CEM-101 is a next-generation oral and intravenous fluoroketolide entering Phase II clinical development for the treatment of community-acquired bacterial pneumonia (CABP).
Macrolides & Infectious Disease
Macrolides are antimicrobial drugs that are active against aerobic and anaerobic gram-positive cocci and are prescribed for the treatment of respiratory tract and soft tissue infections.
Macrolides belong to the polyketide class of natural products. The macrolide ring - a large lactone ring to which one or more deoxy sugars, usually cladinose and desosamine, are attached - is responsible for the antimicrobial properties of this class. By reversibly binding to the 50S subunit of the bacterial ribosome, these drugs block protein synthesis, preventing bacterial growth and reproduction. This action is primarily bacteriostatic, however at higher concentrations, macrolides can be bactericidal. Some of the most commonly prescribed macrolides include erythromycin, azithromycin (Zithromax®) and clarithromycin (Biaxin®).
Ketolides belong to the macrolide class that is used to treat respiratory tract infections. These drugs are effective against macrolide-resistant bacteria because of their ability to bind to two sites on the bacterial ribosome. Examples include telithromycin (Ketek®) and cethromycin.
The spectrum of activity of macrolides includes streptococci as well as atypical bacteria such as Mycoplasma and Legionella and intracellular bacteria such as Chlamydia.
Acquired bacterial resistance to macrolides occurs primarily through post-transcriptional methylation of the 23S bacterial ribosome. This results in cross-resistance to macrolides, lincosamides and streptogramins. Although rare, acquired resistance can also result from the production of drug-inactivating enzymes such as esterases or kinases, as well as the production of active ATP-dependent efflux proteins that transport macrolides out of the cell. As more than 45% of pneumococci are resistant to currently available antibiotics, a new macrolide is greatly needed. To address this need Cempra Pharmaceuticals is developing CEM-101.
Profile of CEM-101
CEM-101 meets the requirements for a highly potent next-generation macrolide that retains activity against drug-resistant strains. In vitro and in vivo studies have shown potent activity against S. pneumoniae as well as an extended spectrum of activity against CA-MRSA, enterococci, M. avium and in animal models of malaria. It is also active against atypical bacteria, such as Legionella, Mycoplasma and Ureaplasma and against gonococci and other organisms that cause genitourinary tract infections. It is 8-16 times more potent than azithromycin and is active against azithromycin-resistant strains. Its activity against resistant strains is driven by its ability to bind to three sites on the bacterial ribosome, compared to two for current macrolides. The binding to three ribosomal sites is expected to limit resistance development.
CEM-101 does not contain a pyridine in the side chain of the molecule that could be associated with visual disturbances and exacerbations of myasthenia gravis that have been observed with telithromycin (Ketek�).
Phase I dose-escalation studies in healthy subjects showed that CEM-101 was safe and well tolerated. PK/PD results suggest that CEM-101 could be a once-daily oral treatment.
Research on CEM-101
Publications
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In Vitro Activity of CEM-101 against Streptococcus pneumoniae and Streptococcus pyogenes with Defined Macrolide Resistance Mechanisms
P McGhee, C Clark, KM Kosowska-Shick, K Nagai, B Dewasse, L Beachel, PC Appelbaum
Antimicrob. Agents Chemother. January 2010 54: 230-238
http://aac.asm.org/cgi/content/abstract/54/1/230
Cellular Accumulation and Pharmacodynamic Evaluation of the Intracellular Activity of CEM-101, a Novel Fluoroketolide, against Staphylococcus aureus, Listeria monocytogenes, and Legionella pneumophila in Human THP-1 Macrophages
S Lemaire, F Van Bambeke, PM Tulkens
Antimicrob. Agents Chemother. September 2009 53: 3734-3743
http://aac.asm.org/cgi/content/abstract/53/9/3734
Multiple Dose Pharmacokinetics and Safety of CEM-101, a New Fluoroketolide, in Healthy Subjects
J.G. Still, K. Clark, T. Degenhardt, D. Scott, P. Fernandes
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CEM-101, a novel fluoroketolide, tested against European clinical isolates from 2009 (first-year surveillance results)
R. Jones, D. Farrell, H. Sader, M. Stilwell, M. Castaheira
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CEM-101, a novel ketolide; in vitro activity against Legionella pneumophila
J. Dubois, P. Fernandes
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CEM-101, a novel ketolide, in vitro activity against resistant strains of Streptococcus pnuemoniae and Haemophilus influenza
J. Dubois, P. Fernandes
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Expanded studies of CEM-101, a novel fluoroketolide, tested against invasive isolates of N. meningitidis, including flouroquinolone-non-susceptible resistant strains
R. Jones, D. Biedenbach, L. Woosley, G.Gerken, M. Castaheira
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CEM-101, a novel fluoroketolide: Activity against recent(2008) isolates of multidrug-resistant (MDR) S. pneumoniae (SPN)
R.N. Jones , M.G. Stilwell H.S. Sader, P. Fernandes
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Activity of CEM-101, a Novel Fluoriketolide, Tested Against Invasive Isolates of N. meningitides (NM) from a Worldwide Collection
DJ Biedenbach, LN Woosley, GD Gerken, HS Sader, RN Jones
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In Vitro Activity of CEM-101 against Legionella Spp.
J Dubois, P Fernandes
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In Vitro Activity of CEM-101 Against Resistant Strains of Staphylococcus aureus
J Dubois, P Fernandes
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Capability of CEM-101 to Select for Resistant Pneumococcal and Group A Streptococcal Clones by Multistep Resistance Selection
C Clark, K Kosowska-Shick, P McGhee, PC Appelbaum
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Proposed Mechanisms to Explain the Unusual Visual Disturbances Associated with Telithromycin
D Bertrand, S Bertrand, P Fernandes
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First Year Antimicrobial Surveillance Results for CEM-101, a Novel Fluoroketolide with Potent Activity Against Pathogens Associated with Community-acquired Bacterial Pneumonia (CABP)
RN Jones, HS Sader, MJ Janechek, GJ Moet
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Evaluation of CEM-101, a Novel Fluoroketolide, in a Rat H. influenzae Pulmonary Infection Model
T Murphy, S Little, R Wu, A Slee, P Fernandes
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Efficacy and Pharmacodynamic Evaluation of CEM-101, a Novel Macrolide, in Murine Infection Models
T.M. Murphy, M. Gaffney, S. Little, R. Wu, A.M. Slee, C. Ong, P. Fernandes
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Antimicrobial Characterization of CEM-101: Activity Against Staphylococci, �-Haemolytic and Viridans Group Streptococci
R.N. Jones, H.S. Sader, D.J. Biedenbach
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Comparative Activities of the Novel Ketolide CEM-101 and Telithromycin (TEL) Towards Streptococcus pneumoniae (SP) Resistant to Macrolides (ML) from Patients with Confirmed Community-Acquired Pneumonia (CAP)
A.Lismond, F. Bambeke, P.M. Tulkens
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Activity of CEM-101 Tested Against Emerging Telithromycin-Resistant �-Haemolytic Streptococci
R.N. Jones, L.N. Woosley, G.J. Moet, P.R. Rhomberg
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SAR of 11, 12-Carbamate Macrolides/Ketolides Linked With 1,4-Substituted-[1,2,3]-Triazoles
C Hwang, J Duffield, Y Chiu, C Liang, S Yao, N Roberts, F Babakhani, P Sears, Y Shue, Y Ichikawa, P Fernandes, D Pereira, A Romero
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Binding and Action of CEM-101, a New Macrolide/Ketolide in Development for Treating Infections with Macrolide-Resistant and Macrolide-Susceptible Bacteria
B Llano-Sotelo, D Klepacki, N Vazquez-Laslop, AS Mankin
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Video: Alexander S. Mankin discusses binding of CEM-101 
Activity of CEM-101 Compared to Other Agents Against Macrolide Susceptible and-Resistant Streptococci
P McGhee, K Nagai, PC Appelbaum
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Antimicrobial Characterization of CEM-101: Activity Against 331 Respiratory Tract Pathogens Including Multidrug-Resistant Pneumococcal Serogroup 19A (MDR-19A) Isolates
RN Jones, DJ Biedenbach, PR Rhomberg, TR Fritsche, HS Sader
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Video: Ronald N. Jones discusses CEM-101 research
Antimicrobial Characterization of CEM-101: Activity Against Enterococci, Uncommon Gram-positive Pathogens, N. gonorrhoeae and Anaerobes
DJ Biedenbach, LM Deshpande, TR Fritsche, HS Sader, RN Jones
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Video: Ronald N. Jones discusses CEM-101 research
Antimicrobial Characterization of CEM-101: Potential Application Against Species Causing Enteritis/Gastroenteritis
RN Jones, HS Sader, TR Fritsche, DJ Biedenbach, M Castanheira
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Video: Ronald N. Jones discusses CEM-101 research
In Vitro Activity of CEM-101, a New Ketolide Antibiotic, Against Chlamydia trachomatis and Chlamydia pneuomoniae
PM Roblin, SA Kohlhoff, MR Hammerschlag
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Antimicrobial Activity of CEM-101 a New Macrolide, Tested Against Diverse Collections of Bacterial Biowarfare/Bioterrorism (BW/BT) Agents
HS Heine, L Miller, J Bassett, K Holman
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Comparative In Vitro Susceptibilities of a New Investigational Macrolide CEM-101 Against Human Mycoplasmas and Urealplasmas
KB Waites, DM Crabb, LB Duffy
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CEM-101, a Novel Macrolide/Ketolide, Shows Improved Intracellular Activity Against Phagocytised S. aureus in Comparison with Azithromycin (AZM), Clarithromycin (CLR), or Telithromycin (TEL)
S Lemaire, F Van Bambeke, PM Tulkens
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Video: Paul Tulkens discusses intracellular activity of CEM-101
Antimicrobial Characterization of CEM-101: PAE, Bactericidal Activity and Combinations
HS Sader, DJ Biedenbach, PR Rhomberg, RN Jones
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Video: Ronald N. Jones discusses CEM-101 research
Antimicrobial Characterization of CEM-101: Single Step, Selection by Passaging and Inducible Resistances
RN Jones, PR Rhomberg, HS Sader
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Video: Ronald N. Jones discusses CEM-101 research
Influence of Inhibitors of P-glycoprotein (P-gp) and Multidrug Resistance-Associated Protein (MRP) on the Accumulation and Intracellular Activity of CEM-101, a Novel Macrolide/Ketolide, in Human THP-1 Macrophages: Comparison with Azithromycin
S Lemaire, F Van Bambeke, PM Tulkens
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Video: Paul Tulkens discusses intracellular activity of CEM-101
Proposed MIC Quality Control Ranges for CEM-101 Using the CLSI Multi-Laboratory M23-A2 Study Design
PR Rhomberg, JE Ross, RN Jones
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Video: Ronald N. Jones discusses CEM-101 research
Assessment of CEM-101 Susceptibility Testing Conditions and Optimization of Disk Diffusion Methods
RN Jones, TR Fritsche, HS Sader, DJ Biedenbach, PR Rhomberg
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Video: Ronald N. Jones discusses CEM-101 research
Evaluation of CEM-101, a Novel Macrolide, in Murine Infection Models
TM Murphy, S Little, M Gaffney, AM Slee, P Fernandes
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Video: Andrew M. Slee discusses CEM-101 data
Single Oral Dose Pharmacokinetics and Safety of CEM-101 in Healthy Subjects
JG Still, K Clark, TP Degenhardt, D Scott, P Fernandes, MJ Gutierrez
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