What is the recommended antibiotic policy for managing infections caused by resistance organisms, such as Extended-Spectrum Beta-Lactamase (ESBL)-producing organisms, Carbapenem-Resistant Enterobacteriaceae (CRE), and Methicillin-Resistant Staphylococcus aureus (MRSA)?

Antibiotic Policy for Resistance Organisms

For carbapenem-resistant Enterobacterales (CRE), novel β-lactam/β-lactamase inhibitor combinations—specifically ceftazidime-avibactam and meropenem-vaborbactam—should be first-line therapy for KPC-producing organisms, while ceftazidime-avibactam plus aztreonam is the preferred regimen for metallo-β-lactamase (MBL)-producing strains. 1, 2

Carbapenem-Resistant Enterobacterales (CRE)

Rapid Diagnostic Testing

• Implement rapid molecular testing to identify specific carbapenemase types (KPC, MBL, OXA-48-like) immediately upon blood culture positivity, as the enzyme class dictates treatment strategy and time to active therapy directly impacts mortality in critically ill patients 1
• Knowledge of the molecular mechanism is crucial because each carbapenemase class confers different susceptibility profiles requiring distinct treatment approaches 1

KPC-Producing CRE Treatment Algorithm

First-Line Options (Strong Recommendation):

• Ceftazidime-avibactam 2.5 g IV every 8 hours infused over 3 hours 1, 2
• Meropenem-vaborbactam 4 g IV every 8 hours 1
• Clinical success rates of 60-80% have been documented with ceftazidime-avibactam for KPC-producing strains 2

Second-Line Options (Conditional Recommendation):

• Imipenem-relebactam 1.25 g IV every 6 hours 1
• Cefiderocol (clinical cure rate 50-70%) 1, 2

Avoid Traditional Regimens: Observational data from 3,352 patients treated with traditional antibiotics (colistin-based combinations) showed approximately one in three patients died with <70% achieving clinical response 1

MBL-Producing CRE (NDM, VIM, IMP)

Preferred Regimen:

• Ceftazidime-avibactam 2.5 g IV every 8 hours PLUS aztreonam (efficacy 70-90% against MBL-producing strains) 2, 3
• MBLs hydrolyze all β-lactams except monobactams (aztreonam), and classic serine β-lactamase inhibitors cannot inhibit them 1

Alternative:

• Cefiderocol may be considered as monotherapy for MBL-producing organisms 3

Site-Specific CRE Recommendations

Bloodstream Infections:

• Duration: 7-14 days 1
• Polymyxin-based combinations (colistin + tigecycline or meropenem by extended infusion) only if novel agents unavailable 1

Complicated Urinary Tract Infections:

• Duration: 5-7 days 1
• Aminoglycosides acceptable as monotherapy: gentamicin 5-7 mg/kg/day IV once daily or amikacin 15 mg/kg/day IV once daily 1

Complicated Intra-Abdominal Infections:

• Duration: 5-7 days 1
• Add metronidazole 500 mg every 6 hours to ceftazidime-avibactam for anaerobic coverage 1
• Tigecycline 100 mg IV loading dose, then 50 mg IV every 12 hours is an alternative 1

Extended-Spectrum Beta-Lactamase (ESBL)-Producing Organisms

Critical Decision Point: Severity Stratification

Critically Ill Patients or Bloodstream Infections:

• Carbapenems (meropenem, imipenem, doripenem) are strongly preferred 3
• The MERINO RCT demonstrated inferior outcomes with piperacillin-tazobactam compared to carbapenems for ESBL bacteremia 3

Non-Bacteremic UTI or Less Severe Infections:

• β-lactam/β-lactamase inhibitor combinations (piperacillin-tazobactam) are acceptable as carbapenem-sparing alternatives 3

Carbapenem-Sparing Strategy

In settings with high carbapenem-resistant K. pneumoniae prevalence:

• Avoid inappropriate carbapenem use to reduce selective pressure for CRE 1, 3
• Consider β-lactam/β-lactamase inhibitor combinations for non-critically ill patients 3
• Extended use of third-generation cephalosporins should be discouraged due to ESBL selection pressure 3, 4

Common Pitfall

• Do not use fluoroquinolones (ciprofloxacin + metronidazole) empirically for hospital-acquired intra-abdominal infections or critically ill patients with ESBL risk factors 1
• Overuse of carbapenems leads to CRE emergence; balance individual patient needs against stewardship principles 3, 4

Methicillin-Resistant Staphylococcus aureus (MRSA)

Complicated Skin and Soft Tissue Infections

• Daptomycin 4 mg/kg IV once every 24 hours for 7-14 days 5
• Administer by IV injection over 2 minutes or IV infusion over 30 minutes in adults 5

MRSA Bacteremia and Right-Sided Endocarditis

• Daptomycin 6 mg/kg IV once every 24 hours for 2-6 weeks 5
• Limited safety data exist for therapy >28 days 5

Critical Limitations

• Daptomycin is NOT indicated for pneumonia (inactivated by pulmonary surfactant) 5
• Not indicated for left-sided endocarditis due to poor outcomes in clinical trials 5
• Not studied in prosthetic valve endocarditis 5

Carbapenem-Resistant Acinetobacter baumannii (CRAB)

Pneumonia

• Colistin (with or without carbapenems) PLUS adjunctive inhaled colistin 1
• Colistin dosing: 5 mg colistin base activity (CBA)/kg IV loading dose, then 2.5 mg CBA × (1.5 × CrCl + 30) IV every 12 hours 1
• Do NOT use tigecycline monotherapy for CRAB pneumonia (strong recommendation against) 1

Bloodstream Infection

• Colistin-carbapenem based combination therapy 1
• Combination therapy preferred over monotherapy for synergistic effect and resistance prevention 1

Difficult-to-Treat Resistant Pseudomonas aeruginosa (DTR-PA)

Definition

• Non-susceptibility to piperacillin-tazobactam, ceftazidime, cefepime, aztreonam, meropenem, imipenem-cilastatin, ciprofloxacin, and levofloxacin 1

Treatment Options

• Ceftolozane-tazobactam 1.5-3 g IV every 8 hours (3 g dose for hospital-acquired/ventilator-associated pneumonia) 1
• Ceftazidime-avibactam 2.5 g IV every 8 hours 1
• Imipenem-cilastatin-relebactam 1.25 g IV every 6 hours 1
• Colistin monotherapy or combination therapy 1

Duration

• 5-10 days for complicated UTI and complicated intra-abdominal infection 1
• 10-14 days for hospital-acquired/ventilator-associated pneumonia and bloodstream infection 1

General Management Principles

Mandatory Consultation

• Infectious disease consultation is highly recommended for all MDRO infections (strong recommendation) 1

Pharmacokinetic Optimization

• Prolonged infusion of β-lactams (3-hour infusion) for pathogens with high MIC (strong recommendation) 1
• Extended-infusion meropenem suggested if MIC ≥8 mg/L 1

Antimicrobial Stewardship

• Perform antimicrobial susceptibility testing or genotypic characterization to guide therapy 1
• Reassess when microbiological results available and consider de-escalation when appropriate 3
• De-escalation associated with lower mortality in ICU patients 3

Resistance Surveillance

• Resistance to ceftazidime-avibactam in KPC-producing isolates reported at 0-12.8% frequency 2
• Mutations in blaKPC-3 gene (D179Y variants) confer 4-16 fold MIC increase to ceftazidime-avibactam 2

Source Control

• Effective source control is essential alongside antimicrobial therapy (reduces mortality by 30-50%) 2
• Surgical or radiological drainage of collections and removal of infected devices are crucial (clinical success rate 80-90%) 2