Treatment of ESBL-Producing Bacterial Infections: BLBLI vs Carbapenems
For critically ill patients with serious ESBL infections (particularly bloodstream infections), carbapenems remain the preferred first-line treatment, while beta-lactam/beta-lactamase inhibitor combinations (BLBLIs) should be reserved for less severe infections, non-bacteremic urinary tract infections, or as carbapenem-sparing alternatives in settings with high carbapenem resistance. 1, 2
Critical Decision Points Based on Infection Severity and Site
Severe/Life-Threatening Infections (BSI, Sepsis, High-Risk Patients)
Group 2 carbapenems (meropenem, imipenem, doripenem) are strongly preferred for critically ill patients with high bacterial loads, bloodstream infections, or when treating serious infections 1
Piperacillin-tazobactam should no longer be considered an alternative to carbapenems for definitive treatment of bloodstream infections due to ESBL-producing strains 3
The evidence supporting carbapenems in this context comes from the MERINO RCT, which demonstrated inferior outcomes with piperacillin-tazobactam compared to carbapenems for ESBL bacteremia 4
Moderate Severity/Non-Bacteremic Infections
Piperacillin-tazobactam may be considered for stable patients with mild-to-moderate infections originating from urinary or biliary sources, particularly when the MIC is ≤4 mg/L 3
For non-bacteremic urinary tract infections due to ESBL-producing Enterobacteriaceae, piperacillin-tazobactam demonstrates comparable clinical response rates (74.4% vs 80.9%) to carbapenems 5
Newer BLBLIs (ceftazidime-avibactam, ceftolozane-tazobactam) are carbapenem-sparing alternatives that should be reserved for multidrug-resistant infections to preserve their activity 1, 3, 6
Urinary Tract Infections Specifically
Carbapenems remain first-line for serious ESBL UTIs, while carbapenem-sparing alternatives should be considered for less severe infections 2
Piperacillin-tazobactam is an effective alternative for non-bacteremic UTIs caused by ESBL-producing organisms 2, 5
Intravenous fosfomycin has high-certainty evidence for complicated UTIs with or without bacteremia 2
Aminoglycosides can be effective but duration should be limited to avoid nephrotoxicity 2
Carbapenem-Sparing Strategies: When and Why
Settings Requiring Carbapenem Avoidance
In areas with high carbapenem-resistant Klebsiella pneumoniae prevalence, carbapenem-sparing regimens are strongly recommended to reduce selection pressure 4, 1, 2
The inappropriate use of carbapenems should be avoided to reduce selective pressure and association with the increase in carbapenem-resistant Enterobacteriaceae (CRE) 4
Carbapenem-sparing treatment is particularly recommended in settings where there is high incidence of carbapenem-resistant K. pneumoniae 4
Specific BLBLI Options for Carbapenem Sparing
Ceftazidime-avibactam plus metronidazole has demonstrated activity against ESBL-producers and some KPC-producing organisms 1
Ceftolozane-tazobactam is the drug of choice for treating MDR/XDR Pseudomonas aeruginosa infections 6
Ceftazidime-avibactam is the best drug available for treating KPC and OXA-48 carbapenemase-producing Enterobacteriaceae 6
Both ceftolozane-tazobactam and ceftazidime-avibactam are carbapenem-sparing agents for treating ESBL-producing Enterobacteriaceae 6
Special Resistance Mechanisms
For metallo-β-lactamase (MBL)-producing Enterobacterales, ceftazidime-avibactam plus aztreonam is strongly recommended 1
Cefiderocol may be considered as an alternative option for MBL-producing organisms 1
Group 1 carbapenems like ertapenem have activity against ESBL-producing pathogens but are not active against Pseudomonas aeruginosa 1
Critical Factors Influencing Treatment Choice
MIC Considerations
Piperacillin-tazobactam might represent an alternative for step-down therapy or for low-to-moderate severity infection when the MIC is ≤4 mg/L 3
The isolate's MIC is a key factor affecting the choice to use BLBLIs 7
Source of Infection
Different susceptibility testing methods and definitions of ESBL vary across studies, and the source of infection interacts with bacterial type 4
For intra-abdominal infections, the main resistance problem is posed by ESBL-producing Enterobacteriaceae 4
Local Epidemiology
Treatment selection must consider local epidemiology of resistance patterns 1, 2
Local bacterial ecology determines whether anti-ESBL coverage is warranted even in community-acquired infections 4
Common Pitfalls to Avoid
Overuse of carbapenems leads to selection pressure and emergence of carbapenem-resistant organisms 1, 2
Extended use of cephalosporins should be discouraged in settings with high incidence of ESBL-producing Enterobacteriaceae due to selective pressure 4, 2
Fluoroquinolones should be avoided in regions with fluoroquinolone resistance rates >20% among E. coli isolates 2
Extended use of fluoroquinolones should be discouraged because of selective pressure (mainly for ESBL-producing Enterobacteriaceae and MRSA) 4
Delayed source control can lead to inadequate treatment of intra-abdominal infections 1
Observational Evidence Nuances
Nine retrospective observational studies comparing carbapenems with carbapenem-sparing regimens (mainly BLBLIs, quinolones, aminoglycosides) found no significant outcome difference, but sample sizes were small with residual confounding 4
The overall certainty of evidence for lack of advantage for carbapenems from observational studies was judged as low for low-risk BSI and very low for high-risk BSI 4
This observational evidence supports no significant advantage to carbapenems in real-life treatment of ESBL BSI, but the certainty is very low 4
Antimicrobial Stewardship Considerations
Rapid identification of the specific resistance mechanism is crucial for optimizing therapy 1
Antibiotic de-escalation has been associated with lower mortality rates in ICU patients and is a key practice for antimicrobial stewardship 4
Patients should be reassessed when microbiological testing results are available, and antimicrobial de-escalation should be considered when appropriate 2