In vitro and in vivo efficacy of liposomal ciprofloxacin formulations against Mycobacterium avium and Mycobacterium abscessus

Project Summary Lung infections by non tuberculous mycobacteriaNTMMycobacterium avium and Mycobacterium abscessus are increasing in incidenceDiseases caused by both Mycobacteria are common in patients with chronic lung conditionse gcystic fibrosisCFnon CF bronchiectasis and emphysemaThe current clinical paradigm is to treat patients with Mavium or Mabscessus lung infections with combination therapy given orally or IVUnfortunatelythese therapies often failor patients do not tolerate them due to side effectsThusthere is a need to develop new anti mycobacterial therapies with better efficacy and improved safety and tolerabilityThe overall objective of this project is to test if three novel preparations designed for maximum efficacy and tolerability in the lungCiprofloxacin for InhalationCFILipoquinDual Release Ciprofloxacin for InhalationDRCFILinhaliqand a recently invented ciprofloxacin nanocrystal liposome formulationprovide effective NTM therapy alone and or in combination with other antimycobacterial agents using in vitro and in vivo models of Mavium and Mabscessus lung infectionAll three formulations are comprised of ciprofloxacin encapsulated in liposomeswhich provide sustained slow release of the ciprofloxacin in the lung from the liposomeallowing for once daily dosingThe DRCFI formulation is a mixture of CFI and free ciprofloxacinThe 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 DRCFIfollowed by the slow release of ciprofloxacin from CFIliposomal componentThe nanocrystals release drug more slowly than the othersAradigm has demonstrated other important advantages of these formulationsavid ingestion by macrophages leading to effective killing of intracellular NTM infectionsand the ability to kill NTM even within biofilms formed by these organisms in the lungThe specific aims arefor M avium complex infectiontest efficacy ofaCFI DRCFI nanocrystals in combination with standard therapies clarithromycin ethambutol and amikacin in macrophage biofilm test systemsbaerosolized CFI DRCFI nanocrystals in combination with systemic clarithromycin ethambutol and amikacin for lung infection in micecimpact of emergence of antibiotic resistance on efficacyfor M abscessus infectiontest efficacy ofaCFI DRCFI nanocrystals in combination with standard of therapy linezolid imipenem in macrophage biofilm test systemsbaerosolized CFI DRCFI nanocrystals in combination with standard therapies systemic linezolid imipenemand cimpact of emergence of antibiotic resistance on efficacyIf an efficacious treatment with CFI or DRCFIalone or in combination with other drugsis identifiedclinical trials will start in patients with Mavium or Mabscessus lung infectionincluding those with HIV AIDSAradigm has sufficient safety data in humans and animals to support long term clinical trials in patients with CFI DRCFI as well as sufficient cGMP manufacturing in place to support large scale clinical trials