CRL-1072 FOR TREATMENT OF MYCOBACTERIUM

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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.