What are the first-line antibiotics for treating Gram-negative infections?

First-Line Antibiotics for Gram-Negative Infections

For serious Gram-negative infections, initiate empiric therapy with an anti-pseudomonal beta-lactam (piperacillin-tazobactam, cefepime, or a carbapenem) as monotherapy in hemodynamically stable patients, or add an aminoglycoside for dual therapy in critically ill patients with septic shock, profound neutropenia, or suspected Pseudomonas aeruginosa infection. 1, 2

Initial Empiric Therapy Based on Clinical Severity

Hemodynamically Stable Patients Without High-Risk Features

• Piperacillin-tazobactam 4.5 grams IV every 6 hours is recommended as first-line monotherapy for community-acquired infections with low risk of multidrug-resistant organisms (MDROs). 1, 3, 4
• Cefepime 2 grams IV every 8 hours is an acceptable alternative monotherapy option. 1
• Meropenem 1 gram IV every 8 hours or imipenem 500 mg IV every 6 hours should be reserved for settings with high ESBL prevalence (>10-20%) or when ESBL-producing organisms are suspected. 1, 2, 5

Critically Ill Patients or Those With High-Risk Features

Mandatory dual therapy is required for: 2

• Severe sepsis or septic shock 1, 2
• Profound neutropenia (<100 cells/μL) 1, 2
• Suspected or confirmed Pseudomonas aeruginosa infection 1, 2
• Known colonization with MDROs 4, 2
• Healthcare-associated or nosocomial infections 4
• Five or more days of hospitalization prior to infection 4
• Prior IV antibiotic use within 90 days 4

Recommended dual therapy regimens: 1, 2

• Meropenem 1-2 grams IV every 8 hours (as 3-hour extended infusion) PLUS gentamicin 5-7 mg/kg/day or amikacin 15-20 mg/kg/day 1, 2
• Cefepime 2 grams IV every 8 hours PLUS an aminoglycoside 1, 2
• Piperacillin-tazobactam 4.5 grams IV every 6 hours PLUS an aminoglycoside 1, 2

Special Population: Febrile Neutropenia

• Cefepime, meropenem, or piperacillin-tazobactam as monotherapy is appropriate for initial empiric therapy in febrile neutropenic patients without hemodynamic instability. 1, 2
• Add vancomycin only if there is evidence of catheter-associated infection, skin/soft tissue infection, or hemodynamic instability. 2
• Maintain dual therapy with beta-lactam plus aminoglycoside for patients with severe and persistent granulocytopenia (<100 cells/μL). 1, 2
• Aminoglycoside monotherapy should never be used due to rapid emergence of resistance. 1

Neonatal Sepsis

• Ampicillin, amoxicillin, or benzylpenicillin PLUS gentamicin is the first-choice regimen for neonatal sepsis to cover Group B Streptococcus and Gram-negative bacteria. 1
• Amikacin PLUS cloxacillin or cefotaxime are second-choice options. 1
• Ceftriaxone should be avoided in neonates due to risk of kernicterus but cefotaxime is acceptable. 1

Hospital-Acquired and Ventilator-Associated Pneumonia

Low Risk of MDROs, Stable Hemodynamics

Choose one of the following: 1

• Piperacillin-tazobactam 4.5 grams IV every 6 hours 1
• Cefepime 2 grams IV every 8 hours 1
• Meropenem 1 gram IV every 8 hours 1
• Levofloxacin 750 mg IV daily 1

High Risk of MDROs or Unstable Hemodynamics

Use an anti-pseudomonal beta-lactam (as above) PLUS one of the following: 1

• Gentamicin 5-7 mg/kg IV daily 1
• Amikacin 15-20 mg/kg IV daily 1
• Levofloxacin 750 mg IV daily 1
• Ciprofloxacin 400 mg IV every 8 hours 1

Intra-Abdominal Infections

• Beta-lactam/beta-lactamase inhibitor (piperacillin-tazobactam or cefoperazone-sulbactam) is recommended as first-line therapy due to activity against Gram-positive, Gram-negative, and anaerobic bacteria. 1
• Start empiric broad-spectrum therapy as soon as possible, ideally after peritoneal fluid collection. 1
• Duration should be 3-5 days or until inflammatory markers normalize in patients with adequate source control. 1

De-escalation Strategy

Critical timing for de-escalation: 4, 2

• Discontinue aminoglycoside after 3-5 days once clinical improvement is evident and susceptibility confirms adequate beta-lactam coverage. 2
• Switch from combination to single-agent therapy based on culture and susceptibility results (typically available at 48-72 hours). 4, 2
• Continue beta-lactam monotherapy if the organism is susceptible. 2
• De-escalation should occur within the first few days in response to clinical improvement. 4

Treatment Duration

• 7 days total for uncomplicated Gram-negative bacteremia. 2
• 14 days for complicated infections including endocarditis, suppurative thrombophlebitis, metastatic infection (osteomyelitis, abscess), persistent bacteremia beyond 72 hours, or catheter-related bloodstream infection with retained long-term catheter. 2

Resistance Considerations and Antibiotic Selection

When to Use Carbapenems Over Other Beta-Lactams

• Use carbapenems (meropenem or imipenem) instead of piperacillin-tazobactam or cephalosporins in settings with high ESBL prevalence (>10-20%). 2
• Carbapenems remain the preferred treatment for serious infections caused by AmpC-producing organisms. 2
• Ertapenem may be preferred over meropenem/imipenem for bloodstream infections without septic shock to preserve broader-spectrum carbapenems for more severe infections. 2
• Piperacillin-tazobactam has reduced efficacy against ESBL-producing organisms and carbapenemase-producing organisms. 3

Carbapenem-Resistant Organisms

• Ceftazidime-avibactam is FDA-approved for complicated intra-abdominal infections (with metronidazole), complicated urinary tract infections, and hospital-acquired/ventilator-associated pneumonia caused by susceptible Gram-negative organisms including Pseudomonas aeruginosa, Klebsiella pneumoniae, and Enterobacter cloacae. 6
• Polymyxin (colistin) combination therapy or ceftazidime-avibactam should be used for carbapenem-resistant Gram-negative bacilli. 2

Fluoroquinolone Considerations

• Patients receiving fluoroquinolone prophylaxis should NOT receive oral empirical therapy with a fluoroquinolone. 1
• Levofloxacin 750 mg IV daily or ciprofloxacin 400 mg IV every 8 hours are acceptable alternatives for hospital-acquired pneumonia in patients with low risk of MDROs. 1

Critical Dosing Considerations

• Administer carbapenems as extended infusions (3-hour infusion for meropenem) to optimize pharmacodynamics. 2
• Use therapeutic drug monitoring for aminoglycosides to optimize efficacy and minimize nephrotoxicity. 2
• Avoid aminoglycosides in combination with other nephrotoxic drugs or in patients with renal dysfunction. 2

Source Control

• Remove short-term intravascular catheters in all cases of catheter-related Gram-negative bacteremia. 2
• For long-term tunneled catheters or implanted devices, remove if bacteremia persists beyond 72 hours of appropriate therapy. 2

Critical Pitfalls to Avoid

• Never use monotherapy in critically ill patients, those with profound neutropenia, or suspected P. aeruginosa infection, as outcomes are significantly worse. 1, 2
• Do not continue combination therapy for the full treatment course once susceptibility confirms single-agent adequacy, as this increases toxicity without benefit. 2
• Never delay antibiotic administration while awaiting culture results, as early appropriate therapy significantly reduces mortality and prevents septic shock. 2, 7, 8
• Avoid excessive use of carbapenems when piperacillin-tazobactam would be effective to prevent emergence of carbapenem-resistant organisms. 4
• Ceftazidime is no longer reliable for empirical monotherapy due to decreasing potency against Gram-negative organisms and poor activity against Gram-positive pathogens. 1