What is the next step in management for a patient with persistent fever, headache, body aches, nausea, and diarrhea despite 1 week of doxycycline (doxycycline) therapy, with normal computed tomography (CT) scan, ultrasound (US), and complete blood count (CBC) results?

Next Steps in Management for Persistent Fever Despite Doxycycline

The most critical next step is to discontinue doxycycline and pursue comprehensive diagnostic imaging and laboratory workup for tickborne rickettsial diseases, occult infections, and alternative diagnoses, as lack of clinical response within 48 hours of doxycycline therapy strongly suggests this is not a doxycycline-responsive infection. 1

Immediate Actions

Discontinue Current Therapy

• Stop doxycycline immediately, as the lack of fever resolution after one week of therapy indicates either an incorrect diagnosis or doxycycline-resistant pathogen 1
• Fever typically subsides within 24-48 hours when doxycycline is initiated in the first 4-5 days of tickborne rickettsial disease; lack of response by 48 hours suggests an alternative diagnosis 1
• Consider that doxycycline itself may be causing drug fever, though this typically occurs after 17+ days of therapy and is rare 2

Reassess for Tickborne Diseases

• Obtain serologic testing for tickborne rickettsial diseases including Rocky Mountain Spotted Fever, ehrlichiosis, and anaplasmosis, even though initial doxycycline failure makes these less likely 1
• Query specifically about tick exposure in the 2-4 weeks prior to symptom onset, as this history may have been missed initially 1
• Note that serologic tests may be negative early in disease course, so negative acute serology does not exclude tickborne illness 1

Second-Line Diagnostic Workup

Advanced Imaging

• Obtain CT scan of sinuses to evaluate for occult chronic sinusitis, which can present with persistent fever and headache 3
• Perform abdominal/pelvic CT with contrast to evaluate for occult intra-abdominal infection or abscess that may have been missed on initial ultrasound 3
• Consider high-resolution chest CT if respiratory symptoms are present or if initial chest CT was non-contrast, as this may reveal bronchiectasis or interstitial disease 3

Laboratory Investigations

• Repeat complete blood count with differential looking specifically for leukopenia, thrombocytopenia, or atypical lymphocytes that suggest tickborne disease 1, 3
• Obtain C-reactive protein and erythrocyte sedimentation rate to quantify degree of inflammation 3
• Draw blood cultures (at least two sets) during or just before fever spikes to identify occult bacteremia 3
• Consider liver function tests, as elevated transaminases can suggest ehrlichiosis or other systemic infections 1

Specialized Testing

• Test for Q fever (Coxiella burnetii) with acute and convalescent serology, as this presents with prolonged fever, headache, and myalgias and does not always respond rapidly to doxycycline 1
• Consider testing for Lyme disease with two-tier serology if in endemic area, though doxycycline should have been effective if this were the diagnosis 4
• Evaluate for viral causes including EBV, CMV, and HIV, which can present with prolonged constitutional symptoms 3

Critical Diagnostic Considerations

Why Doxycycline Failed

• Broad-spectrum antibiotics including penicillins, cephalosporins, aminoglycosides, erythromycin, and sulfa-containing drugs are not effective against rickettsiae, so if an alternative antibiotic was tried before doxycycline, this would not have treated tickborne disease 1
• However, if doxycycline was truly given for one full week without improvement, tickborne rickettsial disease becomes much less likely 1
• Consider that the patient may have a non-infectious cause of fever or a doxycycline-resistant organism 3

Common Pitfalls to Avoid

• Do not continue doxycycline beyond 7 days without clinical improvement, as this increases risk of adverse effects without benefit 1, 5
• Do not assume normal CBC rules out serious infection; ehrlichiosis and anaplasmosis can present with normal or only mildly abnormal counts early in disease 1
• Do not rely solely on geographic location to exclude tickborne diseases, as RMSF should be considered endemic throughout the contiguous United States 1
• Recognize that gastrointestinal symptoms (nausea, diarrhea) may be adverse effects of doxycycline itself rather than the underlying illness 6, 5

Management Algorithm

If Tickborne Disease Still Suspected

• Continue doxycycline only if there is high clinical suspicion for tickborne disease with recent tick exposure and characteristic laboratory findings (leukopenia, thrombocytopenia, elevated transaminases) 1
• Hospitalize if patient has evidence of organ dysfunction, severe thrombocytopenia, mental status changes, or orthostatic hypotension 1

If Alternative Diagnosis More Likely

• Pursue source control if imaging reveals abscess or localized infection requiring drainage 1
• Consider empiric broad-spectrum antibiotics only after blood cultures are obtained and if patient appears clinically ill 3
• Evaluate for non-infectious causes including malignancy, autoimmune disease, and drug fever 3

Follow-Up Timeline

• Reassess within 3-5 days after initiating new diagnostic workup or changing therapy 3
• If fever persists beyond 5-7 days without identified source, strongly consider specialist consultation with infectious disease 1, 3