Most Patients With CF May Get Insufficient Antibiotics to Fight Lung Infections

A new study by Children’s National Health System researchers suggests that the majority of patients with cystic fibrosis (CF) may not achieve blood concentrations of antibiotics sufficiently high enough to effectively fight bacteria causing lung infections known collectively as pulmonary exacerbations, which lead to worsening pulmonary function.¹ Pulmonary exacerbations are typically treated with a combination of at least 2 antibiotics—one of which is typically a β-lactam antibiotic, which are time-dependent in their bactericidal activity, and whose concentrations must exceed a minimum inhibitory concentration (MIC) for a certain period of time.

However, blood concentrations of β-lactam antibiotics are not typically tracked while patients are taking them, notes the study’s lead author, Andrea Hahn, MD, MS. She said the study suggests it is not possible to predict from dosing regimens alone which patients will achieve therapeutically meaningful serum concentrations of antibiotics. Thus, real-time tracking of serum antibiotic concentrations may hold the key to improving clinical outcomes in CF.

The study followed 19 patients with CF between ages 5 and 21 years, who were treated with 29 courses of antibiotics, the most common of which were the β-lactam antibiotics ceftazidime (62%) and meropenem (45%). The study subjects were treated at Children’s National Health System for pulmonary exacerbations between March 2015 and August 2016. The researchers used pharmacokinetic (PK) modeling and MICs of the involved pathogens to determine therapeutic or subtherapeutic β-lactam antibiotic exposure based on the time the antibiotic concentration was above the MIC.

Respiratory (sputum or deep throat culture) samples were collected from the patients on 4 different occasions:

• During well visits to the clinic and at least 30 days after they had received a therapeutic course of antibiotics
• At the beginning of acute pulmonary exacerbation that required intravenous antibiotic therapy (either in the hospital or at home)
• After treatment of the acute pulmonary exacerbation, and
• More than 30 days after the patient completed the course of treatment.

Investigators checked patients’ plasma concentrations of β-lactam antibiotics during each patient’s treatment course, collecting samples at least 4 times:

• A trough (lowest concentration) fewer than 30 minutes before a dose
• A peak 1 hour after infusion of the dose
• A sample 3 to 4 hours after infusion of the dose, and
• A repeat trough fewer than 30 minutes before another dose.

All patients underwent pulmonary function tests at the beginning of pulmonary exacerbations and about once weekly until their antibiotic therapy ended. The investigators created a model to analyze which patients had achieved therapeutic concentrations for the bacteria in their respiratory secretions and correlated the results with those of the patients’ pulmonary function tests to determine which patients had achieved therapeutic concentrations.

There was no difference in age, genotype of CF, or creatinine clearance among the 9 participants (47%) who reached therapeutic concentrations versus the 10 (53%) who did not. Those who achieved sufficiently high antibiotic exposure had more significant improvement of their pulmonary function tests, the researchers note. They discovered that although each patient received recommended antibiotic doses, some patients had high enough serum antibiotic concentrations while others did not.

“Getting adequate treatment is crucial for getting better,” said Hahn. Her team is using the findings from this research to implement an algorithm using different variables to determine antibiotic dosing for CF patients treated at Children’s National Hospital.

New models should incorporate variables such as age, gender, kidney function, Hahn said. Further research is needed to determine whether real-time therapeutic drug monitoring and PK modeling would improve antibiotic blood concentrations in patients with CF and improve their clinical outcomes.

Reference

Hahn A, Jensen C, Fanous H, et al. Relationship of pulmonary outcomes, microbiology, and serum antibiotic concentrations in cystic fibrosis patients. J Ped Pharmacol Ther. 2018;23(5):379-389. doi: 10.5863/1551-6776-23.5.379.