What are the exclusive gram-negative (GN) antibiotics for treating infections caused by gram-negative bacteria?

Exclusive Gram-Negative Antibiotics

Aztreonam is the only truly exclusive gram-negative antibiotic available, with FDA approval for treating infections caused by susceptible gram-negative bacteria including Pseudomonas aeruginosa, while having no activity against gram-positive organisms or anaerobes. 1

Primary Exclusive Gram-Negative Agent

Aztreonam (Monobactam)

• Spectrum: Active exclusively against aerobic gram-negative bacteria including E. coli, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, Enterobacter species, Serratia marcescens, Citrobacter species, and Haemophilus influenzae 1
• No activity: Against gram-positive organisms, anaerobes, Proteus, or Neisseria 1, 2
• FDA-approved indications: UTIs, lower respiratory tract infections, septicemia, skin/soft tissue infections, intra-abdominal infections, and gynecologic infections 1
• Clinical efficacy: Demonstrated 95% cure rate (20/21 patients) in serious gram-negative infections including P. aeruginosa osteomyelitis and soft tissue infections 3
• Dosing: 1g every 8-12 hours for most Enterobacteriaceae; consider 2g every 8 hours for Pseudomonas infections 4

Predominantly Gram-Negative Agents

Polymyxins (Colistin/Polymyxin B)

• Spectrum: Active against gram-negative bacilli including Pseudomonas aeruginosa, Enterobacter aerogenes, E. coli, and Klebsiella pneumoniae 2
• Not indicated: For Proteus or Neisseria infections 2
• Role: Reserved as last-resort therapy for multidrug-resistant gram-negative infections, particularly carbapenem-resistant Acinetobacter baumannii (CRAB) and carbapenem-resistant Pseudomonas aeruginosa (CRPA) 5, 6
• Limitations: Significant nephrotoxicity requiring careful dosing and monitoring; resistance mechanisms limit efficacy 6
• ESCMID guidance: For CRAB resistant to sulbactam, polymyxin can be used if active in vitro, though no preference is stated over high-dose tigecycline 5

Aminoglycosides

• Spectrum: Effective against gram-negative bacteria including P. aeruginosa 5
• No activity: Against anaerobic bacteria, requiring combination with metronidazole for mixed infections 5
• ESCMID recommendations:
  • Suggested over tigecycline for complicated UTIs caused by carbapenem-resistant Enterobacterales (CRE) 5
  • For 3rd-generation cephalosporin-resistant Enterobacterales (3GCephRE) without septic shock, conditionally recommended for short-duration therapy when active in vitro 5
• Limitations: Dose-related nephrotoxicity and ototoxicity; not recommended for routine empiric treatment of community-acquired intra-abdominal infections 5
• Comparative efficacy: Aztreonam showed comparable clinical efficacy to aminoglycosides (tobramycin/amikacin) but with significantly less renal impairment (2/53 vs 9/54 patients) 7

Emerging Combination Therapy for Metallo-β-Lactamase Producers

Aztreonam-Avibactam

• Specific indication: Potent activity against metallo-β-lactamase (MBL)-producing gram-negative pathogens including Enterobacterales, Acinetobacter baumannii, and Pseudomonas aeruginosa 6
• ESCMID recommendation: For severe infections caused by CRE carrying metallo-β-lactamases resistant to new antibiotic monotherapies, aztreonam plus ceftazidime-avibactam combination is suggested (conditional recommendation, moderate evidence) 5
• Alternative: If aztreonam-avibactam unavailable, use aztreonam with ceftazidime-avibactam 6

Clinical Algorithm for Selection

For confirmed gram-negative-only infections:

1. First-line: Aztreonam monotherapy for susceptible organisms 1, 4
2. MBL-producing organisms: Aztreonam-avibactam combination 5, 6
3. Carbapenem-resistant P. aeruginosa with difficult-to-treat resistance and MBL: Cefiderocol preferred over aztreonam-avibactam 6
4. Last resort (XDR/PDR organisms): Colistin, reserved when other options exhausted 6

For empiric therapy when gram-positive coverage needed:

• Combine aztreonam with anti-gram-positive agent (vancomycin, daptomycin, or linezolid) rather than using aminoglycosides 5
• This approach avoids aminoglycoside toxicity while maintaining gram-negative coverage 7

Key Caveats

• Concurrent therapy warning: Beta-lactamase-inducing antibiotics (cefoxitin, imipenem) may antagonize aztreonam activity against Enterobacter and Pseudomonas species; avoid concurrent use 1
• Anaerobic coverage: All exclusive gram-negative agents require addition of metronidazole or another anti-anaerobic agent for polymicrobial infections 1, 5
• Resistance monitoring: Colistin efficacy limited by resistance mechanisms; reserve for situations where aztreonam-based regimens cannot be used 6
• Renal dosing: Adjust aztreonam doses in renal failure 4