What to do for a patient with leukocytosis (increasing white blood cell count) on Zosyn (piperacillin/tazobactam)?

Management of Increasing White Blood Cell Count on Zosyn

Stop Zosyn immediately and investigate for drug-induced leukocytosis, treatment failure requiring source control, or hematologic complications, as piperacillin-tazobactam can cause leukocytosis through drug hypersensitivity reactions and is associated with rare but serious hematologic adverse effects. 1, 2

Immediate Actions

Discontinue Zosyn and Assess for Drug Reaction

• Stop piperacillin-tazobactam immediately if leukocytosis is accompanied by fever, rash, eosinophilia, or organ dysfunction, as the FDA label warns that leukopenia and neutropenia may occur during prolonged therapy, and case reports document drug-induced hypersensitivity reactions causing leukocytosis, hepatitis, and interstitial nephritis. 1, 2
• Check for signs of serum sickness-like syndrome: fever, rash, arthralgias, and elevated liver enzymes, which can present with paradoxical leukocytosis despite being a hypersensitivity reaction. 2
• Monitor for agranulocytosis or thrombocytopenia, which can develop within 14 days of starting Zosyn and may require immediate hematologic intervention. 3, 4

Evaluate for Treatment Failure and Inadequate Source Control

• Perform diagnostic investigation immediately if signs of infection or systemic illness persist beyond 7 days of antibiotic treatment, as this warrants imaging and reassessment of source control per Italian guidelines for intra-abdominal infections. 5
• Obtain CT imaging with IV contrast to identify undrained abscesses, intestinal perforation (extraluminal gas, intra-abdominal fluid), or other surgical pathology requiring intervention. 5
• Check inflammatory markers including C-reactive protein, procalcitonin, and assess for left shift (band neutrophils ≥16% or ≥1500 cells/mm³), which increases the likelihood ratio for bacterial infection to 14.5. 6, 7

Diagnostic Workup

Obtain Peripheral Blood Smear and Complete Blood Count

• Review peripheral smear for toxic granulations, left shift, immature forms (blasts), or atypical lymphocytes to differentiate reactive leukocytosis from hematologic malignancy. 8, 6
• A white blood cell count >100,000/μL constitutes a medical emergency requiring immediate hematology consultation and aggressive IV hydration at 2.5-3 liters/m²/day to prevent tumor lysis syndrome. 8, 7

Rule Out Alternative Causes

• Obtain blood cultures and site-specific cultures before changing antibiotics, as empiric broad-spectrum antimicrobial therapy is mandatory for febrile patients with suspected infection. 6
• Check for Clostridium difficile with stool cultures and toxin testing if diarrhea is present, as this is a common complication of antibiotic therapy. 7
• Assess renal function, liver enzymes, and electrolytes, as piperacillin-tazobactam can cause interstitial nephritis and hepatitis with associated leukocytosis. 7, 2

Management Based on Etiology

If Drug Reaction is Confirmed

• Switch to an alternative antibiotic based on culture data and clinical scenario—consider ertapenem 1g q24h, meropenem 1g q6h by extended infusion, or eravacycline 1mg/kg q12h for intra-abdominal infections. 5
• Consider corticosteroids if acute interstitial nephritis or serum sickness-like syndrome is documented, as steroids have improved outcomes in most cases. 2
• Monitor complete blood count daily until leukocytosis resolves and organ function normalizes. 2

If Inadequate Source Control is Identified

• Perform percutaneous drainage for large abscesses (>3-4 cm) combined with antibiotic therapy for 4 days in immunocompetent patients or up to 7 days in immunocompromised/critically ill patients. 5
• Consider surgical intervention if percutaneous drainage is not feasible in critically ill or immunocompromised patients. 5
• Continue antibiotics for 4 days if source control is adequate in immunocompetent patients, or up to 7 days based on clinical conditions and inflammation indices in high-risk patients. 5

If Hematologic Malignancy is Suspected

• Obtain immediate hematology/oncology consultation if peripheral smear shows blasts, immature cells, or if WBC >100,000/μL with no clear infectious source. 8, 7
• Initiate cytoreduction with hydroxyurea at 50-60 mg/kg/day concurrently with aggressive hydration to achieve 50% WBC reduction within 1-2 weeks. 8
• Consider leukapheresis for symptomatic leukostasis, which can achieve 30-80% WBC reduction within hours, but avoid in acute promyelocytic leukemia due to fatal hemorrhage risk. 8

Critical Pitfalls to Avoid

• Never delay investigation or treatment while awaiting confirmatory testing if hyperleukocytosis (WBC >100,000/μL) is present, as this constitutes a medical emergency. 8, 7
• Do not continue Zosyn if drug-induced leukocytosis with organ dysfunction is suspected, as progression to agranulocytosis or severe hypersensitivity can occur rapidly. 2, 4
• Do not overlook inadequate source control as the cause of persistent leukocytosis—imaging and surgical consultation are essential if infection signs persist beyond 7 days. 5
• Monitor coagulation parameters if bleeding manifestations occur, as beta-lactam antibiotics including piperacillin can cause abnormalities in clotting time, platelet aggregation, and prothrombin time, particularly in patients with renal failure. 1