Consideration of height‐based tobramycin dosing regimens for the treatment of adult cystic fibrosis pulmonary exacerbations

Background Emerging data suggests a possible role for cysteamine as an adjunct treatment for pulmonary exacerbations of cystic fibrosis (CF) that continue to be a major clinical challenge. There are no studies investigating the use of cysteamine in pulmonary exacerbations of CF. This exploratory randomized clinical trial was conducted to answer the question: In future pivotal trials of cysteamine as an adjunct treatment in pulmonary exacerbations of CF, which candidate cysteamine dosing regimens should be tested and which are the most appropriate, clinically meaningful outcome measures to employ as endpoints? Methods and findings Multicentre double-blind randomized clinical trial. Adults experiencing a pulmonary exacerbation of CF being treated with standard care that included aminoglycoside therapy were randomized equally to a concomitant 14-day course of placebo, or one of 5 dosing regimens of cysteamine. Outcomes were recorded on days 0, 7, 14 and 21 and included sputum bacterial load and the patient reported outcome measures (PROMs): Chronic Respiratory Infection Symptom Score (CRISS), the Cystic Fibrosis Questionnaire–Revised (CFQ-R); FEV1, blood leukocyte count, and inflammatory markers. Eighty nine participants in fifteen US and EU centres were randomized, 78 completed the 14-day treatment period. Cysteamine had no significant effect on sputum bacterial load, however technical difficulties limited interpretation. The most consistent findings were for cysteamine 450mg twice daily that had effects additional to that observed with placebo, with improved symptoms, CRISS additional 9.85 points (95% CI 0.02, 19.7) p = 0.05, reduced blood leukocyte count by 2.46x109 /l (95% CI 0.11, 4.80), p = 0.041 and reduced CRP by geometric mean 2.57 nmol/l (95% CI 0.15, 0.99), p = 0.049. Conclusion In this exploratory study cysteamine appeared to be safe and well-tolerated. Future pivotal trials investigating the utility of cysteamine in pulmonary exacerbations of CF need to include the cysteamine 450mg doses and CRISS and blood leukocyte count as outcome measures. Clinical trial registration NCT03000348; www.clinicaltrials.gov.

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Population Pharmacokinetics of Amikacin in Adult Patients with Cystic Fibrosis

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00877-18 ◽

2018 ◽

Vol 62 (10) ◽

Cited By ~ 7

Author(s):

Sílvia M. Illamola ◽

Hoa Q. Huynh ◽

Xiaoxi Liu ◽

Zubin N. Bhakta ◽

Catherine M. Sherwin ◽

...

Keyword(s):

Cystic Fibrosis ◽

Population Pharmacokinetics ◽

Drug Disposition ◽

Adult Patients ◽

Therapeutic Drug ◽

Population Pharmacokinetic ◽

Concentration Data ◽

First Order ◽

Dosing Regimens ◽

Pulmonary Exacerbations

ABSTRACTPractitioners commonly use amikacin in patients with cystic fibrosis. Establishment of the pharmacokinetics of amikacin in adults with cystic fibrosis may increase the efficacy and safety of therapy. This study was aimed to establish the population pharmacokinetics of amikacin in adults with cystic fibrosis. We used serum concentration data obtained during routine therapeutic drug monitoring and explored the influence of patient covariates on drug disposition. We performed a retrospective chart review to collect the amikacin dosing regimens, serum amikacin concentrations, blood sampling times, and patient characteristics for adults with cystic fibrosis admitted for treatment of acute pulmonary exacerbations. Amikacin concentrations were retrospectively collected for 49 adults with cystic fibrosis, and 192 serum concentrations were available for analysis. A population pharmacokinetic model was developed using nonlinear mixed-effects modeling with the first-order conditional estimation method. A two-compartment model with first-order elimination best described amikacin pharmacokinetics. Creatinine clearance and weight were identified as significant covariates for clearance and the volume of distribution, respectively, in the final model. Residual variability was modeled using a proportional error model. Typical estimates for clearance, central and peripheral volumes of distribution, and intercompartmental clearance were 3.06 liters/h, 14.4 liters, 17.1 liters, and 0.925 liters/h, respectively. The pharmacokinetics of amikacin in individuals with cystic fibrosis seems to differ from those in individuals without cystic fibrosis. However, further investigations are needed to confirm these results and, thus, the need for variations in amikacin dosing. Future pharmacodynamic studies will potentially establish the optimal amikacin dosing regimens for the treatment of acute pulmonary exacerbations in adult patients with CF.

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Variation in treatment preferences of pulmonary exacerbations among Australian and New Zealand cystic fibrosis physicians

BMJ Open Respiratory Research ◽

10.1136/bmjresp-2021-000956 ◽

2021 ◽

Vol 8 (1) ◽

pp. e000956

Author(s):

Grace Currie ◽

Anna Tai ◽

Tom Snelling ◽

André Schultz

Keyword(s):

Cystic Fibrosis ◽

Clinical Trials ◽

New Zealand ◽

Treatment Options ◽

Early Response ◽

Treatment Preferences ◽

Dornase Alfa ◽

Clinical Scenarios ◽

Professional Opinion ◽

Pulmonary Exacerbations

BackgroundDespite advances in cystic fibrosis (CF) management and survival, the optimal treatment of pulmonary exacerbations remains unclear. Understanding the variability in treatment approaches among physicians might help prioritise clinical uncertainties to address through clinical trials.MethodsPhysicians from Australia and New Zealand who care for people with CF were invited to participate in a web survey of treatment preferences for CF pulmonary exacerbations. Six typical clinical scenarios were presented; three to paediatric and another three to adult physicians. For each scenario, physicians were asked to choose treatment options and provide reasons for their choices.ResultsForty-nine CF physicians (31 paediatric and 18 adult medicine) participated; more than half reported 10+ years of experience. There was considerable variation in primary antibiotic selection; none was preferred by more than half of respondents in any scenario. For secondary antibiotic therapy, respondents consistently preferred intravenous tobramycin and a third antibiotic was rarely prescribed, except in one scenario describing an adult patient. Hypertonic saline nebulisation and twice daily chest physiotherapy was preferred in most scenarios while dornase alfa use was more variable. Most CF physicians (>80%) preferred to change therapy if there was no early response. Professional opinion was the most common reason for antibiotic choice.ConclusionsVariation exists among CF physicians in their preferred choice of primary antibiotic and use of dornase alfa. These preferences are driven by professional opinion, possibly reflecting a lack of evidence to base policy recommendations. Evidence from high-quality clinical trials is needed to inform physician decision making.

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