Management of Negative C. difficile PCR with Persistent Symptoms
If the C. difficile PCR is negative and symptoms persist, do not repeat testing within 7 days unless there is a clear change in clinical presentation, and instead focus on identifying alternative causes of diarrhea while maintaining contact precautions if clinical suspicion remains high. 1
Do Not Routinely Retest
- Repeat testing within 7 days during the same diarrheal episode has a diagnostic yield of only approximately 2% and is not recommended. 1
- The negative predictive value of highly sensitive tests like NAAT (PCR) exceeds 99%, making a single negative test highly reliable for excluding CDI. 1
- Repeat testing with suboptimal specificity methods risks generating false-positive results that could lead to unnecessary treatment. 1
When to Consider Retesting
- Repeat testing should only be considered in symptomatic patients with high clinical suspicion whose symptoms worsen or who develop new supporting clinical evidence (e.g., marked leukocytosis >15 × 10⁹/L, rising creatinine ≥133 μM, declining albumin <30 g/L, fever, severe abdominal pain). 1, 2
- In epidemic settings where CDI acquisition is more frequent, there may be more value in repeat testing. 1
- If symptoms recur after successful treatment and diarrhea cessation (true recurrence, not persistent symptoms from the same episode), repeat testing is appropriate and should ideally include toxin detection, as 35% of patients with recurrent diarrhea after CDI may test negative. 1
Evaluate for Alternative Diagnoses
- With a negative PCR, shift focus to identifying other causes of diarrhea including other enteropathogens, medication-related causes (especially antibiotics, proton pump inhibitors, chemotherapy), inflammatory bowel disease, ischemic colitis, or post-infectious irritable bowel syndrome. 1, 3
- Up to 35% of patients may experience transient functional bowel disorder during the first two weeks following resolution of CDI, and 4.3% develop post-infectious irritable bowel syndrome lasting more than three months. 1
- Laboratory testing cannot distinguish between asymptomatic colonization and active infection, so clinical context is paramount. 1
Discontinue Empirical CDI Treatment
- If empirical CDI therapy was started while awaiting results, stop it once the negative PCR is confirmed (assuming the patient does not have severe disease with high ongoing suspicion). 2
- Continuing unnecessary CDI treatment risks further microbiome disruption and may delay recognition of the true cause of diarrhea. 2
Infection Control Considerations
- Maintain contact precautions if clinical suspicion remains high despite negative testing, particularly in epidemic settings or if the patient has multiple risk factors (recent hospitalization, antibiotic exposure, advanced age). 1, 2
- If clinical suspicion is low and an alternative diagnosis is identified, contact precautions can be discontinued. 1
Address Modifiable Risk Factors
- Discontinue or minimize offending antibiotics if possible, as continued antibiotic use significantly increases risk of CDI recurrence if the patient does have subclinical infection. 1, 2
- If antibiotics must be continued for another infection, switch to agents less frequently associated with CDI (parenteral aminoglycosides, sulfonamides, macrolides, vancomycin, or tetracycline/tigecycline). 1
- Consider discontinuing proton pump inhibitors if not clearly indicated, as they are associated with increased CDI risk. 1, 4
Common Pitfalls to Avoid
- Do not order "test of cure" after treatment, as over 60% of successfully treated patients remain C. difficile positive. 1
- Do not test asymptomatic patients or those without diarrhea (≥3 unformed stools in 24 hours), as this detects colonization rather than infection. 1, 2
- Do not reflexively treat based on high sensitivity of PCR alone without considering clinical context, as PCR cannot distinguish colonization (present in up to 7% of asymptomatic hospitalized patients) from active infection. 2