Which laboratory tests should be ordered for a patient experiencing fatigue, anxiety, and feeling unwell after completing a course of antibiotics?

Laboratory Evaluation for Post-Antibiotic Fatigue, Anxiety, and Malaise

Initial Essential Laboratory Panel

Order a comprehensive metabolic panel (CMP), complete blood count (CBC) with differential, thyroid-stimulating hormone (TSH), and urinalysis to evaluate for metabolic derangements, hematologic abnormalities, thyroid dysfunction, and occult infection that commonly manifest as fatigue and anxiety after antibiotic exposure.

Core Metabolic Assessment

• Comprehensive metabolic panel (CMP) should be obtained to assess for electrolyte disturbances (particularly hyponatremia and hypokalemia), renal dysfunction, hepatobiliary injury, and glucose abnormalities that can cause fatigue and neuropsychiatric symptoms 1
• Serum glucose measurement is critical because stress hyperglycemia or hypoglycemia can worsen confusion and fatigue in patients recovering from infection 2
• Hepatobiliary enzymes (AST, ALT, alkaline phosphatase, bilirubin) should be checked because antibiotic-associated hepatotoxicity can present with fatigue and malaise 3
• Renal function (creatinine, BUN) must be assessed as antibiotic-associated nephrotoxicity is common (24% of antibiotic-related adverse events) and can cause fatigue 3

Hematologic Evaluation

• Complete blood count with differential is essential to detect antibiotic-associated blood dyscrasias (neutropenia, thrombocytopenia, hemolytic anemia) that occur in 3.3 per 100,000 person-years and increase with multiple antibiotic classes 4
• Evaluate for leukocytosis or bandemia because persistent inflammation-immunosuppression and catabolism syndrome (PICS) can develop after antibiotic treatment for serious infections, manifesting as prolonged fatigue and malaise 5
• Check eosinophil count as eosinophilia (>500 cells/μL) can develop during recovery from severe illness and may indicate ongoing inflammatory processes 5

Thyroid Function

• TSH measurement should be obtained because thyroid dysfunction commonly presents with fatigue, anxiety, and general malaise and may be unmasked or exacerbated during acute illness 1

Infection Screening

• Urinalysis with microscopy is warranted to rule out occult urinary tract infection, which in elderly or immunocompromised patients can present atypically with fatigue and confusion rather than classic urinary symptoms 2, 1
• If urinalysis shows pyuria (≥10 WBC/HPF) or positive leukocyte esterase AND the patient has acute urinary symptoms (dysuria, frequency, urgency, fever >38.3°C, or gross hematuria), obtain urine culture before initiating treatment 6
• Do not treat asymptomatic bacteriuria even if discovered on screening urinalysis, as it affects 15-50% of certain populations and treatment provides no benefit while increasing resistance 6

Secondary Investigations Based on Initial Results

If Persistent Symptoms After Normal Initial Labs

• Consider C-reactive protein (CRP) or erythrocyte sedimentation rate (ESR) to assess for ongoing systemic inflammation, particularly if the patient had recent serious infection or trauma 5
• Vitamin B12 and folate levels should be checked if macrocytic anemia or neuropsychiatric symptoms are prominent, as deficiencies can cause fatigue and anxiety
• Cortisol level (morning) may be indicated if adrenal insufficiency is suspected based on hypotension, hyponatremia, or hyperkalemia 2

If Gastrointestinal Symptoms Present

• Stool testing for Clostridioides difficile toxin is critical if the patient has diarrhea, as C. difficile infection occurred in 6 of 29 patients (21%) with prolonged antibiotic exposure and persistent symptoms 5
• Gastrointestinal adverse events account for 42% of antibiotic-associated adverse drug events and can persist after treatment completion 3

Psychiatric Symptom Evaluation

Antibiotic-Associated Neuropsychiatric Effects

• Recognize that antibiotic exposure is independently associated with increased risk of depression and anxiety, with adjusted odds ratios of 1.23-1.25 for single courses and 1.40-1.56 for recurrent exposures (≥5 courses) 7
• Penicillins and quinolones carry the highest risk for depression, while penicillins and sulfonamides are most associated with anxiety 7
• No specific laboratory test predicts or confirms antibiotic-associated psychiatric symptoms; diagnosis is clinical and based on temporal relationship to antibiotic exposure 7

Common Pitfalls to Avoid

• Do not attribute all post-antibiotic fatigue to "normal recovery" without excluding metabolic, hematologic, and endocrine abnormalities that require specific treatment 1, 3
• Do not order urinalysis or urine culture in asymptomatic patients as this leads to detection and inappropriate treatment of asymptomatic bacteriuria 6
• Do not assume leukocytosis indicates active infection requiring more antibiotics; persistent leukocytosis may represent PICS and further antibiotics can cause harm through colonization with resistant organisms 5
• Do not overlook antibiotic-associated blood dyscrasias, particularly in patients who received multiple antibiotic classes or cephalosporins (RR 13.8) 4
• Do not dismiss anxiety and depression as purely psychological; these symptoms have documented associations with antibiotic-induced gut microbiome disruption 7

Timing and Follow-Up

• Initial laboratory evaluation should be performed within 48-72 hours of symptom onset to detect acute metabolic or hematologic derangements 1
• Repeat abnormal labs in 1-2 weeks to confirm resolution or identify persistent abnormalities requiring further investigation 1
• If symptoms persist beyond 2-4 weeks despite normal initial workup, consider referral to infectious disease or internal medicine for evaluation of post-infectious fatigue syndrome or other chronic complications 8