What do We Know so Far about Ges Carbapenemases, and What Threat do They Pose?

World Health Organization (WHO) bacterial priority pathogens list

Bacteria	Priority group	Resistance type
Enterobacterales	critical	carbapenem-resistant
Enterobacterales		third-generation cephalosporin-resistant
Acinetobacter baumanii		carbapenem-resistant
Salmonella Typhi	high	fluoroquinolone-resistant
Shigella spp.		fluoroquinolone-resistant
Enterococcus faecium		vancomycin-resistant
Non-typhoidal Salmonella		fluoroquinolone-resistant
Neisseria gonorrhoeae		third-generation cephalosporin and/or fluoroquinolone-resistant
Staphylococcus aureus		methicillin-resistant
Pseudomonas aeruginosa		carbapenem-resistant
Group A Streptococci	medium	macrolide-resistant
Streptococcus pneumoniae		macrolide-resistant
Haemophilus influenzae		ampicillin-resistant
Group B Streptococci		penicillin-resistant

Summary of antibiotics that can be used against carbapenemase-producing strains (Rejestr produktów leczniczych 2012; 2014; 2015a; 2015b; Electronic Medicines Compendium 2024; European Medicines Agency 2018; 2020a; 2020b; 2022; 2024b; 2024c)

Substance	Spectrum	Indications
Colistin	P. aeruginosa, K. pneumoniae, E. coli, A. baumanii	Sepsis, lower RTI, UTI, RTI in CF patients
Fosfomycin	K. pneumoniae, E. coli, Citrobacter spp., Proteus spp.	Acute, uncomplicated cystitis; profuse, asymptomatic bacteriuria; UTI prevention before surgery and transurethral diagnostic procedures
Nitrofurantoin	E. coli, enterococci, staphylococci, Citrobacter spp., Klebsiella spp., Enterobacter spp.	Acute or recurrent lower UTI; inflammation of the renal pelvis (spontaneous or after surgery)
Tobramycin	P. aeruginosa, Corynebacterium spp., MSSA, Citrobacter spp., Haemophilus spp., Salmonella spp., Shigella spp, P. vulgaris	HAP (incl. severe pneumonia), exacerbations of lower RTI in CF patients, complicated and recurrent UTI; intra-abdominal infections; skin and soft tissue infections (incl. severe burns)
Amikacin	P. aeruginosa, S. aureus, Citrobacter freundii, E. coli, K. pneumoniae, P. mirabilis, P. vulgaris	HAP (incl. severe pneumonia), abdominal infections (incl. peritonitis and post-operative infections), complicated and recurrent UTI, skin and soft tissue infections and burns; bacterial endocarditis
Cefiderocol	E. coli, K. pneumoniae, P. mirabilis, P. aeruginosa, Enterobacter cloacae complex	Infections caused by aerobic Gram-negative bacteria, complicated UTI, pyelonephritis
Eravacycline	E. coli, K. pneumoniae, S. aureus, E. faecalis, E. faecium, Streptococcus spp.	Complicated intra-abdominal infections in adults
Lefamulin	S. pneumoniae, S. aureus, L. pneumophila, M. pneumoniae, C. pneumoniae	Community-acquired pneumonia (in case of ineffective treatment with recommended drugs)
Imipenem with relebactam	E. coli, H. influenzae, K. pneumoniae, P. aeruginosa, S. mercescens,	HAP, VAP; bacteremia in HAP, infections with aerobic Gram-negative bacteria in case of limited treatment options
Meropenem with vaborbactam	E. coli, K. pneumoniae, Enterobacter cloacae complex, Citrobacter spp., P. aeruginosa, S. mercescens, S. aureus, S. epidermidis, S. agalacitiae, B. fragilis, C. perfringens, Prevotella spp.	Complicated abdominal pneumonia, complicated UTI, pyelonephritis, HAP and VAP
Ceftazidime with avibactam	C. freundii, E. cloacae, E. coli, K. oxytoca, K. pneumoniae, P. aeruginosa, P. mirabilis, S. mercescens	Complicated intra-abdominal infection, complicated UTI, pyelonephritis, HAP, VAP, infections caused by aerobic Gram-negative microorganisms in adults and children > 3 months of age
Plazomycin	E. coli, K. pneumoniae, P. mirabilis, E. cloacae	UTI and pyelonephritis

Drugs against GES carbapenemases producing strains in development (Soszyńska-Morys 2023; European Medicines Agency 2024a)

Substance	Class	Spectrum	Research phase	Additional information
durlobactam + sulbactam	Inhibitor of β-lactamases of classes A, C and D, according to Ambler	Acinetobacter baumanii	Phase 3 clinical trials, completed	The combination shows greater activity against MDR
taniborbactam	Non-β-lactam inhibitor of β-lactamases of classes A, B, C, and D, according to Ambler	P. aeruginosa, Enterobacterales	Phase 3 clinical trials of taniborbactam with cefepime in UTIs, completed	Enables the use of cefepime against carbapenem-resistant strains
cefepime + enmetazobactam	β-lactam (cephalosporin) + β-lactamase inhibitor	ESBL-producing bacteria, Enterobacterales resistant to 3rd generation cephalosporins, Carbapenem-resistant K. pneumoniae	CHMP issued a marketing authorization for a medicinal product containing cefepime and enmetazobactam (2024)	Therapeutic area: pyelonephritis, UTI, HAP and VAP

A comparison of the main features of selected GES-type carbapenemases_ Some of the GES-type antibiotic resistances are ESBL-type enzymes, which do not have carbapenemase properties_ Some of them do have carbapenemase activity_

Enzyme	Mutation	Gene location	Microrganism	Year and country of identification	Referencesm
GES-1	A170G	Plasmid	K. pneumoniae	1998, France	Poiler et al. 2000
GES-2	G170N	Plasmid	P. aeruginosa	2000, South Africa	Poiler et al. 2001
GES-4	G170S	Plasmid	K. pneumoniae	2002, Japan	Queenan and Bush 2007
GES-5	G170S	Chromosomal	P. aeruginosa	2007, Spain	Viedma et al. 2009
GES-6	G170S	Plasmid	K. pneumoniae	2004, Greece	Queenan and Bush 2007
GES-11	G243A	Plasmid	A. baumannii	2008, France	Moubareck et al. 2009
GES-14	G170S, G234A	Plasmid	A. baumannii	2008, described in Belgium	Mabrouk et al. 2017
GES-16	Gln38Glu, G170S	Plasmid	S. marcescens	2011, Brazil	Escandón et al. 2017
GES-18	G170S, V80I	Plasmid	P. aeruginosa	2010, Belgium	Bebrone et al. 2013
GES-20	A165S	Chromosomal	P. aeruginosa	2011, Mexico	Garza-Ramos et al. 2015