Once-daily versus multiple-daily dosing with intravenous aminoglycosides for cystic fibrosis

Background: People with cystic fibrosis, who are chronically colonised with the organism Pseudomonas aeruginosa, often require multiple courses of intravenous aminoglycoside antibiotics for the management of pulmonary exacerbations. The properties of aminoglycosides suggest that they could be given in higher doses less often. Objectives: To assess the effectiveness and safety of once-daily versus multiple-daily dosing of intravenous aminoglycoside antibiotics for the management of pulmonary exacerbations in cystic fibrosis. Search methods: We searched the Cystic Fibrosis Specialist Register held at the Cochrane Cystic Fibrosis and Genetic Disorders Group’s editorial base, comprising references identified from comprehensive electronic database searches, handsearching relevant journals and handsearching abstract books of conference proceedings. Date of the most recent search: 25 November 2013. Selection criteria: All randomised controlled trials, whether published or unpublished, in which once-daily dosing of aminoglycosides has been compared with multiple-daily dosing in terms of efficacy or toxicity or both, in people with cystic fibrosis. Data collection and analysis: The two authors independently selected the studies to be included in the review and assessed the risk of bias of each study. Data were independently extracted by each author. Authors of the included studies were contacted for further information. As yet unpublished data were obtained for one of the included studies. Main results: Fifteen studies were identified for possible inclusion in the review. Four studies reporting results from a total of 328 participants were included in this review. All studies compared once-daily dosing with thrice-daily dosing. One study had a low risk of bias for all criteria assessed; the remaining three included studies had a high risk of bias from blinding, but for other criteria were judged to have either an unclear or a low risk of bias. There was no significant difference between treatment groups in: forced expiratory volume at one second, mean difference 0.33 (95% confidence interval -2.81 to 3.48); forced vital capacity, mean difference 0.29 (95% confidence interval -6.58 to 7.16); % weight for height, mean difference -0.82 (95% confidence interval -3.77 to 2.13); body mass index, mean difference 0.00 (95% confidence interval -0.42 to 0.42); or in the incidence of ototoxicity, relative risk 0.56 (95% confidence interval 0.04 to 7.96). The percentage change in creatinine significantly favoured once-daily treatment in children, mean difference -8.20 (95% confidence interval -15.32 to -1.08), but showed no difference in adults, mean difference 3.25 (95% confidence interval -1.82 to 8.33). Authors’ conclusions: Once- and three-times daily aminoglycoside antibiotics appear to be equally effective in the treatment of pulmonary exacerbations of cystic fibrosis. There is evidence of less nephrotoxicity in children

Intravenous antibiotics for pulmonary exacerbations in people with cystic fibrosis

BACKGROUND: Cystic fibrosis is a multi-system disease characterised by the production of thick secretions causing recurrent pulmonary infection, often with unusual bacteria. Intravenous antibiotics are commonly used in the treatment of acute deteriorations in symptoms (pulmonary exacerbations); however, recently the assumption that exacerbations are due to increases in bacterial burden has been questioned. OBJECTIVES: To establish if intravenous antibiotics for the treatment of pulmonary exacerbations in people with cystic fibrosis improve short- and long-term clinical outcomes. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books. We also searched the reference lists of relevant articles and reviews and ongoing trials registers.Date of last search of Cochrane trials register: 27 July 2015. SELECTION CRITERIA: Randomised controlled trials and the first treatment cycle of cross-over studies comparing intravenous antibiotics (given alone or in an antibiotic combination) with placebo, inhaled or oral antibiotics for people with cystic fibrosis experiencing a pulmonary exacerbation. DATA COLLECTION AND ANALYSIS: The authors assessed studies for eligibility and risk of bias and extracted data. MAIN RESULTS: We included 40 studies involving 1717 participants. The quality of the included studies was largely poor and, with a few exceptions, these comprised of mainly small, inadequately reported studies.When comparing treatment with a single antibiotic to a combined antibiotic regimen, those participants receiving a combination of antibiotics experienced a greater improvement in lung function when considered as a whole group across a number of different measurements of lung function, but with very low quality evidence. When limited to the four placebo-controlled studies (n = 214), no difference was observed, again with very low quality evidence. With regard to the review's remaining primary outcomes, there was no effect upon time to next exacerbation and no studies in any comparison reported on quality of life. There were no effects on the secondary outcomes weight or adverse effects. When comparing specific antibiotic combinations there were no significant differences between groups on any measure. In the comparisons between intravenous and nebulised antibiotic or oral antibiotic (low quality evidence), there were no significant differences between groups on any measure. No studies in any comparison reported on quality of life. AUTHORS' CONCLUSIONS: The quality of evidence comparing intravenous antibiotics with placebo is poor. No specific antibiotic combination can be considered to be superior to any other, and neither is there evidence showing that the intravenous route is superior to the inhaled or oral routes. There remains a need to understand host-bacteria interactions and in particular to understand why many people fail to fully respond to treatment

The Clinical and Economic Impact of Tyrosine Kinase Inhibitor Non-adherence in CML Patients within a US Integrated Healthcare System

Background: Chronic myelogenous leukemia (CML) accounts for 15% of all adult leukemias. Oral tyrosine kinase inhibitors (TKIs) have improved long-term survival significantly, but require strict adherence to the therapy to maximize effectiveness and minimize healthcare resource utilization. Objective: To evaluate adherence to tyrosine kinase inhibitor therapy for incident CML patients, assess predictive factors associated with TKI non-adherence, evaluate laboratory monitoring rates and clinical response between adherent and non-adherent patients, and to compare healthcare resource utilization and costs between these groups. Methods: Retrospective, observational cohort study using databases from the Kaiser Permanente health plan. Newly diagnosed CML patients were identified from 1/1/2007-12/31/2013 with index date as first incident TKI prescription fill. Adherence rates were measured over the 12-month post-index period using the MPR method, with an adherence threshold set at ≥85%. Patient characteristics and covariates were evaluated as potential contributors to non-adherence included age, gender, race, existing comorbidities, and healthcare utilization history. Laboratory monitoring included either hematologic, cytogenetic, or molecular testing during the post-index period. Clinical response/remission or no clinical response/progression was evaluated at the end of the 12-months and compared between the adherent and non-adherent groups. All-cause and CML-related healthcare resource utilization and costs were compared between the two groups as well. Results: 194 CML patients were selected for inclusion into this study. Of the 194 patients, 123(63.4%) were found to be adherent to TKI therapy. Patient age, Deyo-Charlson Comorbidity index, pre-index hospitalization length of stay, and oral antidiabetic and antihyperlipidemic medications were found to be predictive factors associated with non-adherence. Adherent patients were more likely to be adherent to hematologic (100% vs 95.8%) and molecular/cytogenetic testing (91.1% vs 76.1%) than non-adherent patients. Of the 123 adherent patients, 106 (86.2%) achieved clinical response at the end of 12 months, compared to only 3 of the 71 (4.2%) non-adherent patients. Adherent patients had more all-cause and CML-related outpatient visits. Non-adherent patients had more all-cause and CML-related ER and hospital visits, higher hospitalization costs, and higher total mean costs. Conclusion: The results confirm the importance of adherence to TKI therapy on clinical outcomes, healthcare resource utilization, and costs. Presentation: 36:1

Repeated supratherapeutic dosing of strontium ranelate over 15 days does not prolong QT(c) interval in healthy volunteers.

AIMS: The study was performed to assess the safety of strontium ranelate in accordance with the ICH, E14 guidelines for QT/QT(c) studies. Its primary objective was to compare supratherapeutic repeated dosing of strontium ranelate (4 g day⁻¹ for 15 days) with placebo on the largest time-matched mean QT(c) variation, from baseline to under treatment values, in healthy subjects. METHODS: Ninety-six healthy male and female subjects (27.7 ± 7.5 years) were included to receive 1 day of placebo followed by 15 days of supratherapeutic repeated dosing of strontium ranelate (4 g day⁻¹), in a 4 month, randomized, placebo (16 days) and positive-controlled (single dose of moxifloxacin 400 mg preceded by 15 days of placebo), double-blind, double dummy, crossover design. Measurement of QT interval was performed automatically on the ECGs with subsequent manual onscreen over-reading by cardiologists using electronic callipers. RESULTS: The largest time-matched difference in QT(c) I (individual QT correction for heart rate) between moxifloxacin 400 mg and placebo was observed at 2 h post dose (mean [95% CI] 10.62 [7.90, 13.35] ms). For strontium ranelate (4 g day⁻¹) the largest time-matched difference in QT(c) I compared with placebo was observed at 1 h post dose (mean [90% CI] 7.54 [5.17, 9.90] ms). No subject had a QT(c) greater than 480 ms during the study. Both moxifloxacin and strontium ranelate were well tolerated in healthy subjects. CONCLUSIONS: The findings of this study demonstrate that the administration of supratherapeutic repeated oral doses of strontium ranelate (4 g day⁻¹ for 15 days) does not lead to a prolongation of the QT/QT(c) interval above the threshold of regulatory concern

Repeated supratherapeutic dosing of strontium ranelate over 15 days does not prolong QT(c) interval in healthy volunteers.

AIMS: The study was performed to assess the safety of strontium ranelate in accordance with the ICH, E14 guidelines for QT/QT(c) studies. Its primary objective was to compare supratherapeutic repeated dosing of strontium ranelate (4 g day⁻¹ for 15 days) with placebo on the largest time-matched mean QT(c) variation, from baseline to under treatment values, in healthy subjects. METHODS: Ninety-six healthy male and female subjects (27.7 ± 7.5 years) were included to receive 1 day of placebo followed by 15 days of supratherapeutic repeated dosing of strontium ranelate (4 g day⁻¹), in a 4 month, randomized, placebo (16 days) and positive-controlled (single dose of moxifloxacin 400 mg preceded by 15 days of placebo), double-blind, double dummy, crossover design. Measurement of QT interval was performed automatically on the ECGs with subsequent manual onscreen over-reading by cardiologists using electronic callipers. RESULTS: The largest time-matched difference in QT(c) I (individual QT correction for heart rate) between moxifloxacin 400 mg and placebo was observed at 2 h post dose (mean [95% CI] 10.62 [7.90, 13.35] ms). For strontium ranelate (4 g day⁻¹) the largest time-matched difference in QT(c) I compared with placebo was observed at 1 h post dose (mean [90% CI] 7.54 [5.17, 9.90] ms). No subject had a QT(c) greater than 480 ms during the study. Both moxifloxacin and strontium ranelate were well tolerated in healthy subjects. CONCLUSIONS: The findings of this study demonstrate that the administration of supratherapeutic repeated oral doses of strontium ranelate (4 g day⁻¹ for 15 days) does not lead to a prolongation of the QT/QT(c) interval above the threshold of regulatory concern