In a cystic fibrosis patient on daily prophylactic antibiotics and doxycycline for rosacea who presents with three weeks of yellow‑colored diarrhea and abdominal discomfort, what diagnostic tests should be ordered?

Diagnostic Testing for Prolonged Diarrhea in a Cystic Fibrosis Patient on Chronic Antibiotics

Test immediately for Clostridioides difficile infection (CDI) using a two-step algorithm: glutamate dehydrogenase (GDH) screening followed by toxin A/B confirmation, as this patient meets high-risk criteria with three weeks of diarrhea, chronic antibiotic exposure (both prophylactic antibiotics and doxycycline), and a documented history of CDI. 1, 2

Primary Diagnostic Priority: C. difficile Testing

Your patient's presentation is highly suspicious for CDI recurrence based on multiple risk factors:

• Recent antibiotic exposure is the single strongest risk factor for CDI, with one-third of colonized patients developing symptomatic infection within 2 weeks of antibiotic therapy 3
• Chronic prophylactic antibiotics plus doxycycline creates ongoing disruption of normal gut flora 1, 2
• History of prior CDI significantly increases recurrence risk (18-25% within 4 weeks after initial treatment) 2
• Three weeks of diarrhea with yellow stools and abdominal discomfort meets clinical criteria (≥3 unformed stools in 24 hours plus abdominal symptoms) 1, 4

Recommended Testing Algorithm

Two-step approach (highest accuracy):

1. First step: GDH antigen screening test (sensitivity 85-95%, specificity 89-99%) 1
2. Second step: If GDH positive, confirm with toxin A/B enzyme immunoassay (specificity 98-99%) 1, 2

Alternative: Nucleic acid amplification test (NAAT/PCR) for toxin B gene as first step (sensitivity 97%, specificity 93%), followed by toxin confirmation if positive 1, 5

Critical caveat: Do not use toxin EIA alone—its sensitivity is only 70-80%, resulting in missed diagnoses 2, 3. The two-step algorithm balances sensitivity (91%) with specificity (98%) while avoiding false positives from asymptomatic colonization 2, 6

Additional Essential Testing

Stool Studies to Exclude Other Infectious Causes

Before initiating immunosuppressive therapy for presumed CDI, exclude other pathogens:

• Stool culture for invasive bacterial pathogens (Campylobacter, Salmonella, Shigella, E. coli O157:H7) 1
• Stool pathogen panel (reasonable alternative to individual cultures where available) 1
• Ova and parasites examination—particularly important given CF patients' potential exposure through healthcare settings 1

Laboratory Markers of Severity

Order these tests to assess disease severity and guide management intensity:

• Complete blood count to evaluate for leukocytosis (WBC >15,000 cells/mm³ indicates severe CDI) 1, 4
• Serum creatinine (elevation ≥1.5× baseline suggests severe disease) 1, 4
• Serum albumin (hypoalbuminemia <2.5 g/dL associated with severe disease) 4
• Serum lactate (elevation may indicate fulminant disease with organ dysfunction) 1, 4

These markers are particularly important because leukocytosis cannot be used as a severity marker in neutropenic patients 1, though your CF patient is likely not neutropenic unless on specific chemotherapy.

Specialized Testing for CF-Specific Considerations

• Fecal elastase with qualitative fecal fat testing to evaluate for pancreatic insufficiency—an important cause of diarrhea in CF that may coexist with or mimic CDI 1
• Tissue transglutaminase IgA and total IgA to exclude new-onset celiac disease (rare but important cause of diarrhea in patients on immunomodulating therapies) 1

Testing to Avoid

Do not order:

• Repeat C. difficile testing within 7 days of initial negative result during the same diarrheal episode (not cost-effective and increases false positives) 2, 5
• "Test of cure" after treatment—patients may shed spores asymptomatically for up to 6 weeks after successful therapy 2, 4
• Testing if patient is asymptomatic or has formed stools—this detects colonization (10-52% prevalence in certain populations) rather than infection 4, 5

Critical Management Considerations While Awaiting Results

If CDI is confirmed or highly suspected:

• Discontinue doxycycline and prophylactic antibiotics if clinically feasible—continued antibiotic exposure dramatically increases recurrence risk 2, 3
• Avoid antiperistaltic agents (loperamide, diphenoxylate)—these are absolutely contraindicated as they trap toxins against the colonic wall, precipitate toxic megacolon, and mask clinical deterioration 2, 3
• Initiate empirical oral vancomycin 125 mg four times daily if severe symptoms are present (high fever, severe abdominal pain, leukocytosis) before confirmatory testing returns 1, 2

Special Considerations for CF Patients

Doxycycline in CF: While doxycycline has anti-inflammatory properties beneficial for CF lung disease (reduces MMP-9 levels and improves pulmonary outcomes) 7, 8, its chronic use increases CDI risk. The 40 mg anti-inflammatory dose used for rosacea 9 still provides antibiotic selection pressure despite marketing claims, particularly with chronic administration in a patient already on prophylactic antibiotics.

Yellow stools: While nonspecific, yellow diarrhea in CF patients may indicate fat malabsorption from pancreatic insufficiency, bile acid malabsorption, or rapid transit from infection—making fecal elastase testing particularly relevant 1.

Common Pitfalls to Avoid

• Assuming chronic doxycycline at "anti-inflammatory doses" doesn't increase CDI risk—any tetracycline disrupts gut flora and increases susceptibility 1, 2
• Delaying testing because symptoms are chronic (3 weeks)—CDI can present with prolonged symptoms, especially with ongoing antibiotic exposure 2, 4
• Using alcohol-based hand sanitizers alone—these do not inactivate C. difficile spores; handwashing with soap and water is mandatory 2, 3
• Testing only once if clinical suspicion remains high—if initial test is negative but patient has persistent fever, abdominal pain, and diarrhea after stopping antibiotics, obtain 1-2 additional specimens 1, 2