Efficacy of Aerosol MP-376, a Levofloxacin Inhalation Solution, in Models of Mouse Lung Infection Due toPseudomonas aeruginosa

Abstract

Progressive respiratory failure due to Pseudomonas aeruginosa is the leading cause of morbidity and mortality in patients with cystic fibrosis. The pulmonary delivery of antimicrobial agents provides high concentrations of drug directly to the site of infection and attains pharmacokinetic-pharmacodynamic indices exceeding those which can be achieved with systemic dosing. MP-376 is a new formulation of levofloxacin that enables the safe aerosol delivery of high concentrations of drug to pulmonary tissues. In vivo studies were conducted to demonstrate the efficacy of MP-376 in models of mouse pulmonary infection. The superiority of aerosol dosing over systemic dosing was demonstrated in models of both acute and chronic lung infection. In a model of acute lung infection, aerosol treatment with MP-376 once or twice daily reduced the lung bacterial load to a greater extent than aerosol tobramycin or aztreonam did when they were administered at similar or higher doses. The bacterial killing by aerosol MP-376 observed in the lung in the model of acute pulmonary infection translated to improved survival (P < 0.05). In a model of chronic pulmonary infection, aerosol MP-376 had antimicrobial effects superior to those of aztreonam (P < 0.05) and effects similar to those of tobramycin (P > 0.05). In summary, these data show that aerosol MP-376 has in vivo activity when it is used to treat acute and chronic lung infections caused by P. aeruginosa.

Pharmacokinetics and Pharmacodynamics of Aerosolized Antibacterial Agents in Chronically Infected Cystic Fibrosis Patients

“…As summarized in Table 1, the MIC 90 value of ciprofloxacin and levofloxacin for aggregated CF isolates is 8 mg/liter; early colonizers should be more susceptible, while isolates from chronically infected patients should have higher MIC values. An in vitro study (215) and an in vivo mouse lung infection model (216) revealed that levofloxacin exhibited a concentrationor dose-dependent reduction of viable P. aeruginosa counts. Aerosolized levofloxacin doses of 15, 30, and 60 mg/kg of body weight in a chronic lung infection model reduced viable counts by 0.07, 0.62, and 1.25 CFU/lung, whereas the antibacterial effects of intraperitoneally applied identical doses of levofloxacin were significantly lower.…”

“…In a mouse lung infection model comparing aerosolized tobramycin and levofloxacin, it was shown that bacterial loads of P. aeruginosa in the lungs of chronically infected animals were reduced following twice-daily treatment for 3 days with 60 mg/kg of levofloxacin or tobramycin by 3.33 log 10 titers and 2.94 CFU/lung, respectively, compared to the preexposure level (216).…”

“…Beta-lactams. In a chronic P. aeruginosa lung infection model, aztreonam (400 mg/kg) reduced the lung burden by 1.25 CFU/ lung compared to the preexposure level (216). The probabilities of clinical success were calculated for non-CF and CF patients dosed intravenously with 1 g aztreonam every 8 h using a PK/PD target of 50 to 60% TϾMIC (172).…”

“…Likewise, oral administration of fluoroquinolones seems to be as efficacious as aerosolized therapy. These trends are remarkable insofar as both aminoglycosides and fluoroquinolones exert concentration-dependent in vitro activity and efficacy in preclinical infection models (215,216), so it is tempting to assume that aerosolized therapy should result in markedly ameliorated efficacy. Indeed, withinstudy analyses reveal that dose-dependent antipseudomonal activities of either levofloxacin (284,285) or amikacin (170,171) as well as improvements of lung function were demonstrated although within a narrow range only.…”

Inhaled Antibiotics for Gram-Negative Respiratory Infections

“…Finally, compared to aztreonam and tobramycin, in a model of acute lethal lung infection, levofloxacin produced the greatest decrease in the amount of CFU per lung. Surprisingly, levofloxacin also provided the highest survival rate (100%) compared to tobramycin (60%) and aztreonam (20%) (165). The reason for this dramatic difference in survival is unclear, and few animal studies have evaluated both PK and survival as they relate to the treatment of induced infections with inhaled antibiotics, especially in neutropenic animals.…”