What antibiotics are effective against Gram-negative bacteria?

Antibiotics Effective Against Gram-Negative Bacteria

Carbapenems (meropenem, imipenem, ertapenem) are the most reliable antibiotics for treating serious gram-negative bacterial infections, especially those caused by multidrug-resistant organisms. 1

First-Line Antibiotics for Gram-Negative Coverage

Beta-lactams

• Carbapenems:

  • Meropenem (1g IV q8h): Broad spectrum activity against most gram-negative bacteria including Pseudomonas
  • Imipenem/cilastatin (1g IV q6-8h): Similar to meropenem but slightly better gram-positive coverage
  • Ertapenem (1g IV daily): Good for ESBL-producing Enterobacterales but lacks Pseudomonas coverage 1

• Piperacillin-tazobactam (3.37g IV q6-8h): Excellent broad-spectrum activity including Pseudomonas; preferred for many mixed infections 1

• Cephalosporins:

  • 3rd generation (ceftriaxone, cefotaxime): Active against many Enterobacterales but increasing resistance
  • 4th generation (cefepime): Better activity against Pseudomonas and AmpC-producing organisms 2
  • 5th generation/newer agents (ceftazidime-avibactam, ceftolozane-tazobactam): Effective against many carbapenem-resistant organisms 3

Non-Beta-lactams

• Fluoroquinolones (ciprofloxacin, levofloxacin): Good oral bioavailability but increasing resistance rates 1, 4
• Aminoglycosides (gentamicin, amikacin): Useful for synergy in serious infections; nephrotoxicity concerns 1, 5
• Polymyxins (colistin): Reserved for multidrug-resistant infections when other options are unavailable 1

Selection Based on Specific Pathogens

Enterobacterales (E. coli, Klebsiella, Enterobacter)

• Standard strains: Cephalosporins, fluoroquinolones, or aminoglycosides
• ESBL-producing: Carbapenems are preferred; piperacillin-tazobactam may be suitable for non-severe infections 1
• Carbapenem-resistant: Newer agents (ceftazidime-avibactam) or combination therapy with polymyxins 1

Pseudomonas aeruginosa

• First-line: Anti-pseudomonal beta-lactams (piperacillin-tazobactam, ceftazidime, cefepime, meropenem) 6
• Resistant strains: Consider combination therapy (beta-lactam plus aminoglycoside or fluoroquinolone) 1, 7

Acinetobacter species

• First-line: Carbapenems for susceptible strains
• Resistant strains: Polymyxins, sulbactam, or combination therapy 1

Treatment Strategies for Multidrug-Resistant Gram-Negative Infections

Empiric Therapy

• For severe infections with suspected MDR gram-negatives, combination therapy is recommended initially:
  • Beta-lactam (preferably carbapenem) + aminoglycoside or fluoroquinolone 5, 7
  • De-escalate to monotherapy once susceptibilities are known unless treating carbapenem-resistant organisms 1

Definitive Therapy

• For carbapenem-resistant Enterobacterales: Combination therapy is recommended (e.g., polymyxin + meropenem, tigecycline, or aminoglycoside) 1, 8
• For other confirmed susceptible gram-negatives: Monotherapy with the narrowest-spectrum effective agent 1

Special Considerations

Neonatal Sepsis

• High rates of resistance to WHO-recommended first-line antibiotics (ampicillin and gentamicin) in LMICs, with Klebsiella species predominating 1

Intra-abdominal Infections

• Mild to moderate: Amoxicillin-clavulanic acid or cephalosporin + metronidazole
• Severe: Piperacillin-tazobactam or carbapenem 1

Ventilator-Associated Pneumonia

• Empiric therapy should include coverage for Pseudomonas and potentially resistant Enterobacterales 1
• Consider combination therapy initially in critically ill patients 5

Common Pitfalls and Caveats

1. Increasing resistance: Resistance to traditional agents is growing globally; local antibiograms should guide therapy 1, 9

2. Carbapenem stewardship: Limit carbapenem use when alternatives are available to prevent further resistance development 1

3. Aminoglycoside toxicity: Monitor renal function and drug levels when using aminoglycosides; avoid in combination with other nephrotoxic drugs 1

4. Combination therapy rationale: The primary benefit is increasing the likelihood of appropriate empiric coverage rather than synergy 7

5. New agents: Newer antibiotics (ceftazidime-avibactam, ceftolozane-tazobactam, meropenem-vaborbactam) should be reserved for documented resistant infections to preserve their effectiveness 3, 9

The landscape of gram-negative resistance continues to evolve, requiring ongoing vigilance and appropriate antibiotic selection based on local resistance patterns, infection severity, and patient-specific factors.