1. Empiric Antimicrobial Therapy

Rapid initiation of broad-spectrum antibiotics within 1 hour of septic shock recognition is the cornerstone of therapy. The choice of agent must reflect the suspected source of infection, local resistance patterns, patient-specific risk factors, and pharmacokinetic/pharmacodynamic (PK/PD) targets for optimal bacterial killing.

A. Timing and Initiation

• Septic Shock: Administer empiric broad-spectrum antibiotics immediately, with a goal of within 1 hour of identification.
• Sepsis without Shock: Aim for antibiotic delivery within 3 hours of diagnosis, allowing for a more deliberate diagnostic workup.
• Process Improvement: Utilize standardized order sets, sepsis carts, and regular time-to-antibiotic audits to minimize delays and improve compliance.

B. Agent Selection

• Source Control: Base the empiric regimen on the suspected source (e.g., intra-abdominal, pulmonary, urinary, catheter-related).
• Local Antibiogram: Consult local resistance data to ensure reliable coverage for common pathogens, especially gram-negative organisms like Pseudomonas aeruginosa.
• MDR Risk Assessment: Assess for risk factors for multidrug-resistant (MDR) organisms, including prior colonization, recent broad-spectrum antibiotic use, and significant healthcare exposure.
• Anti-MRSA Coverage: Add vancomycin or linezolid if risk factors for methicillin-resistant Staphylococcus aureus (MRSA) are present or if the patient has severe illness.

C. PK/PD Optimization and Dosing

• β-Lactams: Administer a loading dose over 30 minutes, followed by a prolonged (3–4 hours) or continuous infusion to maximize the time the free drug concentration remains above the minimum inhibitory concentration (fT>MIC).
• Aminoglycosides: Use once-daily, high-dose “concentration-dependent” dosing. Monitor peaks (target 8–10 times the MIC) and troughs to ensure efficacy while avoiding nephrotoxicity and ototoxicity.
• Renal Replacement Therapy (RRT): Continuous RRT significantly increases the clearance of hydrophilic drugs (e.g., β-lactams, vancomycin). Consider increasing the dose by approximately 25% or shortening the dosing interval to avoid subtherapeutic concentrations.
• Hepatic Impairment: Expect reduced clearance of lipophilic agents (e.g., linezolid, metronidazole) and potentially altered protein binding. Dose adjustments may be necessary.

D. De-escalation and Stewardship

Antimicrobial stewardship is not a barrier to care but an essential component of it. The goal is to use the right drug, for the right bug, for the right duration.

2. Vasoactive and Hemodynamic Agents

The primary hemodynamic goal in septic shock is to restore tissue perfusion by achieving a mean arterial pressure (MAP) of at least 65 mm Hg. Norepinephrine is the first-line agent, with adjunctive therapies added based on the patient’s response and the dose of catecholamines required.

C. Corticosteroid Adjuncts

Corticosteroids are recommended for patients with persistent vasopressor-dependent shock despite adequate fluid resuscitation and escalating vasopressor requirements.

• Indication: Septic shock requiring ongoing vasopressor support (e.g., norepinephrine ≥0.25 µg/kg/min) to maintain MAP ≥65 mm Hg.
• Recommended Regimen: Hydrocortisone 200 mg/day, administered as a continuous infusion or as 50 mg IV every 6 hours. The addition of fludrocortisone 50 µg enterally once daily has been shown to improve outcomes.
• Monitoring: Closely monitor for hyperglycemia, hypernatremia, hypokalemia, and secondary infections.

3. Monitoring, Pharmacoeconomics, and Quality Considerations

Effective management of septic shock extends beyond drug selection to include ongoing assessment of drug exposure, efficacy markers, potential toxicities, and overall value. This ensures safe, evidence-based, and cost-effective care.

A. Therapeutic Drug Monitoring (TDM) and Efficacy Markers

• Vancomycin TDM: Target an Area Under the Curve (AUC) to MIC ratio of 400–600 mg·h/L to balance efficacy and minimize the risk of acute kidney injury.
• Lactate Clearance: A decrease in serum lactate of at least 10% within the first 2 hours of resuscitation is a key marker of improving perfusion and is associated with improved survival.
• Organ Function: Track daily Sequential Organ Failure Assessment (SOFA) scores to monitor the trajectory of organ dysfunction. Improvement in the SOFA score is a strong indicator of successful resuscitation.

B. Safety Surveillance

• Renal and Hepatic Function: Monitor daily creatinine, BUN, and liver function tests to detect drug-induced organ injury early.
• Hematologic Effects: Check complete blood counts regularly, especially for thrombocytopenia in patients receiving linezolid.
• Metabolic Monitoring: During corticosteroid therapy, monitor blood glucose and electrolytes (sodium, potassium) at least twice daily.

C. Cost-Effectiveness and Resource Allocation

• Dosing Strategies: While prolonged β-lactam infusions may require more pharmacy and nursing resources initially, they can lead to overall cost savings by potentially shortening ICU length of stay.
• Agent Selection: The higher acquisition cost of vasopressin may be offset by a reduction in total norepinephrine dose and a potential decrease in the incidence of new-onset atrial fibrillation or need for RRT.
• Stewardship Integration: Interdisciplinary stewardship rounds, sepsis response teams, and the use of pre-stocked “sepsis carts” can streamline care, improve guideline adherence, and ensure resources are used efficiently.