Antimicrobial Guidelines for the Management of Antibiotic Associated Diarrhea

Antibiotic-associated diarrhea refers to passing loose, watery stools three or more times a day after taking medications used to treat bacterial infections (antibiotics). Most often, antibiotic-associated diarrhea is mild and requires no treatment.

Indian Council of Medical Research, Department of Health Research has issued the ICMR treatment Guidelines for Antimicrobial Guidelines for the Management of Antibiotic Associated Diarrhea. Following are the major recommendations:

Preamble and Case definition

AAD is a broad term that encompasses all diarrheal episodes, inflammatory and non inflammatory, related to the use of antibiotics. Of these, Clostridium difficile associated diarrhea (CDAD), or Clostridium difficile infection (CDI) /Clostridium associated colitis, is the one of the most clinical and public health importance and has become the commonest nosocomial infection in the west. There have been increasing reports of CDAD from India (1,2). Studies on CDAD from India reveals a prevalence range from 7.1 - 26.6%.

The different presentations of CDI are summarized below.

1. Asymptomatic: About 20% of hospitalised patient may be asymptomatic carrier, and have stool positive for C. difficile toxin. They act as reservoir for environmental contamination but do not have diarrhea.


2. C. difficile associated diarrhea with colitis. This is characterised by multiple watery diarrhea > 10 times per day associated with abdominal pain, tenderness and systemic symptoms like, anorexia, nausea, fever and features of dehydration.


3. Fulminant Colitis


4. Recurrent disease - Recurrence of symptoms after successful initial therapy for C. difficile, due to relapse of the initial infecting strain or due to reinfection with a new strain, develops in 10 to 25 percent of cases

CDAD must be differentiated from

• Other causes of antibiotic associated diarrhea


• Unrelated causes of inflammatory diarrhea like Inflammatory bowel disease


• Other infective etiology like Salmonella, Shigella, Entamoeba histolytica


• Non inflammatory or osmotic diarrhea

Common Pathogens

Clostridium difficile

• Cases of hypervirulent strain with severe disease reported less than the west


• An asymptomatic carrier state was noted to be 6% in a hospital survey (3)


• Incidence of mild to moderate CDAD was 10%.


• Most of the cases were responsive to metronidazole.


• The hypervirulent strain NAP1/BI/027 has been responsible for dramatic increases in the frequency, severity, and refractoriness of C. difficile in multiple outbreaks around the world

Clinical Manifestation

C. difficile infection should be suspected in any patient who has one or more risk factors for developing this infection and has abdominal symptoms, predominantly diarrhea. The risk factors for developing CDI include:

• Antibiotics, especially


• Fluroquinolones


• Clindamycin


• Penicillins (Broad spectrum)


• Cephalosporins (Broad spectrum)


• Advanced age


• Severity of illness


• Gastric acid suppression (mainly with proton pump inhibitors)


• Enteral feeding


• Prolonged hospitalization


• Gastrointestinal surgery


• Obesity


• Cancer chemotherapyHematopoietic stem cell transplant

Antibiotic use is the most common cause for this infection and some antibiotics (listed above) are commonly associated with C. difficile colitis. Antibiotics least associated with CDAD include Macrolides, Sulphonamides, Trimethoprim, Aminoglycosides, Tetracycline, Tigecycline, Chloramphenicol, Metronidazole and Vancomycin. It is important to note that C. difficile infection may occur even in the absence of any risk factor .

Investigations

The mainstay of laboratory diagnosis of C. difficile infection (CDI) is toxin assay of a fresh sample of liquid or semiformed stool (to be performed within two hours at room temperature) or preserved at 4 degree Celsius in the refrigerator if the assay is delayed for any reason.

1. Enzyme immunoassay (EIA) for C. difficile toxins A and B

• Most commonly performed assay in clinical practice.


• The sensitivity of EIA for toxins A and B is about 75%; the specificity is high (up to 99%).


• If the initial EIA test is negative, the value of repeating the test is limited and repeat testing is generally discouraged

2. Enzyme immunoassay (EIA) for C. difficile glutamate dehydrogenase (GDH)

• Useful as an initial screening step


• Highly sensitive, and results are available in less than one hour.


• Cannot distinguish between toxigenic and nontoxigenic strains


• Positive results need to be confirmed by more specific tests like toxin assays and /or PCR

3. Real-time PCR tests that detect toxin A and B genes Highly sensitive and specific for diagnosis of C. difficile related diarrhea for the 1st episode but cannot be used as a test of cure and may be less useful if a relapse or re-infection suspected.

4. Cell culture cytotoxicity assay

• The 'gold standard' test for diagnosis of C. difficile


• Labor intensive and takes approximately two days


• Not performed routinely.

5. An algorithmic approach should be utilized for judiciously using these investigations.

6. If PCR assay is available

• Most sensitive and specific test and is recommended.


• If it is positive no further test is required


• If negative and clinical suspicion is high, EIA for toxin or cell culture should be performed

7. If PCR is not available

• EIA for GDH should be performed first


• If positive, it should be confirmed with EIA toxin assay

o positive result may be presumed in the setting of positive EIA for GDH and toxin

o negative result if both EIAs are negative.

8. If EIA GDH and PCR both are not available as might be the case in many centres in India, a fresh sample of liquid stool tested within two hours should be performed for EIA toxin.

• If it is negative and clinical suspicion is high repeat toxin assay should be performed


• Repeat testing and test for cure are not warranted in patients with for diagnosis of C. difficile related diarrhea the 1st episode but cannot be used as a test of cure and may be less useful if a relapse or re-infection suspected.

9. Repeat testing and test for cure are not warranted in patients with positive PCR or toxin assay test who are a symptomatic. There is no clinical role for laboratory tests among asymptomatic patients or among patients on treatment for acute disease, as stool assays may remain positive during or after clinical recovery

10. Colonoscopy or sigmoidoscopy and biopsy (in the setting of diagnostic uncertainty) with visualization of pseudomembrane and ulceration, can be a useful adjunctive tool for diagnosis of C. difficile in the following settings:

• Failure of C. difficile infection to respond to antibiotic therapy


• Atypical presentation with ileus or minimal diarrhea


• Prompt C. difficile diagnosis needed before laboratory results can be obtained


• High clinical suspicion for C. difficile with negative laboratory assay(s)

Resistance Patterns

• The hypervirulent strain NAP1/BI/027 is not commonly reported in India  Most strains respond to metronidazole

Table 1. Treatment Regimen for C. difficile Colitis

You can read the full Guideline by clicking on the link :

Dr Soumya Swaminathan, Director General, Indian Council of Medical Research Secretary, Department of Health Research