Elexacaftor/Tezacaftor/Ivacaftor use in Pediatric Cystic Fibrosis Patients with Advanced Liver Disease.

BACKGROUND: Cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy extends the life expectancy of people with cystic fibrosis (PwCF). However, CFTR modulators have not been well studied in patients with cystic fibrosis liver disease (CFLD), specifically those with advanced liver disease with portal hypertension. The purpose of this report is to describe the use of elexacaftor/tezacaftor/ivacaftor (ETI) in pediatric CF patients with advanced CFLD. METHODS: This retrospective case series included PwCF < 18 years old with baseline advanced CFLD initiated on ETI. RESULTS: Eleven PwCF and advanced CFLD were treated with ETI; six started a reduced dose regimen. No patient required treatment interruption and four patients received dose changes related to increase in transaminase and/or bilirubin elevations. Mean (SD) change in ppFEV1 from prior to ETI to highest value during therapy was 14.27 % (4.25) (p = 0.007). When evaluating the group as whole, AST decreased from baseline to last reported -15.18 (23.23) units/L (p = 0.054) and ALT slightly increased 0.73 (39.13) units/L (p = 0.96). Bilirubin increased minimally overall for patients with mean change from baseline of 0.83 (1.33) mg/dL [range -0.5-3] (p = 0.17). A model for time on ETI showed a significant decrease in AST over time of 0.955 per month of ETI but no other liver biochemistries were significant. No patient experienced decompensation of CFLD. CONCLUSION: ETI therapy in pediatric CF patients with advanced CFLD can be beneficial in improving pulmonary and nutritional outcomes without negative impact on liver biochemistries or hepatic outcomes. Close monitoring is recommended to ensure safety and tolerability.

Educational Initiative to Increase Knowledge for Transition to Adult Care in Adolescents With Cystic Fibrosis.

OBJECTIVE: Preparation for transition from pediatric to adult cystic fibrosis (CF) care is essential for successful self-management in adulthood. The primary objective of this study was to determine if education improved performance on follow-up assessments to increase knowledge for transition into adult care. The secondary objective of this study was to identify areas of greatest educational opportunity for adolescent CF patients. METHODS: A knowledge assessment containing 13 multiple-choice questions was given to patients between 14 and 19 years of age. Three educational handouts covering topics including nutrition, pancreatic enzyme replacement therapy, or vitamins were provided when a question corresponding to the topic was answered incorrectly. The same assessment was completed at the next clinic appointment as a follow-up. The scores of initial and follow-up assessments were compared based on number of correct answers. Additionally, the number of educational handouts provided was analyzed to determine area of greatest educational need. RESULTS: The average score ± SD on the initial assessment was 8.3 ± 1.6 of 13 questions answered correctly. For patients who completed both assessments, scores improved significantly between initial and follow-up assessments (8.4 ± 1.8 before education vs 10.3 ± 1.1 after; p = 0.0008). Nutrition, pancreatic enzyme, and vitamin handouts were given to 14 (70%), 17 (85%), and 20 (100%) patients, respectively. CONCLUSIONS: This pharmacist-driven educational initiative increased knowledge assessment scores after education was provided. Future studies of similar knowledge assessments starting at younger ages and other disease topics may determine if targeted education is the optimal way to build knowledge for transition to adult CF care.

The impact of adopting low-molecular-weight heparin in place of aspirin as routine thromboprophylaxis for patients with hip fracture.

PURPOSE OF THE STUDY: In 2010, the National Institute for Health and Care Excellence (NICE) recommended the use of anticoagulants rather than aspirin as pharmacological thromboprophylaxis after hip fracture. We examine the impact of implementing this change in guidance on the clinical incidence of deep vein thrombosis (DVT). STUDY DESIGN: Demographic, radiographic and clinical data were retrospectively collected for 5039 patients admitted to a single tertiary centre in the UK for hip fracture between 2007 and 2017. We calculated rates of lower-limb DVT and examined the impact of the June 2010 change of departmental policy, from use of aspirin to use of low-molecular-weight heparins (LMWH) in hip fracture patients. RESULTS: Doppler scans were performed in 400 patients in the 180 days after a hip fracture, and identified 40 ipsilateral and 14 contralateral DVTs (p<0.001). The rate of DVT reduced significantly following the 2010 change in departmental policy from aspirin to LMWH in these patients (1.62% vs 0.83%, p<0.05). CONCLUSIONS: The rate of clinical DVT halved following the change from aspirin to LMWH for pharmacological thromboprophylaxis, but the number needed to treat was 127. A figure of <1% for the incidence of clinical DVT in a unit that routinely uses LMWH monotherapy following hip fracture provides a context for discussions of alternative strategies, and for power calculations for future research. These figures are important to policy makers and to researchers as they will inform the design of the comparative studies on thromboprophylaxis agents for which NICE has called.

Evaluation of the safety of piperacillin-tazobactam extended infusion in pediatric cystic fibrosis patients.

BACKGROUND: Patients with cystic fibrosis (CF) may be treated with piperacillin-tazobactam (PZT) for acute pulmonary exacerbations. Extending the infusion of PZT is one strategy to increase efficacy. Direct comparison, with respect to the incidence of acute kidney injury (AKI), between these two strategies has not been evaluated in pediatric patients with CF. The primary objective of this study was to compare the incidence of AKI in pediatric CF patients receiving extended infusion (EI) PZT versus traditional infusion (TI). METHODS: This IRB-approved, retrospective analysis included patients ages 30 days to 18 years that received PZT for at least 48 h between January 1, 2008, and January 1, 2020. PZT was infused over 30 min (TI group) or 4 h (EI group). RESULTS: Two hundred and four patients were included (TI: 109, EI: 95). Median age was 8 years (4-13) and 7 years (3-12) in the TI and EI groups (p = 0.15). The groups did not differ significantly in their baseline characteristics. There were 12 (11%) AKIs in the TI group and 8 (8.4%) in the EI group (p = 0.53). There was one occurrence of serum sickness in the TI group and none in the EI group. The incidence of thrombocytopenia was similar between the two groups. Median treatment duration was 8 days (5-11) and 9 days (5-13) for the TI and EI groups, respectively (p = 0.24). CONCLUSIONS: There was no significant increase in AKI in pediatric patients with CF receiving PZT by EI compared with TI. EI may be utilized to optimize the pharmacokinetics of PZT in pediatric CF patients.

Evaluation of the safety of cefepime prolonged infusions in pediatric patients with cystic fibrosis.

OBJECTIVE: Pediatric cystic fibrosis (CF) patients possess unique pharmacokinetics and may benefit from prolonged beta-lactam infusions to optimize pharmacodynamics. This study compared adverse drug event (ADE) rates with cefepime prolonged (PI) and standard infusions (SI). METHODS: This retrospective study included pediatric patients treated with cefepime for CF exacerbations between 2009 and 2019. One encounter per patient was analyzed with prioritization of SI encounters given sample size limitations. Baseline lab abnormalities, seizure disorders, and bleeding were exclusion criteria. The primary outcome was a composite safety endpoint (acute kidney injury [AKI], hepatotoxicity, hematologic toxicity, neurotoxicity, and hypersensitivity). RESULTS: Of 188 patients, 135 received PI and 53 received SI. Baseline characteristics were similar between groups. More PI patients used CF transmembrane conductance regulator (CFTR) modulators (25% vs. 0%, p < 0.01) or had antibiotic allergies (62% vs. 38%, p = 0.02). Difference in rates of composite safety endpoint was not statistically significant between PI and SI (21 [15.6%] vs. 6 [11.3%] p = 0.46) nor was incidence of AKI (16 [11.8%] vs. 6 [11.3%], p = 0.92). Other ADEs were rarely observed. Length of stay (12.2 vs. 10.1 days, p = 0.06), change in discharge ppFEV1 from admission (13 vs. 12, p = 0.91) or from baseline (-4 vs. -6.5, p = 0.33), and time to next exacerbation (249.7 vs. 192.5 days, p = 0.93) were similar. CONCLUSIONS: No difference in risk of ADEs including AKI was seen with cefepime PI in pediatric CF patients. Clinical outcomes were not significantly different between groups, but sample size may have limited comparison. PI cefepime may be considered in pediatric CF patients to optimize pharmacodynamics.

Beyond the Guidelines: Treatment of Allergic Bronchopulmonary Aspergillosis in Cystic Fibrosis.

OBJECTIVE: To review the available literature addressing alternative allergic bronchopulmonary aspergillosis (ABPA) treatment options for patients with cystic fibrosis (CF). DATA SOURCES: A literature search of PubMed was performed (January 2002 to April 2021) using the following search terms: allergic bronchopulmonary aspergillosis, aspergillus-related lung disease, cystic fibrosis. Manufacturer prescribing information, clinical practice guidelines, and data from ClinicalTrials.gov were incorporated in the reviewed data. STUDY SELECTION AND DATA EXTRACTION: Relevant English-language studies or those conducted in humans were considered for inclusion. DATA SYNTHESIS: Available literature for alternative ABPA treatments in CF is lacking randomized controlled trials, but there is considerable support in case reports and case series describing the benefits in pediatric and adult patients. Recent literature has begun to explore the place in therapy for novel, corticosteroid-sparing treatment approaches. The alternative therapies summarized in this review all resulted in clinical improvement and subsequent discontinuation or dose reductions of oral corticosteroids, with minimal reported adverse drug effects. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: Although corticosteroids are the cornerstone of ABPA management, the toxicities can be significant limitations in an already high-risk patient population. Patients may fail or become intolerant to guideline-recommended therapies and require alternative treatment approaches. CONCLUSIONS: Alternative treatment modalities for ABPA in patients with CF, including azole antifungals, pulsed intravenous glucocorticoids, omalizumab, mepolizumab, and inhaled amphotericin, appear to be efficacious and well tolerated. Pharmacological properties including route of administration, storage and stability, beyond use dating, and adverse effects of the various treatment modalities must be considered when selecting a practical care plan for patients.

A clinician survey of use assessment, documentation, and education about cannabis in persons with cystic fibrosis.

INTRODUCTION: To help open the clinician dialogue regarding cannabis use in persons with cystic fibrosis (CF) in the United States, we aimed to describe current practices of use assessment and documentation processes related to cannabis. METHODS: A cross-sectional, anonymous survey study was distributed via email to CF directors and coordinators and to the Cystic Fibrosis Foundation (CFF) listservs of nurse, pharmacist, dietitian, social worker, and psychology care team members. The survey tool included multiple choice, scaled, and open-ended items, which assessed participants' awareness of current cannabis laws in their state, prescribing practices for medical marijuana, screening and documentation practices, knowledge of and what indications participants believe cannabis and cannabidiol (CBD) could be beneficial. Data were analyzed using descriptive statistics. RESULTS: There were 282 survey participants, with majority as providers (28%) and social workers (29%), representing all US regions. Participants varied in terms of frequency of evaluating cannabis use, with 15.4% "always," 48.4% "sometimes," and 41% "rarely," or "never" asking about it. Regarding recreational versus medical cannabis use, 55.4% and 62.5% reported documentation of each type in the medical record, respectively. Participants reported appetite, pain, and nausea as the top three advocated indications for use. About 35% and 72% of participants felt "slightly" or "not at all" prepared to answer patient/family questions about cannabis and CBD, respectively. CONCLUSIONS: The approach to cannabis use assessment, documentation, and education across CF care centers is variable. There is a need for care team and patient/caregiver education materials about cannabis/CBD and CF.

Impact of a pharmacy technician and pharmacist on time to inhaled tobramycin therapy in a pediatric cystic fibrosis clinic.

BACKGROUND: Cystic fibrosis (CF) patients who grow Pseudomonas aeruginosa on respiratory culture are commonly prescribed inhaled tobramycin (TIS) to eradicate the organism. The objective of this study was to determine the impact of a pharmacy technician/pharmacist team, in conjunction with an integrated health-system specialty pharmacy (IHSSP), on the time from positive culture to prescribing and access to TIS in a pediatric CF clinic. METHODS: A retrospective study of CF patients positive for P. aeruginosa who were prescribed TIS for eradication. RESULTS: The study included 20 patients in the pregroup and 42 patients in the postgroup. Total median (interquartile range) days from positive culture to TIS being shipped to the patient from the pharmacy was significantly different: 15 (10.25-21) days in the pregroup and 9 (7-14) days in the post groups (p = .005). The time from positive culture to TIS prescribing was significantly different: 6 (5-12.75) days in the pregroup and 5 (3.75-6) days in the postgroup (p = .01). In the postgroup median time from prescription to the patient receiving the TIS was significantly different between the two groups 2 (2-5) days IHSSP group versus 6 (3-9) external specialty pharmacy group (p = .003). Time from prescription to prior authorization approval was the same in both groups. CONCLUSIONS: The addition of the pharmacy team reduced time from culture to TIS being received by the patient. Patients able to fill at the IHSSP received their medication sooner than an external specialty pharmacy. The study shows the benefit of an integrated pharmacy model in conjunction with an IHSSP.

Effects of CFTR modulators on pharmacokinetics of tobramycin during acute pulmonary exacerbations in the pediatric cystic fibrosis population.

BACKGROUND: Individuals with cystic fibrosis (CF) require higher dosages of aminoglycosides due to an increased volume of distribution (Vd ) and clearance. Optimal dosing of aminoglycosides in the CF population is essential as repeated exposure to aminoglycosides during acute pulmonary exacerbations increases risk of nephrotoxicity and ototoxicity. To date, no studies have evaluated whether chronic cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy affects pharmacokinetics of aminoglycoside antibiotics in patients with CF. The objective of this study was to determine if the addition of a CFTR modulator affects elimination rate (Ke ) for intravenously administered tobramycin in the pediatric CF population. METHODS: This retrospective study included patients aged 2 to 18 years with CF receiving chronic therapy with a CFTR modulator. Patients included had an admission both pre- and post-chronic CFTR modulator therapy during which they received therapy with IV tobramycin. RESULTS: Thirty-four patients were included in the study. The median time between pre- and post-modulator admissions was 16.5 (13.8) months. Duration of CFTR modulator therapy before post-modulator admission was a median of 8 (10.3) months. There was no significant difference in Ke (hr-1 ) between pre- and post-modulator therapy, 0.41 (0.21) pre and 0.39 (0.09) post (P = .5). Vd and peak concentration were similar between both groups. There was no difference in nephrotoxicity as defined by the pRIFLE criteria (P = .25). CONCLUSIONS: The pharmacokinetic parameters of intravenously administered tobramycin during admission for acute pulmonary exacerbation do not appear to change significantly after initiating chronic therapy with a CFTR modulator. Empiric dose adjustments for patients on CFTR modulators are not recommended.

CATS II Long-term Anthropometric and Metabolic Effects of Maternal Sub-optimal Thyroid Function in Offspring and Mothers.

CONTEXT AND OBJECTIVES: The Controlled Antenatal Thyroid Screening Study I (CATS-I) was a randomized controlled trial investigating the effects of levothyroxine therapy for suboptimal gestational thyroid function (SGTF), comparing outcomes in children of treated (SGTF-T) with untreated (SGTF-U) women during pregnancy. This follow-up study, CATS-II, reports the long-term effects on anthropometric, bone, and cardiometabolic outcomes in mothers and offspring and includes a group with normal gestational thyroid function (NGTF). DESIGN & PARTICIPANTS: 332 mothers (197 NGTF, 56 SGTF-U, 79 SGTF-T) aged 41.2±5.3 years (mean±SD) and 326 paired children assessed 9.3±1.0 years after birth for (i) body mass index (BMI); (ii) lean, fat, and bone mass by dual-energy X-ray absorptiometry; (iii) blood pressure, augmentation index, and aortic pulse-wave-velocity; and (iv) thyroid function, lipids, insulin, and adiponectin. The difference between group means was compared using linear regression. RESULTS: Offspring's measurements were similar between groups. Although maternal BMI was similar between groups at CATS-I, after 9 years (at CATS-II) SGTF-U mothers showed higher BMI (median [interquartile ratio] 28.3 [24.6-32.6] kg/m2) compared with NGTF (25.8 [22.9-30.0] kg/m2; P = 0.029), driven by fat mass increase. At CATS-II SGTF-U mothers also had higher thyroid-stimulating hormone (TSH) values (2.45 [1.43-3.50] mU/L) than NGTF (1.54 [1.12-2.07] mU/L; P = 0.015), since 64% had never received levothyroxine. At CATS-II, SGTF-T mothers had BMI (25.8 [23.1-29.8] kg/m2, P = 0.672) and TSH (1.68 [0.89-2.96] mU/L; P = 0.474) values similar to NGTF mothers. CONCLUSIONS: Levothyroxine supplementation of women with SGTF did not affect long-term offspring anthropometric, bone, and cardiometabolic measurements. However, absence of treatment was associated with sustained long-term increase in BMI and fat mass in women with SGTF.

Outcomes of a methicillin-resistant Staphylococcus aureus (MRSA) eradication protocol in pediatric cystic fibrosis (CF) patients.

OBJECTIVE: Methicillin-resistant Staphylococcus aureus (MRSA) infections in cystic fibrosis (CF) patients have greatly increased in prevalence in the past two decades and may lead to a more rapid rate of lung function decline. The objective of this study was to determine the impact of a MRSA eradication protocol on long-term culture results and clinical outcomes of pediatric CF patients in a real-world setting. METHODS: This was a single-center, retrospective study of children age 30 days to 17 years. Eradication followed the STAR-too study protocol. The primary outcome was the percent of patients with MRSA-negative cultures at 12 months. Secondary outcomes were the percent of patients with negative cultures at 3, 6, and greater than 12 months and changes in clinical outcomes compared to individual baseline. RESULTS: Of the 55 patients who met inclusion criteria, 10 received protocol eradication. Baseline characteristics were similar between eradication and control groups except more eradication patients were on ivacaftor (30% vs 4%; P = .037). Two eradication patients did not receive rifampin due to ivacaftor use. Eradication did not significantly increase the percent of MRSA-negative cultures at 3 months (P = .122), 6 months (P = .058), or 12 months (P = .108); however, did increase culture negativity at greater than 12 months (P = .008). Eradication resulted in no significant differences in clinical outcomes compared to control. CONCLUSIONS: An extensive eradication protocol may lead to an increased clearance rate of long-term CF respiratory cultures but does not appear to affect clinical outcomes. Eradication may be reasonable to attempt; however, more data is needed before routine recommendation in all patients.

Pharmacokinetics of Telavancin in Adult Patients with Cystic Fibrosis during Acute Pulmonary Exacerbation.

Adults with cystic fibrosis (CF) frequently harbor Staphylococcus aureus, which is increasingly antibiotic resistant. Telavancin is a once-daily rapidly bactericidal antibiotic active against methicillin-, linezolid-, and ceftaroline-resistant S. aureus Because CF patients experience alterations in pharmacokinetics, the optimal dose of telavancin in this population is unknown. Adult CF patients (n = 18) admitted for exacerbations received 3 doses of telavancin 7.5 mg/kg of body weight (first 6 patients) or 10 mg/kg (final 12 patients) every 24 h (q24h). Population pharmacokinetic models with and without covariates were fitted using the nonparametric adaptive grid algorithm in Pmetrics. The final model was used to perform 5,000-patient Monte Carlo simulations for multiple telavancin doses. The best fit was a 2-compartment model describing the volume of distribution of the central compartment (Vc ) as a multiple of total body weight (TBW) and the volume of distribution of the central compartment scaled to total body weight (Vθ) normalized by the median observed value (Vc = Vθ × TBW/52.1) and total body clearance (CL) as a linear function of creatinine clearance (CRCL) (CL = CLNR + CLθ × CRCL), where CLNR represents nonrenal clearance and CLθ represents the slope term on CRCL to estimate renal clearance. The mean population parameters were as follows: Vθ, 4.92 ± 0.76 liters · kg-1; CLNR, 0.59 ± 0.30 liters · h-1; CLθ, 5.97 × 10-3 ± 1.24 × 10-3; Vp (volume of the peripheral compartment), 3.77 ± 1.41 liters; Q (intercompartmental clearance), 4.08 ± 2.17 liters · h-1 The free area under the concentration-time curve (fAUC) values for 7.5 and 10 mg/kg were 30 ± 4.6 and 52 ± 12 mg · h/liter, respectively. Doses of 7.5 mg/kg and 10 mg/kg achieved 76.5% and 100% probability of target attainment (PTA) at a fAUC/MIC threshold of >215, respectively, for MIC of ≤0.12 mg/liter. The probabilities of reaching the acute kidney injury (AKI) threshold AUC (763 mg · h · liter-1) for these doses were 0% and 0.96%, respectively. No serious adverse events occurred. Telavancin 10 mg/kg yielded optimal PTA and minimal risk of AKI, suggesting that this FDA-approved dose is appropriate to treat acute pulmonary exacerbations in CF adults. (The clinical trial discussed in this study has been registered at ClinicalTrials.gov under identifier NCT03172793.).

Pharmacokinetic considerations in pediatric pharmacotherapy.

PURPOSE: The changes in physiological functions as children grow and organ systems mature result in pharmacokinetic alterations throughout childhood. These alterations in children result in absorption, distribution, metabolism, and excretion of drugs that are different from those seen in the typical adult diseased population. SUMMARY: Changes in gastrointestinal motility and gastric pH in neonates and infants affect the absorption rate and bioavailability of drugs. Skin absorption rate and extent can be altered by different skin structures and perfusion in young children. Intramuscular and rectal absorption become less predictable in children due to erratic absorption site perfusion and other factors. Children's body compositions also differ greatly from that in adults. Water-soluble drugs distribute more extensively in newborns due to larger water content than in older children and adults. Drug elimination and excretion are also affected in pediatric population due to differences in liver and renal function. Immature enzyme development and renal function result in reduced clearance of drugs in young children. There are limited pharmacokinetic data available for many drugs used in children. CONCLUSION: Considering the changes in pharmacokinetics in children can help pharmacists optimize the dosing and monitoring of drugs and do the best they can to help this vulnerable population.

Safety of Extended Interval Tobramycin in Cystic Fibrosis Patients Less an 6 Years Old.

OBJECTIVES: The primary objective of this study was to assess the nephrotoxicity and ototoxicity risks of extended interval tobramycin in cystic fibrosis (CF) patients who are <6 years old. A secondary objective included analyzing pharmacokinetic parameters in this age group. METHODS: A retrospective chart review was conducted of patients with CF who were <6 years old, admitted for an acute pulmonary exacerbation from January 1, 2003, to January 1, 2014, and treated with intravenous tobramycin. RESULTS: The median baseline serum creatinine (SCr) was 0.26 mg/dL among the 31 patients included in the study. Of the 20 patients who experienced increases in SCr, the absolute median increase was 0.065 mg/dL (0.033-0.1 mg/dL). Abnormal audiograms seen in 4 patients are attributable to middle ear effusion present on exam. The median dose of tobramycin was 11.7 mg/kg (11.3-12 mg/kg), the elimination constant was 0.4 hr-1(0.32-0.47 hr-1), half-life was 1.7 hr (1.5-2.1 hr), volume of distribution was 0.37 L/kg (0.31-0.47 L/kg), and median peaks and troughs fell within ranges of 20 to 30 mg/L (20.9-32.7 mg/L) and <0.01 mg/L, respectively. CONCLUSIONS: Extended interval dosing tobramycin is safe in CF patients who are <6 years old. There was no drug-related ototoxicity, and some nephrotoxicity was observed. When dosed at 12 mg/kg, similar pharmacokinetics were seen among all age groups, and concentrations were within the desired range.

Meropenem time above the MIC exposure is predictive of response in cystic fibrosis children with acute pulmonary exacerbations.

Meropenem exposures from 15 children (8-17 years old) with cystic fibrosis (CF) acute pulmonary exacerbation were analyzed to define the pharmacodynamic threshold required for a positive response. The primary endpoint was the relative increase in forced expiratory volume in 1 s (↑FEV1) between pre- and posttreatment. Meropenem pharmacodynamic indices (fT > MIC, fAUC/MIC, fCmin/MIC) over the first 24 h were estimated for each participant based on their individual parameter estimates and the isolated pathogen with the highest meropenem MIC. Pseudomonas aeruginosa was the most common pathogen (n = 11/15). The mean ± SD ↑FEV1 was 18.8% ± 11.3% posttreatment. The mean (range) fT > MIC exposure was 63% (0-100%). An Emax model determined a significant relationship between fT > MIC and ↑FEV1 (r2 = 0.8, P < 0.0004). 65% fT > MIC was a significant predictor of response; the median (25th, 75th %) ↑FEV1 was 28.5% (22.2%, 31.7%) in those patients who achieved above 65% fT > MIC and 7.8% (1.1%, 12.6%) in those at or below 65% fT > MIC (P = 0.001). This is the first study in CF children to link meropenem exposure with a positive response as measured by ↑FEV1. Larger studies are required to confirm this exposure threshold.

The value of physical performance measurements alongside assessment of sarcopenia in predicting receipt and completion of planned treatment in non-small cell lung cancer: an observational exploratory study.

INTRODUCTION: The presence of muscle mass depletion is associated with poor outcomes and survival in cancer. Alongside muscle mass, assessment of muscle strength or physical performance is essential for the diagnosis of sarcopenia. Non-small cell lung cancer (NSCLC) is a prevalent form of cancer with high mortality, and Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) is commonly used to assess patients' suitability for treatment. However, a significant proportion of patients with good PS are unable to complete multidisciplinary team (MDT)-planned treatment. Little is known about the ability of objective measurements of physical performance in predicting patients' ability to complete MDT-planned treatment and outcomes in NSCLC. OBJECTIVES: We sought to establish whether physical performance, utilising the short physical performance battery (SPPB), alongside muscle mass measurements, was able to predict receipt and completion of MDT-planned treatment, with a focus on chemotherapy in NSCLC. MATERIALS AND METHODS: Participants with NSCLC treated through a single lung cancer MDT and ECOG PS 0-2 were recruited and the following assessed: body composition [bioelectrical impedance (BIA) and whole body dual-energy X-ray absorptiometry (DXA) in a subset], physical performance (SPPB), PS and nutritional status. We recorded receipt and completion of chemotherapy, as well as any adverse effects, hospitalisations, and treatment delays. RESULTS: We included a total of 62 participants with NSCLC, and in 26 of these, the MDT-planned treatment was chemotherapy. Participants with earlier stage disease and weight loss of <10% were more likely to complete MDT-planned treatment (p < 0.001 and p < 0.05). Patients with a higher total SPPB score were more likely to complete more cycles of chemotherapy as well as the full course. Quicker gait speeds and sit-to-stand times were associated with completion of three or more cycles of chemotherapy (all p < 0.05). For every unit increase in SPPB score, there was a 28.2% decrease in adverse events, hospitalisations and delays of chemotherapy (incidence rate ratio 0.718, p = 0.001), whilst ECOG PS showed no correlation with these outcomes. CONCLUSION: Assessing physical performance by SPPB is quick and simple to do in clinical settings and may give better indication of likely chemotherapy treatment course completion than muscle mass alone and ECOG PS. In turn, this may identify specific targets for early functional intervention and impact on MDT decision-making and prudent use of resources.

Safety of intravenous tobramycin in combination with a variety of anti-pseudomonal antibiotics in children with cystic fibrosis.

OBJECTIVES: Previous studies have examined renal safety of once daily intravenous tobramycin in individuals with cystic fibrosis. This has been mainly in combination with ceftazidime in an adolescent or adult population. In this report, we describe our institutional experience of once daily intravenous tobramycin in combination with a variety of second anti-pseudomonal antibiotics in children with cystic fibrosis. METHODS: We present a retrospective review including children with cystic fibrosis, who were admitted for a pulmonary exacerbation from January 2009 to December 2011, and treated using intravenous tobramycin. A literature review of once daily intravenous aminoglycoside dosing in cystic fibrosis was performed to compare our results to existing literature. RESULTS: A total of 35 subjects were divided into once daily dosing (n = 20) versus multiple daily dosing (n = 15) groups. Mean age was 11.3 years (± 5.7) for the once daily dosing group and 13.1 years (± 4.4) for the multiple daily dosing group (p = 0.34). All subjects had normal baseline serum creatinine at admission (once daily dosing 0.49 ± 0.14 mg/dL vs multiple daily dosing 0.62 ± 0.23 mg/dL, p = 0.07). All subjects received intravenous tobramycin, and most received piperacillin-tazobactam as their second anti-pseudomonal antibiotic (once daily dosing 45% and multiple daily dosing 40%). There was no significant change in serum creatinine in either group during antibiotic treatment (once daily dosing 0.08 ± 0.12 mg/dL vs. multiple daily dosing 0.06 ± 0.10 mg/dL, p = 0.43). All subjects had significant improvement in lung function following intravenous antibiotic therapy. CONCLUSION: We show that both once daily dosing and multiple daily dosing of intravenous tobramycin in combination with a variety of second anti-pseudomonal antibiotics were safe in terms of nephrotoxicity in children with cystic fibrosis. These findings are important given existing literature mainly examines once daily tobramycin in combination with ceftazidime, a cephalosporin, and the majority of our patients were on tobramycin with piperacillin-tazobactam, an extended spectrum penicillin plus beta-lactam. This contributes new information not previously examined in a pediatric cystic fibrosis population.

Piperacillin-tazobactam versus cefepime incidence of acute kidney injury in combination with vancomycin and tobramycin in pediatric cystic fibrosis patients.

BACKGROUND: Cystic fibrosis (CF) patients often receive prolonged courses of broad spectrum antibiotics, such as piperacillin-tazobactam or cefepime in combination with vancomycin and tobramycin. The objective of this study was to determine the difference in AKI for pediatric CF patients receiving piperacillin-tazobactam or cefepime in combination with vancomycin and tobramycin. METHODS: IRB approval from a single CF center was obtained for this retrospective cohort study. Charts were evaluated from December 1, 2008 to June 30,2015. Patients were included if they had a diagnosis of CF, age 30 days to 18 years, and received intravenous vancomycin, tobramycin, and piperacillin-tazobactam or cefepime. The primary outcome was difference of AKI incidence in patients receiving piperacillin-tazobactam or cefepime, as defined by modified pediatric risk, injury, failure, loss, end stage renal disease (pRIFLE) criteria. RESULTS: Seventy-one patients were included with a median (interquartile range) age 11 years (7-16) and weight 36.2 kg (22.7-50). AKI was identified in 54.5% (18/33) of patients receiving piperacillin-tazobactam and 13.2% (5/38) of patients receiving cefepime (P ≤ 0.0001). One patient receiving piperacillin-tazobactam experienced acute renal failure. There was a slight difference in length of admission (13 vs 10 days, P = 0.042), but no difference in days to maximum SCr (6 vs 3, P = 0.127) nor FEV1 percent predicted on admission (69% vs 65%, P = 1.00). CONCLUSIONS: AKI occurred in nearly 55% of patients with piperacillin-tazobactam therapy versus 13% of patients with cefepime therapy, which suggests cefepime may be preferred in combination with vancomycin and tobramycin for pediatric CF patients.

Multifaceted quality improvement initiative to decrease pediatric asthma readmissions.

BACKGROUND: Asthma is the most common chronic disease of childhood and a leading cause of hospitalization in children. A primary goal of asthma control is prevention of hospitalizations. A hospital admission is the single strongest predictor of future hospital admissions for asthma. The 30-day asthma readmission rate at our institution was significantly higher than that of other hospitals in the Children's Hospital Association. As a result, a multifaceted quality improvement project was undertaken with the goal of reducing the 30-day inpatient asthma readmission rate by 50% within two years. METHODS: Analysis of our institution's readmission patterns, value stream mapping of asthma admission, discharge, and follow-up processes, literature review, and examination of comparable successful programs around the United States were all utilized to identify potential targets for intervention. Interventions were implemented in a stepwise manner, and included increasing inhaler availability after discharge, modifying asthma education strategies, and providing in-home post-discharge follow-up. The primary outcome was a running 12-month average 30-day inpatient readmission rate. Secondary outcomes included process measures for individual interventions. RESULTS: From a peak of 7.98% in January 2013, a steady decline to 1.65% was observed by July 2014, which represented a 79.3% reduction in 30-day readmissions. CONCLUSION: A significant decrease in hospital readmissions for pediatric asthma is possible, through comprehensive, multidisciplinary quality improvement that spans the continuum of care.