In an adult patient with a severe hospital‑acquired infection and no drug allergies who has a rising total leukocyte count despite meropenem therapy, how should antimicrobial coverage be escalated?

Escalating Antimicrobial Coverage Beyond Meropenem for Persistent Rising TLC

When meropenem fails to control a severe hospital-acquired infection with rising total leukocyte count, escalate immediately to combination therapy with vancomycin (or daptomycin/linezolid) PLUS an aminoglycoside or antipseudomonal fluoroquinolone, while aggressively pursuing source control and obtaining repeat cultures to guide definitive therapy. 1

Immediate Diagnostic Re-evaluation

Before escalating antibiotics, perform urgent reassessment:

• Obtain repeat blood cultures and site-specific cultures immediately, as breakthrough infections are common and may reveal resistant organisms not covered by meropenem 1
• Assess for inadequate source control: Look for undrained abscesses, retained foreign material (catheters, surgical hardware), necrotizing soft tissue infection, or secondary peritonitis requiring surgical intervention 1
• Order CT imaging of chest, abdomen, or sinuses based on clinical suspicion to identify occult fungal infections or localized collections 1
• Review manual differential for persistent left shift (bands ≥16% or absolute band count ≥1,500 cells/mm³), which indicates ongoing bacterial infection despite therapy 1, 2

Antimicrobial Escalation Strategy

Add Gram-Positive Coverage Immediately

Vancomycin is the first addition to meropenem for suspected MRSA or resistant gram-positive organisms:

• Vancomycin 15-20 mg/kg IV every 8-12 hours (target trough 15-20 mcg/mL for serious infections) 1
• Alternative agents: Daptomycin (6-10 mg/kg daily) or linezolid (600 mg every 12 hours) if vancomycin-resistant enterococci or MRSA with vancomycin MIC >2 mcg/mL is suspected 1, 3

Broaden Gram-Negative Coverage with Dual Therapy

Add a second anti-pseudomonal agent to achieve synergy and cover carbapenem-resistant organisms:

• Aminoglycoside option: Amikacin 15-20 mg/kg IV daily (preferred for suspected carbapenem-resistant Enterobacteriaceae) 1
• Fluoroquinolone option: Ciprofloxacin 400 mg IV every 8 hours or levofloxacin 750 mg IV daily (if aminoglycoside contraindicated) 1

Consider Carbapenem-Resistant Organism Coverage

If the patient has risk factors for extensively drug-resistant (XDR) organisms—prior carbapenem exposure, prolonged hospitalization, ICU stay, or known colonization:

• Tigecycline 100 mg IV loading dose, then 50 mg every 12 hours (for carbapenem-resistant Enterobacteriaceae) 1
• Colistin 5 mg/kg loading dose, then 2.5 mg/kg every 12 hours may be added for severe XDR infections 1
• Ceftazidime-avibactam 2.5 g IV every 8 hours is an alternative for KPC-producing organisms, though it lacks anaerobic coverage and requires metronidazole addition 3

Critical Source Control Interventions

Non-infectious causes and inadequate source control are the most common reasons for persistent fever despite appropriate antibiotics 1:

• Remove or replace all indwelling catheters (urinary, central venous, arterial lines) if catheter-related bloodstream infection is suspected 1
• Surgical consultation for potential debridement, drainage, or resection of infected/necrotic tissue 1
• Evaluate for C. difficile infection: Send stool for C. difficile toxin testing and consider empiric oral vancomycin 125 mg four times daily if diarrhea present 1

Empiric Antifungal Coverage

Add amphotericin B or an echinocandin if fever persists >3-5 days on broad-spectrum antibiotics with severe, persistent neutropenia or high-risk features 1:

• Caspofungin 70 mg IV loading dose, then 50 mg daily (preferred in hemodynamically stable patients) 1
• Liposomal amphotericin B 3-5 mg/kg IV daily (if invasive mold infection suspected or echinocandin failure) 1

Monitoring and De-escalation

• Reassess at 48-72 hours: If cultures identify specific pathogens, narrow therapy based on susceptibilities 1, 4
• Continue broad coverage until neutrophil recovery (ANC >500 cells/mm³) if patient remains febrile without identified source 1
• Do NOT empirically switch from one carbapenem to another (e.g., meropenem to imipenem) without microbiologic justification, as this provides no additional benefit 1

Common Pitfalls to Avoid

• Do not add vancomycin for persistent fever alone in hemodynamically stable patients without evidence of gram-positive infection—this practice is discouraged and increases resistance 1
• Avoid undirected antibiotic additions without repeat cultures and imaging, as non-infectious causes (drug fever, thrombophlebitis, underlying malignancy) are common 1
• Do not discontinue meropenem when escalating—maintain broad gram-negative and anaerobic coverage while adding agents for resistant organisms 1, 3
• Recognize that rising TLC may reflect appropriate immune response rather than treatment failure, especially if clinical status is improving 1