated patient equipment. Contact precautions refer to the donning of gowns and gloves upon room entry and removal before exiting the room.1 The use of these methods centers on the idea that individuals with active CDI are the main source of disease dissemination. C difficile spores frequently contaminate health care worker’s hands, during the routine care of individuals with CDI.6,8,20–22 The routine use of gloves may help reduce transmission to other patients. One prospective study analyzed use of vinyl gloves to interrupt transmission. The interventions included reminder signs and making gloves available in every patient’s room. This intervention resulted in a drop in the CDI cases from 7.7 to 1.5 per 1000 patient discharges. The asymptomatic carriage rate also decreased during this intervention.39 Gowns use is also recommended due to potential soiling of health care worker clothing. Nurses’ clothes have been documented to become contaminated with C difficile during routine clinical duties. However, the same study did not specifically assess if the contamination was linked to patient acquisitions or transmissions.40 Importantly, in a randomized controlled trial of intensive care patients, adverse events were not increased for patients on contact precautions compared with patients without contact precautions.41 Current guidelines recommend continuing contact precautions until diarrhea resolution. However, in situations where the spread of CDI is difficult to control, then special contact precautions may need implemented, including empiric placement of patients in contact precautions while waiting for the results of C difficile testing and continuing precautions until the time of discharge.1 Environmental contamination occurs before diagnostic tests for C difficile are ordered.7,42 Therefore, test ordering should occur as soon as there is a suspicion of CDI. This practice allows people to be isolated while results are pending, followed by rapid treatment initiation or isolation discontinuation once the result finalizes. Unfortunately, a delay in diagnosis of several days frequently occurs. Much of the delay is attributable to lack of prompt stool sample collection. In addition, using off-site laboratories may further contribute to a delay, especially in LTCFs.42,43 Furthermore, environmental contamination with C difficile continues to be found at both diarrhea resolution and the end of treatment, with frequencies of 37% and 14%, respectively. Moreover, 1 to 4 weeks after treatment there is a rebound in C difficile colonization, with asymptomatic carriage identified in 56% of patients and environmental contamination found in 50% of rooms.7 As a result, in the acute care setting, extended contact procedures have a role in preventing spore transmission.44 Unfortunately, implementation can be problematic in the LTCFs. Prolonging the duration of contact precautions can be difficult because of the long length of stay in LTCFs and the fact that these facilities try to provide a homelike environment.45,46 In addition, patients experiencing CDI should have a private room with dedicated toileting facilities, to limit interaction with other susceptible individuals. Colonization is more likely among patients exposed to a roommate with C difficile.6 C difficile has been discovered on surfaces throughout the room of patients with C difficile, including toilets, commodes, privacy curtains, call buttons, bedside tables, and floors.5,6,20,22 One intensive care unit compared their rates of C difficile acquisition before and after converting their rooms from multibed to single bed. The transmission
Prevention of Infection due to C difficile
rate decreased by 43%.47 If a single room is not available, then cohorting with other infected patients is considered acceptable.1 Nevertheless, cohorted patients should have dedicated bedside commodes.1,5,22 Notably, one institution demonstrated that admission to a C difficile cohort ward was independently associated with CDI recurrence.48 Unfortunately, not all institutions have the ability to support single isolation rooms. LTCFs in particular may find providing a single isolation room especially challenging. Frequently, LTCFs have shared rehabilitation, dining, or recreational areas. Furthermore, single-use medical device utilization should be implemented whenever feasible. If disposable equipment is not available, then the patients should have dedicated equipment left in their rooms. It is also important to ensure proper disinfection of all reusable equipment between patients.49 CDI spread has been associated with both electronic rectal thermometers and blood pressure cuffs.50–52 C difficile spores can contaminate electronic thermometer handles. Spore transfer to the disposable probe cover may occur during routine use.50 In a randomized trial, the CDI rate was lower with single-use disposable whole thermometers compared with electronic thermometers (relative risk 0.44%; P 5 .026).51 Stethoscopes are another possible transmission vector.53,54 C difficile spore acquisition and transfer by stethoscopes were found to occur as readily as with gloved hands during simulated physical examinations.54 An often-overlooked facet of infection control is care transitions. It is critical that hospitals and LTCFs effectively communicate, because patients continue to shed spores for a prolonged duration.7 Most residents in long-term care settings will require help with multiple activities of daily living and therefore require routine contact with caregivers. Also, about 33% of nursing home residents are bowel-incontinent.45 Moreover, many nursing homes do not have single rooms readily available. Effective handoffs allow the receiving facility to properly prepare and implement isolation procedures.46 Conversely, the receiving facility should not require negative testing for C difficile before accepting a patient because it may take several weeks for tests to become negative after symptoms resolve.7,46 Regrettably, care transitions are often poorly coordinated. Inadequate communication is a major barrier to implementing appropriate prevention procedures.46 Environmental Decontamination
Adequate environmental cleaning practices aid in CDI prevention efforts. C difficile is regularly recovered throughout an infected patient’s rooms.5,6,20,22 The amount of environmental shedding correlates with the degree of patients’ symptoms.5–7 Assignment to a room where the previous occupant had CDI predisposes the new occupant to developing CDI. A study showed that CDI was 2.35 times more likely if the room’s previous occupant had CDI, even after controlling for age, disease severity, proton pump inhibitor (PPI) use, and antibiotic administration.55 Problematically, the spores are incredibly resilient, which makes decontamination extremely challenging. Environmental persistence has been demonstrated after 5 months.5 Spores are resistant to heat (>80 C), acid (pH <2), and a variety of disinfectants, including the quaternary ammonium compounds typically used in health care environments.4,31,56,57 Because of this resilience against commonly used disinfectants, the recommended disinfectant is a chlorine-containing solution (bleach). Chlorine-containing products have been demonstrated to inactivate the spores in vitro.57 In addition, numerous clinical studies support the use of hypochlorite-based solutions.58–62 The recommended concentration is 1000 to 5000 ppm of available chlorine.1 In one study, a hospital switched from a quaternary ammonium disinfectant to a 1:10 hypochlorite solution
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in an attempt to lower their CDI rate. The bone marrow transplant unit experienced a decrease in their CDI rate from 8.6 cases/1000 patient-days to 3.3 cases/1000 patientdays. In addition, there was a rebound to 8.1 cases/1000 patient-days after changing back to a quaternary ammonium solution. Conversely, there was not CDI reduction in 2 other units where the baseline CDI rate was lower, despite using a hypochloritebased disinfectant.59 In another example, a hospital system with a CDI outbreak switched from a quaternary ammonium solution to a 1:10 mixture of sodium hypochlorite (household bleach) for room decontamination at discharge. This solution contains approximately 5000 ppm of available chlorine. The hospital system reported a 48% reduction in CDI rates after the intervention.62 Finally, a randomized trial looked at the effect of daily decontamination of “high-touch” surfaces versus cleaning only when the surfaces were visibly soiled. The trial found a significant reduction in hand contamination if “high-touch” surfaces were cleaned daily.21 Unfortunately, hypochlorite-containing agents have disadvantages that limit routine use. They are corrosive to metals, have a strong odor, and may be irritating to the skin and respiratory tract.59,63 Another obstacle to C difficile prevention is that cleaning by environmental service workers is frequently inadequate.64–68 There is often substantial variation in cleaning practices between individual environmental service workers.67 A survey of environmental service workers identified several barriers to effective room cleaning, including lack of time, insufficient supplies, lack of notification when rooms needed to be cleaned, and lack of training. Only 15% of workers were aware that bleach products are used for C difficile.69 Using fluorescent or ATP bioluminescent markers improves decontamination rates. Fluorescent marker application should occur before cleaning, and after cleaning, it should be assessed whether it was removed during cleaning. Similarly, ATP bioluminescence allows assessment for any remaining organic material after cleaning. However, despite using fluorescent or ATP bioluminescent markers, C difficile is still frequently isolated in the environment.64–68 In one study, the use of fluorescent markers, for monitoring and feedback regarding cleaning thoroughness, only decreased the rate of positive cultures from CDI room from 67% to 57%. This same study was able to reduce the rate of positive CDI room cultures to 7% by implementing daily cleaning by a dedicated disinfection team and requiring supervisor evaluation of rooms at time of discharge through either direct observation or ATP bioluminescence.68 When monitoring of cleaning practices, it is important to ensure that regular feedback is given to environmental service workers for quality improvement purposes, not for punitive purposes.70 A novel development is “no-touch” decontamination techniques. Systems using hydrogen peroxide vapor, hydrogen peroxide aerosols, and ultraviolet light are available. They can successfully reduce environmental contamination with C difficile. However, there are several drawbacks. All require special equipment and can only be used after the patient has left the room. Furthermore, hydrogen peroxide systems require the room to be sealed and can be time consuming compared with conventional methods. In addition, it is not currently clear if these techniques are significantly more effective at decontamination than traditional cleaning with hypochloritecontaining products. Finally, manual cleaning is still required anyways for dust and heavily soiled areas.68,71–74 RISK FACTOR REDUCTION
Some CDI risk factors, such as advanced age and comorbid conditions, are not modifiable. Reducing unnecessary antibiotic exposure, through antimicrobial stewardship,
Prevention of Infection due to C difficile
and avoiding unnecessary gastric acid suppression are both modifiable risk factors that can help protect patients from becoming infected with C difficile. Likewise, probiotic administration may be a potentially beneficial strategy. Finally, vaccines against C difficile are currently in development. Antibiotic Stewardship
The greatest risk factor for CDI acquisition is prior antibiotic exposure. CDI development has been linked with nearly all antibiotics, although the risk varies significantly between different antimicrobial classes.75,76 Administration of fluoroquinolones is a key risk factor influencing the spread of the hypervirulent strain BI/NAP1/027.77 Both the number of antibiotics and duration of therapy increase the CDI risk; however, symptoms have developed even after exposure to a single antibiotic dose.76,78 The risk seems to persist for as long as 3 months after antibiotic discontinuation.75 Restricting high-risk antibiotics controls CDI effectively in outbreak settings. For example, a Boston hospital targeted third-generation cephalosporin and aztreonam prescribing. This intervention significantly reduced the rate of both CDI and antibiotic-resistant Enterobacteriaceae infections.79 In another example, several Northern Ireland hospitals were able to end an outbreak of strain BI/NAP1/027 by restricting fluoroquinolone usage.80 Numerous other studies have demonstrated this decrease in CDI incidence across multiple antibiotic classes, including cephalosporins, clindamycin, and fluoroquinolones.81–83 More recently, a Veterans Administration LTCF initiated an infectious disease consult service and was able to reduce antibiotic use by 30% with a subsequent decline in positive C difficile tests.84 Finally, an academic tertiary-care hospital was able to demonstrate that implementation of a strong antibiotic stewardship program could result in sustained benefits. They examined their institution over a 13-year period and found a 62.8% (P<.0001) reduction in antibiotic use. This reduction resulted in decreasing CDI, MRSA infection, and quinoloneresistant Pseudomonas aeruginosa rates by 43%, 57%, and 72%, respectively.85 In conclusion, efforts to reduce unnecessary antibiotic prescribing and decrease use of high-risk medications can have a substantial impact on C difficile prevention. A reduction of antibiotic use is achievable by implementation of an effective antibiotic stewardship program. Avoiding Gastric Acid Suppression
Numerous studies have correlated CDI development with using acid suppressing drugs, such as H2 receptor blockers and PPIs.86–89 In 2012, the US Food and Drug Administration published a safety notification that the likelihood of CDI increases after PPI administration. The report found an elevation in CDI risk by 1.4- to 2.75-fold in people using PPIs.90 However, not all studies have supported the association between elevated CDI risk and PPIs.91 Regardless, overuse of PPIs is extremely common.88,92,93 Therefore, attempts to avoid unnecessary PPI use should be considered. Probiotics
Probiotics have been increasing in popularity in recent years. In an observational study of 145 US hospitals, probiotics were administered during 2.6% of hospitalizations in 2012, representing about a 3-fold increase from 2006.94 Meta-analyses have reported that probiotics may decrease the CDI risk. However, these studies have several limitations. The type of probiotic used, duration of use, and dose varied widely between included studies. In addition, several studies demonstrated extraordinarily high control group rates of CDI, resulting in a baseline CDI estimate of greater than 5%.95,96 However, the CDI rate in hospitalized patients is usually reported to be closer to
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1%.97 A double-blinded, placebo-controlled, randomized trial investigated CDI incidence after administration of the probiotics lactobacilli and bifidobacteria versus placebo. It randomized 2981 patients over the age of 65 who had received antibiotics. This study did not find any statistical reduction in the CDI incidence. The rates in the probiotic and placebo groups were 0.8% and 1.2%, respectively, representing a relative risk associated with probiotic use of 0.71 with a 95% confidence interval of 0.34 to 1.47 (P value 5 .35).98 Currently, there is inadequate evidence to recommend routinely administering probiotics for CDI prevention. This area requires further research. Vaccination
An area of active research is C difficile vaccine development. Previous evidence demonstrated a function of naturally occurring toxin A antibodies in prevention of acute diarrhea and recurrence of CDI.99,100 In addition, an animal study demonstrated that prior vaccination with toxin B was effective in preventing disease occurrence after exposure to toxigenic strains.101 These studies suggest that immunization against the toxins may be beneficial in disease prevention. A vaccine candidate is currently in phase 3 trials.102 Vaccination against C difficile toxins potentially offers an inexpensive and effective long-term preventative strategy. SUMMARY
C difficile remains a significant problem in the health care setting. Successful prevention efforts typically require a multifaceted bundled approach. A combination of decreased antibiotic use, strict hand hygiene, isolation precautions, and effective environmental decontamination is required, and these can all result in considerable reductions in CDI rates. However, further research is required to develop long-term preventative interventions and efficiently implement current approaches to CDI prevention outside of the acute care setting. REFERENCES
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28. Kaier K, Hagist C, Frank U, et al. Two time-series analyses of the impact of antibiotic consumption and alcohol-based hand disinfection on the incidences of nosocomial methicillin-resistant Staphylococcus aureus infection and Clostridium difficile infection. Infect Control Hosp Epidemiol 2009;30(4):346–53. 29. Vernaz N, Sax H, Pittet D, et al. Temporal effects of antibiotic use and hand rub consumption on the incidence of MRSA and Clostridium difficile. J Antimicrob Chemother 2008;62(3):601–7. 30. Wullt M, Odenholt I, Walder M. Activity of three disinfectants and acidified nitrite against Clostridium difficile spores. Infect Control Hosp Epidemiol 2003;24(10): 765–8. 31. Clabots CR, Gerding SJ, Olson MM, et al. Detection of asymptomatic Clostridium difficile carriage by an alcohol shock procedure. J Clin Microbiol 1989; 27(10):2386–7. 32. Jabbar U, Leischner J, Kasper D, et al. Effectiveness of alcohol-based hand rubs for removal of Clostridium difficile spores from hands. Infect Control Hosp Epidemiol 2010;31(6):565–70. 33. Kundrapu S, Sunkesula V, Jury I, et al. A randomized trial of soap and water hand wash versus alcohol hand rub for removal of Clostridium difficile spores from hands of patients. Infect Control Hosp Epidemiol 2014;35(2):204–6. 34. Oughton MT, Loo VG, Dendukuri N, et al. Hand hygiene with soap and water is superior to alcohol rub and antiseptic wipes for removal of Clostridium difficile. Infect Control Hosp Epidemiol 2009;30(10):939–44. 35. Bettin K, Clabots C, Mathie P, et al. Effectiveness of liquid soap vs. chlorhexidine gluconate for the removal of Clostridium difficile from bare hands and gloved hands. Infect Control Hosp Epidemiol 1994;15(11):697–702. 36. Boyce JM, Ligi C, Kohan C, et al. Lack of association between the increased incidence of Clostridium difficile-associated disease and the increasing use of alcohol-based hand rubs. Infect Control Hosp Epidemiol 2006;27(5):479–83. 37. Kaier K, Frank U, Hagist C, et al. The impact of antimicrobial drug consumption and alcohol-based hand rub use on the emergence and spread of extendedspectrum beta-lactamase-producing strains: a time-series analysis. J Antimicrob Chemother 2009;63(3):609–14. 38. Rupp ME, Fitzgerald T, Puumala S, et al. Prospective, controlled, cross-over trial of alcohol-based hand gel in critical care units. Infect Control Hosp Epidemiol 2008;29(1):8–15. 39. Johnson S, Gerding DN, Olson MM, et al. Prospective, controlled study of vinyl glove use to interrupt Clostridium difficile nosocomial transmission. Am J Med 1990;88(2):137–40. 40. Perry C, Marshall R, Jones E. Bacterial contamination of uniforms. J Hosp Infect 2001;48(3):238–41. 41. Croft LD, Harris AD, Pineles L, et al. The effect of universal glove and gown use on adverse events in intensive care unit patients. Clin Infect Dis 2015;61(4): 545–53. 42. Sunkesula VC, Kundrapu S, Jury LA, et al. Potential for transmission of spores by patients awaiting laboratory testing to confirm suspected Clostridium difficile infection. Infect Control Hosp Epidemiol 2013;34(3):306–8. 43. Kundrapu S, Jury LA, Sitzlar B, et al. Easily modified factors contribute to delays in diagnosis of Clostridium difficile infection: a cohort study and intervention. J Clin Microbiol 2013;51(7):2365–70.
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44. Salgado CD, Mauldin PD, Fogle PJ, et al. Analysis of an outbreak of Clostridium difficile infection controlled with enhanced infection control measures. Am J Infect Control 2009;37(6):458–64. 45. Jones AL, Dwyer LL, Bercovitz AR, et al. The National Nursing Home Survey: 2004 overview. Vital Health Stat 13 2009;(167):1–155. 46. Ye Z, Mukamel DB, Huang SS, et al. Healthcare-associated pathogens and nursing home policies and practices: results from a national survey. Infect Control Hosp Epidemiol 2015;36(7):759–66. 47. Teltsch DY, Hanley J, Loo V, et al. Infection acquisition following intensive care unit room privatization. Arch Intern Med 2011;171(1):32–8. 48. Islam J, Cheek E, Navani V, et al. Influence of cohorting patients with Clostridium difficile infection on risk of symptomatic recurrence. J Hosp Infect 2013;85(1): 17–21. 49. Rutala WA, Gergen MF, Weber DJ. Inactivation of Clostridium difficile spores by disinfectants. Infect Control Hosp Epidemiol 1993;14(1):36–9. 50. Brooks SE, Veal RO, Kramer M, et al. Reduction in the incidence of Clostridium difficile-associated diarrhea in an acute care hospital and a skilled nursing facility following replacement of electronic thermometers with single-use disposables. Infect Control Hosp Epidemiol 1992;13(2):98–103. 51. Jernigan JA, Siegman-Igra Y, Guerrant RC, et al. A randomized crossover study of disposable thermometers for prevention of Clostridium difficile and other nosocomial infections. Infect Control Hosp Epidemiol 1998;19(7):494–9. 52. Manian FA, Meyer L, Jenne J. Clostridium difficile contamination of blood pressure cuffs: a call for a closer look at gloving practices in the era of universal precautions. Infect Control Hosp Epidemiol 1996;17(3):180–2. 53. Alleyne SA, Hussain AM, Clokie M, et al. Stethoscopes: potential vectors of Clostridium difficile. J Hosp Infect 2009;73(2):187–9. 54. Vajravelu RK, Guerrero DM, Jury LA, et al. Evaluation of stethoscopes as vectors of Clostridium difficile and methicillin-resistant Staphylococcus aureus. Infect Control Hosp Epidemiol 2012;33(1):96–8. 55. Shaughnessy MK, Micielli RL, DePestel DD, et al. Evaluation of hospital room assignment and acquisition of Clostridium difficile infection. Infect Control Hosp Epidemiol 2011;32(3):201–6. 56. Marler LM, Siders JA, Wolters LC, et al. Comparison of five cultural procedures for isolation of Clostridium difficile from stools. J Clin Microbiol 1992;30(2): 514–6. 57. Fawley WN, Underwood S, Freeman J, et al. Efficacy of hospital cleaning agents and germicides against epidemic Clostridium difficile strains. Infect Control Hosp Epidemiol 2007;28(8):920–5. 58. Kaatz GW, Gitlin SD, Schaberg DR, et al. Acquisition of Clostridium difficile from the hospital environment. Am J Epidemiol 1988;127(6):1289–94. 59. Mayfield JL, Leet T, Miller J, et al. Environmental control to reduce transmission of Clostridium difficile. Clin Infect Dis 2000;31(4):995–1000. 60. Wilcox MH, Fawley WN, Wigglesworth N, et al. Comparison of the effect of detergent versus hypochlorite cleaning on environmental contamination and incidence of Clostridium difficile infection. J Hosp Infect 2003;54(2):109–14. 61. McMullen KM, Zack J, Coopersmith CM, et al. Use of hypochlorite solution to decrease rates of Clostridium difficile-associated diarrhea. Infect Control Hosp Epidemiol 2007;28(2):205–7.
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62. Hacek DM, Ogle AM, Fisher A, et al. Significant impact of terminal room cleaning with bleach on reducing nosocomial Clostridium difficile. Am J Infect Control 2010;38(5):350–3. 63. Rutala WA, Weber DJ. Uses of inorganic hypochlorite (bleach) in health-care facilities. Clin Microbiol Rev 1997;10(4):597–610. 64. Carling PC, Parry MM, Rupp ME, et al. Improving cleaning of the environment surrounding patients in 36 acute care hospitals. Infect Control Hosp Epidemiol 2008;29(11):1035–41. 65. Boyce JM, Havill NL, Havill HL, et al. Comparison of fluorescent marker systems with 2 quantitative methods of assessing terminal cleaning practices. Infect Control Hosp Epidemiol 2011;32(12):1187–93. 66. Deshpande A, Sitzlar B, Fertelli D, et al. Utility of an adenosine triphosphate bioluminescence assay to evaluate disinfection of Clostridium difficile isolation rooms. Infect Control Hosp Epidemiol 2013;34(8):865–7. 67. Boyce JM, Havill NL, Lipka A, et al. Variations in hospital daily cleaning practices. Infect Control Hosp Epidemiol 2010;31(1):99–101. 68. Sitzlar B, Deshpande A, Fertelli D, et al. An environmental disinfection odyssey: evaluation of sequential interventions to improve disinfection of Clostridium difficile isolation rooms. Infect Control Hosp Epidemiol 2013;34(5):459–65. 69. Jennings A, Sitzlar B, Jury L. A survey of environmental service workers’ knowledge and opinions regarding environmental cleaning. Am J Infect Control 2013; 41(2):177–9. 70. Rupp ME, Fitzgerald T, Sholtz L, et al. Maintain the gain: program to sustain performance improvement in environmental cleaning. Infect Control Hosp Epidemiol 2014;35(7):866–8. 71. Ghantoji SS, Stibich M, Stachowiak J, et al. Non-inferiority of pulsed xenon UV light versus bleach for reducing environmental Clostridium difficile contamination on high-touch surfaces in Clostridium difficile infection isolation rooms. J Med Microbiol 2015;64(Pt 2):191–4. 72. Passaretti CL, Otter JA, Reich NG, et al. An evaluation of environmental decontamination with hydrogen peroxide vapor for reducing the risk of patient acquisition of multidrug-resistant organisms. Clin Infect Dis 2013;56(1):27–35. 73. Manian FA, Griesnauer S, Bryant A. Implementation of hospital-wide enhanced terminal cleaning of targeted patient rooms and its impact on endemic Clostridium difficile infection rates. Am J Infect Control 2013;41(6):537–41. 74. Best EL, Parnell P, Thirkell G, et al. Effectiveness of deep cleaning followed by hydrogen peroxide decontamination during high Clostridium difficile infection incidence. J Hosp Infect 2014;87(1):25–33. 75. Hensgens MP, Goorhuis A, Dekkers OM, et al. Time interval of increased risk for Clostridium difficile infection after exposure to antibiotics. J Antimicrob Chemother 2012;67(3):742–8. 76. Stevens V, Dumyati G, Fine LS, et al. Cumulative antibiotic exposures over time and the risk of Clostridium difficile infection. Clin Infect Dis 2011;53(1):42–8. 77. Pepin J, Saheb N, Coulombe MA, et al. Emergence of fluoroquinolones as the predominant risk factor for Clostridium difficile-associated diarrhea: a cohort study during an epidemic in Quebec. Clin Infect Dis 2005;41(9):1254–60. 78. Privitera G, Scarpellini P, Ortisi G, et al. Prospective study of Clostridium difficile intestinal colonization and disease following single-dose antibiotic prophylaxis in surgery. Antimicrob Agents Chemother 1991;35(1):208–10.
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79. Carling P, Fung T, Killion A, et al. Favorable impact of a multidisciplinary antibiotic management program conducted during 7 years. Infect Control Hosp Epidemiol 2003;24(9):699–706. 80. Aldeyab MA, Devine MJ, Flanagan P, et al. Multihospital outbreak of Clostridium difficile ribotype 027 infection: epidemiology and analysis of control measures. Infect Control Hosp Epidemiol 2011;32(3):210–9. 81. Ludlam H, Brown N, Sule O, et al. An antibiotic policy associated with reduced risk of Clostridium difficile-associated diarrhoea. Age Ageing 1999;28(6): 578–80. 82. Pear SM, Williamson TH, Bettin KM, et al. Decrease in nosocomial Clostridium difficile-associated diarrhea by restricting clindamycin use. Ann Intern Med 1994;120(4):272–7. 83. Valiquette L, Cossette B, Garant MP, et al. Impact of a reduction in the use of high-risk antibiotics on the course of an epidemic of Clostridium difficileassociated disease caused by the hypervirulent NAP1/027 strain. Clin Infect Dis 2007;45(Suppl 2):S112–21. 84. Jump RL, Olds DM, Seifi N, et al. Effective antimicrobial stewardship in a longterm care facility through an infectious disease consultation service: keeping a LID on antibiotic use. Infect Control Hosp Epidemiol 2012;33(12):1185–92. 85. Cook PP, Gooch M. Long-term effects of an antimicrobial stewardship programme at a tertiary-care teaching hospital. Int J Antimicrob Agents 2015; 45(3):262–7. 86. Gordon D, Young LR, Reddy S, et al. Incidence of Clostridium difficile infection in patients receiving high-risk antibiotics with or without a proton pump inhibitor. J Hosp Infect 2016;92(2):173–7. 87. Kwok CS, Arthur AK, Anibueze CI, et al. Risk of Clostridium difficile infection with acid suppressing drugs and antibiotics: meta-analysis. Am J Gastroenterol 2012;107(7):1011–9. 88. McDonald EG, Milligan J, Frenette C, et al. Continuous proton pump inhibitor therapy and the associated risk of recurrent Clostridium difficile infection. JAMA Intern Med 2015;175(5):784–91. 89. Tleyjeh IM, Abdulhak AB, Riaz M, et al. The association between histamine 2 receptor antagonist use and Clostridium difficile infection: a systematic review and meta-analysis. PLoS One 2013;8(3):e56498. 90. FDA Drug Safety Communication: Clostridium difficile-associated diarrhea can be associated with stomach acid drugs known as proton pump inhibitors (PPIs). 2012. Available at: http://www.fda.gov/Drugs/DrugSafety/ucm290510. htm. Accessed February 1, 2016. 91. Novack L, Kogan S, Gimpelevich L, et al. Acid suppression therapy does not predispose to Clostridium difficile infection: the case of the potential bias. PLoS One 2014;9(10):e110790. 92. Kelly OB, Dillane C, Patchett SE, et al. The inappropriate prescription of oral proton pump inhibitors in the hospital setting: a prospective cross-sectional study. Dig Dis Sci 2015;60(8):2280–6. 93. Rashid S, Rajan D, Iqbal J, et al. Inappropriate use of gastric acid suppression therapy in hospitalized patients with clostridium difficile-associated diarrhea: a ten-year retrospective analysis. ISRN Gastroenterol 2012;2012:902320. 94. Yi SH, Jernigan JA, McDonald LC. Prevalence of probiotic use among inpatients: a descriptive study of 145 U.S. hospitals. Am J Infect Control 2016; 44(5):548–53.
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95. Goldenberg JZ, Ma SS, Saxton JD, et al. Probiotics for the prevention of Clostridium difficile-associated diarrhea in adults and children. Cochrane Database Syst Rev 2013;(5):Cd006095. 96. Johnston BC, Ma SS, Goldenberg JZ, et al. Probiotics for the prevention of Clostridium difficile-associated diarrhea: a systematic review and meta-analysis. Ann Intern Med 2012;157(12):878–88. 97. Lucado J, Gould C, Elixhauser A. Clostridium difficile Infections (CDI) in Hospital Stays, 2009. Rockville (MD): Healthcare Cost and Utilization Project (HCUP) Statistical Briefs; 2006. Statistical Brief #124. 98. Allen SJ, Wareham K, Wang D, et al. Lactobacilli and bifidobacteria in the prevention of antibiotic-associated diarrhoea and Clostridium difficile diarrhoea in older inpatients (PLACIDE): a randomised, double-blind, placebo-controlled, multicentre trial. Lancet 2013;382(9900):1249–57. 99. Kyne L, Warny M, Qamar A, et al. Asymptomatic carriage of Clostridium difficile and serum levels of IgG antibody against toxin A. N Engl J Med 2000;342(6): 390–7. 100. Kyne L, Warny M, Qamar A, et al. Association between antibody response to toxin A and protection against recurrent Clostridium difficile diarrhoea. Lancet 2001;357(9251):189–93. 101. Siddiqui F, O’Connor JR, Nagaro K, et al. Vaccination with parenteral toxoid B protects hamsters against lethal challenge with toxin A-negative, toxin B-positive clostridium difficile but does not prevent colonization. J Infect Dis 2012; 205(1):128–33. 102. Study of a Candidate Clostridium difficile Toxoid Vaccine (Cdiffense) in Subjects at Risk for C. difficile Infection. 2013. Available at: https://clinicaltrials.gov/ct2/ show/NCT01887912. Accessed February 1, 2016.
INTRODUCTION
Clostridium difficile is a leading nosocomial pathogen worldwide. It is associated with tremendous morbidity, mortality, and health care expenditures. Prevention is especially difficult because of the durability of the spores and requires implementation of multipronged strategies. Useful methods to prevent C difficile spread include increased hand hygiene, use of contact precautions, and use of sporicidal decontamination agents. In addition, a focus on effective antibiotic stewardship can significantly
Disclosure Statement: None (C.C. Cooper and T. Chopra). Dr R.L.P. Jump is a Co-Principal Investigator on a grant from Pfizer to study disparities in pneumococcal vaccination rates. a Division of Infectious Diseases, Wayne State University, 3990 John R. Street, 5 Hudson, Detroit, MI 48201, USA; b Infectious Disease Section, Medical Division, Geriatric Research Education and Clinical Center (GRECC), Louis Stokes Cleveland Veterans Affairs Medical Center, 10701 East Boulevard, Cleveland, OH 44106, USA; c Division of Infectious Diseases and HIV Medicine, Department of Medicine, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106, USA * Corresponding author. E-mail address: [email protected] Infect Dis Clin N Am - (2016) -–http://dx.doi.org/10.1016/j.idc.2016.07.005 0891-5520/16/ª 2016 Elsevier Inc. All rights reserved.
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decrease the burden of disease.1 The focus of this article is on preventative strategies to reduce the C difficile infection (CDI) frequency. PATHOGENESIS
C difficile causes a spectrum of disease with symptoms ranging from diarrhea to toxic megacolon and death. The principal risk factor is antibiotic exposure, although several other factors also increase the risk for infection, including advanced age, gastric acid suppression, and low albumin/chronic disease states.1 Acquisition occurs through spore ingestion. The pathogenesis centers on the disruption of the indigenous intestinal microbiome. The most common cause of this is systemic antibiotic administration. In individuals with an intact gut microbiome, the spores are unable to find an ecological niche. However, in people with a disrupted gut microbiome, ingested spores are able to germinate and multiply.2 After germination, the bacterium begins secreting a pair of exotoxins, TcdA and TcdB, which disrupt the cell cytoskeleton and ultimately leads to a disease state.3 The spore represents a reservoir for the organism. Spores are able to resist extreme environmental conditions and are capable of persisting for months in the environment.4,5 C difficile spores are difficult to remove from environmental surfaces and from health care worker hands via routine infection control measures. People with CDI shed spores onto their skin and into the environment. Following successful treatment of an episode of symptomatic CDI, people may become asymptomatic carriers of C difficile. These individuals continue to shed C difficile spores into the environment and can serve as a source of dissemination of spores to others.6–8 The asymptomatic carriage prevalence in hospitalized individuals is close to 10%, and in long-term care facilities (LTCFs), the prevalence is approximately 50%.9,10 EPIDEMIOLOGY
CDI has developed into an enormous burden on society. It is now the most frequent cause of gastroenteritis-related deaths across the United States.11 In 2011, C difficile was responsible for 453,000 infections and 29,000 deaths.12 Although still primarily a hospital-acquired pathogen, reports are increasing throughout the community and LTCFs.13,14 CDI imposes major costs on hospital systems, insurance providers, and society as a whole.15 In the United States, the estimated attributable cost was $11,285 per case, and the total annual financial impact was approximately 1.5 billion dollars, between 2011 and 2013.16 The incidence of CDI has dramatically grown in frequency and severity over the last 15 years. This escalation was ultimately connected to an epidemic strain of C difficile, known as BI/NAP1/027. This strain exhibits enhanced toxin production and fluoroquinolone resistance. The discovery of strain BI/NAP1/027 occurred in Pittsburgh, during the year 2000. Reports of outbreaks in Canada and other regions of the United States soon followed. These outbreaks then spread throughout the United Kingdom and Europe.17,18 PREVENTION
As stated above, CDI prevention generally requires several different interventions. These strategies fall into the broad categories of infection control and prevention as well as risk factor reduction.
Prevention of Infection due to C difficile
INFECTION CONTROL AND PREVENTION
Disease transmission occurs through ingestion of C difficile spores, which are the organism’s dormant form. The degree of C difficile colonization increases at a steady rate and approaches 40% after a month of hospitalization.19 Colonization can occur either by exposure to a contaminated environment or through contact with health care workers.6 Infection control and prevention practices seek to reduce transmission of spores to uncolonized individuals. This strategy uses a combination of contact precautions, environmental disinfection, and hand decontamination. Hand Hygiene
Hand hygiene, a fundamental component of infection control, is the most important aspect of preventing C difficile transmission. Contamination of health care worker’s hands with C difficile occurs regularly when caring for a person with CDI, with rates of contamination of up to 59%.6,8,20–22 In fact, touching the patient is not even required; hand contamination can happen just as often after touching “high-touch” surfaces in the room.20,21 Unfortunately, adherence to routine hand hygiene by health care personnel is poor in many settings.23,24 In recent years, use of alcohol-based hand rubs (ABHR) has gained popularity. Hand hygiene rates are higher with the use of ABHR.25,26 Implementing ABHR decreases the frequencies of both methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus (VRE) infections in the hospital.27–29 However, C difficile spores are extremely resistant to destruction by alcohol.30 In fact, the ethanol shock method is used in laboratory settings to assist in isolating C difficile from stool samples.31 Consequently, health care workers who use ABHR to decontaminate their hands may simply be moving spores around the skin. Conversely, it is hypothesized using soap and water physically removes the spores from the skin. Several laboratory studies have compared various forms of hand hygiene. Washing with soap and water was superior to ABHR for spore removal. Soap and water use may lead to a greater than 90% decrease in spore contamination; however, alcohol-based interventions do not reduce the amount of spore contamination.32–34 Other studies have analyzed the benefit of chlorhexidine with mixed results. One study found that the efficacy of chlorhexidine antiseptic exceeded plain soap at removing C difficile.6 However, other studies failed to show any benefit to chlorhexidine washes over plain soap.32,35 Consequently, there is a hypothetical risk that widespread implementation of ABHR could increase CDI incidence. However, no clinical studies have demonstrated this. In an observational study conducted at a Veterans Administration hospital, the CDI rate remained unchanged after implementation of ABHR. However, there was a 21% reduction in health care–acquired MRSA and a 41% reduction in VRE.27 Numerous other studies have also not been able to find an increase in CDI rates with routine ABHR usage.29,36–38 The Cleanyourhands campaign was a national effort in England and Wales to improve hand hygiene rates. The study analyzed the association between hospital procurement rates of soap and ABHR with rates of nosocomial infection. They found increased hospital ordering of soap was independently associated with decreased CDI. Conversely, there was an independent correlation between obtaining elevated quantities of ABHR and decreased MRSA bacteremia. Based on this evidence, the current Society for Healthcare Epidemiology of America–Infectious Diseases Society of America guidelines recommend, “During outbreaks or in settings with hyperendemic CDI, perform hand hygiene with soap and water as the preferred method before exiting the room of a patient with CDI.”1 However, in
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lower-incidence settings, the benefits of soap and water against C difficile need to be weighed against reductions in other nosocomial infections with ABHR. Contact Precautions
Another important aspect to preventing horizontal transfer of spores is instituting isolation procedures. Isolation procedures include contact precautions, individual rooms, and dedicated patient equipment. Contact precautions refer to the donning of gowns and gloves upon room entry and removal before exiting the room.1 The use of these methods centers on the idea that individuals with active CDI are the main source of disease dissemination. C difficile spores frequently contaminate health care worker’s hands, during the routine care of individuals with CDI.6,8,20–22 The routine use of gloves may help reduce transmission to other patients. One prospective study analyzed use of vinyl gloves to interrupt transmission. The interventions included reminder signs and making gloves available in every patient’s room. This intervention resulted in a drop in the CDI cases from 7.7 to 1.5 per 1000 patient discharges. The asymptomatic carriage rate also decreased during this intervention.39 Gowns use is also recommended due to potential soiling of health care worker clothing. Nurses’ clothes have been documented to become contaminated with C difficile during routine clinical duties. However, the same study did not specifically assess if the contamination was linked to patient acquisitions or transmissions.40 Importantly, in a randomized controlled trial of intensive care patients, adverse events were not increased for patients on contact precautions compared with patients without contact precautions.41 Current guidelines recommend continuing contact precautions until diarrhea resolution. However, in situations where the spread of CDI is difficult to control, then special contact precautions may need implemented, including empiric placement of patients in contact precautions while waiting for the results of C difficile testing and continuing precautions until the time of discharge.1 Environmental contamination occurs before diagnostic tests for C difficile are ordered.7,42 Therefore, test ordering should occur as soon as there is a suspicion of CDI. This practice allows people to be isolated while results are pending, followed by rapid treatment initiation or isolation discontinuation once the result finalizes. Unfortunately, a delay in diagnosis of several days frequently occurs. Much of the delay is attributable to lack of prompt stool sample collection. In addition, using off-site laboratories may further contribute to a delay, especially in LTCFs.42,43 Furthermore, environmental contamination with C difficile continues to be found at both diarrhea resolution and the end of treatment, with frequencies of 37% and 14%, respectively. Moreover, 1 to 4 weeks after treatment there is a rebound in C difficile colonization, with asymptomatic carriage identified in 56% of patients and environmental contamination found in 50% of rooms.7 As a result, in the acute care setting, extended contact procedures have a role in preventing spore transmission.44 Unfortunately, implementation can be problematic in the LTCFs. Prolonging the duration of contact precautions can be difficult because of the long length of stay in LTCFs and the fact that these facilities try to provide a homelike environment.45,46 In addition, patients experiencing CDI should have a private room with dedicated toileting facilities, to limit interaction with other susceptible individuals. Colonization is more likely among patients exposed to a roommate with C difficile.6 C difficile has been discovered on surfaces throughout the room of patients with C difficile, including toilets, commodes, privacy curtains, call buttons, bedside tables, and floors.5,6,20,22 One intensive care unit compared their rates of C difficile acquisition before and after converting their rooms from multibed to single bed. The transmission
Prevention of Infection due to C difficile
rate decreased by 43%.47 If a single room is not available, then cohorting with other infected patients is considered acceptable.1 Nevertheless, cohorted patients should have dedicated bedside commodes.1,5,22 Notably, one institution demonstrated that admission to a C difficile cohort ward was independently associated with CDI recurrence.48 Unfortunately, not all institutions have the ability to support single isolation rooms. LTCFs in particular may find providing a single isolation room especially challenging. Frequently, LTCFs have shared rehabilitation, dining, or recreational areas. Furthermore, single-use medical device utilization should be implemented whenever feasible. If disposable equipment is not available, then the patients should have dedicated equipment left in their rooms. It is also important to ensure proper disinfection of all reusable equipment between patients.49 CDI spread has been associated with both electronic rectal thermometers and blood pressure cuffs.50–52 C difficile spores can contaminate electronic thermometer handles. Spore transfer to the disposable probe cover may occur during routine use.50 In a randomized trial, the CDI rate was lower with single-use disposable whole thermometers compared with electronic thermometers (relative risk 0.44%; P 5 .026).51 Stethoscopes are another possible transmission vector.53,54 C difficile spore acquisition and transfer by stethoscopes were found to occur as readily as with gloved hands during simulated physical examinations.54 An often-overlooked facet of infection control is care transitions. It is critical that hospitals and LTCFs effectively communicate, because patients continue to shed spores for a prolonged duration.7 Most residents in long-term care settings will require help with multiple activities of daily living and therefore require routine contact with caregivers. Also, about 33% of nursing home residents are bowel-incontinent.45 Moreover, many nursing homes do not have single rooms readily available. Effective handoffs allow the receiving facility to properly prepare and implement isolation procedures.46 Conversely, the receiving facility should not require negative testing for C difficile before accepting a patient because it may take several weeks for tests to become negative after symptoms resolve.7,46 Regrettably, care transitions are often poorly coordinated. Inadequate communication is a major barrier to implementing appropriate prevention procedures.46 Environmental Decontamination
Adequate environmental cleaning practices aid in CDI prevention efforts. C difficile is regularly recovered throughout an infected patient’s rooms.5,6,20,22 The amount of environmental shedding correlates with the degree of patients’ symptoms.5–7 Assignment to a room where the previous occupant had CDI predisposes the new occupant to developing CDI. A study showed that CDI was 2.35 times more likely if the room’s previous occupant had CDI, even after controlling for age, disease severity, proton pump inhibitor (PPI) use, and antibiotic administration.55 Problematically, the spores are incredibly resilient, which makes decontamination extremely challenging. Environmental persistence has been demonstrated after 5 months.5 Spores are resistant to heat (>80 C), acid (pH <2), and a variety of disinfectants, including the quaternary ammonium compounds typically used in health care environments.4,31,56,57 Because of this resilience against commonly used disinfectants, the recommended disinfectant is a chlorine-containing solution (bleach). Chlorine-containing products have been demonstrated to inactivate the spores in vitro.57 In addition, numerous clinical studies support the use of hypochlorite-based solutions.58–62 The recommended concentration is 1000 to 5000 ppm of available chlorine.1 In one study, a hospital switched from a quaternary ammonium disinfectant to a 1:10 hypochlorite solution
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in an attempt to lower their CDI rate. The bone marrow transplant unit experienced a decrease in their CDI rate from 8.6 cases/1000 patient-days to 3.3 cases/1000 patientdays. In addition, there was a rebound to 8.1 cases/1000 patient-days after changing back to a quaternary ammonium solution. Conversely, there was not CDI reduction in 2 other units where the baseline CDI rate was lower, despite using a hypochloritebased disinfectant.59 In another example, a hospital system with a CDI outbreak switched from a quaternary ammonium solution to a 1:10 mixture of sodium hypochlorite (household bleach) for room decontamination at discharge. This solution contains approximately 5000 ppm of available chlorine. The hospital system reported a 48% reduction in CDI rates after the intervention.62 Finally, a randomized trial looked at the effect of daily decontamination of “high-touch” surfaces versus cleaning only when the surfaces were visibly soiled. The trial found a significant reduction in hand contamination if “high-touch” surfaces were cleaned daily.21 Unfortunately, hypochlorite-containing agents have disadvantages that limit routine use. They are corrosive to metals, have a strong odor, and may be irritating to the skin and respiratory tract.59,63 Another obstacle to C difficile prevention is that cleaning by environmental service workers is frequently inadequate.64–68 There is often substantial variation in cleaning practices between individual environmental service workers.67 A survey of environmental service workers identified several barriers to effective room cleaning, including lack of time, insufficient supplies, lack of notification when rooms needed to be cleaned, and lack of training. Only 15% of workers were aware that bleach products are used for C difficile.69 Using fluorescent or ATP bioluminescent markers improves decontamination rates. Fluorescent marker application should occur before cleaning, and after cleaning, it should be assessed whether it was removed during cleaning. Similarly, ATP bioluminescence allows assessment for any remaining organic material after cleaning. However, despite using fluorescent or ATP bioluminescent markers, C difficile is still frequently isolated in the environment.64–68 In one study, the use of fluorescent markers, for monitoring and feedback regarding cleaning thoroughness, only decreased the rate of positive cultures from CDI room from 67% to 57%. This same study was able to reduce the rate of positive CDI room cultures to 7% by implementing daily cleaning by a dedicated disinfection team and requiring supervisor evaluation of rooms at time of discharge through either direct observation or ATP bioluminescence.68 When monitoring of cleaning practices, it is important to ensure that regular feedback is given to environmental service workers for quality improvement purposes, not for punitive purposes.70 A novel development is “no-touch” decontamination techniques. Systems using hydrogen peroxide vapor, hydrogen peroxide aerosols, and ultraviolet light are available. They can successfully reduce environmental contamination with C difficile. However, there are several drawbacks. All require special equipment and can only be used after the patient has left the room. Furthermore, hydrogen peroxide systems require the room to be sealed and can be time consuming compared with conventional methods. In addition, it is not currently clear if these techniques are significantly more effective at decontamination than traditional cleaning with hypochloritecontaining products. Finally, manual cleaning is still required anyways for dust and heavily soiled areas.68,71–74 RISK FACTOR REDUCTION
Some CDI risk factors, such as advanced age and comorbid conditions, are not modifiable. Reducing unnecessary antibiotic exposure, through antimicrobial stewardship,
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and avoiding unnecessary gastric acid suppression are both modifiable risk factors that can help protect patients from becoming infected with C difficile. Likewise, probiotic administration may be a potentially beneficial strategy. Finally, vaccines against C difficile are currently in development. Antibiotic Stewardship
The greatest risk factor for CDI acquisition is prior antibiotic exposure. CDI development has been linked with nearly all antibiotics, although the risk varies significantly between different antimicrobial classes.75,76 Administration of fluoroquinolones is a key risk factor influencing the spread of the hypervirulent strain BI/NAP1/027.77 Both the number of antibiotics and duration of therapy increase the CDI risk; however, symptoms have developed even after exposure to a single antibiotic dose.76,78 The risk seems to persist for as long as 3 months after antibiotic discontinuation.75 Restricting high-risk antibiotics controls CDI effectively in outbreak settings. For example, a Boston hospital targeted third-generation cephalosporin and aztreonam prescribing. This intervention significantly reduced the rate of both CDI and antibiotic-resistant Enterobacteriaceae infections.79 In another example, several Northern Ireland hospitals were able to end an outbreak of strain BI/NAP1/027 by restricting fluoroquinolone usage.80 Numerous other studies have demonstrated this decrease in CDI incidence across multiple antibiotic classes, including cephalosporins, clindamycin, and fluoroquinolones.81–83 More recently, a Veterans Administration LTCF initiated an infectious disease consult service and was able to reduce antibiotic use by 30% with a subsequent decline in positive C difficile tests.84 Finally, an academic tertiary-care hospital was able to demonstrate that implementation of a strong antibiotic stewardship program could result in sustained benefits. They examined their institution over a 13-year period and found a 62.8% (P<.0001) reduction in antibiotic use. This reduction resulted in decreasing CDI, MRSA infection, and quinoloneresistant Pseudomonas aeruginosa rates by 43%, 57%, and 72%, respectively.85 In conclusion, efforts to reduce unnecessary antibiotic prescribing and decrease use of high-risk medications can have a substantial impact on C difficile prevention. A reduction of antibiotic use is achievable by implementation of an effective antibiotic stewardship program. Avoiding Gastric Acid Suppression
Numerous studies have correlated CDI development with using acid suppressing drugs, such as H2 receptor blockers and PPIs.86–89 In 2012, the US Food and Drug Administration published a safety notification that the likelihood of CDI increases after PPI administration. The report found an elevation in CDI risk by 1.4- to 2.75-fold in people using PPIs.90 However, not all studies have supported the association between elevated CDI risk and PPIs.91 Regardless, overuse of PPIs is extremely common.88,92,93 Therefore, attempts to avoid unnecessary PPI use should be considered. Probiotics
Probiotics have been increasing in popularity in recent years. In an observational study of 145 US hospitals, probiotics were administered during 2.6% of hospitalizations in 2012, representing about a 3-fold increase from 2006.94 Meta-analyses have reported that probiotics may decrease the CDI risk. However, these studies have several limitations. The type of probiotic used, duration of use, and dose varied widely between included studies. In addition, several studies demonstrated extraordinarily high control group rates of CDI, resulting in a baseline CDI estimate of greater than 5%.95,96 However, the CDI rate in hospitalized patients is usually reported to be closer to
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1%.97 A double-blinded, placebo-controlled, randomized trial investigated CDI incidence after administration of the probiotics lactobacilli and bifidobacteria versus placebo. It randomized 2981 patients over the age of 65 who had received antibiotics. This study did not find any statistical reduction in the CDI incidence. The rates in the probiotic and placebo groups were 0.8% and 1.2%, respectively, representing a relative risk associated with probiotic use of 0.71 with a 95% confidence interval of 0.34 to 1.47 (P value 5 .35).98 Currently, there is inadequate evidence to recommend routinely administering probiotics for CDI prevention. This area requires further research. Vaccination
An area of active research is C difficile vaccine development. Previous evidence demonstrated a function of naturally occurring toxin A antibodies in prevention of acute diarrhea and recurrence of CDI.99,100 In addition, an animal study demonstrated that prior vaccination with toxin B was effective in preventing disease occurrence after exposure to toxigenic strains.101 These studies suggest that immunization against the toxins may be beneficial in disease prevention. A vaccine candidate is currently in phase 3 trials.102 Vaccination against C difficile toxins potentially offers an inexpensive and effective long-term preventative strategy. SUMMARY
C difficile remains a significant problem in the health care setting. Successful prevention efforts typically require a multifaceted bundled approach. A combination of decreased antibiotic use, strict hand hygiene, isolation precautions, and effective environmental decontamination is required, and these can all result in considerable reductions in CDI rates. However, further research is required to develop long-term preventative interventions and efficiently implement current approaches to CDI prevention outside of the acute care setting. REFERENCES
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