Novel Beta-Lactams and Beta-Lactamase Inhibitors: Challenges for Laboratory Diagnostics
Speaker: Dr Anna Sramkova
Key Findings
Overview of Beta-Lactam/Beta-Lactamase Inhibitor Combinations:
Newly approved beta-lactam/beta-lactamase inhibitor (BL/BLI) agents were discussed for their use in complicated intra-abdominal infections (cIAIs), complicated urinary tract infections (cUTIs), hospital-acquired bacterial pneumonia (HABP), and ventilator-associated bacterial pneumonia (VABP).
|
Agent |
Composition |
Indications |
|
Ceftazidime/avibactam (CAV)
|
3rd gen. cephalosporin + new reversible BLI (Diazabicyclooctanes-DBOs) |
cIAIs and cUTIs, HABP/VABP
|
|
Ceftalozane/tazobactam (CET) |
5th gen. cephalosporin + BLI |
cIAIs and cUTIs, HABP/VABP |
|
Meropenem/vaborbactam (MEV) |
Carbapenem + boronic acid + non-beta- lactam BLI |
cIAIs and cUTIs, HABP/VABP |
|
Imipenem/relebactam (IPR)
|
Carbapenem + non-beta- lactam bicyclic DBO BLI |
cIAIs and cUTIs, HABP/VABP |
|
Cefepime/enmetazobactam (CEE)
|
4th gen. cephalosporin + penicillanic acid sulfon-based BLI |
cUTIs, HABP/VABP, bacteraemia |
|
Aztreonam/avibactam (AZA) |
Monobactam + new reversible BLI (DBOs) |
cIAIs and cUTIs, HABP/VABP |
|
Sulbactam/durlobactam (SUD) |
Sulfone BLI + non-B-lactam DBO BLI |
HABV/VABP (A. baumannii-calcoaceticus complex)
|
|
Cefideracol (CID)
|
Novel siderophore cephalosporin |
cUTIs, HABP/VABP |
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Antibacterial Spectrum: Most new agents demonstrated strong efficacy against Enterobacterales and Pseudomonas aeruginosa, while some showed selective coverage for anaerobic or limited gram-positive organisms. Cefiderocol and sulbactam-durlobactam were highlighted for activity against Acinetobacter baumannii and carbapenem-resistant strains.
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Mechanisms of Resistance: Four main resistance mechanisms were outlined:
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Enzymatic resistance (mutations or overproduction of genes/enzymes)
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Reduced cell permeability (loss of porins: OmpK35/36 in K. pneumoniae, OprD in P. aeruginosa, and OmpC/F in Enterobacter spp.)
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Efflux pump overexpression, especially in Pseudomonas
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Altered penicillin-binding proteins (PBP) (PBP2/PBP3 mutations)
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Others: Cefiderocol-specific resistance due to siderophore receptor mutation
Diagnostic Workflow:
Specimens from blood cultures or screening swabs processed directly using PCR or positive haemocultures, or grown on selective media (often chromogenic). Pathogen Identification is followed by antimicrobial susceptibility testing (AST), performed via broth microdilution (BMD), E-tests, disk diffusion testing (DDT), and automated systems. Rapid AST from blood cultures was supported. Direct resistance testing was performed through lateral flow immunoassay, NP tests, MALDI-TOF hydrolysis assay, and PCR.
Carbapenemase Detection:
Various methods, such as inhibition-based disk tests, modified carbapenem inactivation method (mCIM), NP tests, lateral flow assay, MALDI-TOF MS, and PCR, were utilized to detect carbapenemases.
Algorithm for Testing Carbapenemase Production:
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Testing for Carbapenemase Production:
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KPC: Treated with cefetazidime-avibactam, meropenem-vaborbactam, imipenem-meropenem, and others,
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OXA-48 treated with cefetazidime-avibactam, aztreonam/avibactam, and others.
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MBL treated with aztreonam/avibactam and cefiderocol.
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Non-Carbapenemase Producers:
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For Enterobacterales and Pseudomonas aeruginosa: Cefetazidime-avibactam, meropenem-vaborbactam, and others.
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For Acinetobacter baumannii: Cefiderocol and sulbactam-durlobactam.
Phenotypic and Rapid Testing Methods:
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Breakpoints for Enterobacterales, Pseudomonas aeruginosa, and Acinetobacter baumannii were evaluated. Cefiderocol lacked clear breakpoints against some pathogens, complicating interpretation. Disc diffusion was noted to overestimate resistance to ceftazidime-avibactam.
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Rapid methods like lateral flow assay and NP tests have been gaining popularity due to their speed and ease of use. Novel methods, including flow cytometry, microfluidics, and morphokinetic analysis, are emerging to reduce time-to-result.
Clinical Significance:
The session underscored the clinical importance of integrating rapid diagnostics and targeted therapy in managing infections. Emerging availability of novel BL/BLI agents and advanced susceptibility testing offers hope in overcoming resistance barriers. Adoption of algorithm-based approaches and stewardship strategies will be critical in optimizing outcomes for critically ill patients.
Clinical perspectives of novel beta-lactams and beta-lactamase inhibitors
Speaker: Dr Parikshit Prayag
Introduction:
Emerging resistance mechanisms in gram-negative pathogens have prompted the clinical adoption of novel β-lactam and β-lactamase inhibitors (BL/BLI) combination. The clinical utility, resistance profiles, and pharmacodynamic considerations of ceftazidime-avibactam, imipenem-relebactam, meropenem-vaborbactam, and newer agents like cefiderocol, sulbactam-durlobactam, and zidebactam-based therapies were reviewed.
Ceftazidime–Avibactam ± Aztreonam:
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Avibactam has been shown to inhibit class A extended-spectrum β-lactamases (ESBL) like CTX-M, SHV, TEM, Class A carbapenemases like Klebsiella pneumoniae carbapenemase (KPC) and Guiana extended-spectrum (GES) enzymes along with Class C β-lactamases (AmpC-type, and certain Class D enzymes (OXA-48) but remains ineffective against Class B enzymes metallo-β-lactamases (MBLs) like New Delhi metallo-β-lactamase (NDM).
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Susceptibility to ceftazidime–avibactam has been observed in ~50% of carbapenem-resistant Klebsiella pneumoniae and ~25% of Escherichia coli. Resistance has been attributed to ESBL/OXA-48 mutations and porin defects.
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Addition of aztreonam has been found to overcome MBL-mediated resistance, especially in isolates co-producing multiple enzymes (SHV, CTX-M, NDM, OXA-48). However, emerging penicillin-binding protein 3 (PBP3) insertions may reduce aztreonam efficacy, particularly in E. coli.
Clinical Evidence and PK/PD:
Ceftazidime–avibactam-based regimens have outperformed polymyxin-based therapies, demonstrating superior clinical outcomes in confirmed susceptibility. A meta-analysis reported reduced 30-day mortality with ceftazidime–avibactam + aztreonam in NMD-producing Enterobacterales. The combination showed favorable pharmacokinetics–pharmacodynamics (PK-PD) with prostate and CNS penetration. An aztreonam–avibactam ratio of 3:1 has been suggested for optimal efficacy.
Imipenem–Relebactam and Meropenem–Vaborbactam:
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Both combinations were effective against Class A and Class C enzymes but not against Class B (MBLs) and Class D (OXA-48) enzymes.
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All three agents— ceftazidime–avibactam, imipenem–relebactam, and meropenem–vaborbactam—have been found effective against KPC-producing isolates.
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No activity has been demonstrated against MBL producers. Among these combinations, only ceftazidime-avibactam showed efficacy against OXA-48.
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Imipenem–relebactam has demonstrated superior efficacy to meropenem–vaborbactam against Pseudomonas, attributed to enhanced minimum inhibitory concentrations (MICs) and reduced impact from non-enzyme resistance.
Cefiderocol:
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Broad in vitro activity has been observed, but resistance has been increasingly reported among NDM-positive Enterobacterales (38%) and Acinetobacter (44%).
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Higher mortality rates have been observed in clinical studies.
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Despite favorable CNS penetration and renal excretion, its clinical use is limited due to emerging resistance.
Ceftolozane–Tazobactam:
Activity has been demonstrated against ESBL- and AmpC-producing Pseudomonas, especially in cases with efflux/porin-related resistance. However, lack of efficacy has been noted against carbapenemase- producing isolates commonly found in India.
Sulbactam–Durlobactam:
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Sulbactam has shown to effectively target PBPs 1 & 3 in Acinetobacter, while durlobactam has been found to inhibit Class A, C, and several Class D enzymes (OXA-23/-24/-51/-58).
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In the ATTACK trial, lower mortality was reported with sulbactam–durlobactam + imipenem vs. colistin. Triple therapy with imipenem has shown synergistic activity in non-MBL strains.
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Its clinical utility in India has been limited due to the absence of MBL inhibition, where co-production of NDM and OXA enzymes is frequently seen.
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The combination has been recommended by IDSA for carbapenem-resistant Acinetobacter baumannii (CRAB) infections; alternative options include ampicillin–sulbactam + polymyxin or minocycline.
Emerging Agents:
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Zidebactam/Cefepime–Zidebactam: Activity has been demonstrated against ESBLs and PBP3-mutated E. coli, while no efficacy has been noted against MBLs and limited activity has been seen against OXA-48 (particularly OXA-181).
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Cefepime–Taniborbactam : Activity has been shown against Class A, C, D, and some Class B enzymes while reduced effectiveness has been reported in NDM-expressing E. coli with PBP3 and porin mutations.
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Other Pipeline Combinations: Combinations such as meropenem- nacubactam, cefiderocol–enmetazobactam, and imipenem–relebactam–taniborbactam are being evaluated in advanced clinical trials.
IDSA Guidelines Summary:
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KPC producing Carbapenem-resistant Enterobacteriaceae (CRE): Ceftazidime-avibactam, imipenem-relebactam, or meropenem-vaborbactam
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NDM-producing CRE: Ceftazidime-avibactam + azetronam or cefiderocol (high resistance concern)
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OXA-48-producing CRE: Ceftazidime-avibactam monotherapy
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MBL-producing Pseudomonas: Aztreonam; limited data
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Difficult-to-treat (DTR) Pseudomonas: Ceftolozane-tazobactam
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KPC-producing Pseudomonas: imipenem-relebactam or ceftazidime-avibactam
Clinical Implications:
In the Indian clinical setting, where co-production of resistance enzymes and non-enzymatic resistance mechanisms are highly prevalent, BL/BLI therapy must be selected based on local resistance profiles and enzyme epidemiology. Continued PK/PD optimization, real-world resistance surveillance, and rational use of these agents will be crucial to sustain the effectiveness of current and emerging agents.
ESCMID, April 11-15, 2025, Vienna
