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Annals of Internal Medicine
Narrative Review: The New Epidemic of Clostridium difficile–
Associated Enteric Disease
John G. Bartlett, MD
Antibiotic-associated diarrhea and colitis were well established soon been more frequent, more severe, more refractory to standard after antibiotics became available. Early work implicated Staphylo- therapy, and more likely to relapse. This pattern is widly distributed coccus aureus, but in 1978 Clostridium difficile became the estab- in the United States, Canada, and Europe and is now attributed to lished pathogen in the vast majority of cases. In the first 5 years a new strain of C. difficile designated BI, NAP1, or ribotype 027 (1978 through 1983), the most common cause was clindamycin, (which are synonymous terms). This strain appears more virulent, the standard diagnostic test was the cytotoxin assay, and standard possibly because of production of large amounts of toxins, and management was to withdraw the implicated antibiotic and treat fluoroquinolones are now major inducing agents along with ceph- with oral vancomycin. Most patients responded well, but 25% alosporins, which presumably reflects newly acquired in vitro resis- relapsed when vancomycin was withdrawn. During the next 20 tance and escalating rates of use. The recent experience does not years (1983 through 2003), the most commonly implicated antibi- change principles of management of the individual patient, but it otics were the cephalosporins, which reflected the rates of use; the does serve to emphasize the need for better diagnostics, early enzyme immunoassay replaced the cytotoxin assay because of recognition, improved methods to manage severe disease and re- speed of results and technical ease of performance; and metroni- lapsing disease, and greater attention to infection control and an- dazole replaced vancomycin as standard treatment, and principles of containment hospitals became infection control and antibiotic Ann Intern Med. 2006;145:758-764.
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control. During the recent past (2003 to 2006), C. difficile has For author affiliation, see end of text.
Diarrhea and colitis due to Clostridium difficile are well- ical significance, and is resistant to fluoroquinolones in
recognized and extensively studied iatrogenic compli- vitro. Successful management of patients with this strain cations of antibiotic use and have been for nearly 30 years.
requires early detection of infection, rapid treatment, and Important risks for infection include hospitalization, ad- implementation of infection control, sometimes including vanced age, gastrointestinal surgery or gastrointestinal pro- cedures, and antibiotic exposure. The most common in- Clostridium difficile was identified as the major cause ducing agents have been clindamycin or broad-spectrum of antibiotic-associated diarrhea and the nearly exclusive cephalosporins, but nearly all agents with an antibacterial cause of pseudomembranous colitis in 1978. Subsequent spectrum may be responsible. The cytotoxin assay that work in the following 2 years defined the clinical features, originally led to the detection of C. difficile in 1978 re- methods of laboratory diagnosis, epidemiology, principles mains the most sensitive diagnostic test, but the enzyme of infection control, and treatment of C. difficile–associated immunoassay is now used by most laboratories because of disease. Clostridium difficile infection is an important and ease of processing, cost, and speed of results. Standard frequent iatrogenic complication, but it has been relatively treatment of C. difficile infection includes withdrawal of easy to manage, with the exception of occasional institu- the inducing agent and use of oral metronidazole or oral tional outbreaks and a nagging problem of relapsing disease vancomycin; metronidazole is preferred in guidelines, but following treatment. However, during the past 5 years, an vancomycin is probably more effective, especially in seri- unanticipated increase in infection has been recognized, ously ill patients. The major complications of treatment are particularly in some locations where C. difficile–associated failure to respond, primarily because of advanced disease disease has become more frequent, more serious, and more with ileus, and relapse or reinfection after treatment is dis- refractory to standard therapy. It now seems that this continued. Prevention principles include hospital infection change is explained by a unique strain of C. difficile that has unusual virulence factors, which may account for in- Against this background, there is a new epidemic of C. creased severity, and fluoroquinolone resistance, which difficile infection that is occurring more frequently and ismore serious and more refractory to therapy. Evidence ofthe severity of the infection includes high rates of toxic megacolon, leukemoid reactions, severe hypoalbuminemia, requirement for colectomy, shock, and death. These com- Key Summary Points . . . . . . . . . . . . . . . . . . . . . . . 759 plications are most common in elderly patients, and theinducing agents are often fluoroquinolones and cephalo- Web-Only
sporins. Analysis of outbreaks in North America implicates a unique strain of C. difficile that produces large amounts of toxin in vitro, produces a binary toxin of uncertain clin- 758 2006 American College of Physicians
Clostridium difficile–Associated Colitis Review Risk Factors
Key Summary Points
Almost all studies include the 3 major risks for infec- Clostridium difficile is the most common identifiable bac- tion with C. difficile: antibiotic exposure, advanced age, terial cause of diarrhea in the United States.
and hospitalization (6 – 8). With regard to antibiotic expo-sure, any antimicrobial agent with an antibacterial spec- Tissue culture assay is the best diagnostic test to detect trum can be the cause, but there is a hierarchical list of the cytotoxin; enzyme immunoassay is the test used in agents that has been subject to change. Clindamycin fol- most hospitals, but it has a sensitivity of only about 75%.
lowed by ampicillin or amoxicillin played prominent rolesin the 1970s, but these were largely supplanted by cepha- A new epidemic strain of C. difficile has emerged that losporins in the 1980s (9, 10). Researchers from Sweden causes more frequent and more serious disease.
showed that advanced age was a risk in population-basedanalyses indicating that the rate per 100 000 persons older Features of severe disease include ileus, toxic megacolon, than 65 years of age was 20 times higher than that in pseudomembrane formation, leukemoid reactions, hyperal- persons younger than 20 years of age (11). The risk asso- buminemia, requirement for colectomy, sepsis, and death.
ciated with hospitalization and chronic care facilities is at-tributed to high rates of C. difficile colonization. Studies Risk factors are use of antibiotics (especially broad-spec- have shown a 20% to 40% rate of colonization in hospi- trum cephalosporins and fluoroquinolones), advanced age, talized adults compared with 2% to 3% in healthy adults hospitalization, and gastrointestinal surgery or gastrointes- (12, 13), reflecting widespread contamination of hospital environments, especially in areas associated with infection(6, 7, 14, 15). Gastrointestinal surgery and gastrointestinal Oral vancomycin is the preferred treatment for seriously ill Clinical Expression
Infection control and antibiotic control are important pre- Clinical disease and C. difficile toxin are present almost exclusively in patients with recent antibiotic exposure (6, 7,12, 16), with rare exceptions (17, 18). A recent reportimplicates gastric acid–suppressive agents as a risk for dis-ease (19), but this has not been consistently observed (20).
Clinical expression of infection almost always includes di- may account for increased frequency. These recent obser- arrhea, but severity of this and constitutional symptoms vations have resulted in renewed interest in an “old patho- (6 – 8, 16, 17) varies widely. Common findings in patients gen.” This review updates the status of C. difficile–associ- with infection include colitis with cramps, fever, fecal leu- ated enteric disease and its management in light of these kocytes, and inflammation on colonic biopsy. Pseudomem- branous colitis represents an advanced stage of disease, andalthough considered “nonspecific,” it is nearly diagnostic ofC. difficile infection (17). The disease is almost always re-stricted to the colon (21). Clostridium difficile infection INITIAL STUDIES (1974 TO 2003)
is a protein-losing enteropathy that is often associated with Antibiotic-associated enterocolitis was generally attrib- hypoalbuminemia and sometimes with anasarca (3). Most uted to Staphylococcus aureus in the first 25 years of the patients have leukocytosis, and this infection is now recog- antibiotic era (1, 2). In 1974, Tedesco and colleagues (3) nized as a prominent cause of leukemoid reactions (22).
reported results of a prospective study of 200 patients given Diagnosis
clindamycin who underwent endoscopy after reporting di- The standard test for infection is detection of C. diffi- arrhea. In this study, 41 (20.5%) patients had diarrhea and cile toxin in stool. The initial report in 1978 (5) used the 20 (10%) had pseudomembranous colitis (3). Despite the tissue culture assay, and no subsequent test has proven ease of recovering S. aureus in stool, tests to detect the superior in terms of sensitivity or specificity (23–25). The organism yielded negative results. This led our group and main limitations of the test are the 24 to 48 hours required others to pursue an alternative putative agent by using the for results, work intensity, and cost (25). Most laboratories hamster model (4) for correlations with observations in now use enzyme immunoassay to detect toxin A or toxins patients. Clostridium difficile was reported as the agent of A and B, but several studies show that these are only about antibiotic-associated pseudomembranous colitis in 1978 (5).
75% sensitive compared with tissue culture assays (23–25) During the ensuing 25 years, researchers established so that repeated tests or empirical treatment may be re- essential data documenting associated risks, clinical fea- quired (26). Alternative methods of detection include de- tures, diagnosis, and management of C. difficile–associated tection of C. difficile by culture, by polymerase chain reac- diarrhea that became widely accepted.
tion testing, or by analysis for the “common antigen” of C. www.annals.org
21 November 2006 Annals of Internal Medicine Volume 145 • Number 10 759
Review Clostridium difficile–Associated Colitis Some laboratories use 1 of these last methods to screen Table. Treatment Recommendations for Clostridium
stool samples, with subsequent testing for the cytotoxin in difficile–Associated Diarrhea*
samples with positive results (25, 28).
Initial treatment
Infection Control
Discontinue implicated antimicrobial agent or agents Standard recommendations of the Society for Health- Institute supportive care: hydration and electrolyte replacement, if care Epidemiology of America for infection control include Avoid antiperistaltics, including narcotics and loperamide the following: patient isolation in a single room, preferably with a bathroom; contact precautions; room cleansing with Oral vancomycin, 125–250 mg 4 times daily for 10 d a 1:10 dilution of bleach; avoidance of rectal thermome- Advantages: ideal pharmacologic profile; unbeaten in clinical trials; only FDA-approved treatment; in vitro activity vs. all strains ters; and soap and water for handwashing rather than al- Disadvantages: high relapse or reinfection rate; promotion of cohol-based hand hygiene (14). Alcohol-based hand clean- acquisition of vancomycin-resistant Enterococcus faecalis; highcost ing is considered inferior because clostridia spores survive Oral metronidazole, 250 mg 4 times daily or 500 mg 3 times daily for alcohol. This is important because health care workers can transmit C. difficile via their hands. Antibiotic control of Advantages: comparable to vancomycin in most clinical trials; preferred according to IDSA, CDC, and SHEA guidelines; low clindamycin or cephalosporins has sometimes been neces- sary during epidemics (29, 30). Attempts to prevent infec- Disadvantages: poor pharmacologic profile; in vitro resistance for some strains; high relapse or reinfection rate; less effective than tion with prophylactic metronidazole or oral vancomycin may actually increase the rate of C. difficile carriage (31).
Infection control: Nosocomial cases
Treatment
Single room with bathroom; barrier precautions; hand hygiene with soap Recommendations for treatment are supportive care, and water; avoidance of rectal thermometers; terminal roomcleaning with 1:10 household bleach withdrawal of the implicated antibiotic, and avoidance of Consider antibiotic restrictions based on epidemiologic associations if C. unnecessary use of drugs with antiperistaltic activity (Ta-
ble). When continued antibiotic treatment is necessary, it
Complications
is best to use agents with a low probability of causing C. Inability to take medications by mouth: IV metronidazole† (500 mg 4 difficile–associated disease, such as urinary antiseptics, tetra- times daily) and vancomycin (500 mg every 6 h by retentionenema or nasogastric tube) cyclines, narrow-spectrum betalactams, macrolides, sulfon- Delayed response and critical illness: consider IVIG (400 mg/kg of body amides, aminoglycosides, vancomycin, metronidazole, and weight)† or surgical consultation for possible colectomy, trimethoprim–sulfamethoxazole (32). It is not clear especially if leukemoid reaction (leukocyte count Ͼ 20 ϫ 109cells/L), renal failure, septic shock, or any combination of these whether mild cases require antibiotic treatment against C. difficile (33). When symptoms are at least moderately se- vere or persistent despite withdrawal of the implicated anti- Withdraw inducing agentSubstitute agent or agents unlikely to cause C. difficile–associated microbial agent, the usual options are oral vancomycin or diarrhea, avoiding clindamycin, broad-spectrum cephalosporins, oral metronidazole (6 – 8, 14, 16, 34). Oral vancomycin is the only drug approved by the U.S. Food and Drug Ad- Repeat treatment with metronidazole or vancomycin using standard ministration for C. difficile enteric infection. It has ideal pharmacologic properties for treating a pathogen that is Oral vancomycin in tapering or pulse dosing (125 mg every other day completely restricted to the colonic lumen because the Biotherapy: Oral lactobacilli, such as Lactinex (Becton–Dickinson, San drug is not absorbed and is found at levels in the colonic Diego, California) (1 g 4 times daily), or Lactobacillus GG lumen that are more than 100 times higher than the high- twice daily for 4–6 wk), or Saccharomyces boulardii (two est minimum inhibitory concentration reported (31, 35, 36).
250-mg capsules twice daily for 4–6 wk) Metronidazole is the preferred treatment agent in Anion exchange resin: oral cholestyramine (4-g packet 3 times daily)†Fecal transplant (30–50 g fresh stool from healthy donor in normal guidelines from the Society for Healthcare Epidemiology saline delivered by enema or nasogastric tube) of America, Infectious Diseases Society of America (IDSA), and the U.S. Centers for Disease Control and Prevention Combinations of above, but do not give vancomycin concurrently with lactobacilli (vancomycin is active against lactobacilli) or (16), presumably because of its low cost and because of the possibly erroneous conclusion that vancomycin promotes fecal colonization with vancomycin-resistant enterococci * CDC ϭ U.S. Centers for Disease Control and Prevention; CFU ϭ colony- more than metronidazole does (37). The pharmacologic forming unit; FDA ϭ U.S. Food and Drug Administration; IDSA ϭ Infectious properties of metronidazole are poor for treating a patho- Diseases Society of America; IV ϭ intravenous; IVIG ϭ intravenous immunoglob- ulin; SHEA ϭ Society for Healthcare Epidemiology of America.
gen in the colonic lumen because its absorption is nearly complete and at detectable levels in stool only in the pres-ence of diarrhea (31, 35, 36) and because some strains of difficile (25, 27, 28). An inherent problem with detection C. difficile are resistant to metronidazole in vitro (38).
of the organism rather than the toxin is that 10% to 30% Comparative trials of vancomycin versus metronidazole of hospitalized patients are colonized without disease (13).
have shown that the drugs are equivalent (39, 40), but 760 21 November 2006 Annals of Internal Medicine Volume 145 • Number 10
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Clostridium difficile–Associated Colitis Review there is some evidence that oral vancomycin is preferred in THE NEW EPIDEMIC OF CLOSTRIDIUM DIFFICILE
seriously ill patients because of relatively high failure rates of metronidazole in recent reports (41), poor response to Investigators from Que´bec, Canada, noted an increase metronidazole when antibiotics for the initial condition in the frequency and severity of C. difficile–associated di- need to be continued (42), and a slower clinical response arrhea in the early 2000s (20, 63– 65). A review of 1771 compared with oral vancomycin treatment (43).
case-patients from 1991 through 2003 in Sherbrooke, The expected response to treatment is rapid deferves- Que´bec, showed that the incidence of C. difficile enteric cence in patients who are febrile and resolution of diarrhea disease per 100 000 people increased 4-fold for the entire over 4 to 6 days (44). In my experience (45) with 189 region and 10-fold for persons older than 65 years of age.
patients with C. difficile enteric infection, including 100 Among those admitted to the hospital in the region, the with endoscopic evidence of pseudomembranous colitis, incidence increased from 3 to 12 per 1000 persons in 1991 96% responded to oral vancomycin. For patients who are to 2002 to 25 to 43 per 1000 persons in 2003 to 2004 seriously ill and cannot take oral medications, it is recom- (63). Furthermore, the disease seemed to be more serious mended that vancomycin be delivered by nasogastric tube and refractory to therapy, as indicated by increased rates oftoxic megacolon, disease requiring colectomy, associated or by enema (46). This may be augmented with intra- shock, or death (20, 63, 66). Indeed, the attributable mor- venous metronidazole, but evidence of efficacy of intra- tality rate was an astonishing 16.7% (66). Five variables venous metronidazole treatment is poor (47). Another op- were associated with these complications: age older than 65 tion, based on previous studies showing a correlation years, acquisition of infection at a hospital, peripheral leu- between clinical expression and serum levels of IgG anti- kocyte count higher than 20 ϫ 109 cells/L, renal failure, body versus C. difficile (48), is intravenous immunoglobu- and immunosuppression (66). The implication is that the lin (49, 50). Results using intravenous immunoglobulin in disease was more frequent, more severe, more refractory to acutely ill patients are variable and anecdotal (49, 50).
therapy, and subject to high rates of relapse (63– 68).
Some patients with advanced disease, especially those with While these developments were occurring in Canada, ileus or toxic megacolon, require colectomy. However, the McDonald and colleagues (68, 69) at the Centers for Dis- frequency of patients with advanced disease was only 0.4% ease Control and Prevention noted reports of increasing at The Johns Hopkins Hospital in the early 1990s (51).
frequency and severity of C. difficile from U.S. physicians, Patients with serious disease who do not respond to stan- including 8 hospital outbreaks in 6 states (68, 69). An dard therapy should be considered for colectomy (51–53).
analysis of the International Classification of Diseases, The mortality rate in reports of 94 patients who had co- Ninth Revision (ICD-9) coding in the United States lectomy for C. difficile–associated colitis was 45% (51–53).
showed an increase 82 000 cases in 1996 to 178 000 in The major complication of antibiotic treatment of C. 2003 (69). There were also other reports of C. difficile difficile infection has been relapse, which is seen in about causing more disease and more serious disease in the 20% of patients treated with metronidazole or vancomycin United States (70, 71) and in other areas of the world (72).
(39, 40, 45). The clinical features of relapse are highly Thus, this seemed to be an experience that was widespread characteristic: The patient reports a recurrence of symp- toms identical to those of the initial illness, usually within Clinical Observations
1 week but up to 6 to 8 weeks after vancomycin or met- Clinical features of the epidemic disease are similar to ronidazole is withdrawn (45, 54). These patients usually the historical experience but more severe. Prominent com- respond well to retreatment, but some have additional re- plications include toxic megacolon, leukemoid reactions, lapses and a small portion have repeated relapses necessi- septic shock, requirement for colectomy, and death (20, tating several courses of antibiotics (45, 54, 55). Relapse is 62–71). The newly implicated class of antibiotics was fluo- caused by the initial strain of C. difficile, but nearly half of roquinolones for most of the recent outbreaks, although patients experiencing relapse may be infected with new cephalosporins still accounted for a substantial portion (20, strains of C. difficile (56). These observations illustrate the paradox that oral vancomycin and metronidazole both Epidemic Strain
cause and cure antibiotic-associated diarrhea. The postu- This epidemic, with a large increase of patients with lated cause of recurrence is failure to mount an immune infection, many experiencing severe complications, raised response as indicated by low serum levels of IgG versus the possibility of a new strain of C. difficile that had unique toxin A (50, 57). Several methods are used to treat relaps- properties accounting for enhanced virulence. This suspi- ing disease, including biotherapy or probiotics (such as cion was confirmed by analysis of epidemic strains from Saccharomyces boulardii and Lactobacillus rhamnosus GG) Que´bec and 8 U.S. sites. Results of the analysis showed a (58 – 61), stool implants (62), immunotherapy (intra- highly characteristic strain, designated BI/NAP1, that has venous immunoglobulin) (48, 49), and tapering or pulse been rare historically and is responsible for the majority of these outbreaks (20, 68, 73). This strain has several appel- www.annals.org
21 November 2006 Annals of Internal Medicine Volume 145 • Number 10 761
Review Clostridium difficile–Associated Colitis lations, according to the biological property tested: NAP1 not standard in most laboratories. Nevertheless, a pathogen by pulsed-field gel electrophoresis, BI on restriction-endo- should be suspected if there is an increase in the occurrence nuclease analysis, toxinotype III, and ribotype 027 on of infection and more severe associated disease as indicated polymerase chain reaction. With regard to unique features, by high rates of serious complications, including toxic 5 factors have been found in nearly all strains that may megacolon, leukemoid reactions, requirement for colec- contribute to the clinical observations.
tomy, shock, or death. Fastidious attention to infection The first of the 5 factors are toxins A and B, which are control is required because infection with this strain may the classic toxins associated with C. difficile–associated dis- be a major nosocomial complication, especially in elderly ease. Most strains of C. difficile produce both toxins, but patients. Outbreaks may require restriction of antibiotic the epidemic strain has been shown to produce substan- use with attention to antibiotics implicated in the epi- tially more toxins A and B in vitro (73). The second factor demic, which now include fluoroquinolones, clindamycin, is toxinotype III. Toxinotyping is based on analysis of the and cephalosporins. Traditional treatment, including oral region of the C. difficile genome known as the pathogenic- metronidazole or oral vancomycin, is recommended. These ity locus (PaLoc) that includes genes that encode for toxin drugs seem to be similar in clinical trials, but many author- A (tcdA) and toxin B (tcdB) and the neighboring regulatory ities now prefer oral vancomycin for more serious disease genes. All BI/NAP1 strains are toxinotype III, but more and for patients who do not respond rapidly to metroni- than 80% of other strains are toxinotype 0 (68, 73). The third factor is the deletion of tcdC, which is an 18 base-pairsequence in the pathogenicity locus (PaLoc) responsible for From John Hopkins University School of Medicine, Baltimore, Mary- downregulation of toxin production (68, 74). The fourth factor is binary toxin, an iota-like toxin similar to that Potential Financial Conflicts of Interest: Consultancies: Dr. Bartlett is on
produced by Clostridium perfringens type E (75). The bi- the HIV advisory boards of Abbott, Bristol-Myers Squibb, and Glaxo- nary toxin is present in the epidemic strain, but its role in the pathogenesis of C. difficile–associated disease is unclear.
It causes fluid accumulation in rabbit ileal loops, but C. Requests for Single Reprints: John G. Bartlett, MD, Department of
difficile strains that possess binary toxin without toxins A Medicine, Johns Hopkins University School of Medicine, 1830 Monu- and B fail to cause disease in hamsters (76). The final factor ment Street, 437, Baltimore, MD 21205; e-mail, [email protected].
is resistance in vitro to fluoroquinolones, which is infre-quently observed in strains collected before 2001 and maybe an important factor in the increased frequency of disease References
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