Targanta Reports Improved Ability of Oritavancin to Stop Bacteria Growth In Vitro Compared With Other Glycopeptide Antibiotics
- Category: Proteins and Peptides
- Published on Wednesday, 04 April 2007 03:00
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MUNICH, Germany | Apr 3, 2007 | Targanta Therapeutics today announced results from two studies showing the improved potency of oritavancin to stop bacterial growth in vitro when tested with a common wetting agent (polysorbate 80) and one study demonstrating the activity of oritavancin against S. pneumoniae in a mouse model of pneumonia. Oritavancin, a novel lipoglycopeptide antibiotic, is Targanta's lead product currently in post- Phase 3 clinical development. These findings were presented at the 17th European Congress of Clinical Microbiology and Infectious Diseases (ECCMID) and 25th International Congress of Chemotherapy (ICC) in Munich, Germany from March 31 - April 3, 2007.
"We are encouraged by the research demonstrating the improved activity of oritavancin when compared with other glycopeptide antibiotics. By combining oritavancin with a common wetting agent, it is evident that the ability of the treatment to inhibit bacteria growth, demonstrated through previous research, may be underestimated based on these recent studies," said Thomas Parr, Ph.D., Chief Scientific Officer, Targanta Therapeutics.
"These data further support oritavancin as a potential treatment for serious bacterial infections, and Targanta will continue to explore this potential through ongoing clinical research."
The following research was presented at the ECCMID/ICC meeting: Effect of polysorbate 80 on oritavancin binding to plastic surfaces implications for susceptibility testing (ECCMID/ICC07-P 1112) -- Influence of polysorbate 80 on susceptibility of gram-positive bacteria to oritavancin (ECCMID/ICC07-P 827) -- Efficacy of oritavancin in a mouse model of Streptococcus pneumoniae pneumonia (ECCMID/ICC07-P 1781)
Study Methods and Results: Effect of polysorbate 80 on oritavancin binding to plastic surfaces implications for susceptibility testing (ECCMID/ICC07-P 1112) Researchers investigated whether polysorbate 80 (P80), a commonly used wetting agent, affects oritavancin (ORI) susceptibility test results. Testing the following both with and without P80, ORI and ciprofloxacin (CIP) were dissolved in water, diluted in cation-adjusted Mueller Hinton Broth (CAMHB) or CAMHB with two percent lysed horse blood (LHB), and dispensed into a microtiter plate for testing. Tests were conducted with Staphylococcus aureus (S. aureus), Enterococcus faecalis (E. faecalis) and Streptococcus pneumoniae (S. pneumoniae). S. aureus bacteria appear most commonly on the skin and nose, E. faecalis in the intestines, and S. pneumoniae in the nasal cavity, and all may lead to deadly infections.(1)
Researchers found that without P80, ORI was rapidly lost from the solution, but inclusion of P80 or LHB promoted recovery of 80 to 100 percent of the agent for up to 24 hours. ORI minimal inhibitory concentrations (MICs) for S. aureus and E. faecalis were 16- to 32- fold lower in the presence of P80, compared with no MIC impact on vancomycin (VAN), teicoplanin (TEI) or CIP. ORI MICs for S. pneumoniae were identical with and without P80, likely as a result of LHB present in the microbiological culture medium for the pneumococcus. In addition, plates with low-binding surfaces demonstrated 4- to 8-fold reductions in ORI MICs without P80.
These findings indicate that the addition of P80 to susceptibility tests minimizes ORI binding to plastic surfaces, which maintains ORI available in solution to stop growth of bacteria. Investigators also concluded that current literature on ORI MICs, without P80, may significantly underestimate its in vitro potency.
Influence of polysorbate 80 on susceptibility of gram-positive bacteria to oritavancin (ECCMID/ICC07-P 827) Following initial observations that P80 reduced ORI MICs for S. aureus and E. faecalis but not for S. pneumoniae, this study examined the effect of P80 on ORI MICs for 301 clinical strains of bacteria from these three genera, in comparison with VAN and TEI. Researchers observed significant reductions in ORI MICs for enterococci and staphylococci with P80 (16- to 32-fold) while P80 had little to no effect on MICs for TEI and VAN. ORI MICs were unchanged with and without P80 for streptococci, which may be related to the inclusion of LHB in the culture medium.
Efficacy of oritavancin in a mouse model of Streptococcus pneumoniae pneumonia (ECCMID/ICC07-P 1781) Streptococcus pneumoniae is one of the leading causes of community- acquired bacterial infections and can cause a number of infections including pneumonia, acute sinusitis, otitis media, bacteremia and meningitis(2). S. pneumoniae is a leading cause of morbidity and mortality in the United States, resulting each year in an estimated 500,000 cases of pneumonia. S. pneumoniae bacteria have been uniformly susceptible to penicillin in the past; however, as multi-drug resistant strains become more prevalent, first-line therapies such as penicillin are not always effective, and advanced agents are being explored to prevent complications or mortality.
In Vivo Researchers tested the in vivo activity of ORI against penicillin- sensitive S. pneumoniae (PSSP) pneumonia in a mouse model, compared with daptomycin (DAP) and ceftriaxone (CTX). During the study, immunocompetent mice were exposed intranasally to one million colony-forming units (CFU) of PSSP. Doses of ORI (32 mg/kg intravenous), DAP (100 mg/kg subcutaneous) and CTX (50 mg/kg subcutaneous) were administered at 1 hour and 4 hours following exposure to PSSP. Results showed that ORI was more active in the mouse pneumonia model than CTX or DAP, with lungs of all mice treated with ORI presenting as sterile, while 40 percent of those that were treated with CTX and none of those treated with DAP presented with sterile lungs.
In a second dose-ranging in vivo model, single doses of ORI (0.25 - 32 mg/kg intravenous) were administered one hour after exposure of mice to PSSP. This study yielded the maximum effect from dosing at 6.49 +/- 0.18 mg/kg, with a dose of 2.76 +/- 0.3 mg/kg resulting in 50 percent of the maximal killing.
In Vitro The in vitro arm of the study tested the antibacterial effect of ORI, DAP and CTX against S. aureus when a pulmonary surfactant preparation (up to 5%, by volume) was added. Results showed a 2- to 4-fold increase in ORI minimal inhibitory concentration (MIC), compared with a greater than or equal to 64-fold increase for DAP MIC and no shift for CTX MIC. Researchers concluded that surfactant only minimally affected the antibacterial activity of ORI when conducted in a laboratory setting.
Oritavancin, Targanta's lead product candidate, is a once-daily, semi- synthetic lipoglycopeptide antibiotic with rapid in vitro bactericidal activity against all clinically relevant serious gram-positive pathogens, including multi-resistant strains. Oritavancin's multiple targets and mechanisms of action work against the development of resistant strains, which is important when treating serious gram-positive infections. To date, over 1,500 individuals have received oritavancin in clinical trials, including two large multi-national Phase 3 studies in complicated skin and skin structure infections performed by former developers Lilly and InterMune, Inc. Targanta expects to file a New Drug Application (NDA) for oritavancin with the U.S. Food and Drug Administration in the second half of 2007.
About Targanta Therapeutics
Targanta Therapeutics is a privately held biopharmaceutical company developing and commercializing antibacterial drugs to treat serious infections in the hospital setting. Its pipeline includes an array of antibacterial agents in various stages of development. The company has operations in Cambridge, MA, Indianapolis, IN, and Montreal, Canada. For further information about Targanta, visit the company website, http://www.targanta.com.
All forward-looking statements and other information included in this press release are based on information available to Targanta as of the date hereof, and Targanta assumes no obligation to update any such forward-looking statements or information. Targanta's actual results could differ materially from those described in Targanta's forward-looking statements.
(1) Centers for Disease Control and Prevention, Coordinating Center for Infectious Diseases / Division of Bacterial and Mycotic Diseases, http://www.cdc.gov/ncidod/dbmd/diseaseinfo/staphylococcus_food_g.htm
(2) Centers for Disease Control and Prevention, Coordinating Center for Infectious Diseases / Division of Bacterial and Mycotic Diseases, http://www.cdc.gov/ncidod/dbmd/diseaseinfo/streppneum_t.htm
SOURCE Targanta Therapeutics