What are the antibiotic (abx) options for Gram-negative coverage?

From the Guidelines

Gram-negative bacterial coverage requires antibiotics that can penetrate the outer lipopolysaccharide membrane characteristic of these organisms, and the most recent guidelines recommend meropenem (1g IV q8h) as a first-line option for broad gram-negative coverage, including ESBL-producing organisms, as stated in the 2017 WSES guidelines for management of intra-abdominal infections 1.

Key Considerations

• The choice of antibiotic should balance spectrum of activity against potential toxicities and the specific gram-negative organisms suspected based on infection site and patient characteristics.
• Local resistance patterns and patient factors, including renal function, allergies, and infection site, should be considered when selecting an antibiotic.
• Empiric therapy should be narrowed once culture results are available to reduce resistance development and minimize adverse effects.

Antibiotic Options

• Third-generation cephalosporins like ceftriaxone (1-2g IV daily) or cefotaxime (1-2g IV q8h) provide excellent gram-negative coverage while sparing Pseudomonas.
• For Pseudomonas coverage, consider ceftazidime (2g IV q8h), cefepime (2g IV q12h), or piperacillin-tazobactam (4.5g IV q6h).
• Fluoroquinolones such as ciprofloxacin (400mg IV q12h or 500-750mg PO BID) provide good gram-negative coverage but increasing resistance limits their use as monotherapy.
• For severe infections, aminoglycosides like gentamicin (5-7mg/kg IV daily) can be added for synergy.

Recent Guidelines

• The 2024 WHO essential medicines and AWaRe recommendations suggest meropenem as a first-line option for severe infections, and amoxicillin-clavulanic acid or ciprofloxacin and metronidazole for non-severe infections 1.
• The 2016 IDSA/ATS guidelines for hospital-acquired and ventilator-associated pneumonia recommend meropenem as a first-line option for severe infections, and piperacillin-tazobactam or cefepime as alternatives 1.
• The 2016 IWGDF guidance on diabetic foot infections recommends considering local resistance patterns and patient factors when selecting an antibiotic, and using meropenem or other broad-spectrum antibiotics for severe infections 1.

From the FDA Drug Label

Colistimethate for Injection, USP has proven clinically effective in treatment of infections due to the following gram-negative organisms: Enterobacter aerogenes, Escherichia coli, Klebsiella pneumoniae and Pseudomonas aeruginosa The antibiotic colistin (IV) provides coverage for certain gram-negative bacteria, including:

• Enterobacter aerogenes
• Escherichia coli
• Klebsiella pneumoniae
• Pseudomonas aeruginosa 2

From the Research

Gram Negative Coverage for Antibiotics

• The carbapenem class of antibiotics, including imipenem and meropenem, have broad-spectrum activity against gram-negative bacteria, including Pseudomonas aeruginosa 3, 4, 5.
• Aztreonam, a monobactam antibiotic, has activity against most aerobic gram-negative bacilli, including Pseudomonas aeruginosa 3.
• Meropenem has enhanced gram-negative activity relative to imipenem-cilastatin and often retains activity against strains resistant to third-generation cephalosporins and imipenem-cilastatin 4.
• Treatment options for urinary tract infections (UTIs) due to gram-negative bacteria include carbapenems, such as meropenem and imipenem, as well as other antibiotics like ceftazidime-avibactam and cefiderocol 6.
• New antimicrobial treatment options for severe gram-negative infections include various β-lactam/β-lactamase inhibitor combinations, eravacycline, plazomicin, and cefiderocol 7.
• The carbapenems are assuming a greater role in the treatment of serious infections due to their stability against extended-spectrum beta-lactamases (ESBLs) and their broad-spectrum activity 5.

Specific Antibiotics for Gram Negative Coverage

• Imipenem: effective against gram-negative bacteria, including Pseudomonas aeruginosa, but resistance is increasing 3, 5.
• Meropenem: has enhanced gram-negative activity relative to imipenem-cilastatin and often retains activity against strains resistant to third-generation cephalosporins and imipenem-cilastatin 4.
• Aztreonam: effective against most aerobic gram-negative bacilli, including Pseudomonas aeruginosa 3.
• Ceftazidime-avibactam: a treatment option for UTIs due to gram-negative bacteria, including ESBL-producing Enterobacteriales 6.
• Cefiderocol: a treatment option for UTIs due to gram-negative bacteria, including carbapenem-resistant Enterobacteriales 6, 7.