Evaluation of a new class of molecules for treating MRSA infective endocarditis

DESCRIPTION (provided by applicant): Lung infections by Mycobacterium avium and Mycobacterium abscessus are increasing in incidence. Diseases caused by both Mycobacteria are common in patients with chronic lung conditions, such as cystic fibrosis (CF), non-CF bronchiectasis and emphysema. In patients with AIDS, the M. avium infection is disseminated. The current clinical paradigm is to treat patients with M. avium or M. abscessus lung infections or M. avium disseminated infection with combination therapy given orally or by IV. Unfortunately, these therapies often fail. Thus, there is a need to develop new anti-mycobacterial therapies for both diseases. The overall objective of this project is test the efficacy of two new formulations of ciprofloxacin (Ciprofloxacin for Inhalation, CFI, Lipoquin(R); and Dual Release Ciprofloxacin for Inhalation, DRCFI, Pulmaquin(R)), developed recently specifically for inhalation a) alone and b) in combination with other anti- mycobacterial agents using in vitro and in vivo models of M. avium and M. abscessus lung infection and M. avium disseminated infection. The superior formulation(s) will then be taken into human clinical trials. Both formulations are comprised of ciprofloxacin encapsulated in liposomes, which provide sustained slow release of the ciprofloxacin from the liposome, allowing for once-daily dosing. The DRCFI formulation is a mixture of CFI and free ciprofloxacin, a non-liposomal solution. The rationale for developing DRCFI is to combine the advantages of an initial transient high concentration of free ciprofloxacin to increase maximum levels in the lung from the free ciprofloxacin component of DRCFI, followed by the slow release of ciprofloxacin from the CFI (liposomal component). Another advantage of these formulations is that the liposomes are avidly ingested by macrophages, bringing the ciprofloxacin into close proximity to the intracellular pathogens, thus further increasing anti-mycobacterial efficacy of the liposomal formulation compared to free ciprofloxacin alone. The specific aims are: 1) to test different concentrations of CFI and DRCFI in the macrophage test system: a) alone and in combination with clarithromycin, ethambutol, and amikacin against 3 clinical isolates of M. avium; b) alone and in combination with imipenem, cefoxitin, and amikacin against 3 clinical isolates of M. abscessus; 2) to test the same regimen of antibiotics against biofilms of M. abscess us and M. avium; 3) to test the in vivo efficacy of CFI and DRCFI in a mouse model of M. aviumor M. abscess us lung infection; and 4) to test the same regimen as Aim 3 for M. avium in a mouse model of M. avium disseminated infection. If an efficacious treatment with CFI or DRCFI (alone or in combination with other drugs) is identified, we will progress into clinical studies in patiens with M. avium or M. abscessus lung infection or with M. avium disseminated infection, including those patients with HIV/AIDS. Aradigm already has sufficient safety data in humans and animals to support long-term clinical studies in patients with CFI and DRCFI as well as sufficient cGMP manufacturing in place to support large-scale clinical trials. PUBLIC HEALTH RELEVANCE PUBLIC HEALTH RELEVANCE: Lung infections by Mycobacterium avium and Mycobacterium abscessus are increasing in incidence (1). M. avium-Mycobacterium intracellulare has become a common complication in patients with chronic lung disease, e.g., emphysema, cystic fibrosis and bronchiectasis (2). They may also give rise to severe respiratory diseases, such as bronchiectasis (3). It is also diagnosed in individuals with immune-suppression. In patients with AIDS, the M. avium infection is in the majority of the cases disseminated (12). Mycobacterium abscessus is associated with infection in patients with CF or follows M. avium infection in patients with chronic pulmonary conditions. Unfortunately, therapies for these infections often fail and the infections further compromise these patients' health. Also, a large percentage of the patients develop infections that are resistant to the available antibiotics, presumably because of inadequate concentrations at the sites of infection. There is thus a need to develop new anti-mycobacterial therapies for both diseases. The objective of this project is to test the efficacy of two new liposomal formulations of ciprofloxacin, developed specifically for inhalation to overcome the problems of systemic therapy, a) alone and b) in combination with other anti-mycobacterial agents, using in vitro and in vivo models of M. avium and M. abscessus lung infection and M. avium disseminated infection.