# Empiric and Targeted Antimicrobial Therapy -- IDSA 2017

## Empiric Therapy

### Recommended Empiric Regimen

- **Vancomycin** plus an **anti-pseudomonal beta-lactam** (cefepime, ceftazidime, or meropenem) is recommended as empiric therapy for healthcare-associated ventriculitis and meningitis (Strong, Low).
- The choice of empiric beta-lactam agent should be based on **local in vitro susceptibility patterns** (Strong, Low).

### Vancomycin Dosing

- In seriously ill adult patients, the vancomycin trough concentration should be maintained at **15-20 mcg/mL** for those receiving intermittent bolus administration (Strong, Low).

### Beta-Lactam Allergy

- For patients with a beta-lactam allergy, **aztreonam** or **ciprofloxacin** may be used for gram-negative coverage as part of the empiric regimen (Strong, Low).

### Adjustment for Known Colonization or Prior Infections

- The empiric antimicrobial regimen should be adjusted based on the patient's history of colonization or infection with drug-resistant organisms (Strong, Low).
  - If history of MRSA: ensure vancomycin is included (standard empiric regimen covers this).
  - If history of multidrug-resistant (MDR) gram-negative organisms: consider meropenem or add intraventricular therapy early.
  - If history of carbapenem-resistant organisms: consider adding colistimethate (IV and/or intraventricular).

## Empiric Therapy Decision Algorithm

```
Suspected healthcare-associated ventriculitis/meningitis
  --> Start empiric therapy: Vancomycin + anti-pseudomonal beta-lactam
      --> Cefepime 2 g IV q8h, OR
      --> Ceftazidime 2 g IV q8h, OR
      --> Meropenem 2 g IV q8h
  --> Beta-lactam allergy?
      --> Vancomycin + aztreonam 2 g IV q6-8h, OR
      --> Vancomycin + ciprofloxacin 400 mg IV q8-12h
  --> Known MDR gram-negative colonization?
      --> Consider meropenem (prolonged infusion over 3 hours) + colistimethate
  --> Obtain CSF cultures BEFORE starting antibiotics (do NOT delay therapy for culture results)
  --> Send device components for culture if removed
  --> Narrow therapy based on culture and susceptibility results
```

## Organism-Specific Targeted Therapy

### Staphylococcal Infections

#### Methicillin-Susceptible *Staphylococcus aureus* (MSSA)

- **Nafcillin** or **oxacillin** is recommended as first-line therapy (Strong, Moderate).
- If beta-lactam allergy: desensitization is preferred. If not feasible, vancomycin is an alternative.

#### Methicillin-Resistant *Staphylococcus aureus* (MRSA)

- **Vancomycin** is recommended (Strong, Moderate).
- If vancomycin MIC >=1 mcg/mL: consider alternative agents (Strong, Moderate).
  - Alternatives include **linezolid**, **daptomycin**, or **trimethoprim-sulfamethoxazole (TMP-SMX)**, with selection based on in vitro susceptibility testing (Strong, Moderate).

#### Coagulase-Negative Staphylococci

- Treatment is based on susceptibility results, following the same principles as for *S. aureus* (Strong, Moderate).
- If the isolate is methicillin-susceptible: nafcillin or oxacillin is preferred.
- If methicillin-resistant: vancomycin is recommended.
- **Add rifampin** if the isolate is susceptible and prosthetic material (shunt, drain) is present (Strong, Low).

### *Propionibacterium acnes* (*Cutibacterium acnes*)

- **Penicillin G** is recommended as first-line therapy (Strong, Moderate).
- Consider adding **rifampin** for device-related infections when the prosthetic material cannot be completely removed (Weak, Low).

### Gram-Negative Infections

#### Susceptible to Third-Generation Cephalosporins

- **Ceftriaxone** or **cefotaxime** is recommended (Strong, Moderate).

#### *Pseudomonas aeruginosa*

- **Cefepime**, **ceftazidime**, or **meropenem** is recommended, based on susceptibility (Strong, Moderate).
- Alternative agents include **aztreonam** or a **fluoroquinolone** (e.g., ciprofloxacin) if susceptible (Strong, Moderate).

#### Extended-Spectrum Beta-Lactamase (ESBL)-Producing Gram-Negative Bacilli

- **Meropenem** is recommended if the isolate is susceptible (Strong, Moderate).

#### Carbapenem-Resistant *Acinetobacter* Species

- **Meropenem** is recommended if the isolate retains susceptibility (Strong, Moderate).
- For carbapenem-resistant isolates: **colistimethate** or **polymyxin B** administered by both intravenous and intraventricular routes is recommended (Strong, Moderate).

### Fungal Infections

#### *Candida* Species

- **Liposomal amphotericin B** with or without **5-flucytosine** is recommended as initial therapy (Strong, Moderate).
- **Fluconazole** may be used as step-down therapy after clinical improvement, if the isolate is susceptible (Strong, Moderate).
- Removal of all infected devices is strongly recommended (Strong, Moderate).

#### *Aspergillus* or *Exserohilum* Species

- **Voriconazole** is recommended as first-line therapy (Strong, Low).

## Summary Table: Organism-Specific Therapy

| Organism | First-Line | Alternatives | Notes |
|---|---|---|---|
| **MSSA** | Nafcillin or oxacillin | Vancomycin (if allergy) | Desensitization preferred over vancomycin |
| **MRSA** | Vancomycin (trough 15-20 mcg/mL) | Linezolid, daptomycin, or TMP-SMX | Use alternative if vancomycin MIC >=1 mcg/mL |
| **CoNS (methicillin-resistant)** | Vancomycin | Linezolid, daptomycin | Add rifampin if prosthetic material present |
| **CoNS (methicillin-susceptible)** | Nafcillin or oxacillin | Vancomycin | Add rifampin if prosthetic material present |
| ***P. acnes*** | Penicillin G | -- | Consider adding rifampin for device infections |
| **Gram-negative (susceptible)** | Ceftriaxone or cefotaxime | -- | Based on susceptibility |
| ***Pseudomonas*** | Cefepime, ceftazidime, or meropenem | Aztreonam, ciprofloxacin | Based on local susceptibility patterns |
| **ESBL-producing GNB** | Meropenem | -- | Only if susceptible |
| ***Acinetobacter* (carbapenem-R)** | Colistimethate or polymyxin B (IV + IVT) | -- | Dual-route administration recommended |
| ***Candida*** | Liposomal amphotericin B +/- 5-FC | Fluconazole (step-down) | Remove all infected devices |
| ***Aspergillus/Exserohilum*** | Voriconazole | -- | -- |

## Intraventricular Antimicrobial Therapy

### Indications

- Intraventricular antimicrobial therapy should be considered when infection responds poorly to systemic therapy alone, or when the causative organism is susceptible only to agents with poor CSF penetration (Strong, Low).

### General Principles

- Target CSF antimicrobial concentrations of **10-20 times the MIC** of the causative pathogen (Strong, Low).
- After intraventricular administration, **clamp the drain for 15-60 minutes** to allow drug distribution (Strong, Low).
- Adjust dosages based on ventricular size and daily CSF drain output (Strong, Low).
- **Do NOT administer beta-lactam antibiotics via the intraventricular route** due to the risk of seizures (Strong, Moderate).

### Intraventricular Vancomycin Dosing

- The initial dose is based on estimated ventricular volume:
  - **Slit ventricles:** 5 mg
  - **Normal-sized ventricles:** 10 mg
  - **Enlarged ventricles:** 15-20 mg

### Intraventricular Aminoglycoside Dosing

- **Gentamicin** or **tobramycin:** 5 mg for an estimated CSF volume of approximately 250 mL.
- **Amikacin:** 30-50 mg.

### Intraventricular Colistimethate

- **10 mg (125,000 IU) once daily** in adults.

### Dosing Frequency Based on CSF Drainage Rate

| Daily CSF Drainage Volume | Dosing Frequency |
|---|---|
| **>100 mL/day** | Once daily |
| **50-100 mL/day** | Every other day |
| **<50 mL/day** | Every third day |

## Treatment Duration

| Pathogen / Scenario | Recommended Duration |
|---|---|
| **CoNS or *P. acnes* (minimal CSF pleocytosis)** | 10 days |
| **CoNS or *P. acnes* (significant CSF pleocytosis)** | 10-14 days |
| ***S. aureus* or gram-negative bacilli** | 10-14 days (some experts recommend 21 days for gram-negative infections) |
| **Repeatedly positive CSF cultures** | 10-14 days after the last positive culture becomes negative |

## Monitoring Response to Therapy

- For patients with external ventricular drains, CSF cultures should be monitored to document sterilization (Strong, Low).
- If clinical improvement is absent after appropriate therapy, repeat CSF analysis should be performed to confirm microbiological and biochemical improvement (Strong, Low).
- Daily CSF cultures and analysis are **not required** for patients with non-shunt external drains if clinical improvement is evident (Strong, Low).

## Limitations

- Most treatment recommendations are based on observational studies, case series, and expert opinion (low quality evidence).
- There are no randomized controlled trials comparing specific antimicrobial regimens for healthcare-associated ventriculitis and meningitis.
- Intraventricular antimicrobial dosing recommendations are extrapolated from limited pharmacokinetic data and case reports.
- Local antimicrobial resistance patterns should guide empiric therapy; the guideline cannot provide universally applicable regimens.
