What is the preferred antibiotic for a patient with a severe bacterial infection, Polymyxin B (Poly B) or Ceftolozane (Ceftolozane)/tazobactam, considering factors such as type of infection, suspected pathogens, and impaired renal function?

Ceftolozane-Tazobactam is Preferred Over Polymyxin B for Multidrug-Resistant Pseudomonas aeruginosa Infections

For severe infections caused by multidrug-resistant or carbapenem-resistant Pseudomonas aeruginosa (CRPA), ceftolozane-tazobactam should be the first-line agent when the organism is susceptible in vitro, with polymyxin B reserved for situations where newer agents are unavailable or the organism is resistant to all other options. 1

Evidence-Based Treatment Algorithm

First-Line Therapy Selection

Ceftolozane-tazobactam demonstrates superior clinical outcomes compared to polymyxin-based regimens:

• Clinical cure rates are significantly higher with ceftolozane-tazobactam (adjusted OR 2.63,95% CI 1.31-5.30), with a number needed to treat of only 5 patients for one additional clinical cure 1, 2
• Nephrotoxicity is dramatically lower with ceftolozane-tazobactam (adjusted OR 0.08,95% CI 0.03-0.22), with a number needed to harm of 4 for polymyxin/aminoglycoside regimens to cause one additional acute kidney injury 1, 2
• The 2022 ESCMID guidelines conditionally recommend ceftolozane-tazobactam for severe DTR-CRPA infections when active in vitro, based on very low certainty evidence 1

Dosing Considerations

For ceftolozane-tazobactam:

• Standard dose: 3 g (ceftolozane 2 g/tazobactam 1 g) every 8 hours for hospital-acquired/ventilator-associated pneumonia 3
• Standard dose: 1.5 g (ceftolozane 1 g/tazobactam 0.5 g) every 8 hours for complicated urinary tract infections 3
• Infusion time: 1 hour for standard dosing 3
• Extended infusions (3 hours) may be necessary to achieve fT >100% MIC in patients with creatinine clearance >90 mL/min or high beta-lactamase expression 4

For polymyxin B (when ceftolozane-tazobactam unavailable):

• Loading dose: 2-2.5 mg/kg regardless of renal function 5, 6
• Maintenance dose: 1.5-3 mg/kg/day divided into 2 daily doses 5, 6
• Critical advantage: No dose adjustment required for renal impairment or continuous renal replacement therapy 5, 6

Renal Function Considerations

Polymyxin B has distinct advantages in renal impairment:

• Polymyxin B is administered as the active drug with plasma concentrations unaffected by renal function 5
• Nephrotoxicity incidence is lower with polymyxin B (11.8%) compared to colistin (39.3%) 5
• A before-after study showed colistin has higher RIFLE-defined nephrotoxicity (adjusted HR 2.27,95% CI 1.35-3.82) compared to polymyxin B 1, 5
• Ceftolozane-tazobactam requires dose adjustment when creatinine clearance falls below 50 mL/min 3

Combination Therapy Recommendations

For severe CRPA infections when using polymyxins:

• The ESCMID guidelines suggest treatment with two in vitro active drugs when using polymyxins, aminoglycosides, or fosfomycin (conditional recommendation, very low certainty) 1
• No recommendation exists for or against combination therapy with ceftolozane-tazobactam for CRPA 1
• Combination therapy with polymyxin B reduces treatment failure by 119 per 1000 patients (RR 0.82,95% CI 0.72-0.93) 6

Critical Pitfalls to Avoid

When using polymyxin B:

• Never omit the loading dose, as this delays therapeutic levels by days 6
• Avoid concurrent neurotoxic agents including aminoglycosides, bacitracin, and colistin 7
• Monitor for polymyxin B-induced myopathy with muscle weakness and elevated creatine kinase 7
• Close renal function monitoring is essential throughout therapy 5, 6

When using ceftolozane-tazobactam:

• The 2016 IDSA/ATS guidelines reserve polymyxins for settings with high prevalence of multidrug resistance and local expertise 1
• Ceftolozane-tazobactam should be used only when organisms are proven or strongly suspected to be susceptible 3

Clinical Outcomes Data

Mortality outcomes are similar between agents:

• No significant difference in 30-day risk-adjusted mortality between ceftolozane-tazobactam and colistin-based regimens (HR 0.58,95% CI 0.16-2.13) 8
• However, clinical success is significantly higher with ceftolozane-tazobactam (RR 1.84,95% CI 1.11-3.06) 8
• Very low-certainty evidence shows no mortality difference between polymyxin B and colistin for CRPA 5

Infection-Specific Considerations

For ventilator-associated pneumonia:

• Ceftolozane-tazobactam 3 g every 8 hours for 8-14 days is FDA-approved 3
• The ASPECT-NP trial showed clinical cure in 4/10 patients with XDR-PA treated with ceftolozane-tazobactam versus 2/5 with meropenem 1
• Polymyxin-based combination therapy showed no mortality benefit in RCTs (21 patients in AIDA, 43 in OVERCOME) 1

For bacteremia:

• Both agents show similar mortality outcomes, but ceftolozane-tazobactam demonstrates superior clinical success 8
• Combination therapy with polymyxin B is recommended for severe infections 6, 9