CDAD and CDAC

Clostridium-Difficile-Associated Diarrhea and Colitis

Clostridium difficile-induced diarrhea (CDAD) and colitis (CDAC) are important nosocomial (hosptial)-acquired infections resulting almost exlusively from antibiotic therapy and certain host factors. The severity of these disorders may range from simple diarrhea that can be resolved easily with antibiotic cessation to fulminant pseudomembranous colitis with fever, severe dehydration, abdominal pain and distention, and plaque formation over part or all of the colon. Community-acquired CDAD and CDAC are far less problematic but nevertheless may affect 20,000 or more people in the United States every year. Knowledge of the risk factors for CDAD and CDAC, including certain antibiotics, and recognition of the entire spectrum of signs and symptoms of this disorder are imperative for good dental practice. Likewise the prevention of recurrence of CDAD by judicious use of antibiotics in its immediate posttreatment period is an important consideration.

Approximately 25 million people in the United States are affected by diarrhea every year, with an ensuing 11,000 deaths.¹ Possibly 10 percent of more of these diarrhea cases are associated with antibiotic use, particularly broad-spectrum agents.² The vast majority of these antibiotic-associated diarrheas (AADs) are not pathologically significant and respond well to discontinuance of the antibiotic and rehydration, if necessary. However, a significant portion of these AADs are a sign of either "benign" colitis or the more serious and potentially fatal pseudomembranous colitis (PMC) caused by Clostridium difficile toxins. It is estimated that 3 million cases of Clostridium difficile-associated diarrhea or colitis may occur every year in the United States, primarily in hospitalized patients, esentially making it a nosocomially acquired disorder.^3-5 However, approximately 20,000 cases are diagnosed every year in the United States in outpatients (community-acquired)^5,6 with a range of 7.7 to 20 cases per 100,000 patient-years worldwide.^6,7 These estimates of community-acquired CDAD may be low due to limited fecal testing for Clostridium difficile or its toxins.⁸ This review will primarily be concerned with CDAD and PMC and their relationship to dental practice, thereby updating a previous review on this subject.⁹

History

Pseudomembranous colitis was first described in 1893 as "diptheric colitis" and from the 1930s to the 1960s was thought to be due to Staphylococcus aureus (staphylococcal enterocolitis).¹⁰ Prior to the introduction of antibiotics, PMC was associated with cardiovascular disease, colonic obstruction, heavy metal intoxication, sepsis, shock, and uremia.¹¹ Antibiotic-associated PMC was first noted in the 1950s with the introduction of penicillins, tetracyclines, and chloramphenicol.10 The association of a clostridial-type toxin with PMC was discovered in 1977,^12,13 and the relationship between Clostridium difficile and AAD and PMC was established in 1977-1978.^14-16 The spectrum of terms for this disorder include pseudomembranous enterocolitis, pseudomembranous colitis, antibiotic-induced colitis (AAC), clindamycin-associated colitis (CAC), antibiotic-associated PMC (AA-PMC), and Clostridium difficile-associated colitis or diarrhea.¹⁷ The common description of this disorder as "clindamycin-associated PMC" is incorrect because virtually any antibiotic can cause this colitis, and it occurs far more commonly with the cephalosporins and extended spectrum penicillins since these agents are used much more often clinically than clindamycin.

Epidemiology

Virtually all cases of CDAD, CDAC, and PMC are associated with antibiotic use, with only a very small percent seen in antibiotic-free patients on cancer chemotherapy. In patients with CDAD or CDAC, 92 percent had antibiotics within two weeks of the onset of the diarrhea and 100 percent within eight weeks. Also, 87 percent were nosocomially acquired.¹⁸

The carriage (colonization) rate for colonic Clostridium difficile or its toxins in healthy adults (asymptomatic carriers) is estimated to be 0.5 percent to 5.0 percent, with an average rate of 2 percent to 3 percent.^4,19,20 Ten to 13 percent of patients entering the hospital may be symptomatic carriers.^21,22 Fourteen percent of critically ill elderly patients and 20 percent of chronically ill elderly may also be asymptomatic carriers.23 The carriage rate in healthy neonates is 25 percent to 85 percent, which falls to 9 percent of children from age 3 months to 24 months.^5,24,25 The carriage rate for adults on antibiotic therapy may be 21 percent,^24,25 which is similar to the 21 percent carrier rate of individuals hospitalized for at least seven days.⁴ This asymptomatic carrier rate may rise to 50 percent of those hospitalized for greater than four weeks.²¹ Up to 40 percent of patients treated for CDAD or PMC may become asymptomatic carriers for an unknown period.²⁶ Asymptomatic carriers may have a reduced risk of CDAD due to colonization with nontoxigenic strains of Clostridium difficile.^4,26,27

Clostridium difficile-associated diarrhea may occur in about 7.8 percent of hospital admissions, and Clostridium difficile is responsible for 20 percent of all nosocomial diarrhea.²² The rate of CDAD in people undergoing hospital surgery is 5.6 percent to 6.9 percent.^18,28 Risk factors for nosocomial CDAD include increased age and length of hospital stay, type and number of antibiotics, enteral feeding, illness severity, reduced host resistance, and increased contact with hospital personnel.^22,29,30 Floors; toilets; mops; bedding; scales; furniture; bedpans; roomates; and the hands, rings and stethescopes of hospital personnel are all sources of Clostridium difficile contamination.²

Of greater importance to dentistry is the potential for CDAD, CDAC, or PMC in the general outpatient population exposed to antibiotics. In a study of 376,590 antibiotic prescriptions provided to more than 280,000 outpatients over four years, four cases of acute AAC were detected.³¹ The incidence rate was calculated to be 1.6 per 100,000 people exposed to ampicillin, 2.9 per 100,000 for dicloxacillin, and 2.6 per 100,000 people exposed to tetracycline.³¹ Interestingly, no cases of AAD were seen in 1,509 people receiving oral or topical clindamycin. In another retrospective study, 51 cases of CDAD occurred in 662,500 person-years (7.7 cases per 100,000 person-years).⁶ All cases recovered, and only six were hospitalized (82 percent were treated on an outpatient basis). The overall risk rate for community-acquired CDAD is this study was less than 1 per 10,000 antibiotic prescriptions, and the risk of hospitalization was 0.5 to 1.0 per 100,000 person-years.⁶ It appears then that the risk for hospitalization from community-acquired, antibiotic-induced diarrhea or colitis is very low.^6,31

It is also of interest to determine if single-dose antibiotic prophylaxis (such as recommended by the American Heart Association³² for the prevention of bacterial endocarditis) and multiple-dose prophylaxis often used for hospital surgery place a patient at-risk for CDAD, CDAC, AAC, or AAD. Nine studies have examined the relation of surgical antibiotic prophylaxis to CDAD or AAD in the hospital setting, with six employing multiple doses^{18, 33-37} and three only a single dose.^38-40 In the studies of multiple antibiotic dosing (some only 24 hours or less, some for several days or longer), such "prophylaxis" is significantly associated with CDAD.^{18, 32-37} In the three studies employing a single prophylaxis dose,^38-40 appearance or selection of Clostridium difficile may occur as well as AAD; but it appears that PMC may be a very low risk since none occurred with single-dose prophylaxis even in the hospital.

No studies have been performed to determine if a single antibiotic dose in the outpatient setting can cause PMC. Judging from the very low incidence in outpatient use with multiple antibiotic dosages and the limited data from single-dose prophylaxis in hospitals, such a risk for CDAC or PMC with single-dose antibiotic prophyalxis is likely to be very low to none.

Pathogenesis

Clostridium difficile is a spore-forming, gram-positive obligate anaerobic bacillus often acquired as a result of cross-infection vial oral ingestion.² It may commonly be found in river, sea, lake, and swimming-pool water; occasionally in tap water; and rarely in domestic animals and raw vegetables.⁴¹ It may or may not be present in soil.⁴¹ Due to its spore-forming properties, the organism may easily survive for long periods in adverse conditions.⁴¹

When the colonic microbial flora is disturbed by antibiotics, toxin-producing Clostridium difficile are either already present or later acquired (as in hospitals or other environments), and the host immune resistance is suppressed and/or colonization resistance (the ability of the normal gut flora to protect the mucosa from colonization by invading pathogenic microorganisms) is depressed, then CDAD may occur.¹¹ CDAD is then a "three hit" disease requiring antibiotic exposure; acquisition of Clostridium difficile; and a third factor relating to host susceptibility or immunity, virulence of the particular Clostridium difficile strain, and/or the type and timing of the antibiotic exposure.²⁶

It appears that there may be little correlation between the genotype and toxin product of the particular strain of Clostridium difficile and the severity of the colitis. It also appears that host resistance is paramount.^42,43 The evidence is equivocal as to whether HIV/AIDS predisposes to the acquisition of CDAD.^44-46 Colonic organisms that are antagonistic to Clostridium difficile and likely to be reduced or eliminated by antibiotics include lactobacilli, Bacteroides species, group D streptococci, Clostridium bifermentans, Escherichia coli, and Peptostreptococcus productus.⁴⁷ Some but not all isolates of Clostridium difficile produce two protein exotoxins (A and B) that are generally but erroneously termed an enterotoxin (A) and a cytotoxin (B).^5,48,49 Cytotoxin A may initiate mucosal cell damage, thereby allowing cytotoxin B to gain access to the underlying mucosal cells (toxin B is much more cytotoxic than toxin A).⁴⁸ These toxins bind to specific receptors in the luminal aspect of the colonic epithelium to catalyze the alteration of Rho proteins (GTP-binding proteins), resulting in the disruption of the F-actin structures, cell rounding, and eventual cell death.^5,48,49

Clostridium difficile-associated diarrhea or PMC may occur as a result of exposure to any antibiotic but is most commonly associated with ampicillin and amoxicillin; cephalosporins, particularly those of the third generation (ceftriaxone, ceftazidime, cefotaxime); and clindamycin.^2,8 The ability of the antibiotic to alter the anaerobic flora of the gut and eliminate colonization resistance appears important in its propensity to induce CDAD or PMC. Antibiotics infrequently associated with CDAD include tetracyclines, sulfonamides, erythromycin, trimethoprim, and the quinolones. CDAD is rarely seen with the aminoglycosides, bacitracin, vancomycin, and metronidazole.²

Clindamycin has been historically indicted in inducing significant PMC, possibly due to an early study that found a 10 percent incidence of colitis in patients exposed to clindamycin.⁵⁰ No other studies have reported such a high incidence of PMC with clindamycin. In 1,509 patients receiving clindamycin, none experienced AAD,³¹ while in other studies, the hospital restriction of clindamycin greatly reduced the incidence of CDAD.^51-53 Extended-spectrum penicillins, third-generation cephalosporins, and clindamycin remain the primary etiologic antibiotics for PMC but much depends on the ancillary factors listed above and whether the drugs are used in hospitalized patients or outpatients.

Signs and Symptoms

The adverse colonic effects of antibiotics may range from simple diarrhea (AAD) to mucosal inflammatory diarrhea or colitis with (CDAD) or without Clostridium difficile (AAC) to the formation of yellow plaques in the colonic mucosa (PMC). Clostridium difficile is cultured in 0 percent to 19 percent of patients with AAD without colitis, 60 percent with AAC without PMC, and 95 percent with PMC.23,25 Clostridium difficile toxins are detected in 11 percent to 27 percent of people with AAD without colitis, 32 percent of those with AAC without PMC, and 97 percent to 100 percent of people with antibiotic-associated PMC.25

The initial sign of diarrhea may appear as early as one to 10 days after initiation of antibiotic therapy^11,48 or as late as six to 10 weeks after the onset of antibiotic use.^11,48,54 Some propose an incubation period after exposure or acquisition of Clostridium difficile of less than a week with a median time of diarrheal onset of two days.^3,4,49 The severity of symptoms may range from a mild diarrhea to fulminant pseudomembranous colitis requiring surgical removal of part or all of the colon to maintain life. Simple "benign" AAD or AAC without fever or leukocytosis usually responds to cessation of the antibiotic.

As the disease progresses, the signs and symptoms include diarrhea with tenderness to the abdomen; profuse green, watery, foul-smelling, bloody diarrhea with abdominal distension; fever; and fecal and blood leukocytosis.⁴⁷ The onset of Clostridium difficile-associated pseudomembranous colitis is heralded by high fever, marked abdominal tenderness, dehydration, and the initiation of 2 mm to 20 mm in diameter raised adherent yellow plaques interspersed between relatively normal, mildly inflammed colonic mucosa.^2,11,26 These plaques begin as patchy epithelial necrosis with a fibrin and leukocyte exudate that may progress to more prominent exudates seen as "volcanic" or "summit' lesions and then on to diffuse epithelial necrosis and ulceration overlaid by a pseudomembrane consisting of fibrin, mucous, leukocytes, and cellular debris.² The pathologic process may terminate anywhere along this continuum.

Most PMC plaques are in the rectum and sigmoid colon, but about 10 percent are found more proximally and go undetected by sigmoidoscopy.² In severe cases, the plaques may coalesce to cover most or all of the colon. In fulminant colitis, the colonic muscle tone may be lost, resulting in toxic colonic dilation (toxic megacolon), paralytic ileus, and/or colonic perforation with ensuing peritonitis.² Possibly 3 percent of patients with CDAD or CDAC develop fulminant colitis with white blood cell counts reaching 40,000 and toxic megacolon greater than 7 cm in diameter.⁵ If the patient survives the CDAD or CDAC, the colon will return to its normal histology with only minor glandular irregularities.²

Diagnosis

Antibiotic-associated diarrhea without fever or leukocytosis is due to an imbalance of the colonic flora caused by the antibiotic; and if it does not progress to colitis, it requires no further diagnostic tests. Definitive diagnosis of CDAD, however, necessitates a certain clinical history and diagnostic information. The ideal definitive diagnostic scheme for CDAD entails a history of watery stools for more than 36 hours or at least three watery bowel movements per day for at least two consecutive days; antibiotic therapy within eight weeks of the onset of the diarrhea; a clinical cure by either metronidazole or vancomycin; no other etiology for the diarrhea; and either a colonic pseudomembrane determined by endoscopy, a stool sample positive for Clostridium difficile toxins, or a positive stool culture for Clostridium difficile.⁵⁴

More pragmatically, CDAD or Clostridium difficile-associated PMC can be diagnosed by the presence of diarrhea and one of the following: a pseudomembrane on colonoscopy, a positive stool cytotoxin assay for toxin B, a stool enzyme assay for toxins A or B, or a positive stool culture for Clostridium difficile.55 Testing should be done on hospitalized patients with a history of antibiotic use in the past 30 days, significant diarrhea (at least three watery, inflammed stools during a 24-hour period), or abdominal pain.26 Preferably, the diagnosis should be made from positive tests for both the organism and its toxin,55 as the cell cytotoxic assay is the most specific for CDAD and the stool culture is the most sensitive for CDAD.

Treatment

Diarrhea will resolve without any further treatment other than antibiotic discontinuance in 15 percent to 25 percent of CDAD cases.²⁶ The antibiotic of choice for CDAD or PMC that does not resolve is metronidazole (250 mg four times a day or 500 mg three times a day orally) for 10 days.²⁶ Vancomycin is generally reserved for those cases that do not respond to metronidazole or in patients who are severely ill because there are serious concerns about selection of vancomycin-resistant organisms in the hospital environment.56 The dose of vancomycin is 125 mg four times daily orally for 10 days.²⁶ Other therapies that have been employed include bacitracin, fusidic acid, teicoplanin, vancomycin plus rifampin, vancomycin in tapering doses, cholestyramine after vancomycin and re-establishment of the colonic flora with lactobacillus, nontoxigenic Clostridium difficile, and Saccharomyces boulardii.²⁶ The use of antiperistaltic agents such as loperamide, atropine, opioids, and diphenoxylate are not indicated because they will not only reduce the diarrhea but also increase intestinal stasis and toxin retention.47 The use of Saccharomyces boulardii, a nonpathogenic yeast, may prevent CDAD relapse57 but may be unsuccessful in preventing AAD.⁵⁸ Yogurt does not prevent CDAD in hamsters,⁵⁹ but passive immunity treatment with IgG antibodies against toxins A and B has been successful in two clinical cases.⁶⁰

Resolution of CDAD occurs in an average of 2.4 days with metronidazole, 2.6 to 4.2 days with vancomycin, 3.4 days with teicoplanin, and 2.5 to 4.1 days with bacitracin.55 The hospital stay for a patient acquiring AAD may be extended up to 18 to 21 days.^61,62 The mortality rates of CDAD and PMC are conspicuously absent in cases studies other than 17 deaths in a recent large-hospital outbreak of Clostridium difficile-induced diarrhea.⁶¹

Relapse Rate

The range for the relapse and recurrence rates of CDAD has been stated to be 4.8 percent to 66 percent,63,64 with more common estimates of 7 percent to 28 percent,⁶⁵ 23 percent,³⁴ 24 percent,⁶⁴ and an average of 20 percent appearing reasonable.⁶⁴ Relapse may be due to incomplete eradication of Clostridium difficile and recurrence due to the acquisition of a new organism. The initial cure rate in one study was 93 percent to 96 percent but with a recurrence rate of 16 percent for metronidazole or vancomycin, 28 percent for fusidic acid, and 7 percent for teicoplanin.⁶⁵ The aymptomatic carriage rate for patients treated with vancomycin or metronidazole may be 13 percent to 16 percent, respectively.⁶⁵ While most individuals with recurrent or relapsing CDAD respond to the same antibiotic regimen as used initially, in a study of recurrent CDAD, the average patient had three recurrences (range 1 to 9).⁶⁴ Recurrent CDAD can become persistent and elude long-term cure for years.⁶⁴

It is not possible to predict which patients will have a recurrence. Two subsets of patients apparently exist: those that respond well after initial treatment and those that are at risk for recurrent CDAD.⁶⁴ Risk factors for recurrence include the spring season; female gender; diarrhea that resolves but recurs within two weeks after treatment antibiotics are terminated; greater exposure to endoscopy; and, most importantly, receiving antibiotics within two months of the initial recurrent CDAD.⁶⁴ It would then appear imperative to refrain from unnecessary antibiotics within the two-month period following cessation of CDAD. Any elective dental treatment that might require antibiotic prophylaxis or, more importantly, therapeutic antibiotics would best be postponed for two months in patients who have just recovered from CDAD or PMC to avoid possible exacerbation by the antibiotic.

Prevention

Three studies have documented the validity of restriction of antibiotic use in the reduction of nosocomial CDAD. With an 80 percent to 90 percent reduction in the use of clindamycin, a resulting 50 to 75 percent decline in CDAD cases was observed.^51-53 Reduction in clindamycin use in one study also resulted in a decline in Clostridium difficile resistant to clindamycin from 91 percent to 39 percent during a two-year period.51 Unfortunately, this clindamycin restriction was more than offset by an increase in the use of imipenem, ticarcillin-clavulanate, and other antibiotics.⁵¹ Other prevention measures include handwashing, gloving, patient education, reducing staff cross-infection, cleaning of surfaces (Clostridium spores are resistant to most common disinfectants), and isolation of patients with CDAD.^66,67

Conclusions

Clostridium difficile-associated diarrhea and PMC are very significant nosocomial infections and are classic examples of antibiotic-induced disease (superinfections) or "diseases of medical progress." The initial cure rate is high with metronidazole or vancomycin, but approximately 20 percent undergo at least one relapse or recurrence. An unknown percent have chronic recurrences, and the mortality rate cannot be ascertained from the literature.

Fortunately for dentistry, the occurrence of antibiotic-induced CDAD in the community is quite rare, with an occurrence rate of 1 per 10,000 antibiotic prescriptions and a hospitalization rate of 0.5 to 1.0 per 100,000 patient-years. Besides early recognition and treatment and the known propensity of certain antibiotics to induce this condition (beta-lactams and clindamycin), an important lesson to be learned is to refrain from unnecessary antibiotics in the first two months following cessation of treatment for CDAD. Elective dental procedures that may require antibiotic prophylaxis or particularly therapeutic antibiotic therapy should be postponed until after this critical period. It is encouraging to know that the risk for CDAD and PMC with single prophylactic antibiotic doses is minimal to none and that clindamycin may once again have an important place in the dental antibiotic armamentarium, particularly against the penicillin-resistant viridans streptococci so prevalent in hospitals and likely to reach community patients in time.

Author

Thomas J. Pallasch, DDS, MS, is a professor of pharmacology and periodontics at the University of Southern California School of Dentistry.

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