What are the newer anti‑Pseudomonas agents, their recommended dosing regimens, and indications for use in multidrug‑resistant infections?

Newer Anti-Pseudomonas Antibiotics: Agents, Dosing, and Indications

For multidrug-resistant Pseudomonas aeruginosa infections, ceftolozane/tazobactam and ceftazidime/avibactam are first-line novel agents, with ceftolozane/tazobactam preferred for pneumonia (3g IV every 8 hours) and ceftazidime/avibactam equally effective for non-pulmonary infections (2.5g IV every 8 hours). 1

Definition of Difficult-to-Treat Resistant Pseudomonas

Difficult-to-treat resistance (DTR) in P. aeruginosa is defined as non-susceptibility to all of the following first-line agents: ceftazidime, cefepime, piperacillin/tazobactam, aztreonam, imipenem/cilastatin, meropenem, levofloxacin, and ciprofloxacin. 1 This definition is critical because it identifies when newer agents become necessary rather than optional.

First-Line Novel β-Lactam/β-Lactamase Inhibitor Combinations

Ceftolozane/Tazobactam

• Dosing for pneumonia: 3g IV every 8 hours (infused over 1 hour). 1
• Dosing for other infections: 1.5g IV every 8 hours. 1
• Primary indication: Preferred for hospital-acquired pneumonia, ventilator-associated pneumonia, and other respiratory infections caused by DTR P. aeruginosa. 1
• Mechanism advantage: Excellent in vitro activity against MDR P. aeruginosa, including many strains resistant to traditional antipseudomonal agents. 2, 3

Ceftazidime/Avibactam

• Standard dosing: 2.5g IV every 8 hours (infused over 2 hours). 1
• Primary indication: Equally effective for non-pulmonary infections including bloodstream infections, complicated urinary tract infections, and complicated intra-abdominal infections (combined with metronidazole). 2, 1
• Mechanism advantage: Avibactam inhibits KPC-type carbapenemases and some OXA-48-like enzymes, providing activity against carbapenem-resistant Enterobacterales in addition to P. aeruginosa. 2
• Important caveat: Monotherapy may increase risk of resistance development during therapy; consider combination therapy for severe infections. 1

Second-Line Novel Agents

Imipenem/Cilastatin/Relebactam

• Dosing: 1.25g IV every 6 hours (infused over 30 minutes). 2
• When to use: May retain activity when ceftolozane/tazobactam and ceftazidime/avibactam resistance is present, particularly when metallo-β-lactamases (MBLs) are absent. 1
• Conditional recommendation: This agent is considered when first-line novel agents show resistance. 2

Cefiderocol

• Dosing: 2g IV every 8 hours (infused over 3 hours). 1
• Primary indication: Preferred when MBLs are present or as an alternative when other novel agents show resistance. 1
• Mechanism advantage: Siderophore cephalosporin with excellent in vitro activity against P. aeruginosa isolates, including those producing metallo-β-lactamases; good stability to all β-lactamases and against porin and efflux pump mutations. 3
• Clinical data: 70.8% clinical cure rate and 12.5% 28-day mortality in recent trials for metallo-β-lactamase producers. 4

Meropenem/Vaborbactam

• Dosing: 4g IV every 8 hours (infused over 3 hours). 2
• Primary indication: First-line treatment for KPC-producing carbapenem-resistant Enterobacterales; limited activity against carbapenem-resistant P. aeruginosa. 2
• Important limitation: Not a primary anti-pseudomonal agent for DTR strains, but useful when KPC-producing organisms are co-pathogens. 2

Treatment Duration by Infection Site

• Pneumonia: 10-14 days. 1
• Bloodstream infections: 10-14 days. 1
• Complicated urinary tract infections: 5-10 days. 1
• Complicated intra-abdominal infections: 5-10 days (novel agents must be combined with metronidazole for anaerobic coverage). 2, 1

Combination Therapy Considerations

Combination therapy should not be routine practice with novel agents but may be considered on a case-by-case basis, particularly after infectious diseases consultation. 1 Severe infections with limited susceptibility options may require treatment with two in vitro active drugs. 1

The rationale for avoiding routine combination therapy with newer agents differs from traditional antipseudomonal therapy: these novel β-lactams have significantly higher potency and broader coverage, reducing the need for synergy that was historically sought with aminoglycoside or fluoroquinolone combinations. 1, 5

Last-Resort Option: Colistin-Based Therapy

• Loading dose: 5mg colistin base activity (CBA)/kg IV. 1
• Maintenance dosing: 2.5mg CBA × [1.5 × CrCl + 30] IV every 12 hours. 1
• When to use: Only when all novel agents show resistance or are unavailable. 1
• Critical toxicity concern: Acute kidney injury occurs in 30-60% of critically ill patients; requires intensive renal monitoring. 4

Tailoring Therapy and De-escalation

Therapy must be tailored once culture and susceptibility results are available. 1 Monotherapy with a highly active antipseudomonal β-lactam is preferred in the absence of compelling indications for combination therapy. 1 Once susceptibility results confirm activity and the patient is improving, de-escalation from combination to monotherapy is appropriate. 4

Critical Pitfalls to Avoid

• Do not use older agents empirically (traditional β-lactams, aminoglycosides, fluoroquinolones) for DTR P. aeruginosa, as they are ineffective by definition. 1
• Avoid carbapenem-based combinations for DTR P. aeruginosa unless meropenem MIC is ≤8 mg/L and extended infusion (>3 hours) is used. 1
• Use proper loading dose and maintenance dosing of colistin to avoid subtherapeutic levels if this last-resort agent is required. 1
• Never assume a β-lactam has antipseudomonal activity: ceftriaxone, cefazolin, ampicillin/sulbactam, and ertapenem do NOT cover Pseudomonas despite being broad-spectrum. 4
• Underdosing leads to treatment failure: use maximum recommended doses for severe infections to prevent resistance development. 4
• Ceftazidime/avibactam monotherapy may increase resistance risk during therapy; monitor clinical response closely. 1

Antimicrobial Stewardship Considerations

The use of carbapenems should be limited to preserve activity of this class because of the concern of emerging carbapenem-resistance. 2 Novel β-lactam/β-lactamase inhibitor combinations (ceftolozane/tazobactam and ceftazidime/avibactam) are valuable for treating infections caused by MDR gram-negative bacteria in order to preserve carbapenems. 2 These agents should be reserved for severe infections as defined by sepsis-3 criteria or documented DTR P. aeruginosa. 2