SBIR-STTR Award

In previous studies, we demonstrated that poloxamer CRL- 1072 enhanced the activity of antibiotics against M. tuberculosis. This project will investigate the potential of this agent for therapy of Mycobacterium avium intracellular (MAI) infections through the following specific aims: 1) Evaluate CRL-1072 for treatment of acute infections with MAI. The MIC of CRL-1072 and FIC index of synergy will be determined in combination with commonly used antibiotics using radiometric methods in broth culture and colony counts in macrophage culture. Therapeutic regimens will then be optimized in beige mice acutely infected with MAI 2) Determine the ability of CRL- 1072 to prevent emergence of clarithromycin resistant organisms in broth and in beige mice using well-characterized MAI organisms, and 3) Use the best regimens defined above to evaluate variability in susceptibility of fresh clinical MAI isolates from AIDS and non-AIDS patients.Proposed commercial application:Novel agents for treating MAI infections in HIV patients are urgently needed because of problems in drug resistance and drug toxicity due to multiple drug administrations. The development of CRL-1072 as a novel agent to increase drug activity and reduce toxicity will fill in the need and thus have profound commercial applications.National Institute of Allergy and Infectious Diseases (NIAID)

Studies in Phase I demonstrated that CRL 1072 is effective against acute infection with Mycobacterium Avium (MAI) in combination with clarithromycin, rifabutin and clindamycin. The goal of Phase II is to recommend a specific combination of drugs in specific dosage forms that will effectively treat drug resistant organisms, reduce the emergence of drug resistant organisms, and minimize toxicity associated with multiple drug therapy of infections with MAI. The first aim is to optimize protocols for using CRL 1072 in combination with clarithromycin, rifabutin and clindamycin in terms of completeness of clearance, recrudescence of infection and emergence of resistance. A standardized beige mouse model has been developed to address these questions. The next aim is to use these methods to investigate the effects of CRL 1072 with several antibiotics on a series of clarithromycin resistant clinical isolates using a U937 macrophage model followed by studies in beige mice. A second copolymer, CRL 1605, has been shown to act via different mechanisms from CRL 1072 and to produce synergy with it. It will be evaluated in an effort to further reduce the dose and toxicity of drug therapy. Next, experiments will be done o develop protocols for oral administration of drugs using the most effective combinations from parental studies. Finally, we will investigate effects of CRL 1072 on the known limiting toxicities of first and second line antimycobacterial drugs.Proposed commercial application:Novel agents for treating MAI infections in HIV patients are needed because of problems in drug resistance and drug toxicity. The development of CRL-1072 s a novel agent to increase drug activity and reduce toxicity will fill in an important need and thus have commercial applications.Thesaurus termsAIDS, Mycobacterium avium, antibacterial agent, combination chemotherapy, communicable disease chemotherapy, drug design /synthesis /production, opportunistic infection, polymer, surfactant clarithromycin, clindamycin, drug resistance, drug screening /evaluation, macrophage, nonhuman therapy evaluation, oral administration, rifamycin laboratory mouse, tissue /cell cultureNational Institute of Allergy and Infectious Diseases (NIAID)