What is the preferred treatment option between Ceftolozane (Ceftolozane + Tazobactam) and Polymyxin B (Polymyxin B) for a patient with a complicated urinary tract infection or intra-abdominal infection due to a drug-resistant Gram-negative organism?

Ceftolozane-Tazobactam vs Polymyxin B for Drug-Resistant Gram-Negative Infections

For complicated urinary tract infections and intra-abdominal infections caused by drug-resistant Gram-negative organisms, ceftolozane-tazobactam is the preferred first-line agent over polymyxin B when the organism is susceptible in vitro, due to superior clinical cure rates and significantly lower nephrotoxicity. 1, 2

Treatment Algorithm by Pathogen and Infection Type

For Carbapenem-Resistant Pseudomonas aeruginosa (CRPA)

Severe infections:

• Use ceftolozane-tazobactam 1.5g IV every 8 hours if active in vitro (conditional recommendation, very low certainty evidence) 1
• Retrospective data demonstrate ceftolozane-tazobactam achieves higher clinical cure (adjusted OR 2.63,95% CI 1.31-5.30) compared to polymyxin/aminoglycoside combinations 1
• Nephrotoxicity is dramatically lower with ceftolozane-tazobactam (adjusted OR 0.08,95% CI 0.03-0.22) versus polymyxins 1

If polymyxin B must be used:

• Employ combination therapy with two in vitro active drugs for severe CRPA infections (conditional recommendation, very low certainty evidence) 1, 2
• No specific combination can be definitively recommended, but options include polymyxin B plus aminoglycosides, fosfomycin, or high-dose extended-infusion carbapenem if meropenem MIC ≤8 mg/L 1, 3

Non-severe or low-risk infections:

• Monotherapy with either agent is acceptable based on in vitro susceptibility and infection source 1, 3

For Carbapenem-Resistant Enterobacterales (CRE)

The pathogen's carbapenemase type determines optimal therapy:

• KPC or OXA-48 producers: Newer beta-lactam/beta-lactamase inhibitors (ceftazidime-avibactam, meropenem-vaborbactam) are preferred over both ceftolozane-tazobactam and polymyxin B 1, 4
• Metallo-beta-lactamase (MBL) producers: Aztreonam plus ceftazidime-avibactam combination is suggested for severe infections (conditional recommendation, moderate certainty evidence) 1, 4
• When only polymyxins/aminoglycosides/tigecycline/fosfomycin are active OR newer agents unavailable: Use combination therapy with more than one in vitro active drug for severe infections (conditional recommendation, moderate certainty evidence) 1, 3

For Carbapenem-Resistant Acinetobacter baumannii (CRAB)

Neither ceftolozane-tazobactam nor polymyxin B is the optimal choice:

• Ampicillin-sulbactam is preferred if susceptible (conditional recommendation, low certainty evidence) 1, 3
• If sulbactam-resistant, polymyxin B or high-dose tigecycline can be used if active in vitro, but no preferred agent can be recommended 1, 3
• Strong recommendation AGAINST polymyxin-meropenem or polymyxin-rifampin combinations for CRAB 1, 2

Dosing Specifications

Ceftolozane-Tazobactam

• cUTI: 1.5g (1g ceftolozane + 0.5g tazobactam) IV over 1 hour every 8 hours 5
• cIAI: 1.5g IV over 1 hour every 8 hours PLUS metronidazole 500mg every 8 hours 6, 5
• Adjust for renal impairment when creatinine clearance <50 mL/min 6, 7

Polymyxin B

• Loading dose: 9 MU (5 mg/kg) for critically ill patients 3
• Maintenance: 4.5 MU twice daily 3
• Consider aerosolized polymyxin B in addition to IV for respiratory tract infections (weak recommendation, low-quality evidence) 3

Evidence Quality and Nuances

Strength of evidence favoring ceftolozane-tazobactam:

• The ASPECT-NP trial showed clinical cure in 4/10 patients with XDR-PA treated with ceftolozane-tazobactam versus 2/5 with meropenem, though specific CRPA data are limited 1
• Real-world multicenter data demonstrate 84.7% clinical success with ceftolozane-tazobactam for various serious infections, with 63% involving P. aeruginosa (66% multidrug-resistant, 45% carbapenem-resistant) 8
• Ceftolozane-tazobactam achieved 100% clinical cure (26/26) versus 93.1% (27/29) for meropenem in cIAI involving P. aeruginosa 9

Limitations of polymyxin B:

• Polymyxin B demonstrates higher nephrotoxicity compared to newer agents, with colistin (related polymyxin) showing adjusted HR 2.27 (95% CI 1.35-3.82) for RIFLE-defined nephrotoxicity versus polymyxin B 1, 3
• Combination therapy data for polymyxins show reduced mortality versus monotherapy (35.7% vs 55.5%; OR 0.46,95% CI 0.30-0.69) for CRE infections, but this still represents substantial mortality 3

Critical Pitfalls to Avoid

Do not use ceftolozane-tazobactam for:

• Carbapenem-resistant Enterobacterales (it lacks activity against carbapenemases) 6, 5
• Confirmed or suspected metallo-beta-lactamase producers 4

Do not use polymyxin B as monotherapy for:

• Severe CRPA infections (combination therapy is strongly suggested) 1, 2, 3

Always obtain susceptibility testing:

• Request ceftolozane-tazobactam susceptibility for all multidrug-resistant Pseudomonas isolates 1
• Determine carbapenemase type before selecting therapy for CRE 4

Antibiotic stewardship considerations:

• Reserve ceftolozane-tazobactam for infections where resistance to older agents is documented or highly suspected 2, 4
• Newer agents should be prioritized over polymyxins when both are active in vitro due to superior safety profiles 2, 3