A point-of-care assay to monitor tobramycin in cystic fibrosis patients

Affinergy, Llc, Durham NC

Investigators

Abstract

SUMMARY/ABSTRACT In the United States, there are over 30,000 individuals living with cystic fibrosis (CF). CF, which is caused by a mutation in the cystic fibrosis transmembrane conductance regulator (CFTR), is the most common life-limiting autosomal recessive disorder in the United States, with pulmonary disease serving as the leading cause of morbidity and mortality. In the lung, mutations in CFTR result in impaired mucociliary clearance and cause an increased risk for lung infections. In particular, infection by the gram negative bacteria Pseudomonas aeruginosa is associated with increased lung inflammation, reduced lung function, increased lung exacerbations, and reduced life span. P. aeruginosa infections are typically treated with the aminoglycoside antibiotic tobramycin. Once a patient is chronically infected with P. aeruginosa, they take an inhaled form of tobramycin for a 28-day course, every other month. Despite this targeted treatment against P. aeruginosa, patients still suffer from lung exacerbations, which require the administration of intravenous tobramycin. While tobramycin is an effective antibiotic against P. aeruginosa, it is associated with both nephrotoxicity and ototoxicity. Tobramycin therapy must therefore be individualized, and therapeutic drug monitoring (TDM) is necessary to ensure that the dosage is within the appropriate range. Typically, tobramycin levels are monitored for a trough value, just prior to the next dose. However, CF patients demonstrate enhanced clearing of tobramycin. Ideally, levels would be taken at 18 hours, and the next dose adjusted if trough levels are too high. Importantly, an increasing number of patients are choosing to receive their tobramycin infusions at home. This outpatient approach reduces exposure to hospital-borne pathogens and allows patients to work, attend school and be close to family. Unfortunately, this complicates efforts to properly manage tobramycin therapy, resulting in wide discordance of monitoring across the country. For those patients who do receive TDM, blood is collected at clinics or by home healthcare nurses, and samples are sent to clinical labs for testing, precluding timely dosage adjustments. Thus, there is an unmet need to develop a precise, affordable, point-of-care method to monitor tobramycin in CF patients undergoing outpatient parenteral tobramycin therapy. To address this need, Affinergy is developing highly sensitive capture and detection reagents for a one-step locking assay that will enable rapid, simple, and affordable monitoring of tobramycin at the point of care. In this Phase I application, we will isolate locking reagents which will recognize tobramycin in complex with a capture reagent to rapidly measure tobramycin concentration in blood, and develop a lateral flow assay that will be easily adaptable to the care regimen of home health nurses. A point-of-care tobramycin assay will allow home health nurses and CF clinical pharmacists to perform timely, actionable TDM in patients receiving home parenteral tobramycin therapy, which has the potential to reduce the risk for adverse events, minimize growth of resistant bacteria and effectively manage pulmonary exacerbations.