Current impact:

• 700,000 deaths annually attributed to AMR
• MDR organisms have limited treatment options
• Resistance detected after every new antibiotic introduction

Projected impact:

• 10 million deaths/year by 2050 if unchecked
• Economic burden estimated at $100 trillion

Timeline:

• FDA approval obtained for new aminoglycoside targeting resistant gram-negatives
• Drug reserved as “last resort” therapy (appropriate stewardship)
• Low sales volume due to targeted use
• Company could not sustain itself financially
• The lesson: Push incentives support development but fail to ensure post-approval sustainability
• New focus: Pull incentives (subscription models) that reward societal value rather than sales volume

Diazabicyclooctanes (DBOs):

• Avibactam
• Relebactam
• Durlobactam (OXA activity!)
• Zidebactam

Mechanism: Covalent, reversible binding to serine β-lactamases

Boronates:

• Vaborbactam
• Taniborbactam (MBL activity!)
• Xeruborbactam (ultra-broad spectrum!)

Mechanism: Reversible binding, broader spectrum including some MBLs

Sulbactam:

• Historically a β-lactamase inhibitor
• Intrinsic activity against A. baumannii
• Binds PBP 1a/1b and PBP3
• Limited by contemporary resistance by class A,C and D enzymes

Durlobactam:

• Novel DBO inhibitor
• Inhibits Class A, C, and D enzymes
• Unique OXA family activity
• Direct antibacterial activity via PBP2

Key points:

✓ First agent specifically developed for CRAB

✓ Novel OXA-family inhibition

✓ Mortality benefit suggested vs. colistin

✓ Significantly reduced nephrotoxicity

✓ FDA approved May 2023

Limitations:

• Limited to A. baumannii
• No activity against MBL-producers
• Requires IV administration
• Background imipenem in trials

The problem:

• MBLs (NDM, VIM, IMP) hydrolyze all β-lactams
• No approved MBL inhibitor exists
• MBL-producers often co-produce serine β-lactamases

The solution:

• Aztreonam is intrinsically stable to MBLs
• Avibactam inhibits co-produced serine enzymes
• Combination restores aztreonam activity

Enmetazobactam:

• N-methyl derivative of tazobactam
• Net-neutral zwitterion
• Enhanced cell wall penetration
• Class A enzyme inhibition

Activity:

• CTX-M, TEM, SHV variants
• NOT serine carbapenemases (KPC)
• No advantages for P. aeruginosa

Target population:

Primarily ESBL-producing Enterobacterales

Primary Analysis (n = 678):

Δ = 21.2% (95% CI: 14.3-27.9%)

• Noninferiority achieved ✓
• Hierarchical superiority achieved ✓

ESBL Subset:

• FEP-ENM: 73.7%
• PIP-TAZ: 51.5%

Where FEP-ENM shines

Taniborbactam:

• Bicyclic boronate inhibitor
• Class A, C, D serine enzymes
• Class B MBL activity:
  • VIM: Yes ✓
  • Most NDM: Yes ✓
  • IMP: Limited
• MDR P.aeruginosa PDC and PER-1/2

Dosing:

• 2.5 g (2 g + 500 mg)
• Every 8 hours
• 2-hour infusion

CERTAIN-1 Trial:

Phase 3 in cUTI/AP showed superiority to meropenem

β-Lactam Enhancer:

• Inhibits class A and C ß-lactamases

• Strong PBP2 binding

• Complements cefepime’s PBP3, PBP1a/1b binding

• Synergistic cell wall disruption

Spectrum:

• Enterobacterales (including CRE)
• XDR P. aeruginosa (including MBL) despite lack of activity against Class B enzymes
• A. baumannii complex

Xeruborbactam:

• Tricyclic boronate inhibitor
• Ultra-broad spectrum BLI:
  • Class A (KPC, CTX-M, TEM, SHV) ✓
  • Class B MBLs (NDM, VIM, IMP) ✓
  • Class C (AmpC) ✓
  • Class D (OXA-23, OXA-48) ✓
• Broadest BLI spectrum in development

Dosing:

• 2-1 g q8h
• 3-hour infusion
• Renal dose adjustment required

Key Trials:

• Phase 3 in cUTI/AP and HABP/VABP
• Targets CRE, MBL-producers, and CRAB

Spectrum:

• MDR Enterobacterales
• ESBL-producers
• Selected gram-positives
• NOT carbapenemase-producers

ADAPT-PO Trial:

• Tebipenem 600 mg PO q8h
• vs. ertapenem 1 g IV daily
• Noninferiority achieved
• Similar safety profile

Spectrum:

• MDR Enterobacterales
• ESBL-producers
• AmpC-producers
• NOT carbapenemase-producers

Development Path:

• Initial Phase 3: Variable results
• REASSURE Trial: Noninferiority to amoxicillin-clavulanate achieved
• NDA resubmitted 2024

Mechanism:

• Inhibits PBPs including PBP2a
• Active against MRSA
• Broad gram-positive/gram-negative activity

Approved Indications:

• S. aureus bacteremia
• Right-sided endocarditis
• ABSSSI
• Community-acquired pneumonia
• Role in HAP/VAP- higher mortality than comparator

Dosing:

• 500 mg IV over 2 hours
• Every 6-8 hours
• Renal adjustment required

ERADICATE Trial:

Noninferior to daptomycin for complicated S. aureus bacteremia

Design Goal:

Reduce myelosuppression and serotonergic effects
seen with linezolid/tedizolid

Spectrum:

• MRSA
• VRE
• Penicillin-resistant S. pneumoniae

Phase 3 (cSSTI):

Noninferior to linezolid with potentially better safety

Availability:

• IV and oral formulations
• Global trial for diabetic foot infection ongoing

Mechanism:

• Enoyl-acyl carrier protein reductase (FabI) inhibitor
• Targets fatty acid synthesis
• Highly selective for S. aureus

Not active against:

• Other gram-positives
• Gram-negatives

Clinical Development:

• Phase 2: Noninferior to vancomycin/linezolid for staphylococcal ABSSSI
• Planned: Bone and joint infection trials

Advantages:

• Narrow spectrum = antimicrobial stewardship friendly
• Novel MOA

Mechanism:

• Inhibits DNA gyrase AND topoisomerase IV
• Distinct binding site from fluoroquinolones
• Active against FQ-resistant strains

Spectrum:

• Gram-positives
• Gram-negatives including MDR E. coli
• MDR N. gonorrhoeae

Dosing (oral):

• uUTI: 1500 mg BID × 5 days
• Gonorrhea: 3000 mg × 2 doses (10-12h apart)

Phase 3 Results:

• Noninferior to nitrofurantoin (uUTI)
• Noninferior to ceftriaxone + azithromycin (gonorrhea)

Mechanism:

• Type II topoisomerase inhibitor
• Unique binding sites on DNA gyrase
• Distinct from fluoroquinolones

Key advantage:

Active against strains resistant to:

• Cephalosporins
• Fluoroquinolones
• Other drug classes

Phase 3 Results:

Single 3-g oral dose:

• Noninferior to IM ceftriaxone + oral azithromycin
• High cure rates for urogenital/rectal infection
• Lower efficacy for pharyngeal infection