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Avibactam (NXL-104; NXL104; Avycaz) is a covalent/reversible non-β-lactam β-lactamase inhibitor approved for use in combination with ceftazidime by the FDA on February 25, 2015 for treating bacterial infections, including those caused by multi-drug resistant gram-negative bacterial pathogens. It inhibits β-lactamase TEM-1 and CTX-M-15 with IC50s of 8 nM and 5 nM, respectively.
Physicochemical Properties
| Molecular Formula | C7H10N3NAO6S |
| Molecular Weight | 287.22 |
| Exact Mass | 287.018 |
| Elemental Analysis | C, 29.27; H, 3.51; N, 14.63; Na, 8.00; O, 33.42; S, 11.16 |
| CAS # | 1192491-61-4 |
| Related CAS # | Avibactam free acid;1192500-31-4;Avibactam sodium hydrate;2938989-90-1;Avibactam sodium dihydrate |
| PubChem CID | 24944097 |
| Appearance | White to off-white solid powder |
| LogP | 0.453 |
| Hydrogen Bond Donor Count | 1 |
| Hydrogen Bond Acceptor Count | 6 |
| Rotatable Bond Count | 3 |
| Heavy Atom Count | 18 |
| Complexity | 462 |
| Defined Atom Stereocenter Count | 2 |
| SMILES | C1C[C@H](N2C[C@@H]1N(C2=O)OS(=O)(=O)[O-])C(=O)N.[Na+] |
| InChi Key | RTCIKUMODPANKX-JBUOLDKXSA-M |
| InChi Code | InChI=1S/C7H11N3O6S.Na/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);/q;+1/p-1/t4-,5+;/m1./s1 |
| Chemical Name | sodium (2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl sulfate |
| Synonyms | NXL104; NXL-104; NXL 104; Avibactam; |
| HS Tariff Code | 2934.99.9001 |
| Storage |
Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month Note: Please store this product in a sealed and protected environment, avoid exposure to moisture. |
| Shipping Condition | Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs) |
Biological Activity
| Targets | CTX-M-15(IC50=5 nM);TEM-1(IC50=8 nM ) |
| ln Vitro |
Monetary antibacterial activity is low for avibactam, which inhibits class A and C β-lactamases but not metallotypes or Acinetobacter OXA carbapenemases[2]. With MIC50 and MIC90 for both 8 mg/L, ceftazidime (HY-B0593)-avibactam (0-256 mg/L) inhibits the growth of 16 blaKPC-2 positive and 1 blaOXA-232 positive Klebsiella pneumonia[4]. |
| ln Vivo | Ceftazidime-Avibactam (0.375 mg/g; s.c.; every 8 hours for 10 days) significantly affects the bacteria and has been shown to have some therapeutic efficacy in an infected mouse model with K. pneumoniae strain Y8[3]. Avibactam (64 mg/kg; s.c.; once) infected neutropenic mice with lung infection exhibits a mean estimated half-life in plasma in the terminal phase of 0.24 h[3]. |
| Enzyme Assay | In a 200 μL reaction volume, 1 μM TEM-1 is incubated with and without 5 μM Avibactam for 5 min at 37°C and subjected to two ultrafiltration cartridge (UFC) steps to remove excess inhibitor (Ultrafree-0.5 with Biomax membrane, 5-kDa cutoff). Centrifugation at 10,600× g for 8 min is performed at 4°C. After each ultrafiltration step, 20 μL retentate are diluted with 180 μL assay buffer to restore the original enzyme concentration. After two UFC treatments, the amount of free Avibactam is quantified by liquid chromotography/MS/MS and found to be<5% of the original concentration. Loss of protein during UFC is assessed by measuring TEM-1 activity (on 4,000-fold dilution) in the acyl-enzyme sample compare with non-UFC-treated enzyme, and loss is found to be <5%[1]. |
| Cell Assay | Cells (~109 cfu) from overnight broth culture are spread on Mueller-Hinton agar supplemented with either (i) Ceftaroline plus Avibactam (1 or 4 mg/L) at 1-16× the MICs or (ii) Ceftaroline at 1 or 4 mg/L plus Avibactam at 1-8× the concentration needed to reduce the Ceftaroline MIC to 1 or 4 mg/L. Colonies are counted after overnight incubation and representatives are retained[2]. |
| Animal Protocol |
Animal Model: Six-week-old BALB/c mice (female), K. pneumoniae strain Y8 infection model[4] Dosage: 0.375 mg/g in combination with Ceftazidime Administration: Subcutaneous injection, 4 h post infection and given every 8 h for 10 days Result: Within 4 days, 70% of the mice in the infection group perished, and in 13 days, every mouse in the PBS group perished. When the antibiotic was given every eight hours for ten days after infection, all of the mice in the treatment group survived; however, when the antibiotic treatment was stopped, all of the mice in the control group perished in four days. When compared to the infected group, the treatment group mice's liver and spleen had reduced CFU counts. |
| References |
[1]. Avibactam is a covalent, reversible, non-β-lactam β-lactamase inhibitor. Proc Natl Acad Sci U S A. 2012 Jul 17;109(29):11663-8. [2]. Characterization of β-lactamase and porin mutants of Enterobacteriaceae selected with ceftaroline + avibactam (NXL104). J Antimicrob Chemother. 2012 Jun;67(6):1354-8. [3]. Pharmacokinetics and penetration of GR20263 and avibactam into epithelial lining fluid in thigh- and lung-infected mice. Antimicrob Agents Chemother. 2015 Apr;59(4):2299-304. [4]. In vitro and in vivo bactericidal activity of ceftazidime-avibactam against Carbapenemase-producing Klebsiella pneumoniae. Antimicrob Resist Infect Control. 2018 Nov 21;7:142. |
| Additional Infomation | Avibactam sodium is an organic sodium salt that is the monosodium salt of avibactam. Used in combination with ceftazidime pentahydrate for the treatment of complicated urinary tract infections including pyelonephritis. It has a role as an EC 3.5.2.6 (beta-lactamase) inhibitor, an antibacterial drug and an antimicrobial agent. It contains an avibactam(1-). |
Solubility Data
| Solubility (In Vitro) |
DMSO :30~57 mg/mL ( 104.45 ~198.44 mM ) Water : 50 ~57 mg/mL(~174.08 mM) |
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.75 mg/mL (9.57 mM) (saturation unknown) in 5% DMSO + 40% PEG300 + 5% Tween80 + 50% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.75 mg/mL (9.57 mM) (saturation unknown) in 5% DMSO + 95% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. Solubility in Formulation 3: ≥ 2.08 mg/mL (7.24 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 4: ≥ 2.08 mg/mL (7.24 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. Solubility in Formulation 5: ≥ 0.55 mg/mL (1.91 mM) (saturation unknown) in 1% DMSO 99% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 6: 5% DMSO+40% PEG300+5% Tween-80+50% Saline: ≥ 2.75 mg/mL (9.57 mM) Solubility in Formulation 7: 140 mg/mL (487.41 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 3.4817 mL | 17.4083 mL | 34.8165 mL | |
| 5 mM | 0.6963 mL | 3.4817 mL | 6.9633 mL | |
| 10 mM | 0.3482 mL | 1.7408 mL | 3.4817 mL |