REDEFINING THE CLOSTRIDIUM DIFFICILE PROBLEM
Incidence of Clostridium difficile (CDI) increased dramatically in the first decade of this century and it is now the most common health care–associated infection in US hospitals.1–5 Much of the increase in CDI incidence, whether in hospitals or the community, is due to emergence of a toxin gene-variant strain, pulse field gel type NAP1, or polymerase chain reaction (PCR) ribotype 027.5–8 This strain is more virulent, producing more toxins A and B and in addition a third toxin, binary toxin, and it has been highly endemic in the United States since approximately 2000. The increasing incidence and burden of CDI in the United States and other countries (Table 1) have been well described in earlier publications,1,2,9 including a recent publication by 2 authors of this study.10
Previous antibiotic treatment is the single most important risk factor for CDI.3 Antibiotic treatment disrupts the normal colonic microbiota, leaving individuals susceptible to CDI when they come in contact with C. difficile spores, which can persist on any surface or device that becomes contaminated. Strategies to minimize inappropriate antibiotic exposure and decrease spore acquisition, essential components to reducing the burden of CDI, are also discussed in detail in an earlier companion CME article.10
Clostridium difficile is not a normal part of the human lower intestinal microbiota, except during early life, but neonates and infants seem to have a natural defense against CDI toxins. They often become colonized with C. difficile bacteria but do not develop infection; animal data suggest that a relative lack of toxin receptors during microbiota establishment in the first year of life may be protective.11 However, although colonization and asymptomatic carriage is not uncommon in these early years, it is rare from approximately the age of 4 years until much later in life, when it increases because of health care and antibiotic exposures.12
Clostridium difficile Transmission and the Role of Asymptomatic Carriers
Transmission of C difficile occurs often in inpatient health care settings.13 Every day spent on a ward with patients with CDI places unaffected patients at a cumulative risk of becoming infected or colonized. In fact, the rate of colonization outpaces the rate of infection. However, patients also come to the hospital colonized; point prevalence estimates for colonization on admission range from 5% to 15%.14–16
There is increasing recognition of the role of asymptomatic carriers as a source for CDI. In a study of more than 1200 CDI cases in hospitalized patients for a 3-year period, only 38% of new cases were linked to a symptomatic CDI infection source.13 Another study using molecular subtyping linked 29% of new CDI cases in hospitalized patients directly to asymptomatic persons.17 One reason for the increased recognition of the role of asymptomatic carriers in disease transmission may be that improved infection control measures in symptomatic patients have decreased their role in C. difficle transmission.12
Signs, Symptoms, and Diagnosis of CDI
There are 2 critical questions in CDI diagnosis. First, what are the clinical characteristics that best identify a patient to test for CDI? And second, which test or combination of tests best identifies patients who are symptomatically infected with toxigenic C. difficile? That is to say, differentiating patients with actual CDI versus those who are colonized with the bacteria but whose diarrhea is not C. difficile associated.
Diarrhea, the most common symptom of CDI, is usually watery, not bloody, and is accompanied by abdominal pain. The minimum symptom duration for suspected CDI should be at least 3 unformed or watery stools per day for 1 to 2 days.18 More severe symptoms may include fever, shock or hypotension, and severe ileus in which diarrhea shuts down. Signs of severe CDI include leukocytosis (white blood cell [WBC] count may be elevated to 15,000/μL or more) and elevated serum creatinine level.
It is important to assess antibiotic exposure because most patients with CDI have had antibiotic exposure in the previous 3 months and to discontinue any current antibiotics.19 The decision to treat empirically or to wait for diagnostic test results is dependent on the severity of patient symptoms.
Changing Diagnostic Criteria and Need for Rapid Diagnosis
There has been a progressive lowering in the number of unformed stools per day that defines potential C. difficile–associated diarrhea or that indicates whom to test.18,20–23 In 1974, diarrhea was defined as a change in bowel habits leading to more than 5 loose movements per day.20 Criteria in 1983 called for at least 6 unformed stools for a period of 36 hours.21 More recently, the definition of diarrhea has been changed to 3 or more bowel movements with a loose or watery consistency in a 24-hour period.18
The revised threshold for C. difficile testing, mirroring these lower numbers of unformed stools per day, is due at least in part to the emergence of epidemic outbreaks caused by the NAP1/027 strain. Outbreaks have increased the urgent need to isolate and test patients with diarrhea early as an infection control measure. The more rapidly fatal CDI associated with this strain has also motivated clinicians to provide earlier and more empiric treatment.
ISSUES IN DIAGNOSTIC TESTING
The decision about which test to use for C. difficile diagnosis is not inconsequential, but there is considerable debate about which test is best. Using more sensitive diagnostic tests may reduce transmission but lead to unnecessary treatment. Data are accumulating that detection of toxin is necessary to diagnose clinically important CDI, whereas more sensitive tests that detect the toxin genes, such as the Nucleic Acid Amplification Test (NAAT), may lead to overdiagnosis by detecting colonized patients with diarrhea from another cause.24–26
To be useful in ruling out CDI and determining with certainty who does not require either treatment or isolation precautions to prevent onward transmission, a diagnostic test must have a high negative predictive value, which is a function of the test's inherent characteristics (ie, sensitivity and specificity) and the prevalence of CDI in the population in which it is being used. In contrast, if what is valued most is to avoid treating and isolating patients who do not have CDI as if they do, a high positive predictive value is needed, which again is a function of the test's inherent characteristics and the prevalence of CDI. If the incorrect population is tested (ie, a low prevalence group), then obtaining a high positive predictive test value will be restricted. Positive predictive test value can change dramatically on the basis of disease prevalence. Planche et al27 described the positive and negative predictive values of a theoretical C. difficile toxin assay in populations with true disease rates ranging from 3% to 25% (Fig. 1).
Testing has advanced considerably since the first 2 criterion standard tests, cell cytotoxicity and culture, were defined for diagnosis of C. difficile in 1979.28,29 Just 4 years later, these tests were replaced by enzyme immunoassay (EIA) for toxin A, which provided a relatively quick, simple, and inexpensive means for CDI diagnosis.30
In the next decade, the latex agglutination test, which was designed to detect toxin A, was found to detect another key enzyme in CDI diagnosis, glutamate dehydrogenase (GDH).31 This test was resurrected as an EIA and continues to be used today as a screening test for C. difficile. However, because GDH occurs in both toxigenic and nontoxigenic C. difficile, this test lacks adequate specificity and must be accompanied by another test to confirm presence of a toxigenic strain.31
In 2000, a toxin A−/B+ strain was identified and associated with outbreaks worldwide. These strains were missed by the EIA for toxin A, which greatly limited the usefulness of the test. An EIA for both toxins A and B replaced it, but there was no monoclonal antibody for toxin B. A polyclonal antibody serum was used, but it was less sensitive than monoclonal antibody for toxin A.32
A 2006 survey found that the most common laboratory test for CDI diagnosis was EIA for toxins A and B (201 [57%] of 350 responses).33 Today, PCR is by far the most common test. Kato et al34 first described PCR in 1993, but it did not become clinically available for laboratory diagnosis of C. difficile–associated diarrhea and colitis until 2010.
Table 2 lists C. difficile tests in order from most to least sensitive. The most sensitive test in use today is culture plus toxin confirmation, but it is too slow to be of practical use. Nucleic Acid Amplification Test (real-time PCR, LAMP [Loop Mediated Isothermal Amplification]) is nearly as sensitive and much faster. Glutamate dehydrogenase EIA is very sensitive but not specific, and cell cytotoxin is also too slow for practical use today. At the lower end of sensitivity are toxins A and B EIA, toxin A EIA, GDH latex test, and endoscopy, which is approximately 50% sensitive.35
Studies continue to spur debate and discussion about CDI testing and diagnosis and the connection between testing method and clinical outcome. In a prospective cohort study that tested 1321 stool samples during a test period of 95,750 patient days, Longtin et al26 found that cases detected by PCR alone were less likely to have a complication of CDI compared with cases detected by EIA/cell cytotoxicity assay (CCA) (3% vs. 39%, P < 0.001). Polymerase chain reaction compared with EIA/CCA detection was also associated with a lower chance of CDI readmission (0% vs. 20%, P = 0.01) and a lower 30-day mortality rate versus EIA/CCA (3% vs. 18%, P = 0.09).26 A later and larger study by this same group confirmed that there are far fewer complications of CDI for patients diagnosed by PCR only (19% vs. 44%, P = 0.02).36 Still, it is not clear how or if differences in diagnostic methods should drive different clinical approaches to patient care.
Planche et al25 provided similar findings using different diagnostic tests. In their study, group 1 patients had positive cell cytotoxin tests (ie, toxin in the stool), group 2 had culture-positive and cell cytotoxin-negative tests (ie, C. difficile in stool but no toxin detected in the stool), and group 3 had both cell- and culture-negative tests (ie, no CDI). Mortality was significantly higher in group 1 (72/435 [16.6%]) compared with group 2 (20/207 [9.7%], P = 0.044) and group 3 (503/5880 [8.6%], P < 0.001). However, when a multivariate analysis accounted for confounding, only the difference between group 1 (positive cell cytotoxin test) and group 3 (no CDI) remained statistically significant for 30-day mortality (odds ratio [OR], 1.61; 95% confidence interval [CI], 1.12–2.31; P = 0.01).25 The multivariate analysis also showed that many of the confounding risk factors were more strongly associated with increased odds of mortality than the test type. Confounders included age older than 65 years (OR, 2.52; 95% CI, 1.98–3.21; P < 0.0001), WBC count greater than 15 × 109/L (OR, 1.94; 95% CI, 1.52–2.47; P < 0.0001), greater than 50% rise in serum creatinine level (OR, 2.25; 95% CI, 1.69–2.99; P < 0.0001), and serum albumin level less than 20 g/L (OR, 2.72; 95% CI, 1.90–3.91; P < 0.0001).25 Similar findings of Longtin and Planche were confirmed in a subsequent study by Polage et al.24
In summary, if laboratories have no clinical input and accept any unformed stool for testing, it may be most appropriate to use a test that better identifies likely CDI, such as a relatively sensitive test for toxin in the stool (eg, cell cytotoxin or GDH coupled with EIA for toxin). Conversely, if patients are screened carefully for clinical symptoms associated with CDI (eg, at least 3 unformed or loose stools in a 24-hour period plus a history of antibiotic exposure), then a highly sensitive test such as NAAT or toxigenic culture, or GDH plus toxin detection, may be best. Neither of these approaches has been established, however, and appropriate testing strategy remains a dilemma. Clinicians should be aware of the test being used in their laboratories. If a NAAT test (PCR or LAMP) is being used, then they should recognize the potential for overdiagnosis, especially if specimens are sent from patients with minimal diarrhea. If EIA toxin testing is being used, it is more likely that a positive test represents CDI, but EIA testing may yield false negatives in patients with CDI because of lack of sensitivity.
MANAGEMENT APPROACHES TO CDI
There are several management strategies for CDI, including “inside the box” treatments (ie, antimicrobial therapy that spares the normal microbiota) and “outside the box” nonantibiotic treatments such as live organism biotherapeutics (eg, nontoxigenic C. difficile, fecal transplants, and their derivatives) or treatments focusing on supplementing or increasing the antibody response to C. difficile toxins (eg, actively through vaccines or passively through monoclonal antibodies). Treatment using luminal (oral) toxin binders has not been successful to date and will not be discussed in this study.
Current Recommendations for Treatment of CDI
Current recommendations for treatment of CDI are presented in Table 3. These recommendations are based on the 2010 guidelines from Infectious Diseases Society of America/Society for Healthcare Epidemiology of America35 but include some alternative treatments based on emerging information and drug availability since the guidelines were published.
Recommended treatment for initial episodes is stratified on the basis of severity (mild to moderate or severe) of CDI assessed by WBC count (> or <15,000 cells/μL), serum creatinine level (> or <1.5 times the premorbid level), and hypotension or shock, ileus, and megacolon, which characterize severe complicated (also called fulminant) CDI. There are separate treatment recommendations for first and subsequent recurrences.35
Current guidelines call for metronidazole treatment for mild to moderate cases and vancomycin for severe cases. However, preferred treatment is moving toward oral vancomycin for all, except the mildest cases, which may be treated with metronidazole. For severe cases, oral fidaxomicin, which was not available at the time the guidelines were published, is an alternative. Fidaxomicin uptake has been slow, largely because of its high cost. However, it may be the best drug available today because it has a similar treatment effect as vancomycin with a significantly lower recurrence rate.
Severe, complicated, or fulminant cases are treated with higher doses of oral vancomycin plus metronidazole IV.35 Tigeclycline IV may be used in place of either vancomycin or metronidazole but has only anecdotal evidence to support its use. Vancomycin may also be given via rectal retention enema for patients with complete ileus. Colectomy and ileostomy should be reserved for patients with severe disease who are not responsive to medical management.
First recurrences are treated on the basis of severity following the same guidelines as the initial episode. Subsequent recurrences, however, are treated with vancomycin in a tapered or pulsed regimen for 5 to 7 weeks. Alternatives include fidaxomicin, vancomycin followed by rifaximin, or a fecal transplant (discussed later). Metronidazole should not be used beyond the first recurrence or for long-term therapy due to cumulative neurotoxicity.35
Tolevamer Trial Provides Data Comparing Vancomycin and Metronidazole
A large, multicenter, randomized, prospective study compared tolevamer (a nonantibiotic, toxin-binding polymer), vancomycin, and metronidazole.18 The trial included patients older than 18 years with primary CDI or recurrent CDI defined as 3 or more loose or watery bowel movements within a 24-hour period along with a positive C. difficile toxin assay result or pseudomembranes on endoscopy and no other likely etiology for the diarrhea. The primary efficacy end point was resolution of diarrhea and absence of severe abdominal discomfort due to CDI for more than 2 consecutive days.18
Although tolevamer was inferior to both vancomycin and metronidazole for the treatment of CDI, vancomycin was significantly better than metronidazole for all patients. Previously, vancomycin superiority data were limited to patients with severe CDI.18
This study also showed a better outcome for treatment-naive versus treatment-experienced patients (OR, 1.814; 95% CI, 1.196–2.753; P = 0.0051) and for mild to moderate versus severe CDI (OR, 1.6; 95% CI, 1.032–2.479; P = 0.0356). The latter finding would be expected but provides additional confirmation of the clinical utility of the current definitions of mild to moderate and severe disease. These findings will likely be incorporated into future guidelines, but a shift toward increased use of vancomycin and decreased use of metronidazole may already be warranted.
Surgical Options for Severe, Complicated CDI
Surgery is recommended for patients with severe, complicated CDI not responding to medical treatment. Colectomy, the current surgical clinical standard, should be performed before serum lactate reaches 5 mmol/L or WBC is greater than 50,000/mm3 to reduce the risk of mortality. Even then, although colectomy has been shown to improve survival, mortality in this population remains high.37
An alternative to colectomy is diverting loop ileostomy followed by intraoperative lavage of 8 L of warmed polyethylene glycol and 500 mg vancomycin every 8 hours. In a case control study, Neal et al37 reported reduced mortality in patients treated with diverting loop ileostomy compared with historic mortality with colectomy (19% vs. 50%; OR, 0.24; P = 0.006). Preservation of the colon was achieved in 39 (93%) of 42 patients and 35 (83%) of these surgeries were performed laparoscopically.
Experimental Treatments With No Food and Drug Administration (FDA) Approval
Fecal Transplants for Recurrent CDI
On the basis of limited data, fecal microbiota transplantation (FMT) seems to be very effective for treatment of recurrent CDI. In a systematic review of FMT research, Drekonja et al38 reported on 2 randomized controlled trials with limited numbers of patients, in which 27 (75%) of 36 patients did not have further recurrence. They also discussed case reports in which 85% of 480 patients had symptom resolution without further recurrence.
In an open-label controlled trial, van Nood et al39 randomized 43 patients 18 years or younger with recurrent CDI to 1 of the following 3 treatments: FMT preceded by an abbreviated regimen of vancomycin and bowel lavage (n = 17), a standard vancomycin regimen (n = 13), and a standard vancomycin regimen with bowel lavage (n = 13). The primary end point, cure without relapse within 10 weeks of initiation of therapy, was met by 81.3% of patients in the FMT group, 30.8% in the vancomycin group, and 23.1% for the vancomycin plus lavage group (P = 0.003 for FMT vs. both vancomycin regimens).39 An additional FMT for those who did not meet the end point in the FMT group led to a 94% cure rate. Repeat FMT is often successful after failure, but with limited data, the focus for now should remain on initial FMT treatment results.
More recently, fecal material has been delivered via frozen FMT capsules. This oral therapy resolved symptoms for 14 (70%) of 20 patients (95% CI, 47%–85%).40 Investigators are working to identify and isolate the live bacterial organisms that can be used in a mixture of defined bacteria to treat recurrent CDI with FMT.41
Administration of Nontoxigenic C. difficile Spores to Prevent CDI Recurrence
Gerding et al42 reported a phase 2 study assessing the effect of administration of nontoxigenic C. difficile spores on CDI recurrence in patients who had clinically recovered after treatment with vancomycin or metronidazole. This double-blind, placebo-controlled, dose-ranging study randomized 173 patients 18 years or older to placebo for 14 days (n = 44) or 1 of following 3 doses of oral liquid formulation of nontoxigenic C. difficile strain M3 (NTCD-M3): 104 spores/d for 7 days (low dose, n = 43), 107 spores/d for 7 days (high-dose/short course, n = 44), or 107 spores/d for 14 days (high-dose/long course, n = 42).42
All doses of NTCD-M3 met the primary outcome—they were well tolerated and seemed to be safe.42 Secondary outcomes measured fecal colonization with NTCD-M3 from end of study drug through week 6 and recurrence of CDI from day 1 through week 6. The NTCD-M3 colonized the gastrointestinal tract and significantly reduced CDI recurrence. The lowest rate of recurrence seen was in the high-dose, 7-day (short course) treatment arm. The CDI recurrence rates were placebo (30%), NTCD-M3 low-dose (15%), NTCD-M3 high-dose/short course (5%), and NTCD-M3 high-dose/long course (15%).
Intravenous Monoclonal Antibodies to Prevent CDI Recurrence
Passive immunity to C. difficile toxins can be achieved by the use of monoclonal antibodies that bind C. difficile toxins A (CDA1, also known as MK-3415 and actoxumab) and B (CDB1, also known as MK-6072 and bezlotoxumab). These were successfully employed together in a double-blind, placebo-controlled phase 2 randomized controlled trial of 200 adults with CDI to prevent recurrent CDI.43 All subjects were first treated with metronidazole or vancomycin and were randomized to receive CDA1/CDB1 intravenous (IV) infusion or placebo. Subjects receiving CDA1/CDB1 had a lower recurrence rate within 12 weeks of enrollment (7% vs. 25% for placebo, P < 0.001). Rates and severity of adverse events were similar. Subsequent animal work in the gnotobiotic piglet model indicated that CDB1 antibody alone was sufficient to protect against CDI, whereas CDA1 had no protective benefit and may have worsened disease.44
Results of 2 phase 3 randomized controlled trials (MODIFY 1 and MODIFY 2) of CDA1/CDB1 and the individual antibody components have been reported in abstract form.45,46 In the MODIFY 1 trial,45 1452 adults receiving standard of care antibiotic therapy for primary or recurrent CDI were randomized to receive either actoxumab alone, bezlotoxumab alone, both monoclonal antibodies, or placebo. The CDI recurrence within 12 weeks was less frequent in patients receiving both monoclonal antibodies (15.9%, P < 0.0001) or bezlotoxumab alone (17.4%, P = 0.0003) compared with the placebo group (27.6%). Actoxumab resulted in a similar CDI recurrence rate as placebo (25.9%) and was dropped from further study.
In MODIFY 2,46 patients with primary or recurrent CDI were randomized to receive bezlotoxumab alone, both monoclonal antibodies, or placebo. The CDI recurrence within 12 weeks was less frequent in patients receiving both monoclonal antibodies (14.9%, P < 0.0001) or bezlotoxumab alone (15.7%, P = 0.0003) compared with placebo (25.7%). The CDI recurrence rates for both monoclonal antibodies and bezlotoxumab alone were similar. These studies suggest that a single monoclonal antibody against toxin B alone is an efficacious adjunctive agent for reducing CDI recurrence confirming studies in the gnotobiotic pig model.
Clostridium difficile infection incidence has increased dramatically in the United States since 2000. Reducing the burden of CDI begins with rapid and accurate testing of patients exhibiting its known signs and symptoms and including recent antibiotic exposure in the patient history. Choosing the right diagnostic test on the basis of the true disease rates in the population at hand is an important but challenging decision. Treatment advances include new information about optimal diagnostics, newer antibiotics, FMT for recurrent CDI, surgical options to colectomy, and in the future administration of monoclonal antibody or nontoxigenic C. difficile spores to reduce disease recurrence.
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46. Gerding D, et al. Phase 3 double-blind study of bezlotoxumab (BEZ) alone & with actoxumab (ACT) for prevention of recurrent C. difficile
infection (rCDI) in patients on standard of care (SoC) antibiotics (MODIFY II) [abstract]. Presented at: Interscience Conference on Antimicrobial Agents and Chemotherapy; Sept 17–21, 2015; San Diego, CA.
Self Assessment Examination
A minimum assessment score of 80% is required.
1. Which presentation is most indicative of Clostridium difficile infection?
A. Bloody diarrhea and abdominal cramping in a 10-year-old boy who recently traveled.
B. Frequent watery diarrhea in a 72-year-old female nursing home resident recently treated for an infection.
C. Intermittent diarrhea and frequent episodes of vomiting in a 36-year-old female waitress.
D. Low-grade fever, watery diarrhea, and muscle aches in a 24-year-old male college student.
2. The minimum symptom duration for suspected CDI is:
A. At least 3 unformed or water stools per day for 1 to 2 days
B. A change in bowel habits leading to more than 5 loose bowel movements per day
C. At least 6 unformed stools for a period of 36 hours
D. One of the above
3. It is important to detect toxin or toxin-producing C. difficile and to diagnose CDI quickly. Which of these tests is both highly sensitive and provides results rapidly?
A. Cell/tissue cytotoxicity assay
B. Polymerase chain reaction
C. Enzyme immunoassay
D. Toxigenic culture
4. First-line treatment for initial CDI episodes is stratified on the basis of:
A. Frequency of unformed bowel movements in the past 24 hours
B. Presence of fever and/or vomiting
C. WBC and creatinine level
D. Inpatient versus community-dwelling status
5. After successful treatment for an initial case of CDI with metronidazole, a patient now presents with confirmed severe CDI; treatment should start with:
A. Surgical consult
B. Fecal transplant
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