Carbapenem Treatment for Severe Bacterial Infections
Primary Recommendation
For patients with bloodstream infections and severe infections caused by third-generation cephalosporin-resistant Enterobacterales (3GCephRE), use a carbapenem (imipenem or meropenem) as targeted therapy. 1
Carbapenem Selection Algorithm
For Third-Generation Cephalosporin-Resistant Enterobacterales (3GCephRE)
Severe infections with septic shock:
- Imipenem or meropenem are strongly recommended as first-line targeted therapy 1
- These provide superior outcomes compared to alternative agents in critically ill patients 1
Bloodstream infections without septic shock:
- Ertapenem may be used instead of imipenem or meropenem 1
- Ertapenem is effective against ESBL-producing pathogens but lacks activity against Pseudomonas aeruginosa and Enterococcus species 2
Non-severe, low-risk infections:
- Consider non-carbapenem alternatives (piperacillin-tazobactam, amoxicillin/clavulanic acid, or quinolones) to preserve carbapenem utility 1
- For complicated urinary tract infections specifically, cotrimoxazole may be appropriate 1
Carbapenem-Resistant Enterobacterales (CRE)
Severe CRE infections:
- First-line: Meropenem-vaborbactam or ceftazidime-avibactam if active in vitro 1
- These newer beta-lactam/beta-lactamase inhibitor combinations show moderate-certainty evidence for efficacy 1
CRE with metallo-beta-lactamases (MBL) or resistance to all other options:
- Cefiderocol is conditionally recommended 1
- For MBL-producing CRE: Aztreonam plus ceftazidime-avibactam combination therapy provides moderate-certainty evidence for reduced mortality 1
Non-severe CRE infections:
- Use older antibiotics active in vitro (aminoglycosides, fosfomycin) based on susceptibility patterns 1
- For complicated urinary tract infections, aminoglycosides (including plazomicin) are preferred over tigecycline 1
Critical caveat: Do not use combination therapy with newer agents (ceftazidime-avibactam, meropenem-vaborbactam, cefiderocol) when monotherapy is effective 1
Carbapenem-Resistant Pseudomonas aeruginosa (CRPA)
Severe infections:
- Ceftolozane-tazobactam if active in vitro (conditional recommendation, very low evidence) 1
- Insufficient evidence exists for imipenem-relebactam, cefiderocol, and ceftazidime-avibactam at this time 1
When using older agents (polymyxins, aminoglycosides, fosfomycin):
- Use combination therapy with two in vitro active drugs 1
- No specific combination can be recommended over others 1
Carbapenem-Resistant Acinetobacter baumannii (CRAB)
CRAB susceptible to sulbactam with pneumonia:
- Ampicillin-sulbactam is suggested 1
CRAB resistant to sulbactam:
- Polymyxin or high-dose tigecycline if active in vitro 1
- Cefiderocol is conditionally recommended AGAINST for CRAB (low-certainty evidence) 1
Severe, high-risk CRAB infections:
- Combination therapy with two in vitro active antibiotics (polymyxin, aminoglycoside, tigecycline, sulbactam combinations) 1
- Strong recommendation AGAINST polymyxin-meropenem or polymyxin-rifampin combinations (high/moderate evidence) 1
Special Carbapenem Considerations
High-Dose Extended-Infusion Meropenem
For CRE with meropenem MIC ≤8 mg/L:
- High-dose extended-infusion meropenem (6g/day, 3-hour infusion) as part of combination therapy may be considered when newer agents are unavailable 1
- Italian cohort data showed improved 14-day survival with this approach, even at MICs up to 16 mg/L 1
For CRAB with meropenem MIC ≤8 mg/L:
- High-dose extended-infusion carbapenem dosing as part of combination therapy is good clinical practice 1
Meropenem vs. Imipenem Selection
Meropenem advantages:
- Better CNS tolerability than imipenem (lower seizure risk) 2
- Slightly greater activity against gram-negative bacilli 2, 3
- Can be administered as IV bolus or infusion 2
- Only carbapenem approved for bacterial meningitis 4
Imipenem advantages:
- Somewhat greater in vitro activity against gram-positive cocci 3
Critical Pitfalls to Avoid
Do NOT use tigecycline for:
- Infections caused by 3GCephRE (strong recommendation against) 1
- Bloodstream infections or hospital-acquired/ventilator-associated pneumonia caused by CRE 1
Do NOT use newer beta-lactam/beta-lactamase inhibitors for 3GCephRE:
- Reserve these agents for extensively resistant bacteria due to antibiotic stewardship considerations 1
Do NOT use cephamycins or cefepime for 3GCephRE infections 1
Avoid carbapenem-based combination therapy for CRE unless meropenem MIC ≤8 mg/L with high-dose extended-infusion dosing 1
Antibiotic Stewardship Principles
Step-down therapy after clinical stabilization:
- Following carbapenems for 3GCephRE, transition to older beta-lactam/beta-lactamase inhibitors, quinolones, cotrimoxazole, or other antibiotics based on susceptibility patterns 1
For pan-resistant carbapenem-resistant gram-negative bacteria:
- Treat with the least resistant antibiotic(s) based on MICs relative to breakpoints 1
Dosing considerations: