Table I.

Examples of Approved Antimicrobials and Antimicrobials in Development for Treatment of CRE.

Antibiotic	Category	Stage of Development	Target; Mechanism of Action	Carbapenemase Spectrumg	Major Resistance Mechanism
Apramycina	Aminoglycoside	Phase 1	30S ribosomal subunit; Protein synthesis inhibition	N.A.	Aminoglycoside 3-N-acetyltransferase subtype IV
Plazomicin	Aminoglycoside	FDA-approved	30S ribosomal subunit; Protein synthesis inhibition	N.A.	16S rRNA ribos om al methyltransferases
Meropenem-vaborbactam	Carbapenem + boronic acid β-lactamase-inhibitor	FDA-approved	PBP/β-lactamase enzyme; Cell wall synthesis inhibition	Class A, C	Not yet determined
Cefepime-taniborbactam	Cephalosporin + cyclic boronate β-lactamase-inhibitor	Phase 3	PBP/β-lactamase enzyme; Cell wall synthesis inhibition	Class A, B, C, D	Not yet determined
Ceftazidime-avibactam	Cephalosporin + diazabicyclooctane β-lactamase-inhibitor	FDA-approved	PBP/β-lactamase enzyme; Cell wall synthesis inhibition	Class A, B, C, D	Carbapenemase mutations129
Aztreonam-avibactamb	Monobactam/diazabicyclooctane β-lactamase-inhibitor	Phase 2	PBP/β-lactamase enzyme; Cell wall synthesis inhibition	Class A, B, C, D	β-lactamase mutations130
Imipenem-relebactam	Carbapenem + diazabicyclooctane β-lactamase-inhibitor	FDA-approved	PBP/β-lactamase enzyme; Cell wall synthesis inhibition	Class A, C	Not yet determined
Meropenem-nacubactam	Carbapenem + diazabicyclooctane β-lactamase-inhibitor	Phase 1	PBP/β-lactamase enzyme; Cell wall synthesis inhibition	Class A, C, (B, D)i	Not yet determined
Cefepime-zidebactam	Cephalosporin + diazabicyclooctane β-lactamase- inhibitor	Phase 1	PBP/β-lactamase enzyme; Cell wall synthesis inhibition	Class A, C, (B, D)i	Not yet determined
Cefpodoxime-ETX0282c	Cephalosporin + diazabicyclooctane β-lactamase-inhibitor	Phase 1	PBP/β-lactamase enzyme; Cell wall synthesis inhibition	Class A, C	Not yet determined
BOS-228 (LYS228)	Monobactam derivative	Phase 2	PBP; Cell wall synthesis inhibition	Class A, B, Ch, D	Efflux pumps
Cefiderocol	Siderophore cephalosporin	FDA-approved	PBP; Cell wall synthesis inhibition	Class A, B, C, D	Mutations in iron uptake genes
Eravacyclined	Fluorinated tetracycline analogue	FDA-approved	30S ribosomal subunit; Protein synthesis inhibition	N.A.	Efflux pumps
Fosfomycine	Phosphoenolpyruvate analogue	FDA-approved	Pyruvyl transferase (MurA); Cell wall synthesis inhibition	N.A.	Mutations in fosfomycin uptake systems; fosfomycin-modifying enzymes
SPR206	Polymyxin	Phase 1	Lipopolysaccharide; Outer membrane disruption	N.A.	Lipid A modification
SPR741f	Polymyxin B derivative (antibiotic potentiator)	Phase 1	Lipopolysaccharide; Outer membrane permeabilization	N.A.	Not yet determined

PBP: Penicillin-binding protein

^aCurrently used in veterinary medicine.

^bCombination not yet available; can be given as aztreonam plus ceftazidime-avibactam.

^cOrally bioavailable.

^dExample of application and power of total de novo synthesis of natural product analogues

^eFor systemic infections, IV form usually used with other antibiotics; only oral form available in the US.

^fNot active alone; used as an outer membrane permeabilizing agent.

^gIndicates activity against strains expressing the indicated molecular classes of carbapenemases and β-lactamases. Class A includes ESBL serine β-lactamases of SHV, TEM, CTX-M types, and the Klebsiella pneumoniae carbapenemase (KPC); class B includes metallo-carbapenemases such as NDM, VIM, and IMP; class C includes chromosomal AmpC and plasmid-borne CMY serine cephalosporinases; and class D includes serine oxacillinases such as OXA-48.¹³¹ Non-β-lactam agents are marked as not applicable (N.A.) in this column. These drugs are often active against CRE based on mechanisms unaffected by carbapenemase expression.

^hOnly active against some members of indicated class. More detail is provided in the text.

ⁱβ-lactamase inhibitor does not inactivate Class B, metallo-carbapenemases and Class D, OXA-carbapenemases; however, β-lactam/β-lactamase inhibitor combination may inhibit strains expressing these carbapenemases based on the intrinsic antimicrobial activity and enhancer effects of the β-lactamase inhibitor.