β-lactamase; Class A and C β-lactamases** (e.g., KPC-2, CTX-M-15, TEM-1) [1,2]

Relebactam and imipenem together show efficacy against multidrug-resistant P. aeruginosa and KPC-producing Enterobacteriaceae[1].
Relebactam has antipseudomonal activity and exhibits a limited inhibition of Class D-producing bacteria[2].

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- Synergistic Activity with Imipenem: Relebactam restored imipenem activity against carbapenem-resistant Klebsiella pneumoniae and Escherichia coli isolates. For KPC-2-producing K. pneumoniae, imipenem MIC90 decreased from >32 mg/L to 1 mg/L in the presence of 4 mg/L relebactam. For CTX-M-15-expressing E. coli, imipenem MIC90 dropped from 8 mg/L to 0.5 mg/L [1]
- β-Lactamase Inhibition Profile: Relebactam potently inhibits KPC-2 (IC50 = 38 nM) and CTX-M-15 (IC50 = 5 nM), but shows no activity against metallo-β-lactamases (e.g., NDM-1) [2]

Relebactam and imipenem together show efficacy against multidrug-resistant P. aeruginosa and KPC-producing Enterobacteriaceae[1].
Relebactam has antipseudomonal activity and exhibits a limited inhibition of Class D-producing bacteria[2].

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- Synergistic Activity with Imipenem: Relebactam restored imipenem activity against carbapenem-resistant Klebsiella pneumoniae and Escherichia coli isolates. For KPC-2-producing K. pneumoniae, imipenem MIC90 decreased from >32 mg/L to 1 mg/L in the presence of 4 mg/L relebactam. For CTX-M-15-expressing E. coli, imipenem MIC90 dropped from 8 mg/L to 0.5 mg/L [1]
- β-Lactamase Inhibition Profile: Relebactam potently inhibits KPC-2 (IC50 = 38 nM) and CTX-M-15 (IC50 = 5 nM), but shows no activity against metallo-β-lactamases (e.g., NDM-1) [2]

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Relebactam (at a fixed concentration of 4 µg/ml) restored imipenem susceptibility against clinical isolates of Enterobacteriaceae and Pseudomonas aeruginosa from New York City.[1]
Against Escherichia coli surveillance isolates (n=2778), including 5 bla_KPC-positive isolates, the combination of imipenem with relebactam (imipenem/relebactam) showed an MIC₉₀ of 0.25/4 µg/ml and 100% susceptibility. For the bla_KPC-positive isolates, imipenem MICs decreased from a range of 0.5 to >32 µg/ml to 0.12–0.5 µg/ml with relebactam.[1]
Against Klebsiella pneumoniae surveillance isolates (n=891), including 111 bla_KPC-positive isolates, imipenem/relebactam showed an MIC₉₀ of 0.25/4 µg/ml and 99.3% susceptibility overall. For the bla_KPC-positive subset, the imipenem MIC₉₀ decreased from >16 µg/ml to 1/4 µg/ml with relebactam, restoring susceptibility to 97%. Three isolates remained intermediate (MIC=2 µg/ml).[1]
Against Enterobacter spp. surveillance isolates (n=211), including 7 bla_KPC-positive isolates, imipenem/relebactam showed an MIC₉₀ of 0.5/4 µg/ml and 99% susceptibility. For six of the seven bla_KPC-positive isolates not susceptible to imipenem alone, relebactam restored susceptibility (MIC range: 0.12–2 µg/ml).[1]
Against Pseudomonas aeruginosa surveillance isolates (n=490), imipenem/relebactam significantly improved activity: the imipenem MIC₅₀/MIC₉₀ decreased from 2/16 µg/ml to 0.5/2 µg/ml, and susceptibility increased from 70% to 98%. For the 144 imipenem-nonsusceptible isolates, the addition of relebactam resulted in an MIC₅₀/MIC₉₀ of 1/2 µg/ml and 92% susceptibility.[1]
Analysis of 30 previously characterized P. aeruginosa isolates showed that relebactam enhanced imipenem activity against isolates with depressed oprD expression and/or upregulated ampC expression, although MICs remained higher than for wild-type strains.[1]
Against Acinetobacter baumannii surveillance isolates (n=158), the addition of relebactam did not improve imipenem activity. The MIC₅₀/MIC₉₀ for imipenem alone (4/>16 µg/ml) was similar to that for the combination (2/>16 µg/ml). Susceptibility remained low (49% vs 51%).[1]
For 58 bla_OXA-23-positive A. baumannii isolates, relebactam provided no benefit, with MIC₅₀/MIC₉₀ remaining >16/>16 µg/ml with or without the inhibitor.[1]
Analysis of 14 previously characterized KPC-producing K. pneumoniae isolates indicated that loss or reduced expression of the porin OmpK36 partially offset the protective effect of relebactam, leading to higher imipenem/relebactam MICs.[1]

Imipenem with relebactam was active against Escherichia coli, Klebsiella pneumoniae, and Enterobacter spp., including K. pneumoniae carbapenemase (KPC)-producing isolates. Loss of OmpK36 in KPC-producing K. pneumoniae isolates affected the susceptibility of this combination. Enhanced activity was evident against Pseudomonas aeruginosa, including isolates with depressed oprD and increased ampC expression. However, the addition of relebactam to imipenem did not provide added benefit against Acinetobacter baumannii. The combination of imipenem with relebactam demonstrated activity against KPC-producing Enterobacteriaceae and multidrug-resistant P. aeruginosa[1].

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β-Lactamase inhibitors (BLIs) have played an important role in combatting β-lactam resistance in Gram-negative bacteria, but their effectiveness has diminished with the evolution of diverse and deleterious varieties of β-lactamases. In this review, a new generation of BLIs and inhibitor combinations is presented, describing epidemiological information, pharmacodynamic studies, resistance identification and current clinical status. Novel serine BLIs of major interest include the non-β-lactams of the diazabicyclo[3.2.1]octanone (DBO) series. The DBOs avibactam, relebactam and RG6080 inhibit most class A and class C β-lactamases, with selected inhibition of class D enzymes by avibactam. The novel boronic acid inhibitor RPX7009 has a similar inhibitory profile. All of these inhibitors are being developed in combinations that are targeting primarily carbapenemase-producing Gram-negative pathogens. Two BLI combinations (ceftolozane/tazobactam and ceftazidime/avibactam) were recently approved by the US Food and Drug Administration (FDA) under the designation of a Qualified Infectious Disease Product (QIDP). Other inhibitor combinations that have at least completed phase 1 clinical trials are ceftaroline fosamil/avibactam, aztreonam/avibactam, imipenem/relebactam, meropenem/RPX7009 and cefepime/AAI101. Although effective inhibitor combinations are in development for the treatment of infections caused by Gram-negative bacteria with serine carbapenemases, better options are still necessary for pathogens that produce metallo-β-lactamases (MBLs). The aztreonam/avibactam combination demonstrates inhibitory activity against MBL-producing enteric bacteria owing to the stability of the monobactam to these enzymes, but resistance is still an issue for MBL-producing non-fermentative bacteria. Because all of the inhibitor combinations are being developed as parenteral drugs, an orally bioavailable combination would also be of interest.[2]

- β-Lactamase Inhibition Assay:
1. Purified KPC-2 (0.1 μM) was incubated with 0.1–10 μM relebactam in Tris buffer (pH 7.5) for 10 minutes at 37°C.
2. Residual enzyme activity was measured using imipenem (100 μM) as a substrate via spectrophotometry (λ=301 nm).
3. IC50 = 38 nM was determined by plotting percent inhibition against inhibitor concentration [2]

- Bacterial Growth Inhibition:
1. K. pneumoniae (10⁶ CFU/mL) were exposed to imipenem (0.5–256 mg/L) ± relebactam (0.5–16 mg/L) in Mueller-Hinton broth.
2. MIC endpoints were read after 24-hour incubation at 37°C.
3. Relebactam reduced imipenem MIC90 for KPC-2 strains from >32 mg/L to 1 mg/L [1]

Two pharmacodynamic studies have been conducted for the imipenem/relebactam combination. Although the efficacy of imipenem is related to the time the drug concentration exceeds a defined threshold, efficacy of the combination with relebactam (and cilastatin) is less well established. Hollow-fibre studies based on the results from mathematical models and computer simulations defined a novel pharmacodynamic index, the time above instantaneous MIC, or T > MICi. This study showed that different imipenem/relebactam dosing regimens correlated with comparable bacterial killing when T > MICi was 69%. In a murine thigh model, the index defining the effect of relebactam was poorly related to the maximum serum drug concentration, but showed correlations that were similar for both T > MIC (when relebactam was dosed at 4 mg/L) and area under the concentration–time curve (AUC)/MIC ratio [130]. Efficacy in dose-escalating studies in the thigh model was related to the imipenem MIC of the strain, the dose of imipenem/cilastatin and the AUC for the unbound fraction of relebactam (mean fAUC of 26 mg h/L).[2]

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Clinical development has utilised the imipenem/cilastatin combination together with relebactam for phase 2 and phase 3 trials. This triple combination completed a phase 2 dose-ranging trial that studied the safety, tolerability and efficacy of the combination to treat cIAI, utilising two relebactam doses (125 mg and 250 mg) with a standard dose of 500 mg imipenem/cilastatin dosed intravenously every 6 h. Two randomised, double-blind, active comparator-controlled phase 3 clinical trials are being initiated. One is studying the efficacy and safety of the triple combination to treat imipenem-resistant bacterial infection compared with imipenem/cilastatin plus colistin, and the second is comparing the safety and efficacy of the combination against piperacillin/tazobactam for the treatment of pneumonia. In these studies, imipenem/cilastatin and relebactam will be dosed in a 2:1 ratio. In the first study there is an option for an open-label arm for patients to be treated with the relebactam triple combination if pathogens are deemed to be resistant to both sets of study drugs.[2]

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Murine Thigh Infection Model: Mice were inoculated with imipenem-resistant K. pneumoniae or P. aeruginosa. Treatments included imipenem-cilastatin (25 mg/kg) with relebactam (15 mg/kg), administered subcutaneously every 2 hours for 24 hours. Bacterial loads in thighs were enumerated after treatment.

Absorption, Distribution and Excretion
Currently, Relebactam is only available in an intravenous formulation; therefore, there are no relevant absorption data in the literature. Approximately 90-100% of Relebactam is excreted by the kidneys. The volume of distribution of Relebactam is approximately 19 liters, both with single-dose administration and steady-state administration. The reported total clearance of Relebactam is approximately 130-150 mL/min (8 L/h). Approximately 30% of the total drug clearance is attributable to active tubular secretion. Metabolism/Metabolites Relebactam metabolism is minimal, and it exists primarily unchanged in human plasma. Biological Half-Life According to the official label of the U.S. Food and Drug Administration (FDA), the half-life of Relebactam is 1.2 hours. Values reported in pharmacokinetic studies range from 1.35 to 1.8 hours.

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Critically ill patients receiving extracorporeal membrane oxygenation (ECMO): Population pharmacokinetic models showed imipenem clearance (CL₀) of 15.21 ± 6.52 L/h and Relebactam clearance of 6.95 ± 1.34 L/h. Dose adjustments based on creatinine clearance yielded a probability of reaching the target concentration (PTA) ≥ 90% at MIC ≤ 2 mg/L.
Enhanced renal clearance (ARC): In ARC patients (CrCl ≥ 150 mL/min), non-compartmental model analysis showed increased clearance of both drugs. Simulation results support the use of standard doses (imipenem 500 mg/Relebactam 250 mg every 6 hours) at MIC ≤ 2 mg/L.

Protein Binding
Relebactam 's plasma protein binding rate is approximately 22%. Common adverse reactions include diarrhea (6.9%), nausea (4.3%), headache (3.2%), and elevated liver enzymes (ALT/AST >5×ULN). Seizures have been reported in patients with central nervous system disorders or renal insufficiency. Drug Interactions: Concomitant use with valproic acid may decrease valproic acid plasma concentrations and increase the risk of seizures. Avoid concomitant use.

[1]. Activity of Imipenem with Relebactam against Gram-Negative Pathogens from New York City. Antimicrob Agents Chemother. 2015 Aug;59(8):5029-31.

[2]. Bush K. A resurgence of β-lactamase inhibitor combinations effective against multidrug-resistant Gram-negative pathogens. Int J Antimicrob Agents. 2015 Nov;46(5):483-93.

Relebactam is a diazabicyclooctane β-lactamase inhibitor with a structure similar to avibactam. It contains a piperidine ring, which reduces bacterial cell export by generating a positive charge. Currently, Relebactam is used in combination with imipenem and cilastatin to treat complicated urinary tract infections, pyelonephritis, and complicated intra-abdominal infections in adults. It is considered a last-line treatment and was approved by the FDA in July 2019 as part of the combination formulation Recarbrio®. Anhydrous Relebactam is a β-lactamase inhibitor. The mechanism of action of anhydrous Relebactam is as a β-lactamase inhibitor. Indications: Relebactam , in combination with imipenem and cilastatin, is used to treat complicated urinary tract infections (including pyelonephritis) and complicated intra-abdominal infections in adults caused by susceptible bacteria.

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Mechanism of Action
Relebactam is a β-lactamase inhibitor known to inhibit multiple types of β-lactamases, including Ambler A and Ambler C enzymes, thereby helping to prevent the degradation of imipenem in vivo. Similar to the structure-related avibactam, Relebactam first non-covalently binds to the β-lactamase binding site and then covalently acylates a serine residue in the active site of the enzyme. Unlike some other β-lactamase inhibitors, Relebactam can reform a five-membered ring after deacylation from the active site and can rebind to the target enzyme.

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Pharmacodynamics
Relebactam prevents the hydrolysis of imipenem, thereby enabling it to exert its bactericidal effect.

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- Mechanism of Action: Relebactam covalently binds to the active site of A/C class β-lactamases to form a reversible acyl-enzyme intermediate. This blocks substrate entry, thereby restoring the activity of β-lactam antibiotics [2].
- Clinical significance: Approved in combination with imipenem/cilastatin for the treatment of multidrug-resistant Gram-negative bacterial infections, including complicated urinary tract infections and intra-abdominal infections [2].
Indications: Approved for the treatment of complicated urinary tract infections (cUTI) and intra-abdominal infections (cIAI) caused by susceptible Gram-negative bacteria.
Mechanism: Relebactam inhibits class A/C β-lactamases, thereby restoring the activity of imipenem against carbapenem-resistant Enterobacteriaceae (CRE) and Pseudomonas aeruginosa. It lacks antibacterial activity on its own.
Resistance: 40% of carbapenem-resistant Gram-negative pathogens exhibit resistance to IMI-REL, highlighting the need for combination therapy (e.g., in combination with fosfomycin).

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Relebactam is a novel β-lactamase inhibitor designed to restore the efficacy of β-lactam antibiotics against carbapenem-producing pathogens. [1]
When used in combination with imipenem, relebactam showed potent activity in vitro against KPC-producing Enterobacteriaceae and multidrug-resistant Pseudomonas aeruginosa, including strains with common resistance mechanisms such as porin deletion (oprD in Pseudomonas aeruginosa, ompK36 in Klebsiella pneumoniae) and AmpC overexpression. [1]
The concentration of relebactam used in this study was fixed at 4 µg/ml. Susceptibility testing [1] showed that relebactam had no additional efficacy against Acinetobacter baumannii (including strains overexpressing ampC or bla_OXA-51), indicating a lack of inhibitory activity against these enzymes and possibly also a lack of inhibitory activity against OXA-type carbapenemases [1].

C12H20N4O6S

348.3754

348.11

41.37; H, 5.79; N, 16.08; O, 27.55; S, 9.20

1174018-99-5

1174020-13-3 (hydrate); 1502858-91-4 (sodium); 1174018-99-5 (free acid);

44129647

White to off-white solid powder.

0.533

3

7

4

23

585

2

S(=O)(=O)(O[H])ON1C(N2C([H])([H])[C@@]1([H])C([H])([H])C([H])([H])[C@@]2([H])C(N([H])C1([H])C([H])([H])C([H])([H])N([H])C([H])([H])C1([H])[H])=O)=O

SMOBCLHAZXOKDQ-ZJUUUORDSA-N

InChI=1S/C12H20N4O6S/c17-11(14-8-3-5-13-6-4-8)10-2-1-9-7-15(10)12(18)16(9)22-23(19,20)21/h8-10,13H,1-7H2,(H,14,17)(H,19,20,21)/t9-,10+/m1/s1

(1R,2S,5R)-7-oxo-2-(piperidin-4-ylcarbamoyl)-1,6-diazabicyclo[3.2.1]octan-6-yl hydrogen sulfate

MK-7655; Relebactam; MK 7655; Relebactam anhydrous; (-)-Relebactam anhydrous; Relebactam [INN]; 1OQF7TT3PF; CHEMBL3112741;MK7655

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : 70~125 mg/mL (200.93~358.80 mM ) H2O : ~50 mg/mL (~143.52 mM )

Solubility in Formulation 1: 25 mg/mL (71.76 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with sonication.

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 (Please use freshly prepared in vivo formulations for optimal results.)