clinicaltrials.gov Identifier: NCT02166476.

Vaborbactam (formerly RPX7009) is a member of a new class of ␤-lactamase inhibitor with pharmacokinetic properties similar to those of many ␤-lactams, including carbapenems. The pharmacokinetics and safety of vaborbactam were evaluated in 80 healthy adult subjects in a first-in-human randomized, placebo-controlled, double-blind, sequential single-and multiple-ascending-dose study. A total of 10 dose cohorts were enrolled in the study, with 6 subjects randomized to receive 250 to 2,000 mg of vaborbactam and 2 subjects randomized to receive placebo in each cohort.

LIS is a safe and effective therapy for the management of CF patients with chronic P. aeruginosa infection.

The pharmacokinetics and tolerability of nebulized MP-376 (levofloxacin inhalation solution [Aeroquin]) were determined in cystic fibrosis (CF) subjects. Ten CF subjects received single 180-mg doses of two formulations of MP-376, followed by a multiple-dose phase of 240 mg once daily for 7 days. Serum and expectorated-sputum samples were assayed for levofloxacin content. Safety was evaluated following the single-and multiple-dose study phases. Nebulized MP-376 produced high concentrations of levofloxacin in sputum. The mean maximum plasma concentration (C max ) ranged between 2,563 and 2,932 mg/liter for 180-mg doses of the 50-and 100-mg/ml formulations, respectively. After 7 days of dosing, the mean C max for the 240-mg dose was 4,691 mg/liter. The mean serum levofloxacin C max ranged between 0.95 and 1.28 for the 180-mg doses and was 1.71 for the 240-mg dose. MP-376 was well tolerated. Nebulized MP-376 produces high sputum and low serum levofloxacin concentrations. The pharmacokinetics, safety, and tolerability were similar for the two formulations. MP-376 240 mg (100 mg/ml) is being advanced into late-stage clinical development.Patients with cystic fibrosis (CF) suffer from recurrent and chronic infections of the lower respiratory tract. Pseudomonas aeruginosa in particular has been implicated as a major risk factor for declining lung function and associated morbidity and mortality in CF patients (5). Aerosol delivery of an antibiotic directly to the lung increases the local concentration of the drug at the site of infection, thereby enhancing bacterial killing and reducing the selection of resistance compared to the outcomes of systemic administration. Currently, a tobramycin solution for inhalation (TOBI; Novartis Pharmaceuticals, East Hanover, NJ) and aztreonam lysine for inhalation (Cayston; Gilead Pharmaceuticals, Seattle, WA) are the two aerosol antibiotics approved in the United States for the management of CF patients with P. aeruginosa. For a number of reasons, including decreased efficacy, drug intolerance, new emerging pathogens, and inconvenient dosing regimens, there is a need for alternative inhaled therapies to treat CF patients with pulmonary infections caused by P. aeruginosa and other bacteria.Levofloxacin is a fluoroquinolone antibiotic with potent activity against key pathogens in CF patients, including P. aeruginosa. Unlike tobramycin, levofloxacin's activity is not reduced in CF sputum (8). In addition, levofloxacin has greater antimicrobial activity than tobramycin and aztreonam in biofilms produced by P. aeruginosa (8). Extensive in vitro and animal pharmacokinetic-pharmacodynamic studies, as well as both retrospective and prospective clinical studies, have established a clear link between the exposure to fluoroquinolones and clinical response (1). While not conducted in patients with CF, studies with levofloxacin show that bacterial killing and clinical efficacy is linked to the plasma area under the concentrationtime curve (AUC)/MIC ratio or maximum plasma concentration (C max )/MIC ...

Meropenem-vaborbactam is a fixed combination of the novel β-lactamase inhibitor vaborbactam and the carbapenem antibiotic meropenem, developed for the treatment of serious infections caused by drug-resistant Gram-negative bacteria. The safety, tolerability, and pharmacokinetics (PK) of vaborbactam and meropenem following single and multiple ascending doses of each study drug administered alone or combined were evaluated in 76 healthy adult subjects in a randomized, placebo-controlled, double-blind study. Subjects were enrolled in 1 of 5 dose cohorts (receiving 250 to 2,000 mg vaborbactam and/or 1,000 to 2,000 mg meropenem) alone or in combination. No subjects discontinued the study due to adverse events (AEs), and no serious AEs were observed. The pharmacokinetics of meropenem and vaborbactam were similar when given alone or in combination; all evaluated plasma PK exposure measures (peak plasma concentration, area under the plasma concentration-time curve [AUC] from time zero to the last measurable concentration area under the plasma concentration-time curve, and AUC from time zero to infinity) were similar for the study drugs alone versus those in combination, indicating no pharmacokinetic interaction between meropenem and vaborbactam. Across all treatments, 47 to 64% of an administered meropenem dose and 75 to 95% of vaborbactam was excreted unchanged in the urine over 48 h postdose. Meropenem and vaborbactam, when given alone or in combination, have similar pharmacokinetic properties, with no plasma or urine PK drug-drug interactions, and are well tolerated. These findings supported further clinical investigation of the combination product. (This study is registered at ClinicalTrials.gov under registration no. NCT01897779.).