Managing antibiotic associated diarrhoea

Diarrhoea is a common adverse effect of antibiotic treatments. Antibiotic associated diarrhoea occurs in about 5-30% of patients either early during antibiotic therapy or up to two months after the end of the treatment.^1–3 The frequency of antibiotic associated diarrhoea depends on the definition of diarrhoea, the inciting antimicrobial agents, and host factors.

Almost all antibiotics, particularly those that act on anaerobes, can cause diarrhoea, but the risk is higher with aminopenicillins, a combination of aminopenicillins and clavulanate, cephalosporins, and clindamycin.¹,⁴,⁵ Host factors for antibiotic associated diarrhoea include age over 65, immunosuppression, being in an intensive care unit, and prolonged hospitalisation.⁶

Clinical presentations of antibiotic associated diarrhoea range from mild diarrhoea to fulminant pseudomembranous colitis. The latter is characterised by a watery diarrhoea, fever (in 80% of cases), leucocytosis (80%), and the presence of pseudomembranes on endoscopic examination. Severe complications include toxic megacolon, perforation, and shock.

Antibiotic associated diarrhoea results from disruption of the normal microflora of the gut by antibiotics. This microflora, composed of 10¹¹ bacteria per gram of intestinal content, forms a stable ecosystem that permits the elimination of exogenous organisms. Antibiotics disturb the composition and the function of this flora and enable overgrowth of micro-organisms that induce diarrhoea. Since demonstration of its role in 1978, Clostridium difficile has emerged as the major enteropathogen of antibiotic associated diarrhoea.³ This anaerobic spore forming bacteria is responsible for 10-25% of cases of antibiotic associated diarrhoea and for virtually all cases of pseudomembranous colitis.³ It works by secreting two potent toxins that cause mucosal damage and inflammation of the colon. Other infectious agents reported to be responsible for antibiotic associated diarrhoea include C perfringens, Staphylococcus aureus, Candida spp, Klebsiella oxytoca, and Salmonella spp.⁷ However, their role in the pathogenesis of diarrhoea is still debated because most of them are considered to be usual commensal bacteria of the gut flora. Antibiotic associated diarrhoea can also result from a decrease in metabolism of carbohydrates and bile acids.⁷

Managing the diarrhoea depends on the clinical presentation and the inciting agent.^7–10 In mild to moderate diarrhoea conventional measures include rehydration or discontinuation of the inciting agent or its replacement by an antibiotic with a lower risk of inducing diarrhoea, such as quinolones, co-trimoxazole, or aminoglycosides. In 22% of cases of diarrhoea related to C difficile, withdrawal of the inciting agent will lead to resolution of clinical signs in three days.¹¹

In cases of severe or persistent antibiotic associated diarrhoea, the challenge is to identify C difficile associated infections since this is the most common identifiable and treatable pathogen. Diagnosis relies on detecting toxins A or B in stools. Tissue culture assay is the gold standard, although it is time consuming. Enzyme immunoassays for toxins A or B have a good specificity but a false negative rate of 10-20%.

Treatment of C difficile related diarrhoea is based on oral metronidazole (250 mg four times daily) or oral vancomycin (125 mg four times daily) for 10 days.¹¹,¹² The response to metronidazole or vancomycin is similar (>90%), and diarrhoea usually resolves in two or three days. The Infectious Diseases Society of America, the American College of Gastroenterology, and the Society for Hospital Epidemiology of America recommend metronidazole as the first line of treatment to prevent the emergence of vancomycin resistant organisms.⁹,¹⁰ Vancomycin should be reserved for those with severe illness, intolerance to metronidazole, failure to respond to metronidazole, or pregnancy. Antiperistaltic agents should be avoided because of the risk of retention of toxins in the lumen. About 20% of patients with C difficile related diarrhoea will relapse. Most patients will respond to another course of metronidazole or vancomycin, but 5% will experience several relapses; the management of these remains controversial.

As antibiotic associated diarrhoea mostly results from a disequilibrium of the normal intestinal flora, research has focused on the benefits of administering living organisms (probiotics or biotherapeutic agents) to restore the normal flora. Numerous probiotics such as Lactobacillus acidophilus, L casei GG, L bulgaricus, Bifidobacterium bifidum, B longum, Enterococcus faecium, Streptococcus thermophilus, or Saccharomyces boulardii have been tested for the treatment and prevention of antibiotic associated diarrhoea.¹³ The benefits of probiotics are unproved as few have been evaluated in double blind placebo controlled studies. The results of the small and open trials of treatment are conflicting.

Most studies with probiotics have assessed their use in preventing antibiotic associated diarrhoea. In this issue D'Souza et al report a meta-analysis of nine randomised double blind trials comparing probiotics with placebo in the prevention of diarrhoea (p 1361).¹⁴ Among these studies, four trials were used S boulardii and five Lactobacillus. Their results suggest that probiotics are useful in prevention. The expected advantages of probiotics include ease of administration, cost effectiveness, and relative lack of side effects. However, several cases of bacteraemia with S boulardii have been reported, which should prompt caution in the use of this yeast in immunosuppressed patients or patients with underlying disorders.

The key measure for preventing antibiotic associated diarrhoea, however, is to limit antibiotic use. Probiotics have proved useful in preventing diarrhoea, but the number of clinical trials is limited and further controlled trials using different probiotics are needed. In the case of C difficile related diarrhoea hygiene measures (single rooms, use of gloves, and handwashing) should be systematically associated with treatment in order to prevent transmission and dissemination of this nosocomial bacteria.

Papers p 1361