What could be the cause of sudden fever in a patient with a history of acute gastroenteritis, who was clinically improving on intravenous (IV) antibiotics for 3 days and was planned for discharge?

Sudden Fever in Improving Gastroenteritis Patient on IV Antibiotics

The most likely causes of sudden fever after 3 days of IV antibiotics in a clinically improving gastroenteritis patient are breakthrough infections (particularly Clostridioides difficile colitis or catheter-related infection), drug fever, or an occult secondary infection requiring reassessment and additional diagnostic workup. 1

Immediate Diagnostic Approach

Reassess for Breakthrough Infections

Recurrent or persistent fever >3 days despite empirical antibiotic therapy mandates a thorough search for a source of infection, including new blood cultures and symptom-directed diagnostic tests. 1

• Obtain new blood cultures (at least two sets) to identify breakthrough bacteremia or catheter-related bloodstream infection 1, 2
• Evaluate for C. difficile infection by analyzing stool for C. difficile toxin using enzyme immunoassays or 2-step antigen assay, as C. difficile-associated diarrhea is a common breakthrough infection in patients receiving antibiotics 1
• Assess vascular catheter sites for signs of infection (erythema, purulence, tenderness), as catheter-related infections are not uncommon causes of recurrent fever 1

Consider Non-Infectious Causes

The IDSA guidelines emphasize that for patients with recurrent or persistent fever, consideration should be given to noninfectious sources, such as drug-related fever, thrombophlebitis, or resorption of blood from a large hematoma. 1

• Drug fever from the IV antibiotics themselves is a recognized cause of persistent fever and should be considered, especially if the patient is otherwise clinically stable 1
• Thrombophlebitis at IV sites can cause fever without obvious signs of infection 1

Diagnostic Workup Algorithm

First-Line Investigations (Perform Immediately)

• New blood cultures (two sets from different sites) 1, 2
• Stool C. difficile toxin assay if any diarrhea persists or recurs 1
• Complete blood count with differential to assess for leukocytosis or other abnormalities 2
• C-reactive protein and erythrocyte sedimentation rate to quantify inflammation 2
• Meticulous physical examination focusing on catheter sites, abdomen, and any new localizing symptoms 1

Second-Line Investigations (If Initial Workup Negative)

• Abdominal CT scan if patient has abdominal pain or persistent diarrhea to evaluate for neutropenic enterocolitis, abscess, or other intra-abdominal pathology 1, 2
• Chest radiography or CT if any respiratory symptoms develop 1, 2
• Urinalysis and urine culture to exclude occult urinary tract infection 2

Management Recommendations

Antibiotic Management

Persistent fever in an otherwise asymptomatic and hemodynamically stable patient is not a reason for undirected antibiotic additions or changes. 1 However, specific modifications are warranted based on findings:

• If C. difficile is suspected clinically (abdominal cramping, diarrhea), initiate empirical treatment with oral vancomycin or metronidazole while awaiting diagnostic results 1
• If drug fever is suspected and patient is clinically stable with negative cultures after 48 hours, consider discontinuing the current antibiotic and observing, or switching to a different class 1, 3
• If breakthrough bacteremia is documented, modify antibiotics based on culture results and susceptibility patterns 1

Observation Period

The median time to defervescence in patients with gastroenteritis on appropriate antibiotics is 2-7 days (median 5 days). 1 Therefore:

• Wait up to 5 days before making empirical antibiotic changes if the patient remains clinically stable without deterioration, unless new culture data or clinical findings mandate earlier modification 1
• Reassess daily for signs of clinical deterioration, which would require immediate antibiotic modification 1

Critical Pitfalls to Avoid

Do Not Add Vancomycin Empirically

There is no proven advantage to adding vancomycin empirically in the setting of persistent or recrudescent fever. A randomized prospective study showed no difference in time-to-defervescence when vancomycin was added to piperacillin-tazobactam after 60-72 hours of persistent fever. 1

Do Not Switch Antibiotics Without Indication

A switch from one empirical monotherapy to another or the addition of an aminoglycoside is not generally useful, unless there is a need for expanded spectrum of coverage as dictated by clinical or microbiologic data. 1

Recognize When Observation Is Appropriate

Many patients with persistent fever will defervesce without intervention once adequate time has passed (typically 5 days), provided they remain clinically stable without documented resistant organisms or new infection sources. 1

Special Considerations for Gastroenteritis

• Most acute gastroenteritis is viral and does not require antibiotics; bacterial causes warranting antibiotics include Shigella, Campylobacter, and severe Salmonella infections 1, 4, 5
• Empirical antibiotic therapy in gastroenteritis is generally reserved for patients with fever and bloody diarrhea, symptoms persisting >1 week, or immunocompromised status 4
• IV antibiotics increase risk of antibiotic-associated diarrhea and C. difficile infection compared to oral antibiotics, with one study showing 25.7% AAD rate with IV antibiotics versus 12.3% without 6