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Infectious diarrhoea
Infection
Infectious diarrhoea
which has a mortality of 1–2% and a relatively high incidence of serious complications such as the haemolytic-uraemic syndrome.2 The increase in foreign travel has further contributed to the importance of infectious diarrhoea in the industrialized world (Figure 1),3 as has the increasing use of broad-spectrum antibiotics and associated antibiotic-related diarrhoea due to Clostridium difficile.
Michael J G Farthing Paul Kelly
Epidemiology The key reservoirs of human enteropathogens are food, water and other humans. Certain human infective agents are carried by animals giving rise to conditions known as zoonoses (such as sal monellosis, campylobacteriosis, giardiasis and cryptosporidiosis). Domestic water supplies, swimming pools, sea water and inland freshwater lakes and rivers also harbour enteropathogens. Faecal–oral transmission is the main route by which these infections are spread and may occur either through ingestion of contaminated food or fluids or by direct person-to-person con tact. The latter is particularly important when only small infec tive doses are required to initiate infection, such as in shigellosis. V. cholerae and other non-cholera vibrios are transmitted by con taminated water, shellfish and other seafood and by person-toperson contact. Foodborne infection, so-called ‘food poisoning’, may be due to true infection of the intestine or related to the ingestion of a pre-formed toxin (Table 1). Intimate sexual contact, notably oro-anal sex, is commonly associated with transmission of enteropathogens. Viruses, such as the norovirus (previously known as small round structured viruses of the Norwalk family), can be spread by aerosol, espe cially as vomiting is an important early symptom of the illness. This probably explains why this infection spreads so rapidly through cruise ships, hotels and hospital wards. Immunodeficiency and reduced gastric acid secretion are well recognized risk factors for intestinal infections.
Abstract Infectious diarrhoea remains a major cause of morbidity and mortality world wide. Viruses, bacteria and protozoa are responsible for the majority of infections which are transmitted most commonly by the faecal-oral route through water, food and person-to-person transmission. Clinical presentation of infectious diarrhoea conforms to three patterns, namely acute watery diarrhoes, dysentery and persistent diarrhoea sometimes with the features of steatorrhoea. Diagnosis still rests heavily on stool microscopy and culture although faecal antigen tests and DNA based assays are under evaluation. Oral rehydration therapy continues to be the most important supportive intervention, particularly in acute watery diarrhoea when death from dehydration and acidosis can be prevented in the vast majority of sufferers. There have been some important advances in the development of new approaches to antibiotic therapy. The non-absorbable antibiotic rifaximin is highly effective in the treatment of traveller’s diarrhoea and is free from the majority of side effects that are associated with systemically absorbed antibiotics. The broadspectrum antimicrobial nitazoxanide has made a major impact on the treatment of cryptosporidiosis but is also effective in giardiasis, amoebiasis and C. difficile infection. Recent evidence suggests that probiotics and prebiotics are effective in the treatment and prevention of a variety of intestinal infections.
Keywords antibiotics; anti-diarrhoeal agents; bacteria; diarrhoea, enteropathogens; probiotics; protozoa; viruses
Spectrum and estimated prevalence of enteropathogens responsible for travellers’ diarrhoea
Infections of the gastrointestinal tract are the most common intestinal disorders. They have their major impact in the develop ing world and are still responsible for the deaths of up to 2–3 million pre-school children each year. Despite industrializa tion, wealth and public health interventions to ensure water quality and sewage disposal, intestinal infections have a major impact in the Western world, including both foodborne (Salmonella spp. and Campylobacter spp.) and waterborne infections (Cryptosporidium parvum and Giardia intestinalis).1 Infectious colitis is an increasingly important condition due to Salmonella spp., Campylobacter jejuni and enterohaemorrhagic E. coli (EHEC) infection
40%
10% 3%
22% 5% 5%
5%
Enterotoxigenic Escherichia coli Michael J G Farthing DSc (Med) MD FRCP FMedSci is Professor of Medicine at St George’s, University of London, London, UK. Competing interests: none declared. Paul Kelly MD FRCP is Reader in Tropical Gastroenterology at St Bart’s and the London School of Medicine, London, UK. Competing interests: none declared.
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10%
Salmonella spp. Aeromonas/ Plesiomonas spp.
Shigella spp. and enterohaemorrhagic Escherichia coli
Protozoa
Campylobacter jejuni
No pathogen isolated
Viruses
Figure 1
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Infection
incubation period and on average lasts 3–5 days. Watery diarrhoea is often accompanied by anorexia, nausea, vomiting, abdominal cramps, bloating and low-grade fever. In adults, severe dehydra tion is uncommon although this may become clinically important in infants, young children and the elderly. Mild cholera may be indistinguishable from other agents that produce acute watery diarrhoea. However, when severe, diarrhoea begins abruptly, with stool volume rates of up to 1 litre per hour.
Microbial pathogens responsible for foodborne diarrhoeal disease Organism
Incubation period (hours)
Recovery
Salmonella spp. Campylobacter jejuni Enterohaemorrhagic Escherichia coli Vibrio parahaemolyticus Yersinia enterocolitica Clostridium perfringens
12–48 48–168 24–168
2–14 days 7–21 days 7–21 days
2–48 2–144 8–22
2–30 days 1–3 days 1–3 days
2–6 1–2 18–36
few hours few hours 10–14 days
Pre-formed toxins Staphylococcus aureus Bacillus cereus Clostridium botulinum
Bloody diarrhoea, dysentery and colitis The organisms responsible for acute bloody diarrhoea are the invasive bacterial enteropathogens (Shigella spp., Salmonella spp. Campylobacter jejuni and EHEC) and the protozoan Entamoeba histolytica. There is often a prodromal illness of low-grade fever, headache, anorexia and lassitude. Incubation period is variable but can range from 1 to 7 days. Following an initial period of watery diarrhoea, stool volume may actually decrease with the appearance of blood and mucus in the stools. Moderate or severe, cramping lower abdominal pain is an important feature of a dysenteric illness, as is tenesmus and rectal prolapse, partic ularly in children with shigellosis. There may be fever and mild abdominal distension with some tenderness over the colon. Clinically it can be difficult to distinguish acute infectious coli tis from non-specific inflammatory bowel disease. Any form of severe colitis can give rise to abdominal tenderness, distension and, in some cases, reduced bowel sounds due to ileus. Procto sigmoidsocopy should form part of the initial clinical assessment and may confirm the presence of colitis.
Table 1
Causes Infective diarrhoea presents in a variety of ways, the recognition of which may assist clinical diagnosis and early management. The three major patterns are: • acute watery diarrhoea • bloody diarrhoea (dysentery), usually due to an infective enterocolitis • persistent diarrhoea, sometimes with steatorrhoea and evidence of an enteropathy. The major organisms responsible for these clinical syndromes are summarized in Table 2. However, there is considerable over lap between these clinical patterns with some organisms (such as Shigella spp. and Campylobacter jejuni) presenting initially as acute watery diarrhoea but then progressing to a dysenteric ill ness with fever and bloody diarrhoea. Similarly, giardiasis may start as acute watery diarrhoea but eventually become persistent with features of malabsorption.
Persistent diarrhoea In adults, G. intestinalis is the most common cause of per sistent diarrhoea, often associated with anorexia, abdominal bloating, substantial weight loss and overt steatorrhoea. The other intracellular protozoa are also relatively common causes of persistent diarrhoea, particularly in the immunocomprised (C. parvum, microsporidia, Cyclospora and Isospora). In chil dren, enteropathogenic E. coli (EPEC) is an important organ ism to consider. Any cause of persistent diarrhoea in infants and young children can result in failure to thrive and growth retardation. Strongyloides stercoralis infection may also cause chronic diarrhoea and malabsorption although this is more common in the hyper-infection syndrome.
Clinical presentation Acute watery diarrhoea Rotavirus infection, the most common cause of acute diarrhoea in infants and young children, is often preceded by a brief pro dromal illness with fever and mild respiratory symptoms, which is followed by vomiting and diarrhoea. If fluid and electrolyte losses are not replaced promptly then dehydration and metabolic acidosis soon follow. The degree of dehydration can be assessed clinically by noting skin tone and tissue turgor, dryness of mucous membranes, intra-ocular tension and, in young infants, depression of the anterior fontanelle. As the degree of dehydration increases, there is impairment of consciousness, ultimately leading to stupor and coma. Typically, the illness lasts about 7 days. Adenovirus is a more prolonged illness with pronounced respiratory symptoms. Acute watery diarrhoea in adults is usually bacterial in origin, most commonly due to enterotoxigenic E. coli (ETEC) in travellers or one of the foodborne pathogens in the indigenous population of industrialized countries. ETEC usually begins after a short
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Diagnosis Although the majority of episodes of acute infective diarrhoea resolve without the need for identifying a specific aetiological agent, persistent diarrhoea and bloody diarrhoea always require further investigation. It is particularly important in severely ill patients when delay in starting appropriate treatment might significantly alter the outcome. Confident exclusion of an infec tive aetiology is rarely achieved in less than 24–48 hours and, although imprecise, clinical assessment is important for guid ing management during this early phase of the illness. Rou tine laboratory investigations are of limited diagnostic value as anaemia, a raised neutrophil count and evidence of an inflamma tory process with a raised erythrocyte sedimentation rate (ESR), C-reactive protein and platelet count occur in infective colitis and non-specific inflammatory bowel disease. The cornerstone of 252
© 2007 Elsevier Ltd. All rights reserved.
Infection
Causes of infectious diarrhoea by clinical pattern Enteropathogen
Acute watery diarrhoea
Dysentery
Persistent diarrhoea
Viruses Rotavirus Enteric adenovirus (types 40, 41) Norovirus and other SRSV’s Calicivirus Astrovirus Cytomegalovirus
+ + + + + +
− − − − − +
− − − − − +
Bacteria Vibrio cholerae and other vibrios Enterotoxigenic Escherichia coli (ETEC) Enteropathogenic E. coli (EPEC) Enteroaggregative E. coli (EAEC) Enteroinavsive E. coli (EIEC) Enterohaemorraghic E. coli (EHEC) Shigella spp. Salmonella spp. Campylobacter spp. Yersinia spp. Clostridium difficile Mycobacterium tuberculosis
+ + + + + + + + + + + −
− − − − + + + + + + + +
− − + + − − + + + + + +
Protozoa Giardia intestinalis Cryptosporidium parvum Microsporidia Isospora belli Cyclospora cayetanensis Entamoeba histolytica Balantidium coli
+ + + + + + +
− − − − − + +
+ + + + + + +
Helminths Strongyloides stercoralis Schistosoma spp.
− −
− +
+ +
Table 2
evidence-based management is identification of the aetiological agent which ultimately relies on stool microscopy and culture. Serology is of limited value in the diagnosis of intestinal infection. However, in amoebic colitis, serology is positive in 80–90% of patients and serology can detect Yersinia enterocolitica infection although results are not usually positive for at least 10–14 days after the onset of the illness. Antibody ELISAs are now avail able for the diagnosis of strongyloidiasis and schistosomiasis and should be regarded as first-line screening tests for travellers returning from endemic areas.
Recent evidence suggests that a single dose of ondansetron, the 5-HT3 receptor antagonist, reduces vomiting and is a useful adjunct to rehydration therapy in childen.4 In severe dehydra tion in infants and young children, intravenous rehydration is mandatory. Food should be commenced as soon as the individual wishes to eat and drink normally. Breastfeeding should be con tinued in infants. In most cases in adults, a formal ORS is usually not required but it is recommended that they should increase oral fluids, such as salty soups (sodium), fruit juices (potassium) and take carbohydrates (salty crackers, rice, bread, pasta, potatoes) to provide glucose for the glucose–sodium co-transport.
Treatment
Anti-diarrhoeal therapy The most commonly used anti-motility agent is loperamide.5 The efficacy of loperamide is probably most effective when combined with an antibiotic.6 Anti-motility agents are not recommended for children and young infants due to concerns about respira tory depression. An important advance in anti-diarrhoeal ther apy has been the development of an enkephalinase inhibitor,
Fluid and electrolyte replacement Oral fluid and electrolyte replacement is usually effective except when losses are very severe or there is associated profound vomiting. Dehydration occurs more quickly in infants and young children and therefore early administration of an oral rehydration solution (ORS) is advised to prevent dehydration and acidosis.
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r acecadotril, which has pro-absorptive activity because of its abil ity to potentiate endogenous enkephalins in the intestine. This is an effective agent for reducing stool weight and bowel frequency, it can be safely used in children and does not cause rebound constipation, which can be a problem with anti-motility agents.7
recommended, these include dysenteric shigellosis, cholera, pseudomembranous colitis, and some protozoal infections. There are several diseases in which the indications are less clear, but treatment is usually recommended, such as infection with the noncholera vibrios, prolonged or protracted infection with yersinia, early in the course of campylobacteriosis, aeromonas and plesi omonas infections, and outbreaks of EPEC diarrhoea in nurseries. Patients should be treated if they are debilitated, particularly with malignancy, immunosuppressed, have an abnormal cardiovascular system, have valvular, vascular, or orthopaedic prostheses, have
Antimicrobial therapy Antibiotic therapy for infectious diarrhoea is controversial (Table 3).8–16 Mild illnesses probably do not need antibiotic treatment, although there are infections in which treatment is
Antimicrobial therapy for acute infectious diarrhoea Organism
Efficacy of antimicrobial therapy Drug of choice
Alternative choice
Bacteria Vibrio cholerae
Proven
Tetracycline 500 mg qds 3 days, ciprofloxacin 1000 mg single dose
Enterotoxigenic Escherichia coli (ETEC) Enteropathogenic E. coli (EPEC) Enteroinvasive E. coli (EIEC) Enterohemorrhagic E. coli (EHEC) Shigella sp
Proven
Ciprofloxacin 500 mg bd 3–5 days, norfloxacin 400 mg bd 3–5 days
Trimethoprim-sulfamethoxazole (TMP-SMX), doxycyline, norfloxacin, ciprofloxacin 3 days Ciprofloxacin 500 mg single dose
Salmonella sp
Doubtful efficacy in enterocolitis, proven efficacy in severe salmonellosis (dysentery, fever) Possible efficacy in campylobacter enteritis, proven efficacy in campylobacter dysentery/sepsis Doubtful efficacy in Yersinia enteritis, proven efficacy in Yersinia septicaemia Proven
Campylobacter sp
Yersinia sp
Clostridium difficile Protozoa Giardia intestinalis Cryptosporidium parvum Isospora belli Cyclospora cayetanensis Encephalitozoon intestinalis Enterocytozoon bieneusi Entamoeba histolytica
Balantidium coli
Possible Possible Probably harmful
? same as Shigella spp. Possibly fluoroquinolone
Proven efficacy in dysenteric shigellosis
TMP-SMX* 2 tabs bd 5 days, ciprofloxacin 500 mg bd 5 day, other quinolones – norfloxacin, fleroxacin, cinoxacin Ciprofloxacin 500 mg bd 10–14 days, third generation cephalosporins 10–14 days. Carrier state: Norfloxacin 400 mg bd 28 days Erythromycin 250–500 mg qds 7 days
Short-term quinolone Cefixime 400 mg daily 5–7 days OR other third generation ephalosporins, nalidixic acid 1g qds 5–7 days TMP-SMX, ampicillin, amoxycillin
Ciprofloxacin 500 mg bd 7–10 days
Tetracycline 250 mg qds 7–10 days
Metronidazole 400 mg tds 7–10 days
Vancomycin 125 mg qds 7–10 days, fusidic acid, teicoplanin
Metronidazole 400 mg tds 7–10 days Nitazoxanide 500 mg bd 3–14 days TMP-SMX 2 tabs qds 10 days TMP-SMX 2 tabs bd 7 days Albendazole 400 mg bd 4 weeks, fumagillin 60 mg 14 days Metronidazole 750 mg tds 5 days, diloxanide furoate 500 mg tds 10 days Metronidazole 400 mg tds 10 days
Tinidazole 2g single dose Paromomycin 500 mg qds 7–10 days
Proven Proven Proven Proven Proven Proven
Proven
Ciprofloxacin 500 mg bd 5–7 days, azithromycin 500 mg od 3 days
Paromomycin 25–35 mg/kg tds 7–10 days Tetracycline 500 mg qds 10 days
*TMP-SMX of limited value because of resistance patterns.
Table 3
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haemolytic anaemia (especially if salmonellosis is involved), or are extremely young or old. Treatment is also advised for those with prolonged symptoms and those who relapse.
Vaccines Although parenteral vaccines for cholera and typhoid have been available for many years their efficacy is low. The major thrust of vaccine development in recent years has focused on oral vac cines to ensure that there is the capacity for a local protective immune response in the gut. A whole cell-B subunit oral cholera vaccine has been subjected to extensive field trials and shown to be moderately effective. More recently, a genetically engineered live oral cholera vaccine has been developed which appears to be as effective after a single dose. These cholera vaccines also have some protective effects against travellers’ diarrhoea caused by other organisms and the whole cell-B subunit vaccine is currently marketed in some countries for travellers’ diarrhoea. Although initial attempts to develop vaccines against rotavirus infection were seriously curtailed by the occurrence of intussus ception, two new vaccines have been demonstrated to be safe and are now available. Vaccines for shigella and salmonella are also under development.
Probiotics A recent meta-analysis would support the view that probiotics can shorten the duration of acute diarrhoeal illness in children by one day.17 Although a meta-analysis also suggests that probiotics benefit antibiotic-associated diarrhoea,18 further studies are required to provide a definitive answer.
Prevention Chemoprophylaxis: Broad-spectrum antibiotics taken at approx imately half the therapeutic dose can prevent certain intestinal infections, particularly cholera (tetracycline) and travellers’ diar rhoea (fluoroquinolones). Their use in the latter, however, is not generally recommended because of concerns about adverse effects and emerging drug resistance (Figure 2). The nonantibiotic preparation bismuth subsalicylate is an alternative but less effective than antibiotics.
Complications Haemolytic-uraemic syndrome Shigella dysenteriae type 1 infection has been known for several decades to cause haemolytic-uraemic syndrome (HUS) and it is now well established that this is also responsible for a substan tial proportion of the mortality associated with EHEC infection. HUS which consists of a triad of features, acute renal failure, thrombocytopenia and microangiopathic haemolytic anaemia is also described with Salmonella typhi, Campylobacter jejuni and Yersinia pseudotuberculosis infections. HUS occurs in about 6% of patients with EHEC infection and carries a mortality of 3–5%.2
Probiotics and prebiotics: the concept that the gut can be colo nized with harmless bacteria that will protect against the harm ful effects of enteropathogens has been around for more than a century since the time of Louis Pasteur. The evidence for their efficacy as a prophylactic remains controversial but some studies have clearly demonstrated a protective effect against rotavirus infection in children. Prebiotics, such as oligofructose, encourage proliferation of probiotics such as bifidobacteria. Oligofructose decreases the relapse rate following metronidazole or vancomy cin treatment of C. difficile infection.19 This is a rapidly develop ing field and it is likely that genetically modified organisms with improved efficacy will be available in the future.
Non-septic arthritis and Reiter’s syndrome These symptoms are commonly associated with several inva sive organisms including Salmonella spp., Shigella spp., Yersinia enterocolitica and Campylobacter jejuni. More than 70% of patients who develop non-septic arthritis are HLA B27 positive. Non-septic arthritis may be associated with iritis and conjunc tivitis which may occur in up to 90% of patients with arthritis following shigellosis and up to 25% of those with salmonella, campylobacter or yersinia infections. The term ‘Reiter’s syn drome’ is reserved for the classic triad of symptoms consisting of arthritis, urethritis and conjunctivitis. Again HLA B27 positivity strongly predicts the likelihood of developing Reiter’s syndrome and is indicative of its severity.
Determining the advisability of prophylaxis against travellers’ diarrhoea during a stay of less than 3 weeks in a high-risk area of Latin America, Africa or Southern Asia Yes
Does the traveller have an important underlying health impairment? Yes
Yes
No
Will the trip be ruined if the traveller has a brief illness that might force a change in itinerary?
Guillain-Barré syndrome There is now a clear link between Campylobacter jejuni infec tion and the Guillain-Barré syndrome.20 If the syndrome follows Campylobacter infection, it appears to be predominantly a motor disorder and has a particularly poor outcome with an increased risk of requiring ventilatory support and of having severe disability at one year.
No
Is the traveller unable to follow careful dietary restrictions but willing to take chemoprophylaxis? Yes
Consider antibiotic prophylaxis
Consider bismuth subsalicylate prophylaxis (safer but less effective than antibiotic prophylaxis)
No
No prophylaxis advised
Septic arthritis Purulent synovitis during enteric infection is relatively rare occurring in 0.2–2.5% of individuals with Salmonella infec tion. Infection is usually mono-articular involving the large joints. Symptoms begin within two weeks of the gastrointestinal
Figure 2
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s ymptoms but may occur as late as seven weeks. There is no association with HLA B27.
9 DuPont HL, Jiang Z -D, Ericsson CD, et al. Rifaximin versus ciprofloxacin for the treatment of traveler’s diarrhea: A randomised, double-blind clinical trial. Clin Infect Dis 2001; 33: 1807–15. 10 Casburn-Jones AC, Farthing MJG. Management of infectious diarrhoea. Gut 2004; 53: 296–305. 11 Farthing MJG. Treatment options for the eradication of intestinal protozoa. Nat Clin Pract Gastroenterol Hepatol 2006; 3: 436–45. 12 Zaat JO, Mank T, Assendelft WJ. Drugs for treating giardiasis. Cochrane Database Syst Rev 2000: CD000217. 13 Rossignol JF, Ayoub A, Ayers MS. Treatment of diarrhea caused by Giardia intestinalis and Entamoeba histolytica or E. dispar: a randomized, double-blind, placebo-controlled study of nitazoxanide. J Infect Dis 2002; 184: 381–84. 14 Amadi B, Mwiya M, Musuku J, et al. Effect of nitazoxanide on morbidity and mortality in Zambian children with cryptosporidiosis: a randomized controlled trial. Lancet 2002; 360: 1375–80. 15 Zulu I, Kelly P, Njobvu L, et al. Nitazoxanide for persistent diarrhoea in Zambian acquired immune deficiency syndrome patients: a randomized-controlled trial. Aliment Pharmacol Ther 2005; 21: 757–63. 16 Molina JM, Tourneur M, Chevret S, et al. Fumagillin treatment of intestinal microsporidiosis. N Engl J Med 2002; 346: 1963–69. 17 Huang JS, Bousvaros A, Lee JW, Diaz A, Davidson EJ. Efficacy of probiotic use in acute diarrhea in children: A meta-analysis. Dig Dis Sci 2002; 47: 2625–34. 18 Szajewska H, Mrukowicz J. Meta-analysis: non-pathogenic yeast Saccharomyces boulardii in the prevention of antibiotic-associated diarrhoea. Aliment Pharmacol Therap 2005; 22: 365–72. 19 Lewis S, Burmeister S, Brazier J. Effect of the prebiotic oligofructose on relapse of Clostridium difficile-associated diarrhea: a randomized, controlled study. Clin Gastroenterol Hepatol 2005; 3: 442–48. 20 Rees JH, Soudain SE, Gregson NA, et al. Campylobacter jejuni infection and Guillain-Barré syndrome. N Engl J Med 1995; 333: 1374–79. 21 Spiller RC. Postinfectious irritable bowel syndrome. Gastroenterology 2003; 124: 1662–71.
Irritable bowel syndrome There is emerging evidence that acute intestinal infection can lead on to diarrhoea predominant irritable bowel syndrome (IBS) following clearance of the enteropathogen.21 It has been pro posed that this may be related to subclinical ‘inflammation’ and an increase in 5-hydroxytryptamine containing enterochromaffin cells. Management is the same as for other causes of IBS. ◆
References 1 Wheeler JG, Sethi D, Cowden JM, et al. Study of infeticous intestinal disease in England: rates in the community, presenting to general practice, and reported to national surveillance. BMJ 1999; 318: 1046–50. 2 Boyce TG, Swerdlow DL, Griffin PM. Escherichia coli O157:H7 and the hemolytic-uremic syndrome. N Engl J Med 1995; 333: 364–68. 3 Handszuh H, Waters SR. Travel and tourism patterns. In: DuPont HL, Steffen R, eds. Textbook of travel medicine and health. Decker: Hamilton, 1997. 4 Freedman SB, Adler M, Seshadri R, Powell EC. Oral ondansetron for gastroenteritis in a pediatric emergency department. N Engl J Med 2006; 354: 1698–705. 5 Kaplan MA, Prior MJ, McKonly KI, et al. A multicentre randomised controlled trial of a liquid loperamide product versus placebo in the treatment of acute diarrhoea in children. Clin Pediatr 1999; 38: 579–91. 6 Murphy GS, Bodhidatta L, Echeverria P, et al. Ciprofloxacin and loperamide in the treatment of bacillary dysentery. Ann Intern Med 1993; 118: 582–86. 7 Salazar-Lindo E, Santisteban-Ponce J, Chea-Woo E, Gutierrez M. Racecadotril in the treatment of acute watery diarrhea in children. N Engl J Med 2000; 343: 463–67. 8 Salam I, Katelaris P, Leigh-Smith S, et al. A randomised placebocontrolled trial of single dose ciprofloxacin in treatment of travellers’ diarrhoea. Lancet 1994; 344: 1537–39.
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which has a mortality of 1–2% and a relatively high incidence of serious complications such as the haemolytic-uraemic syndrome.2 The increase in foreign travel has further contributed to the importance of infectious diarrhoea in the industrialized world (Figure 1),3 as has the increasing use of broad-spectrum antibiotics and associated antibiotic-related diarrhoea due to Clostridium difficile.
Michael J G Farthing Paul Kelly
Epidemiology The key reservoirs of human enteropathogens are food, water and other humans. Certain human infective agents are carried by animals giving rise to conditions known as zoonoses (such as sal monellosis, campylobacteriosis, giardiasis and cryptosporidiosis). Domestic water supplies, swimming pools, sea water and inland freshwater lakes and rivers also harbour enteropathogens. Faecal–oral transmission is the main route by which these infections are spread and may occur either through ingestion of contaminated food or fluids or by direct person-to-person con tact. The latter is particularly important when only small infec tive doses are required to initiate infection, such as in shigellosis. V. cholerae and other non-cholera vibrios are transmitted by con taminated water, shellfish and other seafood and by person-toperson contact. Foodborne infection, so-called ‘food poisoning’, may be due to true infection of the intestine or related to the ingestion of a pre-formed toxin (Table 1). Intimate sexual contact, notably oro-anal sex, is commonly associated with transmission of enteropathogens. Viruses, such as the norovirus (previously known as small round structured viruses of the Norwalk family), can be spread by aerosol, espe cially as vomiting is an important early symptom of the illness. This probably explains why this infection spreads so rapidly through cruise ships, hotels and hospital wards. Immunodeficiency and reduced gastric acid secretion are well recognized risk factors for intestinal infections.
Abstract Infectious diarrhoea remains a major cause of morbidity and mortality world wide. Viruses, bacteria and protozoa are responsible for the majority of infections which are transmitted most commonly by the faecal-oral route through water, food and person-to-person transmission. Clinical presentation of infectious diarrhoea conforms to three patterns, namely acute watery diarrhoes, dysentery and persistent diarrhoea sometimes with the features of steatorrhoea. Diagnosis still rests heavily on stool microscopy and culture although faecal antigen tests and DNA based assays are under evaluation. Oral rehydration therapy continues to be the most important supportive intervention, particularly in acute watery diarrhoea when death from dehydration and acidosis can be prevented in the vast majority of sufferers. There have been some important advances in the development of new approaches to antibiotic therapy. The non-absorbable antibiotic rifaximin is highly effective in the treatment of traveller’s diarrhoea and is free from the majority of side effects that are associated with systemically absorbed antibiotics. The broadspectrum antimicrobial nitazoxanide has made a major impact on the treatment of cryptosporidiosis but is also effective in giardiasis, amoebiasis and C. difficile infection. Recent evidence suggests that probiotics and prebiotics are effective in the treatment and prevention of a variety of intestinal infections.
Keywords antibiotics; anti-diarrhoeal agents; bacteria; diarrhoea, enteropathogens; probiotics; protozoa; viruses
Spectrum and estimated prevalence of enteropathogens responsible for travellers’ diarrhoea
Infections of the gastrointestinal tract are the most common intestinal disorders. They have their major impact in the develop ing world and are still responsible for the deaths of up to 2–3 million pre-school children each year. Despite industrializa tion, wealth and public health interventions to ensure water quality and sewage disposal, intestinal infections have a major impact in the Western world, including both foodborne (Salmonella spp. and Campylobacter spp.) and waterborne infections (Cryptosporidium parvum and Giardia intestinalis).1 Infectious colitis is an increasingly important condition due to Salmonella spp., Campylobacter jejuni and enterohaemorrhagic E. coli (EHEC) infection
40%
10% 3%
22% 5% 5%
5%
Enterotoxigenic Escherichia coli Michael J G Farthing DSc (Med) MD FRCP FMedSci is Professor of Medicine at St George’s, University of London, London, UK. Competing interests: none declared. Paul Kelly MD FRCP is Reader in Tropical Gastroenterology at St Bart’s and the London School of Medicine, London, UK. Competing interests: none declared.
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Salmonella spp. Aeromonas/ Plesiomonas spp.
Shigella spp. and enterohaemorrhagic Escherichia coli
Protozoa
Campylobacter jejuni
No pathogen isolated
Viruses
Figure 1
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Infection
incubation period and on average lasts 3–5 days. Watery diarrhoea is often accompanied by anorexia, nausea, vomiting, abdominal cramps, bloating and low-grade fever. In adults, severe dehydra tion is uncommon although this may become clinically important in infants, young children and the elderly. Mild cholera may be indistinguishable from other agents that produce acute watery diarrhoea. However, when severe, diarrhoea begins abruptly, with stool volume rates of up to 1 litre per hour.
Microbial pathogens responsible for foodborne diarrhoeal disease Organism
Incubation period (hours)
Recovery
Salmonella spp. Campylobacter jejuni Enterohaemorrhagic Escherichia coli Vibrio parahaemolyticus Yersinia enterocolitica Clostridium perfringens
12–48 48–168 24–168
2–14 days 7–21 days 7–21 days
2–48 2–144 8–22
2–30 days 1–3 days 1–3 days
2–6 1–2 18–36
few hours few hours 10–14 days
Pre-formed toxins Staphylococcus aureus Bacillus cereus Clostridium botulinum
Bloody diarrhoea, dysentery and colitis The organisms responsible for acute bloody diarrhoea are the invasive bacterial enteropathogens (Shigella spp., Salmonella spp. Campylobacter jejuni and EHEC) and the protozoan Entamoeba histolytica. There is often a prodromal illness of low-grade fever, headache, anorexia and lassitude. Incubation period is variable but can range from 1 to 7 days. Following an initial period of watery diarrhoea, stool volume may actually decrease with the appearance of blood and mucus in the stools. Moderate or severe, cramping lower abdominal pain is an important feature of a dysenteric illness, as is tenesmus and rectal prolapse, partic ularly in children with shigellosis. There may be fever and mild abdominal distension with some tenderness over the colon. Clinically it can be difficult to distinguish acute infectious coli tis from non-specific inflammatory bowel disease. Any form of severe colitis can give rise to abdominal tenderness, distension and, in some cases, reduced bowel sounds due to ileus. Procto sigmoidsocopy should form part of the initial clinical assessment and may confirm the presence of colitis.
Table 1
Causes Infective diarrhoea presents in a variety of ways, the recognition of which may assist clinical diagnosis and early management. The three major patterns are: • acute watery diarrhoea • bloody diarrhoea (dysentery), usually due to an infective enterocolitis • persistent diarrhoea, sometimes with steatorrhoea and evidence of an enteropathy. The major organisms responsible for these clinical syndromes are summarized in Table 2. However, there is considerable over lap between these clinical patterns with some organisms (such as Shigella spp. and Campylobacter jejuni) presenting initially as acute watery diarrhoea but then progressing to a dysenteric ill ness with fever and bloody diarrhoea. Similarly, giardiasis may start as acute watery diarrhoea but eventually become persistent with features of malabsorption.
Persistent diarrhoea In adults, G. intestinalis is the most common cause of per sistent diarrhoea, often associated with anorexia, abdominal bloating, substantial weight loss and overt steatorrhoea. The other intracellular protozoa are also relatively common causes of persistent diarrhoea, particularly in the immunocomprised (C. parvum, microsporidia, Cyclospora and Isospora). In chil dren, enteropathogenic E. coli (EPEC) is an important organ ism to consider. Any cause of persistent diarrhoea in infants and young children can result in failure to thrive and growth retardation. Strongyloides stercoralis infection may also cause chronic diarrhoea and malabsorption although this is more common in the hyper-infection syndrome.
Clinical presentation Acute watery diarrhoea Rotavirus infection, the most common cause of acute diarrhoea in infants and young children, is often preceded by a brief pro dromal illness with fever and mild respiratory symptoms, which is followed by vomiting and diarrhoea. If fluid and electrolyte losses are not replaced promptly then dehydration and metabolic acidosis soon follow. The degree of dehydration can be assessed clinically by noting skin tone and tissue turgor, dryness of mucous membranes, intra-ocular tension and, in young infants, depression of the anterior fontanelle. As the degree of dehydration increases, there is impairment of consciousness, ultimately leading to stupor and coma. Typically, the illness lasts about 7 days. Adenovirus is a more prolonged illness with pronounced respiratory symptoms. Acute watery diarrhoea in adults is usually bacterial in origin, most commonly due to enterotoxigenic E. coli (ETEC) in travellers or one of the foodborne pathogens in the indigenous population of industrialized countries. ETEC usually begins after a short
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Diagnosis Although the majority of episodes of acute infective diarrhoea resolve without the need for identifying a specific aetiological agent, persistent diarrhoea and bloody diarrhoea always require further investigation. It is particularly important in severely ill patients when delay in starting appropriate treatment might significantly alter the outcome. Confident exclusion of an infec tive aetiology is rarely achieved in less than 24–48 hours and, although imprecise, clinical assessment is important for guid ing management during this early phase of the illness. Rou tine laboratory investigations are of limited diagnostic value as anaemia, a raised neutrophil count and evidence of an inflamma tory process with a raised erythrocyte sedimentation rate (ESR), C-reactive protein and platelet count occur in infective colitis and non-specific inflammatory bowel disease. The cornerstone of 252
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Infection
Causes of infectious diarrhoea by clinical pattern Enteropathogen
Acute watery diarrhoea
Dysentery
Persistent diarrhoea
Viruses Rotavirus Enteric adenovirus (types 40, 41) Norovirus and other SRSV’s Calicivirus Astrovirus Cytomegalovirus
+ + + + + +
− − − − − +
− − − − − +
Bacteria Vibrio cholerae and other vibrios Enterotoxigenic Escherichia coli (ETEC) Enteropathogenic E. coli (EPEC) Enteroaggregative E. coli (EAEC) Enteroinavsive E. coli (EIEC) Enterohaemorraghic E. coli (EHEC) Shigella spp. Salmonella spp. Campylobacter spp. Yersinia spp. Clostridium difficile Mycobacterium tuberculosis
+ + + + + + + + + + + −
− − − − + + + + + + + +
− − + + − − + + + + + +
Protozoa Giardia intestinalis Cryptosporidium parvum Microsporidia Isospora belli Cyclospora cayetanensis Entamoeba histolytica Balantidium coli
+ + + + + + +
− − − − − + +
+ + + + + + +
Helminths Strongyloides stercoralis Schistosoma spp.
− −
− +
+ +
Table 2
evidence-based management is identification of the aetiological agent which ultimately relies on stool microscopy and culture. Serology is of limited value in the diagnosis of intestinal infection. However, in amoebic colitis, serology is positive in 80–90% of patients and serology can detect Yersinia enterocolitica infection although results are not usually positive for at least 10–14 days after the onset of the illness. Antibody ELISAs are now avail able for the diagnosis of strongyloidiasis and schistosomiasis and should be regarded as first-line screening tests for travellers returning from endemic areas.
Recent evidence suggests that a single dose of ondansetron, the 5-HT3 receptor antagonist, reduces vomiting and is a useful adjunct to rehydration therapy in childen.4 In severe dehydra tion in infants and young children, intravenous rehydration is mandatory. Food should be commenced as soon as the individual wishes to eat and drink normally. Breastfeeding should be con tinued in infants. In most cases in adults, a formal ORS is usually not required but it is recommended that they should increase oral fluids, such as salty soups (sodium), fruit juices (potassium) and take carbohydrates (salty crackers, rice, bread, pasta, potatoes) to provide glucose for the glucose–sodium co-transport.
Treatment
Anti-diarrhoeal therapy The most commonly used anti-motility agent is loperamide.5 The efficacy of loperamide is probably most effective when combined with an antibiotic.6 Anti-motility agents are not recommended for children and young infants due to concerns about respira tory depression. An important advance in anti-diarrhoeal ther apy has been the development of an enkephalinase inhibitor,
Fluid and electrolyte replacement Oral fluid and electrolyte replacement is usually effective except when losses are very severe or there is associated profound vomiting. Dehydration occurs more quickly in infants and young children and therefore early administration of an oral rehydration solution (ORS) is advised to prevent dehydration and acidosis.
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r acecadotril, which has pro-absorptive activity because of its abil ity to potentiate endogenous enkephalins in the intestine. This is an effective agent for reducing stool weight and bowel frequency, it can be safely used in children and does not cause rebound constipation, which can be a problem with anti-motility agents.7
recommended, these include dysenteric shigellosis, cholera, pseudomembranous colitis, and some protozoal infections. There are several diseases in which the indications are less clear, but treatment is usually recommended, such as infection with the noncholera vibrios, prolonged or protracted infection with yersinia, early in the course of campylobacteriosis, aeromonas and plesi omonas infections, and outbreaks of EPEC diarrhoea in nurseries. Patients should be treated if they are debilitated, particularly with malignancy, immunosuppressed, have an abnormal cardiovascular system, have valvular, vascular, or orthopaedic prostheses, have
Antimicrobial therapy Antibiotic therapy for infectious diarrhoea is controversial (Table 3).8–16 Mild illnesses probably do not need antibiotic treatment, although there are infections in which treatment is
Antimicrobial therapy for acute infectious diarrhoea Organism
Efficacy of antimicrobial therapy Drug of choice
Alternative choice
Bacteria Vibrio cholerae
Proven
Tetracycline 500 mg qds 3 days, ciprofloxacin 1000 mg single dose
Enterotoxigenic Escherichia coli (ETEC) Enteropathogenic E. coli (EPEC) Enteroinvasive E. coli (EIEC) Enterohemorrhagic E. coli (EHEC) Shigella sp
Proven
Ciprofloxacin 500 mg bd 3–5 days, norfloxacin 400 mg bd 3–5 days
Trimethoprim-sulfamethoxazole (TMP-SMX), doxycyline, norfloxacin, ciprofloxacin 3 days Ciprofloxacin 500 mg single dose
Salmonella sp
Doubtful efficacy in enterocolitis, proven efficacy in severe salmonellosis (dysentery, fever) Possible efficacy in campylobacter enteritis, proven efficacy in campylobacter dysentery/sepsis Doubtful efficacy in Yersinia enteritis, proven efficacy in Yersinia septicaemia Proven
Campylobacter sp
Yersinia sp
Clostridium difficile Protozoa Giardia intestinalis Cryptosporidium parvum Isospora belli Cyclospora cayetanensis Encephalitozoon intestinalis Enterocytozoon bieneusi Entamoeba histolytica
Balantidium coli
Possible Possible Probably harmful
? same as Shigella spp. Possibly fluoroquinolone
Proven efficacy in dysenteric shigellosis
TMP-SMX* 2 tabs bd 5 days, ciprofloxacin 500 mg bd 5 day, other quinolones – norfloxacin, fleroxacin, cinoxacin Ciprofloxacin 500 mg bd 10–14 days, third generation cephalosporins 10–14 days. Carrier state: Norfloxacin 400 mg bd 28 days Erythromycin 250–500 mg qds 7 days
Short-term quinolone Cefixime 400 mg daily 5–7 days OR other third generation ephalosporins, nalidixic acid 1g qds 5–7 days TMP-SMX, ampicillin, amoxycillin
Ciprofloxacin 500 mg bd 7–10 days
Tetracycline 250 mg qds 7–10 days
Metronidazole 400 mg tds 7–10 days
Vancomycin 125 mg qds 7–10 days, fusidic acid, teicoplanin
Metronidazole 400 mg tds 7–10 days Nitazoxanide 500 mg bd 3–14 days TMP-SMX 2 tabs qds 10 days TMP-SMX 2 tabs bd 7 days Albendazole 400 mg bd 4 weeks, fumagillin 60 mg 14 days Metronidazole 750 mg tds 5 days, diloxanide furoate 500 mg tds 10 days Metronidazole 400 mg tds 10 days
Tinidazole 2g single dose Paromomycin 500 mg qds 7–10 days
Proven Proven Proven Proven Proven Proven
Proven
Ciprofloxacin 500 mg bd 5–7 days, azithromycin 500 mg od 3 days
Paromomycin 25–35 mg/kg tds 7–10 days Tetracycline 500 mg qds 10 days
*TMP-SMX of limited value because of resistance patterns.
Table 3
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haemolytic anaemia (especially if salmonellosis is involved), or are extremely young or old. Treatment is also advised for those with prolonged symptoms and those who relapse.
Vaccines Although parenteral vaccines for cholera and typhoid have been available for many years their efficacy is low. The major thrust of vaccine development in recent years has focused on oral vac cines to ensure that there is the capacity for a local protective immune response in the gut. A whole cell-B subunit oral cholera vaccine has been subjected to extensive field trials and shown to be moderately effective. More recently, a genetically engineered live oral cholera vaccine has been developed which appears to be as effective after a single dose. These cholera vaccines also have some protective effects against travellers’ diarrhoea caused by other organisms and the whole cell-B subunit vaccine is currently marketed in some countries for travellers’ diarrhoea. Although initial attempts to develop vaccines against rotavirus infection were seriously curtailed by the occurrence of intussus ception, two new vaccines have been demonstrated to be safe and are now available. Vaccines for shigella and salmonella are also under development.
Probiotics A recent meta-analysis would support the view that probiotics can shorten the duration of acute diarrhoeal illness in children by one day.17 Although a meta-analysis also suggests that probiotics benefit antibiotic-associated diarrhoea,18 further studies are required to provide a definitive answer.
Prevention Chemoprophylaxis: Broad-spectrum antibiotics taken at approx imately half the therapeutic dose can prevent certain intestinal infections, particularly cholera (tetracycline) and travellers’ diar rhoea (fluoroquinolones). Their use in the latter, however, is not generally recommended because of concerns about adverse effects and emerging drug resistance (Figure 2). The nonantibiotic preparation bismuth subsalicylate is an alternative but less effective than antibiotics.
Complications Haemolytic-uraemic syndrome Shigella dysenteriae type 1 infection has been known for several decades to cause haemolytic-uraemic syndrome (HUS) and it is now well established that this is also responsible for a substan tial proportion of the mortality associated with EHEC infection. HUS which consists of a triad of features, acute renal failure, thrombocytopenia and microangiopathic haemolytic anaemia is also described with Salmonella typhi, Campylobacter jejuni and Yersinia pseudotuberculosis infections. HUS occurs in about 6% of patients with EHEC infection and carries a mortality of 3–5%.2
Probiotics and prebiotics: the concept that the gut can be colo nized with harmless bacteria that will protect against the harm ful effects of enteropathogens has been around for more than a century since the time of Louis Pasteur. The evidence for their efficacy as a prophylactic remains controversial but some studies have clearly demonstrated a protective effect against rotavirus infection in children. Prebiotics, such as oligofructose, encourage proliferation of probiotics such as bifidobacteria. Oligofructose decreases the relapse rate following metronidazole or vancomy cin treatment of C. difficile infection.19 This is a rapidly develop ing field and it is likely that genetically modified organisms with improved efficacy will be available in the future.
Non-septic arthritis and Reiter’s syndrome These symptoms are commonly associated with several inva sive organisms including Salmonella spp., Shigella spp., Yersinia enterocolitica and Campylobacter jejuni. More than 70% of patients who develop non-septic arthritis are HLA B27 positive. Non-septic arthritis may be associated with iritis and conjunc tivitis which may occur in up to 90% of patients with arthritis following shigellosis and up to 25% of those with salmonella, campylobacter or yersinia infections. The term ‘Reiter’s syn drome’ is reserved for the classic triad of symptoms consisting of arthritis, urethritis and conjunctivitis. Again HLA B27 positivity strongly predicts the likelihood of developing Reiter’s syndrome and is indicative of its severity.
Determining the advisability of prophylaxis against travellers’ diarrhoea during a stay of less than 3 weeks in a high-risk area of Latin America, Africa or Southern Asia Yes
Does the traveller have an important underlying health impairment? Yes
Yes
No
Will the trip be ruined if the traveller has a brief illness that might force a change in itinerary?
Guillain-Barré syndrome There is now a clear link between Campylobacter jejuni infec tion and the Guillain-Barré syndrome.20 If the syndrome follows Campylobacter infection, it appears to be predominantly a motor disorder and has a particularly poor outcome with an increased risk of requiring ventilatory support and of having severe disability at one year.
No
Is the traveller unable to follow careful dietary restrictions but willing to take chemoprophylaxis? Yes
Consider antibiotic prophylaxis
Consider bismuth subsalicylate prophylaxis (safer but less effective than antibiotic prophylaxis)
No
No prophylaxis advised
Septic arthritis Purulent synovitis during enteric infection is relatively rare occurring in 0.2–2.5% of individuals with Salmonella infec tion. Infection is usually mono-articular involving the large joints. Symptoms begin within two weeks of the gastrointestinal
Figure 2
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s ymptoms but may occur as late as seven weeks. There is no association with HLA B27.
9 DuPont HL, Jiang Z -D, Ericsson CD, et al. Rifaximin versus ciprofloxacin for the treatment of traveler’s diarrhea: A randomised, double-blind clinical trial. Clin Infect Dis 2001; 33: 1807–15. 10 Casburn-Jones AC, Farthing MJG. Management of infectious diarrhoea. Gut 2004; 53: 296–305. 11 Farthing MJG. Treatment options for the eradication of intestinal protozoa. Nat Clin Pract Gastroenterol Hepatol 2006; 3: 436–45. 12 Zaat JO, Mank T, Assendelft WJ. Drugs for treating giardiasis. Cochrane Database Syst Rev 2000: CD000217. 13 Rossignol JF, Ayoub A, Ayers MS. Treatment of diarrhea caused by Giardia intestinalis and Entamoeba histolytica or E. dispar: a randomized, double-blind, placebo-controlled study of nitazoxanide. J Infect Dis 2002; 184: 381–84. 14 Amadi B, Mwiya M, Musuku J, et al. Effect of nitazoxanide on morbidity and mortality in Zambian children with cryptosporidiosis: a randomized controlled trial. Lancet 2002; 360: 1375–80. 15 Zulu I, Kelly P, Njobvu L, et al. Nitazoxanide for persistent diarrhoea in Zambian acquired immune deficiency syndrome patients: a randomized-controlled trial. Aliment Pharmacol Ther 2005; 21: 757–63. 16 Molina JM, Tourneur M, Chevret S, et al. Fumagillin treatment of intestinal microsporidiosis. N Engl J Med 2002; 346: 1963–69. 17 Huang JS, Bousvaros A, Lee JW, Diaz A, Davidson EJ. Efficacy of probiotic use in acute diarrhea in children: A meta-analysis. Dig Dis Sci 2002; 47: 2625–34. 18 Szajewska H, Mrukowicz J. Meta-analysis: non-pathogenic yeast Saccharomyces boulardii in the prevention of antibiotic-associated diarrhoea. Aliment Pharmacol Therap 2005; 22: 365–72. 19 Lewis S, Burmeister S, Brazier J. Effect of the prebiotic oligofructose on relapse of Clostridium difficile-associated diarrhea: a randomized, controlled study. Clin Gastroenterol Hepatol 2005; 3: 442–48. 20 Rees JH, Soudain SE, Gregson NA, et al. Campylobacter jejuni infection and Guillain-Barré syndrome. N Engl J Med 1995; 333: 1374–79. 21 Spiller RC. Postinfectious irritable bowel syndrome. Gastroenterology 2003; 124: 1662–71.
Irritable bowel syndrome There is emerging evidence that acute intestinal infection can lead on to diarrhoea predominant irritable bowel syndrome (IBS) following clearance of the enteropathogen.21 It has been pro posed that this may be related to subclinical ‘inflammation’ and an increase in 5-hydroxytryptamine containing enterochromaffin cells. Management is the same as for other causes of IBS. ◆
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