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Cystic fibrosis patients may receive insufficient antibiotics to fight lung infections

The majority of paediatric patients with cystic fibrosis may not achieve blood concentrations of antibiotics sufficiently high enough to effectively fight bacteria responsible for pulmonary exacerbations, leading to worsening pulmonary function, indicates a study led by researchers at Children's National Health System as well as the George Washington University School of Medicine & Health Sciences and the University of Southern California School of Pharmacy. Additionally, the study findings show that it's impossible to predict solely from dosing regimens which patients will achieve therapeutically meaningful antibiotic concentrations in their blood.

The findings suggest that closely monitoring blood antibiotic concentrations could prove key to improving clinical outcomes.

Cystic fibrosis, a genetic condition that affects about 70,000 people worldwide, is characterised by a build-up of thick, sticky mucus in patients' lungs. There, the mucus traps bacteria, causing patients to develop frequent lung infections that progressively damage these vital organs and impair patients' ability to breathe.

These infections, which cause a host of symptoms collectively known as pulmonary exacerbations, are typically treated with a combination of at least two antibiotics with unique mechanisms. One of these drugs is typically a Beta-lactam antibiotic, a member of a family of antibiotics that includes penicillin derivatives, cephalosporins, monobactams and carbapenems.

Although all antibiotics have a minimum concentration threshold necessary to treat infections, Beta-lactam antibiotics are time-dependent in their bactericidal activity. Their concentrations must exceed a minimum inhibitory concentration for a certain period. However, explains study lead author Dr Andrea Hahn, an infectious disease specialist at Children's National, blood concentrations of Beta-lactam antibiotics aren't typically tracked while patients receive them.

Since antibiotic dosing often doesn't correlate with cystic fibrosis patients' clinical outcomes, Hahn and colleagues examined whether patients actually achieved serum antibiotic concentrations that are therapeutically effective.

The researchers collected data from 19 patients seen at Children's Cystic Fibrosis Centre. For each patient, the researchers collected respiratory secretions on four different occasions: When they were at the clinic for a well-visit; at the beginning of an acute pulmonary exacerbation that required intravenous antibiotic therapy; after treating that acute pulmonary exacerbation; and more than 30 days after the patient completed the treatment course.

The researchers also checked plasma drug concentrations of Beta-lactam antibiotics during each patient's treatment course. They collected samples at a minimum of four time points: a trough of fewer than 30 minutes before a dose; a peak one hour after a dose was infused; a sample three to four hours after the dose was infused; and a repeat trough fewer than 30 minutes before another dose.

In addition, all the patients underwent pulmonary function tests at the start of their exacerbations and about once weekly until their antibiotic therapy ended.

Using these data points, the researchers constructed a model to determine which patients had achieved therapeutic concentrations for the bacteria found in their respiratory secretions. They then correlated these findings with the results of patients' pulmonary function tests. Just 47 percent of patients had achieved therapeutic concentrations. Those who achieved significantly high antibiotic exposure had more improvement on their pulmonary function tests compared with patients who didn't.

Paradoxically, they discovered that although each patient received recommended antibiotic doses, some patients had adequately high serum antibiotic concentrations while others did not.

Hahn notes that real-time monitoring of antibiotic blood concentrations could help doctors stay on top of whether patients are being adequately dosed. The research team is investigating this in a new study.

Another way to ensure patients receive therapeutically meaningful levels of antibiotics is to develop new models that incorporate variables such as age, gender and creatinine clearance – a measure of kidney function that can be a valuable predictor of metabolism – to predict drug pharmacokinetics. Using findings from this research, Hahn adds, Children's National already has implemented an algorithm using different variables to determine antibiotic dosing for patients treated at the hospital.

"Getting adequate treatment is crucial for getting better," she says. "At Children's National, we are implementing policies to make sure that happens for our patients with cystic fibrosis, infusing new research insights into patients' ongoing clinical care."

Objectives: To determine the frequency of subtherapeutic exposure to intravenously administered β-lactam antibiotics in a cohort of cystic fibrosis (CF) patients who were treated for a pulmonary exacerbation, and its impact on pulmonary function.
Methods: Nineteen CF patients between the ages of 5 and 21 years treated at Children's National Health System for a pulmonary exacerbation were followed between March 2015 and August 2016 in a prospective, longitudinal study. Pharmacokinetic modeling and minimum inhibitory concentrations (MICs) of the involved pathogens were used to determine therapeutic or subtherapeutic β-lactam antibiotic exposure based on the time the antibiotic concentration was above the MIC. Clinical outcomes were measured by spirometry values.
Results: The 19 participants were treated with a total of 29 courses of antibiotics. The most common β-lactam antibiotics used in a treatment course were ceftazidime (62%) and meropenem (45%). There was no difference in age, CF genotype, or creatinine clearance between 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.
Conclusions: We found that sufficient antibiotic exposure during treatment of CF pulmonary exacerbations was associated with improved pulmonary function. Moreover, it was impossible to predict, solely from the dosing regimen used, which patients were going to reach therapeutic β-lactam antibiotic serum concentrations. This suggests that CF patients may benefit from closer monitoring of their β-lactam exposure and bacterial MIC for optimal clinical outcomes.

Andrea Hahn, Caroline Jensen, Hani Fanous, Hollis Chaney, Iman Sami, Geovanny F Perez, Stan Louie, Anastassios C Koumbourlis, James E Bost, John N van den Anker

[link url=""]Children’s National Health System material[/link]
[link url=""]Journal of Paediatric Pharmacology and Therapeutics abstract[/link]

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