Association of Intensity of Antipseudomonal Antibiotic Therapy With Risk of Treatment-Emergent Organisms in Children With Cystic Fibrosis and Newly Acquired Pseudomonas Aeruginosa.

BACKGROUND: While Pseudomonas aeruginosa (Pa) eradication regimens have contributed to a decline in Pa prevalence in people with cystic fibrosis (CF), this antibiotic exposure might increase the risk of acquisition of drug-resistant organisms. This study evaluated the association between antipseudomonal antibiotic exposure intensity and acquisition risk of drug-resistant organisms among children with CF and new Pa infection. METHODS: We utilized data from the Early Pseudomonas Infection Control Clinical Trial (EPIC CT), a randomized controlled trial comparing Pa eradication strategies in children with CF and new Pa. The exposure was the number of weeks of oral or inhaled antipseudomonal antibiotics or ever versus never treatment with intravenous antipseudomonal antibiotics during the 18 months of EPIC CT participation. Primary outcomes were risks of acquisition of several respiratory organisms during 5 years of follow-up after EPIC CT estimated using Cox proportional hazards models separately for each specific organism. RESULTS: Among 249 participants, there was no increased acquisition risk of any organism associated with greater inhaled antibiotic exposure. With each additional week of oral antibiotics, there was an increased hazard of Achromobacter xylosoxidans acquisition (HR, 1.24; 95% CI: 1.02-1.50; P = .03). Treatment with intravenous antibiotics was associated with an increased hazard of acquisition of multidrug-resistant Pa (HR, 2.47; 95% CI: 1.28-4.78; P = .01) and MRSA (HR, 1.57; 95% CI: 1.03-2.40; P = .04). CONCLUSIONS: Results from this study illustrate the importance of making careful antibiotic choices to balance the benefits of antibiotics in people with CF while minimizing risk of acquisition of drug-resistant organisms.

A comparison of clinic and home spirometry as longtudinal outcomes in cystic fibrosis.

BACKGROUND: The COVID-19 pandemic has accelerated the transition to telehealth, including the use of home spirometry in cystic fibrosis. Evaluating the accuracy and precision of longitudinal home spirometry is a requisite for telehealth-based research. This secondary analysis of a CF study (eICE) evaluates whether there are cross-sectional or longitudinal differences between home and clinic spirometry. METHODS: Participants age ≥14 years with ppFEV1>25 were recruited from 2011-2015, issued a home spirometer, and asked to complete spirometry efforts twice per week for one year. Clinic spirometry was collected at baseline and every three months. Cross-sectional differences between clinic spirometry and the closest home spirometry measurement were analyzed. Longitudinally, we apply 5 methods to analyze the precision of home spirometry, and differences between clinic vs. home data. RESULTS: Home spirometry is estimated to be 2.0 (95% CI: 0.3, 3.5) percentage points lower than clinic spirometry cross-sectionally. Longitudinally, the estimates of 12-month change in home spirometry varied by analysis method from -2.6 to -1.0 ppFEV1/ year, with precision markedly different. However, home spirometry change estimates were qualitatively similar to the clinic results: -3.0 ppFEV1/year (95% CI: -4.1, -1.9). CONCLUSIONS: To leverage the potential cost, feasibility and convenience of home spirometry, the differences with clinic spirometry must be acknowledged. Significantly lower ppFEV1 in home devices shows that direct comparison to clinic spirometers may induce a spurious change from baseline, and additional variability in home devices impacts statistical power. The effect of coaching, setting, and equipment must be understood to use and improve home spirometry in CF.

Evaluating assumptions of definition-based pulmonary exacerbation endpoints in cystic fibrosis clinical trials.

BACKGROUND: Cystic fibrosis (CF) pulmonary exacerbations can be serious respiratory events and reduction in exacerbation rate or risk are important efficacy endpoints for CF therapeutic trials. Variability in exacerbation diagnoses and treatment have led drug developers to employ "objective" exacerbation definitions combining antimicrobial treatment (AT) and the presence of ≥4 of 12 respiratory criteria (first published by Fuchs et al. [NEJM 1994;331(10):637-42]). Assumptions underlying this approach have yet to be formally evaluated. METHODS: Respiratory events (RE) observed during a 48-week trial of ataluren (NCT02139306), a read-through agent for premature nonsense codons, were compared across six exacerbation definitions: any AT, intravenous AT (IVAT), ≥4 Fuchs criteria present, AT plus ≥4 Fuchs criteria, IVAT plus ≥4 Fuchs criteria, and investigator assessment. Fuchs definitions were evaluated by assessing missingness of individual criteria and associations between criteria presence and clinician exacerbation assessment. RESULTS: Among 751 RE, more than one third had ≥4 Fuchs criteria present but were not assessed as exacerbations by investigators. Data for ≥1 and for 4 Fuchs criteria, respectively, were missing for ~ 90% and >30% of RE. Only 6/12 Fuchs criteria were present more often when investigators assessed RE as exacerbations than when they did not. CONCLUSIONS: "Objective" definitions have shortcomings inconsistent with their purpose of optimizing exacerbation capture in clinical trials : 1) they capture events clinicians do not consider exacerbations, 2) are prone to data missingness which can bias the likelihood of meeting the definition, and 3) employ criteria that are not associated with investigator assessment of exacerbation.

Revision surgeries are associated with significant increased risk of subsequent cerebrospinal fluid shunt infection.

BACKGROUND: The object of this study was to determine whether cerebrospinal fluid (CSF) shunt revision(s) are associated with increased risk of CSF shunt infection, after adjusting for baseline factors that contribute to infection risk. METHODS: This was a retrospective cohort study of 579 children aged 0-18 years who underwent initial CSF shunt placement between January 01, 1997 and October 12, 2006 at a tertiary care children's hospital. The outcome of interest was CSF shunt infection. Data for all subsequent CSF shunt revisions leading up to and including the initial CSF shunt infection, when applicable, were obtained. The likelihood of infection was determined using a Cox proportional hazard model accounting for patient characteristics and CSF shunt revisions, and is reported using hazard ratios (HR) with 95% confidence intervals (CI). RESULTS: There were 123 children who developed infection. Baseline factors independently associated with hazard of infection included age 0 to <6 months at CSF shunt placement (HR 2.4, 95% CI: 1.02-6.7) and myelomeningocele (HR 0.4, 95% CI: 0.2-0.8). Controlling for baseline factors, the risk of infection after shunt revision was significantly greater than at the time of initial placement (HR 3.0, 95% CI: 1.9-4.7), and this risk increased as numbers of revisions increased (≥2 revisions HR 6.5, 95% CI: 3.6-11.4). CONCLUSIONS: Although younger age is associated with increased hazard of infection, subsequent CSF shunt revision significantly increases infection risk.

Treatment and microbiology of repeated cerebrospinal fluid shunt infections in children.

BACKGROUND: A small group of children have second and even more cerebrospinal fluid (CSF) shunt infections (SIs). We sought to describe the treatment approaches used for, and the microbiology of, repeated SIs. METHODS: The study population included 31 children with second shunt infection (SI-2) among those undergoing initial CSF shunt placement and treatment for initial infection at Primary Children's Medical Center. CSF SI was defined as follows: (1) presence of bacteria in Gram stain and/or culture of CSF, wound, and/or pseudocyst; (2) visible hardware; (3) abdominal pseudocyst; or (4) presence of bacteria in a blood culture in children with a ventriculoatrial shunt. Infection rates were generated using per-patient denominators, and the concordance of organisms across infections was summarized. RESULTS: Of the 31 children with SI-2, most were less than 6 months of age at initial shunt placement (81%), male (77%), and with ventriculoperitoneal shunts (71%). Of total, 18 developed SI-3 and 8 developed SI-4. Infection rates were 60% (95% confidence interval [CI]: 42%-75%, n = 18/30) for SI-3 and 47% (95% CI: 26%-69%, n = 8/17) for SI-4. The median time to SI-3 was 477 days (range, 5-828) and to SI-4 it was 2137 days (range, 9-2137). Gram-positive organisms predominated (93% of SI-2, 94% of SI-3). The majority of SI-2 demonstrated Gram-stain concordance with both the initial (first) SI (58%, 95% CI: 41%-74%) and with the following (third) SI (78%, 95% CI: 55%-91%). CONCLUSIONS: Children with SI-2 experience high subsequent reinfection rates with a long time to reinfection.