What is the recommended treatment for carbapenem-resistant Enterobacter (E. cloacae) complex infections?

Treatment of Carbapenem-Resistant Enterobacter cloacae Complex

For carbapenem-resistant Enterobacter cloacae complex infections, ceftazidime-avibactam 2.5 g IV every 8 hours infused over 3 hours is the recommended first-line treatment, with meropenem-vaborbactam 4 g IV every 8 hours or imipenem-cilastatin-relebactam 1.25 g IV every 6 hours as alternative options. 1, 2

Treatment Algorithm Based on Carbapenemase Type

The optimal antibiotic selection depends critically on identifying the specific carbapenemase mechanism:

For KPC-Producing Isolates (Class A Carbapenemase)

• First-line: Ceftazidime-avibactam 2.5 g IV every 8 hours infused over 2-3 hours 1, 2
• Alternative: Meropenem-vaborbactam 4 g IV every 8 hours infused over 3 hours 1, 2
• Alternative: Imipenem-cilastatin-relebactam 1.25 g IV every 6 hours 1, 3
• All three agents have activity against KPC and Class C (AmpC) β-lactamases 1

For OXA-48-Like Producing Isolates (Class D Carbapenemase)

• First-line: Ceftazidime-avibactam 2.5 g IV every 8 hours 1, 2
• Avibactam inhibits some Class D enzymes like OXA-48 1

For Metallo-β-Lactamase Producers (NDM, VIM, IMP)

• Mandatory combination therapy: Ceftazidime-avibactam 2.5 g IV every 8 hours PLUS aztreonam 4, 2, 5, 6
• This combination is essential because avibactam does NOT inhibit Class B metallo-β-lactamases 1, 4
• The mechanism: aztreonam retains activity against MBL-producers but is inactivated by co-existing β-lactamases, while avibactam protects aztreonam from degradation 5, 6
• This combination has demonstrated 100% synergy rates in vitro and improved survival in infection models 6

Combination Therapy Considerations

Monotherapy is generally preferred for most carbapenem-resistant Enterobacter cloacae complex infections, with combination therapy reserved for specific high-risk scenarios. 1

When to Use Combination Therapy:

• Severe sepsis or septic shock: Polymyxin-based combinations (colistin plus tigecycline or carbapenem) reduce mortality compared to monotherapy (35.7% vs 55.5% mortality) 1
• High INCREMENT-CPE mortality scores: Combination therapy shows mortality benefit in this subgroup 1
• MBL-producing organisms: Ceftazidime-avibactam plus aztreonam is mandatory, not optional 4, 2, 5
• KPC-3 producers with prior ceftazidime-avibactam exposure: Consider ceftazidime-avibactam plus carbapenem or colistin due to "see-saw effect" resistance mutations 1, 4

Colistin-Based Combination Regimen (for severe infections when newer agents unavailable):

• Loading dose: Colistin 300 mg CMS (9 MU) IV infused over 0.5-1 hour 1
• Maintenance: 300-360 mg CMS (9-10.9 MU) IV divided in two doses daily 1
• Combination partner: Tigecycline (loading 200 mg, then 100 mg IV every 12 hours for high-dose regimen) or carbapenem 1

Treatment Duration and Monitoring

• Bloodstream infections: 7-14 days, individualized based on clinical response 7
• Respiratory tract infections: Typically 7 days for uncomplicated cases 4
• Monitor clinical response within 48-72 hours and obtain follow-up cultures if treatment failure occurs 7
• Perform susceptibility testing to guide therapy, particularly determining MICs and carbapenemase type 1, 4, 7, 2

Dosing Adjustments for Renal Impairment

All three first-line agents require dose reduction in renal dysfunction 3:

Imipenem-cilastatin-relebactam adjustments:

• CrCl 60-89 mL/min: 1 g (imipenem 400 mg/cilastatin 400 mg/relebactam 200 mg) IV every 6 hours 3
• CrCl 30-59 mL/min: 0.75 g (300/300/150 mg) IV every 6 hours 3
• CrCl 15-29 mL/min: 0.5 g (200/200/100 mg) IV every 6 hours 3
• Hemodialysis: 0.5 g IV every 6 hours, timed after dialysis sessions 3

Critical Pitfalls to Avoid

Antibiotic Selection Errors:

• Never use first or second-generation cephalosporins against Enterobacter due to intrinsic resistance 2
• Avoid third-generation cephalosporins due to high likelihood of resistance development during therapy, particularly for E. cloacae 2
• Do not use ceftazidime-avibactam monotherapy for MBL-producers as avibactam lacks activity against Class B enzymes 1, 4, 2
• Avoid tigecycline monotherapy for bloodstream infections due to low serum concentrations 1, 2

Resistance Development:

• Prior ceftazidime-avibactam exposure increases risk of resistance emergence, particularly in KPC-3 producers 1, 4
• The "see-saw effect" can occur where ceftazidime-avibactam resistance develops but meropenem MICs paradoxically decrease to susceptible range 1
• Obtain rapid carbapenemase testing to guide appropriate therapy and prevent treatment delays 7, 2

Clinical Management:

• Time to appropriate therapy directly impacts outcomes in critically ill patients with bloodstream infections 2
• Source control remains a priority to optimize outcomes and shorten treatment duration 7
• Monitor for nephrotoxicity especially with polymyxins and aminoglycosides 1, 7

Site-Specific Considerations

• Pneumonia: Meropenem-vaborbactam may be preferred due to better lung penetration 2
• Urinary tract infections: Single-dose aminoglycosides can be considered as alternative for complicated UTI 1
• Bloodstream infections: Avoid tigecycline monotherapy; use newer β-lactam/β-lactamase inhibitors or combination therapy 1, 2