Pii: s0924-8579(99)00149-

International Journal of Antimicrobial Agents 14 (2000) 65 – 69 Symposium on the treatment of diarrhoeal disease Diarrhoea: a significant worldwide problem Digesti6e Diseases Research Centre, St Bartholomews and The Royal London School of Medicine and Dentistry, Turner St., Abstract
Diarrhoea is a problem, not only of the developing world, but also of the Western world. However, the economic implications of diarrhoeal diseases are particularly evident in the poorer countries. The most common worldwide cause of diarrhoea isintestinal infection and infants, pre-school children, the elderly, and those with congenital or acquired immunodeficiency run ahigh risk of contracting such infections. Diarrhoeal disease can be classified into three major clinical syndromes: acute waterydiarrhoea, bloody diarrhoea, and persistent diarrhoea. A number of different micro-organisms can cause infectious diarrhoea,depending on the clinical setting. The development of oral rehydration solution has provided a simple approach to rehydrationand maintenance of hydration in patients with acute watery diarrhoea, and has been implemented worldwide under the auspicesof the World Health Organization. However, rehydration does not treat the diarrhoea itself, which will persist until the infectionresolves. Since the drugs currently used for the treatment of diarrhoea, such as the opiate agents and antibiotics, have limitations,the search continues for a drug that acts predominantly on secretory pathways without affecting gastrointestinal motility. Noveltherapeutic approaches include 5-HT and 5-HT receptor antagonists, calcium – calmodulin antagonists, and s-receptor agonists.
Another approach has concentrated on the antisecretory role of the neurotransmitter, enkephalin, and has resulted in thedevelopment of the enkephalinase inhibitor, racecadotril. This drug has true antisecretory activity, and has demonstrated goodefficacy and tolerability in clinical trials. 2000 Published by Elsevier Science B.V. and international Society of Chemotherapy.
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Keywords: Antisecretory agents; Diarrhoeal diseases; Enteropathogens; Oral rehydration solution 1. Introduction
excessive fluid and electrolyte losses, which result indehydration and acidosis [3,4]. Thus, the majority of Intestinal infection is the most common cause of these deaths are avoidable providing fluid and elec- diarrhoea worldwide and is responsible for the deaths trolyte losses are replaced promptly.
of 3 – 4 million individuals each year, the majority of The major burden of infectious diarrhoea falls upon whom are pre-school children [1,2]. In some countries individuals, particularly infants and young children, in the developing world children may suffer many who live in the developing world. However, despite attacks of acute diarrhoea every year, each of which industrialization, wealth, and public health interven- contributes to the infection-malnutrition cycle and con- tions to ensure water quality and sewage disposal, acute sequent impaired growth and development. The seventh intestinal infections are increasing in the Western cholera pandemic continues to produce high morbidity world. This is particularly due to foodborne infections and mortality in many parts of the developing world such as Salmonella spp., Campylobacter jejuni, and en- including the Indian subcontinent, sub-saharan Africa, terohaemorrhagic Escherichia coli O157:H7 [5]. Water- and some parts of Central and South America. Most of borne infection is also important in the developed the deaths from acute infectious diarrhoea result from world, particularly as a result of contamination ofdomestic water supplies with the cysts of Giardia intes-tinalis and Cryptosporidium par * Tel.: + 44-171-2957191; fax: + 44-171-2957192.
E-mail address: [email protected] (M.J.G. Farthing) contributing to the rise in acute infectious diarrhoea in 0924-8579/00/$20 2000 Published by Elsevier Science B.V. and international Society of Chemotherapy. All rights reserved.
PII: S 0 9 2 4 - 8 5 7 9 ( 9 9 ) 0 0 1 4 9 - 1 M.J.G. Farthing / International Journal of Antimicrobial Agents 14 (2000) 65 – 69 the industrialized world include the widespread use of 3. Who is at risk?
broad-spectrum antibiotics, impaired host immunitydue to HIV infection, anti-cancer chemotherapy, and Several groups of individuals are at increased risk the increase in foreign travel from Western countries of intestinal infections (Table 1). Infants, pre-school children, and the elderly are particularly susceptible.
During the first few months of life the breastfed in-fant is relatively protected from intestinal infection, 2. Global impact of infectious diarrhoea
but exposure to enteropathogens increases during theweaning period as the protective benefits of maternal It has been estimated that there may be as many as milk are lost. As the infant and young child develops, 4 billion cases of acute diarrhoea each year world- acquired immunity to the common enteropathogens wide. In the economically deprived parts of the world increases such that the age-specific prevalence of such as the Indian subcontinent, Africa, and Latin many intestinal infections decreases during adoles- America, children may experience between three and cence and early adult life. The elderly appear to have ten episodes of diarrhoea each year [2]. Even in the increased susceptibility to infection partly due to de- wealthy industrialized world acute diarrhoea in chil- clining immune function and possibly also to de- dren has a significant morbidity and mortality. In the creased gastric acid secretion. This is especially USA it has been estimated that there are up to 8 evident in those with pernicious anaemia and with million consultations for acute diarrhoea each year gastric atrophy as a result of chronic infection with resulting in 250 000 hospital admissions and more than 500 deaths. The economic implications of di- Congenital and acquired immunodeficiency is recog- arrhoeal disease are self-evident, but are particularly nized as a major risk factor for intestinal infection.
damaging to poor countries where the case manage- Common variable immune deficiency is classically as- ment of acute diarrhoeal disease in a child may result sociated with protozoal infections, particularly giar- in the consumption of a significant proportion of the total healthcare budget for that individual. HIV-re- underscored the importance of cellular immunity in lated diarrhoea emphasizes this point; of the 22 mil- the host defence against enteric infection; in this set- lion individuals predicted to be infected with HIV by ting, intracellular protozoa such as C. par6um, Mi- the year 2000, 10 million will reside in Africa, 9 mil- crosporidium spp., Isospora belli, and Cyclospora lion in Asia, and 2 million in Latin America with cayetanensis predominate [6]. Anti-cancer chemother- only 1 million in Europe. Thus, the most economi- apy is also associated with opportunistic intestinal in- cally vulnerable communities in the world will face a fection including that due to cytomegalovirus and major pressure on their already compromised health- Clostridium difficile. The widespread use of broad- spectrum antibiotics in cancer patients and in manyother groups of hospitalized and ambulant individualshas demonstrated the clinical relevance of antibiotic-associated diarrhoea, much of which is attributable toopportunistic infection with C. difficile although other Groups at special risk of infectious diarrhoea The importance of gastric acid as a physical barrier to intestinal infection has been re-emphasized by thewidespread use of acid inhibitory drugs such as the H -receptor antagonists and the proton pump in- hibitors [7,8]. There is evidence that these agents sig- nificantly increase the risk of acquiring an intestinal bacterial infection, particularly in the elderly.
Congenital immunodeficiency(common variable immune deficiency) 4. What are the clinical patterns of infection?
Infective diarrhoeal disease can be classified into three major clinical syndromes: acute watery di-arrhoea, bloody diarrhoea, and persistent diarrhoea.
Acute watery diarrhoea produces rapid loss of fluid The elderly and cancer patients are atincreased risk and electrolytes, and can produce profound dehydra-tion with alteration in consciousness and vascular col- M.J.G. Farthing / International Journal of Antimicrobial Agents 14 (2000) 65 – 69 Table 2Enteropathogens responsible for infectious diarrhoeaa BacteriaV. cholerae and other vibrios HelminthsStrongyloides stercoralis a ETEC, enterotoxigenic E. coli; EIEC, enteroinvasive E. coli; EHEC, enterohaemorrhagic E. coli.
lapse in infants and young children. In children, watery 5. What is the cause?
diarrhoea is usually due to rotavirus or to entericadenoviruses, whereas enterotoxigenic E. coli and The microbial enteropathogens responsible for acute Vibrio cholerae are more common in adults.
watery diarrhoea, dysentery, and persistent diarrhoea Bloody diarrhoea is usually due to invasive en- are shown in Table 2. However, the spectrum of organ- teropathogens such as Shigella spp., Salmonella spp., isms varies depending on the clinical setting. The range and Campylobacter jejuni. These organisms predomi- of organisms commonly encountered in HIV-related nantly infect the distal ileum and colon. Enterohaemor- diarrhoea (Table 3) differs from those organisms com- rhagic E. coli has emerged as an important dysenteric monly isolated from travellers (Table 4) [9,10]. Simi- organism in the industrialized world and, like the other larly, a number of organisms are predominantly invasive pathogens, may be complicated by the responsible for water- and foodborne infections. Some haemolytic-uraemic syndrome and thrombotic throm-bocytopenic purpura [5]. In addition, these infectionsmay be complicated by reactive arthritis or a complete Table 3Enteropathogens responsible for HIV-related diarrhoea Reiter’s syndrome (arthritis, uveitis, and conjunctivitis).
Recently it has become evident that infection with Campylobacter jejuni is an important cause of the Isospora belliCyclospora cayetanensis Persistent diarrhoea can be due to continuing infec- tions with many of the organisms cited above, although the intracellular protozoa (C. par6um, Cyclospora cayetanensis, Microsporidium spp.) have emerged as Vibrio parahaemolyticusClostridium difficile important causes of HIV-related persistent diarrhoea Mycobacterium a6ium complex [6]. In children, enteropathogenic and enteroaggregative E. coli are also important.
M.J.G. Farthing / International Journal of Antimicrobial Agents 14 (2000) 65 – 69 drating and maintaining hydration in individuals with Prevalence of microbial enteropathogens in travellers’ diarrhoeaa watery diarrhoea, stool volumes do not decrease andsometimes doubts in the mind of a child’s carer as to whether the treatment is actually working. Reducing the osmolality of standard glucose-electrolyte solutions either by re- ducing the sodium and glucose content or by using a polymer such as rice starch has been shown to reduce Aeromonas and Plesiomonas spp.
stool volume in some circumstances [11]; however, the diarrhoea will still continue until the infection resolves.
Antidiarrhoeal medications such as loperamide, diphenoxylate, or codeine phosphate are widely used by adults with acute diarrhoea, but are contraindicated in infants and young children because of concerns about the possible central effects of opiate or opioid antidi- arrhoeal agents and the fact that administration of these drugs to a child might detract from the impor- tance of giving the life-saving intervention, namely oral Antimicrobial chemotherapeutic agents are indicated a ETEC, enterotoxigenic E. coli; EIEC, enteroinvasive E. coli.
for the treatment of infectious diarrhoea in a number ofsituations [10,12,13]. Tetracycline and a variety of other agents are effective in reducing the duration and sever- Microbial pathogens responsible for food- and waterborne disease ity of cholera and other acute watery diarrhoeas such asthat due to enterotoxigenic E. coli, which is common in travellers. Antibiotics are also indicated for dysentericshigellosis, typhoid, and other dysenteric pathogens Giardia intestinalisCryptosporidium par6um when dictated by the clinical severity of the infection.
The use of antibiotics for the treatment of enterohaem- orrhagic E. coli remains controversial as there is some Staphylococcus aureusBacillus cereus evidence that antibiotics may increase the risks of an individual developing haemolytic-uraemic syndrome.
Some of the enteropathogens that cause persistent diarrhoea such as Giardia intestinalis, Isospora belli, Cyclospora cayetanensis, and one of the Microsporidium Yersinia enterocoliticaVibrio parahaemolyticus spp. — Encephalitozoon intestinalis, are amenable to antimicrobial chemotherapy although Cryptosporidiumpar6um continues to be relatively unresponsive to mostagents tested to date. Recent studies with the newer organisms that cause food poisoning colonize and pro- liferate within the intestine, whereas others produce ithromycin), nitazoxanide, and albendazole suggest that preformed toxins in the food which are then available the situation may change in the future.
to act immediately on the intestine and produce di-arrhoea and often vomiting (Table 5).
7. Novel therapeutic targets
6. How should we treat diarrhoea?
There is, however, a continuing search for an agent that will reduce fluid and electrolyte losses during infec- A major advance during the second half of this tious diarrhoea, and that acts predominantly on secre- century was the development of glucose-electrolyte so- tory pathways without having a profound effect on lutions for the oral rehydration of infants and young intestinal motility [14]. The drive towards the develop- children with acute watery diarrhoea [3,4]. Because of ment of an intestinal antisecretory agent has required its simplicity this therapeutic approach has been imple- basic research into basal and stimulated secretory pro- mented worldwide under the auspices of the World cesses in the intestine, and it has become clear that a Health Organization and is estimated to have saved variety of neural and neurohumoral mechanisms are millions of lives. However, despite its efficacy in rehy- involved in intestinal secretory processes.
M.J.G. Farthing / International Journal of Antimicrobial Agents 14 (2000) 65 – 69 There is now compelling evidence that cholera toxin References
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[10] Farthing MJG, Du Pont HL, Guandalini S, Keusch GT, Stef- tion of these receptors inhibits the action of adenylate fen R. Treatment and prevention of travellers’ diarrhoea. Gas- cyclase and inhibits the secretory process. The effects of endogenous enkephalin can be potentiated by inhibiting [11] Thillainayagam AV, Hunt JB, Farthing MJG. Enhancing clini- the enzyme, enkephalinase, which is responsible for its cal efficacy of oral rehydration therapy: is low osmolality the degradation. Such an agent has now been developed: it key? Gastroenterology 1998;114:192 – 210.
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indicate that it has a place in the management of [13] Kelly MP, Farthing MJG. Intestinal protozoa. In: Schlossberg D, editor. Current therapy of infectious diseases. St. Louis:Mosby, 1992:574 – 7.
[14] Farthing MJG. Pathophysiology of infective diarrhoea. Eur J 8. Conclusions
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[15] Turvill JL, Kasapidis P, Farthing MJG. Sigma ligand, ig- mesine, inhibits cholera toxin and E. coli enterotoxin-induced Infective diarrhoea continues to be a major problem jejunal secretion in the rat. Gastroenterology 1997;112:A414.
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required to manage the many millions of attacks of [18] Turvill JL, Farthing MJG. Enkephalins and enkephalinase in- infective diarrhoea that take place throughout the world hibitors in intestinal fluid and electrolyte absorption. Eur J each year. Oral rehydration therapy continues to be the Gastroenterol Hepatol 1997;9:877 – 80.
cornerstone of management for acute watery diarrhoea, [19] Roge´ J, Baumer Ph, Be´rard H, Schwartz JC, Lecomte JM.
and antimicrobial chemotherapeutic agents have a place The enkephalinase inhibitor, acetorphan, in acute diarrhea: a in the treatment of some infections. The development of double-blind controlled trial versus loperamide. Scand J Gas-troenterol 1993;28:352 – 4.
antisecretory agents as an adjunct to rehydration therapy [20] Beaugerie L, Baumer Ph, Chaussade S, Be´rard H, Rozenbaum should reduce fluid requirements by decreasing faecal W, Pialous G, et al. Treatment of refractory diarrhoea in losses, and will thus provide both symptomatic and AIDS with acetorphan and octreotide: randomized crossover physiological benefits to the sufferer.
study. Eur J Gastroenterol Hepatol 1996;8:485 – 9.

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