# Antimicrobial Therapy for Infective Endocarditis — AHA 2015

## General Principles

- Parenteral (IV) bactericidal antimicrobial therapy is the standard of care for IE
- Therapy should be initiated **after at least 3 sets of blood cultures** are obtained from separate venipuncture sites (Class I, Level of Evidence A)
- Prolonged courses (4-6 weeks) are required to eradicate organisms within vegetations where antibiotic penetration is limited
- Empiric therapy should be initiated after blood cultures are drawn, then narrowed based on culture and susceptibility results
- Aminoglycoside dosing should target appropriate serum levels: gentamicin peak 3-4 mcg/mL, trough < 1 mcg/mL
- Vancomycin dosing: target AUC24/MIC >= 400, typically achieved with trough serum concentrations of 10-15 mcg/mL (up to 15-20 mcg/mL for serious infections)

## Streptococcal Native Valve Endocarditis

### Highly Penicillin-Susceptible Viridans Group Streptococci (VGS) and S. gallolyticus (MIC <= 0.12 mcg/mL)

**Preferred regimens (choose one):**

| Regimen | Drug | Dose | Route | Frequency | Duration |
|---|---|---|---|---|---|
| **A (monotherapy)** | Penicillin G sodium | 12-18 million units/24 hours | IV | Continuously or in 4-6 equally divided doses | 4 weeks |
| **A (alternative)** | Ceftriaxone sodium | 2 g/dose | IV or IM | Once daily | 4 weeks |
| **B (short course)** | Penicillin G sodium OR ceftriaxone | As above | IV | As above | 2 weeks |
| | PLUS Gentamicin sulfate | 3 mg/kg/dose | IV or IM | Once daily | 2 weeks |
| **C (penicillin allergy)** | Vancomycin | 30 mg/kg/24 hours | IV | In 2 equally divided doses | 4 weeks |

- 2-week regimen B is appropriate for **uncomplicated NVE** in patients with normal renal function, no cranial nerve VIII impairment, and no cardiac abscess
- Ceftriaxone plus gentamicin 2-week combination achieves cure rates comparable to 4-week monotherapy (Class IIa, Level of Evidence B)

### Relatively Penicillin-Resistant VGS and S. gallolyticus (MIC > 0.12 to < 0.5 mcg/mL)

| Drug | Dose | Route | Frequency | Duration |
|---|---|---|---|---|
| Penicillin G sodium OR ampicillin sodium | 24 million units/24 hours (penicillin) OR 12 g/24 hours (ampicillin) | IV | In 4-6 equally divided doses | 4 weeks |
| PLUS Gentamicin sulfate | 3 mg/kg/dose | IV or IM | Once daily | 2 weeks |
| **Alternative:** Vancomycin | 30 mg/kg/24 hours | IV | In 2 equally divided doses | 4 weeks |

- For strains with MIC >= 0.5 mcg/mL, treat as enterococcal IE

## Streptococcal Prosthetic Valve Endocarditis

| Drug | Dose | Route | Frequency | Duration |
|---|---|---|---|---|
| Penicillin G sodium OR ceftriaxone sodium | 24 million units/24 hours (penicillin) OR 2 g/dose (ceftriaxone) | IV | In 4-6 divided doses (penicillin) or once daily (ceftriaxone) | **6 weeks** |
| WITH or WITHOUT Gentamicin sulfate | 3 mg/kg/dose | IV or IM | Once daily | 2 weeks |
| **Alternative:** Vancomycin | 30 mg/kg/24 hours | IV | In 2 equally divided doses | **6 weeks** |

- Prosthetic valve IE requires a minimum of **6 weeks** of therapy (versus 4 weeks for NVE)

## Staphylococcal Native Valve Endocarditis

### MSSA (Methicillin-Susceptible S. aureus)

| Drug | Dose | Route | Frequency | Duration |
|---|---|---|---|---|
| **Preferred:** Nafcillin or oxacillin | 12 g/24 hours | IV | In 4-6 equally divided doses | **6 weeks** |
| **Non-anaphylactoid penicillin allergy:** Cefazolin | 6 g/24 hours | IV | In 3 equally divided doses | **6 weeks** |
| **Alternative:** Daptomycin | 6 mg/kg/dose | IV | Once daily | **6 weeks** |

- The use of gentamicin in addition to an anti-staphylococcal penicillin for NVE is **not recommended** due to lack of proven clinical benefit and increased nephrotoxicity risk (Class III, Level of Evidence B)
- Rifampin is **not recommended** for staphylococcal NVE

### MRSA (Methicillin-Resistant S. aureus) or True Penicillin Allergy

| Drug | Dose | Route | Frequency | Duration |
|---|---|---|---|---|
| **Preferred:** Vancomycin | 30 mg/kg/24 hours | IV | In 2 equally divided doses | **6 weeks** |
| **Alternative:** Daptomycin | 6 mg/kg/dose (some experts recommend higher doses up to 8-10 mg/kg) | IV | Once daily | **6 weeks** |

- Daptomycin is a reasonable alternative to vancomycin for S. aureus NVE (Class IIa, Level of Evidence B)
- Daptomycin is inactivated by pulmonary surfactant and should **not** be used for left-sided IE with concurrent pneumonia

## Staphylococcal Prosthetic Valve Endocarditis

### MSSA — Prosthetic Valve

| Drug | Dose | Route | Frequency | Duration |
|---|---|---|---|---|
| Nafcillin or oxacillin | 12 g/24 hours | IV | In 4-6 equally divided doses | **>= 6 weeks** |
| PLUS Rifampin | 900 mg/24 hours | IV or PO | In 3 equally divided doses (300 mg every 8 hours) | **>= 6 weeks** |
| PLUS Gentamicin sulfate | 3 mg/kg/24 hours | IV or IM | In 2-3 equally divided doses | **2 weeks** |

### MRSA — Prosthetic Valve

| Drug | Dose | Route | Frequency | Duration |
|---|---|---|---|---|
| Vancomycin | 30 mg/kg/24 hours | IV | In 2 equally divided doses | **>= 6 weeks** |
| PLUS Rifampin | 900 mg/24 hours | IV or PO | In 3 equally divided doses (300 mg every 8 hours) | **>= 6 weeks** |
| PLUS Gentamicin sulfate | 3 mg/kg/24 hours | IV or IM | In 2-3 equally divided doses | **2 weeks** |

- Rifampin is essential for prosthetic valve staphylococcal IE because of its activity against biofilm-associated organisms on prosthetic material
- Start rifampin **3-5 days after** initiation of the primary anti-staphylococcal agent and gentamicin, once blood cultures have cleared
- Monitor for rifampin drug interactions (cytochrome P450 induction): warfarin, cyclosporine, and other agents

## Enterococcal Endocarditis

### Susceptible to Penicillin, Gentamicin, and Vancomycin

**Option 1: Ampicillin + Gentamicin**

| Drug | Dose | Route | Frequency | Duration |
|---|---|---|---|---|
| Ampicillin sodium | 12 g/24 hours | IV | In 6 equally divided doses (2 g every 4 hours) | 4-6 weeks |
| PLUS Gentamicin sulfate | 3 mg/kg/24 hours | IV or IM | In 3 equally divided doses (1 mg/kg every 8 hours) | 4-6 weeks |

**Option 2: Double Beta-Lactam (Ampicillin + Ceftriaxone)**

| Drug | Dose | Route | Frequency | Duration |
|---|---|---|---|---|
| Ampicillin sodium | 12 g/24 hours | IV | In 6 equally divided doses (2 g every 4 hours) | 6 weeks |
| PLUS Ceftriaxone sodium | 4 g/24 hours | IV or IM | In 2 equally divided doses (2 g every 12 hours) | 6 weeks |

- Ampicillin + ceftriaxone is recommended as a **reasonable alternative** to ampicillin + gentamicin for *E. faecalis* IE, and is the **preferred regimen** for patients with CrCl < 50 mL/min to avoid aminoglycoside nephrotoxicity (Class IIa, Level of Evidence B)
- Duration: **4 weeks** if symptoms < 3 months duration; **6 weeks** if symptoms >= 3 months duration or prosthetic valve IE

### High-Level Aminoglycoside Resistance (HLAR)

- Ampicillin + ceftriaxone for 6 weeks is the recommended regimen for *E. faecalis* with HLAR
- For *E. faecium* with HLAR, consult infectious disease specialists

### Vancomycin-Resistant Enterococci (VRE)

- Linezolid 600 mg IV or PO every 12 hours for >= 8 weeks, or daptomycin 6-8 mg/kg IV once daily for >= 8 weeks may be considered
- **Infectious disease consultation is essential** for VRE IE

### Alternative Regimen (Penicillin Allergy)

| Drug | Dose | Route | Frequency | Duration |
|---|---|---|---|---|
| Vancomycin | 30 mg/kg/24 hours | IV | In 2 equally divided doses | 6 weeks |
| PLUS Gentamicin sulfate | 3 mg/kg/24 hours | IV or IM | In 3 equally divided doses | 6 weeks |

## HACEK Organisms

HACEK organisms include: *Haemophilus* species, *Aggregatibacter* species, *Cardiobacterium hominis*, *Eikenella corrodens*, and *Kingella* species.

| Setting | Drug | Dose | Route | Frequency | Duration |
|---|---|---|---|---|---|
| **NVE** | Ceftriaxone sodium | 2 g/dose | IV or IM | Once daily | **4 weeks** |
| **PVE** | Ceftriaxone sodium | 2 g/dose | IV or IM | Once daily | **6 weeks** |
| **Alternative (NVE)** | Ampicillin-sulbactam | 12 g/24 hours (ampicillin component) | IV | In 4 equally divided doses | **4 weeks** |
| **Beta-lactam allergy** | Fluoroquinolone (e.g., ciprofloxacin) | Based on susceptibility | IV or PO | As appropriate | **4 weeks (NVE) / 6 weeks (PVE)** |

- Do not use ampicillin alone because many HACEK strains produce beta-lactamase
- HACEK organisms may require prolonged incubation (up to 2-3 weeks) for isolation

## Culture-Negative Endocarditis

- Occurs in 5-10% of IE cases
- Common causes: prior antibiotic exposure, fastidious organisms (*Bartonella*, *Coxiella burnetii*, *Tropheryma whipplei*, fungi)
- Serological testing for *Bartonella* and *Coxiella burnetii* should be performed
- Empiric therapy should cover the most likely organisms based on clinical context:
  - **NVE:** Ampicillin-sulbactam 12 g/24 hours IV plus gentamicin 3 mg/kg/24 hours IV for 4-6 weeks
  - **PVE (early, < 1 year after surgery):** Vancomycin plus gentamicin plus cefepime for 6 weeks (cover staphylococci, enterococci, gram-negatives)
  - **PVE (late, > 1 year after surgery):** Treat as for NVE
- **Infectious disease consultation** is strongly recommended for all culture-negative IE cases

## Monitoring and Duration Principles

- Repeat blood cultures every 24-48 hours until clearance is documented
- The duration of therapy is counted from the **first day of negative blood cultures** (not from start of antibiotics)
- For patients undergoing valve surgery, the duration of postoperative antibiotic therapy depends on culture results of the excised valve tissue:
  - **Valve culture negative:** Complete the preoperative planned course
  - **Valve culture positive:** Full postoperative course (6 weeks for most organisms)
- Renal function and aminoglycoside/vancomycin levels should be monitored at least twice weekly

## Limitations

- Antimicrobial regimens are based on a combination of observational studies, small clinical trials, and expert consensus; large randomized controlled trials specific to IE are limited
- Daptomycin data for left-sided IE are limited; its role beyond right-sided staphylococcal NVE remains under investigation
- Optimal dosing of daptomycin (standard 6 mg/kg vs high-dose 8-10 mg/kg) for IE has not been definitively established
- The growing prevalence of antibiotic-resistant organisms (MRSA, VRE, ESBL-producing organisms) continues to challenge empiric and targeted therapy
