Therapeutic drug monitoring of antibiotics is safe, effective: Study

Strategy was linked to less lung function decline in 32 CF patients

Patricia Inácio, PhD avatar

by Patricia Inácio, PhD |

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Monitoring the concentration of antibiotics in the blood — a clinical practice called therapeutic drug monitoring — was linked to fewer pulmonary exacerbations and less lung function decline in people with cystic fibrosis (CF), a small study reports.

The study, “Therapeutic drug monitoring in cystic fibrosis and associations with pulmonary exacerbations and lung function,” was published in the journal Respiratory Medicine.

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Pulmonary exacerbations associated with lung function decline in patients

Pulmonary exacerbations — times when respiratory symptoms suddenly worsen — are associated with a decline of lung function in CF patients, as measured by the forced expiratory volume in one second (FEV1), a measure of how much air can be exhaled in one second after a deep breath.

Guidelines in the U.S. and in Europe recommend early detection and treatment of pulmonary exacerbations with intravenous (into-the-vein) antibiotics along with airway clearance therapy. To achieve optimal treatment efficiency, antibiotics need to be kept at adequate levels in the blood.

Now, a team led by researchers at the University of Florida hypothesized that therapeutic drug monitoring (TDM) could improve the outcomes of CF patients treated with beta-lactam antibiotics. TDM measures the levels of a medication in the bloodstream to make sure it is both safe and effective.

The researchers conducted a retrospective analysis of 32 CF patients (19 women, median age of 27 years) followed at the University of Florida Health Shands Hospital from March 2016 to June 2017 for pulmonary exacerbations. They compared the incidence of pulmonary exacerbations and the patients’ lung function before and after being on TDM for one year.

Seventeen patients (53%) carried two copies of the F508del mutation, the most common CF-causing mutation. The median percentage predicted of FEV1 at the study’s start (baseline) was 41.5%. Patients qualified for treatment with CFTR modulators, a specialized group of CF therapies, were allowed to maintain the treatment.

Using the strategy of either continuous or extended infusion of antibiotics, there is a strong association between TDM of beta-lactams and decreased cystic fibrosis exacerbations, increased time to exacerbation and decline in lung function.

All patients tested positive for P. aeruginosa

All 32 patients tested positive for Pseudomonas aeruginosa, a type of bacteria that commonly infects the lungs of people with CF. Nineteen patients were treated with piperacillin-tazobactam, a beta-lactam/beta-lactamase antibiotic combination, at a dose of 4.5 g delivered intravenously every six hours. The remaining 13 patients received cefepime, a beta-lactam antibiotic delivered intravenously at 2 g every eight hours.

Antibiotic concentrations were measured after these intermittent infusions. If they were below the therapeutic level, the dosing was adjusted or switched to a continuous infusion.

Most patients (90%) treated with piperacillin-tazobactam with an initial daily dose of 18 g did not achieve the goal concentration of 64 micrograms per milliliter (mcg/mL) before the next antibiotic dose (called trough concentration). The median concentration of antibiotic before TDM was 13.3 mcg/mL. After changes in infusion strategy and daily dosage, the median medication dose was 18 g per 24 hours and the median concentration before the next dose increased to 58.4 mcg/mL.

Patients treated with cefepime received an initial dose of 6 g per 24 hours. Their median concentration before the next dose was 15.1 mcg/mL and 77% of patients did not reach the goal concentration of 32 mcg/mL. After adjusting dosages and extending infusions, the median 24-hour dosage remained at 6 g, but the median concentration increased to 44.6 mgc/mL.

When the scientists compared the number of exacerbations before and after TDM, they observed a significant reduction, from a mean of 1.91 to 1.31 exacerbation per year. The time to experience a first exacerbation also was longer after TDM, a mean of 230.6 days compared to 195.4 days before TDM. This difference was larger in patients with two or more exacerbations per year, for whom the time to first exacerbation significantly increased from a mean of 103.7 days before TDM to 196.2 days after TDM.

In addition, the decline in FEV1 as a result of an exacerbation was smaller after TDM when compared to before the intervention, 4.9 versus 9.7.

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Therapeutic drug monitoring ‘a safe strategy to use in cystic fibrosis patients’

As for safety, a 66-year-old woman experienced premature ventricular contractions, which are extra heartbeats beginning in the heart’s lower chambers (called ventricles). She also experienced tremors and felt unwell during continuous infusion with 18 g of piperacillin-tazobactam. Although the link between these symptoms and high antibiotic doses is unknown, her symptoms resolved after two days when the dose was reduced to 13.5 g per day.

Overall, these findings show that “using the strategy of either continuous or extended infusion of antibiotics, there is a strong association between TDM of beta-lactams and decreased cystic fibrosis exacerbations, increased time to exacerbation and decline in lung function among this small cohort of cystic fibrosis patients with moderate/severe disease,” the researchers wrote. “We also found that this [is] a safe strategy to use in cystic fibrosis patients.”

The team noted the study was limited by the small number of participants, which precluded having a control group.