In vitro, cethromycin has marked activity against these pathogens with the ability to overcome both efflux and methylation mechanisms of resistance in S. pneumoniae.[1]
The antibacterial activity of cethromycin is mediated through dual mechanisms of action: binding to the bacterial target, the 23S rRNA of the 50S subunit of the ribosome to prevent the translation of bacterial messenger RNAs into new proteins and interacting with partially assembled 50S subunit precursors to inhibit the complete formation of bacterial ribosomes.Cethromycin is able to overcome methylation-mediated resistance via a second point of contact with the ribosome . In addition, the enhanced binding of cethromycin is helpful in overcoming bacterial resistance mediated via efflux mechanisms, resulting in increases in antibacterial activity compared to both macrolide agents and the marketed ketolide agent, telithromycin . Cethromycin retains activity against clinical isolates of telithromycin-resistant S. pneumoniae, a phenomenon believed to be the result of the enhanced binding kinetics.[1]
The reduced activity of cethromycin against enteric Gram-negative bacteria should limit the collateral damage often seen with quinolone treatment yet preserve the favorable activity against susceptible and resistant CAP-causative pathogens.[1]

In vitro, cethromycin has marked activity against these pathogens with the ability to overcome both efflux and methylation mechanisms of resistance in S. pneumoniae.[1]
The antibacterial activity of cethromycin is mediated through dual mechanisms of action: binding to the bacterial target, the 23S rRNA of the 50S subunit of the ribosome to prevent the translation of bacterial messenger RNAs into new proteins and interacting with partially assembled 50S subunit precursors to inhibit the complete formation of bacterial ribosomes.Cethromycin is able to overcome methylation-mediated resistance via a second point of contact with the ribosome . In addition, the enhanced binding of cethromycin is helpful in overcoming bacterial resistance mediated via efflux mechanisms, resulting in increases in antibacterial activity compared to both macrolide agents and the marketed ketolide agent, telithromycin . Cethromycin retains activity against clinical isolates of telithromycin-resistant S. pneumoniae, a phenomenon believed to be the result of the enhanced binding kinetics.[1]
The reduced activity of cethromycin against enteric Gram-negative bacteria should limit the collateral damage often seen with quinolone treatment yet preserve the favorable activity against susceptible and resistant CAP-causative pathogens.[1]

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Cethromycin is a novel ketolide antibiotic with marked in vitro activity against Gram-positive bacteria relevant to community-acquired pneumonia (CAP), specifically Streptococcus pneumoniae, Staphylococcus aureus, Haemophilus influenzae, and Moraxella catarrhalis.[1]
The compound has the ability to overcome both efflux and methylation mechanisms of resistance in S. pneumoniae.[1]
It retains activity against clinical isolates of telithromycin-resistant S. pneumoniae, attributed to enhanced binding kinetics.[1]
Its antibacterial activity against common enteric Gram-negative bacteria is reduced, which is hypothesized to limit collateral damage to gut flora compared to fluoroquinolones.[1]

In two global Phase III non-inferiority studies (CL05-001 and CL06-001) involving adult patients with mild-to-moderate community-acquired pneumonia (CAP), Cethromycin (300 mg once daily for 7 days) demonstrated clinical efficacy comparable to clarithromycin (250 mg twice daily for 7 days).[1]
In the integrated analysis of both studies, the clinical cure rate in the Intent-to-Treat (ITT) population was 83.0% for Cethromycin compared to 84.8% for clarithromycin. In the Per Protocol clinically evaluable (PPc) population, the clinical cure rate was 92.8% for Cethromycin compared to 94.9% for clarithromycin. The studies met predefined non-inferiority criteria.[1]
Bacterial eradication rates for key pathogens (S. pneumoniae, H. influenzae, S. aureus, M. catarrhalis, C. pneumoniae, L. pneumophila, M. pneumoniae) in the ITT and PPc populations were generally comparable between Cethromycin and clarithromycin treatment groups.[1]
Cethromycin showed clinical activity against both erythromycin-susceptible and erythromycin-resistant S. pneumoniae isolates in the ITT population (Clinical cure rate: 80.8% for susceptible, 80.0% for resistant). Bacterial eradication rates were 84.6% for susceptible and 80.0% for resistant isolates.[1]
In a small subset of subjects with S. pneumoniae bacteremia (ITT population), Cethromycin showed a clinical cure rate of 60% (3 out of 5 subjects) compared to 20% (1 out of 5 subjects) for clarithromycin.[1]

Absorption, Distribution and Excretion
The absorption kinetics of cetramycin are non-linear. In healthy adults, after five consecutive oral doses of 150 mg cetramycin, the calculated Cmax, Tmax, and AUC0-24 values were 0.181 ± 0.084 μg/ml, 2.01 ± 1.30 h, and 0.902 ± 0.469 μgh/ml, respectively. Similarly, the values for a 300 mg dose were 0.500 ± 0.168 μg/ml, 2.09 ± 0.03 h, and 3.067 ± 1.205 μgh/ml, respectively. In another study, a single oral dose of 150 mg cetramycin resulted in a Cmax of 318 ± 161 ng/ml, a Tmax of 1.79 ± 0.50, an AUC0-24 of 1596 ± 876 ngh/ml, and an AUC0-∞ of 1662 ± 907 ngh/ml. Cetramycin is primarily excreted via bile, with 87.2% of the initial dose recovered in feces and only 7.0% in urine. Of the radioactive material recovered in feces, 35.7% was unmetabolized cetramycin and 39.8% was N-demethylated metabolites. The remaining radioactive material was roughly evenly distributed among three minor metabolites and a group of unidentified other products. Five oral doses of 150 mg cetramycin resulted in an apparent volume of distribution (VOD) of 1433 ± 843 L and an apparent steady-state VOD of 1453 ± 997 L. The values corresponding to the 300 mg dose were 761 ± 293 L and 769 ± 272 L, respectively. Cetramycin is known to accumulate in epithelial lining fluid, alveolar cells, and polymorphonuclear leukocytes. It has been reported that the clearance rate of cetramycin in patients who take 300 mg orally once daily is approximately 63 L/h. Metabolites/Metabolites Although one study identified seven cetramycin metabolites, extensive studies on the metabolism of cetramycin have not been conducted. Metabolites in the feces of patients who received a single 150 mg oral dose were analyzed. The major recovered products were unmetabolized cetramycin and an inactive N-demethylated metabolite. Most metabolism likely occurs in the liver and is at least partially mediated by CYP3A4.

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Biological Half-Life
After five oral doses of 150 mg or 300 mg cetramycin, the plasma half-lives were 4.85 ± 1.10 hours and 4.94 ± 0.66 hours, respectively. The half-life of a single oral dose of 150 mg cetramycin was measured to be 5.66 ± 0.77 hours.

Protein Binding
At concentrations ranging from 0.1 to 30.0 μg/ml, human plasma protein binding of cetramycin ranged from 86.7% to 95.6%. In Phase III clinical trials, cetramycin was generally safe and well-tolerated. [1] In the pooled studies, the most common adverse events occurring during treatment with cetramycin (≥2% in any group of subjects) were diarrhea (8.5%), nausea (6.2%), taste disturbance (9.3%), and headache (3.8%). [1] The proportion of subjects reporting taste disturbance (disordered taste) was statistically significantly higher in the cetramycin group (9.3%) compared to clarithromycin (4.0%). [1] No clinically significant safety signals similar to those described above were identified. Adverse reactions associated with the ketolactone telithromycin (e.g., visual disturbances, sudden loss of consciousness, hepatotoxicity, exacerbation of myasthenia gravis) were detected during the trials. [1]
In both treatment groups, some patients reported transient increases in liver function indicators (alanine aminotransferase [ALT], aspartate aminotransferase [AST], gamma-glutamyl transferase [GGT], total bilirubin, and direct bilirubin), but no subjects experienced symptoms of hepatotoxicity. No subjects experienced simultaneous significant increases in aminotransferases and bilirubin (Heyd's Law). [1]

[1]. Cethromycin versus clarithromycin for community-acquired pneumonia: comparative efficacyand safety outcomes from two double-blinded, randomized, parallel-group, multicenter, multinational noninferiority studies. Antimicrob Agents Chemot.2012 Apr;56(4):2037-47.

Cethromycin is a 3-keto (ketolactone) derivative of erythromycin A, possessing an 11,12-carbamate group and an O-6 linked aromatic ring system. Developed jointly by Abbott Laboratories, Taisho Pharmaceutical, and Advanced Life Sciences, sectramycin was originally planned for marketing under the brand name Restanza for the treatment of community-acquired pneumonia. However, after completing Phase III clinical trials, the U.S. Food and Drug Administration (FDA) deemed its safety profile good but its efficacy insufficient. Subsequently, sectramycin received orphan drug designation from the FDA for the prevention of inhaled anthrax, plague caused by Yersinia pestis, and tularemia caused by Tularemia. Cethromycin has also been investigated, alone or in combination with zolidofasine, for the treatment of gonorrhea, and has recently been considered a potential treatment for hepatic malaria sporozoan infections. Drug Indications Cethromycin currently has no FDA-approved indications; it was granted orphan drug designation in 2007 for the prevention of inhalational anthrax and in 2009 for the prevention of plague caused by Yersinia pestis and tularemia caused by Tularemia. Mechanism of Action Respiratory infections can be caused by a variety of bacteria, therefore treatment regimens need to be carefully considered, and antibiotics effective against a variety of potential pathogens should be selected. Like other macrolide antibiotics, cetramycin binds to the 23S rRNA of the 50S subunit of bacterial ribosomes. This binding is mainly mediated by regions II and V of the rRNA, blocking peptide chain exit channels and thus inhibiting bacterial protein synthesis. In addition, cetramycin can also bind to ribosomal intermediates in ribosome biosynthesis, inhibiting the formation of functional 70S bacterial ribosomes. Due to the similarity of ribosome sequences and structures among different species, cetramycin has broad-spectrum antibacterial activity against a variety of Gram-positive, Gram-negative, and atypical bacteria.

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Pharmacodynamics
Cetaramycin binds to the 50S subunit of bacterial ribosomes, inhibiting ribosome assembly and bacterial protein synthesis. Adverse reactions such as diarrhea, nausea, vomiting, and headache may be due to non-targeted inhibition of intracellular molecules in mammalian cells.

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Cephalosporins are once-daily oral ketolactone antibiotics currently under development for outpatient treatment of mild to moderate community-acquired pneumonia (CAP). [1]
Their antibacterial activity is mediated through a dual mechanism: binding to the 23S rRNA of the bacterial 50S ribosomal subunit to inhibit protein translation, and interacting with partially assembled 50S subunit precursors to inhibit complete ribosome formation. This dual action may help it overcome certain resistance mechanisms. [1]
This drug does not contain the pyridine moiety, while telithromycin does. It is speculated that the pyridine moiety is one of the causes of some serious adverse reactions of telithromycin (e.g., hepatotoxicity, visual disturbances). [1]
Both phase III studies were prospective, double-blind, randomized, parallel-group, multicenter, multinational non-inferiority trials conducted in accordance with good clinical practice guidelines. [1]
Cethromycin may be a treatment option that is effective against common community-acquired pneumonia (CAP) pathogens and macrolide-resistant CAP pathogens while maintaining an acceptable safety profile. [1]

C42H59N3O10

765.93196

765.42

C, 65.86; H, 7.76; N, 5.49; O, 20.89

205110-48-1

156417

Solid powder

1.22g/cm3

927.1ºC at 760mmHg

514.5ºC

0mmHg at 25°C

1.578

5.438

2

12

8

55

1410

13

CC[C@H]1OC(=O)[C@H](C)C(=O)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)C[C@H](N(C)C)[C@H]2O)[C@](C)(OC/C=C/C2C=NC3=CC=CC=C3C=2)C[C@@H](C)C(=O)[C@H](C)[C@H]2NC(O[C@]12C)=O

PENDGIOBPJLVBT-ONLVEXIXSA-N

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)/b15-14+/t23-,24-,25+,26+,27-,31+,32-,35-,36-,37-,39+,41-,42-/m1/s1

(3aS,4R,7R,9R,10R,11R,13R,15R,15aR)-10-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-4-ethyl-3a,7,9,11,13,15-hexamethyl-11-(((E)-3-(quinolin-3-yl)allyl)oxy)octahydro-2H-[1]oxacyclotetradecino[4,3-d]oxazole-2,6,8,14(1H,7H,9H)-tetraone

Cethromycin; ABT-773; ABT 773; ABT773; A-195773; A 195773; A195773; Abbott-195773; Abbott195773; Abbott 195773

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~100 mg/mL (~130.56 mM)

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*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.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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 (Please use freshly prepared in vivo formulations for optimal results.)