Antimicrobial Chemotherapy, 5th Edition
Part 4 - Therapeutic Use of Antimicrobial Agents
Gastrointestinal disease caused by bacteria, viruses, protozoa, and helminths are among the commonest infections suffered by mankind. Worldwide it has been estimated that on any one day 200 million people are suffering from acute infective gastroenteritis. Over 2 million children in Asia, Africa, and Latin America die each year of gastrointestinal infection. The very young, elderly, and malnourished are particularly at risk from the electrolyte and fluid losses that complicate severe diarrhoea or vomiting. Restoration of fluids and electrolytes is the mainstay of treatment; oral rehydration therapy has had a significant impact in reducing mortality in developing countries. Even in countries with well developed healthcare systems the true numbers of cases of infective gastroenteritis are certainly greater than those diagnosed in symptomatic patients, and greater still than those detected by testing faecal samples. Fig. 21.1 shows that for every one case of intestinal infection identified by laboratory testing, many more people have symptoms of this infection. This under-reporting of cases of gastroenteritis means that the full socio-economic impact of these infections, for example lost workdays, is unknown but certainly considerable.
Transmission and acquisition
Gastrointestinal pathogens are transmitted directly from person to person or indirectly through faecal contamination of the environment, food, or water supply. Viral gastroenteritis, which is highly infectious and affects all ages, is often transmitted by aerosols from vomit. Some pathogens, most notably salmonellae, are common to human beings and animals. The high frequency of gastroenteritis in developing countries reflects the scarcity of clean water supplies or safe sewage disposal, the close proximity of human beings living with animals, and the extent of poverty and malnutrition.
Travel-associated diarrhoea often affects residents of industrial countries travelling to developing countries. The onset is usually within 5-15 days of arrival and generally follows ingestion of salads, raw vegetables and untreated water (or ice). Enterotoxigenic Escherichia coli is the most common cause.
Fig. 21.1 Under ascertainment of gastroenteritis in England. From: Handysides S. Underascertainment of infectious intestinal disease.Communicable Disease and Public Health 1999; 2: 78-79.
There are major differences in the numbers of micro-organisms needed to cause gastroenteritis. For example, the infective dose of shigella is about 10-100 bacteria, whereas ingestion of 105-108 bacteria are required to cause salmonella or Escherichia coli gastroenteritis. This partly explains the ease of spread and epidemic nature of some types of gastroenteritis, e.g. Shigella sonnei dysentery in young children.
Viral gastroenteritis is also highly infectious, affects all ages, and has become much more common in recent years in the UK and Europe. The term ‘winter vomiting disease’ is sometimes used but this name is misleading because cases are increasingly seen throughout the year. Most importantly, viral gastroenteritis spreads rapidly, typically among people in close contact, such as children in nurseries, patients and healthcare workers in hospitals, and holidaymakers on cruise ships. Such outbreaks can severely affect normal activity—in a hospital it can force wards closures and cancellations of operations. In viral gastroenteritis not only is the diarrhoea infectious, but crucially vomiting creates a ‘cloud’ of virus that can contaminate surfaces or possibly be inhaled by others.
Food may be contaminated by various gut pathogens, or their toxins at source, in the abattoir, subsequent to marketing, or during preparation. When illness occurs as a sudden outbreak that can be traced to a common foodstuff, the term food poisoning is used. Non-microbial food poisoning occasionally results from the ingestion of chemicals, fungi, and other toxins such as scombrotoxin and ciguatoxin.
The incubation period of gastrointestinal infections varies according to the ingested dose, the site of infection in the gut, and the pathogenic mechanism of diarrhoea. The shortest incubation periods are seen with Staphylococcus aureus food poisoning where a preformed toxin produces symptoms within 0.5-8 h of ingestion. Longer incubation periods are associated with salmonellosis and shigellosis, in which microbial replication within the bowel may take a day or so before symptoms occur. Symptoms of nausea and vomiting are more frequently associated with small-bowel infection. Large-bowel involvement is often associated with tenderness over the colon. In dysentery, diarrhoea is accompanied by a profuse, bloody exudate. Regardless of the major site of action, colicky pain is the commonest symptom associated with gastrointestinal infection. The severity of illness is essentially dictated by the degree of fluid loss. Losses of less than 3% body weight are usually undetectable. As fluid and electrolyte loss increase then mental impairment occurs. Once fluid loss exceeds 10% body weight, oliguria, cyanosis, and cardiovascular collapse develop and may be fatal unless rapidly corrected. Systemic symptoms of fever, headache, and rigors are seen in shigellosis and salmonellosis where the intestinal mucosa is involved. Bacteraemia may complicate a severe attack of gastrointestinal salmonellosis and occasionally result in metastatic infection such as septic arthritis.
The management of acute gastroenteritis is largely dictated by the severity of the illness. Most attacks are self-limiting and adequate oral fluid replacement is usually possible. Admission to hospital may be required if vomiting persists or clinical dehydration develops from severe or protracted diarrhoea. Other indications include extremes of age, fever, abdominal pain, and other significant pre-existing disease. In most instances, oral fluid replacement is successful. In infants oral treatment with a glucose-electrolyte solution is usually given; milk feeding is temporarily stopped as lactose deficiency frequently complicates gastroenteritis in early childhood. Gut bacteria break down unhydrolysed lactose remaining in the bowel to lactic and acetic acid, which produce diarrhoea through the effects of an osmotic load. Older children and adults can usually replace fluid losses by drinking water, fruit juices, or soft drinks. Few patients require intravenous fluid and electrolyte replacement. However, under such circumstances normal saline and bicarbonate are usually rapidly effective in the severely dehydrated.
The glucose-salts solution recommended for oral rehydration by the World Health Organization (WHO) and the United Nations Children's Fund (UNICEF) is shown in Table 21.1. Over-the-counter preparations available in the UK generally contain less sodium chloride and more glucose. They may be useful in moderate attacks of diarrhoea, but are not as effective as the WHO formulation in severe dehydration. Glucose facilitates the absorption of sodium (and hence water) on a 1:1 molar basis in the small intestine; sodium and potassium are needed to replace the body losses of these essential ions during diarrhoea (and vomiting); and citrate corrects the acidosis that occurs as a result of diarrhoea and dehydration.
Use of antibiotics in gastrointestinal infections
Since most episodes of acute gastroenteritis are self-limiting, antibiotics are not generally indicated. Furthermore, the use of antibiotics carries the risk of directly irritating an inflamed bowel mucosa, or of inducing diarrhoea due to Clostridium difficile infection (see below). In addition, their use may encourage transferable drug resistance (see Chapter 10).
There are some specific circumstances where antibiotics are appropriate for gastrointestinal infections and associated with clear benefits.Table 21.2 summarizes the chief indications for antimicrobial therapy.
Gut sedatives and adsorbents
Various agents are frequently prescribed for the symptomatic control of gastrointestinal symptoms, yet there is little definite evidence for their efficacy. They act by slowing gastrointestinal motility or fluid adsorption.
Diphenoxylate with atropine, loperamide, and codeine slow gastrointestinal motility, and may have an additional mild analgesic effect. Adsorbants include kaolin, chalk, aluminium hydroxide, and cellulose, which tend to increase the stool bulk. Their use should not minimize the importance of adequate fluid and electrolyte replacement. This is especially important in infancy and early childhood where bowel sedatives may induce an ileus and mask fluid loss. Moreover, excessive dosing with diphenoxylate may induce respiratory depression in the young child. Bowel sedatives should also be used cautiously in those with fever or bloody diarrhoea since it is possible to potentiate toxin mediated or invasive bacterial disease.
Table 21.1 Formula for oral rehydration glucose-salts solution recommended by the World Health Organization (updated 2003)
Viral infections of the bowel commonly cause sporadic and epidemic disease in the community and in healthcare institutions. Numerically the most important are infections with norovirus (including ‘Norwalk’ virus) and rotavirus, which often causes diarrhoea in infants and young children. Several other viruses, including enteric adenoviruses, caliciviruses, and astroviruses may also be involved. The infections are usually self-limiting and antimicrobial chemotherapy (even if it were available) is not indicated. Severe infections respond to fluid replacement therapy. Rotavirus vaccines are becoming available, and should prove especially beneficial in reducing mortality in children in developing countries.
Cholera is prevalent throughout the Indian subcontinent and South-east Asia from where it has spread to many parts of Africa and central and South America. Vibrio cholerae multiplies and survives, possibly for years, in the environment, and as such does not require a human host to maintain its life cycle. V. cholerae is present in large numbers in the stools of infected patients, and is spread primarily by faecal contamination of water supplies.
The onset of cholera is sudden with the development of profuse, pale, watery diarrhoea, which may reach several litres a day; the classical rice-water stools that are isotonic with plasma. The patient rapidly becomes dehydrated and, unless fluid and electrolytes are replaced, becomes apathetic and confused with subsequent hypotension and death. Mortality is highest in old, very young, or malnourished people.
Cholera is one of the few gastrointestinal infections for which there is little argument concerning the merits of antibiotic treatment as an adjunct to fluid and electrolyte replacement therapy. The duration of diarrhoea is decreased and the volume of stool is reduced by almost half by the use of an oral tetracycline such as doxycycline, prescribed as a single dose of 300 mg in adults. Resistance to tetracyclines is, unfortunately, increasing. Alternatives include co-trimoxazole, azithromycin, or ciprofloxacin (although fluoroquinolone resistant strains have emerged in India). The vibrio is eliminated from the bowel and toxin production ceases rapidly. The carrier state does not occur but transmission from dead bodies has been reported.
Table 21.2 Major gastro-intestinal infections and appropriate antimicrobial therapy
Campylobacter jejuni (or occasionally Campylobacter coli) is among the commonest causes of sporadic acute gastrointestinal infection throughout the world. The organism produces infection in all age groups, but most frequently in young adults and pre-school children. Epidemics have occurred involving several thousand people following the ingestion of contaminated milk or water supplies. Campylobacters cause infection in domestic and farm animals, poultry and wild birds, and hence there are many opportunities for spread to humans. Importantly, campylobacter infection is occasionally complicated by the development of Guillain-Barré syndrome or reactive arthritis.
Campylobacter gastroenteritis generally lasts for a few days, but may occasionally be more protracted with marked abdominal symptoms of colicky pain and tenderness as well as profuse diarrhoea. Acute appendicitis may be mimicked. Attacks are self-limiting and managed mainly by increasing the oral fluid intake. Although campylobacter infection is common, fatalities are rare. Excretion ceases soon after clinical recovery. Antibiotic therapy is not beneficial in most cases. Cases with severe or prolonged symptoms may benefit from oral therapy with erythromycin or a fluoroquinolone such as ciprofloxacin. However, the prevalence of resistance to these agents has increased, probably related to their use in animal husbandry.
Helicobacter pylori is an important cause of chronic gastritis and gastroduodenal ulceration. It is also likely to be responsible for some cases of gastric carcinoma. Treatment of H. pylori infection usually involves 7 days' therapy with two antibiotics (various combinations of clarithromycin, metronidazole and amoxicillin are often used) together with a proton pump inhibitor such as omeprazole. Approximately 10% of patients fail treatment.
There is evidence for increasing antibiotic resistance among H. pylori strains, particularly in individuals who have previously received metronidazole. Resistance to metronidazole occurs in approximately 50% of infected individuals in many European countries with levels of up to 90% in developing countries. Resistance to clarithromycin is currently below 10% in many European countries, but rates may be increasing. Pretreatment resistance to clarithromycin can reduce the effectiveness of therapy by about 50%. Resistance to amoxicillin or tetracycline is presently uncommon.
Gastrointestinal salmonellosis is second only to campylobacter as a bacterial cause of community acquired gastrointestinal infection; several thousand cases are reported annually in the UK. There are more than 2400 different serotypes of Salmonella enterica, although relatively few regularly cause human disease. Some common serotypes are Typhimurium, Enteritidis, Hadar, and Virchow. Frozen poultry and eggs are a common source of infection, which is easily transmitted among battery hens and during the evisceration of carcasses. Measures to control infection in chickens have markedly reduced the incidence of salmonella infection in the UK.
Illness is commonly associated with systemic features of fever and malaise, in addition to the gastrointestinal symptoms. Bloodstream invasion may occur following mucosal penetration. Bloodstream infection complicating salmonella gastroenteritis is more likely in the very young and the elderly, and in those with underlying diseases such as alcoholism, cirrhosis, and AIDS. Achlorhydria from pernicious anaemia, atrophic gastritis, gastrectomy, or therapy with H2-receptor antagonists or proton pump inhibitor enhances the risk of salmonellosis by eliminating the protection afforded by the normal gastric acid so that the number of bacteria needed to be ingested to cause infection is reduced.
Treatment of acute gastrointestinal salmonellosis is essentially directed at the replacement of any lost fluid or electrolytes, either by mouth or intravenously. Antibiotics are usually unnecessary unless there is secondary bloodstream invasion, since they do not reduce the duration of illness. Antibiotic treatment may also be associated with increased incidence of carriage of salmonellae. For severe or invasive infections fluoroquinolones are useful, although resistance is becoming more common. Co-trimoxazole or a cephalosporin, such as ceftriaxone, provide alternative choices. The emergence of multiresistant strains, some with transferable genes, compromises treatment choices in some parts of the world. Local epidemiological surveillance data can help guide empirical therapy.
Enteric (typhoid and paratyphoid) fever
Enteric fever is caused by Salmonella enterica serotypes Typhi or Paratyphi A, B, or C. This is primarily a septicaemic illness acquired by ingestion of the bacterium followed by mucosal invasion. The pathogen gains access to the lymphatics and blood from where it infects the liver and other parts of the reticuloendothelial system. The bowel is also involved since the lymphoid tissue in Peyer's patches is inflamed and often ulcerates. Notably, constipation is more common than diarrhoea. Perforation and peritonitis are not uncommon in untreated cases. Enteric fever is potentially fatal and, unlike gastrointestinal salmonellosis, should always be treated with antibiotics. The bacteria are often located intracellularly and drugs active in vitro may not evoke a satisfactory clinical response.
The antibiotic of choice for enteric fever is ciprofloxacin, which produces the most rapid resolution of fever and best cure rates. Treatment must be continued for 2 weeks and, even so, relapse may occur. Relapses should be treated for a further 2 weeks. Resistance to fluoroquinolones has emerged. Alternative agents with variable activity include chloramphenicol, co-trimoxazole, and high-dose amoxicillin. For multiresistant strains cephalosporins such as ceftriaxone or cefixime (which can be given orally) have proved useful. Because of the threat of multiresistant strains, the susceptibility of clinical isolates should be tested in the laboratory whenever possible. In severe infection steroids given in the first 48 h may be beneficial.
Although typhoid vaccines are available they are not recommended for international travel unless there is a high risk of exposure.
Salmonellae may be excreted in faeces for several weeks after clinical recovery. If this continues for more than 3 months it is likely that the patient will become a persistent carrier. Chronic carriage is uncommon (<5%) but more frequent in infants and in people with biliary disease (including bile stones) or schistosomal bladder infection. The chronic carrier is normally harmless to the individual, but may be a threat to the household and the community if lapses in personal hygiene cause contamination of food or water supplies. Importantly, humans are the only natural host for Salmonella Typhi and so it is important to identify and treat carriers as a public health control measure. Chronic excretion precludes employment as a food handler. Ciprofloxacin is the preferred treatment for carriers; alternatively, prolonged high-dosage ampicillin may be curative.
Shigellosis in its most severe form is characterized by profuse diarrhoea with blood and pus; i.e. classic bacillary dysentery. Infection is more common in underdeveloped countries where sanitation and levels of hygiene are low. In developed countries shigellosis (usually caused by Sh. sonnei) occurs particularly among young children in nurseries and schools, and also in long-stay institutions such as prisons and psychiatric hospitals. The spectrum of illness ranges from mild diarrhoea to a fulminating attack of dysentery. The more severe forms of disease are associated with Shigella dysenteriae, whereas milder symptoms are caused by Sh. sonnei. Shigella flexneri and Shigella boydiitend to produce disease of intermediate severity. Shigella spp. are among the most virulent gastrointestinal pathogens, requiring only few bacteria to produce disease. The bacteria multiply in the small bowel with subsequent invasion of the mucosa of the terminal ileum and colon. The intense inflammatory response produces a hyperaemic bowel which readily bleeds, although bloodstream invasion is uncommon. Some strains, notably Sh. dysenteriae, produce an enterotoxin (Shiga toxin) that stimulates fluid secretion in the small bowel, so that watery diarrhoea may precede frank dysentery. Occasionally, haemolytic uraemic syndrome (see below) occurs.
Treatment of shigellosis is dependent on the severity of the diarrhoea and blood loss. Mild attacks, including most Sh. sonnei cases, may be managed by oral rehydration with glucose-salts solution. More severe cases may require admission to hospital and intravenous fluids. In severe shigellosis there is a definite place for antibiotic therapy. In addition treatment is sometimes used to shorten symptoms and bacterial excretion, particularly in outbreaks. Three days of treatment with oral ciprofloxacin, co-trimoxazole, ampicillin, or tetracycline have been widely used. However, resistance to each of these agents occurs, and laboratory testing of susceptibility is important.
Distinct types of Esch. coli cause a wide spectrum of gastrointestinal infection.
- Enterotoxigenic Esch. colicause most cases of traveller's diarrhoea. The toxins have many similarities to cholera toxin and the pathophysiology of the illness is similar, though fatalities are uncommon.
- Enteropathogenic Esch. coliis now largely confined to developing countries where it remains a leading cause of severe diarrhoea in the very young.
- Entero-invasive Esch. colican produce severe invasive (dysentery-like) infection of the bowel, but are fortunately uncommon.
- Enterohaemorrhagic Esch. coli(principally Esch. coli O157) produce a shiga-like toxin. In addition to haemorrhagic colitis these strains can cause renal impairment and haemolysis (haemolytic uraemic syndrome); this develops in approximately 5% of affected children during outbreaks.
- Entero-aggregative Esch. colishow characteristic patterns of adherence to epithelial cells.
Antimicrobial therapy is usually unnecessary in the treatment of gastrointestinal infections with Esch. coli. Indeed, in haemolytic uraemic syndrome antibiotic administration is contraindicated because of the chance of exacerbating symptoms, presumably because of antibiotic-mediated bacterial cell lysis and toxin release.
The use of antibiotics to prevent traveller's diarrhoea is not recommended because of the possibility of encouraging the emergence of multiresistant strains, the risk of side effects, and the generally mild nature of the infection. If diarrhoea develops fluoroquinolones can alleviate symptoms within 24 h. If the importance of the trip warrants the use of prophylaxis, fluoroquinolones, tetracyclines, or co-trimoxazole appear to be effective.
Infection with Yersinia enterocolitica may produce mesenteric adenitis, terminal ileitis, and acute diarrhoea. Erythema nodosum and a reactive arthritis may complicate such infections. The illness is usually self-limiting and, unless complicated by extra-gastrointestinal symptoms, is infrequently suspected. Ciprofloxacin, co-trimoxazole, or tetracycline are effective in severe cases.
Some protozoa and helminths may cause symptoms ranging from mild diarrhoea to severe dysentery. These are considered in Chapters 5and 30.
The use of antimicrobial agents is sometimes complicated by diarrhoea. This is most often due to a direct effect on gut motility or the bowel mucosa. However, about 20% of cases are caused by toxin producing strains of Clostridium difficile. C. difficile may have a competitive advantage over the normal gut flora following antibiotic exposure, notably in the elderly.
Less commonly, Clostridium perfringens and Staph. aureus may also cause antibiotic-associated diarrhoea. Colitis and occasionally pseudomembranous colitis can complicate C. difficile infection, and severe cases may require surgical intervention (colectomy). Some C. difficile strains are associated with epidemic infection, especially in hospitals, and strains with increased virulence have been found in North America and Europe. Such strains cause more severe disease and decrease the chances of survival.
All antibiotics may induce C. difficile infection, but clindamycin or broad-spectrum β-lactam antibiotics are most commonly incriminated. This condition is, ironically, treated with antibiotics after stopping the causative agent. Oral metronidazole or vancomycin is usually effective, though a quarter to a third of patients may have recurrent symptoms. These recurrences are most often due to new infections as opposed to relapse and emphasize the importance of host response in determining outcome. Use of vancomycin as a first line agent is discouraged since there is an absence of robust data showing improved effectiveness compared with metronidazole and it is considerably more expensive. Alternatives therapeutic approaches are needed.
A wide variety of information about specific gastrointestinal pathogens is available from the UK Health Protection Agency at: http://www.hpa.org.uk/infections/topics_az/list.htm
World Health Organization information about oral rehydration with glucose-salts solution is available at: http://www.who.int/childadolescenthealth/New_Publications/CHILD_HEALTH/WHO_FCH_CAH_06.1.pdf