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

Treatment of Carbapenem-Resistant Enterobacter cloacae Complex in Urine

For carbapenem-resistant Enterobacter cloacae complex urinary tract infections, ceftazidime-avibactam 2.5 g IV every 8 hours is the 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, 3

Treatment Algorithm Based on Carbapenemase Type

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

KPC-Producing Isolates

• First-line: Ceftazidime-avibactam 2.5 g IV every 8 hours infused over 2-3 hours 1, 2, 3
• 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

OXA-48-Like Producing Isolates

• First-line: Ceftazidime-avibactam 2.5 g IV every 8 hours 1, 2, 3

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

• Mandatory combination therapy: Ceftazidime-avibactam 2.5 g IV every 8 hours PLUS aztreonam 2, 3
• Avibactam lacks activity against Class B metallo-β-lactamases, making monotherapy ineffective 3

Alternative Treatment Options

Plazomicin

• Plazomicin 15 mg/kg IV every 12 hours is recommended for complicated UTI due to carbapenem-resistant Enterobacteriaceae 1

Single-Dose Aminoglycosides

• For simple cystitis (not complicated UTI), a single-dose aminoglycoside is an alternative option 1, 3
• Aminoglycosides achieve urinary concentrations that remain above therapeutic levels for days after a single dose 1

Colistin-Based Therapy

• Colistin demonstrates high in vitro activity (95-100%) against carbapenem-resistant Enterobacteriaceae in urinary isolates 4
• However, colistin should be reserved for situations where newer agents are unavailable or ineffective 1

Clinical Efficacy Data

Ceftazidime-Avibactam

In the pivotal trial for ceftazidime-nonsusceptible urinary pathogens, ceftazidime-avibactam demonstrated superior outcomes compared to best available therapy (primarily carbapenems): 5

• Combined clinical and microbiological cure: 70.1% vs 54.0% (treatment difference 16.1%) 5
• Microbiological cure: 71.5% vs 56.9% (treatment difference 14.6%) 5
• For Enterobacter cloacae specifically: 54.5% microbiological cure rate 5

Meropenem-Vaborbactam

The TANGO-II trial demonstrated that meropenem-vaborbactam monotherapy was noninferior to best available treatment for carbapenem-resistant Enterobacteriaceae infections, including complicated UTI 1

Treatment Duration

• Complicated UTI: 7-14 days, individualized based on clinical response 3
• Simple cystitis: Single-dose aminoglycoside may be sufficient 1

Critical Pitfalls to Avoid

Inappropriate Antibiotic Selection

• Never use first or second-generation cephalosporins against Enterobacter due to intrinsic resistance 2, 3
• Avoid third-generation cephalosporins due to high likelihood of resistance development during therapy, particularly for E. cloacae 2, 3
• Do not use ceftazidime-avibactam monotherapy for MBL-producers as avibactam lacks activity against Class B enzymes 3

Tigecycline Limitations

• Avoid tigecycline monotherapy for bloodstream infections due to low serum concentrations, even if the urinary source has seeded the blood 1, 3
• Tigecycline achieves low urinary concentrations and is not approved for UTI 1

Resistance Development

• A "see-saw effect" has been observed with ceftazidime-avibactam in KPC-3 producers, where resistance to ceftazidime-avibactam emerges with concurrent restoration of carbapenem susceptibility 1
• Prior ceftazidime-avibactam administration is a risk factor for resistance development 1

Diagnostic Considerations

Rapid carbapenemase testing is crucial to guide appropriate therapy selection, as the carbapenemase type determines optimal treatment 2, 3

Local epidemiology should inform empiric choices: in China and many Asian countries, KPC-producing strains predominate, while OXA-48 is more common in certain European and Middle Eastern regions 1

Combination Therapy Considerations

For uncomplicated UTI due to carbapenem-resistant Enterobacter cloacae complex, monotherapy with newer β-lactam/β-lactamase inhibitors is generally preferred 3

Combination therapy should be reserved for: 1, 3

• Severe sepsis or septic shock from urinary source
• MBL-producing isolates (mandatory combination with aztreonam)
• High INCREMENT-CPE mortality scores

Polymyxin-based combinations reduce mortality compared to monotherapy (35.7% vs 55.5%) in severe infections, but this data primarily reflects bloodstream infections rather than isolated UTI 1, 3