What is the recommended treatment for infections caused by Enterobacterales?

Treatment of Enterobacterales Infections

Resistance-Based Treatment Algorithm

The treatment of Enterobacterales infections must be stratified by resistance pattern and infection severity, with carbapenems remaining the gold standard for third-generation cephalosporin-resistant strains in severe infections, while newer beta-lactam/beta-lactamase inhibitor combinations are reserved for carbapenem-resistant organisms. 1

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Third-Generation Cephalosporin-Resistant Enterobacterales (3GCephRE)

Severe Infections and Bloodstream Infections

• Carbapenems (imipenem or meropenem) are strongly recommended as targeted therapy for patients with bloodstream infections and severe infections due to 3GCephRE 1
• Ertapenem may be substituted for imipenem or meropenem in bloodstream infections without septic shock 1
• Fourth-generation cephalosporins (cefepime) can be used if Extended-Spectrum beta-lactamase (ESBL) is absent 1

Non-Severe, Low-Risk Infections

• For low-risk, non-severe infections, carbapenem-sparing options include piperacillin-tazobactam, amoxicillin-clavulanate, or fluoroquinolones (where susceptibility permits) 1
• Avoid first and second-generation cephalosporins entirely—they are ineffective against Enterobacter infections 1, 2
• Avoid third-generation cephalosporins due to high likelihood of resistance development during therapy, particularly for E. cloacae 1, 2

Complicated Urinary Tract Infections (cUTI)

• For cUTI without septic shock, aminoglycosides (when active in vitro) for short durations or IV fosfomycin are conditionally recommended 1
• Cotrimoxazole may be considered for non-severe cUTI 1

Step-Down Therapy

• Once patients are stabilized following carbapenem therapy, step-down to older beta-lactam/beta-lactamase inhibitors, fluoroquinolones, cotrimoxazole, or other antibiotics based on susceptibility patterns is good clinical practice 1

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Carbapenem-Resistant Enterobacterales (CRE)

KPC-Producing CRE

• First-line options are ceftazidime-avibactam 2.5g IV q8h infused over 2-3 hours OR meropenem-vaborbactam 4g IV q8h infused over 3 hours 1, 2
• Imipenem-relebactam or cefiderocol are potential alternatives 1
• Meropenem-vaborbactam is preferred for pneumonia due to better lung penetration 2
• Meropenem-vaborbactam monotherapy has shown higher clinical cure rates and decreased mortality compared to best available therapy 2

OXA-48-Like Producing CRE

• Ceftazidime-avibactam 2.5g IV q8h should be the first-line treatment option 1, 2

Metallo-Beta-Lactamase (MBL)-Producing CRE

• Ceftazidime-avibactam plus aztreonam is strongly recommended as first-line therapy 1, 2
• This combination displayed in vitro synergy and resulted in 30-day mortality of 19.2% versus 44% with other regimens (P = 0.007) 1
• Cefiderocol may be considered as an alternative, with 75% clinical cure in MBL-producing CRE subgroup 1
• Highest mortality rates were observed with colistin-containing regimens 1

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Critical Antibiotic Stewardship Considerations

Reserve New Beta-Lactam/Beta-Lactamase Inhibitors

• The new beta-lactam/beta-lactamase inhibitors should be avoided for 3GCephRE infections due to antibiotic stewardship considerations—they are reserved for extensively resistant bacteria 1

Avoid Tigecycline in Specific Situations

• Tigecycline is not recommended for infections caused by 3GCephRE 1
• Avoid tigecycline monotherapy for bloodstream infections due to low serum concentrations 2
• Tigecycline carries an increased all-cause mortality risk (0.6% absolute increase, 95% CI 0.1-1.2) and should be reserved only when alternative treatments are not suitable 3

Rapid Molecular Testing

• Rapid molecular identification of carbapenemase type is crucial for guiding appropriate therapy 1, 2
• Molecular tests associated with rapid communication reduce median time to optimal antibiotic therapy from 14.7 hours to 4.7 hours 1
• In patients colonized or potentially infected with ESBL-producing or CRE, molecular tests lead to faster administration of appropriate therapy and can reduce mortality 1

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Intra-Abdominal Infections Specific Considerations

Empiric Coverage Requirements

• Antimicrobial regimens must have activity against gram-negative Enterobacteriaceae, gram-positive cocci, and obligate anaerobes 1
• Metronidazole should be administered as the preferred anti-anaerobic agent in combination regimens 1

Source Control Priority

• Patients with complicated intra-abdominal infections and sepsis/septic shock require urgent source control procedures 1
• Damage control surgery should be considered in selected critically ill patients with ongoing sepsis 1

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Common Pitfalls to Avoid

• Never delay appropriate therapy—time to active antibiotic therapy influences outcomes in critically ill patients with bloodstream infections 2
• Do not use cephamycins (cefoxitin, cefmetazole) or cefepime for 3GCephRE infections—insufficient evidence supports their use 1
• Fluoroquinolones are no longer appropriate first-line treatment in many geographic regions due to resistance prevalence 1
• Piperacillin-tazobactam use in ESBL infections is controversial and should be avoided in severe infections 1

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Duration of Therapy

• For complicated skin and skin structure infections or complicated intra-abdominal infections: 5-14 days 3
• For community-acquired bacterial pneumonia: 7-14 days 3
• Antimicrobial therapy should continue until further debridement is no longer necessary, the patient has improved clinically, and fever has been resolved for 48-72 hours 1
• Procalcitonin monitoring may be useful to guide antimicrobial discontinuation 1