NAV

Durlobactam

Identification

Summary

Durlobactam is a non-beta-lactam, beta-lactamase inhibitor used to treat hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia.

Brand Names
Xacduro
Generic Name
Durlobactam
DrugBank Accession Number
DB16704
Background

Durlobactam is a diazabicyclooctane non-beta-lactam, beta-lactamase inhibitor. It is typically given in combination with sulbactam to protect it from degradation by certain serine-beta-lactamases.4 The combination product of durlobactam and sulbactam was first approved by the FDA in May 2023.3 It is used to treat hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia (HABP/VABP), caused by susceptible isolates of Acinetobacter baumannii-calcoaceticus complex.4

Type
Small Molecule
Groups
Approved, Investigational
Structure
3D
Similar Structures
Weight
Average: 277.25
Monoisotopic: 277.03685626
Chemical Formula
C8H11N3O6S
Synonyms
  • (2S,5R)-2-CARBAMOYL-3-METHYL-7-OXO-1,6-DIAZABICYCLO(3.2.1)OCT-3-EN-6-YL SULFATE
  • Durlobactam
  • SULFURIC ACID, MONO((2S,5R)-2-(AMINOCARBONYL)-3-METHYL-7-OXO-1,6-DIAZABICYCLO(3.2.1)OCT-3-EN-6-YL) ESTER
External IDs
  • ETX 2514
  • ETX-2514
  • ETX2514
  • WHO 10824
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Pharmacology

Indication

In combination with sulbactam, durlobactam is indicated in adults for the treatment of hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia (HABP/VABP), caused by susceptible isolates of Acinetobacter baumannii-calcoaceticus complex.4

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Associated Conditions
Indication TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Used in combination to treatNosocomial pneumonia caused by acinetobacter baumannii-calcoaceticus complexCombination Product in combination with: Sulbactam (DB09324)•••••••••••••••••••••
Used in combination to treatVentilator associated bacterial pneumonia (vabp) caused by acinetobacter baumannii-calcoaceticus complexCombination Product in combination with: Sulbactam (DB09324)•••••••••••••••••••••
Contraindications & Blackbox Warnings
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Pharmacodynamics

Durlobactam has an extended spectrum of activity compared to other β-lactamase inhibitors with a displayed potent inhibition against class A, C, and D serine β-lactamases.1,2 Durlobactam is not active against class B metallo-β-lactamases, which is an enzyme class rarely observed in Acinetobacter clinical isolates.1 Durlobactam alone does not have antibacterial activity against Acinetobacter baumannii-calcoaceticus complex isolates.4

Mechanism of action

Durlobactam is a diazabicyclooctane non-beta-lactam, beta-lactamase inhibitor. When given in combination with sulbactam, it protects sulbactam from degradation by certain serine-beta-lactamases.4 Durlobactam is carbamoylated by β-lactamase by the serine nucleophile in the enzyme active site: The covalent bond between durlobactam and β-lactamase is reversible due to recyclization by the sulfated amine group on durlobactam, demonstrating that durlobactam can be exchanged from one enzyme molecule to another, also known as acylation exchange.1

Absorption

Durlobactam demonstrated dose-proportional pharmacokinetics across the dose range studied (0.25 times the recommended single dose to 2 times the recommended single dose infused over 3 hours every 6 hours), with the Cmax, AUC0-24, and AUC0-6/ELF plasma ratio calculated to be 29.2 ± 13.2 µg/mL, 471 ± 240 h.µg/mL, and 0.37 respectively.4

Volume of distribution

The volume of distribution of durlobactam as stead state (ss) was estimated to be 30.3 ± 12.9 L.4

Protein binding

The binding of durlobactam to human serum proteins was 10%.4

Metabolism

Durlobactam is minimally metabolized.4

Route of elimination

The major route of elimination of durlobactam is through the kidney, with 78% of durlobactam excreted unchanged in the urine.4

Half-life

The elimination half-life of durlobactam was calculated to be 2.52 ± 0.77 h.4

Clearance

The clearance of durlobactam was calculated to be 9.96 ± 3.11 L/h.4

Adverse Effects
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Toxicity

While durlobactam is removable by hemodialysis, there is limited clinical information regarding the use of hemodialysis to treat overdosage.4

Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
Integrate drug-drug
interactions in your software
AcenocoumarolThe risk or severity of bleeding can be increased when Durlobactam is combined with Acenocoumarol.
AmbroxolThe risk or severity of methemoglobinemia can be increased when Durlobactam is combined with Ambroxol.
ArticaineThe risk or severity of methemoglobinemia can be increased when Durlobactam is combined with Articaine.
BCG vaccineThe therapeutic efficacy of BCG vaccine can be decreased when used in combination with Durlobactam.
BenzocaineThe risk or severity of methemoglobinemia can be increased when Durlobactam is combined with Benzocaine.
Food Interactions
No interactions found.

Products

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Product Ingredients
IngredientUNIICASInChI Key
Durlobactam sodiumF78MDZ9CW91467157-21-6WHHNOICWPZIYKI-IBTYICNHSA-M
Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing EndRegionImage
XacduroDurlobactam sodium (0.5 g/2.5mL) + Sulbactam sodium (1 g/5mL)Injection, powder, for solution; Injection, powder, lyophilized, for solution; KitIntravenousLaJolla Pharmaceutical Company2023-06-06Not applicableUS flag

Categories

Drug Categories
Classification
Not classified
Affected organisms
Not Available

Chemical Identifiers

UNII
PSA33KO9WA
CAS number
1467829-71-5
InChI Key
BISPBXFUKNXOQY-RITPCOANSA-N
InChI
InChI=1S/C8H11N3O6S/c1-4-2-5-3-10(6(4)7(9)12)8(13)11(5)17-18(14,15)16/h2,5-6H,3H2,1H3,(H2,9,12)(H,14,15,16)/t5-,6+/m1/s1
IUPAC Name
[(1R,2S,5R)-2-carbamoyl-3-methyl-7-oxo-1,6-diazabicyclo[3.2.1]oct-3-en-6-yl]oxidanesulfonic acid
SMILES
CC1=C[C@@H]2C[N@]([C@@H]1C(N)=O)C(=O)N2OS(O)(=O)=O

References

General References
  1. Shapiro AB, Moussa SH, McLeod SM, Durand-Reville T, Miller AA: Durlobactam, a New Diazabicyclooctane beta-Lactamase Inhibitor for the Treatment of Acinetobacter Infections in Combination With Sulbactam. Front Microbiol. 2021 Jul 19;12:709974. doi: 10.3389/fmicb.2021.709974. eCollection 2021. [Article]
  2. Papp-Wallace KM, McLeod SM, Miller AA: Durlobactam, a Broad-Spectrum Serine beta-lactamase Inhibitor, Restores Sulbactam Activity Against Acinetobacter Species. Clin Infect Dis. 2023 May 1;76(Suppl 2):S194-S201. doi: 10.1093/cid/ciad095. [Article]
  3. Keam SJ: Sulbactam/Durlobactam: First Approval. Drugs. 2023 Sep;83(13):1245-1252. doi: 10.1007/s40265-023-01920-6. [Article]
  4. FDA Approved Drug Products: XACDURO (sulbactam for injection; durlobactam for injection), co-packaged for intravenous use [Link]
ChemSpider
57617784
RxNav
2639089
ChEMBL
CHEMBL4298137
ZINC
ZINC000220881117
Wikipedia
Durlobactam

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3CompletedTreatmentAcinetobacter Baumannii-calcoaceticus Complex / Bacteremia / Colistin Resistant ABC / Hospital-Acquired Pneumonia / Ventilator Associated Bacterial Pneumonia (VABP)1
2CompletedTreatmentAcute Tubulo-Interstitial Nephritis / Complicated Urinary Tract Infection1
1CompletedBasic ScienceHealthy Volunteers (HV)1
1CompletedTreatmentAcinetobacter Baumannii Infection1
1CompletedTreatmentAcinetobacter Baumannii-calcoaceticus Complex Infections2

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Injection, powder, for solution; injection, powder, lyophilized, for solution; kitIntravenous
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US9309245No2016-04-122033-04-02US flag
US9623014No2017-04-182033-04-02US flag
US9968593No2018-05-152035-11-17US flag
US10376499No2019-08-132035-11-17US flag

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility6.08 mg/mLALOGPS
logP-1.6ALOGPS
logP-1.6Chemaxon
logS-1.7ALOGPS
pKa (Strongest Acidic)-1.9Chemaxon
pKa (Strongest Basic)-4.6Chemaxon
Physiological Charge-1Chemaxon
Hydrogen Acceptor Count5Chemaxon
Hydrogen Donor Count2Chemaxon
Polar Surface Area130.24 Å2Chemaxon
Rotatable Bond Count3Chemaxon
Refractivity57.57 m3·mol-1Chemaxon
Polarizability23.67 Å3Chemaxon
Number of Rings2Chemaxon
Bioavailability1Chemaxon
Rule of FiveYesChemaxon
Ghose FilterNoChemaxon
Veber's RuleNoChemaxon
MDDR-like RuleNoChemaxon
Predicted ADMET Features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSsplash10-004i-0090000000-51913970e3af2d6d8a93
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSsplash10-004i-0190000000-4f2372d4210e80d2c0a4
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSsplash10-003r-2090000000-a4cddac708230a0b78f8
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSsplash10-00kr-0910000000-408812c715b78aa6779d
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSsplash10-001u-9800000000-a0921f32f8dddbd6719e
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSsplash10-0002-9300000000-ccff29813ca0e3647789
Predicted 1H NMR Spectrum1D NMRNot Applicable
Predicted 13C NMR Spectrum1D NMRNot Applicable
Chromatographic Properties
Collision Cross Sections (CCS)
Not Available

Transporters

Details1. Solute carrier family 22 member 6
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
Sodium-independent organic anion transmembrane transporter activity
Specific Function
Involved in the renal elimination of endogenous and exogenous organic anions. Functions as organic anion exchanger when the uptake of one molecule of organic anion is coupled with an efflux of one ...
Gene Name
SLC22A6
Uniprot ID
Q4U2R8
Uniprot Name
Solute carrier family 22 member 6
Molecular Weight
61815.78 Da
References
  1. FDA Approved Drug Products: XACDURO (sulbactam for injection; durlobactam for injection), co-packaged for intravenous use [Link]

Drug created at July 19, 2021 18:27 / Updated at March 08, 2024 01:21