Gastro-intestinal infections

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37 Gastro-intestinal infections

J.W. Gray

Key points

• There are many different microbial causes of gastro-intestinal infections.
• Gastroenteritis is the most common syndrome of gastro-intestinal infection, but some gastro-intestinal pathogens can cause systemic infections.
• Fluid and electrolyte replacement is the mainstay of management of gastroenteritis.
• Most cases of gastroenteritis that occur in developed countries are mild and self-limiting, and do not require antibiotic therapy.
• Antibiotic therapy should be considered for patients with underlying conditions that predispose to serious or complicated gastroenteritis, or where termination of faecal excretion of pathogens is desirable to prevent further spread of the infection.
• Clostridium difficile is a very important cause of diarrhoea in hospitals. Strict control measures are required, and cases should be treated with oral metronidazole or vancomycin.
• Antibiotic therapy is also essential for life-threatening systemic infections, such as enteric fever.
• Where possible, antibiotic therapy should be delayed until a microbiological diagnosis has been established.
• The fluoroquinolones, for example, ciprofloxacin, are currently the most useful antibiotics for treating most bacterial gastro-intestinal infections, but resistance rates are increasing in many pathogens.
• Antibiotic resistance in gastro-intestinal pathogens is an escalating problem.

Gastro-intestinal infections represent a major public health and clinical problem worldwide. Many species of bacteria, viruses and protozoa cause gastro-intestinal infection, resulting in two main clinical syndromes. Gastroenteritis is a non-invasive infection of the small or large bowel that manifests clinically as diarrhoea and vomiting. Other infections are invasive, causing systemic illness, often with few gastro-intestinal symptoms. Helicobacter pylori, and its association with gastritis, peptic ulceration and gastric carcinoma, is discussed in Chapter 12.

Epidemiology and aetiology

In Western countries, the average person probably experiences one or two episodes of gastro-intestinal infection each year. Infections are rarely severe and the vast majority of cases never reach medical attention. Nevertheless, they are of considerable economic importance. In the UK, viruses such as rotaviruses, adenoviruses and noroviruses are probably the most common causes of gastroenteritis. Campylobacter, followed by non-typhoidal serovars of Salmonella enterica, are the most common reported causes of bacterial gastroenteritis. Cryptosporidiosis is the most commonly reported parasitic infection. In developing countries, the incidence of gastro-intestinal infection is at least twice as high and the range of common pathogens is much wider. Infections are more often severe and represent a major cause of mortality, especially in children.

Gastro-intestinal infections can be transmitted by consumption of contaminated food or water or by direct faecal–oral spread. Air-borne spread of viruses that cause gastroenteritis also occurs. The most important causes of gastro-intestinal infection, and their usual modes of spread, are shown in Table 37.1. In developed countries, the majority of gastro-intestinal infections are food borne. Farm animals are often colonised by gastro-intestinal pathogens, especially Salmonella and Campylobacter. Therefore, raw foods such as poultry, meat, eggs and unpasteurised dairy products are commonly contaminated and must be thoroughly cooked to kill such organisms. Raw foods also represent a potential source of cross-contamination of other foods, through hands, surfaces or utensils that have been inadequately cleaned. Food handlers who are excreting pathogens in their faeces can also contaminate food. This is most likely when diarrhoea is present, but continued excretion of pathogens during convalescence also represents a risk. Food handlers are the usual source of Staphylococcus aureus food poisoning, where toxin-producing strains of S. aureus carried in the nose or on skin are transferred to foods. Bacterial food poisoning is often associated with inadequate cooking and/or prolonged storage of food at ambient temperature before consumption. Water-borne gastro-intestinal infection is primarily a problem in countries without a sanitary water supply or sewerage system, although outbreaks of water-borne cryptosporidiosis occur from time to time in the UK. Spread of pathogens such as Shigella or enteropathogenic Escherichia coli by the faecal–oral route is favoured by over-crowding and poor standards of personal hygiene. Such infections in developed countries are most common in children and can cause troublesome outbreaks in paediatric wards, nurseries and residential children’s homes.

Table 37.1 Important causes of gastro-intestinal infection, their modes of spread and pathogenic mechanisms

Causative agent Chief mode(s) of spread Pathogenic mechanisms
Bacteria
Campylobacter Food, especially poultry, milk Mucosal invasion
    Enterotoxin
Salmonella enterica, non-typhoidal serovars Food, especially poultry, eggs, meat Mucosal invasion
    Enterotoxin
Salmonella enterica serovars Typhi and Paratyphi Food, water Systemic invasion
Shigella Faecal–oral Mucosal invasion
    Enterotoxin
Escherichia coli
Enteropathogenic Faecal–oral Mucosal adhesion
Enterotoxigenic Faecal–oral, water Enterotoxin
Enteroinvasive Faecal–oral, food Mucosal invasion
Verotoxin-producing Food, especially beef Verotoxin
Staphylococcus aureus Food, especially meat, dairy produce Emetic toxin
Clostridium perfringens Food, especially meat Enterotoxin
Bacillus cereus
Short incubation period Food, especially rice Emetic toxin
Long incubation period Food, especially meat and vegetable dishes Enterotoxin
Vibrio cholerae O1, O139 Water Enterotoxin
Vibrio parahaemolyticus Seafoods Mucosal invasion
    Enterotoxin
Clostridium difficile Faecal–oral (nosocomial) Cytotoxin
    Enterotoxin
Clostridium botulinum Inadequately heat-treated canned/ preserved foods Neurotoxin
Protozoa
Giardia lamblia Water Mucosal invasion
Cryptosporidium Water, animal contact Mucosal invasion
Entamoeba histolytica Food, water Mucosal invasion
Viruses Food, faecal–oral, respiratory secretions Small intestinal mucosal damage

Treatment with broad-spectrum antibiotics alters the bowel flora, creating conditions that favour superinfection with micro-organisms (principally Clostridium difficile) that can cause diarrhoea. C. difficile infection (CDI) may be associated with any antibiotic but clindamycin, the cephalosporins and the fluoroquinolones are most commonly implicated. CDI is most common in patients with serious underlying disease and in the elderly. Although some sporadic cases are probably due to overgrowth of endogenous organisms, person-to-person transmission also occurs in hospitals and care homes, sometimes resulting in large outbreaks.

Pathophysiology

Development of symptoms after ingestion of gastro-intestinal pathogens depends on two factors. First, sufficient organisms must be ingested and then survive host defence mechanisms, and second, the pathogens must possess one or more virulence mechanisms to cause disease.

Host factors

Healthy individuals possess a number of defence mechanisms that protect against infection by enteropathogens. Therefore, large numbers of many pathogens must be ingested for infection to ensue; for example, the infective dose for Salmonella is typically around 105 organisms. Other species, however, are better able to survive host defence mechanisms; for example, infection with Shigella or verotoxin-producing E. coli (VTEC) can result from ingestion of fewer than 100 organisms. VTEC (principally E. coli O157) are especially important because of the risk of a life-threatening complication, haemolytic uraemic syndrome (HUS).

Gastric acidity

Most micro-organisms are rapidly killed at normal gastric pH. Patients whose gastric pH is less acidic, as for example, following treatment with antacids or ulcer-healing drugs, are more susceptible to gastro-intestinal infections. There is a particularly strong association between proton pump inhibitor use and CDI.

Intestinal motility

It is widely held that intestinal motility helps to rid the host of enteric pathogens, and that anti-motility agents are therefore potentially hazardous in patients with infective gastroenteritis. Despite this, self-medication with antidiarrhoeals is commonly practised, and in otherwise healthy individuals is probably safe.

Resident microflora

The resident microflora of the lower gastro-intestinal tract, largely composed of anaerobic bacteria, help to resist colonisation by enteropathogens.

Immune system

Phagocytic, humoral and cell-mediated elements are important in resistance to different pathogens. Individuals with inherited or acquired immunodeficiencies are therefore susceptible to specific gastro-intestinal infections, depending on which components of their immune system are affected.

Organism factors

The first requirement of gastro-intestinal pathogens is that they are able to adhere to the gut wall and colonise the intestine. The symptoms of gastro-intestinal infection can then be mediated by various mechanisms (see Table 37.1).

Toxins

Toxins produced by gastro-intestinal pathogens can be classified as enterotoxins, neurotoxins and cytotoxins. Enterotoxins act on intestinal mucosal cells to cause net loss of fluid and electrolytes. The classic enterotoxin-mediated disease is cholera, the result of infection with toxigenic serotypes of Vibrio cholerae. Many other bacteria produce enterotoxins, including enterotoxigenic E. coli and Clostridium perfringens. The emetic toxins of S. aureus and Bacillus cereus are neurotoxins that induce vomiting by an action on the central nervous system. The symptoms of botulism are mediated by a neurotoxin that blocks release of acetylcholine at nerve endings. Cytotoxins cause mucosal destruction and inflammation (see later). The pathogenicity of C. difficile is mediated by two exotoxins, TcdA and TcdB, both of which are potent cytotoxic enzymes that damage the human colonic mucosa. Verotoxins are potent cytotoxins that cause direct damage to small-vessel endothelial cells, which is exacerbated by stimulation of production of inflammatory mediators by non-endothelial cells. This causes multiorgan microvascular injury, expressed most commonly as haemorrhagic colitis and HUS.

Mucosal damage

Cytotoxins are important in mediating mucosal invasion, but other mechanisms are also involved. Enteropathogenic E. coli causes diarrhoea by damaging microvilli when it adheres to the intestinal mucosa. Organisms such as Shigella and enteroinvasive E. coli express surface proteins that facilitate mucosal invasion. Diarrhoea due to mucosal damage may be due to reduction in the absorptive surface area or the presence of increased numbers of immature enterocytes which are secretory rather than absorptive.

Systemic invasion

The lipopolysaccharide outer membrane and possession of an antiphagocytic outer capsule are important virulence factors in invasive Salmonella infections.

Clinical manifestations

Many cases of gastro-intestinal infection are asymptomatic or cause subclinical illness. Gastroenteritis is the most common syndrome of gastro-intestinal infection, presenting with symptoms such as vomiting, diarrhoea and abdominal pain. The term ‘dysentery’ is sometimes applied to infections with Shigella (bacillary dysentery) and Entamoeba histolytica (amoebic dysentery), where severe colonic mucosal inflammation causes frequent diarrhoea with blood and pus. Table 37.2 shows the most important causative agents of gastroenteritis together with a brief description of the typical illness that each causes. However, the symptoms experienced by individuals infected with the same organism can differ considerably. This is important because it means that it is rarely possible to diagnose the cause of gastroenteritis on clinical grounds alone.

Table 37.2 Characteristic clinical features of various causes of gastroenteritis

Causative agent Incubation period Symptoms (syndrome)
Campylobacter 2–5 days Bloody diarrhoea
    Abdominal pain
    Systemic upset
Salmonella 6–72 h Diarrhoea and vomiting
    Fever; may be associated bacteraemia
Shigella 1–4 days Diarrhoea, fever (bacillary dysentery)
Escherichia coli
Enteropathogenic 12–72 h Infantile diarrhoea
Enterotoxigenic 1–3 days Traveller’s diarrhoea
Enteroinvasive 1–3 days Similar to Shigella
Verotoxin-producing 1–3 days Bloody diarrhoea (haemorrhagic colitis)
    Haemolytic uraemic syndrome
Staphylococcus aureus 4–8 h Severe nausea and vomiting
Clostridium perfringens 6–24 h Diarrhoea
Bacillus cereus
Short incubation period 1–6 h Vomiting
Long incubation period 6–18 h Diarrhoea
Vibrio cholerae O1, O139 1–5 days Profuse diarrhoea (cholera)
Vibrio parahaemolyticus 12–48 h Diarrhoea, abdominal pain
Clostridium difficile Usually occurs during/just after antibiotic therapy Diarrhoea, abdominal pain, pseudomembranous enterocolitis
Giardia lamblia 1–2 weeks Watery diarrhoea
Cryptosporidium 2 days–2 weeks Watery diarrhoea
Entamoeba histolytica 2–4 weeks Diarrhoea with blood and mucus (amoebic dysentery), liver abscess
Viruses 1–2 days Vomiting, diarrhoea
    Systemic upset

Gastro-intestinal manifestations of infection with VTEC range from non-bloody diarrhoea to haemorrhagic colitis. In addition, VTEC are the most important cause of HUS, a serious complication which is most common in young children and the elderly. HUS is defined by the triad of microangiopathic haemolytic anaemia, thrombocytopenia and acute renal dysfunction. The mortality is about 5% and up to half the survivors suffer long-term renal damage.

The clinical spectrum of CDI ranges from asymptomatic carriage to life-threatening pseudomembranous colitis (so-called because yellow-white plaques or membranes consisting of fibrin, mucus, leucocytes and necrotic epithelial cells are found adherent to the inflamed colonic mucosa).

Enteric fever, resulting from infection with S. enterica serovars Typhi and Paratyphi, presents with symptoms such as headache, malaise and abdominal distension after an incubation period of 3–21 days. During the first week of the illness, the temperature gradually increases, but the pulse characteristically remains slow. Without treatment, during the second and third weeks, the symptoms become more pronounced. Diarrhoea develops in about half of cases. Examination usually reveals splenomegaly, and a few erythematous macules (rose spots) may be found, usually on the trunk. Serious gastro-intestinal complications such as haemorrhage and perforation are most common during the third week. Symptoms begin to subside slowly during the fourth week. In general, paratyphoid fever is less severe than typhoid fever.

Botulism typically presents with autonomic nervous system effects, including diplopia and dysphagia, followed by symmetrical descending motor paralysis. There is no sensory involvement.

Gastro-intestinal infections are often followed by a period of convalescent carriage of the pathogen. This usually lasts for no more than 4–6 weeks but can be for considerably longer, especially for Salmonella.

Investigations

Many cases of gastroenteritis outside hospital are mild and short lived, and microbiological investigation may not be necessary. However, investigations are always recommended where antibiotic therapy is being considered (Fig. 37.1), where there are public health concerns (e.g., if the sufferer works in the food industry) and for gastro-intestinal infections in hospitalised patients.

image

Fig. 37.1 Pathway for the investigation and management of patients with symptoms of acute gastroenteritis.

The mainstay of investigation of diarrhoeal illness is examination of faeces. Bacterial infections are usually diagnosed by stool culture. Various selective culture media designed to suppress growth of normal faecal organisms and/or enhance the growth of a particular pathogen are used. When sending specimens to the laboratory, it is important that details of the age of the patient, the clinical presentation and recent foreign travel are provided so that appropriate media for the likely pathogens can be selected. Several tests are available for rapid detection of C. difficile toxin, or of toxigenic C. difficile, in faeces: early and accurate diagnosis is crucial for the control of C. difficile in hospitals. Sigmoidoscopy is used to diagnose pseudomembranous colitis.

Various other procedures are sometimes useful in investigating patients with suspected bacterial gastroenteritis. Blood cultures should be taken from patients with severe systemic upset and are especially important when enteric fever is suspected. In enteric fever, the causative organism may also be cultured from urine or bone marrow. In S. aureus and B. cereus food poisoning, the pathogen can sometimes be isolated from vomitus. In cases of food poisoning, suspect foods may also be cultured. In general, serological investigations are of little value in the diagnosis of bacterial gastroenteritis. However, demonstration of serum antibodies to E. coli O157 can be helpful in confirming the cause of the HUS. Serological tests for typhoid and paratyphoid fever are available, but the results must be interpreted with caution. Botulism is diagnosed by demonstration of toxin in serum.

Parasitic infestations are usually detected by microscopic examination of faeces. Electron microscopy has been largely superseded by immunological and molecular-based detection techniques for detection of enteric viruses.

Treatment

Many gastro-intestinal infections are mild and self-limiting and never reach medical attention. Where treatment is required, there are three main therapeutic considerations. Fluid and electrolyte replacement is the cornerstone of treatment of diarrhoeal disease. Most patients can be managed with oral rehydration regimens, but severely dehydrated patients require rapid volume expansion with intravenous fluids. Symptomatic treatment with antiemetics and anti-motility (antidiarrhoeal) agents is sometimes used, especially as self-medication. Antimicrobial agents may be useful both in effecting symptomatic improvement and in eliminating faecal carriage of pathogens and therefore reducing the risk of transmitting infection to others.

Antiemetics and antidiarrhoeal drugs are discussed in Chapters 34 and 14, respectively. This chapter focuses on the place of antibiotic therapy in gastro-intestinal infections.

Antibiotic therapy

The requirement for antibiotic treatment in gastro-intestinal infection depends on the causative agent, the type and severity of symptoms and the presence of underlying disease. Antibiotics are ineffective in some forms of gastroenteritis, including bacterial intoxications and viral infections. For many other infections, such as salmonellosis and campylobacteriosis, effective agents are available, but antimicrobial therapy is often not clinically necessary. Serious infections such as enteric fever always require antibiotic therapy.

Conditions for which antibiotic therapy is not available or not usually required

The symptoms of S. aureus and short incubation period B. cereus food poisoning and botulism are usually caused by ingestion of preformed toxin, and therefore antibiotic therapy would not influence the illness. Pathogens such as C. perfringens, Vibrio parahaemolyticus and enteropathogenic E. coli usually cause a brief self-limiting illness that does not require specific treatment.

None of the presently available antiviral agents are useful in viral gastroenteritis. While most viral infections are self-limiting, chronic viral gastroenteritis can occur in immunocompromised patients. Where possible, immunosuppression should be reduced. Immunoglobulin-containing preparations, administered orally or directly into the duodenum via a nasogastric tube, have also been reported to be effective in managing chronic viral gastroenteritis in immunocompromised patients. As well as human serum immunoglobulin, antibodies from other species (e.g. immunised bovine colostrum) have been used. Immunotherapy of viral gastroenteritis remains experimental, and dosages and frequency of administration of immunoglobulin preparations cannot be recommended (Mohan and Haque, 2002).

At least one study has found that the risk of HUS in children with diarrhoea due to VTEC was much higher in those who received antibiotics. On that basis, it is advised in the UK that antibiotics are contraindicated in children with VTEC infection (National Collaborating Centre for Women’s and Children’s Health, 2009).

Conditions for which antimicrobial therapy may be considered

The place for antibiotics in the management of uncomplicated gastroenteritis due to bacteria such as Salmonella and Campylobacter is not clear cut. Certain antibiotics are reasonably effective in reducing the duration and severity of clinical illness and in eradicating the organisms from faeces. However, many microbiologists are cautious about the widespread use of antibiotics in diarrhoeal illness because of the risk of promoting antibiotic resistance (Sack et al., 1997). Another difficulty with respect to antibiotic prescribing is that it is not usually possible to determine the aetiological agent of diarrhoea on clinical grounds, and stool culture takes at least 48 h. Patients with severe illness, especially systemic symptoms, may require antibiotic therapy before the aetiological agent has been established. In such circumstances, a fluoroquinolone antibiotic such as ciprofloxacin would usually be the most appropriate empiric agent, at least in patients in whom CDI is considered unlikely or has been excluded. Otherwise, it is reasonable to limit antibiotic use to microbiologically proven cases where there is serious underlying disease and/or continuing severe symptoms. Antibiotics may also be used to try to eliminate faecal carriage, for example, in controlling outbreaks in institutions, or in food handlers who may be prevented from returning to work until they are no longer excreting gastro-intestinal pathogens.

Campylobacteriosis

Erythromycin is effective in terminating faecal excretion of Campylobacter. Some studies have shown that treatment commenced within the first 72–96 h of illness can also shorten the duration of clinical illness, especially in patients with severe dysenteric symptoms. The recommended dosage for adults is 250–500 mg four times a day orally for 5–7 days, and for children 30–50 mg/kg/day in four divided doses. Clarithromycin 250–500 mg (children under 1 year, 7.5 mg/kg; 1–2 years, twice a day; 3–6 years, 125 mg; 7–9 years, 5–7 days) or azithromycin 500 mg (children 10 mg/kg) once daily for 3 days are also effective. Ciprofloxacin, at a dose of 500 mg twice daily orally for adults, may also be effective in Campylobacter enteritis. However, whereas resistance rates to erythromycin have generally remained below 5%, resistance to ciprofloxacin has emerged, exceeding 10% in the UK and 50% in some countries (Dingle et al., 2005).

Salmonellosis

Most cases of Salmonella gastroenteritis are self-limiting and antibiotic therapy is unnecessary. However, antimicrobial therapy of salmonellosis is routinely recommended for infants aged under 6 months and immunocompromised patients, who are susceptible to complicated infections. Most antibiotics, even those with good in vitro activity, do not alter the course of uncomplicated Salmonella gastroenteritis. However, the fluoroquinolones, such as ciprofloxacin, can often shorten both the symptomatic period and the duration of faecal carriage. Ciprofloxacin resistance is now seen in up to 10% of non-typhoidal serovars of S. enterica in some countries but is still uncommon in the UK (Murray et al., 2005). The recommended dose of ciprofloxacin for adults is 500 mg twice daily orally for 1 week. Fluoroquinolones are not licensed for this indication in children, although there is increasing evidence that they can safely be given to children. The recommended dose of ciprofloxacin in childhood is 7.5 mg/kg twice daily orally. Trimethoprim at a dose of 25–100 mg twice daily orally may be used in children if it is preferred not to use a fluoroquinolone.

Ciprofloxacin given orally at a dose of 500–750 mg twice daily in adults (7.5–12.5 mg/kg twice daily in children) or 200 mg intravenously twice daily in adults (5–7.5 mg/kg twice daily in children) is recommended for invasive salmonellosis. Alternative agents include ampicillin or amoxicillin, trimethoprim or chloramphenicol (see under enteric fever). However, resistance to these agents is more common than resistance to ciprofloxacin, and they are not recommended as empiric therapy.

E. coli infections

While most infections with enteropathogenic E. coli can be managed conservatively, small trials suggest that trimethoprim may be effective, especially in controlling nursery or hospital outbreaks. On the basis that enteroinvasive E. coli are closely related to Shigella and cause a similar clinical syndrome, similar therapy may be appropriate. Antibiotic therapy for traveller’s diarrhoea caused by enterotoxigenic E. coli infection is often unnecessary, but troublesome symptoms will often respond to a single dose of ciprofloxacin or azithromycin, the need for further doses depending on clinical response. Alternatively, a 3–5 day course of trimethoprim may be given, although resistance is becoming increasingly common in some areas. Rifaximin is a new non-absorbable antibiotic that is available in a number of countries. It appears to be as effective as ciprofloxacin in treating E. coli-predominant traveller’s diarrhoea but is ineffective in patients with inflammatory or invasive enteropathogens (Robins and Wellington, 2005). The dose for adults is 200 mg three times per day for 3 days.

Conditions for which antimicrobial therapy is usually indicated

Shigellosis

Shigella sonnei, which accounts for most cases of shigellosis in the UK and most other industrialised countries, usually causes a mild self-limiting illness. Even if not required on clinical grounds, antibiotic therapy for shigellosis is usually recommended in order to eliminate faecal carriage, and therefore prevent person-to-person transmission. In contrast to salmonellosis, a number of antibiotics may be effective in shortening the duration of illness and terminating faecal carriage. This is especially true of strains of S. sonnei that are endemic in industrialised countries, whereas in developing countries, Shigella species that are multiple antibiotic resistant are an increasing problem. The fluoroquinolones are highly effective in shigellosis and resistance is rare; therefore, they are often considered to be the treatment of choice, especially in adults and/or for treating imported infections. The dose of ciprofloxacin is 500 mg twice daily orally in adults (7.5 mg/kg twice daily in children). Amoxicillin is an alternative first-line drug for S. sonnei infections acquired in the UK, where around 90% of isolates are susceptible. The dose of amoxicillin is 250–500 mg three times daily in adults, and 62.5–125 mg three times daily in children. Azithromycin (doses as for campylobacteriosis) is increasingly recommended as an alternative agent for shigellosis, especially in children (Jain et al., 2005). Third-generation cephalosporins such as ceftriaxone are another option for severe shigellosis. Trimethorpim resistance is now common, so this agent can no longer be recommended as empiric therapy. Antibiotic therapy is usually given for a maximum of 5 days.

Enteric fever

Treatment should be commenced as soon as a clinical diagnosis of enteric fever is made. Fluoroquinolones remain widely used as the first-choice treatment for typhoid and paratyphoid fevers. When treating isolates that are fully sensitive, the clinical response is at least as rapid as with the older treatments, there is a lower relapse rate, and convalescent faecal carriage is shortened. However, the proportion of isolates with reduced susceptibility to fluoroquinolones has increased to around 75%. Although most of these isolates have minimum inhibitory concentration (MIC) values below those regarded as fully resistant, treatment failures have been reported. Resistance to other antibiotics that have been commonly used to treat enteric fever, such as co-trimoxazole, chloramphenicol and ampicillin, is now frequent. These agents therefore cannot be recommended as alternatives to fluoroquinolones for empiric treatment of enteric fever, but may be useful in patients with bacterial isolates that are confirmed as sensitive. Doses of ciprofloxacin are as outlined for non-typhoidal salmonellosis. The usual dose of chloramphenicol is 50 mg/kg/day in four divided doses, and for ampicillin 100 mg/kg/day in four divided doses. Two weeks of antibiotic therapy is usually recommended, although shorter courses of ciprofloxacin (7–10 days) may be as effective.

Alternative agents that have been reported to be successful where treatment failure with fluoroquinlones has occurred include intravenous carbapenems or third-generation cephalosporins (e.g. ceftriaxone 75 mg/day; maximum dose 2.5 g/day) or oral azithromycin at a dose of 20 mg/kg/day (maximum 1000 mg) for at least 5 days. Time taken for clearance of bacteraemia may be longer with azithromycin, but the relapse rate appears to be lower than with β-lactam antibiotics such as ceftriaxone. There is some evidence that gatifloxacin, a new-generation fluoroquinolone, may be more effective than ciprofloxacin or ofloxacin in the treatment of infections where isolates have decreased fluoroquinolone susceptibility.

Chronic carriers of Salmonella

Patients may become chronic carriers after Salmonella infection, especially in the presence of underlying biliary tract disease. Oral ciprofloxacin 500–750 mg twice daily continued for 2–6 weeks is usually effective in eradicating carriage and has largely superseded the use of oral amoxicillin at a dose of 3 g twice daily.

Cholera

Fluid and electrolyte replacement is the key aspect of the management of cholera. However, antibiotics do shorten the duration of diarrhoea and therefore reduce the overall fluid loss, and also rapidly terminate faecal excretion of the organism. Effective agents include tetracyclines, erythromycin, trimethoprim, ampicillin or amoxicillin, chloramphenicol, ciprofloxacin and furazolidine. However, antibiotic resistance is being increasingly seen, and in particular, V. cholerae O139 is intrinsically resistant to furazolidine and trimethoprim. Choice of antibiotics is therefore governed by knowledge of local resistance patterns, which may vary between outbreaks. Tetracycline 250 mg four times daily, or doxycycline 100 mg once daily by mouth, is probably the most widely used therapy in adults. Ampicillin, amoxicillin or erythromycin are generally the preferred agents for children. Although clinical cure can be achieved after a single dose of antibiotics, treatment is usually given for 3–5 days to ensure eradication of V. cholerae from faeces.

C. difficile infection

The first objective is to diagnose CDI as soon as possible so that appropriate treatment and infection control measures can be put in place. Clinicians must consider the diagnosis in any patient where there is no clear alternative diagnosis for their diarrhoea. Stool samples must be sent to the laboratory immediately, and the laboratory must make testing available 7 days per week. Once the diagnosis is confirmed, attention must be paid to the patient’s hydration and nutrition, non-essential antibiotic therapy or gastro-intestinal active drugs must be stopped and the patient’s condition closely monitored. Although mild cases may resolve without specific therapy, treatment of all hospitalised patients with diarrhoea due to C. difficile is recommended, to shorten the duration of illness and to reduce environmental contamination and therefore the risk of nosocomial transmission.

Oral metronidazole 400 mg three times daily for 10 days is the treatment of choice for mild to moderate CDI. For severe CDI, oral vancomycin is recommended at a dose of 125 mg four times daily for 10 days. In patients unable to take oral medication, either drug can be administered via a nasogastric tube. Where there is no response to initial treatment, the dose of vancomycin can be increased to up to 500 mg four times daily, together with intravenous metronidazole 500 mg three times daily. Addition of oral rifampicin (300 mg twice daily) or administration of intravenous immunoglobulin (400 mg/kg) can also be considered.

Recurrence of symptoms occurs in about 20% of patients treated for CDI. Although some recurrences are due to germination of spores that have persisted in the colon since the original infection, it is recognised that some of these cases are due to reinfection, rather than relapse caused by the original strain (Loo et al., 2004). Most recurrences respond to a further 10–14 day course of metronidazole or vancomycin, but a few patients experience repeated recurrences. There is no reliable means of managing these patients. Options include:

• a supervised trial of anti-motility agents alone (if there are no abdominal symptoms or signs of severe CDI)
• tapering or pulse therapy with oral vancomycin given for 4–6 weeks
• a 2-week course of oral vancomycin 125 mg four times daily and oral rifampicin 300 mg twice daily
• intravenous immunoglobulin, especially if the patient’s albumin status worsens
• donor stool transplant.

Trial data do not currently support the use of probiotics for the treatment or prevention of CDI (Department of Health and Health Protection Agency, 2009).

Cryptosporidiosis

Cryptosporidiosis in immunocompetent individuals is generally self-limiting. However, in immunosuppressed patients, severe diarrhoea can persist indefinitely and can even contribute to death. HIV-infected patients on highly active antiretroviral therapy (HAART) now have a much lower incidence of cryptosporidiosis due to immune reconstitution, and possibly a direct anti-cryptosporidium effect of protease inhibitors. There is no reliable antimicrobial therapy. Azithromycin, which is readily prescribable, is partially effective at a dose of 500 mg once daily (10 mg/kg once daily in children). Treatment should be continued until Cryptosporidium oocysts are no longer detectable in faeces (typically 2 weeks), to minimise the risk of relapse post-treatment. Occasionally, therapy has to be continued indefinitely to prevent relapse. Most other agents that have been recommended for treatment of cryptosporidiosis, for example, nitazoxanide, spiramycin, paromomycin and letrazuril, are not licensed in the UK. These can usually be sourced from special order manufacturing or importing companies (Smith and Corcoran, 2004). Of these agents, nitazoxanide has FDA approval in the USA, and has been shown to be effective in clinical trials at a dose of 500 mg twice daily (adults and children aged 12 years and over) for 3 days (children 1–3 years 100 mg bd; 4–11 years 200 mg bd). However, it is not effective unless the patient is able to mount an appropriate immune response.

Giardiasis

Metronidazole is the treatment of choice for giardiasis. Various oral regimens are effective, for example, 400 mg three times daily (7.5 mg/kg in children) for 5 days, or 2 g/day (children 500 mg to 1 g) for 3 days. Alternative treatments are tinidazole 2 g as a single dose, or mepacrine hydrochloride 100 mg (2 mg/kg in children) three times daily for 5–7 days. Nitazoxanide is a new thiazolide antiparasitic drug (discussed under cryptosporidiosis) that has also been licensed for treatment of giardiasis in some countries, but is not currently available in the UK. A single course of treatment for giardiasis has a failure rate of up to 10%. A further course of the same or another agent is often successful. Sometimes, repeated relapses are due to reinfection from an asymptomatic family member. In such cases, all affected family members should be treated simultaneously.

Amoebiasis

The aim of treatment in amoebiasis is to kill all vegetative amoebae and also to eradicate cysts from the bowel lumen. Metronidazole is highly active against vegetative amoebae and is commonly the treatment of choice for acute amoebic dysentery and amoebic liver abscess. The dose for adults is 800 mg (children 100–400 mg) three times daily for 5–10 days. To eradicate cysts, metronidazole therapy is followed by a 5-day course of diloxanide furoate 500 mg three times daily (20 mg/kg daily in three divided doses for children). Tinidazole has recently been shown to reduce clinical failure and be better tolerated than metronidazole (Gonzales et al., 2009). The dose of tinidazole for adults is 2 g daily for 2–3 days, and for children, 50–60 mg/kg daily for 3 days.

Asymptomatic excretors of cysts living in areas with a high prevalence of E. histolytica infection do not merit treatment because most individuals quickly become reinfected. However, asymptomatic excretors of cysts in Europe or North America are usually treated with diloxanide furoate for 5–10 days: metronidazole and tinidazole are relatively ineffective in this situation.

Patient care

People excreting gastro-intestinal pathogens are potentially infectious to others. Liquid stools are particularly likely to contaminate the hands and the environment. All cases of gastro-intestinal infection should be excluded from work or school at least until the patients are symptom free; hospitalised patients should be isolated in a single room. Patients should be advised on general hygiene, and in particular, on thorough handwashing and drying after visiting the toilet and before handling food.

In most countries, many gastro-intestinal infections are statutorily notifiable. Following notification, the authorities will judge whether the implications for public health merit investigation of the source of infection, contact screening or follow-up clearance stool samples from the original case.

Common therapeutic problems in the management of gastro-intestinal infection are summarised in Table 37.3. Problems associated with specific gastro-intestinal infections are summarised in Table 37.4.

Table 37.3 Practice points: general problems with treatment of gastro-intestinal infections

Problems Resolution
Difficult or impossible to make a rapid aetiological diagnosis Hospital laboratories are expected to offer rapid testing for C. difficile 7 days per week
New, more accurate, diagnostic tests for viral gastroenteritis are becoming more widely available Few other recent improvements in the diagnosis of bacterial or parasitic infections
Clinical effectiveness and cost-effectiveness of antibiotic therapy for many bacterial gastro-intestinal infections are not clearly established Without reliable data showing benefit, antimicrobial therapy is not used in the majority of infections
No specific therapies for viral gastroenteritis Infections in otherwise healthy individuals are generally self-limiting
  Various non-evidence-based experimental treatments have been used to manage immunocompromised patients with protracted diarrhoea
Acute illness may be followed by a period of non-infective diarrhoea Cautious use of antidiarrhoeal medication may be indicated at this stage

Table 37.4 Practice points: problems with treatment of specific gastro-intestinal infections

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Case studies

Case 37.1

A 12-year-old boy is admitted to hospital with a history of fever, weight loss and malaise 1 week after returning from visiting relatives in Pakistan. Whilst there he was diagnosed as having typhoid fever, and although details are sketchy, it seems that he received treatment with ciprofloxacin. The only other medical history of note is that he experienced an anaphylactic reaction after taking penicillin 4 years ago. Twenty-four hours after admission, S. enterica serovar Typhi is isolated from a blood culture.

Questions

1. Why might the patient not have responded fully to the treatment given in Pakistan?
2. Which antibiotic would now be most appropriate as empiric therapy?

Answers

1. Strains of S. enterica serovar Typhi that have reduced susceptibility to fluoroquinolones are common in the Indian subcontinent. Although these strains are not usually fully fluoroquinolone resistant, treatment failures have been reported, even when an appropriate dose regimen has been used: in this case, there is not even any assurance that the treatment regimen in Pakistan was adequate.
2. Given the lack of assurance of the adequacy of the ciprofloxacin treatment in Pakistan, one option would be to re-treat with ciprofloxacin. However, given the high likelihood that the strain will have reduced susceptibility to ciprofloxacin, it would be more logical to use an alternative agent. Of those, carbapenems and cephalosporins are beta-lactam antibiotics that would be best avoided, given the history of anaphylaxis following penicillin exposure. Azithromycin would appear, therefore, to be the empiric treatment of choice in this case.

Case 37.2

A mother brings her 6-year-old daughter to her primary care doctor because she has a 2-day history of bloody diarrhoea and abdominal pain. The family had been on a farm visit the previous weekend and had eaten food when there. The mother is anxious for her child to be treated with antibiotics because they will be going on their summer holiday in one week.

Questions

1. Give three possible infective causes of the girl’s symptoms.
2. How should the clinician respond to the mother’s request for antibiotics?

Answers

1. The two commonest bacterial gastro-intestinal infections, campylobacteriosis and salmonellosis, can both present in this way. Many other bacterial and protozoan causes of gastroenteritis can also cause similar symptoms. One bacterium that is especially important to consider in this case, where there is a history of a farm visit, is E. coli O157. Every effort should be made to obtain a stool sample from the patient for microbiological examination.
2. It would not be appropriate to treat this girl’s symptoms empirically with antibiotics for a number of reasons. First, antibiotic therapy may make no difference to the speed of clinical resolution; second, where antibiotics are justified, the choice of drug will depend on the aetiological agent; and third, antibiotics are contraindicated in infection with E. coli O157, which must feature in the differential diagnosis in this case.

Case 37.3

A businessman is planning a short trip to Egypt. During previous visits to the area, he has experienced troublesome diarrhoea despite being careful about hygiene. Although the diarrhoea has not made him seriously unwell, it has caused him considerable inconvenience during business discussions.

Question

Are there any antimicrobials that he could take to prevent this problem?

Answer

Although traveller’s diarrhoea is not usually serious, it can cause considerable inconvenience whether the sufferer is travelling for leisure or business reasons. Simple measures that can help prevent traveller’s diarrhoea include taking care with food and drinks (only bottled water from reputable sources should be used). There are two approaches to antibiotic use in traveller’s diarrhoea. Either the drug can be taken prophylactically to try to prevent diarrhoea developing, or treatment can be commenced with the onset of diarrhoea. The latter approach is generally preferred because it limits unnecessary exposure to antibiotics and the response to treatment is usually rapid. However, there are instances such as in this case where the inconvenience of even short-lived diarrhoea may be great enough to justify use of prophylaxis.

The choice of antibiotics for traveller’s diarrhoea has been made more complicated by the increasing prevalence of antibiotic resistance in many developing countries. Drugs such as amoxicillin or trimethoprim no longer have a role. A fluoroquinolone, such as ciprofloxacin, still represents a reasonable first choice, with azithromycin as a possible alternative in areas where fluoroquinolone resistance is known to be common. For travellers from countries where it can be prescribed, rifaximin may be the agent of choice. For travellers to areas where infections such as amoebic dysentery or giardiasis are common, it may be appropriate to take a supply of metronidazole that can be started if there is no response to the first-line antibacterial prophylaxis.

Case 37.4

An 80-year-old woman on an elderly care ward develops watery diarrhoea and abdominal pain 4 days after commencing therapy with ciprofloxacin for a urinary tract infection. C. difficile toxin is detected in a stool sample. Five patients on that ward have also had C. difficile-associated diarrhoea during the past 2 months.

Questions

1. How should this patient be managed?
2. What measures might be taken to try to reduce the number of cases of C. difficile-associated diarrhoea on the ward?

Answers

1. Treatment with ciprofloxacin should be discontinued. Four-day antibiotic therapy for a urinary tract infection will often suffice, but if further treatment is required, an antibiotic that is less likely to disturb the bowel flora should be prescribed. Metronidazole is the preferred first-line treatment for mild to moderate CDI. The patient should be closely monitored for the frequency and severity of the diarrhoea. Oral vancomycin might be indicated later if her illness became more severe. The patient should be isolated to reduce the risk of spread of the infection.
2. There are two elements to control of C. difficile in hospitals. First, it is necessary to ensure that antibiotic prescribing is rational. There should be an antibiotic-prescribing policy that minimises use of antibiotics in general, and in particular, restricts use of antibiotics that are associated with a high risk of C. difficile (2nd- and 3rd-generation cephalosporins, clindamycin and fluoroquinolones). Compliance with the policy must be assured through measures such as checking of prescriptions, multidisciplinary antibiotic ward rounds, education of prescribers, and audits of antibiotic prescribing. Second, strict infection control precautions must be enforced, along with improved standards of environmental cleanliness, to reduce the risk of patients being exposed to the bacterium.

References

Dingle K.E., Clarke L., Bowler I.C. Ciprofloxacin resistance among human Campylobacter isolates 1991–2004: an update. J. Antimicrob. Chemother.. 2005;55:395-396.

Department of Health and Health Protection Agency. Clostridium Difficile Infection: How to Deal with the Problem. London: Department of Health; 2009.

Gonzales M.L.M., Dans L.F., Martinez E.G. Antiamoebic drugs for treating amoebic colitis. Cochrane Database of Systematic Reviews.. 2009. Issue 2 Art No. CD006085. doi:10.1002/14651858.CD006085

Jain S.K., Gupta A., Glanz B., et al. Antimicrobial-resistant Shigella sonnei: limited antimicrobial treatment options for children and challenges of interpreting in vitro azithromycin susceptibility. Pediatr. Infect. Dis. J.. 2005;24:494-497.

Loo V.G., Libman M.D., Miller M.A., et al. Clostridium difficile: a formidable foe. Can. Med. Assoc. J.. 2004;171:47-48.

Mohan P., Haque K. Oral immunoglobulin for the prevention of rotavirus infection in low birth weight infants. Cochrane Database of Systematic Reviews.. 2002. Issue 3. Art. No.: CD003740. doi:10.1002/14651858.CD003740

Murray A., Coia J.E., Mather H., et al. Ciprofloxacin resistance in non-typhoidal Salmonella serotypes in Scotland, 1993–2003. J. Antimicrob. Chemother.. 2005;56:110-1104.

National Collaborating Centre for Women’s and Children’s Health. Diarrhoea and Vomiting Caused by Gastroenteritis: Diagnosis, Assessment and Management in Children Younger Than 5 Years. London: RCOG Press; 2009.

Robins G.W., Wellington K. Rifaximin: a review of its use in the management of traveller’s diarrhea. Drugs. 2005;65:1697-1713.

Sack R.B., Rahman M., Yunus M., et al. Antimicrobial resistance in organisms causing diarrheal disease. Clin. Infect. Dis.. 1997;24(Suppl. 1):S102-S105.

Smith H.V., Corcoran G.D. New drugs and treatment for cryptosporidiosis. Curr. Opin. Infect. Dis.. 2004;17:557-564.

Further reading

Bhan M.K., Bahl R., Bhatnagar S. Typhoid and paratyphoid fever. Lancet. 2005;366:749-762.

DuPont H.L. What’s new in enteric infectious diseases at home and abroad. Curr. Opin. Infect. Dis.. 2005;18:407-412.

Loeb M., Smaill F., Smieja M., editors. Evidence-Based Infectious Diseases. Oxford: Wiley-Blackwell, 2009.

Starr J. Clostridium difficile associated diarrhoea: diagnosis and treatment. Br. Med. J.. 2005;331:498-501.

Townes J.M. Acute infectious gastroenteritis in adults. Seven steps to management and prevention. Postgrad. Med.. 2004;115:11-19.

Yoshikawa T.T., Norman D.C., editors. Diseases in the Ageing. A Clinical Handbook. New York: Springer, 2009.

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