Relationship of Pulmonary Outcomes, Microbiology, and Serum Antibiotic Concentrations in Cystic Fibrosis Patients

Abstract

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.

Changes in microbiome diversity following beta-lactam antibiotic treatment are associated with therapeutic versus subtherapeutic antibiotic exposure in cystic fibrosis

“…While no statistical differences were noted, trends were present that showed patients receiving therapeutic antibiotics had a higher relative improvement of FEV 1 , and FEV 1 /FVC at post-recovery compared to onset of the exacerbation than those in the subtherapeutic group (FEV 1 28.8 vs 14.8, p = 0.11; FEV 1 / FVC 9 vs 1.1, p = 0.07). This corroborates our findings previously published on this same cohort of patients where significant differences were found in non-normalized pulmonary function between the two groups, with higher recovery in those achieving therapeutic beta-lactam drug exposure 31 .…”

“…Another study found a strong correlation between poor lung function and low species richness 8 , while two others showed that lower alpha diversity, measured by Shannon diversity index, was associated with worsening pulmonary function 28,30 . Our previously published analysis of this patient cohort comparing antibiotic PK and lung function found subtherapeutic beta-lactam antibiotic exposure was associated with less improvement of lung function 31 . In this study, we also saw similar trends using normalized lung function data.…”

“…The participants were stratified into therapeutic and subtherapeutic groups, on the basis of whether their beta-lactam exposure met appropriate T > MIC parameters (40% for carbapenems, 50% for penicillins, and 60% for cephalosporins) 22,23,37 . A full description of the determination of T > MIC has been published elsewhere, but in brief the highest MIC identified within a patient's exacerbation culture against the beta-lactam antibiotics used for treatment was used 31 . If the patient grew only normal respiratory flora, the MIC used was the median MIC of the study patients who grew P. aeruginosa.…”

Importance of beta-lactam pharmacokinetics and pharmacodynamics on the recovery of microbial diversity in the airway of persons with cystic fibrosis

“…A sparse PK sampling design was used similar to the one we had previously published. 11 Briefly, samples were collected after achieving steady state (>24 hours after initiation of antibiotics) and were obtained at four time points: trough (×2), peak (1 hour after infusion), and mid-dose (3-4 hours after infusion). Samples were placed on ice and processed immediately to maintain concentration integrity, and then were frozen at −80°C.…”

“…There the free drug plasma concentrations for ceftriaxone, ceftazidime, piperacillin, and meropenem were determined from each sample using multiplex liquid chromatography-mass spectroscopy. 11 PK/PD modeling PK modeling of beta-lactam antibiotics was performed using Bayesian estimation in MW/Pharm V.3.80 (Mediware), as previously published. 8 9 11 Briefly, study subject age, weight, height, serum creatinine (measured at hospital admission), antibiotic dose, and measured plasma concentrations were all incorporated into the model to develop the time-concentration curve.…”