Pharmacokinetics of oral antimycobacterials and dosing guidance for Mycobacterium avium complex treatment in cystic fibrosis.

BACKGROUND: Treatment failure of Mycobacterium avium complex (MAC) pulmonary disease occurs in about 30% of people with cystic fibrosis (CF) and may be a result of abnormal drug concentrations. METHODS: Prospective, cross-over, single-dose PK study of 20 pancreatic insufficient individuals with CF and 10 healthy controls (HC). CF subjects received simultaneous doses of oral azithromycin, ethambutol, and rifampin in the fasting state and with food and pancreatic enzymes, separated by two weeks. HC received fasting doses only. A non-compartmental model was used to estimate PK parameters of drugs and metabolites. RESULTS: Azithromycin maximum concentration (Cmax ) was higher and rifampin Cmax was lower in fasting CF subjects compared to HC, while other PK measures, including those for ethambutol, were similar. Addition of food and enzymes did not improve the Cmax of the antimycobacterial drugs. Nineteen of 20 CF subjects had one or more abnormal Cmax z-scores in either the fasting or fed state (or both), when compared to HC. CONCLUSION: PK profiles of azithromycin and ethambutol were similar between CF and HC, except azithromycin Cmax was slightly higher in people with CF after a single dose. Rifampin PK parameters were altered in persons with CF. Addition of food and enzymes in CF subjects did not improve PK parameters. Standard dosing guidelines should be used as a starting point for people with CF initiating MAC therapy and therapeutic drug monitoring should be routinely performed to prevent the possibility of treatment failure due to abnormal drug concentrations. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02372383 Prior abstract publication: 1. Martiniano S, Wagner B, Brennan L, Wempe M, Anderson P, Nick J, Sagel S. Pharmacokinetics of oral MAC antibiotics in cystic fibrosis. Am J Resp Crit Care Med A4842-A4842, 2017. 2. Martiniano SL, Wagner BD, Brennan L, Wempe MF, Anderson PL, Nick JA, Sagel SD. Pharmacokinetics of oral MAC antibiotics in cystic fibrosis. J Cyst Fibros 16: S52-53, 2017.

Detection of bacterial pathogens using home oropharyngeal swab collection in children with cystic fibrosis.

BACKGROUND: Collection of respiratory cultures for airway microbiology surveillance is an essential component of routine clinical care in cystic fibrosis (CF). The COVID-19 global pandemic has necessitated increased use of telehealth, but one limitation of telehealth is the inability to collect respiratory specimens. We initiated a protocol for at-home collection of oropharyngeal (OP) swabs from children with CF. METHODS: Home respiratory specimen collection was offered during telehealth encounters. Home OP swab kits were sent to participating families via mail with instructions for collection and return. Specimens were returned by overnight shipping or dropped off at a hospital lab for processing and culture. We evaluated demographic data and compared culture results from the home-collected specimen to the most recent specimen collected in clinic. We also tracked the frequency of newly identified Pseudomonas aeruginosa. RESULTS: Home OP swab kits were sent to families of 33 children with CF (range 1.5-19 years). OP swab kits were successfully returned from 19 children (range 1.5-19 years). One or more CF pathogens grew from 79% of the specimens. For four individuals, the home collected specimen demonstrated the new growth of P. aeruginosa. CONCLUSIONS: Home collection of OP swabs for bacterial culture is feasible in children with CF across a range of ages. Most home-collected specimens demonstrated growth of one or more CF pathogens and results were similar to recent in-clinic specimens, suggesting acceptable sample collection technique. Anti-pseudomonal therapy was initiated for four children based on the growth of P. aeruginosa from the home respiratory specimen.

Effect of an antioxidant-rich multivitamin supplement in cystic fibrosis.

BACKGROUND: Despite supplementation with standard multivitamins and pancreatic enzymes, deficiencies of vitamins D and K and antioxidants are common in cystic fibrosis (CF). METHODS: In this non-randomized, open-label study, AquADEKs® softgels were given daily over 12 weeks to 14 CF subjects (mean age 15 years, range 10-23) without a preceding wash-out period. Both pancreatic sufficient and insufficient subjects were enrolled. Plasma vitamin and antioxidant levels, urine 8-isoprostane levels, anthropometric measures, and pulmonary function were determined at baseline, 6 and 12 weeks. RESULTS: Daily supplementation significantly increased plasma beta(ß)-carotene, coenzyme Q10, and γ-tocopherol concentrations, decreased proteins induced in vitamin K absence (PIVKA-II) levels, but did not normalize vitamin D and K status in all subjects. Vitamin A levels did not exceed the normal range for any subject during the entire study period. Modest improvements in weight percentile and pulmonary function were observed. Change in plasma ß-carotene concentrations weakly correlated with changes in weight and body mass index percentiles. CONCLUSIONS: In this study, AquADEKs® increased systemic antioxidant levels, while maintaining vitamin A levels in the normal range, and improved but did not completely normalize vitamin D and K status. Increased ß-carotene levels were associated with improved growth parameters. These results warrant further clinical evaluation in CF.

Frequency of ASCA seropositivity in children with cystic fibrosis.

OBJECTIVE: To determine the frequency of anti-Saccharomyces cerevisiae antibodies (ASCA) seropositivity in pediatric patients with cystic fibrosis (CF) and correlate ASCA with clinical features. METHODS: Prospective study of children with CF aged 2 to 21 years enrolled from The Children's Hospital Cystic Fibrosis Center. Exclusion criteria included Crohn disease, immunodeficiency or immunoglobulin A deficiency. The frequency of ASCA (ASCA immunoglobulin A and immunoglobulin G) was measured by an enzyme-linked immunosorbent assay kit provided by Inova, Inc. (San Diego, CA). The CF Foundation database was queried for clinical data on ASCA seropositive patients. RESULTS: Seventeen (20.7%) of 82 patients were seropositive for ASCA. Of these, eight had immunoglobulin A antibodies, six had immunoglobulin G antibodies and three had both. ASCA seropositivity in CF patients was significantly greater than the general population (20.7% versus 4%, P < 0.0001), using an exact binomial test on a single proportion. The 95% confidence limits around our observed proportion were 12.6% to 31.1%. Of 17 ASCA positive patients, 1 (5.8%) had a history of meconium ileus, 14 (82.4%) had DeltaF508 gene mutation, 9 (52.9%) had positive sputum cultures for fungal organisms, and 17 (100%) had an ideal body weight % >or=85%. CONCLUSION: Patients with CF have a higher frequency of ASCA seropositivity than the general population. When evaluating CF patients for Crohn disease, ASCA should be used with caution. The reasons for higher ASCA seropositivity in CF patients are unknown, but may include exposure to fungal organisms via intestinal or pulmonary sources.