What empiric antibiotics should be given to an adult with suspected gram‑negative bacteremia, normal renal function and no known ESBL‑producing organisms?

Empiric Antibiotic Selection for Gram-Negative Bacteremia

For an adult with suspected gram-negative bacteremia, normal renal function, and no known ESBL organisms, initiate an anti-pseudomonal β-lactam (piperacillin-tazobactam 4.5g IV every 6 hours, cefepime 2g IV every 8 hours, or meropenem 1g IV every 8 hours) as monotherapy if hemodynamically stable; add an aminoglycoside (gentamicin 5-7 mg/kg IV daily) for critically ill patients, those with septic shock, or suspected multidrug-resistant organisms. 1, 2

Risk Stratification Determines Monotherapy vs. Combination Therapy

Standard-risk patients (hemodynamically stable, non-neutropenic, no septic shock, no known MDR colonization) should receive anti-pseudomonal β-lactam monotherapy:

• Piperacillin-tazobactam 4.5g IV every 6 hours is the preferred first-line agent in settings without high ESBL prevalence 1, 2
• Alternative monotherapy options include cefepime 2g IV every 8 hours or meropenem 1g IV every 8 hours 1

High-risk patients require combination therapy with an anti-pseudomonal β-lactam PLUS an aminoglycoside 1, 2:

• Critically ill or septic shock patients 3, 2
• Neutropenic patients (absolute neutrophil count <500/mm³) 3
• Hemodynamically unstable patients 1
• Known colonization with MDR Pseudomonas aeruginosa or ESBL-producing organisms 3, 1

The rationale for combination therapy in high-risk patients is to increase the likelihood of adequate empiric coverage rather than to exploit synergy, as mortality is primarily determined by receiving at least one active agent initially 4, 5

Specific Antibiotic Regimens

For standard-risk patients (monotherapy):

• Piperacillin-tazobactam 4.5g IV every 6 hours 1, 2
• OR cefepime 2g IV every 8 hours 1
• OR meropenem 1g IV every 8 hours (reserve for high ESBL prevalence settings) 1

For high-risk patients (combination therapy):

• Piperacillin-tazobactam 4.5g IV every 6 hours PLUS gentamicin 5-7 mg/kg IV daily 1, 2
• OR cefepime 2g IV every 8 hours PLUS gentamicin 5-7 mg/kg IV daily 1
• OR meropenem 1g IV every 8 hours PLUS gentamicin 5-7 mg/kg IV daily (for suspected ESBL or carbapenem-resistant organisms) 1

Critical Timing and Administration

Administer antibiotics within one hour of recognizing sepsis or septic shock, as delayed administration beyond this window significantly increases mortality 2. Do not wait for culture results before initiating therapy 1, 2.

Agents to Avoid

Third-generation cephalosporins (ceftriaxone, cefotaxime) should NOT be used empirically due to rising resistance rates and their role in driving ESBL emergence 1. These agents lack adequate anti-pseudomonal activity and are increasingly ineffective against E. coli and Klebsiella species 3.

Fluoroquinolones (ciprofloxacin, levofloxacin) are discouraged for empiric therapy because E. coli resistance rates exceed 20-30% in most regions 1. Reserve fluoroquinolones only for definitive therapy after susceptibility confirmation 6.

De-escalation Strategy (Critical for Antimicrobial Stewardship)

Once culture and susceptibility results are available (typically 24-72 hours):

• Discontinue the aminoglycoside after 3-5 days once clinical improvement is evident and β-lactam susceptibility is confirmed 1, 2
• Switch from combination to single-agent therapy guided by susceptibility testing 1, 2
• This de-escalation approach is associated with lower ICU mortality and reduced nephrotoxicity without compromising outcomes 1, 6

If gram-negative bacteremia is not confirmed or an alternative diagnosis is established, discontinue empiric gram-negative coverage entirely 3.

Duration of Therapy

Uncomplicated bacteremia with adequate source control: 7-14 days total 1, 2

Complicated infections requiring 4-6 weeks of therapy include 3, 1:

• Persistent bacteremia >72 hours despite appropriate antibiotics and source control
• Endocarditis or suppurative thrombophlebitis
• Metastatic infection or osteomyelitis
• Inability to achieve adequate source control

Essential Source Control Measures

Source control is as important as antibiotic selection and must be addressed concurrently 1:

• Remove short-term intravascular catheters immediately in all cases of catheter-related gram-negative bacteremia 2
• Remove long-term catheters if bacteremia persists beyond 72 hours despite appropriate therapy 3, 1
• Drain abscesses and remove infected foreign bodies 5

Common Pitfalls to Avoid

Never use aminoglycoside monotherapy for gram-negative bacteremia, as outcomes are significantly worse than β-lactam-based regimens 3. Aminoglycosides should only be used in combination with a β-lactam 3, 1.

Do not continue combination therapy beyond 3-5 days if the patient is clinically improving and susceptibility results confirm adequate β-lactam coverage, as prolonged aminoglycoside use increases nephrotoxicity risk without improving outcomes 1, 2.

Avoid empiric carbapenems in standard-risk patients without high ESBL prevalence, as this drives carbapenem resistance; reserve meropenem for settings with documented high ESBL rates or when ESBL organisms are strongly suspected 1.

Monitoring and Reassessment

Obtain blood cultures before initiating antibiotics, but do not delay therapy 1. Repeat blood cultures at 48-72 hours to document clearance of bacteremia 1, 7. If bacteremia persists despite appropriate therapy and source control, evaluate for endovascular infection, metastatic foci, or inadequate source control 3, 1.