What broad‑spectrum antibiotics and non‑traditional agents are currently in the development pipeline, including beta‑lactam–beta‑lactamase inhibitor (BLI) combinations, oral penems, and other novel agents?

Broad-Spectrum Antibiotics Currently in Development Pipeline

The antibiotic development pipeline as of 2023 contains only 57 traditional antibacterial agents globally, with merely 12 presenting true novelty (new chemical class, mode of action, or target), and critically, only four of these novel agents demonstrate activity against WHO critical priority pathogens including multidrug-resistant Enterobacterales and Acinetobacter baumannii. 1

Current State of the Pipeline

Overall Pipeline Assessment

• By end of 2023, the global clinical pipeline included 57 traditional antibacterial agents, representing an inadequate response to the accelerating resistance crisis 1
• Only 12 compounds demonstrate genuine novelty through new chemical classes, mechanisms of action, novel targets, or absence of cross-resistance to existing antibiotics 1
• The remaining 45 agents lack novelty, creating significant concern for cross-resistance development with existing antibiotics 1
• Only four novel agents show activity against at least one WHO critical priority pathogen (MDR Enterobacterales and Acinetobacter baumannii), representing a critical gap in addressing the most urgent resistance threats 1

Key Challenges Limiting Pipeline Development

• Scientific difficulties in developing new molecules against gram-negative pathogens remain substantial 1
• Low profitability compared to other therapeutic areas continues to deter pharmaceutical investment 1
• Rapid resistance development threatens the longevity of new agents even before market introduction 1

Beta-Lactam/Beta-Lactamase Inhibitor (BL-BLI) Combinations

Recently Approved Combinations (2016-2020)

Ceftazidime/Avibactam

• Approved for multidrug-resistant Enterobacterales and carbapenem-resistant Pseudomonas aeruginosa 2
• Demonstrates activity against KPC and OXA-48 carbapenemases, making it valuable for carbapenem-sparing strategies 1
• Should be reserved for patients colonized with carbapenem-resistant Enterobacteriaceae (CRE) or upon rapid molecular identification of genetic determinants 1
• Requires metronidazole addition for anaerobic coverage in polymicrobial intra-abdominal infections 3
• Dosing: 2.5g IV every 8 hours 4

Ceftolozane/Tazobactam

• First-line option for difficult-to-treat resistant Pseudomonas aeruginosa (DTR-PA) 1
• Preserves activity against AmpC and ESBL producers 1
• Effective carbapenem-sparing option for ESBL-producing Enterobacterales 3
• Requires metronidazole for anaerobic coverage in intra-abdominal infections 3
• Dosing: 1.5-3g IV every 8 hours 4

Meropenem/Vaborbactam

• Active against KPC-producing strains but lacks activity against OXA-48 producers 1
• Provides intrinsic anti-anaerobic coverage, eliminating need for metronidazole addition 1
• Treatment option for ESBL, KPC, and AmpC-producing Enterobacterales 2
• Similar activity to meropenem alone against Pseudomonas aeruginosa 2

Imipenem/Cilastatin/Relebactam

• Alternative option for difficult-to-treat resistant Pseudomonas aeruginosa 1, 4
• Activity against ESBL, KPC, and AmpC-producing Enterobacterales 2
• Enhanced activity against Pseudomonas aeruginosa compared to imipenem alone 2
• Dosing: 1.25g IV every 6 hours 4

Agents in Active Development (Phase 2-3 Clinical Trials)

Cefepime/Zidebactam

• Demonstrates in vitro activity against metallo-β-lactamases (MBLs), addressing a critical gap 2
• Shows activity against carbapenem-resistant Pseudomonas aeruginosa 2
• Active against carbapenem-resistant Acinetobacter baumannii, one of the most challenging pathogens 2

Aztreonam/Avibactam

• Specifically designed for MBL-producing Enterobacterales 2
• Combines aztreonam's intrinsic stability to MBLs with avibactam's inhibition of serine β-lactamases 2

Meropenem/Nacubactam

• Novel mechanism combining β-lactamase inhibition with direct antibacterial activity 2
• In vitro activity against MBL-producing organisms 2

Cefepime/Taniborbactam

• Boronic acid-based inhibitor with activity against MBLs 2
• Demonstrates activity against carbapenem-resistant Pseudomonas aeruginosa 2

Sulbactam/Durlobactam

• Specifically targets carbapenem-resistant Acinetobacter baumannii 2
• Addresses critical unmet need for this WHO priority pathogen 2

Novel Beta-Lactamase Inhibitor Classes

Diazabicyclooctanones (Non-β-lactam inhibitors)

• Include avibactam, relebactam, and nacubactam 5, 6
• Active against Ambler class A (ESBLs, serine carbapenemases), class C (AmpC), and class D (OXA-48) β-lactamases 5
• Represent new scaffolds for future inhibitor design 6

Boronic Acid Inhibitors

• Include vaborbactam and taniborbactam 5, 6
• Provide alternative mechanism for β-lactamase inhibition 6

Oral Penems and Other Novel Oral Agents

Critical Pipeline Gap

• Significant deficiency exists in orally administered agents with broad-spectrum gram-negative activity 7
• This gap severely limits outpatient management options for multidrug-resistant infections 7
• No oral penems currently in advanced clinical development as of 2019-2020 data 7

Non-Traditional Agents Under Investigation

Antibody-Based Therapies

• One antibody-drug conjugate (ADC) in clinical evaluation as of October 2019 7
• Monoclonal antibodies under investigation represent novel approach to bacterial infections 7

Novel Pharmacophores

• New antibacterial pharmacophores under early investigation, though specific details limited in pipeline 7
• Focus on mechanisms distinct from traditional β-lactam activity 7

Critical Unmet Needs in the Pipeline

Metallo-β-Lactamase Coverage

• Substantial gap exists for agents active against β-metallolactamases, with only four compounds in development showing MBL activity (cefepime-zidebactam, aztreonam-avibactam, meropenem-nacubactam, cefepime-taniborbactam) 7, 2
• None of the currently approved BL-BLI combinations demonstrate activity against MBL-producing organisms 2

Specific Pathogen Gaps

• Multidrug-resistant Acinetobacter baumannii remains critically underserved, with only sulbactam-durlobactam and cefepime-zidebactam showing in vitro activity 7, 2
• New treatments for multidrug-resistant gonorrhea remain inadequate 7

Oral Administration Routes

• Severe shortage of orally bioavailable agents for outpatient management of resistant infections 7
• Limits step-down therapy options and increases healthcare costs through prolonged IV therapy requirements 7

Important Clinical Considerations

Resistance Development Concerns

• Current guidelines risk increasing usage of new antibiotics, potentially accelerating resistance development 1
• Cross-resistance likely with non-novel agents comprising majority of pipeline 1
• Antibiotic stewardship efforts insufficient to balance access strategies across countries 1

Evidence Limitations

• Most new antibiotics lack evidence in target populations (patients with actual MDR infections) by time of approval 1
• Phase 3 trials typically recruit populations with few MDR pathogens, limiting real-world applicability 1
• Resistance development assessment within approval studies inadequate 1

Access Inequality

• Critical inequality exists in global access to new antibiotics 1
• Availability and usage highly variable across countries following regulatory approval 1
• No uniform regulation for introducing new last-resort antibiotics into clinical practice 1