Identification
- Summary
Plazomicin is an aminoglycoside antibiotic used to treat complicated urinary tract infections.
- Brand Names
- Zemdri
- Generic Name
- Plazomicin
- DrugBank Accession Number
- DB12615
- Background
Developed by Achaogen biopharmaceuticals, plazomicin is a next-generation aminoglycoside synthetically derived from Sisomicin. The structure of plazomicin was established via appending hydroxylaminobutyric acid to Sisomicin at position 1 and 2-hydroxyethyl group at position 6' 1. It was designed to evade all clinically relevant aminoglycoside-modifying enzymes, which contribute to the main resistance mechanism for aminoglycoside therapy 1. However, acquired resistance of aminoglycosides may arise through over expression of efflux pumps and ribosomal modification by bacteria, which results from amino acid or rRNA sequence mutations 1. Like other aminoglycosides, plazomicin is ineffective against bacterial isolates that produce 16S rRNA methyltransferases Label. Plazomicin mediates the antibacterial activity against pathogens including carbapenem-resistant (CRE) and extended-spectrum beta-lactamase (ESBL) producing Enterobacteriaceae. It mediates the antibacterial activity by binding to bacterial 30S ribosomal subunit and inhibiting protein synthesis Label. On June 28th, 2018, plazomicin sulfate was approved by the FDA for use in adult patients for the treatment of complicated urinary tract infections (cUTI) including Pyelonephritis. It is marketed as Zemdri and is administered via once-daily intravenous infusion.
- Type
- Small Molecule
- Groups
- Approved, Investigational
- Structure
Structure for Plazomicin (DB12615)
- Weight
- Average: 592.691
Monoisotopic: 592.34319177 - Chemical Formula
- C25H48N6O10
- Synonyms
- Plazomicin
- External IDs
- ACHN 490
- ACHN-490
- ACHN490
Pharmacology
- Indication
Plazomicin is indicated for the treatment of patients 18 years of age or older with Complicated Urinary Tract Infections (cUTI) including Pyelonephritis, who have limited or no alternative treatment options. It should only be used to treat infections that are proven or strongly suspected to be caused by susceptible microorganisms Label.
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Indication Type Indication Combined Product Details Approval Level Age Group Patient Characteristics Dose Form Treatment of Complicated urinary tract infection •••••••••••• ••••• ••••••••• Treatment of Pyelonephritis •••••••••••• ••••• ••••••••• - Contraindications & Blackbox Warnings
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Plazomicin exerts its antibacterial activity in a dose-dependent manner with a post-antibiotic effect ranging from 0.2 to 2.6 hours at 2X MIC against Enterobacteriaceae, as demonstrated by in vitro studies Label. In clinical trials comprising of hospitalized adult patients with cUTI (including pyelonephritis), resolution or improvement of clinical cUTI symptoms and a microbiological outcome of eradication were observed at day 5 following the first dose administration of plazomicin Label. Plazomicin has shown to elicit nephrotoxic, ototoxic, and neuromuscular blocking effects. In clinical trials, it did not induce any clinically relevant QTc-prolonging effects Label.
- Mechanism of action
Plazomicin exerts a bactericidal action against susceptible bacteria by binding to bacterial 30S ribosomal subunit 1. Aminoglycosides typically bind to the ribosomal aminoacyl-tRNA site (A-site) and induce a conformational change to further facilitate the binding between the rRNA and the antibiotic 5. This leads to codon misreading and mistranslation of mRNA during bacterial protein synthesis 5.
Plazomicin demonstrates potency against Enterobacteriaceae, including species with multidrug-resistant phenotypes such as carbapenemase-producing bacteria and isolates with resistance to all other aminoglycosides 1,2,3. Its antibacterial activity is not inhibited by aminoglycoside modifying enzymes (AMEs) produced by bacteria, such as acetyltransferases (AACs), phosphotransferases (APHs), and nucleotidyltransferases (ANTs) 4,Label. Plazomicin was shown to be effective against Enterobacteriaceae in presence of some beta-lactamases Label. In clinical settings and in vivo, bacteria shown to be susceptible toward plazomicin include Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, and Enterobacter cloacae Label. Other aerobic bacteria that may be affected by plazomicin are Citrobacter freundii, Citrobacter koseri, Enterobacter aerogenes, Klebsiella oxytoca, Morganella morganii, Proteus vulgaris, Providencia stuartii, and Serratia marcescens Label.
Target Actions Organism A30S ribosomal protein S11 inhibitorEnterobacteriaceae bacterium (strain FGI 57) U30S ribosomal protein S14 inhibitorEscherichia coli (strain K12) - Absorption
Administration of 15 mg/kg plazomicin by 30-minute IV infusion resulted in peak plasma concentrations of 73.7 ± 19.7 μg/mL in healthy adult subjects and 51.0 ± 26.7 μg/mL in patients with complicated urinary tract infections (cUTI) Label. The area under the curve (AUC) were 257 ± 67.0 μg.h/mL in healthy adults and 226 ± 113 μg.h/mL in cUTI patients Label.
- Volume of distribution
The mean (±SD) volume of distribution is 17.9 (±4.8) L in healthy adults and 30.8 (±12.1) L in cUTI patients Label.
- Protein binding
The extent of plasma protein binding in humans is approximately 20% Label. The degree of protein binding was concentration-independent across the range tested in vitro (5 to 100 mcg/mL) Label.
- Metabolism
Plazomicin is not reported to undergo significant metabolism Label.
- Route of elimination
Plazomicin predominantly undergoes renal excretion, where 56% of the total administered drug was recovered in the urine within 4 hours following a single 15 mg/kg IV dose of radiolabeled plazomicin in healthy subjects. About less than 0.2% and 89.1% of the total drug were recovered within 168 hours in feces and urine, respectively Label.
- Half-life
The mean (±SD) half-life of plazomicin was 3.5 h (±0.5) in healthy adults with normal renal function receiving 15 mg/kg plazomicin via intravenous infusion Label.
- Clearance
Following administration of 15 mg/kg plazomicin by 30-minute IV infusion, the mean (±SD) total body clearance in healthy adults and cUTI patients is 4.5 (±0.9) and 5.1 (±2.01) L/h, respectively Label.
- Adverse Effects
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In case of suspected overdose, plazomicin therapy should be discontinued with initiation of supportive care. Maintenance of glomerular filtration and careful monitoring of renal function is recommended. Hemodialysis may be used to facilitate drug elimination, and this may be especially clinically useful in patients with compromised renal function Label.
- 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.
Drug Interaction Integrate drug-drug
interactions in your softwareAbacavir Abacavir may decrease the excretion rate of Plazomicin which could result in a higher serum level. Abemaciclib The excretion of Abemaciclib can be decreased when combined with Plazomicin. Aceclofenac Aceclofenac may decrease the excretion rate of Plazomicin which could result in a higher serum level. Acemetacin Acemetacin may decrease the excretion rate of Plazomicin which could result in a higher serum level. Acenocoumarol The risk or severity of bleeding can be increased when Plazomicin is combined with Acenocoumarol. - Food Interactions
- No interactions found.
Products
Drug product information from 10+ global regionsOur datasets provide approved product information including:dosage, form, labeller, route of administration, and marketing period.Access drug product information from over 10 global regions.- Product Ingredients
Ingredient UNII CAS InChI Key Plazomicin sulfate A78L6MT746 1380078-95-4 SFTBRKHJMASSAP-BGJNVEJLSA-N - Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Zemdri (plazomicin) Injection 500 mg/10mL Intravenous Achaogen, Inc. 2018-07-16 Not applicable US 
Zemdri (plazomicin) Injection 500 mg/10mL Intravenous Cipla Therapeutics Inc. 2018-07-16 Not applicable US Zemdri (plazomicin) Injection 500 mg/10mL Intravenous Cipla USA Inc. 2018-07-16 Not applicable US
Categories
- ATC Codes
- J01GB14 — Plazomicin
- Drug Categories
- Agents that produce neuromuscular block (indirect)
- Aminoglycoside Antibacterials
- Anti-Bacterial Agents
- Antibacterials for Systemic Use
- Antiinfectives for Systemic Use
- Carbohydrates
- Drugs that are Mainly Renally Excreted
- Drugs that are Mainly Renally Excreted with a Narrow Therapeutic Index
- Gentamicins
- Glycosides
- MATE 1 Inhibitors
- MATE 2 Inhibitors
- MATE inhibitors
- Narrow Therapeutic Index Drugs
- Nephrotoxic agents
- Chemical TaxonomyProvided by Classyfire
- Description
- This compound belongs to the class of organic compounds known as gamma amino acids and derivatives. These are amino acids having a (-NH2) group attached to the gamma carbon atom.
- Kingdom
- Organic compounds
- Super Class
- Organic acids and derivatives
- Class
- Carboxylic acids and derivatives
- Sub Class
- Amino acids, peptides, and analogues
- Direct Parent
- Gamma amino acids and derivatives
- Alternative Parents
- O-glycosyl compounds / Aminocyclitols and derivatives / Aminosaccharides / Cyclohexylamines / Cyclohexanols / Oxanes / N-acyl amines / Monosaccharides / Tertiary alcohols / 1,3-aminoalcohols show 11 more
- Substituents
- 1,2-aminoalcohol / 1,3-aminoalcohol / Acetal / Alcohol / Aliphatic heteromonocyclic compound / Alkanolamine / Amine / Amino saccharide / Aminocyclitol or derivatives / Carbonyl group show 30 more
- Molecular Framework
- Aliphatic heteromonocyclic compounds
- External Descriptors
- Not Available
- Affected organisms
- Pseudomonas aeruginosa
- Escherichia coli
- Acinetobacter
- Enterobacter
- Klebsiella pneumoniae
Chemical Identifiers
- UNII
- LYO9XZ250J
- CAS number
- 1154757-24-0
- InChI Key
- IYDYFVUFSPQPPV-PEXOCOHZSA-N
- InChI
- InChI=1S/C25H48N6O10/c1-25(37)11-38-24(18(35)21(25)29-2)41-20-15(31-22(36)16(33)5-6-26)9-14(28)19(17(20)34)40-23-13(27)4-3-12(39-23)10-30-7-8-32/h3,13-21,23-24,29-30,32-35,37H,4-11,26-28H2,1-2H3,(H,31,36)/t13-,14+,15-,16+,17+,18-,19-,20+,21-,23-,24-,25+/m1/s1
- IUPAC Name
- (2S)-4-amino-N-[(1R,2S,3S,4R,5S)-5-amino-4-{[(2S,3R)-3-amino-6-{[(2-hydroxyethyl)amino]methyl}-3,4-dihydro-2H-pyran-2-yl]oxy}-2-{[(2R,3R,4R,5R)-3,5-dihydroxy-5-methyl-4-(methylamino)oxan-2-yl]oxy}-3-hydroxycyclohexyl]-2-hydroxybutanamide
- SMILES
- CN[C@@H]1[C@@H](O)[C@@H](O[C@H]2[C@@H](C[C@H](N)[C@@H](O[C@H]3OC(CNCCO)=CC[C@H]3N)[C@@H]2O)NC(=O)[C@@H](O)CCN)OC[C@]1(C)O
References
- General References
- Karaiskos I, Souli M, Giamarellou H: Plazomicin: an investigational therapy for the treatment of urinary tract infections. Expert Opin Investig Drugs. 2015;24(11):1501-11. doi: 10.1517/13543784.2015.1095180. Epub 2015 Sep 30. [Article]
- Denervaud-Tendon V, Poirel L, Connolly LE, Krause KM, Nordmann P: Plazomicin activity against polymyxin-resistant Enterobacteriaceae, including MCR-1-producing isolates. J Antimicrob Chemother. 2017 Oct 1;72(10):2787-2791. doi: 10.1093/jac/dkx239. [Article]
- Zhang Y, Kashikar A, Bush K: In vitro activity of plazomicin against beta-lactamase-producing carbapenem-resistant Enterobacteriaceae (CRE). J Antimicrob Chemother. 2017 Oct 1;72(10):2792-2795. doi: 10.1093/jac/dkx261. [Article]
- Lopez-Diaz MD, Culebras E, Rodriguez-Avial I, Rios E, Vinuela-Prieto JM, Picazo JJ, Rodriguez-Avial C: Plazomicin Activity against 346 Extended-Spectrum-beta-Lactamase/AmpC-Producing Escherichia coli Urinary Isolates in Relation to Aminoglycoside-Modifying Enzymes. Antimicrob Agents Chemother. 2017 Jan 24;61(2). pii: AAC.02454-16. doi: 10.1128/AAC.02454-16. Print 2017 Feb. [Article]
- Dlugosz M, Trylska J: Aminoglycoside association pathways with the 30S ribosomal subunit. J Phys Chem B. 2009 May 21;113(20):7322-30. doi: 10.1021/jp8112914. [Article]
- External Links
- PubChem Compound
- 42613186
- PubChem Substance
- 347828829
- ChemSpider
- 26390008
- 2049549
- ChEMBL
- CHEMBL1650559
- ZINC
- ZINC000068150640
- PDBe Ligand
- EDS
- Wikipedia
- Plazomicin
- PDB Entries
- 6cd7 / 7lh5
- FDA label
- Download (436 KB)
Clinical Trials
- Clinical Trials
Phase Status Purpose Conditions Count 3 Completed Treatment Acute Pyelonephritis (AP) Due to CRE / Bloodstream Infections (BSI) Due to CRE / Complicated Urinary Tract Infection (cUTI) Due to CRE / Hospital-Acquired Bacterial Pneumonia (HABP) Due to CRE / Ventilator-Associated Bacterial Pneumonia (VABP) Due to CRE 1 3 Completed Treatment Acute Tubulo-Interstitial Nephritis / Complicated Urinary Tract Infection 1 2 Completed Treatment Acute Tubulo-Interstitial Nephritis / Complicated Urinary Tract Infection 1 1 Completed Treatment Cardiac Effects in Normal Healthy Volunteers 1 1 Completed Treatment End Stage Renal Disease (ESRD) 1
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Injection Intravenous 500 mg/10mL - Prices
- Not Available
- Patents
Patent Number Pediatric Extension Approved Expires (estimated) Region US8383596 No 2013-02-26 2031-06-02 US US9688711 No 2017-06-27 2028-11-21 US US9266919 No 2016-02-23 2028-11-21 US US8822424 No 2014-09-02 2028-11-21 US
Properties
- State
- Not Available
- Experimental Properties
- Not Available
- Predicted Properties
Property Value Source Water Solubility 12.3 mg/mL ALOGPS logP -2.2 ALOGPS logP -6.1 Chemaxon logS -1.7 ALOGPS pKa (Strongest Acidic) 12.48 Chemaxon pKa (Strongest Basic) 9.89 Chemaxon Physiological Charge 5 Chemaxon Hydrogen Acceptor Count 15 Chemaxon Hydrogen Donor Count 11 Chemaxon Polar Surface Area 269.29 Å2 Chemaxon Rotatable Bond Count 13 Chemaxon Refractivity 145.09 m3·mol-1 Chemaxon Polarizability 62.27 Å3 Chemaxon Number of Rings 3 Chemaxon Bioavailability 0 Chemaxon Rule of Five No Chemaxon Ghose Filter No Chemaxon Veber's Rule No Chemaxon MDDR-like Rule Yes Chemaxon - Predicted ADMET Features
- Not Available
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
- Chromatographic Properties
Collision Cross Sections (CCS)
Adduct CCS Value (Å2) Source type Source [M-H]- 232.88329 predictedDeepCCS 1.0 (2019) [M+H]+ 235.17397 predictedDeepCCS 1.0 (2019) [M+Na]+ 241.26787 predictedDeepCCS 1.0 (2019)
Targets
- Kind
- Protein
- Organism
- Enterobacteriaceae bacterium (strain FGI 57)
- Pharmacological action
- Yes
- Actions
- Inhibitor
- General Function
- Located on the platform of the 30S subunit, it bridges several disparate RNA helices of the 16S rRNA. Forms part of the Shine-Dalgarno cleft in the 70S ribosome.
- Specific Function
- Rrna binding
- Gene Name
- rpsK
- Uniprot ID
- L0LZJ6
- Uniprot Name
- 30S ribosomal protein S11
- Molecular Weight
- 13858.85 Da
References
- Denervaud-Tendon V, Poirel L, Connolly LE, Krause KM, Nordmann P: Plazomicin activity against polymyxin-resistant Enterobacteriaceae, including MCR-1-producing isolates. J Antimicrob Chemother. 2017 Oct 1;72(10):2787-2791. doi: 10.1093/jac/dkx239. [Article]
- Kind
- Protein
- Organism
- Escherichia coli (strain K12)
- Pharmacological action
- Unknown
- Actions
- Inhibitor
- General Function
- Structural constituent of ribosome
- Specific Function
- Binds 16S rRNA, required for the assembly of 30S particles and may also be responsible for determining the conformation of the 16S rRNA at the A site.
- Gene Name
- rpsN
- Uniprot ID
- P0AG59
- Uniprot Name
- 30S ribosomal protein S14
- Molecular Weight
- 11580.36 Da
Transporters
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Inhibitor
- Curator comments
- Inhibition of MATE1 renal transporter was observed in vitro with an IC50 value of 1300 mcg/mL.
- General Function
- Monovalent cation:proton antiporter activity
- Specific Function
- Solute transporter for tetraethylammonium (TEA), 1-methyl-4-phenylpyridinium (MPP), cimetidine, N-methylnicotinamide (NMN), metformin, creatinine, guanidine, procainamide, topotecan, estrone sulfat...
- Gene Name
- SLC47A1
- Uniprot ID
- Q96FL8
- Uniprot Name
- Multidrug and toxin extrusion protein 1
- Molecular Weight
- 61921.585 Da
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Inhibitor
- Curator comments
- Inhibition of MATE2-K renal transporter was observed in vitro with an IC50 value of 338 mcg/mL.
- General Function
- Drug transmembrane transporter activity
- Specific Function
- Solute transporter for tetraethylammonium (TEA), 1-methyl-4-phenylpyridinium (MPP), cimetidine, N-methylnicotinamide, metformin, creatinine, guanidine, procainamide, topotecan, estrone sulfate, acy...
- Gene Name
- SLC47A2
- Uniprot ID
- Q86VL8
- Uniprot Name
- Multidrug and toxin extrusion protein 2
- Molecular Weight
- 65083.915 Da
References
- Zmedri FDA label [File]
Drug created at October 20, 2016 23:13 / Updated at February 21, 2021 18:53