Extracolonic Manifestations of Clostridium difficile Infections

Introduction Infection with Clostridium difficile is a common complication of antibiotic therapy. The usual clinical scenario is of pseudomembranous colitis manifesting as fever and diarrhea, usually within 4–9 days of starting antibiotic therapy. This is occasionally complicated by the development of toxic megacolon, necessitating urgent surgical intervention. All antibiotics have the potential to cause pseudomembranous colitis, and while clindamycin is the antimicrobial best known for it, broad-spectrum cephalosporins are now the most commonly implicated agents. Not well appreciated by many clinicians, though, is the ability of C. difficile to cause disease at sites other than the colon. We recently encountered 2 such extracolonic manifestations of C. difficile infection in 1 week (reactive arthritis and small bowel involvement) which prompted a review of the available literature. Since we could not find a comprehensive review in the general medical literature (using MEDLINE [National Library of Medicine, Bethesda, MD] from 1966 to October 2000), we undertook the writing of this article to aid clinicians dealing with noncolonic problems in patients known to be infected with C. difficile. In the original report of C. difficile, published by Hall and O’Toole (24) in 1935, the bacterium was named “the difficult clostridium” because it grew slowly in culture and early attempts at isolation were unsuccessful. This Gram-positive, spore-forming, obligate anaerobic bacillus is now recognized as the major cause of pseudomembranous colitis (6,33). Once present in the colon, C. difficile produces both an enterotoxin (toxin A) and a cytotoxin (toxin B) (71). While toxin A has been implicated as the cause of C. difficile-associated diarrhea and pseudomembranous colitis (29), the contributions of these toxins to the extracolonic manifestations of C. difficile infection are unknown. When initially isolated from extraintestinal sites, C. difficile was considered to be of questionable pathologic significance (64). However, it is now clear that such isolates are indeed clinically significant. Knowledge of the clinical presentation of these extracolonic manifestations of infection will help in patient care and disease management. Topics to be discussed include small bowel involvement, bacteremia, visceral abscess formation, infection of implanted prosthetic devices, encephalopathy, reactive arthritis, and osteomyelitis. Where possible, the clinical presentation, proposed mechanisms of pathogenesis, and treatment options are summarized for each of the clinical conditions discussed. Case Reports Both patients were seen at Sinai Hospital of Baltimore in June 2000. Small bowel involvement An 83-year-old woman was admitted to the medical service for confusion and an Escherichia coli urinary tract infection. Further evaluation of her mental status change revealed evidence of late-latent syphilis but no evidence of neurosyphilis. The urinary tract infection was treated with oral trimethoprim-sulfamethoxazole, and intramuscular penicillin was administered weekly as syphilis treatment. The patient acutely decompensated on hospital day 8 and was found to have an acute abdomen. Computed tomography (CT) scanning (Figure 1) revealed abnormalities of both the colon and distal small intestine. At laparotomy, an inflammatory process was found throughout the colon as well as the distal and middle thirds of the small intestine. All the involved areas of bowel had pseudomembranes, were judged clinically to be nonviable, and were resected. Histopathologic examination of the excised small and large bowel demonstrated changes consistent with C. difficile-related infection, and the stool C. difficile toxin assay was positive. Postoperatively, the patient had a complicated course, could not be weaned from ventilatory support, and ultimately was discharged to a chronic-care facility.Fig. 1: Preoperative computed tomographic scan of the abdomen showing dilated small bowel with thickened, inflamed wall (arrows) due to small bowel Clostridium difficile infection.Clostridium difficile -related reactive arthritis A 36-year-old man with newly diagnosed acute myelogenous leukemia was admitted for induction chemotherapy. He became profoundly neutropenic and then febrile. Empiric therapy with imipenem-cilastatin was initiated. Five days later diarrhea developed together with severe right lower quadrant pain. A CT scan of the abdomen demonstrated right-sided colitis. Stool was positive for C. difficile toxin A. Therapy with oral metronidazole was started. On day 5 of metronidazole therapy, left knee pain, swelling, and tenderness developed. The knee joint effusion was drained and revealed cloudy fluid with a white cell count of 67,000/mm3. There were no crystals found on fluid microscopy, serum uric acid had been normal throughout, and fluid and blood cultures remained negative. A diagnosis of C. difficile related reactive arthritis was made. The patient was managed with nonsteroidal antiinflammatory drugs and physical therapy. Fourteen days later the swelling had subsided and the patient was able to bear weight on the affected knee again. Small Intestinal Involvement The normal flora of the small intestine changes dramatically as it approaches the connection with the colon. The distal third of the small intestine provides an environment hospitable to anaerobic bacteria. Despite this, involvement of the small intestine in infections with C. difficile is rare even when there is infection of the immediately adjacent right colon. Previously reported cases of small bowel involvement are summarized in Table 1. It is noteworthy that most of the reported patients had surgically altered intestinal anatomies. This, then, may be a predisposing factor to small bowel susceptibility to pseudomembranous enteritis. It has been reported that after an ileostomy, ileal flora may change to resemble fecal flora (77). This leads to the hypothesis that surgical alteration of the small bowel could lead to bacterial colonization resembling the colon, resulting in the increased susceptibility to C. difficile infection. Kralovich et al (35) postulate that the constant peristaltic activity of the small bowel and mechanical action of the ileocecal valve prevent C. difficile from colonizing the small bowel. They reported a patient with C. difficile infection of a bypassed segment of ileum created during a jejunal-ileal bypass performed 30 years earlier. The authors propose that ileal hypomotility may have contributed to its becoming colonized and infected with C. difficile.TABLE 1: Small intestinal involvementTABLE 1: ContinuedApel et al (4) report that there are histologic changes in the small intestine epithelium when fecal flow is altered, and Yee et al (81) note that the patient they reported demonstrated abnormal epithelium of the ileorectal anastomosis with histologic features similar to colonic epithelium. These changes may have made the local milieu more conducive to this infection. The cases discussed by Shortland et al (61) and Kralovich et al (35) are fascinating in that the only parts of the small bowel that developed pseudomembranous colitis were the segments used as a conduit from the ureters following cystoscopy, and the bypassed and defunctionalized small bowel, respectively. The colitis affecting the colon in both cases stopped abruptly at the ileocecal valve—that is, there were no plaques at the terminal ileum. This appears to indicate that the normal small bowel is not usually susceptible to developing infection with C. difficile; however, as in the case we presented, such infections may occasionally occur even in the absence of apparent predisposing factors. Overall, when the small bowel is involved with infection with C. difficile, the mortality rate is high, with 4 of 7 reported patients dying. Cellulitis and Soft Tissue Involvement Cases in adults Smith and King (64) reported the first 2 cases of C. difficile-related cellulitis in adult patients, and in each case the development of cellulitis followed local trauma. The first case was of a soldier in 1943 hit with a shell fragment in the thigh. The patient died, and C. sporogenes, C. sphenoides, and C. difficile were isolated from the patient’s wound. The second case was described in 1957 involving a patient who fractured his femur in an airplane accident. An anaerobic streptococcus was isolated along with C. difficile. The same authors reported a case of an abscess in the vaginal vault of a 45-year-old woman. C. difficile was isolated in addition to anaerobic streptococci and a non-spore-forming obligate anaerobic bacterium. Eastwood (19) reported a case of a 28-year-old man who developed a perianal abscess about 3 months after beginning antituberculous therapy. Pus drained from the abscess grew E. coli, Citrobacter freundii, Streptococcus viridans, and a Clostridium species later identified as C. difficile. Eastwood noted that this case of C. difficile infection was not accompanied or preceded by diarrhea. Recently, a case of C. difficile-induced necrotizing fasciitis of the thigh following multiple trauma due to a motor vehicle accident has been reported (7). The patient, a 59-year-old woman, had negative blood cultures, with a pure growth of C. difficile being cultured from the involved thigh. The patient survived with intensive surgical and medical management. Pediatric cases Katner, Pankey, and colleagues (30) described the first case of cellulitis in an infant due to C. difficile with neurologic complications that eventually lead to death. A 3-month-old female developed a 5-cm tender brownish blue macular lesion over her left hip. The lesion was aspirated and grew a pure growth of C. difficile. The baby began jerking her right upper extremity and twitching at the mouth. She then rapidly deteriorated and died. Danielsson et al (17) also reported a case of a perirectal abscess, this in a 15-year-old girl with Crohn disease. C. difficile was isolated, along with Bacteroides fragilis ss fragilis, S. epidermidis, E. coli, and Propionibacterium acnes. Because C. difficile is a spore-forming bacterium found in the environment, it would seem likely that it could cause cellulitis following a traumatic event such as a war wound or a motor vehicle accident. Furthermore, because approximately 4% of individuals are asymptomatic colonic carriers of C. difficile, a lower extremity wound could readily become infected with the C. difficile spores shed from the anus. Thus, Smith and King (64) proposed that the wounds in the patients’ thighs may have been con-taminated with fecal matter resulting in these infections. Similarly, Katner, Pankey, and colleagues (30) proposed that C. difficile may have infected the skin of the patient they presented via contaminated diaper pins, especially considering the high carriage rate of C. difficile in the stool of infants (14). They did not believe the infection spread hematogenously, as blood cultures demonstrated no growth, and there was no other identifiable source of infection found. It is likely that the local in vivo production of toxins A and B contributes to the soft tissue infections. Bacteremia and Sepsis Syndrome Bacteremia There have been 9 cases of C. difficile bacteremia reported. The first was by Smith and King (64) who reported C. difficile bacteremia in a 5-month-old baby boy with a 3-week history of coryza, cough, and anorexia. They assumed at the time that the source of infection was the respiratory tract, and were unsure of the pathologic significance of the positive blood culture. Spencer et al (67) reported a case of polymicrobial bacteremia in 1984. The 2 organisms that grew on culture were C. difficile and Bacteroides fragilis. Five years later, Gerard et al (23) presented a case of polymicrobial bacteremia with C. difficile during an attack of acute diverticulitis. The other organisms isolated were E. coli, Enterococcus faecalis, and Bacteroides vulgatus. The reported cases are summarized in Table 2. Of note, the majority of cases are of polymicrobial bacteremia, with C. difficile being just 1 isolate among other usual bowel flora. The mortality rate is low, with 2 of 10 reported patients dying. The prevailing theory explaining the pathophysiology of these events is that in the setting of pseudomembranous colitis, colonic inflammation permits transient bacteremia to develop.TABLE 2: BacteremiaSepsis syndrome Chatila and Manthous (12) reported the first cases of C. difficile-related sepsis syndrome in 1995. They reported 4 patients with C. difficile infection who presented with acute abdomens and sepsis syndrome. One patient surgical while the were managed The sepsis syndrome in 4 et al reported 3 cases of sepsis syndrome following large intestinal C. difficile infection. of the 3 patients were treated and 3 patients died. to the proposed pathophysiology of blood sepsis syndrome in the setting of acute pseudomembranous colitis, there is in the literature mechanisms of Chatila and Manthous (12) that sepsis be by the inflammatory of severe The same authors also note that severe is at in to of by both C. difficile toxins A and as well as the to toxin A (71). The toxins then the via the ultimately to the of and the development of sepsis syndrome. the tract as a of toxins and When this is for in the setting of pseudomembranous colitis, it no such Involvement abscess The first report of C. difficile abscess was by and colleagues in In that patient, cultures of blood and fluid grew C. difficile, but there was no of abscess on CT At however, a abscess was in the upper of the cultures of the abscess grew C. difficile. In et al reported a case of C. difficile bacteremia with a polymicrobial Five months presentation, the patient had positive cultures for 4 species of Clostridium with a normal CT On the second hospital blood cultures were positive for C. difficile A CT scan revealed a of in the A was and a abscess was found of of the grew C. difficile and The patient did well on and metronidazole et al reported a patient who developed 2 after being admitted for with and with a segment of small bowel, a 10 abscess was and C. difficile was isolated in culture. of fluid were negative. The authors that abscess followed due to as a complication of and colleagues reported a case of a patient who was admitted to the intensive care because of a the the patient developed diarrhea and He had been treated with and revealed a abscess, by CT drained grew C. difficile and was used to the infection. A CT scan 4 later demonstrated that the abscess was drained and the patient but 2 months later from respiratory et al also reported a case of a patient treated The abscess was by and the was drained C. difficile toxin B was from cultured Thus, abscess may from bacteremia, or other events such as et al noted that patients with a history of bacteremia are at for developing In C. difficile bacteremia was from to months the manifestations of the abscess These cases that C. difficile be considered in the diagnosis of the cause of a abscess even at a time from a of pseudomembranous colitis abscess reported the only known case of C. difficile abscess in a patient with no antibiotic therapy or history of diarrhea. A man had fluid from a drained during and was demonstrated to have C. difficile. of the fluid was negative and blood cultures were not but the that the to the via the The patient was treated with and and The reported cases of visceral abscess are summarized in Table the available reported it be seen that such visceral are only clinically to months after the colonic Involvement The first 2 of C. difficile isolated from fluid were by Smith and King (64). They both in the first in a man with severe acute and and the second in a man with a and The authors that the likely source of infection was the respiratory they were unsure at that time of the pathologic significance of these et al reported a case of following in a C. difficile was the only following and after and no growth of They that the patient the resulting in an to multiple attempts at of the The patient to treatment with et al reported a case of a man who developed a effusion days after surgical of a from the upper of the left of the effusion were identified as C. difficile and C. The of C. difficile was noted to cytotoxin Syndrome arthritis is as the of an acute inflammatory following an at a from the source A of patients with reactive arthritis a of and as syndrome first described this in a soldier after an of diarrhea. The bacterial of reactive arthritis following infections are and In and described the first case of pseudomembranous colitis with arthritis, at that time it had not been that C. difficile the colitis. There are now reported cases of reactive arthritis to C. difficile infection. In and the following for C. difficile-induced reactive 1) of arthritis together with or following the of diarrhea colitis diarrhea time after a of antimicrobial therapy of C. difficile involvement positive stool culture or assay for no diagnosis for the arthritis or diarrhea is, no other identified The cases reported in the literature are summarized in Table the reported cases it be seen that the most commonly involved are the knee and the of The of reactive arthritis appears to on days after the of colonic The is with an of days is not Both patients positive for and not this may reactive the of this process is have been proposed in an to reactive arthritis following C. difficile infection. et al and et al found an it to be A) C. difficile toxin A in patients, that was not found in with C. difficile colitis The patients’ of arthritis with of this It was that arthritis in this setting from a to intestinal bacterial The of reactive arthritis with C. difficile also may be to that proposed for intestinal bypass syndrome et al found and during following or to intestinal were also bacterial in the Furthermore, there were 2 cases of that preceded the that may an of and that intestinal bacterial could to the via increased that could in a inflammatory They propose that C. difficile toxin and the of the both the bowel to become more bacterial to to the In of this, and that patients with have increased bowel and that when a patient who is positive an intestinal infection, the bowel bacterial to the this that joint inflammation be by increased intestinal in patients who are positive the absence of bacteremia or the isolation of C. difficile in blood or joint fluid cultures, involvement of the is as a of this of reactive arthritis is have a of joint fluid and nonsteroidal antiinflammatory therapy. has as being with of the of therapy is to the in these the colitis. and described the first case of by C. difficile in A man developed a that had been following a femur in a accident. were positive for C. difficile. therapy was to the patient A woman with cell who presented with 2 areas of was reported by et al in of the C. difficile. The patient was treated with and and et al described a case of to bacteremia with In et al described a case of a patient with cell who developed C. difficile of the Infection of of implanted prosthetic are surgical and medical management. When C. difficile prosthetic devices, the appears to be et al reported the case of a patient who developed C. difficile-associated diarrhea following and a The patient was treated with oral months later was for of the because of pain. An abscess with the was cultured and grew C. difficile. It was demonstrated to be the same as that from months earlier. et al reported a patient who had a of a with of a knee and months later the patient was with traumatic of his An with was performed and anaerobic culture pure growth of a The patient was treated with and but when the antibiotics were stopped 4 months later, the inflammation grew more severe and a The was cultured and the same Clostridium species as that isolated 5 months and was identified as C. difficile. The patient eventually et al a woman with a history of due to of the who was admitted to the hospital for of a cell months after was noted in her left and thigh. scanning white blood cell by abnormal white blood cell the left Pus was drained and culture C. difficile. cultures were but a stool was positive for C. difficile The patient eventually later of The authors of the first case that following treatment for with and the patient developed C. difficile-associated diarrhea. The diarrhea may have contaminated the skin of the and with spores of C. difficile. is similar to that proposed for the of cellulitis by C. the of the patient’s fractured the wound could have become contaminated with the spores or of C. difficile that were not by surgical and et al 2 mechanisms of as C. difficile may have spread from the tract to the with abscess Of note, patient demonstrated by the absence of and by an present The authors proposed that this may have to of bacteremia, and An is that the may have the joint via an in the of patients with C. difficile infections have noted the of cases of in this This has been to the of high of C. difficile In of this, the development of mental status changes in patients with C. difficile colitis therapy of the known colonic infection. However, of the of C. difficile in of the is in the literature. Cases of C. difficile colitis have been proposed to be related to the infant syndrome. et al reported 2 cases of infant syndrome with of C. difficile toxin in the patients’ Katner, Pankey, and colleagues (30) considered the of the 3-month-old patient in report to be related to the of C. difficile Clostridium difficile is most commonly with colonic infection. It however, also cause disease in a of other Small bowel involvement is with surgical on the small intestine and is with a mortality rate of 7 When with bacteremia, the infection is, as polymicrobial in with usual colonic flora. The mortality rate among patients with C. difficile bacteremia is 2 of 10 reported abscess the with 1 reported case of abscess these are only recognized to months after the of diarrhea or other colonic C. difficile-related reactive arthritis is in and is not related to the patient’s is not The most commonly involved are the knee and in of arthritis an of days after the of diarrhea and is a an of days to such as necrotizing and prosthetic also skin and infections traumatic the of or the patient’s C. difficile spores with the development of clinical infection. It is noteworthy that for cases involving the small intestine and reactive arthritis, most of the cases of extracolonic C. difficile disease not to be related to antibiotic The for this is We that clinicians will become more of these extracolonic manifestations of infection, that they may be recognized and treated and early diagnosis may also to prevent and patient and of hospital