What antibiotics offer broader coverage, higher potency, or better safety than polymyxins for multidrug‑resistant Gram‑negative infections?

Antibiotics Superior to Polymyxins for Multidrug-Resistant Gram-Negative Infections

For multidrug-resistant Gram-negative infections, newer beta-lactam/beta-lactamase inhibitor combinations (ceftazidime-avibactam, ceftolozane-tazobactam, meropenem-vaborbactam, imipenem-relebactam) should be prioritized over polymyxins due to superior clinical cure rates, dramatically lower nephrotoxicity, and better safety profiles. 1, 2

Treatment Algorithm by Pathogen

Carbapenem-Resistant Enterobacterales (CRE)

First-line agents (use instead of polymyxins):

• Ceftazidime-avibactam 2.5 g IV every 8 hours is the preferred first-line treatment for KPC and OXA-48 producers, with treatment duration of 7-14 days for bloodstream infections 2
• Meropenem-vaborbactam 4 g IV every 8 hours may be preferred for pneumonia due to better lung penetration 2
• Imipenem-cilastatin-relebactam 1.25 g IV every 6 hours is an alternative first-line option 2

For Metallo-β-Lactamase (MBL) producers:

• Ceftazidime-avibactam 2.5 g IV every 8 hours PLUS aztreonam is the preferential choice, with significantly lower 30-day mortality (19.2% vs 44%) compared to other active antimicrobial agents 2
• Never use ceftazidime-avibactam monotherapy for MBL producers, as avibactam lacks activity against Class B enzymes 2

Carbapenem-Resistant Pseudomonas aeruginosa (CRPA)

First-line agents (use instead of polymyxins):

• Ceftolozane-tazobactam 1.5g IV every 8 hours is the preferred first-line agent if active in vitro, achieving higher clinical cure rates (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
• Ceftazidime-avibactam is preferred over ceftolozane-tazobactam for CRPA when available 1

When polymyxins must be used for severe CRPA:

• Combination therapy with two in vitro active drugs is suggested (polymyxin plus aminoglycoside, fosfomycin, or carbapenem if MIC ≤8 mg/L) 3, 4, 1
• Very low-certainty evidence suggests an advantage of polymyxin combined with another active antibiotic over polymyxin alone 3, 1

Carbapenem-Resistant Acinetobacter baumannii (CRAB)

First-line agents (use instead of polymyxins):

• Ampicillin-sulbactam is more advantageous than polymyxins if the organism is susceptible to sulbactam 1
• For sulbactam-resistant CRAB, polymyxin B or colistin remain treatment options, but evidence does not clearly favor one over the other 1

Critical evidence against specific polymyxin combinations:

• Strong recommendation AGAINST polymyxin-meropenem combination therapy for CRAB infections based on high-certainty evidence from RCTs 3, 4
• Strong recommendation AGAINST polymyxin-rifampin combination therapy for CRAB infections, as three RCTs showed no advantage to colistin-rifampin over colistin monotherapy with respect to 30-day mortality 3, 4

Comparative Safety Profile

Polymyxin B vs. Colistin:

• Polymyxin B demonstrates lower nephrotoxicity compared to colistin, with colistin showing higher RIFLE-defined nephrotoxicity (adjusted HR 2.27,95% CI 1.35-3.82) 3, 1
• If polymyxins must be used, polymyxin B is preferred over colistin due to this safety advantage 3

Newer agents vs. Polymyxins:

• The Infectious Diseases Society of America recommends using newer agents like ceftolozane-tazobactam over polymyxin B when available and active in vitro due to lower nephrotoxicity 4, 1
• The American College of Clinical Microbiology recommends ceftolozane-tazobactam as the preferred first-line agent over polymyxin B for complicated urinary tract infections and intra-abdominal infections due to superior clinical cure rates and significantly lower nephrotoxicity 1

When Polymyxins Are Appropriate

Polymyxins should only be used when:

• Newer beta-lactam/beta-lactamase inhibitors are unavailable, inactive in vitro, or contraindicated 4, 1
• The organism is pan-resistant to all other available agents 3, 4
• For pan-resistant organisms, select treatment with the least resistant antibiotic(s) based on MICs relative to breakpoints, combined with optimal source control 3, 4

Critical Pitfalls to Avoid

• Never use tigecycline monotherapy for CRE bloodstream infections or pneumonia, as it has poor plasma concentrations and performs poorly in bacteremic patients 2
• Never use tigecycline for meningitis due to poor CSF penetration 2
• Avoid polymyxin-carbapenem combinations for CRAB based on high-certainty evidence showing no benefit 3, 4
• Avoid polymyxin-rifampin combinations for CRAB based on RCT evidence showing no mortality benefit 3, 4

Monitoring Requirements When Polymyxins Are Used

• Therapeutic drug monitoring should be utilized when available 3, 4
• Regular monitoring of renal function is strongly recommended during treatment 1
• Follow-up cultures are recommended in case of treatment failure to detect resistance development 3, 2
• Optimal source control should always be prioritized to improve outcomes 3, 4