Clostridium difficile-associated diarrhea and colitis: clinical manifestations, diagnosis, and treatment

PURPOSE: This review examines the pathogenesis, clinical manifestations, diagnosis, and current medical and operative strategies in the treatment of Clostridium difficile diarrhea and colitis. Prevention and future avenues of research are also investigated. METHODS: A review of the literature was conducted with the use of MEDLINE. RESULTS: C. difficile is a gram-positive, spore-forming bacterium capable of causing toxigenic colitis in susceptible patients, usually those receiving antibiotics. Overgrowth of toxigenic strains may result in a spectrum of disease, including becoming an asymptomatic carrier, diarrhea, self-limited colitis, fulminant colitis, and toxic megacolon. Diagnosis requires a high index of suspicion and depends on clinical data, laboratory stool studies (enzyme-linked immunoabsorbent assay and cytotoxin test), and endoscopy in selected cases. Protocols for treatment of primary and relapsing infections are provided in algorithm format. Discontinuation of antibiotics may be enough to resolve symptoms. Medical management with oral metronidazole or vancomycin is the first-line therapy for those with symptomatic colitis. Teicoplanin, Saccharomyces spp. and Lactobacillus spp., and intravenous IgG antitoxin are reserved for more recalcitrant cases. Refractory or relapsing infections may require vancomycin given orally or other newer modalities. Fulminant colitis and toxic megacolon warrant subtotal colectomy. Cost, in terms of extended hospital stay, medical and surgical management, and, in some cases, ward closure, is thought to be formidable. Review of perioperative antibiotic policies and analysis of hospital formularies may contribute to prevention and decreased costs. CONCLUSION: C. difficile diarrhea and colitis is a nosocomial infection that may result in significant morbidity, mortality, and medical costs. Standard laboratory studies and endoscopic evaluation assist in the diagnosis of clinically suspicious cases. Appropriate perioperative antibiotic dosing, narrowing the antibiotic spectrum when treating infections, and discontinuing antibiotics at appropriate intervals prevent toxic sequelae.     

Colitis associated to chemotherapy with 5-fluorouracil

Antitumoral agents, especially when administered in combination, can induce pseudomembranous colitis, due to their antimitotic and antibacterial properties. Although patients given 5-fluorouracil frequently show nonspecific colitis or diarrhea without colitis, very few cases of proven pseudomembranous colitis have been described during 5-fluorouracil monotherapy. We describe the second case reported in the English literature of a typical pseudomembranous colitis occurring in a patient given 5-fluorouracil as a single antimitotic agent for colonic cancer. Intestinal injury was not preceded by antibiotic therapy. Although both stool and pseudomembrane culture did not yield C. difficile, oral vancomycin was started. This treatment led to a prompt improvement of intestinal symptoms and colitis was resolved in one week.     

Fluoride treatment for facial nerve stimulation caused by cochlear implants in otosclerosis

Clostridium difficile (C. difficile) pseudomembraneous colitis was diagnosed in a 13-year-old boy with Hodgkin's disease 3 months after autologous bone marrow transplantation. Hematopoiesis was fully reconstituted at the time. C. difficile infection occurred after gall bladder empyema had been treated conservatively with i.v. antibiotics and prophylactic 4-week administration of oral amoxicillin. C. difficile colitis was diagnosed early and intensive supportive therapy combined with administration of i.v. and subsequently oral vancomycin therapy failed. It is a phenomenon rarely seen and successful eradication of the clostridium infection was only achieved by a combination of higher dose vancomycin with metronidazole. During the post-colitis recovery the patient experienced a relapse of Hodgkin's disease and died following further surgical intervention 137 days post-transplantation.     

Clostridium difficile infections. Current aspects

Clostridium difficile is a gram-positive anaerobe that forms subterminal spores. It is now one of major nosocomial pathogens, mainly in older patients, because of its ability to persist in the environment and to become established in the gastrointestinal tract once the natural microflora has been modified by antibiotic therapy. Toxigenic strains of C. difficile produce toxin A (enterotoxin) or toxin B (cytotoxin) or both with cause the cytotoxic effect "rounding". C. difficile can spread from patient to patient and, probably, the primary way by which the organism is spread is by health care workers. C. difficile causes intestinal diseases ranging by mild diarrhea (antibiotic associated diarrhea) to fatal pseudomembranous colitis (PMC). The current therapy is based on oral administration of metronidazole or vancomycin . In patients non responders or that continue to relapse can be used other forms of therapy: antibiotic (teicoplanine, bacitracine, rifamixine); anion exchange resin (colestipol, colestiramine); probiotic therapy (S. boulardii, lactobacilli and fecal enemas). New and improved studies will lead to new and better ways of treating patients and better understanding of this unusual pathogen and how it causes diseases.     

Lipid metabolism in pregnancy. VIII. Effects of dietary fat versus carbohydrate on lipoprotein and hepatic lipids and tissue triglyceride lipases

From 1324 patients with antibiotic-associated diarrhea (AAD) 1643 stool samples were analyzed by a cell test for Clostridium difficile toxin in stool filtrates and cultivation for occurrence of C. difficile strains. In patients with no detectable toxin in their stool strains of C. difficile were isolated in 2.2% whereas when toxin was detectable, the isolation rate varied from 17% to 36%. Furthermore, there was a correlation between toxin titre in stool filtrate and production of cytotoxin in vitro by the corresponding C. difficile strains. Five clostridial strains, not belonging to the species C. difficile, were found to produce typical cytotoxin in vitro. However, five strains identified as C. difficile by biochemical reactions and gas liquid chromatography, did not produce an extracellular cytotoxin. The antibiotic susceptibility patterns of the Clostridium strains were investigated. No correlation was recognized between antibiotic resistance of isolated Clostridium strains and the AAD-inducing antibiotic penicillins and linco/clindamycin. Neither did cases of relapse of diarrheal disease after vancomycin treatment harbour C. difficile strains with increased resistance to vancomycin. It is concluded that the pathogenesis of antibiotic-associated enterocolitis is more complex than a mere intestinal overgrowth of resistant strains of C. difficile.     

Oral antimicrobial prophylaxis in bone marrow transplant recipients: randomized trial of ciprofloxacin versus ciprofloxacin-vancomycin

The optimal oral antimicrobial prophylactic regimen for bone marrow transplant recipients remains to be elucidated. We randomized 84 patients to receive either oral ciprofloxacin or ciprofloxacin plus vancomycin at hospital admission. Patients were monitored for bacteremias and clinical parameters, and stool and throat swab surveillance cultures were performed. The addition of vancomycin resulted in a significant decrease in the frequency of patients with surveillance cultures positive for coagulase-negative staphylococci (stool cultures, 44 versus 23%; throat swab cultures, 37 versus 19%) and alpha-hemolytic streptococci (throat swab cultures, 90 versus 60%). The frequencies of positivity for Candida spp. and gram-negative organisms on surveillance cultures were comparable. Despite these results, no differences in the incidences of bacteremias (12 of 41 versus 12 of 43 patients) or clinical parameters such as number of days to first fever, total number of febrile days, length of stay, and number of transfusions could be demonstrated. Because of a lack of efficacy of vancomycin and emerging problems with vancomycin-resistant isolates, vancomycin should not be used in oral antimicrobial prophylaxis regimens.     

Review article: antibiotic-induced Clostridium difficile infection

The great majority of cases of Clostridium difficile infection are hospital-acquired, and the reported incidence in England and Wales has increased sixfold between 1990 and 1993, with at least 17 patients dying in a recent large nosocomial outbreak. C. difficile infection accounts for an average 3-week increased length of stay in hospital. Acquisition of a toxigenic strain of Clostridium difficile may be followed by asymptomatic carriage, diarrhoea, colitis or pseudomembranous colitis. Antibiotic treatment and older age are major risk factors for the development of symptomatic disease, but less well-defined differences in strain virulence and host susceptibility are also probably important. Accurate data on the relative risks of different antibiotics to induce symptomatic C. difficile infection are scarce, but third-generation cephalosporins are frequently implicated. New kits are becoming available for the laboratory diagnosis of C. difficile infection but many of these lack sensitivity. Oral metronidazole or vancomycin are the main treatment options but avoidance of further antibiotics should also be encouraged where possible. The role of environmental C. difficile spores, which are highly resistant to conventional disinfectants, needs to be defined. Proven strategies for the prevention of C. difficile infection are required, in particular protocols to ensure that cross-infection does not occur.     

Etiological agents of infectious diarrhea: implications for requests for microbial culture

Gastrointestinal infections remain a frequent disease worldwide. In order to increase our knowledge of the epidemiology for our patient population, we retrospectively analyzed the results obtained for stool samples received at the clinical microbiology laboratory of the University Hospital of Geneva during a 4-year period. A total of 13,965 specimens from 7,124 patients (1.96 specimens per patient) were cultured, yielding 369 (2.6%) Salmonella spp., 408 (2.9%) Campylobacter spp., and 79 (0.6%) Shigella spp. The cumulative positivity rate of 6.1% decreased to 2.7% when patients received antimicrobial agents (P < 0.001). The positivity rate for 5,912 specimens obtained from patients hospitalized for < or = 3 days was 12.6%, whereas it dropped to 1.4% for patients hospitalized for > 3 days (P < 0.001). Of 3,837 stool samples originating from pediatric patients, 8.8% were positive, and 5.1% of 10,128 samples from adults were positive (P < 0.001). The cytotoxin of Clostridium difficile was detected in 379 of 3,723 samples analyzed (10.2%), and rotaviruses were detected in 190 of 1,601 samples (11.9%). We recommend that the use of cultures for enteric bacterial pathogens be restricted to patients hospitalized for < or = 3 days, with the exceptions of follow-up samples, specimens from immunocompromised patients, and patients whose first sample was culture negative or in the rare event of nosocomial food-borne outbreaks. For patients under antimicrobial therapy, testing for cytotoxin of C. difficile should primarily be requested; this analysis should also be accepted for samples from patients not receiving antimicrobial agents at the time of specimen collection. By applying these restrictions, we could have saved at least $5,000 annually.     

Contrast media enhanced magnetic resonance angiography for determining patency of a coronary bypass. A comparison with coronary angiography]

BACKGROUND: More data on the efficacy and safety of ciprofloxacin in pediatric cystic fibrosis patients are needed. METHODS: One hundred eight pediatric cystic fibrosis patients (ages 5 to 17 years) with acute bronchopulmonary exacerbations entered a randomized multicenter trial designed to compare the safety and efficacy of antipseudomonas therapy with oral ciprofloxacin (15 mg/kg twice daily; maximum dosage 750 mg twice daily) or intravenous ceftazidime plus tobramycin (CAZ/TM) for 14 days. RESULTS: Clinical improvement was observed in 93% of patients treated with oral ciprofloxacin and in 96% of those receiving parenteral therapy. Transient suppression of Pseudomonas aeruginosa was achieved in 63% of patients at the end of the course of iv CAZ/TM therapy and in 24% receiving ciprofloxacin. Ultrasound examination and nuclear magnetic resonance imaging scans showed no evidence of cartilage toxicity in any of the ciprofloxacin-treated patients. Musculoskeletal adverse events were reported with similar frequency in the two groups of patients (7% in the group receiving ciprofloxacin therapy and 11% in the IV CAZ/TM group). The only sustained musculoskeletal symptom was a case of synovitis in a patient receiving parenteral CAZ/TM. CONCLUSION: Ciprofloxacin thus appears to be safe and effective for use in young patients with bronchopulmonary exacerbation of cystic fibrosis.     

Critical enhancement of the in-medium nucleon-nucleon cross section at low temperatures

As part of an 18-month carcinogenicity study, 680 Syrian hamsters (Mesocricetus auratus) received daily gavage doses of fenazaquin, an experimental miticide. Mortality associated with severe enteritis was noticed beginning when the hamsters were 4 months old and ranged from one to five deaths per month until the hamsters were about 10 months old, when 41 deaths occurred in a 1-month period. Ante- and postmortem findings were consistent with those reported for antibiotic-induced enteritis in hamsters. Clostridium difficile was isolated from 12 of the 13 samples of cecal contents analyzed. Toxin assays of C. difficile isolates collected from 11 affected animals were positive for both cyto- and enterotoxins. Daily oral administration of vancomycin hydrochloride at a dose of 20 mg/kg was initiated when the hamsters were about 10 months old. Deaths due to C. difficile enteritis were significantly decreased within 2 weeks, and treatment was continued for 3 months. A trial withdrawal period for a subset of 64 hamsters (approximately 16% of the total population) was initiated to evaluate survival after discontinuation of the antibiotic treatment. Clostridium difficile enteritis recurred within 2 weeks and caused 19 deaths during the next month; therefore, these hamsters were returned to daily vancomycin treatment for the remainder of the study. With the exception of severe gaseous distention of the ceca, which caused death in 17 (< 4% of the total population) of the affected hamsters, vancomycin treatment did not cause any major adverse effects.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pseudomonas aeruginosa as a cause of infectious diarrhoea

Pseudomonas aeruginosa is not generally considered a cause of infectious diarrhoea. However, it was the predominant organism isolated from the faeces of 23 unrelated, hospital outpatients investigated in the course of a year for persistent (> 1 week duration) diarrhoea. To investigate the possible aetiological role of P. aeruginosa, these patient histories were reviewed and a selection of their faecal isolates were investigated in vitro (n > or = 10) and in vivo (n = 2) for virulence. The patients had a mean age of 60 years, were receiving antibiotics and/or had an underlying illness. Extensive microbiological investigations identified no other potential or recognized enteropathogen in the faeces of 20 of these patients. More than 40% of the isolates tested were able to adhere to HEp-2 cells and exhibited twitching motility (type IV pili), properties indicative of their ability to colonize the human intestine. Cytotoxic activity was demonstrated in bacterium-free cell supernatants of over 80% of isolates; supernatants of four isolates tested in infant mice were weakly enterotoxigenic. Two isolates intragastrically inoculated into clindamycin pre-treated rats established persistent infections and induced signs and symptoms of enteritis. Overall these findings suggest that P. aeruginosa can cause diarrhoea particularly in immunodeficient individuals.     

Review article: treatment of Clostridium difficile infection

AIM: A systematic review of controlled trials of therapy of Clostridium difficile intestinal infection using methodology described by the Cochrane Collaboration. METHODS: Trials were identified by searching computer databases over the years 1978-1996. Trials were included if they were (a) prospective randomized, controlled trials and (b) included patients with symptomatic disease. The primary end-point was clinical resolution of diarrhoea. Secondary end-points were clinical relapse and stool clearance of C. difficile and C. difficile toxin. RESULTS: Nine trials (469 patients) satisfying the inclusion criteria were identified. Two trials were placebo controlled. Six trials compared vancomycin to other antibiotics (fusidic acid, bacitracin, teicoplanin and metronidazole). For clinical resolution response rates ranged from 21 (placebo) to 100% (vancomycin). On pooling the trials, no antibiotic showed clear therapeutic superiority. Rates of clinical relapse ranged from 5 to 42%. Only one trial showed significant advantage of one antibiotic over another for prevention of relapse (teicoplanin vs. fusidic acid). CONCLUSION: The published data are limited, and further studies are required.     

Levofloxacin versus ciprofloxacin, flucloxacillin, or vancomycin for treatment of experimental endocarditis due to methicillin-susceptible or -resistant Staphylococcus aureus

Levofloxacin is the L isomer of ofloxacin, a racemic mixture in which the L stereochemical form carries the antimicrobial activity. Levofloxacin is more active than former quinolones against gram-positive bacteria, making it potentially useful against such pathogens. In this study, levofloxacin was compared to ciprofloxacin, flucloxacillin, and vancomycin for the treatment of experimental endocarditis due to two methicillin-susceptible Staphylococcus aureus (MSSA) and two methicillin-resistant S. aureus (MRSA) isolates. The four test organisms were susceptible to ciprofloxacin, the levofloxacin MICs for the organisms were low (0.12 to 0.25 mg/liter), and the organisms were killed in vitro by drug concentrations simulating both the peak and trough levels achieved in human serum (5 and 0.5 mg/liter, respectively) during levofloxacin therapy. Rats with aortic endocarditis were treated for 3 days. Antibiotics were injected with a programmable pump to simulate the kinetics of either levofloxacin (350 mg orally once a day), ciprofloxacin (750 mg orally twice a day), flucloxacillin (2 g intravenously four times a day), or vancomycin (1 g intravenously twice a day). Levofloxacin tended to be superior to ciprofloxacin in therapeutic experiments (P = 0.08). More importantly, levofloxacin did not select for resistance in the animals, in contrast to ciprofloxacin. The lower propensity of levofloxacin than ciprofloxacin to select for quinolone resistance was also clearly demonstrated in vitro. Finally, the effectiveness of this simulation of oral levofloxacin therapy was at least equivalent to that of standard treatment for MSSA or MRSA endocarditis with either flucloxacillin or vancomycin. This is noteworthy, because oral antibiotics are not expected to succeed in the treatment of severe staphylococcal infections. These good results obtained with animals suggest that levofloxacin might deserve consideration for further study in the treatment of infections due to ciprofloxacin-susceptible staphylococci in humans.     

Infection due to Clostridium difficile among elderly residents of a long-term-care facility

In a study of the epidemiology of infection due to Clostridium difficile at long-term-care facilities, we conducted point-prevalence surveys and obtained stool samples from residents receiving antibiotics and from those developing diarrhea during 1 year at a 350-bed nursing home and an adjoining 280-bed chronic-care hospital. C. difficile and/or its cytotoxin was detected in 236 specimens from 94 residents. Only 16 (17%) of these 94 individuals had diarrhea at the time C. difficile was detected. The prevalence of C. difficile infection ranged from 2.1% to 8.1% in the nursing home and from 7.1% to 14.7% in the hospital. The organism was recovered from six (8.8%) of 68 residents receiving antibiotics, and four of the six developed antibiotic-associated diarrhea. The receipt of antibiotic treatment within the previous 8 weeks (odds ratio [OR], 7.9), the presence of a nasogastric or gastrostomy feeding tube (OR, 6.5), urinary and fecal incontinence (OR, 2.5), and the presence of more than three underlying diseases (OR, 2.0) were statistically significant independent variables associated with C. difficile infection. Typing of isolates by restriction-endonuclease analysis indicated that most C. difficile infections at this long-term-care facility were associated with endogenous enteric carriage of the organism, with little evidence of cross-infection.     

Laparoscopic resection of a benign true cyst of the spleen with the harmonic scalpel producing high levels of CA 19-9 and carcinoembryonic antigen

BACKGROUND: Oral ingestion of immunoglobulins in humans has been shown to be effective as prophylaxis against enteric infections. However, its therapeutic effect in children with infectious diarrhea has hitherto not been proven. We treated children with rotavirus diarrhea with immunoglobulins extracted from immunized bovine colostrum (IIBC) containing high titers of antibodies against four rotavirus serotypes. METHODS: In this double blind placebo-controlled trial, 80 children with rotavirus diarrhea were randomly assigned to receive orally either 10 g of IIBC (containing 3.6 g of antirotavirus antibodies) daily for 4 days or the same amount of a placebo preparation. The daily stool output (grams/kg/day), intake of oral rehydration solution (ml/kg/day), stool frequency (number of stools/day) and presence of rotavirus in stool were monitored for the 4 days during treatment. RESULTS: Children who received IIBC had significantly less daily and total stool output and stool frequency and required a smaller amount of oral rehydration solution than did children who received placebo (P < 0.05). Clearance of rotavirus from the stool was also earlier in the IIBC group compared with the placebo group (mean day, 1.5 vs. 2.9, P < 0.001). No adverse reactions from the colostrum treatment were observed. CONCLUSIONS: Treatment with antirotavirus immunoglobulin of bovine colostral origin is effective in the management of children with acute rotavirus diarrhea.     

Association of Clostridium difficile with enterocolitis and lactose intolerance in a foal

Diagnoses of Clostridium difficile enterocolitis and lactose intolerance were made in a neonatal foal with persistent diarrhea. It was determined that the foal had lactose intolerance on the basis of the results of a lactose tolerance test, and a diagnosis of C difficile enterocolitis was subsequently made. The foal responded to oral administration of metronidazole and lactase. Lactose intolerance is a secondary problem most commonly associated with rotavirus infection, but it can be caused by any condition affecting the small intestine. Because C difficile can affect the small intestine in foals, it was presumably the cause of the lactose intolerance in this foal with persistent diarrhea. Oral administration of lactase was not initially successful in this foal, most likely because of ongoing C difficile enterocolitis. Presumably, metronidazole was an effective treatment for C difficile enterocolitis and administration of lactase allowed for normal digestion of milk until endogenous lactose production returned. Clostridium difficile enterocolitis and lactose intolerance should be considered as differential diagnoses in neonatal foals with diarrhea, especially when the foal is bright and alert.     

Chimeric brains generated by intraventricular transplantation of fetal human brain cells into embryonic rats

OBJECTIVE: To determine whether bacterial stool cultures (BSC) are useful in initial evaluation of children with symptoms of nosocomial diarrhea. To answer this question we performed a retrospective record review to determine the yield of BSC in children who developed diarrhea after the third hospital day (HD-3). METHODS: The hospital computer record keeping system was utilized to compile the result of BSC collected from children and adolescents ages 0 to 20 years between January 1, 1988, and October 31, 1996. All specimens were analyzed for Salmonella, Shigella, Yersinia and Campylobacter. We reviewed hospital charts of all children who developed a positive BSC beyond HD-3 to determine the time of onset of diarrhea and clinical circumstances. RESULTS: A total of 11 516 BSCs were submitted from 9262 children during the 8 1/2-year period. Five hundred sixty-eight (6.6%) of 9262 children had at least 1 positive BSC. Two thousand five hundred seventy-two children had the first BSC submitted after HD-3 and 13 (0.5%) of these children had a positive result. Chart review of these 13 children demonstrated that 6 had onset of diarrhea during the first 3 hospital days. Therefore only 7 children met our criteria for having nosocomially acquired diarrhea caused by a bacterial pathogen. Children whose first BSC was submitted after HD-3 accounted for 3767 (46%) of the total 8126 inpatient BSCs and in excess of $21000 annually in patient billing charges. CONCLUSION: In the absence of a known exposure the isolation of a bacterial pathogen from the stool of children with onset of diarrhea beyond HD-3 is a rare event. Under most circumstances BSC should not be part of the initial evaluation of children with symptoms of nosocomial diarrhea.     

Clostridium difficile and older adults: what primary care providers should know

Clostridium difficile poses particular risk for older adults, who are subject to more serious symptoms than younger patients. Antibiotic exposure and other risk factors are associated with the pathogenesis of C. difficile-associated disease. Treatment goals include prescribing anti-C. difficile activity agents (when indicated), attending to volume status and prescribing oral rehydration therapy as needed, avoiding the use of antiperistaltic drugs, discontinuing any offending antibiotics, avoiding the indiscriminate use of broad-spectrum antibiotics, providing supportive therapy, following infection control protocols, and eliminating environmental contaminants.     

Atypical presentation of Clostridium difficile colitis in patients with cystic fibrosis

OBJECTIVE: This report describes the unusual presentation of Clostridium difficile colitis in five patients with cystic fibrosis and the role of CT in first suggesting the correct diagnosis in this group of patients. Because of the absence of watery diarrhea and the presence of abdominal bloating and decreased stooling, cystic fibrosis patients with C. difficile colitis will be treated for stool impaction, meconium ileus equivalent, or distal intestinal obstruction syndrome. CT of the abdomen, performed in these five patients because of their lack of improvement after standard therapy for stool impaction, showed an extensive pancolitis later confirmed to be caused by C. difficile infection. CONCLUSION: In patients with cystic fibrosis, imaging findings of a pancolitis should raise the possibility of C. difficile colitis despite the lack of watery diarrhea. Anticlostridial treatment can be initiated before bacteriologic confirmation is obtained.     

Artificial light and early-life exposure in age-related macular degeneration and in cataractogenic phototoxicity

Cryptosporidium has received increasing attention as a pathogen in normal as well as immunocompromised persons. We report a case of cryptosporidiosis occurred in a 18-months-old-girl who was treated with spiramycin for 8 days with complete resolution of diarrhea within the first days of therapy; follow-up stool examination was negative for the protozoan. The incidence of diarrhea due to Cryptosporidium seems to be higher than it was reported before: so fecal samples, when negative for other etiological agents, should be examined for Cryptosporidium oocysts. Spiramycin seems to be an effective and well-tolerated drug: treatment is recommended in children with prolonged and/or severe diarrhea when Cryptosporidium seems to be the etiological cause of the disease.