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Correspondence: Sherwood L. Oxford Academic. Google Scholar. Cite Cite Sherwood L. Select Format Select format. Permissions Icon Permissions. Abstract In John Bartlett began trials investigating the problem of antibiotic-associated diarrhea and pseudomembranous colitis. Issue Section:.
Download all slides. The discovery of a disease goes through cycles, initiated by an astute clinical observation that is typically followed by paths of misadventure to, ultimately, the definitive discovery, which is supported by laboratory investigations and reinforced with bedside findings Table 1.
The first step in the discovery of pseudomembranous enterocolitis was the description by Finney, a surgeon, at Johns Hopkins Hospital in [ 1 ]. Finney's patient had undergone a gastroenterostomy for an ulcerated pylorus, did well during the first 10 days, but then developed bloody diarrhea and died 5 days later. Over the subsequent 50 years, several series and individual reports recounted a similar story. What clearly separates this case from the modern version of this illness— Clostridium difficile antibiotic-associated diarrhea CDAD —are the clinical setting of surgery and hypotension, the rapidly fatal outcome, and the involvement of both the small and large intestine.
Oddly, reenactments of Finney's original case and others with these characteristics have virtually disappeared from clinical practice during the past 70 years. In addition, the modern version of this illness brings in a new ingredient, prior exposure to antibiotics. By the s, cases of antibiotic-associated diarrhea and colitis, which were less severe than Finney's case and only occasionally involved pseudomembranes in the colon, emerged in our hospitals [ 2 ].
As an intern at Bellevue Hospital, it fell to me to perform Gram stains on the diarrheal stool of such patients. Of course, I often encountered gram-positive cocci that grew Staphylococcus aureus in culture.
It was not surprising in that era that this pathogen could be recovered in the fecal stream, because a high percentage of our patients had nasopharyngeal colonization with S. This intestinal illness could not be reproduced with staphylococci in animal models. In time, while the clinical condition persevered and became more common, its association with staphylococci fell into the dustbin of discarded diseases.
Other misdirections that went astray included subsequent efforts to implicate antibiotic-associated diarrhea and its extreme presentation, pseudomembranous colitis, with vascular insufficiency, and neonatal necrotizing enterocolitis, which were similarly unproductive. The link of diarrhea cases and colitis with antibiotics became apparent for me in with a publication in The Lancet of a series of 8 cases from New Zealand with 3 deaths, tying cases of pseudomembranous colitis to prior treatment with lincomycin [ 3 ].
The pathological course of this illness was a severe inflammatory process with and without pseudomembranes, which involved the large intestine but spared the small.
As I revisit the early history of the discovery of C. This was accomplished by demonstrating the pathological similarities, then the relationship to clindamycin exposure, and finally the beneficial effect of vancomycin treatment [ 4—6 ]. Not only was this model useful for encouraging studies on what was to become an effective treatment of this disease, but it set in motion the process of eventually identifying the causative microorganism, which was accomplished within 2 years of these initial studies.
It began with the discovery of a toxin-producing Clostridium in the cecum of infected hamsters. With direct inoculation of cecal contents from an infected hamster into tissue culture WI human lung fibroblasts as described by Chang et al [ 7 ], cytopathogenic effects were observed within 2 to 4 hours Figure 1.
He noted that these effects were prevented by an antitoxin that had been raised in horses in the late s from several species of Clostridium associated with gas gangrene.
Subsequent studies showed that the anti— Clostridium sordellii component of this complex antiserum was responsible for inhibiting the cytopathogenic effects.
The discovery of the cytotoxin assay was the breakthrough discovery that led to unraveling the Clostridium difficile toxin story, delineating its epidemiology, and identifying patients at risk see text for details. The role of toxin-producing Clostridium in this illness was illuminated in the definitive article published in The New England Journal of Medicine in [ 8 ], which noted that patients with pseudomembranous colitis had a positive cytotoxicity test from stool material, whereas those with uncomplicated antibiotic-associated diarrhea did not.
This strain did cross-react with C. At the onset, this disease was mislabeled as caused by C. However, this may represent antigenic cross-reactivity between clostridial toxins. Other clostridial species may cause this disease, but the weight of evidence strongly supports the pathogenic role of C. Besides forming the basis of the discovery of this pathogen, this observation led to the cytotoxicity assay in tissue culture [ 7 ], which became the basis of laboratory diagnosis of this infection for many years and is still used in some clinical laboratories.
Taylor et al [ 10 ] worked in the laboratory on the toxin identified in tissue culture, separating 2 toxins differing in biological activity and physical properties. This nomenclature has persevered, along with subsequent description of the second toxin, toxin B, and it spawned investigations that have opened up the chemistry and mode of action of these 2 toxins from C.
The relationship between antibiotics as therapy and inciting agents in CDAD was an early focus of Bartlett and his colleagues. Vancomycin proved to be highly effective in delaying death in the hamster model [ 6 ]. On the other hand, methylprednisolone showed disappointing outcomes [ 11 ], an observation that was later verified in patients. Dzink and Bartlett [ 12 ] published antimicrobial susceptibilities of C.
Besides the early association of lincomycin and its newer version, clindamycin, Bartlett et al [ 13 ] added cephalosporins to the list of implicated drugs, and opined that this class would become, as it has, a major predecessor to CDAD. Chang, on a trip to China, observed that bacitracin was being used empirically by Chinese physicians for antibiotic-associated diarrhea.
A small study in Boston showed that indeed bacitracin could be used as an alternative treatment for CDAD [ 14 ].
Although the drug was successful in patients with CDAD, it had a noxious taste and could not be used clinically. In another study, Bartlett and his colleagues described cases of pseudomembranous colitis with positive C.
Early on in this work, Bartlett established a close collaboration between laboratory investigations and bedside observations. Indeed, this interaction drove the research and produced many of its most important findings in both arenas.
Thus, he extended his vancomycin findings in hamsters to patients in an affiliation with Tedesco, and Tedesco et al [ 15 ] showed that this antibiotic was highly effective in treating patients with CDAD.
Bartlett also noted what was to become a major qualification in the usually good outcome of vancomycin treatment—the propensity to relapse. Studies of stools collected sequentially showed that vancomycin failed to eliminate C. This experience emphasizes the importance of adequate follow-up in patients treated with oral vancomycin for antibiotic-associated diarrhea or colitis due to C. The discovery of the cytotoxicity assay [ 7 ], the breakthrough component that led to unraveling the toxin story and the pathological events, laid the foundation for Bartlett's several studies of CDAD epidemiology and descriptions of the populations at risk for acquiring this infection.
He collaborated with several clinical groups to obtain fecal specimens in specific subpopulations to define their relationship to CDAD [ 17 ]. The survey among children revealed 13 toxin-positive stools among 45 healthy neonates who had not been exposed to antibiotics. The number of toxin-positive stools fell dramatically among the 4—month-old group. Among adults, the assay results were positive for C.
At the other end of the spectrum, CDAD was identified as a risk factor in elderly patients, an observation that has been verified and received much attention in recent years [ 19 ]. Since the late s, when Bartlett shifted his attention to human immunodeficiency virus HIV and other scientific interests, his output of articles on CDAD declined.
However, he and colleagues have recently published articles on the history of this disease [ 21 ], the incidence in persons with HIV infection [ 22 ], the importance of antimicrobial stewardship in preventing CDAD [ 23 ], modern methods of diagnosis [ 24 ], and new CDAD treatments [ 25 ].
Most recently, just before the announcement of this symposium, he published an article with colleagues, Dutta et al [ 26 ], on the newest twist in the CDAD labyrinth—fecal microbial transplantation. Although a great deal has been learned, major elements are still left in obscurity Table 3.
Visitors and hospital staff coming into the patient room will need to wear gloves and yellow gowns to prevent them from picking up C. Patients must wash their hands before they go to another part of the hospital for tests or treatments. Staff transferring the patient and helping with the tests also need to wear gowns and gloves, and wash their hands carefully.
Because C. Visitors mush wash their hands when they enter and leave the patient room. They must also put on yellow gowns and gloves when they enter the room. If any visitors are experiencing diarrhea, they should not visit the patient until they are better. Infection Control should also be notified of this immediately.
Patients will get better. Occasionally, the diarrhea can come back. If this happens, patients will need to be treated again. Once it is certain that the diarrhea will not reoccur, the C. The increase in incidence and severity of Clostridium difficile associated disease has been documented in US and UK surveillance systems. In Canada, the number of cases and deaths associated with C.
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