What are the recommended antibiotics for Gram-negative coverage?

Gram-Negative Coverage Antibiotics

For empiric gram-negative coverage, piperacillin-tazobactam 4.5g IV every 6 hours or cefepime 2g IV every 8 hours are the preferred first-line agents for most serious infections, with fluoroquinolones (ciprofloxacin 400mg IV every 8 hours or levofloxacin 750mg IV daily) or aminoglycosides (gentamicin 5-7 mg/kg IV daily) as alternatives or adjunctive therapy. 1

Primary Beta-Lactam Options

Broad-Spectrum Penicillins

• Piperacillin-tazobactam provides comprehensive gram-negative coverage including Pseudomonas aeruginosa, Enterobacteriaceae, and anaerobes at 4.5g IV every 6 hours 1, 2
• This agent is FDA-approved for urinary tract infections, intra-abdominal infections, skin infections, pneumonia, and septicemia caused by susceptible gram-negative organisms 2
• Extended infusions may optimize pharmacodynamic parameters for difficult-to-treat organisms 1

Cephalosporins

• Cefepime 2g IV every 8 hours covers most Enterobacteriaceae and Pseudomonas, with enhanced stability against AmpC beta-lactamases 1
• Ceftazidime 2g IV every 8 hours provides excellent Pseudomonas coverage but has reduced gram-positive activity 1
• Ceftriaxone 2g IV daily or cefotaxime 2g IV every 6-8 hours are appropriate for community-acquired infections without Pseudomonas risk 1

Critical caveat: For cefepime, organisms with MIC ≥4 μg/mL have significantly increased clinical failure rates (OR 9.13 for MIC 4 μg/mL, OR 6.79 for MIC 8 μg/mL), requiring higher dosing regimens (2g every 8 hours) for serious infections 3, 4

Carbapenems

• Meropenem 1g IV every 8 hours or imipenem 500mg IV every 6 hours provide the broadest gram-negative coverage including ESBL-producing organisms 1
• Ertapenem 1g IV daily covers community-acquired gram-negatives but lacks Pseudomonas activity 1
• Reserve carbapenems for high-severity infections, ESBL producers, or settings with high resistance rates 1, 5

Non-Beta-Lactam Alternatives

Fluoroquinolones

• Ciprofloxacin 400mg IV every 8 hours or levofloxacin 750mg IV daily provide excellent gram-negative coverage 1
• Particularly useful for beta-lactam allergic patients or as combination therapy 1
• Must be combined with metronidazole when anaerobic coverage is needed due to increasing Bacteroides resistance 1

Aminoglycosides

• Gentamicin 5-7 mg/kg IV daily, tobramycin 5-7 mg/kg IV daily, or amikacin 15-20 mg/kg IV daily provide concentration-dependent killing of gram-negatives 1
• Should not be used as monotherapy; combine with beta-lactams for synergy 1
• Require therapeutic drug monitoring and dose adjustment for renal function 1

Monobactams

• Aztreonam 2g IV every 8 hours is a gram-negative-only agent, useful for beta-lactam allergic patients 1, 6
• FDA-approved for UTIs, lower respiratory infections, septicemia, skin infections, intra-abdominal infections, and gynecologic infections caused by susceptible gram-negatives 6
• Must be combined with agents covering gram-positives and anaerobes for polymicrobial infections 6

Clinical Decision Algorithm

For Community-Acquired Infections (Mild-Moderate Severity)

• Use ceftriaxone 2g IV daily or cefotaxime 2g IV every 6-8 hours for most community-acquired gram-negative infections 1
• Add metronidazole 500mg IV every 8 hours if anaerobic coverage needed 1
• Alternative: fluoroquinolone monotherapy (levofloxacin 750mg IV daily or moxifloxacin 400mg IV daily) for respiratory infections 1

For Hospital-Acquired/Healthcare-Associated Infections

• Low risk for MDR organisms: Use piperacillin-tazobactam 4.5g IV every 6 hours, cefepime 2g IV every 8 hours, or meropenem 1g IV every 8 hours as monotherapy 1
• High risk for MDR organisms or unstable hemodynamics: Combine antipseudomonal beta-lactam with either fluoroquinolone or aminoglycoside 1

For Suspected Pseudomonas Infections

• Use double gram-negative coverage (beta-lactam plus fluoroquinolone or aminoglycoside) in patients with: prior IV antibiotic use within 90 days, septic shock, ARDS, ≥5 days hospitalization, or acute renal replacement therapy 1
• Preferred combinations: piperacillin-tazobactam 4.5g IV every 6 hours plus ciprofloxacin 400mg IV every 8 hours 1

For Carbapenem-Resistant Organisms

• Colistin (5 mg/kg IV loading dose, then 2.5 mg × [1.5 × CrCl + 30] IV every 12 hours) is the primary option 1
• Consider adjunctive inhaled colistin for pneumonia (1.25-15 MIU divided every 8-12 hours) 1
• Polymyxins should be reserved for settings with high MDR prevalence and local expertise 1

Critical Pitfalls to Avoid

• Never use clindamycin alone for suspected gram-negative infections—it has no activity against aerobic gram-negatives and must be combined with aminoglycosides or fluoroquinolones 7
• Avoid aminoglycoside monotherapy as meta-analyses show lower clinical response rates despite no mortality difference 1
• Do not use cefepime at standard doses (1g every 12 hours) for organisms with MIC ≥4 μg/mL—increase to 2g every 8 hours 3, 4
• Avoid tigecycline for gram-negative pneumonia due to FDA boxed warning regarding increased mortality 1
• Do not combine beta-lactamase inducers (cefoxitin, imipenem) with aztreonam due to in vitro antagonism 6

Specific Pathogen Considerations

Gram-Negative Enteric Bacilli (E. coli, Klebsiella, Enterobacter)

• First-line: ceftazidime, cefepime, cefotaxime, or ceftriaxone plus gentamicin 1
• Alternative: piperacillin-tazobactam 240 mg/kg/day (pediatric dosing) or 4.5g every 6 hours (adult) 1

HACEK Group Organisms

• Preferred: ceftriaxone or cefotaxime 1
• Alternative: ampicillin-sulbactam or ampicillin plus aminoglycoside for susceptible organisms 1

Acinetobacter Species

• If sensitive to more than polymyxin: ampicillin-sulbactam 3g IV every 6 hours or carbapenems 1, 5
• If only polymyxin-sensitive: colistin plus carbapenem or ampicillin-sulbactam 1