Identification

Name
Avibactam
Accession Number
DB09060
Type
Small Molecule
Groups
Approved
Description

Avibactam is a non-β-lactam β-lactamase inhibitor that is available in combination with ceftazidime (Avycaz). This combination was approved by the FDA on February 25, 2015 for the treatment of complicated intra-abdominal infections in combination with metronidazole, and the treatment of complicated urinary tract infections, including pyelonephritis caused by antibiotic resistant-pathogens, including those caused by multi-drug resistant gram-negative bacterial pathogens. As there is limited clinical safety and efficacy data, Avycaz should be reserved for patients over 18 years old who have limited or not alternative treatment options.

Structure
Thumb
Synonyms
Not Available
External IDs
NXL 104 / NXL-104 / NXL104
Product Ingredients
IngredientUNIICASInChI Key
Avibactam sodium9V824P8TAI1192491-61-4RTCIKUMODPANKX-JBUOLDKXSA-M
Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing End
AvycazAvibactam sodium (0.5 g/1) + Ceftazidime pentahydrate (2 g/1)Powder, for solutionIntravenousAllergan2014-12-26Not applicableUs
ZaviceftaAvibactam (500 mg) + Ceftazidime (2000 mg)Injection, powder, for solutionIntravenousPfizer Ireland Pharmaceuticals2016-06-24Not applicableEu
Categories
UNII
7352665165
CAS number
1192500-31-4
Weight
Average: 265.24
Monoisotopic: 265.03685626
Chemical Formula
C7H11N3O6S
InChI Key
NDCUAPJVLWFHHB-UHNVWZDZSA-N
InChI
InChI=1S/C7H11N3O6S/c8-6(11)5-2-1-4-3-9(5)7(12)10(4)16-17(13,14)15/h4-5H,1-3H2,(H2,8,11)(H,13,14,15)/t4-,5+/m1/s1
IUPAC Name
[(2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl]oxidanesulfonic acid
SMILES
[H]OS(=O)(=O)ON1C(=O)N2C([H])([H])[C@@]1([H])C([H])([H])C([H])([H])[C@@]2([H])C(=O)N([H])[H]

Pharmacology

Indication

AVYCAZ (ceftazidime-avibactam), in combination with metronidazole, is indicated for the treatment of complicated intra-abdominal infections caused by the following susceptible microorganisms: Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Providencia stuartii, Enterobacter cloacae, Klebsiella oxytoca, and Pseudomonas aeruginosa in patients 18 years or older. AVYCAZ is also indicated for the treatment of complicated urinary tract infections including pyelonephritis caused by the following susceptible microorganisms: Escherichia coli, Klebsiella pneumoniae, Citrobacter koseri, Enterobacter aerogenes, Enterobacter cloacae, Citrobacter freundii, Proteus spp., and Pseudomonas aeruginosa in patients 18 years or older.

Associated Conditions
Pharmacodynamics
Not Available
Mechanism of action

Avibactam is a non-β lactam β-lactamase inhibitor that inactivates some β-lactamases (Ambler class A β-lactamases, including Klebsiella pneumoniae carbapenemases, Ambler class C and some Ambler class D β-lactamases) by a unique covalent and reversible mechanism, and protects ceftazidime from degradation by certain β-lactamases. Avibactam rapidly reaches the periplasm of bacteria at high enough concentrations to restore activity of ceftazidime against ceftazidime-resistant, β-lactamase-producing strains. Avibactam does not decrease the activity of ceftazidime against ceftazidime­ susceptible organisms.

TargetActionsOrganism
ABeta-lactamase TEM
inhibitor
Escherichia coli
ABeta-lactamase CTX-M
inhibitor
Escherichia coli
ABeta-lactamase AmpC
inhibitor
Enterobacter cloacae
ABeta-lactamase SHV-1
inhibitor
Escherichia coli
ABeta-lactamase SHV-2
inhibitor
Escherichia coli
ABeta-lactamase SHV-1
inhibitor
Klebsiella pneumoniae
AClass D OXA-48 carbapenemase
inhibitor
Klebsiella pneumoniae
ACarbapenem-hydrolyzing beta-lactamase KPC
inhibitor
Klebsiella pneumoniae
ABeta-lactamase CTX-M-15
inhibitor
Escherichia coli
AExtended-spectrum beta-lactamase PER-1
inhibitor
Pseudomonas aeruginosa
Absorption
Not Available
Volume of distribution

The steady state volumes of distribution of avibactam and ceftazidime is 22.2L and 17L respectively.

Protein binding

5.7%-8.2% of avibactam is bound to plasma protein, and less than 10% of ceftazidime is protein bound.

Metabolism

No metabolism of avibactam was observed in human liver preparations. Unchanged avibactam is the major drug-related component in human plasma and urine. 80-90% of ceftazidime is eliminated as unchanged .

Route of elimination

Avibactam and ceftazidime are excreted mainly by the kidneys.

Half life

Ceftazidime-avibactam has a half life of ~2.7-3.0 hours.

Clearance

Avibactam and ceftazidime has a clearance of ~12L/h and ~7L/h respectively.

Toxicity

Avycaz is contraindicated in patients with known serious hypersensitivity to avibactam-containing products, ceftazidime or other members of the cephalosporin class.

Affected organisms
  • Pseudomonas aeruginosa
  • Escherichia coli
  • Proteus vulgaris
  • Klebsiella
  • Enterobacter
  • Citrobacter
  • Proteus mirabilis
  • Providencia stuartii
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
(R)-warfarinThe risk or severity of bleeding can be increased when Avibactam is combined with (R)-warfarin.
(S)-WarfarinThe risk or severity of bleeding can be increased when Avibactam is combined with (S)-Warfarin.
4-hydroxycoumarinThe risk or severity of bleeding can be increased when Avibactam is combined with 4-hydroxycoumarin.
AcenocoumarolThe risk or severity of bleeding can be increased when Avibactam is combined with Acenocoumarol.
AcyclovirThe excretion of Avibactam can be decreased when combined with Acyclovir.
Adenovirus type 7 vaccine liveThe therapeutic efficacy of Adenovirus type 7 vaccine live can be decreased when used in combination with Avibactam.
Aminohippuric acidThe excretion of Avibactam can be decreased when combined with Aminohippuric acid.
Anthrax immune globulin humanThe therapeutic efficacy of Anthrax immune globulin human can be decreased when used in combination with Avibactam.
Anthrax vaccineThe therapeutic efficacy of Anthrax vaccine can be decreased when used in combination with Avibactam.
ApalutamideThe excretion of Avibactam can be decreased when combined with Apalutamide.
Food Interactions
No interactions found.

References

General References
  1. Stachyra T, Levasseur P, Pechereau MC, Girard AM, Claudon M, Miossec C, Black MT: In vitro activity of the {beta}-lactamase inhibitor NXL104 against KPC-2 carbapenemase and Enterobacteriaceae expressing KPC carbapenemases. J Antimicrob Chemother. 2009 Aug;64(2):326-9. doi: 10.1093/jac/dkp197. Epub 2009 Jun 2. [PubMed:19493866]
  2. Das S, Li J, Armstrong J, Learoyd M, Edeki T: Randomized pharmacokinetic and drug-drug interaction studies of ceftazidime, avibactam, and metronidazole in healthy subjects. Pharmacol Res Perspect. 2015 Oct;3(5):e00172. doi: 10.1002/prp2.172. Epub 2015 Aug 25. [PubMed:26516584]
  3. MacVane SH, Crandon JL, Nichols WW, Nicolau DP: In vivo efficacy of humanized exposures of Ceftazidime-Avibactam in comparison with Ceftazidime against contemporary Enterobacteriaceae isolates. Antimicrob Agents Chemother. 2014 Nov;58(11):6913-9. doi: 10.1128/AAC.03267-14. Epub 2014 Sep 15. [PubMed:25223999]
  4. Pages JM, Peslier S, Keating TA, Lavigne JP, Nichols WW: Role of the Outer Membrane and Porins in Susceptibility of beta-Lactamase-Producing Enterobacteriaceae to Ceftazidime-Avibactam. Antimicrob Agents Chemother. 2015 Dec 14;60(3):1349-59. doi: 10.1128/AAC.01585-15. [PubMed:26666933]
  5. Ehmann DE, Jahic H, Ross PL, Gu RF, Hu J, Kern G, Walkup GK, Fisher SL: Avibactam is a covalent, reversible, non-beta-lactam beta-lactamase inhibitor. Proc Natl Acad Sci U S A. 2012 Jul 17;109(29):11663-8. doi: 10.1073/pnas.1205073109. Epub 2012 Jul 2. [PubMed:22753474]
  6. Ehmann DE, Jahic H, Ross PL, Gu RF, Hu J, Durand-Reville TF, Lahiri S, Thresher J, Livchak S, Gao N, Palmer T, Walkup GK, Fisher SL: Kinetics of avibactam inhibition against Class A, C, and D beta-lactamases. J Biol Chem. 2013 Sep 27;288(39):27960-71. doi: 10.1074/jbc.M113.485979. Epub 2013 Aug 2. [PubMed:23913691]
  7. Aktas Z, Kayacan C, Oncul O: In vitro activity of avibactam (NXL104) in combination with beta-lactams against Gram-negative bacteria, including OXA-48 beta-lactamase-producing Klebsiella pneumoniae. Int J Antimicrob Agents. 2012 Jan;39(1):86-9. doi: 10.1016/j.ijantimicag.2011.09.012. Epub 2011 Oct 29. [PubMed:22041508]
External Links
PubChem Compound
9835049
PubChem Substance
310264997
ChemSpider
8010770
BindingDB
50339145
ChEBI
85984
ChEMBL
CHEMBL1689063
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Avibactam
FDA label
Download (301 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedBasic ScienceBacterial Infections / Complicated skin infection bacterial1
1CompletedBasic ScienceHealthy Male Volunteers1
1CompletedBasic ScienceHealthy Male and Female Japanese Volunteers1
1CompletedBasic ScienceHealthy Volunteers1
1Not Yet RecruitingBasic SciencePharmacokinetics of Avycaz in ICU Patients1
2CompletedTreatmentComplicated Intra-Abdominal Infections1
2CompletedTreatmentComplicated Urinary Tract Infections1
2CompletedTreatmentUrinary Tract Infections (UTIs)1
4CompletedOtherCystic Fibrosis (CF)1
Not AvailableRecruitingNot AvailableBacterial Infections / Critical Illness / Renal Failure1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
Powder, for solutionIntravenous
Injection, powder, for solutionIntravenous
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US7112592No2002-02-242022-02-24Us
US8178554No2001-07-242021-07-24Us
US7612087No2006-11-122026-11-12Us
US8471025No2011-08-122031-08-12Us
US8835455No2010-10-082030-10-08Us
US8969566No2012-06-152032-06-15Us
US9284314No2012-06-152032-06-15Us
US9695122No2012-06-152032-06-15Us

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility15.0 mg/mLALOGPS
logP-1.8ALOGPS
logP-3.6ChemAxon
logS-1.2ALOGPS
pKa (Strongest Acidic)-2ChemAxon
pKa (Strongest Basic)-3.9ChemAxon
Physiological Charge-1ChemAxon
Hydrogen Acceptor Count5ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area130.24 Å2ChemAxon
Rotatable Bond Count3ChemAxon
Refractivity52.48 m3·mol-1ChemAxon
Polarizability22.39 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 GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Taxonomy

Description
This compound belongs to the class of organic compounds known as alpha amino acid amides. These are amide derivatives of alpha amino acids.
Kingdom
Organic compounds
Super Class
Organic acids and derivatives
Class
Carboxylic acids and derivatives
Sub Class
Amino acids, peptides, and analogues
Direct Parent
Alpha amino acid amides
Alternative Parents
Piperidinecarboxamides / 1,3-diazepanes / Imidazolidinones / Organic sulfuric acids and derivatives / Primary carboxylic acid amides / Organic carbonic acids and derivatives / Azacyclic compounds / Organopnictogen compounds / Organonitrogen compounds / Organic oxides
show 2 more
Substituents
Alpha-amino acid amide / Piperidinecarboxamide / 2-piperidinecarboxamide / 1,3-diazepane / Diazepane / Imidazolidinone / Piperidine / Imidazolidine / Organic sulfuric acid or derivatives / Carboxamide group
show 13 more
Molecular Framework
Aliphatic heteropolycyclic compounds
External Descriptors
azabicycloalkane, ureas, monocarboxylic acid amide, hydroxylamine O-sulfonic acid (CHEBI:85984)

Targets

Kind
Protein
Organism
Escherichia coli
Pharmacological action
Yes
Actions
Inhibitor
General Function
TEM-type are the most prevalent beta-lactamases in enterobacteria; they hydrolyze the beta-lactam bond in susceptible beta-lactam antibiotics, thus conferring resistance to penicillins and cephalosporins. TEM-3 and TEM-4 are capable of hydrolyzing cefotaxime and ceftazidime. TEM-5 is capable of hydrolyzing ceftazidime. TEM-6 is capable of hydrolyzing ceftazidime and aztreonam. TEM-8/CAZ-2, TEM-16/CAZ-7 and TEM-24/CAZ-6 are markedly active against ceftazidime. IRT-4 shows resistance to beta-lactamase inhibitors.
Specific Function
Beta-lactamase activity
Gene Name
bla
Uniprot ID
P62593
Uniprot Name
Beta-lactamase TEM
Molecular Weight
31514.865 Da
References
  1. Ehmann DE, Jahic H, Ross PL, Gu RF, Hu J, Kern G, Walkup GK, Fisher SL: Avibactam is a covalent, reversible, non-beta-lactam beta-lactamase inhibitor. Proc Natl Acad Sci U S A. 2012 Jul 17;109(29):11663-8. doi: 10.1073/pnas.1205073109. Epub 2012 Jul 2. [PubMed:22753474]
Kind
Protein
Organism
Escherichia coli
Pharmacological action
Yes
Actions
Inhibitor
General Function
Not Available
Specific Function
Beta-lactamase activity
Gene Name
blaCTX-M-14
Uniprot ID
Q9L5C7
Uniprot Name
Beta-lactamase
Molecular Weight
30979.09 Da
References
  1. Aktas Z, Kayacan C, Oncul O: In vitro activity of avibactam (NXL104) in combination with beta-lactams against Gram-negative bacteria, including OXA-48 beta-lactamase-producing Klebsiella pneumoniae. Int J Antimicrob Agents. 2012 Jan;39(1):86-9. doi: 10.1016/j.ijantimicag.2011.09.012. Epub 2011 Oct 29. [PubMed:22041508]
Kind
Protein
Organism
Enterobacter cloacae
Pharmacological action
Yes
Actions
Inhibitor
General Function
Beta-lactamase activity
Specific Function
Not Available
Gene Name
ampC
Uniprot ID
Q93CA2
Uniprot Name
Beta-lactamase
Molecular Weight
41341.41 Da
References
  1. Aktas Z, Kayacan C, Oncul O: In vitro activity of avibactam (NXL104) in combination with beta-lactams against Gram-negative bacteria, including OXA-48 beta-lactamase-producing Klebsiella pneumoniae. Int J Antimicrob Agents. 2012 Jan;39(1):86-9. doi: 10.1016/j.ijantimicag.2011.09.012. Epub 2011 Oct 29. [PubMed:22041508]
Kind
Protein
Organism
Escherichia coli
Pharmacological action
Yes
Actions
Inhibitor
General Function
Beta-lactamase activity
Specific Function
Not Available
Gene Name
bla
Uniprot ID
P0AD63
Uniprot Name
Beta-lactamase SHV-1
Molecular Weight
31223.635 Da
References
  1. Aktas Z, Kayacan C, Oncul O: In vitro activity of avibactam (NXL104) in combination with beta-lactams against Gram-negative bacteria, including OXA-48 beta-lactamase-producing Klebsiella pneumoniae. Int J Antimicrob Agents. 2012 Jan;39(1):86-9. doi: 10.1016/j.ijantimicag.2011.09.012. Epub 2011 Oct 29. [PubMed:22041508]
Kind
Protein
Organism
Escherichia coli
Pharmacological action
Yes
Actions
Inhibitor
General Function
Beta-lactamase activity
Specific Function
This enzyme hydrolyzes cefotaxime, ceftazidime and other broad spectrum cephalosporins.
Gene Name
bla
Uniprot ID
P0A9Z7
Uniprot Name
Beta-lactamase SHV-2
Molecular Weight
31253.655 Da
References
  1. Aktas Z, Kayacan C, Oncul O: In vitro activity of avibactam (NXL104) in combination with beta-lactams against Gram-negative bacteria, including OXA-48 beta-lactamase-producing Klebsiella pneumoniae. Int J Antimicrob Agents. 2012 Jan;39(1):86-9. doi: 10.1016/j.ijantimicag.2011.09.012. Epub 2011 Oct 29. [PubMed:22041508]
Kind
Protein
Organism
Klebsiella pneumoniae
Pharmacological action
Yes
Actions
Inhibitor
General Function
Not Available
Specific Function
Beta-lactamase activity
Gene Name
bla
Uniprot ID
P0AD64
Uniprot Name
Beta-lactamase SHV-1
Molecular Weight
31223.635 Da
References
  1. Aktas Z, Kayacan C, Oncul O: In vitro activity of avibactam (NXL104) in combination with beta-lactams against Gram-negative bacteria, including OXA-48 beta-lactamase-producing Klebsiella pneumoniae. Int J Antimicrob Agents. 2012 Jan;39(1):86-9. doi: 10.1016/j.ijantimicag.2011.09.012. Epub 2011 Oct 29. [PubMed:22041508]
Kind
Protein
Organism
Klebsiella pneumoniae
Pharmacological action
Yes
Actions
Inhibitor
General Function
Penicillin binding
Specific Function
Not Available
Gene Name
OXA-48
Uniprot ID
A0A023W3H0
Uniprot Name
Class D OXA-48 carbapenemase
Molecular Weight
16920.07 Da
References
  1. Aktas Z, Kayacan C, Oncul O: In vitro activity of avibactam (NXL104) in combination with beta-lactams against Gram-negative bacteria, including OXA-48 beta-lactamase-producing Klebsiella pneumoniae. Int J Antimicrob Agents. 2012 Jan;39(1):86-9. doi: 10.1016/j.ijantimicag.2011.09.012. Epub 2011 Oct 29. [PubMed:22041508]
Kind
Protein
Organism
Klebsiella pneumoniae
Pharmacological action
Yes
Actions
Inhibitor
General Function
Beta-lactamase activity
Specific Function
Hydrolyzes carbapenems, penicillins, cephalosporins and monobactams with varying efficiency.
Gene Name
bla
Uniprot ID
Q9F663
Uniprot Name
Carbapenem-hydrolyzing beta-lactamase KPC
Molecular Weight
31114.99 Da
References
  1. Aktas Z, Kayacan C, Oncul O: In vitro activity of avibactam (NXL104) in combination with beta-lactams against Gram-negative bacteria, including OXA-48 beta-lactamase-producing Klebsiella pneumoniae. Int J Antimicrob Agents. 2012 Jan;39(1):86-9. doi: 10.1016/j.ijantimicag.2011.09.012. Epub 2011 Oct 29. [PubMed:22041508]
Kind
Protein
Organism
Escherichia coli
Pharmacological action
Yes
Actions
Inhibitor
General Function
Beta-lactamase activity
Specific Function
Not Available
Gene Name
blaUOE-1
Uniprot ID
Q9EXV5
Uniprot Name
Beta-lactamase UOE-1
Molecular Weight
31143.3 Da
References
  1. Aktas Z, Kayacan C, Oncul O: In vitro activity of avibactam (NXL104) in combination with beta-lactams against Gram-negative bacteria, including OXA-48 beta-lactamase-producing Klebsiella pneumoniae. Int J Antimicrob Agents. 2012 Jan;39(1):86-9. doi: 10.1016/j.ijantimicag.2011.09.012. Epub 2011 Oct 29. [PubMed:22041508]
Kind
Protein
Organism
Pseudomonas aeruginosa
Pharmacological action
Yes
Actions
Inhibitor
General Function
Beta-lactamase activity
Specific Function
Not Available
Gene Name
per1
Uniprot ID
P37321
Uniprot Name
Extended-spectrum beta-lactamase PER-1
Molecular Weight
33572.575 Da
References
  1. Aktas Z, Kayacan C, Oncul O: In vitro activity of avibactam (NXL104) in combination with beta-lactams against Gram-negative bacteria, including OXA-48 beta-lactamase-producing Klebsiella pneumoniae. Int J Antimicrob Agents. 2012 Jan;39(1):86-9. doi: 10.1016/j.ijantimicag.2011.09.012. Epub 2011 Oct 29. [PubMed:22041508]

Transporters

Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Substrate
General Function
Organic anion transmembrane transporter activity
Specific Function
Mediates hepatobiliary excretion of numerous organic anions. May function as a cellular cisplatin transporter.
Gene Name
ABCC2
Uniprot ID
Q92887
Uniprot Name
Canalicular multispecific organic anion transporter 1
Molecular Weight
174205.64 Da
Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Substrate
General Function
Sodium-independent organic anion transmembrane transporter activity
Specific Function
Plays an important role in the excretion/detoxification of endogenous and exogenous organic anions, especially from the brain and kidney. Involved in the transport basolateral of steviol, fexofenad...
Gene Name
SLC22A8
Uniprot ID
Q8TCC7
Uniprot Name
Solute carrier family 22 member 8
Molecular Weight
59855.585 Da

Drug created on May 11, 2015 15:50 / Updated on November 02, 2018 08:52