What is the initial approach to treating Citrobacter (C.) freundii, C. braakii, C. koseri, and Enterococcus (E.) faecalis infections?

Approach to Citrobacter and Enterococcus faecalis Infections

Initial Empiric Therapy

For critically ill patients with suspected Citrobacter or E. faecalis infections, initiate broad-spectrum empiric therapy immediately with an anti-pseudomonal beta-lactam (such as piperacillin-tazobactam, cefepime, or a carbapenem) plus coverage for enterococci with ampicillin or vancomycin, based on local resistance patterns and patient risk factors. 1, 2

Risk Stratification for Empiric Coverage

Gram-Negative Coverage (Citrobacter species):

• Critically ill patients, those with sepsis, neutropenia, or femoral catheters require immediate empiric gram-negative coverage 1, 2
• Patients with recent colonization or infection with multidrug-resistant (MDR) gram-negative pathogens should receive two antimicrobial agents of different classes with gram-negative activity as initial therapy 1, 3, 4
• Recommended dual therapy: anti-pseudomonal beta-lactam plus an aminoglycoside 3, 4

Enterococcal Coverage (E. faecalis):

• Empiric anti-enterococcal therapy is indicated for health care-associated infections, postoperative infections, patients with prior cephalosporin exposure, immunocompromised patients, and those with valvular heart disease or prosthetic intravascular materials 1
• Initial therapy should target E. faecalis specifically 1

Definitive Therapy Based on Culture Results

Citrobacter Species (C. freundii, C. braakii, C. koseri)

Once Citrobacter is identified, de-escalate to targeted monotherapy based on susceptibility testing within 24-72 hours. 2, 4

Preferred agents based on susceptibility:

• Carbapenems (imipenem, meropenem, doripenem) remain the most reliable agents against Citrobacter species 5, 6
• Cefepime or cefpirome are effective alternatives for susceptible isolates 5
• Fluoroquinolones may be used but resistance has increased significantly over time 5
• Avoid broad-spectrum cephalosporins (3rd generation) as monotherapy due to high rates of resistance emergence during therapy (5.0% in Enterobacter/Citrobacter) 7

Critical pitfall: Citrobacter species possess chromosomally encoded AmpC beta-lactamases and can develop resistance during therapy with broad-spectrum cephalosporins, particularly C. freundii 7. This resistance emergence occurs in 2.6-8.3% of cases treated with 3rd generation cephalosporins 7.

Enterococcus faecalis

Ampicillin is the drug of choice for ampicillin-susceptible E. faecalis. 1

Alternative agents:

• Vancomycin for ampicillin-resistant isolates 1
• Piperacillin-tazobactam can be used based on susceptibility 1
• Linezolid or daptomycin for ampicillin- and vancomycin-resistant isolates 1

Combination therapy considerations:

• The role of combination therapy (cell wall-active agent plus aminoglycoside) for E. faecalis bacteremia without endocarditis is unresolved 1
• One large series found combination therapy (gentamicin plus ampicillin) more effective than monotherapy when catheters were retained 1
• For catheter salvage attempts, use systemic therapy plus antibiotic lock therapy 1

Duration of Therapy

Standard duration: 7-14 days for uncomplicated infections 1, 2, 4

Extended therapy (>14 days) required for:

• Endocarditis 1
• Suppurative thrombophlebitis 1, 3
• Metastatic infection 1, 3
• Persistent bacteremia >72 hours despite appropriate therapy 1, 3

Catheter Management

For Gram-Negative (Citrobacter) Catheter-Related Bloodstream Infections:

Remove the catheter if:

• Persistent bacteremia or severe sepsis despite systemic and antibiotic lock therapy 1
• Short-term catheter is involved 1
• Evaluate for endovascular and metastatic infection if catheter removal is required 1

For Enterococcal Catheter-Related Bloodstream Infections:

Catheter can be retained with:

• Systemic antibiotic therapy for 7-14 days 1
• Antibiotic lock therapy in addition to systemic therapy 1
• Close monitoring with follow-up blood cultures 1

Remove the catheter if:

• Persistent bacteremia >72 hours after initiating appropriate therapy 1
• Signs of endocarditis, new murmur, or embolic phenomena 1
• Suppurative thrombophlebitis 1

Evaluation for Endocarditis

Transesophageal echocardiography (TEE) is indicated for E. faecalis bacteremia if: 1

• New murmur or embolic phenomena
• Prolonged bacteremia or fever >72 hours despite appropriate therapy
• Radiographic evidence of septic pulmonary emboli
• Presence of prosthetic valve or other endovascular foreign bodies

Note: The risk of endocarditis with enterococcal catheter-related infections is relatively low (1.5% in one multicenter study), but E. faecalis carries higher endocarditis risk than E. faecium 1

Special Considerations

For intra-abdominal infections:

• Tigecycline is FDA-approved for complicated intra-abdominal infections caused by C. freundii and E. faecalis (vancomycin-susceptible) 8
• However, tigecycline carries a black box warning for increased all-cause mortality and should be reserved for situations when alternative treatments are not suitable 8

For biliary tract infections with malignant bile duct invasion:

• Higher risk of resistance emergence during therapy with broad-spectrum cephalosporins 7
• Consider carbapenem-based therapy from the outset 7

Common Pitfalls to Avoid

• Do not use 3rd generation cephalosporins as monotherapy for Citrobacter infections due to high risk of resistance emergence (particularly with C. freundii) 7
• Do not delay catheter removal in cases of persistent bacteremia >72 hours despite appropriate antimicrobial therapy 1
• Do not assume all enterococci are E. faecalis—empiric therapy for vancomycin-resistant E. faecium is not recommended unless the patient is at very high risk 1
• Do not continue dual gram-negative therapy once susceptibility results confirm adequate single-agent coverage 2, 4
• Do not overlook the need for TEE in enterococcal bacteremia with persistent fever or bacteremia >72 hours 1