A Clinical Review and Critical Evaluation of Imipenem-Relebactam: Evidence to Date

Figures & data

Figure 1 PRISMA flow diagram. Of the 122 articles identified, 60 articles were excluded. The majority of articles were excluded as they were commentary or discussions or they were irrelevant to the purpose of this review article. Two articles were excluded as they included data for pediatric patients and one excluded as it was a meta-analysis with repetitive data. Sixty articles were screened for inclusion for this review article.

Notes: PRISMA figure adapted from Liberati A, Altman D, Tetzlaff J, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. Journal of clinical epidemiology. 2009;62(10). Creative Commons.

Table 1 Studies of I-R Susceptibilities of Select Gram-Negative Bacteria. MIC₅₀ and MIC₉₀ are the Minimum Inhibitory Concentrations for 50% and 90% of Isolates, Respectively. Imipenem Susceptibility is Based on FDA-Approved MIC Breakpoints as Follows: Enterobacterales, Susceptible (S) ≤1 µg/mL, Intermediate (I) 2 µg/mL, Resistant (R) ≥4 µg/mL; P. aeruginosa, S ≤2 µg/mL, I 4 µg/mL, R ≥8 µg/mL; A. baumannii, S <2 µg/mL, I 4 µg/mL, R >8 µg/mL; Anaerobic Bacteria, S ≤4 µg/mL, I 8 µg/mL, R ≥16 µg/mL

Organism	Number of Isolates	I-R MIC (μg/mL)		Percent Susceptible
		MIC50	MIC90
Enterobacterales
Non-proteeae Enterobacterales^Citation6	3143	0.12	0.5	99.1
CRE^Citation6	130	0.5	2	78.5
CRE^Citation29	62	NR	NR	71
CRE^Citation26	96	0.5	1	100
CRE^Citation27	200	≤0.25	0.5	NR
OXA-48-like CRE^Citation30	20	4	≥32	15
KPC Enterobacterales^Citation23	110	0.25	1	90.9
Colistin-resistant Enterobacterales^Citation27	97	≤0.25	≤0.25	NR
NDM Enterobacterales^Citation23	31	32	NR	0
Escherichia coli
E. coli^Citation17	10,866	NR	NR	99.9
E. coli^Citation21	2778	0.25	0.25	100
MDR E. coli^Citation17	2020	NR	NR	99.2
Klebsiella pneumoniae
K. pneumoniae^Citation17	3519	NR	NR	94.4
K. pneumoniae^Citation21	891	0.25	0.25	99.3
K. pneumoniae^Citation7	1591	0.12	1	94.8
KPC K. pneumoniae^Citation17	133	NR	NR	99.2
KPC K. pneumoniae^Citation21	111	0.25	1	97
KPC K. pneumoniae^Citation30	92	≤0.25	0.5	100
KPC K. pneumoniae^Citation31	295	0.25	1	98
CR K. pneumoniae^Citation7	179	2	>32	54.2
Enterobacter spp.
Enterobacter spp.^Citation21	211	0.25	0.5	99
Enterobacter spp.^Citation19	96	0.25	1	92
Enterobacter spp.^Citation7	772	0.12	0.5	96.8
E. cloacae^Citation17	944	NR	NR	95.8
CR E. cloacae^Citation17	49^a	NR	NR	18.4
CR E. cloacae^Citation7	34	4	8	26.5
Serratia marcescens
Serratia marcescens^Citation23	9	1	8	67
Citrobacter spp.
Citrobacter spp.^Citation19	4	0.25	2	75
P. aeruginosa
P. aeruginosa^Citation21	490	0.5	2	98
P. aeruginosa^Citation8	845	0.5	2	94.2
P. aeruginosa^Citation17	1959	NR	2	93.9
P. aeruginosa^Citation7	1705	0.25	2	94.7
P. aeruginosa^Citation32	42	NR	1–64	64
P. aeruginosa^Citation35	538	0.25	2	91.5
P. aeruginosa^Citation36	1445	0.5	1	97.3
CR P. aeruginosa^Citation21	144	1	2	92
CR P. aeruginosa^Citation8	251	2	4	80.5
CR P. aeruginosa^Citation7	477	2	32	81.1
CR P. aeruginosa^Citation6	227	2	8	78
A. baumannii
A. baumannii^Citation21	158	2	>16	51
A. baumannii^Citation8	72	4	>32	45.8
A. baumannii^Citation7	486	32	>32	10.3
Anaerobic bacteria
B. fragilis^Citation39	38	0.125	2	NR
B. fragilis^Citation38	220	0.25	0.5	99.1
Bacteroides non-fragilis spp.^Citation38	231	0.25	1	99.6
B. cacae^Citation38	10	0.25	0.25	100
B. vulgatus^Citation38	22	0.5	1	100
B. uniformis^Citation38	22	0.25	0.5	100
B. ovatus^Citation38	43	0.25	0.5	100
B. thetaiotaomicron^Citation38	103	0.25	0.5	99
Parabacteroides distasonis^Citation38	24	0.5	1	100

Note: ^a81.6% (40/49) of isolates carried MBL and/or OXA-48-like carbapenemases.

Abbreviations: CR, carbapenem-resistant; CRE, carbapenem-resistant Enterobacterales; NDM, New Delhi metallo-beta-lactamase; NR, not reported.

Table 2 I-R Breakpoints^a. There are Both FDA-Approved Breakpoints and EUCAST Breakpoints for I-R. For FDA-Approved Breakpoints: Enterobacterales is Susceptible (S) at ≤1 µg/mL, Intermediate (I) at 2 µg/mL, and Resistant (R) at ≥4 µg/mL; P. aeruginosa is S at ≤2 µg/mL, I at 4 µg/mL, and R at ≥8 µg/mL; Anaerobic Bacteria is S ≤4 µg/mL, I at 8 µg/mL, and R at ≥16 µg/mL. For EUCAST Breakpoints, Enterobacterales, P. aerguinosa, Anaerobic Bacteria, and A. baumannii are All S at ≤2 µg/mL and R at >2 µg/mL. Relebactam Concentrations are Fixed at 4 µg/mL

Pathogen	FDA-Approved Breakpoints			EUCAST Breakpoints
	S	I	R	S	R
Enterobacterales^b	≤1	2	≥4	≤2	>2
P. aeruginosa	≤2	4	≥8	≤2	>2
Anaerobes^c,d	≤4	8	≥16	≤2	>2
Acinetobacter	NR	NR	NR	≤2	>2

Notes: ^aMinimum inhibitory concentrations (µg/mL). The concentration of relebactam is fixed at 4 µg/mL. ^bIncludes Klebsiella aerogenes, Enterobacter cloacae, Escherichia coli, Klebsiella pneumoniae, Citrobacter freundii, Klebsiella oxytoca. Excludes Morganella spp. ^cIncludes Bacteroides caccae, Bacteroides fragilis, Bacteroides ovatus, Bacteroides stercoris, Bacteroides thetaiotaomicron, Fusobacterium nucleatum, Parabacteroides distasonis. ^dAgar dilution method.

Abbreviations: S, susceptible; I, intermediate; r, resistant; NR, not reported.

Table 3 Characteristics of I-R. Pharmacokinetics of I-R are Similar to That of Imipenem-Cilastatin. It is an Intravenous Antimicrobial Dosed at 1.25 g Every 6 Hours and is Renally Dose-Adjusted for Patients with CrCl Less Than 60 mL/Min. I-R is Minimally Metabolized and 90% is Excreted in the Urine Unchanged

Formulation	Intravenous
Dosing	1.25 g (imipenem 500 mg, cilastatin 500 mg, and relebactam 250 mg) infused over 30 minutes every 6 hours
Renal dose adjustments	Estimated CrCl (mL/min)	Recommended dose
	60–89	1 g every 6 hours
	30–59	0.75 g every 6 hours
	15–29	0.5 g every 6 hours
	ESRD on HD	0.5 g every 6 hours
	< 15	Not recommended unless HD within 48 hours
Cmax	Imipenem: 104.3 μM Relebactam: 64.0 μM
AUC0-24hr	Imipenem: 573.9 μM-hr Relebactam: 427.3 μM-hr
Protein binding	Relebactam: 22%
Volume of distribution	Imipenem: 24.3 L Cilastatin: 13.8 L Relebactam: 19.0 L
Metabolism	Relebactam: minimal
Excretion	90% unchanged in urine

Table 4 Summary of I-R Clinical Trial Data. There are Four Clinical Trials Evaluating I-R for the Treatment of cIAIs, cUTIs, HABP, and VABP. The Two Phase 2 Trials Compared I-R at Two Different Doses to Imipenem Alone. The Primary Outcome of Favorable Clinical Response Was Similar Among All Three Treatment Groups for Both Studies for the Treatment of cIAIs and cUTIs. RESTORE-IMI 1 Compared I-R to Imipenem Plus Colistin for the Treatment of cIAIs, cUTIs, HABP, and VABP. Favorable Overall Response Was Similar Between the Groups; However Mortality Was Significantly Lower in the I-R Group. RESTORE-IMI 2 Compared I-R to Piperacillin-Tazobactam for the Treatment of HABP and VABP. Preliminary Data Suggests Day 28 All-Cause Mortality Was Lower in the I-R Group and Favorable Clinical Response Was Higher in the I-R Group

Trial	Study Design	Indications	Comparator	Results
Lucasti et al^Citation45	Prospective, multicenter, double-blind, randomized controlled phase 2 trial	cIAIs	I-R 500–250 mg I-R 500–125 mg IMI alone	Favorable clinical response I-R 500–250 mg: 96.3% I-R 500–125 mg: 98.8% IMI alone: 95.2%
Sims et al^Citation46	Prospective, double-blind, randomized phase 2 dose-ranging trial	cUTIs	I-R 500–250 mg I-R 500–125 mg IMI alone	Favorable clinical response I-R 500–250 mg: 97.1% I-R 500–125 mg: 98.7% IMI alone: 98.8%
RESTORE-IMI1^Citation47	Prospective, multicenter, double-blind, randomized controlled phase 3 trial	cIAIs cUTIs HABP VABP	I-R IMI+CST	Favorable overall response I-R: 71.4% IMI+CST: 70% Day 28 all-cause mortality I-R: 9.5% IMI+CST: 30%
RESTORE-IMI2^Citation48	Double-blind randomized, controlled phase 3 trial	HABP VABP	I-R TZP	Day 28 all-cause mortality I-R: 15.9% TZP: 21.3% Favorable clinical response at EFU I-R: 61% TZP: 55.8%

Abbreviations: IMI, imipenem; cIAIs, complicated intra-abdominal infections; cUTI, complicated urinary tract infections; HABP, hospital-acquired bacterial pneumonia; VABP, ventilator-associated bacterial pneumonia; IMI+CST, imipenem plus colistin; I-R, imipenem-relebactam; TZP, piperacillin-tazobactam; EFU, early follow-up.

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