Clostridium difficile

Clostridium difficile

Clostridium difficile Robin B. McFee, DO, MPH, FACPM, and George G. Abdelsayed, MD, FACP, FACG Clostridium difficile (C diff) is a Gram-positive, spor...

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Clostridium difficile Robin B. McFee, DO, MPH, FACPM, and George G. Abdelsayed, MD, FACP, FACG Clostridium difficile (C diff) is a Gram-positive, spore-forming, toxinproducing, anaerobic rod bacteria that results in millions of human infections worldwide annually. The annual incidence of C diff associated diarrhea (CDAD; some refer to it as C diff associated disease) in the USA is more than 250,000 cases, according to the Centers for Disease Control and Prevention (CDC).1 Clearly CDAD is emerging as one of the most significant hospital-acquired infections (HAI) among US and Canadian health care facilities (HCF) with increasing incidence rates.1-14 C diff was first linked to illness in 1978 when it was identified as the pathogen causing pseudomembranous colitis (PMC). C diff toxins are found in ⬃ 95% of patients with PMC. It is the leading cause of antibioticassociated diarrhea (AAD); accounting for approximately 15%-25% of all episodes of AAD. C diff associated illness is often written as CDAD as well as AAD and other applicable terms. Outbreaks of CDAD occur in acute care, long-term care, and community settings, although most commonly, at least for the moment, in hospitals and other HCF.15-20 While it has been a well-recognized cause of health care associated diarrhea for approximately 30 years, the pathogenicity has evolved and it has emerged as a leading pathogen of concern over the last few years, particularly with regard to the newly described virulent antibioticresistant strains.8,10,13,14,21-25 The organism can, like other spore-forming bacteria including Bacillus anthracis, exist in a vegetative form, which is the most common, or in spore form.8,10-12,23 While the vegetative form is highly sensitive to oxygen, the spore form is heat stable and able to survive a variety of harsh conditions, including the acidic environment of the human stomach and on hospital surfaces even after exposure to a variety of commercial disinfectants. There are several strains of C diff; most can cause diarrheal disease. Species with genes encoding for toxins produce 1 of 2 exotoxins— primarily toxin A and toxin B. Most strains producing toxins produce

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both A and B, although rare isolates have demonstrated only 1 of the 2.8,10-12,21-25 Toxin production is associated with diarrheal disease. Severe outbreaks with fatalities have been reported in the USA, Great Britain, and Canada.13,16-19,25-29 In one Canadian outbreak of 177 who were admitted with a diagnosis of C diff, at least 61 died. New virulent strains are emerging and are associated with increased morbidity and mortality.12,14,24,30 This increased virulence may be the result of a new gene sequence in what is referred to as a “hyper virulent” C diff strain NAP 1/027, which appears to change toxin binding. This strain is more resistant to metronidazole (Flagyl), which is considered first-line treatment. Vancomycin remains a viable alternative; however, there are concerns over C diff becoming more resistant to vancomycin. The CDC in 2005 noted that several states have reported increased rates of CDAD, noting more severe illness and an increase in mortality. Whether the increasing severity and incidence of C diff is due to changes in populations at risk, more virulent strains, antimicrobial resistance, or a combination, the answers are yet to be fully characterized. Given the limited number of antimicrobials effective against C diff, and the potential for outbreaks, Joint Commission Accreditation Healthcare Organizations (JCAHO), the Canadian Ministry of Health (CMS), and Medicare are directing significant effort against this pathogen in addition to an overall effort to reduce the incidence of HAI.29-35 JCAHO’s 2009 National Patient Safety Goals requires hospitals to “implement evidencebased practices to prevent health care associated infections due to multiple drug resistant organisms in acute care hospitals.” According to JCAHO/CMS— hospital-acquired C diff infection is 1 of the 9 new proposed “never events” (ie, Medicare will no longer pay a higher rate to HCF if the infection is acquired during a hospital stay).31

Epidemiology The rates of C diff infection have been increasing significantly over the last 15 years in the USA, North America, and internationally.1-14,21-27,30,31,36-39 It is the leading cause of AAD, accounting for approximately 15%-25% of all episodes.2,4,12,21,30,36,37,40 In Quebec, the incidence in CDAD increased from 35.6 cases per 100,000 persons in 1991 to 156.3 per 100,000 in 2003. The severity of infection—those cases classified as “complicated”—increased from 7.1% in 1991-1992 to 18.2% in 2003. In the UK there has been a 72% increase in C diff between 2005 and 2006.27 Looking at it from the perspective of human impact, the number of death certificates listing C diff as a factor in hospital deaths went from 440

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1200 in 2001 to 6840 in 2006 according to the Office for National Statistics. According to the Health Protection Agency, as of November 2007 the number of new cases of C diff was 13,360 for the year. United States data reveal a regional difference in CDAD rates with greater numbers of cases in the Northeastern region compared to midwestern and western regions. Of interest, the frequency of CDAD was greatest in hospitals with ⬎ 500 beds and also increased length of stay.23 Rates were greatest for patients ⬎ 65 years of age. From 1991 to 2003 a 10-fold increase in the incidence of CDAD occurred in this age group.23,41 Data from the CDC reveal that, among hospitalizations with a discharge diagnosis of CDAD, there was a dramatic increase from 31/100,000 persons in 1996 to 61/100,000 in 2003.1 Of patients acquiring CDAD in hospitals or nursing homes, CDAD was considered associated or causative with death in 0.6%-1.5%. Of concern, the attributable 1-year mortality rate from CDAD was approximately 17% based on 1 study. CDAD costs an estimated $3669-$7234 additional per patient hospitalization.4 Colonization with C diff is possible at all ages; it may or may not be associated with clinical disease.8,10,11,21-23,25,30 The organism can be cultured from the stool of 3%-5% of healthy adults, and approximately 10%-30% of hospitalized adult patients are colonized. Estimates suggest even higher rates for children. The rates of stool colonization with toxigenic C diff is highest in neonates, involving approximately 50% or more. Most C diff is acquired in the hospital. Despite high colonization rates with toxin-producing strains, most patients with C diff remain free of diarrhea or CDAD.8,10,23 As a result, the finding of C diff in a stool culture poses a clinical challenge to interpret.8,10,23,42 Moreover, it does not guarantee C diff is the cause of the patients diarrhea. Clinical disease (CDAD) or C diff colitis can be seen in all age groups but mostly in elderly and hospitalized patients.

Risk Factors Research reveals that some of the measures hospitals have implemented to reduce HAI may in fact increase the risk for C diff. In a recent Canadian study, it was discovered that antibiotics used to prevent postoperative infections increased the risk of C diff. According to the study, when a sole antibiotic was given accompanying surgery, a 21-fold increase in the risk of C diff occurred: from 0.07% to 1.5% of patients. While the use of alcohol-based hand sanitizers has been credited with reducing bacterial spread, concerns about their general effectiveness DM, July 2009


against C diff spores persist. Given they may not kill the spores, it is likely C diff can be transferred between patients, even health care workers, and thus contributes to the spread.8,32,43 Although C diff usually occurs during or after the use of antibiotics, other risk factors are emerging. Old age (⬎65 years), as mentioned earlier, and chronic, serious illnesses—which often go hand in hand with advancing age—are risk factors, as well as poor underlying health. Other situations which have the potential to alter bowel flora, such as the postoperative state and infusion of potent chemotherapeutic agents are also recognized risk factors. Other risk factors for colonization with or CDAD include serum albumin concentration ⬍ 3 g/dL, less than 1 year since admission to a long-term care facility, hospital admission within 3 months of diagnosis, use of proton pump inhibitor (PPI) and/or histamine 2 (H2RA) receptor antagonist therapy, having been given 3 or more antibiotics, use of specific antibiotics from the fluoroquinolones or cephalosporin class, female gender, and prior renal failure.2,8,10,15,20,21,23,24,36,38,39,44,45 Flouroquinolones carry an adjusted hazard ratio of 3.4. Of note, the risk for C diff infection doubles after 3 days of antibiotic therapy. Studies revealing an increase in CDAD with patients on PPI or H2RA posit the mechanism for increased C diff infection.8,10,23,38,39 These 2 medication classes are prescribed for patients with gastric reflux and other gastrointestinal (GI) symptoms such as “heartburn” and similar symptoms that are related to gastric acidity.8,10,23,38,39 By reducing the gastric acid, these medications have led to an increase in pH. This alteration in pH may disrupt the normal GI flora and allow pathogen overgrowth or colonization. In an evaluation of CDAD at a Montreal Hospital, of 1187 patients who received antibiotics, 9.3% developed CDAD who were on PPI, compared with 4.4% who did not receive PPI. The effect based on these data of PPI on CDAD was greatest among patients receiving low-risk antibiotics such as cefazolin compared to those taking fluoroquinolones and cephalosporins of the second and third generation. Results of another study showed an elevated risk of developing CDAD in hospitalized patients with acid suppressive therapy, especially when PPIs were used.38 In a study to determine the relationship between CDAD and PPI use in African American and Hispanic patients—a retrospective review of medical records involving 640 cases with CDAD over 9 years— diagnosed by the presence of C diff toxin in the stools was conducted. Six hundred fifty age- and sex-matched patients with diarrhea but absent C diff toxin in stools were used as controls.39 Not surprisingly CDAD was 442

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associated with using antibiotics or chemotherapy. Of the 608 cases receiving antibiotics or chemotherapy, 274 also received PPI within the preceding 3 months. Of the 579 controls who received antibiotics or chemotherapy, 169 (29%) also received PPI within preceding 3 months. CDAD was also associated with using PPI. Their findings indicated that PPI may be an emerging and potentially modifiable risk factor for CDAD. This underscores the importance of vigilance in prescribing PPI, particularly hospitalized patients, those taking multiple antibiotics and/or suffering from multiple comorbidities. Results from a population-based case-control study conducted in the UK, of 1672 cases of community-acquired CDAD analyzed for concurrent PPI and H2RA therapy, showed that patients on PPI were 2.9 times and H2RA users were 2.0 times as likely to become infected as nonusers.46 Another case-control study demonstrated that PPI use within 8 weeks preceding CDAD was also associated with an increased relative risk for C diff infection.47 In some epidemiologic studies, the use of cancer chemotherapy has been associated with C diff diarrhea without exposure to antibiotics, but this remains a relatively rare phenomenon. Opioids and opiate medications may pose a risk for toxic megacolon. Because these drugs have antiperistaltic effects, the exposure time for toxin can be at least theoretically increased. The risk factors for increasingly severe C diff infection include increased heart rate, a decline in respiratory status requiring mechanical ventilation, immunosuppression, prior bowel surgery—not associated with CDAD, hypotension requiring vasopressor support, oliguria, and in the white blood cell (WBC) analysis, the appearance of ⬎ 30% “bands”— immature WBC.23,48 Several factors are considered necessary to be present for the development of diarrhea. The patient needs the following: I. To receive a sufficient overall amount of antibiotic to alter the normal intestinal flora II. To be infected with C diff (while the strain of C diff must be a toxin producer).

Microbiology and Pathogenicity C diff is a Gram-positive, spore-forming, anaerobic rod-shaped bacterium.1,8,10,42 It is difficult to isolate in culture (eg, the name “difficile”), requiring anaerobic conditions and special media to grow in the laboratory.42 The organism can exist in a vegetative or spore form; the former DM, July 2009


is the most common. The vegetative form is highly sensitive to oxygen; it is readily killed by even brief exposure. The spore form is heat stable and able to survive in a wide array of adverse environmental conditions including gastric acidity and may resist some commercial disinfectants, making it difficult to eradicate from the HCF, another factor that 90% of C diff infections occur in hospitals.2,8,10-12,15,21,22,25,26,29,31-34,49 C diff has also been isolated from a variety of sources— hands of health care workers, fomites such as toilet seats and sinks, endoscopy equipment, and other instruments. Asymptomatic infected hospital patients also serve as a reservoir. Transmission occurs by the fecal-oral route, from person to person, and fomite/instrument to patient. The initial infection is felt to parallel other bacterial infections that cause acute enteric disease and the percent of patients who will develop diarrheal disease. However it is the interaction of antibiotics and C diff that may ultimately determine whether the patient becomes colonized after acute infection and whether CDAD or colitis will occur. C diff reproduces in the intestinal crypts and releases toxins A and B.10 These toxins then cause severe inflammation. Toxin A attracts neutrophils and monocytes. Toxin B degrades the colonic epithelial cells. C diff emerges as a colonizer and pathogen, often referred to as part of the phenomenon “bacterial overgrowth” when commensal or beneficial bowel bacteria— our normal flor—are killed off by antibiotics. Because the normal flora often hold C diff growth in check, when they are suppressed, C diff toxins are allowed to be produced, which, at least in part, are responsible for the clinical manifestations of diarrhea, abdominal cramping, leukocytosis, and low-grade fever. Without the selective pressure of the antibiotics, the acute infection should be self-limited. These toxins include Toxin A, Toxin B, and the newly identified cytolethal distending toxin (CDT).8,10,14,23 Toxins A and B are exotoxins that bind to receptors in the intestinal tract. Toxins A and B are responsible for inflammation, fluid, and mucous secretion as well as damage to the intestinal mucosa (Fig 1).10 Toxin A is responsible for the activation and recruitment of inflammatory mediator. Toxin B demonstrates cytotoxic effects. Most strains causing CDAD produce toxin A and B. Some strains of C diff lack the gene for toxins A and B; these nontoxigenic strains do not cause diarrheal disease. There are C diff isolates elaborating only 1 of the 2 toxins. These cause necrosis and inflammation of intestinal cells. Some strains of C diff elaborate other toxins, which also can damage the intestinal mucosa as well as cause increased fluid release into the intestinal lumen. The result of C diff infection and its toxins can be colitis—the most severely affected sections 444

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FIG 1. Photomicrograph of a hematoxylin and eosin stain of the case patient’s colonic mucosa just on the edge of the pseudomembranous lesions. Intact mucosa appears to the left with normal architecture of deep crypts and villi. On the right, destruction of the mucosa with severe inflammatory response extending deep into the lamina propria and expulsion of mucous and cellular debris from the crypts into the lumen of the large intestine, giving the appearance of a volcanic eruption. It is this expulsed material. [Courtesy of Jeannette Guarner, MD, The Centers for Disease Control and Prevention (CDC)].

of the large intestine being the distal colon and rectum.7,8,10,12,22,23 Depending on the severity of the infection and toxin effects, pseudomembranous colitis may result. A newly identified strain of C diff, designated North American pulsed field gel electrophoresis type 1 (NAP 1), produces 16 times more toxin A and 23 times more toxin B than other strains. NAP 1 also produces a third toxin, a binary toxin.10,50,51 Of note, this strain is resistant to the fluoroquinolones gatifloxacin and moxifloxacin.10,50,51 The major genes comprising the pathogenicity locus (PaLoc) include tcdA, tcdB, tcdC, tcdD, and tcdE; tcdA and tcdB encode for the toxins A and B, respectively. TcdC encoded protein negatively regulates production of toxins A and B; tcdD is a polymorphic locus that positively regulates. Some alleles may contribute to more virulent strains of C diff. TcdE encodes a protein that may be involved in toxin release from the cell.23,52-54 Variations in the PaLoc sequence determine which of the 22 toxinotypes by which C diff strains are grouped. Toxinotyope XI does not produce toxin A or B due to truncation of tcdA. Because pathogenesis is credited with toxins, toxinotype XI is considered nonpathogenic. ToxiDM, July 2009


notypes I-VII, IX, XII-XV, and XVIII-XXII all produce toxins A and B. Toxinotypes VIII, X, XVI, and XVII produce only toxin B. Given some diagnostic assays only detect toxin A, strains that only produce toxin B can pose a diagnostic challenge.23,53 A more recently identified binary toxin—CDT— cdtA and cdtB encode proteins that comprise the enzymatic and binding components of this toxin. CDT-producing strains are not relegated to 1 toxinotype.23,51 Recent outbreaks suggest CDT could contribute to the increased pathogenicity of more recently identified C diff strains. In 2001, the CDC studied 187 isolates from a multifacility outbreak. The isolates were genotyped and assigned designations including NAP 1/027 based on the order identified and their genetic factors. Isolates BI/NAP 1 tested positive for binary toxin CDT and possessed tcdC allele. Of note, the median concentrations of toxins A and B were significantly higher in NAP 1/027 strains.23,50,55

Clinical Illness C diff is the most common cause of infectious diarrhea and antibioticassociated diarrhea in HCF.1,2,4,8,10,12,16,22,23 C diff infection can occur as sporadic cases or nosocomial outbreaks. Not surprisingly, the primary symptoms are watery diarrhea, fever, abdominal pain, and/or tenderness.1,2,8,10,22,23 Historically, CDAD has usually been mild but could in rare cases result in emergency bowel surgery or death.1,8,10,22,23,26,27,30 Increasingly C diff is becoming both antimicrobial resistant and more virulent, causing greater morbidity. Symptoms associated with C diff infection usually begin several days after receiving antibiotics but can also occur 2 months after antibiotic exposure. The exact incubation period from ingestion of C diff to manifestation of disease has not been established. Symptoms can appear immediately after antimicrobial therapy is initiated or several weeks after such therapy is completed. In one study of cancer patients who were being treated as outpatients, the median interval from hospital discharge to CDAD was 20.3 days. Historically, the antibiotics most commonly associated with CDAD and C diff infection were broad-spectrum such as clindamycin and broadspectrum penicillins.2,56 However virtually any antibacterial agent including cephalosporins, ampicillin, and fluoroquinolones have been associated with CDAD. Cases have even been reported after just a single dose for surgical prophylaxis.1,2,8,10,23,56 It is important to bear in mind that not all cases of AAC are caused by C diff. Antibiotics can themselves cause diarrhea and abdominal pain or 446

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distention. Nevertheless, the astute clinician should not ignore C diff as a possible diagnosis or the risk factors that can lead to CDAD. There is a broad range of symptoms possible with C diff infection from asymptomatic carriage to fulminant, life-threatening colitis. The following are the most common clinical manifestations1,8,10,22,23: I. Asymptomatic carriage Approximately 3%-5% of adults and 50% of neonates are infected with C diff and most remain without symptoms. About 25%-30% of hospitalized adults are also C diff carriers; most acquired it in the HCF. Factors predisposing to asymptomatic carriage have not been fully determined. II. Mild-to-moderate diarrhea One of the most common presentations of C diff infection is mild to moderate watery diarrhea, which is usually not bloody. Abdominal cramping may occur. Patients do not appear toxic and systemic illness is not present. Intestinal damage is not anticipated; sigmoidoscopy usually does not reveal significant abnormalities. III. C diff colitis without pseudomembranes This is a more severe form of C diff characterized by fever, malaise, high-volume diarrhea where stools may have some trace blood, and moderate-to-severe abdominal pain. Leukocytosis is common and may serve as a diagnostic clue. On sigmoidoscopy colitis is patchy and moderate. No pseudomembranes are present. IV. Pseudomembranous colitis (PMC) PMC is a systemic illness; patients have abdominal pain and tenderness, fever, and severe diarrhea that may be bloody. Marked elevations of the WBC in the range of 30-50 ⫻ 109/L can be observed and may serve as a diagnostic clue. Destruction of the mucosa with severe inflammatory response can extend deep into the lamina propria, causing expulsion of cellular debris and mucous from the crypts into the lumen of the large intestine. This expulsed material forms the pseudomembrane (Fig 1) (CDC/Public Domain). Within the pseudomembrane10 clostridium can be seen (Fig 2) (CDC/Public Domain). A surgical consult as well as consultation with gastroenterology and infectious disease specialists are appropriate and should be initiated. Abdominal imaging such as a kidneys, ureters, bladder (KUB) or computed tomographic scan may demonstrate bowel wall thickening and other abnormalities including pneumatosis or “thumbprinting”— which is a radiographic manifestation of severe colonic edema.8,10,21,22 DM, July 2009


FIG 2. Photomicrograph of immunohistochemical stain of the pseudomembrane. This stain uses genus-specific antibodies and demonstrates numerous Clostridium species within the pseudomembrane. (Courtesy of Jeannette Guarner, MD, CDC). (Color version of figure is available online.)

Lower GI endoscopy shows the presence of pseudomembranes, which represent yellow inflammatory plaques.10,21,22 Most severe cases of PMC become a pancolitis; pseudomembranes can be seen with sigmoidoscopy.21 Only about 10% involve the right side alone, are associated with ileus but not diarrhea, and require colonoscopy as the sigmoidoscopy is not likely to reveal pseudomembranes. V. Acute abdomen with sepsis syndrome Rarely, C diff can present with the picture of “sepsis” syndrome: fever, hypotension, and an acute abdomen; distention and rebound tenderness may be clinical findings. The differential diagnosis includes an abdominal perforation. Patients in this clinical state will have ileus but not likely to have diarrhea. A surgical consult should be obtained immediately. In this setting, peritonitis is possible. A WBC count of 20 ⫻ 109/L and elevated creatinine levels are also indicators of severe infection. Abdominal radiographs will reveal dilated colon. Megacolon is also possible. Laboratory tests may reveal leukocytosis. Serositis with large pleural and peritoneal effusions may be present. Sigmoidoscopy or colonoscopy is relatively contraindicated owing to the risk for perforation. Proctoscopy may be safe with minimal air insufflation and can be useful in providing a more rapid diagnosis. 448

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VI. Recurrent C diff diarrhea1,8,22,23 While most cases of CDAD are successfully treated and resolve without sequelae, 10%-20% relapse. Fortunately most patients with first-time relapse are successfully treated and no further illness ensues. A few cases have repeat relapses, which may be due to metronidazole resistance, reinfection, and/or persistence of spore in the GI tract. When is a second infection a relapse or reinfection? While there are several definitions, none are universally agreed on. Regardless, 12%-24% of patients develop a second episode of CDAD within 2 months of the initial diagnosis. If a patient has 2 or more episodes of CDAD, the risk for recurrences increases to 50%-65%.

Diagnosis and Laboratory Detection1,8,10,21-23,42 Overview CDAD should be considered in the hospitalized patient who develops diarrhea during or soon after receiving antibiotics. Patients who are receiving antibiotics at home or in a long-term facility who develop diarrhea are also at risk for C diff. The diagnosis of C diff (CDAD) is typically based on the appropriate clinical context— history of recent antibiotic use and diarrhea, along with possibly other symptoms—fever, abdominal discomfort, in combination with laboratory testing. Although it is critical to consider C diff early on, especially in highly debilitated patients, laboratory testing will be confirmatory. It is important to recognize the limitations of the tests and the need to follow protocols for proper sample selection and handling. When in doubt, contact the health facility laboratorian for the latest information. The current cornerstone of laboratory diagnosis is the detection of toxin from fecal samples, with fecal toxin assay using cell cytotoxicity neutralization assay (CCNA) considered the gold standard. CCNA is more sensitive than toxin detection by immunoassays but the time required (upwards of 3 days), requirement for special facilities, and labor-intensive are a drawback.42 Toxin enzyme immunoassays are easier to perform and can be rapidly obtained but have lower sensitivity compared to CCNA or toxigenic C diff culture. These immunoassays are less than ideal as sole diagnostic tests. DM, July 2009


The most commonly used laboratory tests among those available include the following1,8,10,22,23,42: I. Stool culture—isolation of C diff Isolation of C diff organism in stool culture requires specialized laboratory techniques. It has high sensitivity and specificity. It is a labor-intensive procedure and requires 72-96 hours to complete. Because C diff is present in a relatively high percentage of patients—asymptomatic or with clinical illness—interpreting a positive culture can be a challenge. Moreover, it is generally accepted that the toxin(s) causes most of the clinical disease and diarrhea; thus, merely identifying the organism may not be the etiology of the illness. Some strains do not produce toxins. Therefore culture should be considered in consultation with infectious disease and/or gastroenterology specialists. The primary advantage of anaerobic culture is the ability to molecularly type strains, which can be helpful in an outbreak. II. Cytotoxin assay The current mainstay of laboratory diagnosis has been detecting toxin from fecal samples. The “gold standard” remains fecal toxin assay by CCNA. This test is based on identifying C diff toxin B in cell culture. It remains the standard, given it has high sensitivity and specificity. However, like other tissue culture tests, it is both expensive and labor intensive. While the majority of CDAD-causing isolates produce both toxins A and B, less commonly isolates elaborate only 1 of the 2 toxins. Because many of the diagnostic laboratory methods to detect C diff detect only toxin B, if the strain only elaborates A, it can influence the test results. This test can take 24-48 hours. III. Enzyme immunoassay for C diff toxin This is becoming a replacement for the cytotoxin essay in some HCF. Enzyme immunoassay has good sensitivity and excellent specificity for detecting toxin A and/or B, are rapid, commercially available, and less expensive compared to cytotoxin assay. Turnaround time is short— often just a few hours. Sensitivity is between 65% and 85%. While the specificity is high— often 95%-100%—to obtain a valid result, 100-1000 pg of toxin A or B must be present. IV. Enzyme-linked immunosorbent assays Differing in their ability to detect toxin subtypes, 2 reagent categories are available— one to detect toxin A and the other for toxin B. Because 1%-2% of C diff strains produce toxin B only, it would not be detected using the toxin A reagent. 450

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V. Latex agglutination assay This test detects glutamate dehydrogenase—a constitutively expressed enzyme in C diff strains. Results can be obtained relatively rapidly. Sensitivity is 58%-68% and specificity is 90%-96%. VI. Real-time polymerase chain reaction (PCR) Laboratories are increasingly developing/using real-time PCR diagnostics for C diff detection that targets tcdB. The caveat is that, given none of these assays is 100% sensitive, it is reasonable to submit a repeat stool specimen if the first one yielded a negative result. In rare cases toxin-negative results may occur even after repeat testing. Diagnosis may thus be established via colonoscopy unless contraindicated clinically. Other tests include fecal leukocyte testing which, although it may be associated with a positive toxin, lacks specificity for C diff. Detection of the C diff specific enzyme glutamate dehydrogenase antigen (GDH) may be an alternative to culture in the future. A recent study evaluated a 2-step algorithm—part 1 involved screening stool specimens using a bioassay for C diff GDH. Screen-positive samples were then tested for toxin by a rapid toxin A/B assay.42 Toxin-negative specimens were subjected to stool cultures. According to the authors, their GDH algorithm allowed exclusion of C diff if the GDH screen was negative. GDH-positive samples should be further evaluated. They asserted their approach was rapid (⬃ 4 hours) and eliminated the need for routine culture in over 90% of stool samples.42

Treatment General Consideration1,8,10,22,23 In most cases of CDAD, the first consideration should be discontinuing the offending/inciting antibiotic(s) unless there is a compelling clinical contraindication. Attention to electrolyte normalization, fluid replacement, and then C diff targeted antibiotic therapy should next be considered. Antimotility agents, too often given to elderly patients who present with diarrhea, especially in long-term care facilities, should be avoided, especially when the etiology of the diarrhea has yet to be established. Antimotility agents have the potential to increase the tissue toxin exposure time and thus risk of toxin-associated damage. Some authorities consider empiric treatment without positive test results to be inappropriate. However, in the setting of recent antibiotic therapy, other risk factors for CDAD, or a severely ill patient for whom delayed treatment may predispose to fulminant disease, it may be appropriate to DM, July 2009


treat while awaiting test results. Also, bear in mind that the initial test may be inconclusive. Again in the setting of “at-risk” for CDAD, a follow-up test should be considered. C diff targeted antimicrobials typically consist of metronidazole (Flagyl) and vancomycin. Metronidazole (Flagyl) is generally considered first-line treatment when intervention is indicated. However metronidazole resistance is being reported. Oral vancomycin is highly effective. Again vancomycin-resistant C diff and enterococci remain a concern. Although intravenous vancomycin is an alternative, some consider oral treatment the preferred route of administration, offering at least a theoretical advantage of placing the medication directly into the gastrointestinal tract. Treatment protocols have also included probiotics, and bile acid sequestrants such as cholestyramine.22 In rare cases intravenous immunoglobulin has been administered. CDAD treatment guidelines are available from a variety of professional organizations including the Society for Healthcare Epidemiology of America, American College of Gastroenterology, and the American Society of Health System Pharmacists to name a few.23,57-59 In treating infectious diarrhea, the Infectious Diseases Society of America has developed guidelines.60 Summing these up, the mainstay for treating CDAD emphasizes supportive care, close monitoring for decompensation, and worsening of clinical status. Rehydration and withdrawal of the suspected causative agent, which is at least the antibiotic, as well as other agents that may be contributing to diarrhea are included in treatment.

Antibiotics in the Treatment of C diff Associated Diarrhea Antibiotics used to treat CDAD can be administered orally, intravenously, or rectally. Some may also be given through nasogastric tubes and through percutaneous endoscopic gastrostomy (PEG) access. Oral metronidazole, which, as mentioned earlier, remains first-line therapy and is eliminated primarily in the urine, although 6%-15% is eliminated in feces.8,10,23,61 Oral vancomycin is not absorbed in the gastrointestinal tract (GIT) and is eliminated unchanged in the feces.62 However when the colon is perforated due to serious CDAD, transfer to the bloodstream can occur. Studies have been conducted to compare the efficacy of oral metronidazole to oral vancomycin. In a prospective, randomized controlled clinical trial comparing metronidazole, 250 mg PO 4 times/d to vancomycin, 500 mg PO 4 times/d with each given over a 10-day course of therapy, there were fewer treatment failures with vancomycin.63 Relapse 452

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rates were similar for both treatment groups. Moreover, when comparing the differences in the duration of symptoms between the 2 treatment options, in a study involving 58 patients randomized to either group, those treated with vancomycin had a shorter duration of symptoms. Vancomycin patients had 3 days of symptoms compared to 4.6 days in the metronidazole group. Another study revealed that CDAD patients initially treated with metronidazole had a 79% higher risk of complications compared to those initially treated with vancomycin.41 It is important and worth repeating that patients must be monitored for treatment failure. Also, the clinicians should be aware of other mechanisms such as underlying illnesses, osmotic imbalance, and, in the community setting, nonadherence, that can cause diarrhea. A variety of oral vancomycin dosing approaches have been compared. A study involving 46 hospitalized patients with underlying complicated health problems and CDAD were randomized to receive either 125 or 500 mg vancomycin 4 times/d over 10 days. The results indicated that treatment response and relapse rates were similar and both regimens appeared to be well tolerated by the patients. Based on this and other studies, depending on the severity of underlying C diff infection, the lower dose would be a reasonable approach; higher dosage would be used for more severe or progressing illness. Although the empiric use of metronidazole has been endorsed by the American College of Gastroenterology in seriously ill patients until C diff can be confirmed, clinical judgment and the patient considerations must be taken into account whether to use metronidazole or vancomycin. CDAD has relapse rates of 10%-25%.64 In one study, if a patient had a recurrence of CDAD, he/she had a 65% likelihood of another.65 Various treatment regimens have been explored in an attempt to reduce recurrences. One study compared a variety of dosing schedules—including varying the dose/intensity—pulse dosing and dose tapering strategies for recurrent CDAD. Tapered or pulse-dosage vancomycin, 125 or 500 mg every 2-3 days for 3 weeks, resulted in fewer recurrences compared with those who received the traditional dosing protocol. In this study, the most effective tapering dose strategy included vancomycin, 500 mg d⫺1 or 1 g/d, with dosage decreases to 125 mg/d over 19-25 days.

Other Antibiotics Fusidic acid is a bacteriostatic antibiotic that inhibits RNA translation.66 In a randomized, controlled, double-blind study in patients with CDAD, treatment with fusidic acid was compared to metronidazole. Cure rates were DM, July 2009


similar as was recurrence of diarrhea.67 Nevertheless, metronidazole remains the drug of choice between the 2 based on available data and research. Teicoplanin, which is a glycopeptides antibiotic similar to vancomycin, interferes with cell wall synthesis by inhibiting peptidoglycan polymerization.68 A randomized, prospective study compared 500 mg oral vancomycin given 4 times/d to 100 mg teicoplanin administered PO twice/d in a 10-day course of treatment. Rates of cure, recurrence, and asymptomatic carriage did not differ significantly between the 2 groups. Given the challenge of treating CDAD, numerous treatment strategies have and continue to be evaluated. A randomized clinical trial compared fusidic acid, teicoplanin, metronidazole, and vancomycin in patients with CDAD. Metronidazole and vancomycin were administered at 500 mg PO 3 times/d over 10 days; teicoplanin was dosed at 400 mg PO twice/d over 10 days after being solubilized in tea.69 The fusidic acid schedule was not well described. Nevertheless, tecioplanin was clinically superior to fusidic acid in initial cure rates, persistence of cytotoxin, and reappearance rates. Teicoplanin was superior to metronidazole in cytotoxin persistence rates. Clinical cure rates did not differ markedly between the metronidazole, teicoplanin, or vancomycin patient groups. Of note, increased teicoplanin resistance has been observed. Rifaximin, indicated for Escherichia coli traveler’s diarrhea, is a poorly absorbed derivative of Rifamycin. It was administered in a small series of 8 women who had experienced at least 4 recurrences of CDAD after their last vancomycin treatment but before their symptoms recurred. Dosing regimen of rifaximin ranged from 400 to 800 mg daily in 2 or 3 divided doses over 14 days.70 Seven of the 8 women did not have a recurrence in follow-up periods that ranged from 51 to 431 days. Rimoplanin is a macrocyclic depsipeptide under development. It is active in vitro against strains of C diff that exhibited reduced vancomycin sensitivity and resistance to metronidazole.

Adjunctive Therapies Exchange Resins. Cholestyramine and colestipol are anion exchange resins that are used in the treatment of hypercholesterolemia.23,71,72 It is thought these resins are able to bind C diff toxin B. As such, they have been considered as an adjunctive treatment for CDAD. In a small study involving 12 patients with antibiotic-associated pseudomembranous colitis who were given cholestyramine, the diarrhea resolved after a mean duration of 2.1 days. The authors in that study recommend continuing the cholestyramine for 5 days after the diarrhea resolved to prevent the recurrence of diarrhea. Further study is warranted. It is worth noting that these resins pose a challenge in drug 454

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interactions, including the ability to bind and thus potentially interfere with the action of vancomycin. However, in a study involving 11 patients experiencing recurrent CDAD who received vancomycin and cholestyramine, all responded to treatment and were asymptomatic at their 6-week follow-up. Unanswered was— did the patients improve because of both agents or because the strain of C diff was vancomycin sensitive? An old adage in toxicology—separate the patient from the poison and the poison from the patient— often still holds true as a valid approach. Because the toxins are the primary cause of clinical illness, methods to separate the toxin from the patient continue to be sought. Tolevamer, which is a high molecular weight soluble anionic polymer, with a mechanism of action similar to the anion exchange resin cholestyramine, has been shown to bind C diff toxins A and B. A randomized controlled clinical trial was undertaken to evaluate the effectiveness of tolevamer. In the study tolevamer at 1 g 3 times/d or 2 g 3 times/d for 14 days was compared to vancomycin, 125 mg PO 4 times/d over 10 days for CDAD. Tolevamer given at 6 g/d demonstrated shorter time to diarrhea resolution (2.5 days) compared with 3 g/d (4.0 days). However, vancomycin demonstrated the shortest time to diarrhea resolution at 2.0 days. Cure rates were also highest with vancomycin. Whether combination therapy with resin being administered in a time-separated regimen from the vancomycin would have a synergistic or additive effect remains to be further evaluated. Nevertheless, it may still confer some clinical benefit and is worth considering.23 Nisin—a food preservative that is an inhibitory polycyclic peptide with comparable bacteriocidal kinetics as vancomycin—is being studied as a potential therapy in the treatment of CDAD.23 Interestingly Nisin has been shown to prevent Clostridium botulinum spore germination.73 If such capability were also against C diff spore germination, that would offer a significant advance in preventing clinical relapse. More research is necessary. Intravenous immune globulin (IVIG) has been used with some success. The rationale that requires additional investigation—immunity against C diff infection can occur.23,74 In a study of patients colonized with C diff, those who remained asymptomatic had significantly larger increase in serum antitoxin A immunoglobulin G compared to those who developed CDAD. Increasing antitoxin A immune globulin G (IgG) levels may result in asymptomatic C diff carriage. The mechanism still needs further study. The use of IVIG in the treatment of CDAD is not approved by the Food and Drug Administration, presumably because the research supporting this practice involves case reports and uncontrolled trials. One such retrospective study analyzed 18 patients with severe CDAD eligible to receive IVIG. The 18 patients received 1 dose of 200-300 mg kg⫺1 IVIG DM, July 2009


along with IV metronidazole with or without oral or rectal vancomycin. Cases were matched to patients receiving standard therapy—IV metronidazole or PO vancomycin or both drugs. The results showed no significant difference between those who received IVIG with standard therapy compared to those who received standard therapy alone. Whether small sample size or inadequate dose of IVIG accounted for these results is unknown. Other studies have been conducted involving IVIG and have shown varied results. Of patients who experienced improvement, IVIG response took 7-13 days. However, there were methodological challenges, including small sample sizes and varied treatment protocols introduced. While there is at least a theoretical benefit to selected patients with IVIG, larger studies are necessary with comparison groups following more standardized protocols. Probiotics. Probiotics are live microorganisms that are considered to affect host flora composition by their putative ability to colonize the colon in the hope these benign microbes can outcompete pathogens and prevent CDAD. They have also been used as a preventive measure to reduce antibiotic-associated diarrhea. Various probiotics have been proposed. These include Lactobacillus species and Saccharomyces.23,75 Lactobacillus. Some lactobacillus species—Lactobacillus paracasei and Lactobacillus plantarum—have shown in vitro activity against C diff strains and partially comprise the normal intestinal flora. In clinical studies, some double-blind placebo-controlled and others case reports, there are conflicting results in benefit derived from lactobacillus in conjunction with metronidazole.75 Saccharomyces. Saccharomyces boulardii probiotic cultures have also been studied in CDAD for both initial and recurrent infection. The mechanism of action remains to be fully elucidated. However the proposed mechanism suggests the production of a protease by S boulardii that catalyzes the inactivation of C diff toxin A receptor. A randomized study was conducted involving 151 patients whereby 73 received S boulardii twice daily and 78 received a placebo.76 The rate of diarrhea development was lower in the S boulardii group 1.4% compared to 9% for the placebo group. Of the patients who developed diarrhea, 2 tested positive for C diff and these were from the placebo group. Other studies have failed to demonstrate a clinical benefit from S boulardii. The risk of fungemia has been reported associated with Saccharomyces. Further study is needed to identify the overall clinical benefit of probiotics, under what circumstance or subpopulation of patient, which species should be used and at what dosing regimen, including which antibiotic is best suited to be given concomitantly. 456

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Oligofructose. Oligofructose is metabolized by fecal bifidobacteria. These bacteria colonize the colon, competing with pathogen bacteria. As a preventive measure, mixed results have been reported. In a study involving 435 patients ⬎ 65 years old being treated with broad-spectrum antibiotics, they were randomized to receive either placebo or oligofructose.77 While higher levels of fecal bifidobacteria were observed, there was no significant difference between the groups in CDAD. Another study demonstrated benefit in relapse rate reduction among C diff patients given oligofructose and standard medical therapy compared with standard therapy alone. While the clinical value of oligofructose remains in question, it is a low-risk intervention and may confer a benefit. Fecal Bacteriotherapy. Replenishing the normal flora in patients with recurrent CDAD via enema has been rarely used. Some patients have responded but the potential to introduce fecal bacteria that may include pathogens is potentially problematic. While unpleasant in thought, the technique of stool transplantation, whereby stool from healthy donors is infused into the patient, usually via a nasogastric tube, has been shown to be effective in eradication of the infection, particularly in the subset of the patients with multiply recurrent and resistant C diff.78

Management for Specific Clinical Scenarios1,8,10,22,23 Asymptomatic. Generally, treatment of asymptomatic persons is not indicated; neither vancomycin or metronidazole have been proven of benefit for this population. Of note, high intraluminal metronidazole levels are obtained in the presence of diarrhea; in asymptomatic patients, such levels, (eg, therapeutic benefit) is unlikely.

Mild-to-Moderate C diff Associated Diarrhea Metronidazole (Flagyl) therapy should be initiated: 500 mg orally 3 times a day or 250 mg orally, given 4 times a day for 10 days. Re-evaluate the patient to ensure clinical improvement. When metronidazole cannot be used or is contraindicated, when metronidazole associated with treatment failure, or in patients with progressing illness, vancomycin at 125 mg orally given 4 times a day is a suitable alternative.

C diff Colitis With or Without Pseudomembrane Oral metronidazole or vancomycin remains first-line therapy. Ileus can complicate these cases, compromising delivery of adequate doses to the colon. Intravenous metronidazole may be given concomitantly with oral antibiotics; hepatobiliary secretion leads to high levels of drug in the stool. Use of a nasogastric tube may enhance antibiotic delivery. Other DM, July 2009


methods include retention enemas of vancomycin and surgical creation of an access point through the transverse colon, sometimes referred to as a “blow hole” through which vancomycin solution can be administered.

C diff Toxic Megacolon This form of CDAD generally does not respond to antibiotic management alone and may require surgical intervention. In some cases total colectomy may be lifesaving. It is important to bring in gastroenterology, GI surgical, and infectious disease specialists early in the management of these complex patients.

Recurrent C diff Mild relapses often resolve without the use of antibiotics, which may still be used depending on the clinical situation. Moderate-to-severe cases should be treated with a second course of metronidazole. For patients with multiple relapses, several treatment strategies have been proposed but data are lacking to recommend one regimen as significantly superior over another cocktail. Reported regimens include vancomycin in combination with any of the following: rifampin, bacitracin, cholestyramine (a binding resin), fecal enemas, ingestion of nontoxigenic C diff strains, and Lactobacillus GG or S boulardii (probiotic agent). Engaging infectious disease and gastroenterology specialists early in the management of these patients is warranted. In patients with severe CDAD, intracolonic vancomycin preparations have successfully been used. (An important caveat is that intracolonic drug administration can pose the risk of perforation of the inflamed sites from the catheters.) Intracolonic vancomycin is often combined with oral or intravenous metronidazole or oral vancomycin. Various treatment regimens have been proposed and used. These include the following: I. An intracolonic bolus dose of 2 g vancomycin followed by 100 mg intracolonic doses every 6 hours plus an additional 100 mg intracolonic dose give after each watery stool combined with 125 mg oral vancomycin 4 times/d for 14 days. II. An intracolonic dose of vancomycin 2 g every 24 hours after adjusting for renal function. Mixing 500 mg in 1 L 0.9% NaCl injection has been used as a retention enema using a balloon catheter. III. Patients can also receive colonic infusions after colostomy. IV. Transabdominal vancomycin injections have been successfully used to treat CDAD pseudomembranous colitis. 458

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V. Combination intravenous and intracolonic vancomycin. a. Vancomycin 1 g IV followed by 1 g/L enemas every 6 hours. Bear in mind IV vancomycin is mostly cleared by the kidneys. That it is present in the bowel in a sufficient amount to effectively treat CDAD requires additional research even though this regimen has been successfully used. It is important to recognize the risk reward of administering antibiotics in the health care and community setting. As such, if possible, once the patient has been successfully treated for CDAD, antibiotics should be avoided ideally for 2 months. If a relapse in CDAD occurs, the same regimen used to initially treat the first course should be used. Clearly CDAD and C diff infection pose a complex clinical challenge to the physician given the endemic nature of this bacteria in the health care setting, host considerations, antimicrobial resistance, toxin production, and alertness of the provider to treat this illness early. While much research is underway and the above guidelines have been used successfully, the optimal therapeutic cocktail and dose regimen remain at this point based on a variety of clinical considerations. It is vital to use an expert team approach involving infectious disease and gastroenterology specialists early in the management of CDAD patients.

Special Populations The Food and Drug Administration has assigned nitazoxanide “investigational status” for the treatment of diarrheal disease in patients with acquired immune deficiency syndrome. Nitazoxanide has demonstrated in vitro and in vivo activity against C diff. In an open-label study involving 35 CDAD patients who did not respond to metronidazole who were subsequently administered nitazoxanide, 500 mg given twice/d, 26 initially responded, of which 7 had a recurrence.23

Antibiotic Resistance With the increased incidence and severity in CDAD, some have been associated with metronidazole treatment failure. While the number of patients being treated with metronidazole requiring the addition or substitution of vancomycin remained constant between 1991 and 2002, the number of patients with inadequate response to metronidazole between 2003 and 2004 increased by 2½ times. The probability of recurrent CDAD was higher in patients treated solely with metronidazole across age groups. DM, July 2009


While C diff remains sensitive to metronidazole and vancomycin, antibiotic resistant CDAD is worrisome. In 2002, the resistance rate to metronidazole was 6.3%, while that rate was 3.1% for reduced vancomycin sensitivity. Given the increase in vancomycin-resistant enterococci infections, will the widespread use in CDAD promote greater resistance?

Prevention1,2,8,10,22,23,29,31-33,79,80 Preventing CDAD as well as HAI requires 2 separate yet critically important approaches—preventing the spread of C diff through strict infection control and reducing the patient’s risk of illness once exposed. Host factors, prescribing patterns, and infection control are critical components to protecting patients from C diff.

Antibiotic Use As mentioned earlier, the judicious and appropriate use of antibiotics can be beneficial. The use of antibiotics to suppress C diff in an asymptomatic patient has not demonstrated clinical value and may in fact contribute to pathogen overgrowth of normal flora and/or promote antimicrobial resistance.

Probiotics As described earlier, some studies suggest a benefit with probiotics, while others have failed to observe clinical value. There are numerous microbes that can be used, and perhaps the optimal strain or combination of probiotics has yet to be identified.

Hygiene The most effective approach to decrease the spread of C diff is the combination of vigilant hand hygiene and the use of isolation/infectioncontrol practices. Contaminated health care workers’ hands in outbreak settings are well documented. Alcohol-based products are not generally considered effective in killing C diff spores; washing hands with soap and water, especially when caring for CDAD patients, should be emphasized and enforced. Back in 1994 the Hospital Infection Control Practices Advisory Committee Guideline for Isolation Precautions in Hospitals recommended contact precautions for symptomatic patients, including the use of private rooms, or cohorting similarly ill groups. Mandating the use of gloves and gowns when entering a patient’s room and having ready access to receptacles for removing these barriers on 460

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exiting have demonstrated benefit and can reduce the spread of C diff. Enforcement of contact precautions among staff, visitors, and health care personnel is essential. These practices must be integrated as part of routine practice activities in the appropriate clinical setting.

Infection Control Practices Strict attention to well-accepted infection-control practices is a critically important component to a broad strategy of reducing what is quickly becoming epidemic if not endemic as a HAI. Environmental contamination occurs in 34%-58% of sites in hospitals, including carpets, clothing, blood pressure cuffs, telephones, commodes, tube feeding equipment, thermometers, scales, and call buttons, especially in the bathrooms. This contamination occurred even after conventional disinfectants were used. Environmental contamination with C diff is largely due to the persistence of the spores, which are highly resistant to routine disinfectants. C diff spores can last on dry surfaces for weeks or longer! Not surprisingly, the rate of surface contamination increases in proportion to the severity of diarrheal illness and the patient’s continence. High touch areas— control switches, bed rails, commodes, faucets, door handles, for example—should be cleaned frequently. Unfortunately, and well recognized, compliance with infection-control measures is inconsistent—and generally suboptimal at best. Financial constraints have limited infection-control measures, surveillance systems, and cleaning and pressure to turn over rooms rapidly has had a negative effect on reducing the spread of CDAD. Fortunately the use of either unbuffered or phosphate-buffered hypochlorite (bleach) solutions is relatively inexpensive and has been shown to decrease the rates of contamination; studies suggest cleaning with bleach may reduce CDAD rates. Given patient care items have been implicated in outbreaks, dedicated personal use items—rectal thermometers, reusable electric razors, and other items—solely for individual CDAD patients are strongly suggested. Medical supply companies are beginning to market disposable barriers for stethoscope and blood pressure cuffs. Hospital Infection Control Practices Advisory Committee Guidelines recommend meticulous cleaning of CDAD patient items, especially commodes.

Education Continuous education and updates for health care workers including nonclinical staff on CDAD, HAI, and emerging pathogens are important DM, July 2009


and should be part of the infection-control measures. Included in these programs should be regularly reviewed protocols and practices in antibiotic, PPI, and other medication uses. A multidisciplinary approach with regular communication throughout the facility is suggested.

Vaccine Development23,81,82 One of the approaches to reduce the incidence of C diff infection is the development of an effective vaccine. Antibody-mediated antitoxic immunity is an area researchers are exploring in the hope it holds promise against CDAD. The basis of vaccine development is to identify proteins on the pathogen that are immunogenic, that is, able to promote an appropriate, effective immune response in the host such that when challenged by the bacteria or virus, clinical disease is prevented. Many proteins have been identified that hold promise for C diff vaccine. These include the flagellar cap protein FLiD, flagellin protein FLiC, a carboxyl-terminated domain of a cell wall protein, a protease cell wall protein 84, as well as toxins A and B. A study evaluating the immunogenicity of the various targets mentioned above was conducted involving 17 patients with CDAD. Antibodies to FliC and FliD were developed in 15 patients. Only 2 patients developed antibodies to the cell wall protein 84, and 14 to the carboxyl-terminated domain of the cell wall protein. Of note, when high levels of antitoxin A IgG are present, it may be associated with resistance to CDAD development. The clinical value of antitoxin B IgG is unclear. Because there are strains that produce only toxin B, there remains the potential for clinical benefit from antibodies to toxin B. In a study healthy adults were randomized to receive a vaccine containing purified C diff toxins A and B, with or without an adjuvant. All recipients experienced a significant rise in antitoxin A and B IgG. The use of adjuvant resulted in higher concentrations of antitoxin. No significant adverse effects were reported. When the same type of vaccine was administered to patients with recurrent CDAD, 2 experienced increases in antitoxin A and B. Both were able to have their oral vancomycin discontinued without recurrence of C diff. While these limited results are encouraging, more research is needed and a variety of approaches are being explored to develop the ideal vaccine. Clearly an effective vaccine to prevent CDAD would be a public health achievement of enormous proportion and confer significant clinical benefit, reducing widespread morbidity and mortality. 462

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Discussion Rates of bacterial infection in HCF—whether acute care hospitals or long-term care sites—are on the rise. Many of the pathogens involved are increasingly resistant to antibiotics. Given the number of deaths associated with HAI exceeds that associated with many of the top 10 causes of death in the USA, the need to address this problem is reinforced. The incidence of C diff disease is increasing and so is the mortality rate. In 2000, it was 12%; by 2003, it had reached 18%. This death rate is approaching the levels of the 1970s before clinicians knew what they were up against. To underscore the severity of this disease and the risk it poses to our patients, a study from the Davis Jewish Hospital in Montreal demonstrates what we are up against. Among 94 consecutive patients with CDAD, 18 had to be admitted to the ICU in fulminant disease, 12 developed acute renal failure that required dialysis, 8 required colectomy, 21 had relapses, and 21 died. One death is too many from an illness, if that outcome could have or should have been prevented. While we devote our efforts to treating disease, health care workers are woefully inadequate in our prevention activities. The abysmal rate of hand washing among physicians and nurses has been well described throughout the medical literature. One need not read the latest journals to recognize this; merely watch colleagues in the rest room to see the hand washers from the quick-exit folks. It makes you question the sanity of shaking hands in the twenty-first century! Although a profound grasp of the obvious, the practice of not washing hands “religiously” is inexcusable behavior. As a profession dedicated to the sanctity of life, promoting health, and treating the sick, would it not be nice if we did not contribute to disease? Clostridium species remain a significant cause of morbidity and mortality—whether Clostridium perfringens, C botulinum, or C difficile. However C diff is an endemic and emerging pathogen capable of causing large-scale outbreaks. C diff associated disease is increasing in both incidence and severity. A recently identified strain has caused several outbreaks of clinically very severe illness in North American and abroad. Analysis of this strain indicates it produces 16 times the amount of C diff toxin A and 23 times as much C diff toxin B compared with other circulating strains. With the potential for rapidly progressive illness and death, the clinician must remain vigilant for CDAD, diagnose it early, and treat it rapidly. DM, July 2009


Beyond better attention to infection control, including hand hygiene, we need to more frequently evaluate the risks as well as benefits of the interventions we apply to our patients, especially elderly people, whether outpatient, hospitalized, or in long-term facilities. The use of PPI and H2RA has dramatically increased; this may set the stage in the right clinical setting for C diff overgrowth. How often do we re-evaluate our patients and take them off medications no longer necessary? Chronic disease management may be the medicine of the twenty-first century, but not all patients need to be “lifers” on all the medications. While many patients will come to the hospital already taking PPI and H2RA, some will be started on these medications, especially in the intensive care unit (ICU). Is the widespread prescribing of PPI and H2RA for “stress ulcer” prophylaxis really appropriate or effective given the relatively low incidence of life-threatening stress ulcer bleeding compared to the incidence of CDAD? Although used largely in the ICU setting to reduce the risk for gastroduodenal ulceration and bleeding, one questions whether this practice has reduced mortality. In a meta-analysis of stress ulcer prophylaxis with 2 drugs that reduce gastric acidity (H2RA, antacids), higher mortality rates were observed. Sucralfate appears effective at reducing stress ulceration with little reduction of gastric acidity. Often the sickest patients unfortunately are going to be likely at greater risk for adverse outcomes; their underlying debilitation and/or acute illness— especially in a HCF—will make them a setup for an HAI, including C diff. As clinicians we walk the tightrope of lions on one side and tigers on the other—if we treat the infection and/or try to prevent one type, will we set the stage for C diff or HAI? If we do not prevent or aggressively treat, will the primary infection of concern win out? the selection of antibiotics, carefully reevaluating and monitoring the patient, including after antimicrobial therapy, may reduce the risk or severity of C diff and HAI. Although newer antibiotics are being developed, microbes have demonstrated an uncanny ability to adapt and develop resistance. While antibiotic restriction has been recommended, and clearly restricting clindamycin use has demonstrated some benefit in CDAD, this is but one issue warranting further research. Reaching out to infectious disease specialists for guidance, especially when treating patients in a HCF, may assist us in more appropriate antibiotic selection. Moreover, while research is identifying novel ways to treat HAI, including vaccines, many of these interventions are yet years away. The best strategy for illness remains prevention. 464

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Conclusions HAI and C diff have emerged as critical challenges for health care. Over the last few years, dramatic increases in the number of C diff outbreaks as well as deaths have occurred. The emergence of a highly virulent C diff strain underscores the danger of CDAD and HAI. There is a dramatic loss of surge capacity in HCF and as the care paradigm continues to change, in the coming years increasingly sicker and older patients will be admitted to HCF. They will then be sent into the community under the care of lesser trained “caregivers”—and with it an expansion of infections out of the health care environment. The resulting likelihood of acquiring an HAI will increase. Preventing HAI and CDAD is a complex challenge. The causes often involve widespread antibiotic use, other medications that are commonly prescribed, as well as the breakdown of hygiene and environmental control measures. Environmental infection control often lags behind as hospital overcrowding and time constraints place enormous pressures on housekeeping to turn over rooms. Resources, especially at many inner city public hospitals, are limited, which may prevent replacing soiled cleaning products as frequently as recommended or necessary. Infection control must be considered an ongoing process not a discrete action. Anyone working in HCFs must realize and accept the responsibility to protect our patients beyond merely fulfilling our job description—physician, nurse, dietician, or therapist. We are all linked— clinician, patient, visitor, staff. We must work together as our foes— microbes—are dangerous and persistent and have the ability to evolve and adapt. Infection control must be a priority daily—the administration must provide continuous leadership and resources. However, without such support, HAI will continue to be problematic. With or without willing leadership from administrators and medical and nursing leaders, cost remains a powerful driver in HCF policies and infection-control measures. JCAHO and other nations’ health care oversight organizations have made this issue a top priority. The United States government likely will start penalizing HCFs by restricting reimbursement when HAI occur. Regardless of the investment and attention— reimbursement, avoidance of penalties, or failed certification visits— balanced against human suffering, preventable death, and the billions of dollars in added health care costs associated with HAI, clearly greater investment in infection control must be expended. DM, July 2009


We have a responsibility as health care professionals to address the underlying and preventable causes of HAI, including, perhaps especially, C diff by greater attention to our own personal infection-control practices, including hand hygiene, and selection of therapeutic interventions as well as that of our colleagues. Without our collective commitment to reducing HAI and C diff infections, increasing numbers of our patients will acquire these, and many will face an untimely death unless dramatic change occurs in health care.



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