A 35-year-old man with a history of intravenous drug use presents with fever, new cardiac murmur, and septic emboli. Blood cultures grow Gram-positive cocci in clusters. What is the drug of choice for empirical therapy of infective endocarditis pending susceptibility testing?

Explanation

## Drug of Choice for Staphylococcal Endocarditis **Key Point:** Nafcillin (or oxacillin) is the first-line agent for empirical therapy of endocarditis caused by methicillin-sensitive *Staphylococcus aureus* (MSSA). ### Clinical Context - Gram-positive cocci in clusters = *Staphylococcus aureus* - IVDU with endocarditis = high risk for *S. aureus* (including MRSA) - Empirical therapy must cover MSSA until susceptibilities are known ### Why Nafcillin? 1. **Antistaphylococcal Beta-Lactamase Resistance** - Nafcillin is a beta-lactamase-resistant penicillin (antistaphylococcal penicillin) - Resists enzymatic degradation by *S. aureus* beta-lactamase - Superior to penicillin G (which is susceptible to beta-lactamase) 2. **Excellent Cardiac Valve Penetration** - Achieves high concentrations in vegetations - Bactericidal against MSSA 3. **Dosing in Endocarditis** - 2 g IV every 4 hours (high-dose regimen) - Total daily dose: 12 g - Prolonged therapy: 4–6 weeks for native valve, 6 weeks for prosthetic valve 4. **Superior to Cephalosporins** - Nafcillin has better outcomes than cephalosporins in MSSA endocarditis - Cross-reactivity with cephalosporins in penicillin-allergic patients is ~1–3% (low risk) ### Comparison Table | Agent | Beta-Lactamase Resistant | MSSA Coverage | Valve Penetration | Endocarditis DOC? | | --- | --- | --- | --- | --- | | Nafcillin | ✓ (antistaphylococcal) | Excellent | Excellent | **Yes** | | Oxacillin | ✓ (antistaphylococcal) | Excellent | Excellent | **Yes** | | Penicillin G | ✗ (susceptible to beta-lactamase) | Poor | Good | No | | Cephalexin | ✓ (1st gen) | Moderate | Moderate | No (oral, inadequate for endocarditis) | | Amoxicillin | ✗ (susceptible to beta-lactamase) | Poor | Moderate | No | **Clinical Pearl:** If MRSA is suspected (risk factors: IVDU, healthcare exposure, prior MRSA colonization), add vancomycin until susceptibilities are known. Once MSSA is confirmed, switch to nafcillin monotherapy. **High-Yield:** Antistaphylococcal penicillins (nafcillin, oxacillin) are superior to penicillin G for *S. aureus* endocarditis because they resist beta-lactamase degradation and achieve better valve penetration. **Mnemonic:** **NAF = Native valve, Antistaphylococcal, First-line** — Nafcillin is the empirical choice for MSSA endocarditis.