What newer agents are recommended for treating severe infections caused by multidrug-resistant Gram-negative bacteria?

Newer Agents for Treating Severe Infections Caused by Multidrug-Resistant Gram-Negative Bacteria

For severe infections caused by multidrug-resistant Gram-negative bacteria, meropenem-vaborbactam or ceftazidime-avibactam should be used as first-line therapy if the pathogen is susceptible in vitro. 1

Recommended Agents Based on Resistance Mechanism

Carbapenem-Resistant Enterobacterales (CRE)

• For KPC-producing CRE infections:

  • Meropenem-vaborbactam or ceftazidime-avibactam are the preferred first-line options if active in vitro 1
  • Imipenem-relebactam or cefiderocol are recommended alternatives when the first-line agents are not available or susceptible 1

• For OXA-48-producing CRE infections:

  • Ceftazidime-avibactam should be the first-line treatment option 1
  • Ceftazidime-avibactam is active against OXA-48 carbapenemases but inactive against metallo-β-lactamases 1

• For metallo-β-lactamase (MBL)-producing CRE infections (NDM, VIM, IMP):

  • Ceftazidime-avibactam plus aztreonam combination is the preferred treatment 1
  • Cefiderocol may be considered as an alternative option 1

Carbapenem-Resistant Pseudomonas aeruginosa (CRPA)

• Ceftolozane-tazobactam is recommended as first-line therapy if active in vitro 1
• Insufficient evidence exists for imipenem-relebactam, cefiderocol, and ceftazidime-avibactam, though they may be considered based on susceptibility testing 1
• For difficult-to-treat CRPA infections resistant to newer agents, combination therapy with two in vitro active drugs is suggested 1

Carbapenem-Resistant Acinetobacter baumannii (CRAB)

• For CRAB susceptible to sulbactam, ampicillin-sulbactam is recommended 1
• For CRAB resistant to sulbactam, polymyxins or high-dose tigecycline can be used if active in vitro 1
• Cefiderocol is conditionally recommended against for CRAB infections 1

Monotherapy vs. Combination Therapy

• For CRE infections susceptible to and treated with ceftazidime-avibactam, meropenem-vaborbactam, or cefiderocol, combination therapy is not recommended 1
• For severe infections caused by CRE carrying metallo-β-lactamases, aztreonam and ceftazidime-avibactam combination therapy is suggested 1
• For severe infections caused by CRE susceptible only to polymyxins, aminoglycosides, tigecycline, or fosfomycin, treatment with more than one drug active in vitro is suggested 1

Clinical Evidence and Efficacy

• Ceftazidime-avibactam has shown promising results in observational studies for treating KPC-producing CRE infections, with higher rates of microbiological eradication and clinical cure compared to other regimens 1
• Meropenem-vaborbactam demonstrated increased clinical cure and decreased 28-day mortality compared to best available therapy in the TANGO-II trial 1
• Ceftolozane-tazobactam has shown efficacy against carbapenem-resistant Pseudomonas aeruginosa in clinical studies 1, 2
• Cefiderocol, a novel siderophore cephalosporin, has activity against various carbapenem-resistant Gram-negative bacteria, including those producing metallo-β-lactamases 2

Considerations and Caveats

• Resistance to newer agents can develop rapidly. Resistance to ceftazidime-avibactam in KPC-producing isolates has been reported, occurring in up to 3.7-8.1% of treated patients 1
• The choice of agent should be guided by in vitro susceptibility testing whenever possible 1
• For non-severe infections, older antibiotics may be considered under antibiotic stewardship principles if active in vitro 1
• High-dose tigecycline is not recommended for bloodstream infections and hospital-acquired/ventilator-associated pneumonia 1
• Aminoglycosides, including plazomicin, are suggested for complicated urinary tract infections caused by CRE 1

Emerging Agents

• Plazomicin, a novel aminoglycoside, shows activity against many carbapenem-resistant Enterobacterales 3
• Eravacycline, a novel tetracycline derivative, has activity against some multidrug-resistant Gram-negative pathogens 3, 2
• Aztreonam-avibactam combination is under development and shows promise for metallo-β-lactamase-producing organisms 4

The landscape of treatment options for multidrug-resistant Gram-negative infections has expanded significantly with these newer agents, providing critical alternatives when traditional antibiotics fail 5, 3.