1. Therapeutic Principles in Endocarditis

Effective endocarditis therapy is a cornerstone of critical care infectious diseases, combining bactericidal antimicrobial regimens with adequate penetration into the vegetation over a pathogen-specific duration. The primary goals are to sterilize the vegetation and bloodstream, prevent embolic complications, and preserve or restore valve function.

Key Therapeutic Goals

• Bactericidal Activity: Therapy must achieve drug concentrations that actively kill the pathogen, not merely inhibit its growth. This is crucial for eradicating bacteria within the protected niche of a vegetation.
• Adequate Vegetation Penetration: The drug’s ability to reach the site of infection is influenced by factors like lipophilicity and protein binding.
• Sufficient Duration: Treatment courses are prolonged. Native-valve endocarditis caused by susceptible streptococci may require 4 weeks, whereas staphylococcal or prosthetic-valve infections demand 6 weeks or more.

2. Pathogen-Specific First-Line Regimens

Once culture and susceptibility results are available, therapy must be tailored to the specific pathogen. The table below outlines standard first-line regimens for the most common causative organisms in native valve endocarditis (NVE). Prosthetic valve endocarditis (PVE) generally requires longer durations and often includes adjunctive rifampin for staphylococcal infections.

3. Adjunctive and Second-Line Agents

Certain clinical scenarios, such as prosthetic valve infections, resistant organisms, or intolerance to first-line agents, necessitate alternative or adjunctive therapies.

A. Rifampin for Prosthetic Valve Staphylococcal Endocarditis

Rifampin is a key adjunctive agent for treating staphylococcal (both MSSA and MRSA) PVE. Its ability to penetrate bacterial biofilm on prosthetic material is crucial for eradicating the infection.

• Regimen: Rifampin 300 mg PO/IV q8h, added after initial bacteremia clearance and continued for the duration of therapy (≥6 weeks).
• Considerations: Rifampin is a potent inducer of CYP450 enzymes, requiring a thorough review of drug-drug interactions. It can also cause hepatotoxicity, necessitating weekly monitoring of liver function tests.

B. Double Beta-Lactam Therapy for Enterococcal Endocarditis

For enterococcal endocarditis where aminoglycosides are contraindicated (e.g., pre-existing renal disease, ototoxicity) or in cases of high-level aminoglycoside resistance, a double beta-lactam combination is the preferred alternative.

• Regimen: Ampicillin 2 g IV q4h + Ceftriaxone 2 g IV q12h for 6 weeks.
• Rationale: This combination provides synergy against many strains of Enterococcus faecalis by saturating different penicillin-binding proteins, achieving bactericidal activity without the nephrotoxicity of aminoglycosides.

C. Antifungal Therapy

Fungal endocarditis is a rare but life-threatening condition with very high mortality. It almost always requires a combination of aggressive, prolonged antifungal therapy and surgical intervention (valve replacement).

• Initial Therapy: Liposomal Amphotericin B is often the initial agent of choice. An echinocandin (e.g., caspofungin, micafungin) may be used as an alternative or in combination.
• Step-Down Therapy: Once the patient is stabilized and susceptibilities are known, therapy may be transitioned to a long-term oral azole (e.g., fluconazole, voriconazole).

4. Pharmacokinetic/Pharmacodynamic (PK/PD) and Delivery Considerations

Achieving therapeutic drug targets is challenging in critically ill patients, whose physiology can dramatically alter drug distribution and clearance. Long-term therapy also requires careful planning for vascular access and potential transition to outpatient care.

PK/PD Optimization in Critical Illness

• Increased Volume of Distribution: Sepsis and fluid resuscitation can increase the volume of distribution for hydrophilic antibiotics (e.g., beta-lactams, vancomycin). Loading doses may be necessary to rapidly achieve therapeutic concentrations.
• Augmented Renal Clearance (ARC): Some critically ill patients exhibit creatinine clearance >130 mL/min, leading to subtherapeutic drug levels. Higher doses or more frequent administration may be required. Early therapeutic drug monitoring (TDM) is crucial.
• Continuous Renal Replacement Therapy (CRRT): Most beta-lactams are cleared by CRRT, but standard ICU dosing is often sufficient. Aminoglycoside and vancomycin dosing must be adjusted based on TDM.

Vascular Access and Outpatient Parenteral Antimicrobial Therapy (OPAT)

A peripherally inserted central catheter (PICC) is the preferred vascular access for long-term IV therapy. In carefully selected, stable patients, treatment can be completed in an outpatient setting.

• OPAT Eligibility: Patient must be clinically stable, afebrile, with clearing blood cultures and resolving inflammatory markers. Strong social support and a structured OPAT program are essential.
• Oral Step-Down: The POET trial demonstrated that in stable patients with left-sided endocarditis, transitioning to oral antibiotics after at least 10 days of IV therapy was non-inferior to continued IV therapy. This should only be done in consultation with an ID specialist and with highly bioavailable agents.

5. Monitoring and Guideline Controversies

Systematic monitoring for both efficacy and safety is paramount to successful outcomes. Clinicians must also be aware of evolving evidence and areas of controversy in clinical guidelines.

Systematic Monitoring Plan