Cethromycin

Identification

Summary

Cethromycin is a ketolide antibiotic with broad-spectrum activity against Gram-positive, Gram-negative, and atypical bacteria that may be useful for treating several conditions including community-acquired pneumonia, inhalation anthrax, plague, and tularemia.

Generic Name
Cethromycin
DrugBank Accession Number
DB06419
Background

Cethromycin is a 3-keto (ketolide) derivative of erythromycin A with an 11,12-carbamate group and an O-6-linked aromatic ring system.1 Cethromycin represents a joint development effort by Abbott Laboratories, Taisho Pharmaceuticals, and Advanced Life Sciences, intended to be marketed under the trade name Restanza for the treatment of community-acquired pneumonia.13,1 However, after completing phase III clinical trials, it was deemed safe but not sufficiently efficacious by the FDA.1

Since this time, cethromycin has received FDA orphan drug designations for the prophylactic treatment of anthrax inhalation, plague due to Yersinia pestis, and tularemia due to Francisella tularensis.11 It has also been investigated, by itself or together with zoliflodacin, for the treatment of gonorrhea,8,10 and was recently suggested as a possible treatment for liver-stage Plasmodium sporozoite infection.9

Type
Small Molecule
Groups
Investigational
Structure
Thumb
Weight
Average: 765.945
Monoisotopic: 765.420045112
Chemical Formula
C42H59N3O10
Synonyms
  • Cethromycin
  • Céthromycine
  • Cethromycinum
  • Cetromicina
External IDs
  • A-195773
  • ABBOTT-195773
  • ABT-773

Pharmacology

Indication

Cethromycin currently has no FDA-approved indications; it was granted orphan drug designation for the prophylactic treatment of inhalation anthrax in 2007 and for the prophylactic treatment of both plague due to Yersinia pestis and tularemia due to Francisella tularensis in 2009.11

Pharmacology
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Associated Conditions
Contraindications & Blackbox Warnings
Contraindications
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Pharmacodynamics

Cethromycin binds to the 50S subunit of the bacterial ribosome to inhibit both ribosome assembly and bacterial protein synthesis.1,3,3 Adverse effects such as diarrhea, nausea, vomiting, and headache may be due to off-target inhibition of molecules within mammalian cells.13

Mechanism of action

Respiratory tract infections can be caused by numerous strains of bacteria, requiring careful consideration of treatment and antibiotics effective against a broad spectrum of potential pathogens. Cethromycin, like other macrolide antibiotics, binds to the 23S rRNA of the 50S subunit of the bacterial ribosome. This binding, primarily mediated through regions II and V of the rRNA, occludes the peptide exit tunnel and inhibits bacterial protein synthesis. In addition, cethromycin is capable of binding to ribosomal intermediates during ribosome biogenesis, inhibiting the formation of functional 70S bacterial ribosomes. Due to the sequence and structural similarity of ribosomes between species, cethromycin displays broad-spectrum activity against diverse Gram-positive, Gram-negative, and atypical bacteria.1,3,3

TargetActionsOrganism
A23S ribosomal RNA
antagonist
Enteric bacteria and other eubacteria
Absorption

Cethromycin displays non-linear absorption kinetics. In healthy adults administered 150 mg cethromycin orally once daily for five doses, the calculated Cmax, Tmax, and AUC0-24 values were 0.181 ± 0.084 μg/ml, 2.01 ± 1.30 hrs, and 0.902 ± 0.469 μg*h/ml, respectively. Similarly, the corresponding values for a 300 mg dose were 0.500 ± 0.168 μg/ml, 2.09 ± 0.03 hrs, and 3.067 ± 1.205 μg*h/ml, respectively.2

In another study using a single oral dose of 150 mg cethromycin, the Cmax was 318 ± 161 ng/ml, the Tmax was 1.79 ± 0.50, the AUC0-24 was 1596 ± 876 ng*h/ml, and the AUC0-∞ was 1662 ± 907 ng*h/ml.7

Volume of distribution

Cethromycin given in five 150 mg oral doses had an apparent volume of distribution at the terminal elimination phase of 1433 ± 843 L, and an apparent steady-state volume of distribution of 1453 ± 997 L. The corresponding values for a 300 mg dose was 761 ± 293 L and 769 ± 272 L.2 Cethromycin is known to accumulate in the epithelial lining fluid and alveolar cells,2 as well as within polymorphonuclear leukocytes.6

Protein binding

Cethromycin displays 86.7 to 95.6% human plasma protein binding over a range of concentrations between 0.1 to 30.0 μg/ml.2

Metabolism

Extensive studies of cethromycin metabolism have not been conducted, although one study identified seven metabolites within feces of patients administered a single 150 mg oral dose. The major recovered products were unchanged cethromycin and an inactive N-desmethyl metabolite. It is likely that most of the metabolism occurs in the liver and is mediated, at least in part, by CYP3A4.12

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Route of elimination

Cethromycin is primarily excreted by the biliary route, with 87.2% of an initial dose recovered in feces and only 7.0% in urine. Unchanged cethromycin accounted for 35.7% of the radioactivity recovered in feces and an N-desmethyl metabolite for 39.8%; the remaining radioactivity was approximately evenly divided between three minor metabolites and a group of uncharacterized additional products.12

Half-life

Cethromycin given in five oral doses of 150 or 300 mg has a plasma half-life of 4.85 ± 1.10 and 4.94 ± 0.66 hrs, respectively.2 A single oral dose of 150 mg produced a measured half-life of 5.66 ± 0.77 hrs.7

Clearance

Cethromycin clearance in patients receiving a once-daily oral dose of 300 mg is reported to be approximately 63 L/h.2

Adverse Effects
Adverseeffects
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Toxicity

Toxicity information regarding cethromycin is not readily available. Patients experiencing an overdose are at an increased risk of severe adverse effects such as diarrhea, nausea, vomiting, abdominal pain, and headaches. Symptomatic and supportive measures are recommended.13,1

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
AbametapirThe serum concentration of Cethromycin can be increased when it is combined with Abametapir.
AbataceptThe metabolism of Cethromycin can be increased when combined with Abatacept.
AbemaciclibThe serum concentration of Abemaciclib can be increased when it is combined with Cethromycin.
AbirateroneThe metabolism of Cethromycin can be decreased when combined with Abiraterone.
AcalabrutinibThe metabolism of Acalabrutinib can be decreased when combined with Cethromycin.
AcenocoumarolThe serum concentration of Acenocoumarol can be increased when it is combined with Cethromycin.
AcetyldigitoxinThe serum concentration of Acetyldigitoxin can be increased when it is combined with Cethromycin.
AdalimumabThe metabolism of Cethromycin can be increased when combined with Adalimumab.
AfatinibThe serum concentration of Afatinib can be increased when it is combined with Cethromycin.
AlbendazoleThe metabolism of Albendazole can be decreased when combined with Cethromycin.
Interactions
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Food Interactions
No interactions found.

Products

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International/Other Brands
Restanza

Categories

Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as aminoglycosides. These are molecules or a portion of a molecule composed of amino-modified sugars.
Kingdom
Organic compounds
Super Class
Organic oxygen compounds
Class
Organooxygen compounds
Sub Class
Carbohydrates and carbohydrate conjugates
Direct Parent
Aminoglycosides
Alternative Parents
Quinolines and derivatives / 1,3-dicarbonyl compounds / Benzenoids / Pyridines and derivatives / Oxazolidinones / Oxanes / Carbamate esters / Heteroaromatic compounds / 1,2-aminoalcohols / Trialkylamines
show 13 more
Substituents
1,2-aminoalcohol / 1,3-dicarbonyl compound / Acetal / Alcohol / Amine / Amino acid or derivatives / Aminoglycoside core / Aromatic heteropolycyclic compound / Azacycle / Benzenoid
show 27 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not Available
Affected organisms
  • Bacteria

Chemical Identifiers

UNII
J0086219X6
CAS number
205110-48-1
InChI Key
PENDGIOBPJLVBT-AMXFZXBBSA-N
InChI
InChI=1S/C42H59N3O10/c1-11-32-42(8)36(44-40(50)55-42)25(4)33(46)23(2)21-41(7,51-18-14-15-28-20-29-16-12-13-17-30(29)43-22-28)37(26(5)34(47)27(6)38(49)53-32)54-39-35(48)31(45(9)10)19-24(3)52-39/h12-17,20,22-27,31-32,35-37,39,48H,11,18-19,21H2,1-10H3,(H,44,50)/t23-,24-,25+,26+,27-,31+,32-,35-,36-,37-,39+,41-,42-/m1/s1
IUPAC Name
(3aS,4R,7R,9R,10R,11R,13R,15R,15aR)-10-{[(2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyloxan-2-yl]oxy}-4-ethyl-3a,7,9,11,13,15-hexamethyl-11-{[3-(quinolin-3-yl)prop-2-en-1-yl]oxy}-tetradecahydro-1H-oxacyclotetradeca[4,3-d][1,3]oxazole-2,6,8,14-tetrone
SMILES
[H]C(CO[C@]1(C)C[C@@H](C)C(=O)[C@H](C)[C@H]2NC(=O)O[C@]2(C)[C@@H](CC)OC(=O)[C@H](C)C(=O)[C@H](C)[C@H]1O[C@@H]1O[C@H](C)C[C@@H]([C@H]1O)N(C)C)=C([H])C1=CC2=C(C=CC=C2)N=C1

References

Synthesis Reference

Yat Sun Or, Zhenkun Ma, Richard F. Clark, Daniel T. Chu, Jacob J. Plattner. "6-o-substituted ketolides having antibacterial activity". Patent WO1998009978A1, Issued March 12, 1998.

General References
  1. Mansour H, Chahine EB, Karaoui LR, El-Lababidi RM: Cethromycin: a new ketolide antibiotic. Ann Pharmacother. 2013 Mar;47(3):368-79. doi: 10.1345/aph.1R435. Epub 2013 Mar 5. [Article]
  2. Conte JE Jr, Golden JA, Kipps J, Zurlinden E: Steady-state plasma and intrapulmonary pharmacokinetics and pharmacodynamics of cethromycin. Antimicrob Agents Chemother. 2004 Sep;48(9):3508-15. doi: 10.1128/AAC.48.9.3508-3515.2004. [Article]
  3. Champney WS, Pelt J: The ketolide antibiotic ABT-773 is a specific inhibitor of translation and 50S ribosomal subunit formation in Streptococcus pneumoniae cells. Curr Microbiol. 2002 Sep;45(3):155-60. doi: 10.1007/s00284-001-0110-9. [Article]
  4. Vimberg V, Xiong L, Bailey M, Tenson T, Mankin A: Peptide-mediated macrolide resistance reveals possible specific interactions in the nascent peptide exit tunnel. Mol Microbiol. 2004 Oct;54(2):376-85. doi: 10.1111/j.1365-2958.2004.04290.x. [Article]
  5. Edelstein PH: Pneumococcal resistance to macrolides, lincosamides, ketolides, and streptogramin B agents: molecular mechanisms and resistance phenotypes. Clin Infect Dis. 2004 May 15;38 Suppl 4:S322-7. doi: 10.1086/382687. [Article]
  6. Garcia I, Pascual A, Ballesta S, del Castillo C, Perea EJ: Accumulation and activity of cethromycin (ABT-773) within human polymorphonuclear leucocytes. J Antimicrob Chemother. 2003 Jul;52(1):24-8. doi: 10.1093/jac/dkg290. Epub 2003 Jun 12. [Article]
  7. Pletz MW, Preechachatchaval V, Bulitta J, Allewelt M, Burkhardt O, Lode H: ABT-773: pharmacokinetics and interactions with ranitidine and sucralfate. Antimicrob Agents Chemother. 2003 Mar;47(3):1129-31. doi: 10.1128/aac.47.3.1129-1131.2003. [Article]
  8. Jacobsson S, Alirol E, Unemo M: In vitro activity of the ketolide cethromycin in multidrug-resistant clinical Neisseria gonorrhoeae isolates and international reference strains. J Chemother. 2019 Sep;31(5):246-251. doi: 10.1080/1120009X.2019.1615724. Epub 2019 May 20. [Article]
  9. Sullivan DJ, Liu Y, Mott BT, Kaludov N, Martinov MN: Discovery of Novel Liver-Stage Antimalarials through Quantum Similarity. PLoS One. 2015 May 7;10(5):e0125593. doi: 10.1371/journal.pone.0125593. eCollection 2015. [Article]
  10. Foerster S, Drusano G, Golparian D, Neely M, Piddock LJV, Alirol E, Unemo M: In vitro antimicrobial combination testing of and evolution of resistance to the first-in-class spiropyrimidinetrione zoliflodacin combined with six therapeutically relevant antimicrobials for Neisseria gonorrhoeae. J Antimicrob Chemother. 2019 Dec 1;74(12):3521-3529. doi: 10.1093/jac/dkz376. [Article]
  11. FDA Orphan Drug Designations and Approvals [Link]
  12. Human Disposition and Metabolism of Orally Administered (14C)ABT-773 [Link]
  13. Clinical Trial NCT00336505 [Link]
KEGG Drug
D02391
KEGG Compound
C12020
PubChem Compound
447451
PubChem Substance
310264871
ChemSpider
34991522
ChEBI
29506
ChEMBL
CHEMBL3989904
Wikipedia
Cethromycin

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3CompletedTreatmentPneumonia2

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
Not Available
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.00489 mg/mLALOGPS
logP4.6ALOGPS
logP5.75ChemAxon
logS-5.2ALOGPS
pKa (Strongest Acidic)9.22ChemAxon
pKa (Strongest Basic)8.61ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count10ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area162.82 Å2ChemAxon
Rotatable Bond Count8ChemAxon
Refractivity204.58 m3·mol-1ChemAxon
Polarizability84.61 Å3ChemAxon
Number of Rings5ChemAxon
Bioavailability0ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
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/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

Targets

Drugtargets2
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Kind
Nucleotide
Organism
Enteric bacteria and other eubacteria
Pharmacological action
Yes
Actions
Antagonist
In prokaryotes, the 23S rRNA is part of the large subunit (the 50S) that joins with the 30S small subunit to create the functional 70S ribosome. The ribosome is comprised of 3 RNAs: the 23S, the 16S and the 5S ribosomal RNAs. The 23S and the 5S associate with their respective proteins to make up the large subunit of the ribosome, while the 16S RNA associates with its proteins to make up the small subunit.
References
  1. Mansour H, Chahine EB, Karaoui LR, El-Lababidi RM: Cethromycin: a new ketolide antibiotic. Ann Pharmacother. 2013 Mar;47(3):368-79. doi: 10.1345/aph.1R435. Epub 2013 Mar 5. [Article]
  2. Champney WS, Pelt J: The ketolide antibiotic ABT-773 is a specific inhibitor of translation and 50S ribosomal subunit formation in Streptococcus pneumoniae cells. Curr Microbiol. 2002 Sep;45(3):155-60. doi: 10.1007/s00284-001-0110-9. [Article]
  3. Vimberg V, Xiong L, Bailey M, Tenson T, Mankin A: Peptide-mediated macrolide resistance reveals possible specific interactions in the nascent peptide exit tunnel. Mol Microbiol. 2004 Oct;54(2):376-85. doi: 10.1111/j.1365-2958.2004.04290.x. [Article]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
Inhibitor
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
References
  1. Mansour H, Chahine EB, Karaoui LR, El-Lababidi RM: Cethromycin: a new ketolide antibiotic. Ann Pharmacother. 2013 Mar;47(3):368-79. doi: 10.1345/aph.1R435. Epub 2013 Mar 5. [Article]
  2. Liang JH: Introduction of a nitrogen-containing side chain appended on C-10 of cethromycin leads to reduced CYP3A4 inhibition (WO2014049356A1). Expert Opin Ther Pat. 2015 Jan;25(1):119-23. doi: 10.1517/13543776.2014.971754. Epub 2014 Oct 18. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Oxygen binding
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP3A5
Uniprot ID
P20815
Uniprot Name
Cytochrome P450 3A5
Molecular Weight
57108.065 Da
References
  1. Katz DA, Grimm DR, Cassar SC, Gentile MC, Ye X, Rieser MJ, Gordon EF, Polzin JE, Gustavson LE, Driscoll RM, O'dea RF, Williams LA, Bukofzer S: CYP3A5 genotype has a dose-dependent effect on ABT-773 plasma levels. Clin Pharmacol Ther. 2004 Jun;75(6):516-28. [Article]

Transporters

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
Inhibitor
General Function
Xenobiotic-transporting atpase activity
Specific Function
Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.
Gene Name
ABCB1
Uniprot ID
P08183
Uniprot Name
Multidrug resistance protein 1
Molecular Weight
141477.255 Da
References
  1. Mansour H, Chahine EB, Karaoui LR, El-Lababidi RM: Cethromycin: a new ketolide antibiotic. Ann Pharmacother. 2013 Mar;47(3):368-79. doi: 10.1345/aph.1R435. Epub 2013 Mar 5. [Article]

Drug created on March 19, 2008 16:33 / Updated on February 21, 2021 18:52