key: cord-0034023-634bzeyh authors: Dupouy-Camet, Jean title: Single Dose Treatments in Tropical Infectious Diarrhoea: The Place of Secnidazole date: 2012-12-01 journal: Drug Investig DOI: 10.1007/bf03260003 sha: 28b7049a95dfbf2a1e514e5e934f4fcbc30f6218 doc_id: 34023 cord_uid: 634bzeyh Single dose treatments have the important advantages of simple administration, excellent compliance, short-lived side effects (if any) and short period of drug pressure. However, drugs used for single dose treatments must possess important characteristics, namely, long half-life, effective concentration in tissues over a long period, and low toxicity. In tropical medicine, such drugs are an important advance in the treatment of malaria (mefloquine and halofantrine), schistosomiasis (praziquantel and metrifonate), filariasis (ivermectin), and genitourinary tract and intestinal infections. Intestinal infections are one of the most frequent problems in tropical medicine. While a large number of cases of diarrhoea are of viral (rotavirus) or bacterial (Salmonella, Escherichia coli) origin, necessitating only oral rehydration, some are of parasitological origin (Giardia, Entamoeba histolytica, Strongyloides, Trichuris, Schistosoma) and can be cured by a single dose treatment (tinidazole, secnidazole, ivermectin, albendazole, praziquantel). Secnidazole is the nitroimidazole with the longest half-life and is, therefore, used in single dose treatments for Giardia, acute intestinal amoebiasis and E. histolytica cyst carriers. Single dose treatments of most intestinal parasites will be a major advance in the management of tropical infectious diarrhoea. In the next decade, opportunistic intestinal infections (Cryptosporidium, Isospora, Enterocytozoon) in AIDS patients that are refractory to treatment could be the major problem. In the past, the treatment of tropical diseases has been hampered by lengthy therapy involving repeated drug administration, low compliance and a high risk of possible side effects. A well known example is the treatment of bilharziasis by niridazole, which necessitated hospitalisation of patients for a week because of possible psychosis. Currently, only a single dose of praziquantel or metrifonate is required to treat bilharziasis in outpatients.l1. 2 1 Important advances in tropical medicine have been achieved with the development of single dose treatments. This was the case for malaria, with the use of new drugs with long half-lives such as sulfadoxine-pyrimethamine, mefloquine or halofantrineP-5 1 A real opportunity to lower the incidence of filariasis and onchocerciasis throughout the world was provided by the development of ivermectin, with treatment requiring 2 tablets every 6 to 12 months. [6, 71 Ivermectin has also proven its efficiency for scabies[81 and cutaneous larva migrans.[91 Single dose treatments are also widely used for the treatment of genitourinary infections, e.g. pefloxacin in gonorrhoea and bladder infections, and tinidazole or secnidazole in genital trichomoniasis and vaginal bacteriosis) lO-13] One of the major threats to health in tropical countries is diarrhoea. Recently, the WHO estimated that there are 3 to 5 billion individuals with diarrhoea each year and 5 to 10 million die) 14] In tropical countries, children under the age of 5 are particularly susceptible, and diarrhoea accounts for 7% of deaths in this age group. In addition, the development of AIDS led to the frequent occurrence of devastating and treatment-resistant diarrhoeas. Lastly, intestinal infections occur in thousands of travellers each year. IIS ] Some of these intestinal infections will be of bacterial or parasitic origin and potentially curable by single dose treatments. This paper will review the main causes of infectious diarrhoea in tropical areas and highlight the cases where singlc dose therapy is possible. Bacterial food poisoning will not be discussed because diarrhoea is due to ingested toxins and not to the development of microorganisms in the intestine. Microbial diarrhoea may result from 2 mechanisms: perturbation of fluid or sodium absorption (toxigenic), or invasion and damage to the mucosa. Several types of diarrhoea exist. These include watery acute diarrhoea from toxins, bloody and exudative dysentery with abdominal pain, caused by gut-invading pathogens, and chronic diarrhoea, often of parasitic origin. Because of the difficulty of surveillance, there have been few communitybased studies of the enteropathogens associated with diarrhoea. Among 8139 patients with diarrhoea in Bangladesh, Black et al. 116 ] reported 26% with enterotoxinogenic Escherichia coli, 12% with Vibrio cholerae, 5% with Shigella, 4% with Entamoeba histolytica, 2% with Giardia and less than I % with Salmonella. In other studies with children under the age of 5, enterotoxinogenic E. coli, Campylobacter, Shigella and Rotavirus accounted for 9 to 28%, 3 to 25%, 1 to 13% and 8 to 46%, respectively.IIS] However, several pathogens are often involved, and it is difficult to establish a correlation between gastrointestinal symptoms and an individual pathogen. For parasitic infections, information can be obtained from residents of industrialised countries who acquired a single infection during travel in tropical countries. 117 ] Causes and mechanisms of tropical infectious diarrhoea are summarised in table 1. In most cases, diarrhoea results from the ingestion of food or water contaminated by human or animal faeces. Rotaviruses are the most common cause of dehydrating diarrhoeal illness in children under the age of 2. Diarrhoea associated with this pathogen is due to disorganised enterocyte renewal and migration. Increased shedding of infected cells in the lumen of the small intestine occurs and the new enterocytes have the characteristics of undifferentiated secretory crypt cells)18] Production of neurohumoral inflammatory mediators was also reported. Other less commonly involved viruses include Norwalk virus, adenoviruses, astrovirus, and coronavirus. Viruses are transmitted by the faecal-oral route or, less frequently, by the respiratory route. E. coli comprise most of the bacterial human intestinal flora. Several types of E. coli can cause diarrhoea by different mechanisms: enterotoxigenic, enteroinvasive, enteropathogenic, and enteroadherent. Enterotoxigenic E. coli are the most common cause of diarrhoea in young children and in travellers. These organisms may elaborate multiple virulence determinants, including fimbrial adhesins, and heat labile and heat stable enterotoxins. Enteroinvasive E. coli cause dysentery by invading epithelial cells of the colon in a similar manner to Shigella. Enteropathogenic E. coli have no recognisable toxin. They do not invade epithelium but attach themselves to enterocytes, inducing an alteration in cell shape and localised destruction of the brush border. 1 19 ] Drug Invest. 8 (Suppl. 1) 1994 Other bacteria involved in enteritis are Shigella, Salmonella, Campylobacter and Yersinia, which invade host gut epithelium, primarily the ileum and the colon. Mucosal ulcerations with an acute inflammatory response with neutrophil infiltrates and microabscesses in the lamina propria are common features. This local inflammatory response (associated with toxins of bacterial origin) causes secretion, and the damaged epithelium is unable to reabsorb fluids from gut lumen. Salmonella and Campylobacter are found in the intestine of many vertebrates and are present in water and contaminated food. Humans are the only natural host of Shigella, and contamination usually results from person to person transmission. A very small inoculum of Shigella (less than 10) can produce a human infection.f 20 ] Humans are the only known host for cholera, but an inoculum of at least 10 9 Vibrio is required to produce acute cholera, especially in individuals with normal gastric acidity. Vibrio cause diarrhoea through secretion of a potent toxin, which inhibits adenyl ate cyclase of enterocytesPO] Intestinal parasites can produce all forms of diarrhoeal illnesses, including acute watery diarrhoea, dysentery or chronic diarrhoea. Most of these infections are common in tropical areas. Giardiasis and cryptosporidiosis are also frequent in industrialised countries, particularly in institutions or daycare centres.l 21 ,22] Giardia spp. are among the most frequent protozoa in the intestinal tract, and as few as 10 cysts can initiate infection. After excystation, the trophozoite attaches to the epithelium of the small intestine by a ventral disk. Although the majority of infected individuals are symptom free, a villous atrophy resulting from direct physical injury, giardial proteinases and activation of mucosal T cells by giardial antigens may be observedP3, 24] Cryptosporidium is known to occur in many wild and domestic animals (calves) but is now very frequent in AIDS patients,l2S,26] Easier diagnosis through the use of special stains, developed to detect mycobacteria, have shown that Cryptosporidium is also an important cause of diarrhoea in immunocompetent individuals. [24] Villous atrophy is common and can be accompanied by an inflammatory infiltrate of the lamina propria. The brush border is severely damaged by the intraepithelial development of Cryptosporidia. I 27 ] Isospora belli is a rare pathogen in immunocompetent individuals. In AIDS patients, the pathogenic changes in the bowel are similar to those observed with Cryptosporidium. Microsporidia spp. are intracellular, sporeforming protozoa, now commonly described in AIDS patients but also found in immunocompetent patients (Datry, personal communication 1994). The mechanism of diarrhoea is unclear as the brush border appears normal, but small infiltrates of mononucleated cells can be observed in the lamina propria.128,29] The newly described Cyclospora spp. (or CLB for Cyanobacteria-like bodies) belong to the coccidian group and have been observed in diarrhoeal stools from several parts of the world. The mechanism of pathogenicity is unknown but could be similar to Isospora. 130] E. histolytica is predominantly a colonic enteropathogen, but extracolonic disease, particularly liver abscesses, can develop. Although an estimated 500 million people are infected by this parasite, only 1.5 million will develop symptomatic disease, resulting in 50 to 100 000 deaths) 31] This gap between the number of infected and symptomatic people has led some authors to consider the hypothesis that 2 species of E. histolytica exist: one pathogenic, the other nonpathogenic. [32] This hypothesis was confirmed by isoenzyme analysis, which showed an association between a specific pattern and pathogenicity)33] However, this now widely accepted hypothesis was discussed by some authors claiming that a change of pattern was possible after bacterial influence,l34] Experimental studies in vitro have shown that the cytolytic potential of E. histolytica was dramatically increased when associated with bacteria. 134] The first step in invasion is adhesion to the epithelium, mediated by a galactose binding protein. [35, 36] Following con-tact, cytolysis occurs rapidly and is dependent on phospholipase activity, pore-forming peptides and proteolytic enzymes. E. histolytica trophozoites kill and phagocytise cells such as enterocytes and neutrophils, thus allowing deeper penetration in the intestine wall. Balantidium coli, a large but rare ciliate protozoa living in pig intestine, can provoke a dysenteric syndrome very similar to that produced by E. histolytica. It is found in tropical countries where close contact between humans and animals exist (Africa south of Sahara, South America). Other intestinal protozoa can be found in the stools: flagellates such as Chilomastix mesnili or Trichomonas intestinalis, amoebas such as E. coli, E. hartmanni, Endolimax nana, Pseudolimax butschlii, Dientamoeba fragilis. Although this point is discussed, for most authors these parasites are nonpathogenic (except D. fragilis) and do not require any treatment. Despite the high prevalence of intestinal helminthic infections, only a few intestinal helminths that invade the gut mucosa cause symptomatic diarrhoea.!17] Adults or larvae of Trichinella sp., Strongyloides stercoralis, Trichuris trichiura, Capillaria philipensis and, to a lesser extent, Hymenolepis nana and hookworms are present in the wall of the intestine. Eggs of Schistosoma spp. can be found in the submucosa and lamina propria of the bowel. Trichinella is found worldwide and is transmitted to humans by the ingestion of inadequately cooked meat (especially pork and horse) containing infective larvae. Trichinella spiralis usually induces diarrhoea during the few days preceding the occurrence of the systemic symptoms, i.e. fever, facial oedema and myalgias. [37] Chronic diarrhoea has been described in Inuit populations, who are frequently re-infected by the parasite. [ T. trichiuria is very common worldwide, infecting at least 800 million people. This worm has a very thin anterior head, which penetrates the mucosa of the caecum. Inflammation is usually mild or absent, but an increased number of mucosal macrophages and mast cells can lead to local anaphylaxis and diarrhoea.l 40 ] Diarrhoea occurs only in heavy infections and correlates with the number of eggs recovered per gram of faeces. 117 1 C. philipensis, which is particularly prevalent in the Philippines and Thailand among raw-fish eaters, shares with S. stercoralis the ability to replicate within its host. [41] All stages of the parasite are found within the mucosa, where they cause inflammation and a flattening of villi. The parasite is responsible for chronic diarrhoea leading to significant loss of weight, and cachexia, which may be fatal. Infection with S. stercora/is follows skin contact with water or mud contaminated with faeces containing infective larvae.l 42 ] Females of Strongyloides invade the proximal small intestinal mucosa and cause partial villous atrophy and inflammatory infiltrates. The colonic mucosa can also be severely damaged during disseminated strongyloidiasis, particularly in immunosuppressed patients where the continuous internal replication of the parasite increases the size of the adult population. In this syndrome, millions of filariform larvae can penetrate the wall of the small intestine, causing mucosal ulcerations and bacterial invasion leading to septicaemia and peritonitisJ43] More In addition to the general immunosuppression caused by loss of T cells in AIDS patients, there are also changes in the gut-associated lymphoid tissue and in nonspecific mechanisms of host resis-tanceJ46] In AIDS patients all of the pathogens described above can be a cause of diarrhoea, but those most commonly found are Cryptosporidium, Microsporidium, Cytomegalovirus, Giardia, Salmonella, Shigella and Mycobacterium avium-intracellulare. Cryptosporidium, which causes selflimited diarrhoea in immunocompetent patients, may result in severe, refractory diarrhoea in AIDS patients.125,29,471 Diagnostic procedures are based on the visualisation of the causative agent in a faecal sample, which may require several days before a definitive diagnosis can be made. Newer techniques including enzyme-linked immunoabsorbent assay (ELISA), monoclonal antibodies, and polymerase chain reaction (PCR) may shorten the time to diagnosis but are frequently expensive. We will highlight some simple approaches to the diagnosis of diarrhoea that can be found in the 'Manual of Basic Techniques for a Health Laboratory' .148J Details on more sophisticated methods are reported in the recent reviews of Cook l49 ] and Guerrant and Bobak.1141 Faecal leucocyte examination is useful and inexpensive. A fresh stool sample, preferably containing mucus, is mixed with 2 drops of saline and examined microscopically under a coverslip. A high leucocyte or erythrocyte count of 20 to 50 per high power field suggests an invasive colonic disease of bacterial or protozoal origin. The absence of leucocytes suggests a small intestinal toxigenic diarrhoea of viral or bacterial origin. Subsequent cultures (Salmonella, Shigella and Drigalski media) and specific biochemical tests are required to diagnose Salmonella or Shigella infection. A keen microbiologist will be able to recognise the curved Gram-negative bacillus of Vibrio on wet mounts. Viruses can be detected in stools by ELISA or by latex agglutination, but this detection is reserved for specialised laboratories)49] For dysenteric syndromes or persisting diarrhoea, parasitological investigations should be carried out. Finding live E. histolytica or Giardia Lamblia (also known as G. intestinalis and G. duodenalis) or trophozoites requires careful examination of a fresh faecal sample. Lugol's iodine can be useful to stain the characteristic nuclei of Entamoeba and to aid differentiation from intestinal macrophages. Concentration techniques using formalin and ether sedimentation, with or without zinc sulfate flotation, are recommended to increase the sensitivity of detection of parasites)50] However, these techniques, which require chemicals and centrifugation, may be difficult to carry out in some laboratories and may destroy trophozoites. The simple Kato thick smear techniquel51I can also be used, but this technique is not very effective in demonstrating protozoan parasites. Single dose treatments have a number of important advantages that result in excellent compliance: I) administration is simple, possible in mass treatments, and the intake of the drug can be checked easily; 2) side effects, if any, will last for a short period and will not interrupt treatment; and 3) the rate of emergence of resistant organisms could be lowered by the short period of drug pressure. Continuous metronidazole exposure of Giardia over several months resulted in the occurrence of resistant strains) 53 l However, possible disadvantages include the following: I) absorption could be impaired in patients with diarrhoea or malnutrition; 2) side effects could be more important, because of higher serum concentrations; 3) patients could be disappointed when symptoms persist while they are not receiving any treatment; and 4) the ease of such treatments can lead to frequent self-medication in countries where prescriptions are not required. The basic treatment for every infectious diarrhoea, particularly in children, includes rehydration by oral solutions such as the standard WHO solutionJ54,55] Single dose treatments are mainly used for parasitological and some bacterial infections. Quinolones can be used in single dose for shigellosis or traveller'S diarrhoea (e.g. pefloxacin or norfloxacin in a single dose of 800mg), and a single dose regimen with doxycycline has been effective in cholera outbreaks. 156 ] The single dose treatments that can be prescribed for parasitic diarrhoea are detailed in table II. All parasites de- Secnidazole has pharmacological characteristics that make this drug useful for single dose treatments of intestinal amoebiasis and giardiasis. Secnidazole is the nitroimidazole with the longest half-life in vivo)13] It is rapidly distributed throughout the body and achieves high concentrations in the target biological tissues and organs. [63, 64] The distribution half-life of secnidazole is close to 10 minutes, The time of appearance (tmax) of the maximum concentration (C max) is one hour and blood levels range from 27 to 68. However, data on the concentrations of secnidazole in other tissues and fluids are lacking, but they should be similar to those reported for metronidazole and tinidazole. For these drugs, the maximal concentration (expressed as a percentage of serum concentration) was 70% in the colon, 55% in bile, and 110% in the ileum) 67 1 Three days after oral administration or secnidazole, mean serum values of 4 mglL were well above the minimum inhibitory concentrations (MICs) of Giardia, Entamoeba histolytica and Trichomonas vaginalis (see below) lfig. IJ. For tinidazole and ornidazole, serum concentrations 72 hours after intake were 1.3 and 0.8 mg/L, respectivelyJ63,68] The anti protozoal activity of nitroimidazoles is linked to the ferredoxin oxidoreductase-mediated reduction of the nitro groupJ69] A short-lived re-duction product, the protonated one-electron nitro radical anion, oxidises microbial DNA, resulting in strand breaks and cell death ( fig. 2) . DNAs with high adenine-thymidine contents (e.g. Trichomonas and Entamoeba) are more susceptible to oxidative damages) 70] In the presence of oxygen, reduction of the nitro group cannot occur; therefore, the nitroimidazoles are toxic only for anaerobic cells or organisms. [7I] Giardia, Trichomonas and Entamoeba, with no mitochondria, are anaerobic protozoa in which ferredoxin oxidoreductase is a key enzyme for anaerobic glycolysis. In animal studies, secnidazole was found to be twice as active as metronidazole for amoebiasis, with serum concentrations of 3 to 6 mg/L.[n) 3] In in vitro assays to test the antigiardial activity of drugs,f74] concentrations inhibiting 50% of the growth of Giardia were 0.15 mg/L for secnidazole, 0.38 mg/L for quinacrine, 0.41 mg/L for furazolidone and 1.15 mg/L for metronidazole. [75] Secnidazole in a single dose of 2g (or 30 mg/kg) is very effective treatment for giardiasis, in common with other long-acting nitroimidazoles [76] [77] [78] and for acute intestinal amoebiasis, where other nitroimidazoles require 2 or 3 doses. [79] [80] [81] [82] The WHO recommended secnidazole as the only nitroimidazole for use as a single dose treatment for amoebic dysentery.[83J When prescribed for several days, secnidazole is also active against cysts [82, 84, 85] and hepatic amoebiasis.f79,82] Treatment failures have been reported with nitroimidazoles but these may be linked to malabsorption or reinfection.f 74 ,86] Experimentally, it was possible to induce in vitro resistance of Giardia to metronidazole and Entamoeba to emetine by continuous drug exposure over several months.f53,87] The MICs were SOO-fold higher than those before drug exposure. However, the few reports of in vivo resistance to nitroimidazoles are not convincing. Toxicity studies in a mouse model have shown the very low toxicity of secnidazole, with a lethal dose for 50% (LD50) of approximately 2.5 g/kg. In long term studies, secnidazole was well tolerated by dogs at a dosage of 400 mg/kg/day for 1 month; however 200 mglkg/day for 3 months produced some neurological effects. Tests of mutagenicity using Salmonella typhi and E. coli were positive. [72] The effect of nitroimidazoles on human DNA is of concern, but this interaction requires a nitroreductase, which is only present in anaerobic microorganisms. In the late seventies, the possible carcinogenicity of metronidazole was evaluated in animal studies. However, the methodology used was questionable, and carcinogenicity in humans is not considered to be a problem.f88] Although no evidence of any teratogenic effect has been observed in experimental studies of secnidazole, [72] the drug should not be administered during the first trimester of pregnancy or during lactation because secnidazole can be detected in the placenta and breast milk. This could be a potential limitation for mass treatment. However, a review of more than 2000 pregnant women treated with metronidazole did not identify an in creased incidence of malformations. [88, 89] The only real but rare contraindication to secnidazole is a known hypersensitivity to nitroimidazoles (urticaria). Ingestion with alcohol can provoke an an- tabuse-like effect, and close monitoring is recommended if the patient is taking warfarin. f6 ] Side effects common to all nitroimidazoles include gastrointestinal disturbances (abdominal pain, diarrhoea, a metallic taste, nausea), headache, and dizziness. These side effects are significantly lowered by evening administration [ II] Urticaria, leucopenia, and neurological complications (such as paraesthesias) have not been reported for secnidazole. Patients with intestinal amoebiasis may be reluctant to receive single dose regimens for a disease with such a bad reputation, but intestinal symptoms of amoebiasis can disappear in a few hours following treatment with secnidazole. L79 ] Diarrhoea causing poor drug absorption could be responsible for treatment failures reported by some authors treating giardiasis in children. However, data concerning the absorption of nitroimidazoles in the presence of diarrhoea are lacking. In contrast, some studies have shown that malnourished children have increased serum concentrations of metronidazole.l 90 ] Despite higher serum concentrations, side effects are less frequent than those observed with long term metronidazole therapy. [761 In most cases, the treatment of tropical infectious diarrhoea will require oral rehydratation. In some instances (e.g. shigellosis, intestinal amoebiasis, giardiasis, bilharzia, strongyloidosis), a single dose treatment will be effective, producing a significant advance in the management of these infections. Unfortunately, some parasites are naturally resistant to existing drugs (cryptosporidiosis) or require long courses of treatment (microsporidiosis, C. philipensis). Moreover, some pathogens that are usually easily cured prove to be relatively refractory to treatment in immunosuppressed patients. Prevention of tropical infectious diarrhoea should be a high priority for international health authorities. Faecal contamination of water and the environment is of crucial importance in transmission and is linked to poor socioeconomic conditions and inadequate sanitation. [91] The development of vaccines against enteric pathogens is an area of active research, [15] but prevention of diarrhoea could be achieved by education (hand-washing), sanitation (disposal of excreta), and improved availability and quality of water. A propos du traitement de 700 cas de bilharziose par les medicaments recents: oxamniquine, praziquantel, oltipraz Long term effects of single dose metrifonate on the control of urinary schistosomiasis in an endemic area Bunnag 0, et al. 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