1. Empiric Antimicrobial Selection

Empiric therapy must cover aerobic gram-negatives, anaerobes, and—when indicated—enterococci, tailored to patient risk factors and the unit antibiogram. The goal is to provide adequate coverage early while minimizing unnecessary breadth.

A. Pathogen Epidemiology and Resistance Patterns

• Primary Pathogens: Enterobacterales (e.g., E. coli, Klebsiella spp.), Pseudomonas aeruginosa, and Bacteroides fragilis are the most common isolates. Enterococcus spp. are found in up to 20% of healthcare-associated intra-abdominal infections (HA-IAI).
• MDR Risk Factors: Prior antibiotic use, recent hospitalization, or exposure to healthcare settings increase the risk for multidrug-resistant (MDR) organisms. Local rates of extended-spectrum β-lactamase (ESBL) or carbapenemase-producing organisms exceeding 10% warrant broader empiric coverage.

B. First-line Regimens

Beta-lactam/β-lactamase inhibitor combinations and carbapenems remain the cornerstones of therapy. Dosing must be optimized to achieve pharmacokinetic/pharmacodynamic (PK/PD) targets, especially in the setting of sepsis-induced physiological changes.

C. Expanded-Spectrum and Rescue Agents

Novel β-lactam/β-lactamase inhibitor combinations should be reserved for patients with high-risk factors for, or confirmed infections with, MDR pathogens to mitigate resistance pressure.

• Ceftolozane-tazobactam + metronidazole: Excellent for ESBL-producing Enterobacterales and MDR Pseudomonas.
• Ceftazidime-avibactam + metronidazole: Key agent for carbapenem-resistant Enterobacterales (CRE) and refractory Pseudomonas.
• Imipenem-cilastatin-relebactam: Covers imipenem-nonsusceptible pathogens, including some CRE.

2. Second-Line and Adjunctive Therapies

Anti-enterococcal or antifungal agents are added based on culture data, specific patient risk profiles, and failure to respond to initial therapy.

A. VRE-Active Agents

Coverage for vancomycin-resistant Enterococcus (VRE) is indicated for patients with prior VRE colonization, significant healthcare exposure, or positive cultures.

B. Antifungal Therapy

Empiric antifungal therapy with an echinocandin is recommended for critically ill patients with cIAI who have specific risk factors for invasive candidiasis, such as recent abdominal surgery, anastomotic leaks, or persistent sepsis despite broad-spectrum antibacterial coverage.

• Agent: Anidulafungin (or other echinocandins like caspofungin, micafungin).
• Dosing: Anidulafungin 200 mg IV load, then 100 mg IV daily.
• Monitoring: Monitor LFTs weekly; watch for infusion-related histamine reactions.

3. PK/PD Optimization

Altered physiology in sepsis (e.g., capillary leak, augmented renal clearance) and the use of organ support modalities mandate a PK/PD-guided approach to dosing to ensure therapeutic drug exposures.

• Volume of Distribution (Vd): Sepsis-induced capillary leak and aggressive fluid resuscitation can expand the Vd of hydrophilic drugs (like β-lactams) by 20–50%. Front-loaded or higher initial doses are essential to achieve therapeutic concentrations quickly.
• Protein Binding: Hypoalbuminemia increases the free (active) fraction of highly bound drugs, which can alter both efficacy and toxicity.
• Killing Characteristics:
  • Time-dependent (β-lactams): The primary goal is to maximize the duration that free drug concentrations remain above the MIC (%fT>MIC).
  • Concentration-dependent (aminoglycosides, daptomycin): The goal is to maximize the peak concentration relative to the MIC (Cmax/MIC) to leverage concentration-dependent killing and the post-antibiotic effect.

4. Dosing Adjustments in Organ Dysfunction

Antimicrobial dosing must be dynamically tailored to account for renal impairment, hepatic dysfunction, and states of augmented clearance to prevent toxicity and therapeutic failure.

A. Renal Impairment and Renal Replacement Therapy (RRT)

Continuous renal replacement therapy (CRRT) can significantly increase the clearance of small, water-soluble drugs like β-lactams. Dosing should be based on the effluent rate (e.g., for meropenem, 1 g IV q8h is often appropriate for a rate of 25 mL/kg/h). Therapeutic drug monitoring (TDM), when available, is invaluable for precise dosing in this population.

B. Augmented Renal Clearance (ARC)

ARC (defined as CrCl > 130 mL/min) is common in young, critically ill trauma or sepsis patients. It can lead to subtherapeutic concentrations of renally cleared antibiotics. Standard doses may be insufficient; higher doses or continuous infusions are necessary to achieve PK/PD targets.

5. Route of Administration and Delivery

The choice of vascular access and formulation is crucial for optimizing drug delivery, ensuring safety, and facilitating timely transition to oral therapy.

• Central vs. Peripheral Access: Central venous catheters are preferred for continuous or extended infusions and for administering vesicant agents. Peripheral lines may be suitable for standard, intermittent infusions of non-irritant drugs.
• IV to Oral Conversion: A patient is a candidate for switching to oral therapy when they are hemodynamically stable, have a functioning gastrointestinal tract, and the identified pathogen is susceptible to a highly bioavailable oral agent.
• High-Bioavailability Agents (>90%): Linezolid, fluoroquinolones, and metronidazole are excellent candidates for an early oral switch, which can reduce the risk of line-related complications and shorten ICU length of stay.

6. Monitoring Plan

A structured monitoring plan is essential to ensure efficacy, detect toxicity early, and comply with antimicrobial stewardship principles.

• Therapeutic Drug Monitoring (TDM):
  • Vancomycin: Target an AUC/MIC ratio of 400–600 mg·h/L, typically achieved with trough goals of 15-20 mg/L or via Bayesian dosing software.
  • Aminoglycosides: Target a peak/MIC ratio of ≥8–10 with a suppressed trough (<1 mg/L) to maximize efficacy and minimize nephrotoxicity.
• Efficacy Endpoints: Monitor for improvement in vital signs, normalization of leukocyte count, and resolution of abdominal signs. Consider repeat imaging if the patient fails to improve by day 5–7.
• Safety Monitoring: Check serum creatinine at least every 48 hours, obtain a CBC to monitor for cytopenias (especially with linezolid), and check weekly CPK levels for patients on daptomycin.

7. Pharmacoeconomic Considerations

Effective management of cIAI involves balancing drug acquisition costs with clinical outcomes and long-term stewardship goals.

• Acquisition Cost vs. Outcomes: While generic β-lactams are highly cost-effective, novel inhibitors may cost 5–10 times more. Their use can be justified in select cases where they are shown to reduce length of stay or prevent treatment failure with MDR pathogens.
• Stewardship-Driven Cost Reduction: The most significant cost savings come from optimizing therapy duration. For patients with adequate source control, a short course of therapy (e.g., 4 days) has been shown to be non-inferior to longer courses and markedly lowers drug costs and selective pressure.

8. Integrated Clinical Pathways

A successful pharmacotherapy plan integrates agent selection, dosing protocols, and monitoring into a cohesive clinical pathway. The following flowchart illustrates a typical decision-making process for empiric therapy.