1. Empiric Antimicrobial Strategies

Critically ill patients with severe SSTIs or suspected osteomyelitis require immediate broad empiric coverage for MRSA, MSSA, and—when indicated—gram-negative/anaerobic pathogens. Initiate broad-spectrum therapy within 1 hour in patients with systemic signs or hemodynamic instability. Dosing must account for altered PK/PD in sepsis and organ dysfunction, with vigilant monitoring to balance efficacy and toxicity.

2. Targeted Therapy and De-escalation

Promptly narrow antimicrobial coverage once culture and susceptibility results are available. This core principle of antimicrobial stewardship minimizes toxicity, reduces the risk of resistance, and can lower costs.

A. Culture-Directed Narrowing

• If MRSA is isolated: Continue vancomycin or daptomycin. If the isolate is also clindamycin-susceptible (and D-test negative), clindamycin can be considered for uncomplicated SSTIs without bacteremia.
• If MSSA is isolated: De-escalate from vancomycin to a beta-lactam like nafcillin or cefazolin. This is crucial, as beta-lactams are more effective against MSSA than vancomycin.
• For prosthetic osteomyelitis: Once the infection is controlled, add rifampin to the primary anti-staphylococcal regimen to penetrate biofilm. Never use rifampin as monotherapy due to rapid resistance development.

B. Oral Step-Down Therapy

Transitioning from IV to oral therapy is appropriate when the patient meets all of the following criteria:

1. Clinical Stability: Afebrile, hemodynamically stable, and improving inflammatory markers.
2. Source Control Achieved: Any necessary surgical debridement or drainage has been completed.
3. Functional GI Tract: Patient is able to tolerate oral intake without issues.

Common oral step-down options include:

• For MRSA: Doxycycline, clindamycin, or trimethoprim–sulfamethoxazole.
• For MSSA: Dicloxacillin or cephalexin.

3. Pharmacotherapy Agent Deep Dive

A detailed understanding of each agent’s mechanism, dosing, monitoring, and pitfalls informs optimal selection and management.

4. PK/PD & Organ Dysfunction Adjustments

Sepsis, critical illness, and organ support therapies significantly alter drug pharmacokinetics (PK) and pharmacodynamics (PD). Dosing regimens must be adapted to these changes to ensure therapeutic targets are met.

• Sepsis & Increased Volume of Distribution (Vd): In sepsis, capillary leak leads to a larger Vd for hydrophilic drugs like vancomycin and beta-lactams. This necessitates higher loading doses to rapidly achieve therapeutic concentrations.
• Augmented Renal Clearance (ARC): Some critically ill patients, particularly younger patients with trauma or sepsis, may have a CrCl > 130 mL/min. In these cases, standard doses may be cleared too quickly, requiring more frequent dosing or continuous infusions to maintain therapeutic levels.
• Continuous Renal Replacement Therapy (CRRT): Drug clearance on CRRT is complex. Dosing must be adjusted based on the specific modality and filter. For vancomycin, a common approach is 15–20 mg/kg q24-48h with close therapeutic drug monitoring (TDM). Daptomycin is typically dosed q48h.
• Hepatic Impairment: Linezolid dosing is generally unchanged. Use nafcillin and rifampin with caution and monitor LFTs closely.
• Infusion Strategies: For time-dependent antibiotics like beta-lactams, extended or continuous infusions maximize the time the drug concentration remains above the MIC (%T > MIC), which can improve outcomes in severe infections.

5. Administration & Delivery Devices

The mode of delivery can impact pharmacokinetics, drug stability, and patient mobility, particularly in the context of Outpatient Parenteral Antimicrobial Therapy (OPAT).

• Continuous Infusion: Best for beta-lactams (e.g., cefazolin, piperacillin-tazobactam) to optimize %T > MIC. Requires a dedicated IV line and pump.
• Intermittent Bolus: Standard for concentration-dependent drugs like daptomycin and aminoglycosides. Also used for linezolid.
• Vascular Access: Caustic or vesicant agents like vancomycin and nafcillin should ideally be administered through a central venous catheter to prevent phlebitis and extravasation injury. Peripherally inserted central catheters (PICCs) or midlines are common choices for prolonged IV therapy or OPAT.
• OPAT Considerations: When selecting an agent for OPAT, consider its stability at room temperature, dosing frequency (q24h or q12h is preferable to q4h), and the capacity for home monitoring.

6. Monitoring Framework

A systematic approach to monitoring ensures therapeutic efficacy while detecting and mitigating potential toxicities early.

7. Pharmacoeconomics

Effective stewardship involves balancing direct drug acquisition costs with the total cost of care, which includes monitoring, length of stay, and OPAT resources.

• Drug Costs: Generic agents like vancomycin and nafcillin have low acquisition costs but may require more intensive monitoring. Branded agents like daptomycin and linezolid are more expensive but may offer advantages in specific scenarios (e.g., vancomycin failure, need for oral step-down).
• Total Cost of Care: A higher-cost agent that facilitates earlier discharge or avoids toxicity (e.g., nephrotoxicity) may be more cost-effective overall.
• Oral vs. IV Therapy: The OVIVA trial demonstrated that for complex bone and joint infections, oral antibiotic therapy was non-inferior to IV therapy. This supports early oral step-down to reduce costs, length of stay, and catheter-related complications.
• OPAT: Outpatient therapy shifts costs from inpatient care to home infusion services. The overall economic benefit depends on the specific drug, its administration requirements, and the local healthcare infrastructure.

8. Clinical Decision Algorithms & Controversies

Standardized algorithms can guide therapy, but clinicians must also navigate areas of ongoing debate and evolving evidence.