What empiric broad‑spectrum IV antibiotics, dosing, and adjunctive measures should be started within one hour for an adult with sepsis of unknown source, including options for β‑lactam allergy, multidrug‑resistant risk, renal impairment, and when to initiate norepinephrine for hypotension after fluid bolus?

Antibiotics in Sepsis: Immediate Management Protocol

Administer IV broad-spectrum antibiotics within one hour of recognizing sepsis or septic shock—this is the single most critical intervention, as each hour of delay increases mortality by approximately 7.6%. 1, 2

Time-Critical Actions Within the First Hour

Blood Cultures and Diagnostic Workup

• Obtain at least two sets of blood cultures (aerobic and anaerobic) before antibiotics—one drawn percutaneously and one through any vascular access device in place >48 hours 1
• Never delay antibiotics beyond 45 minutes waiting for cultures; if obtaining cultures will cause significant delay, start antibiotics immediately 1, 2
• Measure lactate level immediately and remeasure within 2-4 hours if elevated (≥2 mmol/L), targeting normalization as a marker of adequate tissue perfusion 1, 2

Empiric Antibiotic Selection for Unknown Source

For community-acquired sepsis without risk factors:

• Start an extended-spectrum β-lactam as monotherapy: 1, 2
  • Piperacillin-tazobactam 4.5 g IV q6h (or 3.375 g q6h if renal impairment), OR
  • Cefepime 2 g IV q8h, OR
  • Meropenem 1 g IV q8h
• Administer β-lactams as prolonged infusions (over 3-4 hours) after an initial loading dose to optimize pharmacodynamics 3

For septic shock, neutropenia, or multidrug-resistant organism risk:

• Use combination therapy with extended-spectrum β-lactam PLUS either: 1
  • Aminoglycoside (gentamicin 5-7 mg/kg IV q24h or tobramycin 5-7 mg/kg IV q24h), OR
  • Fluoroquinolone (ciprofloxacin 400 mg IV q8h or levofloxacin 750 mg IV q24h)
• This combination is specifically recommended for Pseudomonas aeruginosa coverage in patients with respiratory failure and septic shock 1

For suspected Streptococcus pneumoniae bacteremia with septic shock:

• Add azithromycin 500 mg IV q24h or another macrolide to the β-lactam 1

β-Lactam Allergy Considerations

For documented severe β-lactam allergy (anaphylaxis, Stevens-Johnson):

• Aztreonam 2 g IV q8h PLUS vancomycin 15-20 mg/kg IV q8-12h (target trough 15-20 mcg/mL) PLUS fluoroquinolone (ciprofloxacin 400 mg IV q8h) 2, 4
• Aztreonam has no cross-reactivity with other β-lactams and covers gram-negative organisms including Pseudomonas 4

For mild β-lactam allergy (rash only, no anaphylaxis):

• Consider using a carbapenem (meropenem 1 g IV q8h), as cross-reactivity with penicillins is <1% 4

Dosing Adjustments for Renal Impairment

For patients on continuous renal replacement therapy (CRRT):

• Use unadjusted doses similar to normal renal function initially, as CRRT clearance is unpredictable 5
• Standard dosing: ceftazidime/cefepime 2 g q8h, piperacillin-tazobactam 4.5 g q6h, meropenem 1 g q8h 5
• Consider therapeutic drug monitoring if available, as 53% of patients may have excessive drug levels requiring adjustment 5

For severe renal impairment (CrCl <30 mL/min) NOT on CRRT:

• Reduce β-lactam doses by 50% and extend intervals (e.g., piperacillin-tazobactam 3.375 g q8h, meropenem 500 mg q12h) 5

Hemodynamic Resuscitation and Vasopressor Initiation

Fluid Resuscitation

• Administer 30 mL/kg crystalloid bolus (either balanced crystalloids or normal saline) rapidly over 5-10 minutes for hypotension or lactate ≥4 mmol/L 1, 2
• Reassess hemodynamic status frequently using dynamic parameters (pulse pressure variation, stroke volume variation) or static variables (capillary refill, skin mottling, mental status, urine output) 1, 2
• After the initial 2 liters, less is more—further fluid administration should be carefully weighed using dynamic assessment and echocardiography 3

Vasopressor Therapy

• Initiate norepinephrine as first-line vasopressor if hypotension persists despite adequate fluid resuscitation 1, 2
• Target mean arterial pressure (MAP) ≥65 mmHg 1, 2
• Do not delay vasopressor initiation while attempting to obtain additional vascular access—start through peripheral IV if necessary 2
• Add epinephrine if additional pressor support is needed; vasopressin 0.03 units/min can be combined with norepinephrine to raise MAP or reduce norepinephrine dose 2
• Avoid dopamine except in highly selected circumstances 2

Daily Antimicrobial Reassessment and De-escalation

Combination Therapy Duration

• Discontinue combination therapy within 3-5 days once clinical improvement is evident 1, 6, 7
• Narrow to targeted single-agent therapy as soon as culture susceptibilities are available 1

Total Treatment Duration

• Typical duration is 7-10 days for most sepsis cases 1, 6, 7
• Consider shorter courses if rapid clinical response, effective source control, and no immunodeficiency 8, 3
• Longer courses may be appropriate for slow clinical response, undrainable foci, S. aureus bacteremia, fungal/viral infections, or neutropenia 1

Procalcitonin-Guided Therapy

• Use procalcitonin levels to support discontinuing empiric antibiotics in patients with no subsequent evidence of infection 1, 3
• Procalcitonin should guide decisions to stop (not start) antibiotic treatment 3

Source Control

• Identify and control the infection source within 12 hours when feasible 1, 2, 8
• Use the least invasive effective intervention (e.g., percutaneous drainage rather than open surgery) 1, 2
• Remove intravascular access devices promptly if they are a possible infection source, after establishing alternative access 1, 2

Critical Pitfalls to Avoid

• Never delay antibiotics for imaging studies—obtain cultures and start antibiotics first, then image 8
• Avoid monotherapy in septic shock until pathogen susceptibilities are known, as combination therapy improves outcomes 8, 4
• Do not use hydroxyethyl starches—they are contraindicated in sepsis 2
• Avoid inadequate initial dosing, especially in critically ill patients with altered drug distribution—use loading doses and prolonged infusions for β-lactams 3, 5
• Do not continue combination therapy beyond 3-5 days without clear indication, as this increases toxicity and resistance without benefit 1, 6, 7