Defining the Importance of Age-Related Changes in Drug Clearance to Optimizing Aminoglycoside Dosing Regimens for Adult Patients with Cystic Fibrosis.

BACKGROUND AND OBJECTIVE: The number of adults living with cystic fibrosis (CF) has increased and will continue to do so with the approval of cystic fibrosis transmembrane conductance regulator (CFTR) modulators. Because systemic aminoglycosides are commonly administered for CF pulmonary exacerbations, we sought to define optimized dosing regimens using a population pharmacokinetic modeling and simulation approach. METHODS: Adult CF patients admitted for pulmonary exacerbation, receiving at least 72 h of systemic gentamicin, tobramycin, or amikacin, with measured concentrations were included. Covariates [e.g., age, weight, creatinine clearance (CRCL)] were screened. Population modeling was completed using Monolix, and simulations were conducted in R. Simulated exposures were calculated using noncompartmental analysis. Once-daily fixed (10 mg/kg) and exposure-matched dosing (i.e., 15, 10, 7.5, 6 mg/kg for ages 20, 30, 40, and 50 years, respectively) strategies were compared. First-24 h exposures were evaluated for each strategy according to the probability of target attainment (PTA) (ratio of peak plasma concentrations relative to the minimum inhibitory concentration [Cmax/MIC] or ratio of the area under the concentration-time curve to MIC [AUC/MIC]) and the probability of toxic exposure (PTE) (trough concentration, Ctrough > 2 mg/l). RESULTS: Forty-eight adult patients (55% female) were included. A one-compartment model best fit the data. Estimates for volume of distribution (V) and clearance (CL) were 22 l and 5.57 l/h, respectively. Weight significantly modified CL and V. Age significantly modified CL and was more influential than CRCL. PTA was > 90% at MICs ≤ 1 mg/l for fixed doses of 10 mg/kg and for exposure-matched doses at MIC ≤ 1 mg/l. Exposure-matched dosing reduced PTE roughly 50% in patients aged 40 and 50 years vs. fixed dosing. CONCLUSIONS: Exposure-matching maintained PTA at MICs ≤ 1 mg/l while reducing toxicity risk in older patients compared to fixed dosing. Confirmatory studies are needed.

Exploring the Relationship between FEV1 Loss and Recovery and Aminoglycoside Pharmacokinetics in Adult Patients with Cystic Fibrosis: Implications for Clinical Dosing Strategies.

OBJECTIVE: Systemic aminoglycosides remain a cornerstone of treatment for cystic fibrosis (CF) pulmonary exacerbations (PEx); however, the impact of aminoglycoside pharmacokinetics (PK) on outcomes is not well defined in adult CF patients. Our objective was to assess the impact of increasing PK exposures on the clinical outcomes of PEx treatment in adult CF patients receiving high-dose and standard-dose extended-interval aminoglycosides. METHODS: We conducted a retrospective study of adult CF patients treated with an intravenous aminoglycoside for a PEx. Serum amikacin, gentamicin, and tobramycin levels and forced expiratory volume over 1 second (FEV1 ) data were used to evaluate exposure-response relationships. PK parameters were estimated using a Bayesian approach to obtain area under the curve (AUC)0-24 hr , maximum concentration (Cmax0-24 hr ), and minimum concentration (Cmin0-24 hr ) estimates. The primary efficacy end point was a 90% recovery of baseline FEV1 by 30 days posttreatment. Toxicity included signs or symptoms of ototoxicity, vestibular toxicity, or renal toxicity. Multivariate linear mixed-effects models of FEV1 were used for exposure-response analysis. RESULTS: The study included 51 patients who contributed 188 FEV1 observations. There were 3.0 ± 1.7 (mean ± SD) aminoglycoside concentrations per patient. The mean AUC0-24 hr , Cmax0-24 hr , and Cmin0-24 hr across all agents and patients were 156 ± 96 mg*hr/L, 29.9 ± 12.7 mg/L, and 0.35 ± 0.66 mg/L, respectively. A total of 42 amikacin-, gentamicin-, or tobramycin-treated patients contributed to the efficacy analysis, of whom 85.7% experienced recovery posttreatment. Of the 51 included patients, 6 (11.8%) experienced seven toxicity events. In exploratory exposure-response analyses, neither AUC0-24 hr nor Cmax0-24 hr was associated with FEV1 values after adjusting for clinical covariates and baseline FEV1 . CONCLUSIONS: Increasing aminoglycoside AUC0-24 hr and Cmax0-24 hr were not associated with FEV1 during PEx treatment. Although individualizing aminoglycoside dosing in adult CF patients is necessary to minimize toxicity risk, more work is needed to define optimally safe and effective dosing strategies for this population.

Antibiotic duration and changes in FEV1 are not associated with time until next exacerbation in adult cystic fibrosis: a single center study.

BACKGROUND: Pulmonary exacerbations (PEx) are a major driver of morbidity and mortality in cystic fibrosis and reducing their frequency by extending the time between them is an important therapeutic goal. Although treatment decisions for exacerbations are often made based on dynamic changes in lung function, it is not clear if these changes truly impact future exacerbation risk. We analyzed adults with chronic Pseudomonas aeruginosa infection to determine whether changes in FEV1 or duration of intravenous antibiotic therapy were associated with time to the next pulmonary exacerbation. METHODS: Medical records and Cystic Fibrosis Foundation Patient Registry data were examined retrospectively to assess whether various patient-specific demographic factors and exacerbation-specific characteristics were associated with time until next exacerbation using the Andersen-Gill model in order to control for previous exacerbation frequency history. RESULTS: We examined 59 patients with 221 CF pulmonary exacerbations over a 3-year study period. Mean age was 28.2 years and mean baseline FEV1 was 62% predicted. In our univariable model, fall in FEV1 at onset of exacerbation (median absolute -3% predicted change), recovery of FEV1 with treatment (median absolute +3% predicted change) and duration of IV antibiotics (median 16 days) were not associated with time to next exacerbation (median 93.5 days). Paradoxically each one-year increase in age was associated with a reduction in hazard of PEx by 3% (HR 0.97, P = 0.03, 95% CI 0.95-1.00). CONCLUSIONS: FEV1 drop and recovery associated with onset and treatment of a CF pulmonary exacerbation or duration of intravenous antibiotics were not predictive of time until next exacerbation. Our finding that older age may be associated with decreased hazard of exacerbation is likely due to a healthy survivor effect and should be controlled for in clinical trials of pulmonary exacerbations.

Type III secretion phenotypes of Pseudomonas aeruginosa strains change during infection of individuals with cystic fibrosis.

Pseudomonas aeruginosa is a frequent cause of respiratory exacerbations in individuals with cystic fibrosis. An important virulence determinant of this pathogen is its type III protein secretion system. In this study, the type III secretion properties of 435 P. aeruginosa respiratory isolates from 56 chronically infected individuals with cystic fibrosis were investigated. Although it had been previously reported that 75 to 90% of P. aeruginosa isolates from patients with hospital-acquired pneumonia secreted type III proteins, only 12% of isolates from cystic fibrosis patients did so, with nearly all of these isolates secreting ExoS and ExoT but not ExoU. Despite the low overall prevalence of type III protein-secreting isolates, at least one secreting isolate was cultured from one-third of cystic fibrosis patients. Interestingly, the fraction of cystic fibrosis patient isolates capable of secreting type III proteins decreased with duration of infection. Although 90% of isolates from the environment, the presumed reservoir for the majority of P. aeruginosa strains that infect patients with cystic fibrosis, secreted type III proteins, only 49% of isolates from newly infected children, 18% of isolates from chronically infected children, and 4% of isolates from chronically infected adults with cystic fibrosis secreted these proteins. Within individual patients, isolates of clonal origin differed in their secretion phenotypes, indicating that as strains persisted in cystic fibrosis patient airways, their type III protein secretion properties changed. Together, these findings indicate that following infection of cystic fibrosis patient airways, P. aeruginosa strains gradually change from a type III protein secretion-positive phenotype to a secretion-negative phenotype.