Antibiotic associated diarrhea

Important members of this toxin family are Clostridium difficile toxins A and B, which are implicated in antibiotics-associated diarrhea and pseudomembranous colitis. The large clostridial cytotoxins are single-chain toxins with molecular masses of 250-308 kDa. The enzyme domain is located at the N terminus. The toxins are taken up from an acidic endosomal compartment. They glucosylate RhoA at Thr37 also, Rac and Cdc42 are substrates. Other members of this toxin family such as Clostridium sordellii lethal toxin possess a different substrate specificity and modify Rac but not Rho. In addition, Ras subfamily proteins (e.g., Ras, Ral, and Rap) are modified. As for C3, they are widely used as tools to study Rho functions [2] [4]. 

Repeated oral administration of an antibiotic that reaches very high concentrations within the GI lumen could have profound effects on intestinal flora [ 12,13]. As expected, rifaximin markedly reduced fecal bacterial counts during oral intake but the effect was short-lasting since the bacterial population recovered within 1-2 weeks from the end of treatment (table 4) [82], Most importantly, fungal colonization occurred very rarely. Indeed, Candida albicans, which has been implicated in the pathogenesis of antibiotic-associated diarrhea [82, 83], was isolated from the fecal samples of only 2 out of 10 patients given 1,200 mg of rifaximin daily [81] and in none of the volunteers taking 800 mg daily [82],... 

Surawicz CM Antibiotic-associated diarrhea and pseudomembranous colitis Are they less common with poorly absorbed antimicrobials Chemotherapy 2005 51(suppl 1 ) 81—89. 

Antibiotic-associated diarrhea Pseudomembranous colitis Clostridium difficile Rifaximin Clostridium difficile-assodated diarrhea... 

Diarrhea is a well-known complication of antibiotic therapy. Rates of antibiotic-associated diarrhea (AAD) vary from 5 to 25%. Some antibiotics are more likely to cause diarrhea than others, specifically, those that are broad spectrum and those that target anaerobic flora. This paper reviews the effects of antibiotics on the fecal flora as well as host factors which contribute to AAD. Clinical features and treatment of AAD are also described. Prevention of AAD rests on wise antibiotic policies, the use of probiotics and prevention of acquisition in the hospital setting. Data from clinical trials suggest that poorly absorbed antimicrobials might have a decreased risk of causing AAD and Clostridium difficile-associated disease, as concluded from studies of antibiotics used for preoperative bowel decontamination and poorly absorbed antibiotics used for traveler s diarrhea. Controlled trials would prove this but are not yet available. Probiotics may be a good adjunct to poorly absorbed antibiotics to minimize the risk of diarrhea associated with antibiotics. 

Bergogne-Berezin E Treatment and prevention of antibiotic associated diarrhea. Int J Antimicrob Agents 2000 16 521-526. 

Bartlett JG Antibiotic-associated diarrhea. Clin Infect Dis 1992 15 573-581. 

Surawicz CM, Elmer GW, Speelman P, McFarland LV, Chinn J, Van Belle G Prevention of antibiotic-associated diarrhea by Saccharo-myces boulardii. A prospective study. Gastroenterology 1989 96 981-998. 

Clausen MR, Bonnen H, Tvede M, Mortensen PB Colonic fermentation to short-chain fatty acids is decreased in antibiotic-associated diarrhea. Gastroenterology 1991 101 1497-1504. 

Krause R, Schwab E, Bachhiesl D, Daxbock F, Wenisch C, Krejs GJ, Reisinger EC Role of Candida in antibiotic-associated diarrhea. J Infect Dis 2001 184 1065-1069. 

McFarland LV Epidemiology, risk factors and treatments for antibiotic-associated diarrhea. Dig Dis 1998 16 292-307. 

Arvola T, Laiho K, Torkkeli S, Mykkanen H, Salminen S, Maunula L, Isolauri E Prophylactic Lactobacillus GG reduces antibiotic-associated diarrhea in children with respiratory infections A randomized study. Pediatrics 1999 104 e64. 

Probiotic bacteria for infectious and antibiotic-associated diarrhea... 

Adverse drug reactions can be classified simply according to their onset or severity. ADRs are occasionally classified as acute/ subacute/ or latent. Acute events are those observed within 60 minutes after the administration of a medication and include anaphylactic shock/ severe bronchoconstrictioii/ and nausea or vomiting (17). Subacute reactions occur within 1 to 24 hours and include maculopapular rasly serum sicknesS/ allergic vasculitiS/ and antibiotic-associated diarrhea or colitis. Latent reactions require 2 or more days to become apparent and include eczematous eruptions/ organ toxicity/ and tardive dyskinesia. 

Almost all antibacterial agents have been observed to cause diarrhea in a variable proportion of patients (114,115). The proportion depends not only on the antibiotic, but also on the clinical setting (in-patient/out-patient), age, race, and the definition of diarrhea. Severe colonic inflammation develops in a variable proportion of cases, and in some cases pseudomembranous colitis occurs (116-121). Since 1977, much evidence has accumulated that the most important causative agent in antibiotic-associated diarrhea is an anaerobic, Gram-positive, toxin-producing bacterium, C. difficile (122-124). 

Clostridium difficile has been isolated in 11-33% of patients with antibiotic-associated diarrhea, 60-75% of patients with antibiotic-associated colitis, and 96-100% of patients with pseudomembranous colitis (117,134,135). However, about 2% of the adult population are asymptomatic carriers (127). Primary symptomless colonization with C. difficile reduces the risk of antibiotic-associated diarrhea (136). Infants up to 2 years seem to be refractory to pseudomembranous colitis, although a high percentage may be carriers of C. difficile (135,137). The reasons for this are unknown. It has been speculated that infants lack receptors for the toxin. 

Therapy consists of withdrawal of the antibiotic when diarrhea occurs and replacement of fluid and electrolyte losses. In less severe cases of antibiotic-associated diarrhea, no further treatment is needed. However, in patients with pseudomembranous colitis, a more intensive approach is usually required. When a toxic syndrome develops, fluid losses within the bowel can be very large. In these cases, a central venous line offers the chance to measure central venous pressure. Usually there is also loss of serum proteins and in some cases blood, which need appropriate replacement. In the rare cases with fulminant colitis and toxic megacolon, surgical intervention may be necessary (165,166). 

The role of anion exchange resins (colestyramine and colestipol), which bind C. difficile toxin, is still controversial (172). If ion exchange resins are given at all, they should not be given together with vancomycin, because they also bind the antibiotic (173). Attempts to restore the intestinal flora with Lactobacillus GG (174), or with fecal enemas (175) from healthy volunteers have shown some favorable results in less severe cases. However, esthetic and infectious concerns may be an obstacle. It also has been suggested that treatment with Saccharomyces bou-lardii may help prevent the development of antibiotic-associated diarrhea (176). Its value in the prevention and treatment of relapses has still to be demonstrated. Antimotility agents have been associated with an increased incidence of antibiotic-related diarrhea and can worsen symptoms when the disease is already estab-hshed (177). They should therefore be avoided. 

Hogenauer C, Hammer HF, Krejs GJ, Reisinger EC. Mechanisms and management of antibiotic-associated diarrhea. Clin Infect Dis 1998 27(4) 702-10. 

The most prominent adverse reaction of the lincosamides is diarrhea, which varies from mildly loose bowel movements to life-threatening pseudomembranous colitis (see monograph on Beta-lactam antibiotics). Almost all antimicrobial drugs have been associated with severe diarrhea and colitis however, lincomycin and clindamycin have been particularly incriminated. The incidence of clindamycin-induced diarrhea in hospital is 23%. Diarrhea resolves promptly after withdrawal in most cases. It seems to be dose-related and may result from a direct action on the intestinal mucosa. Severe colitis due to C. difficile is not dose-related and occurs in 0.01-10% of recipients. Clustering of cases in time and place suggests the possibility of cross-infection. Even low doses of clindamycin, in some cases after topical administration, can cause marked alterations in several intestinal functions related to bowel flora (23). There was reduced susceptibility of C. difficile to clindamycin in 80% of French isolates in 1997 (24). Lincomycin was among the antibiotics that were most often associated with the development of antibiotic-associated diarrhea in a Turkish study of 154 patients other associated antibiotics were azithromycin and ampicillin (25). 

In a prospective study patients treated with antibiotics, including clindamycin, for 3 days had a significantly lower frequency of antibiotic-associated diarrhea than those treated for longer periods (28). 

Clindamycin can rarely cause antibiotic-associated diarrhea after short-term use as vaginal cream (33). 

Gorenek L, Dizer U, Besirbellioglu B, Eyigun CP, Hacibektasoglu A, Van Thiel DH. The diagnosis and treatment of Clostridium difficile in antibiotic-associated diarrhea. Hepatogastroenterology 1999 46(25) 343-8. 

Antibiotic-associated diarrhea can develop with any antibacterial agent. Vancomycin has been implicated as a rare cause of diarrhea associated with Clostridium difficile (56), despite the fact that vancomycin is often used to treat it. 

A few other cases of antibiotic-associated diarrhea with vancomycin have been described in association with C. difficile. This paradoxical association, although very uncommon, should be considered in patients who develop diarrhea during vancomycin therapy. 

Hnrley BW, Ngnyen CC. The spectrnm of psendomembra-nons enterocohtis and antibiotic-associated diarrhea. Arch Intern Med 2002 162(19) 2177-84. 

B Antibiotic-associated diarrhea due to C difficile can occur with any antibiotic, but particularly with clindamycin. With the administration of antibiotics, normal Gl flora is inhibited, which allows C. difficile to overgrow. Metronidazole is the treatment of choice for C. difficile infections. Although oral vancomycin also has activity against C. difficile, it is typically used as second-line treatment... 

Pseudomembranous colitis (PMC) was first reported in 1893 and was associated with antibiotic therapy in 1955. Although described in the preantibiotic era, the incidence increasingly has been associated with antibiotic administration. C. difficile is thought to be the cause in 10% to 20% of patients experiencing antibiotic-associated diarrhea, 50% to 75% of those with antibiotic-associated colitis, and greater than 90% of those with antibiotic-associated pseudomembranous colits. It is also the most common cause of nosocomial diarrhea, infecting 16% to 20% of inpatients, one-third of whom are symptomatic. ... 

C. difficile infection may cause a spectrmn of disease from mild antibiotic-associated diarrhea to pseudomembranous entercohtis. In cohtis without pseudomenbrane formation, patients present with malaise, abdominal pain, nausea, anorexia, watery diarrhea, low-grade fever, and leukocytosis. PMC is characterized by more severe illness, with severe abdominal pain, perfuse diarrhea, high fever, marked leukocytosis, and classic pseudomembrane formation evident with sigmoidoscopic examination. Symptoms can start a few days after the start of antibiotic therapy or several weeks after antibiotics have been discontinued. The onset of illness is often abrupt. 

Bacitracin is available in ophthalmic and dermatologic ointments the antibiotic also is available as a powder for the preparation of topical solutions. The ointments are applied directly to the involved surface one or more times daily. A number of topical preparations of bacitracin, to which neomycin or polymyxin or both have been added, are available, and some contain the three antibiotics plus hydrocortisone. For open infections such as infected eczema and infected dermal ulcers, the local application of the antibiotic may be of some help in eradicating sensitive bacteria. Bacitracin rarely produces hypersensitivity. Suppurative conjunctivitis and infected comeal ulcer respond well to the topical use of bacitracin when caused by susceptible bacteria. Bacitracin has been used with limited success for eradication of nasal carriage of staphylococci. Oral bacitracin has been used with some success for the treatment of antibiotic-associated diarrhea caused by C. difficile. Serious nephrotoxicity results from the parenteral use of bacitracin. Hypersensitivity reactions rarely result from topical application. 

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