An Open-label, Dose-escalation Study to Evaluate the Pharmacokinetics of Inhaled Teicoplanin in Cystic Fibrosis Patients

Cystic Fibrosis (CF) is the most common autosomal recessive lethal disorders affecting 1:2.500 newborns among Caucasians. CF patients are peculiarly susceptible to infection and colonization of the respiratory tract with pathogens. In particular, Methicillin-resistant Staphylococcus aureus (MRSA) has become the third most prevalent bacterium in CF in the U.S. and has been increasing in other countries. Apart from the difficulty of treating the infection because of its antimicrobial resistances, MRSA is transmissible between individuals with and without CF. Chronic MRSA infection is associated with worse outcomes, and treatment/eradication is challenging. Antibiotic dosing and choices should be optimized to minimize further resistance and to maximize chances of successful therapy. Yet, MRSA has several mechanisms to escape clearance by the immune system and antibiotic killing. For these reasons, a better understanding of preventive measures and early therapy is of key importance. In consideration of all these assessments there is an emerging consensus that MRSA is an important pathogen in CF rather than simply a marker of severe disease. However, to date there are no guidelines or recommendations on the choice of antibiotics for MRSA in CF. Glycopeptides are an important class of antibiotics active against Gram-positive pathogens. These include teicoplanin and vancomycin, which are currently in widespread use and are active against MRSA. Teicoplanin is often preferred to vancomycin for intravenous treatment because of its better safety profile but its use in MRSA lung infection is limited by its limited lung penetration. Teicoplanin is mainly used for injection/infusion. Inhalation of anti-microbial drugs is a cornerstone in the treatment of patients with CF, since inhaled antibiotics decrease the rate of decline of lung function, improve the quality of life, and reduce the frequency of exacerbations and hospital admissions. It is expected that, using inhalation route, efficacy would be improved and risk of resistance reduced. At present, no antibiotic active against MRSA is available as an inhaled formulation. The objective of this phase I, first-in-man clinical study is to identify the dose providing, after single inhalation administration, a sputum Teicoplanin concentrations exceeding the drug concentration required to inhibit bacterial growth for at least 8 hours, while minimizing the development of resistance.