Antimicrobial Chemotherapy, 4th Edition
The therapeutic use of antimicrobial agents
- G. Finch
Gastrointestinal infections are among the commonest infections suffered by mankind. World-wide it has been estimated that on any one day 200 million people are suffering from acute infective gastroenteritis. In developing countries, diarrhoeal disease superimposed on severe protein–calorie malnutrition is responsible for much mortality, especially in children less than 2 years of age. Even in the UK the morbidity produced is profound and the economic impact signifi-cant. For example, approximately 4.3 million working days per year are lost as a result of acute diarrhoea, much of which is infective in origin. Death may occur from electrolyte and fluid loss, particularly in the very young, elderly, or malnourished who can ill withstand the severe metabolic disturbances that sometimes accompany acute infectious diarrhoea.
Gastrointestinal pathogens are transmitted directly from person to person or indirectly through faecal contamination of the environment, food, or water supply. Hence the high frequency of such infections in underdeveloped countries where the absence of a clean water supply or safe sewage disposal compound the problems of poverty and malnutrition. Some pathogens, most notably salmonellae, are common to both humans and animals.
Travel-associated diarrhoea is common and often affects residents of industrial countries travelling to developing countries. The onset is usually within a week of arrival. A wide variety of pathogens are linked to this condition (Table 22.1). Enterotoxigenic Escherichia coli is the most common cause worldwide, though the relative frequency varies geographically. Poor sanitation, lack of clean water and low standards of hygiene contribute to the problem, which is primarily food and water borne.
Table 22.1 Causes (per cent) of travel-associated diarrhoea
Food may be contaminated by various gut pathogens or their toxins. When illness occurs as a sudden outbreak which can be traced to a common meal, 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 pre-formed toxin produces symptoms within 0.5–8 h of ingestion. Longer incubation periods are associated with salmonellosis and shigel-losis, in which microbial replication within the bowel may take a day or so before disease is produced.
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 per cent body weight are usually undetectable. Once fluid loss exceeds 10 per cent 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.
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 replacements are successful. In infants oral treatment with glucose–electrolyte solution is usually given and milk feeding temporarily stopped since lactose deficiency frequently complicates gastroenteritis in early childhood. Therefore, unhydrolysed lactose remaining in the bowel is broken down by gut organisms 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 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 Organiztion (WHO) and the United Nations Children's Fund (UNICEF) is shown in Table 22.2. Over-the-counter preparations available in the UK generally contain less sodium chloride and more glucose. They are not as effective as the WHO formulation in severe dehydration.
Table 22.2 Formula for oral rehydration fluid recommended by the World Health Organization
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 producing diarrhoea from superinfection. In addition, their use may encourage transferable drug resistance. Widespread use in some countries has led to the emergence of multiresistant salmonellae, shigellae, and campylobacters.
None the less, there are some specific circumstances where antibiotics are appropriate for gastrointestinal infections and associated with clear benefits. Table 22.3 summarizes the chief indications for antimicrobial therapy.
Table 22.3 Major gastrointestinal infections and their antimicrobial therapy
Bowel sedatives and adsorbents
Various agents are available for the symptomatic control of gastrointestinal symptoms. They are frequently prescribed, yet there is little definite evidence for their efficacy. They act either by slowing gastrointestinal motility or by 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 invasive bacterial disease.
Viral infections of the bowel are common and produce both sporadic and epidemic disease. Many viruses may cause infection; however, numerically the most important is rotavirus, which causes both community- and hospital-acquired gastroenteritis. The virus can be demonstrated by electron microscopy. Several other viruses may be associated with acute gastroenteritis; these include enteric adenoviruses, Norwalk agent, caliciviruses, astroviruses, and ‘small round structured’ viruses. The infections are usually self limiting and antimicrobial chemotherapy is not indicated.
Cholera is an important world-wide cause of serious gastrointestinal infection. It is prevalent throughout the Indian subcontinent and south-east Asia from where it has spread to many parts of Africa and to central and South America. The infection is spread by faecal contamination of water supplies. The cholera vibrio is present in large numbers in the stools of infected patients. The present pandemic is largely caused by the El Tor biotype.
The onset of cholera is sudden with the development of profuse, pale, watery diarrhoea which may reach several litres a day; the so-called ricewater stools which are isotonic with plasma. The patient rapidly becomes dehydrated and, unless fluid and electrolytes are replaced, becomes apathetic with subsequent hypotension and death. Mortality is highest in old, very young, or malnourished people.
Recognition of the pathophysiological role of cholera enterotoxin in the production of the disease by activating cyclic AMP, which in turn stimulates water and
electrolyte secretion by the intestinal epithelial cells, has justified the empirical benefit of a glucose–electrolyte oral replacement regimen. The addition of glucose considerably reduces the total volume of replacement fluid required by enhancing the absorption of sodium and water from the small bowel.
Cholera is one of the few gastrointestinal diseases for which there is little argument concerning the merits of antibiotic treatment as an adjunct to fluid replacement therapy. It has been shown that the duration of cholera is abbreviated by 60 per cent by the use of an oral tetracycline such as doxycycline, prescribed as a single dose of 300 mg in adults. Alternatives include ciprofloxacin or co-trimoxazole. The vibrio is eliminated from the bowel and toxin production ceases rapidly. The carrier state does not occur. Resistance to tetracycline is, unfortunately, increasing and may limit the usefulness of antibiotic therapy in the future.
Campylobacter jejuni is now recognized as one of the commonest world-wide causes of acute gastrointestinal infection, which may be sporadic or epidemic. 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. The organism itself is widespread in nature, producing infection in both domestic and farm animals, including poultry, and hence there are many opportunities for spread to human beings.
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 by increasing the oral fluid intake. More severe attacks sometimes require hospitalization, and under these circumstances oral antibiotic treatment with erythromycin or a quinolone such as ciprofloxacin is indicated, although the latter is contraindicated in childhood.
There is little information to suggest that any of the different salts or esters of erythromycin has any advantage over erythromycin base, although the former are more readily absorbed from the bowel. The drugs are well tolerated, but occasional gastrointestinal intolerance may aggravate the patient's condition. Campylobacter infection is common, but fatalities are rare. Excretion ceases soon after clinical recovery.
Helicobacter pylori is now known to be an important cause of chronic gastritis and gastroduodenal ulceration. Various treatment regimens are aimed at eradicating the organism. These include 7 days' treatment with clarithromycin in combination with either amoxycillin or metronidazole, to which is added a proton pump inhibitor such as omeprazole. An alternative is 14 days' treatment with
a bismuth salt in combination with metronidazole and tetracycline. There is evidence for increasing drug resistance among H. pylori strains.
Gastrointestinal salmonellosis is second only to campylobacter as a cause of gastrointestinal infection in the UK, where several thousand cases are reported annually. There are more than 1700 different serotypes of salmonella, all of which are now considered to belong to a single species, Salmonella enterica. Relatively few cause human disease with any regularity. 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.
Illness is commonly associated with systemic features of fever and malaise, in addition to the gastrointestinal symptoms. Bloodstream invasion may also occur following mucosal penetration. This occurs more frequently in very young children, old people, and those with underlying diseases such as alcoholism, cirrhosis, and AIDS. Achlorhydria from pernicious anaemia, atrophic gastritis, gastrectomy, H2-receptor antagonists, or the use of proton pump inhibitors enhances the risk of salmonellosis by eliminating the protection afforded by the normal gastric acid.
Treatment of acute gastrointestinal salmonellosis is essentially directed at the replacement of any lost fluid or electrolytes, either by mouth or intravenously. Until recently antibiotics were considered to be contraindicated in the management of gastrointestinal salmonellosis, unless there is secondary bloodstream invasion, since they do not reduce the duration of illness and may prolong the period of excretion. However, for severe or invasive infections fluoroquinolones have gained increasing use. Apart from the fluoroquinolones, co-trimoxazole or a cephalosporin, such as ceftriaxone, provide alternative choices.
This is caused by Salmonella serotypes Typhi or Paratyphi A, B, or C. The illness is usually designated typhoid or paratyphoid fever when the aetiological agent is known. Enteric fever is primarily a septicaemic illness acquired by ingestion. The gastrointestinal mucosa is readily penetrated, and 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. Constipation is more common than diarrhoea. Perforation and peritonitis are not uncommon in the untreated disease.
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 drug of choice 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. Alternative agents include chloramphenicol, co-trimoxazole, and high-dose amoxycillin. An increasing number of infections are caused by multi-resistant strains, so the susceptibility of clinical isolates should be tested in the laboratory.
Salmonellae may be excreted in the stool 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. 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. For this reason chronic excretion precludes employment requiring the handling of food. Prolonged high-dose ampicillin therapy may be curative, although ciprofloxacin is now preferred.
In its severe form shigellosis produces classic bacillary dysentery characterized by profuse diarrhoea with blood and pus. Infection is world-wide but is more common in underdeveloped countries where sanitation and levels of hygiene are low. In the UK outbreaks occur 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 often associated with Shigella dysenteriae, whereas milder attacks are associated with Sh. sonnei, which is the most frequent isolate in the UK. Sh. flexneri and Sh. boydiitend to produce disease of intermediate severity, although there is considerable individual variation.
Shigella spp. are among the most virulent gastrointestinal pathogens, requiring only a few bacteria to produce disease. The organism multiplies 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. Despite the severity of the infection, bloodstream invasion is uncommon. Some strains, notably Sh. dysenteriae, produce an enterotoxin which stimulates fluid secretion within the small bowel, so that watery diarrhoea may precede frank dysentery.
Treatment of shigellosis is dependent on the severity of the diarrhoea and blood loss. Mild attacks may be managed with fluid and electrolyte replacement by mouth, whereas more severe cases may require hospitalization and intravenous fluids. In shigellosis there is a definite place for antibiotic therapy for the severe attack, and to curtail the milder attacks associated with epidemic disease. Unfortunately, resistance among Shigella is increasing, and laboratory testing of antibiotic susceptibility is important.
Ciprofloxacin, co-trimoxazole, ampicillin, or tetracycline have been widely used and may be administered orally provided they are shown to be active in
vitro. Ciprofloxacin is contraindicated in childhood and tetracyclines should be avoided in children under 8 years of age. Antibiotic therapy shortens the illness, controls symptoms, and speeds elimination of the organism from the bowel. For most mild attacks of Sh. sonnei, antibiotics are unnecessary.
Infection with Yersinia enterocolitica may produce mesenteric adenitis, terminal ileitis, and acute diarrhoea. For obscure reasons it is more common in Scandinavia, but its occurrence is world-wide. Erythema nodosum and a reactive arthritis may complicate such infections. The illness is usually self limiting and, unless complicated by extragastrointestinal symptoms, is infrequently suspected. Ciprofloxacin, co-trimoxazole, or tetracycline are effective if an antibiotic appears justified.
Food may be contaminated at source, in the abattoir, subsequent to marketing, or during preparation. Storing at ambient temperatures encourages microbial growth, hence the importance of adequate refrigeration. Foods frequently associated with outbreaks of disease include poultry, meats, shellfish, and those containing dairy products, notably cream. Cooked food and raw foods should be sold under separate arrangements to avoid cross-contamination. Foodhandlers may excrete salmonellae and contaminate food by lapses in personal hygiene, and staphylococcal food poisoning can result from contamination of food from infected skin lesions.
Clostridium perfringens produces powerful exotoxins which may contaminate meats, gravies, and sauces that are either inadequately refrigerated or partially reheated. True mucosal invasion is uncommon with Cl. perfringens food poisoning, although a severe invasive infection, enteritis necroticans, may rarely occur. This has been described from New Guinea where pork feasts produce disease known locally as ‘pig bel’.
Occasional outbreaks of gastroenteritis are caused by Bacillus cereus, most frequently in association with the reheating of rice in restaurants. The organism is ubiquitous and produces disease by elaborating an enterotoxin. The disease is self limiting.
Botulism is fortunately a rare disease which develops after ingesting inadequately sterilized canned products. Spores of Cl. botulinumproduce a powerful neurotoxin that is readily absorbed from the gut and produces neural paralysis which in particular affects the respiratory musculature. Treatment is aimed at supporting the patient while the fixed neurotoxin undergoes degradation. Prompt treatment with antitoxin is essential to prevent more severe disease.
In most forms of food poisoning antimicrobial chemotherapy is contra-indicated. Treatment is essentially supportive, with the notable exception of the use of specific
antitoxin for botulism. Symptomatic bloodstream invasion complicating gastrointestinal salmonellosis, severe shigellosis, or campylobacteriosis requires antimicrobial therapy as discussed above.
Acute gastroenteritis is common among travellers to tropical and subtropical regions where it has been known to generations of travellers as ‘Delhi belly’, ‘Gyppy tummy’, or ‘Montezuma's revenge’. In many instances disease is caused by enterotoxin-producing strains of Esch. coli. The toxins have many similarities to the cholera toxin and the pathophysiology of the illness is similar. Enterotoxigenic strains differ from the enteropathogenic Esch. coli formerly responsible for outbreaks of infantile gastroenteritis, which is associated with a few clearly defined serotypes. Other kinds of pathogenic Esch. coli are recognized:
- enteroinvasivestrains that can produce severe invasive infection of the bowel, but are fortunately uncommon
- enterohaemorrhagicstrains that produce a toxin detectable by a cytotoxic effect on Vero tissue culture cells (Vero toxin), and have been associated with haemorrhagic colitis and the haemolytic uraemic syndrome
- enteroaggregativestrains that show characteristic patterns of adherence to epithelial cells.
Antimicrobial therapy is generally unnecessary in the management of traveller's diarrhoea and other infections caused by Esch. coli. For severe infection, or if the patient is immunocompromised, has inflammatory bowel disease, or a previous history of severe traveller's diarrhoea, use of an oral quinolone such as norfloxacin or ciprofloxacin may be considered. These agents are still unlicensed for use in children. Attempts at chemoprophylaxis against traveller's diarrhoea with oral doxycycline, co-trimoxazole, or a quinolone have had some success, but their widespread use is not recommended except in the higher risk groups mentioned. Drug resistance among Esch. coli strains is an increasing problem in developing and tropical countries where enterotoxigenic strains are endemic; resistance would inevitably increase further with widespread prophylactic use.
Paradoxically, the use of antimicrobial agents is occasionally complicated by diarrhoea. This is usually due to a direct irritating effect on the bowel mucosa. However, alteration of the bowel flora may rarely be followed by frank infection with Candida spp. or Staph. aureus.
A more serious consequence of antibiotics is disease caused by toxin-producing strains of Clostridium difficile. In severe cases bloody diarrhoea and a frank colitis develop. The bowel appearances are characteristic and aptly described by
the term ‘pseudomembranous colitis’. Use of clindamycin or β-lactam antibiotics are most frequently complicated by this disease which occurs in sporadic or epidemic form in hospital practice. The condition is potentially fatal and should be treated with oral metronidazole or vancomycin.
Symptoms ranging from mild diarrhoea to severe dysentery may be caused by some protozoa and helminths. These are considered inChapter 5 and Chapter 31.