What are the recommended therapeutic options for treating antibiotic-resistant infections?

Antibiotic Resistance and New Therapeutic Options

First-Line Agents for Carbapenem-Resistant Enterobacterales (CRE)

For infections caused by KPC-producing carbapenem-resistant Enterobacterales, ceftazidime-avibactam and meropenem-vaborbactam should be your first-line treatment options, with imipenem-relebactam and cefiderocol as alternatives. 1

• Ceftazidime-avibactam demonstrates superior outcomes compared to traditional regimens, with 28-day mortality of 18.3% versus 40.8% for other active agents in KPC-producing K. pneumoniae bloodstream infections 1
• Meropenem-vaborbactam shows higher clinical cure rates (64.3% vs 33.3%) and reduced 28-day mortality (17.9% vs 33.3%) compared to best available therapy for CRE infections 1, 2
• These newer β-lactam/β-lactamase inhibitor combinations are significantly safer than colistin-based regimens, with lower nephrotoxicity rates 1

Dosing for CRE Infections

For pneumonia and bloodstream infections:

• Ceftazidime-avibactam: 2.5 g IV every 8 hours for 10-14 days 1
• Meropenem-vaborbactam: 4 g IV every 8 hours for 10-14 days 1
• Imipenem-relebactam: 1.25 g IV every 6 hours for 10-14 days 1

For complicated urinary tract infections:

• Same agents at same doses but for 5-7 days 1
• Aminoglycosides (gentamicin 5-7 mg/kg/day or amikacin 15 mg/kg/day) are acceptable alternatives for UTIs only 1

Carbapenem-Resistant Pseudomonas aeruginosa (CRPA)

For difficult-to-treat P. aeruginosa, prioritize ceftolozane-tazobactam or ceftazidime-avibactam over colistin-based regimens. 1

• Ceftolozane-tazobactam: 1.5-3 g IV every 8 hours (use 3 g dose for hospital-acquired or ventilator-associated pneumonia) 1
• Ceftazidime-avibactam: 2.5 g IV every 8 hours 1
• Colistin monotherapy or combination therapy remains an option when newer agents are unavailable or resistance is documented 1

Treatment Duration for CRPA

• Complicated UTI and intra-abdominal infections: 5-10 days 1
• Hospital-acquired pneumonia and bloodstream infections: 10-14 days 1

Carbapenem-Resistant Acinetobacter baumannii

For pneumonia caused by carbapenem-resistant A. baumannii, use colistin with or without a carbapenem (if MIC ≤32 mg/L), plus adjunctive inhaled colistin. 1

• IV colistin: 5 mg CBA/kg loading dose, then 2.5 mg CBA × (1.5 × CrCl + 30) every 12 hours 1
• Inhaled colistin: 1.25-15 MIU/day in 2-3 divided doses 1
• Carbapenem addition: Imipenem-cilastatin 500 mg IV every 6 hours or meropenem 2 g IV every 8 hours (infused over >3 hours) if carbapenem MIC ≤32 mg/L 1
• Alternative regimen: Colistin + tigecycline (100 mg loading, then 50 mg every 12 hours) + sulbactam (6-9 g/day in 3-4 divided doses) 1

Vancomycin-Resistant Enterococci (VRE)

Linezolid 600 mg IV every 12 hours is the first-line treatment for all VRE infections regardless of site. 1

• For bloodstream infections, daptomycin 8-12 mg/kg IV daily is an alternative, with consideration of adding a β-lactam if daptomycin MIC is 3-4 mg/mL 1
• For uncomplicated UTIs, fosfomycin 3 g PO single dose or nitrofurantoin 100 mg PO four times daily are appropriate 1
• Treatment duration: 10-14 days for bloodstream infections, at least 7 days for pneumonia, 5-7 days for complicated UTIs 1

Febrile Neutropenia with Suspected Resistance

For high-risk febrile neutropenia patients, initiate piperacillin-tazobactam monotherapy, adding amikacin or vancomycin only when resistance is suspected or the patient is clinically unstable. 1

• Low-risk patients: Ciprofloxacin plus amoxicillin-clavulanate 1
• High-risk patients: Piperacillin-tazobactam as monotherapy 1
• Add second agents (amikacin or vancomycin) for: clinically unstable patients, suspected resistant infections, or centers with high rates of resistant pathogens 1
• Avoid aminoglycosides in neutropenic sepsis when possible due to toxicity concerns 1

Hospital-Acquired and Ventilator-Associated Pneumonia

Piperacillin-tazobactam demonstrates the lowest mortality and adverse event rates among β-lactams for empiric therapy of hospital-acquired pneumonia. 1

• Piperacillin-tazobactam shows lower mortality (RR 0.56,95% CI 0.34-0.92) compared to other β-lactams 1
• Cefepime is associated with higher mortality (RR 1.39,95% CI 1.04-1.86) and should be avoided when alternatives exist 1
• Short-course therapy (7-8 days) is preferred over long-course (10-15 days), providing 4 more antibiotic-free days and reduced recurrence of multidrug-resistant VAP 1

Complicated Intra-Abdominal Infections

For non-severe community-acquired intra-abdominal infections, use amoxicillin-clavulanate as first-line; for severe infections, use ceftriaxone or cefotaxime plus metronidazole. 1

Non-Severe Infections

• First choice: Amoxicillin-clavulanate 1
• Second choice: Ciprofloxacin plus metronidazole 1

Severe Infections

• First choice: Ceftriaxone or cefotaxime plus metronidazole 1
• Second choice: Piperacillin-tazobactam or meropenem 1
• Add ampicillin if enterococcal coverage is needed and not provided by the primary regimen 1

For CRE-Associated Intra-Abdominal Infections

• Ceftazidime-avibactam 2.5 g every 8 hours plus metronidazole 500 mg every 6 hours 1
• Imipenem-relebactam 1.25 g IV every 6 hours 1
• Tigecycline or eravacycline as alternatives 1

Critical Pitfalls to Avoid

Never delay empiric broad-spectrum therapy while awaiting cultures in critically ill patients—inadequate initial therapy significantly increases mortality even if corrected later. 3, 4

• Initial inadequate therapy cannot be remedied by subsequent modification once culture results return 4
• De-escalation should occur at 2-4 days based on culture results and clinical improvement, not earlier 4
• Avoid prolonged courses without documented persistent infection, as this drives resistance 3
• Do not use aminoglycoside monotherapy except for uncomplicated UTIs due to high failure rates 1
• Tigecycline monotherapy is contraindicated for pneumonia due to FDA warnings about increased mortality 1