Antibiotic-Associated Diarrhoea

Diarrhoea is a common adverse effect associated with antibiotic therapy. Almost all antibiotics can cause diarrhoea due to disruption of the normal microflora of the gut. However, antibiotics with the greatest risk are those that are broad-spectrum and those with activity against anaerobic bacteria.

Antibiotics with a particularly high risk of causing diarrhoea include:

• Lincosamides (i.e. clindamycin, lincomycin)
• Aminopenicillins (i.e. amoxicillin, ampicillin)
• Aminopenicillin + clavulanic acid combinations
• Cephalosporins
• Quinolones

Other factors that may increase the risk of antibiotic-associated diarrhoea include older age (i.e. over 65 years), immunosuppression, prolonged hospitalisation, and the concomitant use of a proton pump inhibitor.

Antibiotic-associated diarrhoea is often mild, with symptoms generally resolving soon after the course is finished. In many cases, no specific treatment is required. However, severe presentations can occur that require medical intervention.

Severe presentations

Clostridioides difficile (previously known as Clostridium difficile) is a major pathogen involved in antibiotic-associated diarrhoea. This anaerobic spore-forming bacteria is thought to be responsible for up to 25% of all antibiotic-associated diarrhoea and almost all cases of pseudomembranous colitis.

Pseudomembranous colitis is a severe inflammation of the intestinal lining and a serious complication of antibiotic use. This condition results from disruption of the normal microbiome, which allows for the overgrowth of C. difficile. This bacterium can produce toxins, most notably toxin A (TcdA) and toxin B (TcdB).

While both toxin A and toxin B are cytotoxic, toxin B is between 100 and 1,000 times as potent as toxin A. Up to 12% of strains infecting humans also produce a third toxin, known as binary toxin or C. difficile transferase (CDT). The presence of CDT is usually associated with higher virulence, which may be related to enhanced adherence of C. difficile to the intestinal epithelium.

The clinical presentation of pseudomembranous colitis typically includes profuse, watery or mucoid diarrhoea, fever, and abdominal cramps. Blood may also be present in the stool. On endoscopic examination, pseudomembranes can be seen. Potential complications include toxic megacolon, colonic perforation, and shock.

C. difficile infection can occur at any time during antibiotic use and for some months after completing the course.

Treatment of C. difficile infection

Any antibiotics implicated in causing the antibiotic-associated diarrhoea should be ceased wherever possible. The timely discontinuation of causative antibiotic therapy is associated with a reduced risk of recurrence and may also improve symptoms.

The Therapeutic Guidelines make the following recommendations for the treatment of adults with a first episode of C. difficile disease:

Mild to moderate disease

• Metronidazole 400mg orally or enterally, 8-hourly for 10 days OR
• Vancomycin 125mg orally or enterally, 6-hourly for 10 days.

Severe disease

• Vancomycin 125mg orally or enterally, 6-hourly for 10 days.
  • In complicated cases, add metronidazole 500mg IV, 8-hourly for 10 days
  • In the presence of ileus, consider adding vancomycin 500mg in 10mL sodium chloride 0.9%. Administer as a retention enema every 6 hours.

Expert advice is required for all patients with severe disease. A patient would be considered to have severe disease if they have leucocytosis, severe abdominal pain, elevated serum creatinine, elevated blood lactate, low serum albumin, high fever, or organ dysfunction.

Vancomycin must be given orally or enterally for the treatment of C. difficile infection. Intravenous vancomycin is ineffective in these cases as it has poor penetration into the lumen of the colon. It is also worth noting that vancomycin has poor oral absorption. Therefore, the oral route is not appropriate for the treatment of any systemic infection.

Vancomycin is available as a capsule for oral administration. The capsules may be given without regard to food but should be swallowed whole. As the capsules contain a semi-solid material, they are not appropriate for administration via an enteral feeding tube. Alternatively, the injectable form can be given orally or enterally. For example, a 500mg vial of vancomycin powder for injection can be dissolved in 10mL of water for injection to give a 50mg/mL solution. Vancomycin does have a very unpleasant taste; flavouring syrups may be added prior to administration to improve palatability.

Other therapies

• Fidaxomicin

Fidaxomicin is sometimes used for the treatment of recurrent or refractory disease. The Therapeutic Guidelines do not currently recommend fidaxomicin for the treatment of severe disease due to a lack of data in this setting. However, some international guidelines do recommend fidaxomicin as a first-line option for initial infections. For example, the 2021 update to the Clinical Practice Guideline by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA).

Fidaxomicin is a novel antibiotic known as a macrocycle. It has a narrow spectrum of activity, being bactericidal against C. difficile and minimally active against other flora of the gastrointestinal tract. Due to its poor oral absorption, its activity is predominantly confined to the intestinal lumen.

Two randomised controlled trials comparing fidaxomicin and oral vancomycin found similar rates of diarrhoea resolution at ten days (88% vs 86%, respectively). However, sustained clinical response was superior for fidaxomicin (71% vs 57%).

The usual dose is 200mg orally twice daily for 10 days. Tablets can be taken without regard to food and may be crushed if required. Patients who are allergic to macrolide antibiotics (e.g. azithromycin, clarithromycin) may have a higher risk of fidaxomicin hypersensitivity.

• Rehydration

When treating C. difficile infection, the importance of rehydration in addition to antibiotic therapy should not be underestimated. Oral rehydration may be sufficient for patients with minimal or no dehydration. However, parenteral rehydration is recommended if ileus or features of severe dehydration are present.

A variety of oral rehydration products are available. While some are ready to use, many require reconstitution. Incorrect preparation of these products can worsen dehydration. Therefore, it is important that they are always prepared exactly as directed.

Sodium chloride 0.9% or lactated Ringer solution are often used for intravenous rehydration. If the intravenous route is not appropriate, sodium chloride 0.9% may be administered via the subcutaneous route.

• Antimotility agents

Antimotility agents have traditionally been avoided in patients with active C. difficile infection. This is due to the belief that these agents may increase the risk of complications by prolonging the intestinal contact time of bacterial toxins.

Some small studies have challenged this idea, suggesting that antimotility agents may be safe for C. difficile infection when administered in conjunction with appropriate antimicrobial therapy. However, larger randomised studies are required to confirm what place antimotility agents may have. The product information for loperamide and diphenoxylate cites pseudomembranous colitis as a contraindication to their use.

Antimicrobial optimisation

Antimicrobial resistance has been highlighted as one of the causes of epidemic outbreaks of C. difficile. Polymerase chain reaction (PCR) ribotyping is a molecular typing technique often used with C. difficile to facilitate surveillance and outbreak investigations. C. difficile ribotype 027 has been found to have reduced susceptibility to many antibiotics, including metronidazole, rifampicin, moxifloxacin, clindamycin, and imipenem. This strain is also considered to be hypervirulent, with higher morbidity and mortality rates compared to other strains. Outbreaks of ribotype 027 have occurred in Australia and many countries worldwide.

Antimicrobial stewardship (AMS) is a crucial strategy to limit the emergence of antimicrobial resistance. The goal of AMS programs is to promote and support the optimal use of antimicrobials. Activities that fall under the AMS umbrella include audits, formulary restrictions, therapeutic drug monitoring, and education. One meta-analysis demonstrated that AMS activities could reduce the incidence of C. difficile infections by 32% in hospital patients.

The Australian Commission on Safety and Quality in Healthcare (the Commission) has been monitoring the national burden of C. difficile infection in Australian public hospitals since 2016. The most recent data published by ACSQHC shows that separations with a diagnosis of C. difficile infection increased by 29% from 2020 to 2021.

However, the rate of healthcare-associated hospital-onset infection has been declining over recent years. This suggests that hospital-based strategies to prevent C. difficile infection are effective. The implementation of effective AMS programs is thought to be one of the most important strategies in reducing the risk of C. difficile. The Commission notes that reducing the inappropriate prescribing of antimicrobials has significantly impacted the incidence of hospital-associated infection. Other effective measures highlighted by the Commission are early detection and appropriate testing, environmental cleaning programs, the use of single rooms and en-suites, and transmission-based precautions in addition to standard precautions for symptomatic patients.

Optimising infection control measures and minimising unnecessary antibiotic use should be prioritised within the hospital environment to reduce the burden of C. difficile disease.