Intravenous versus oral antibiotics for eradication of Pseudomonas aeruginosa in cystic fibrosis (TORPEDO-CF): a randomised controlled trial.

BACKGROUND: Chronic pulmonary infection with Pseudomonas aeruginosa is one of the most important causes of mortality and morbidity in cystic fibrosis. If antibiotics are commenced promptly, infection can be eradicated. The aim of the trial was to compare the effectiveness and safety of intravenous ceftazidime and tobramycin versus oral ciprofloxacin in the eradication of P aeruginosa. METHODS: We did a multicentre, parallel group, open-label, randomised controlled trial in 72 cystic fibrosis centres (70 in the UK and two in Italy). Eligible participants were older than 28 days with an isolate of P aeruginosa (either the first ever isolate or a new isolate after at least 1 year free of infection). Participants were excluded if the P aeruginosa was resistant to, or they had a contraindication to, one or more of the trial antibiotics; if they were already receiving P aeruginosa suppressive therapy; if they had received any P aeruginosa eradication therapy within the previous 9 months; or if they were pregnant or breastfeeding. We used web-based randomisation to assign patients to 14 days intravenous ceftazidime and tobramycin or 12 weeks oral ciprofloxacin. Both were combined with 12 weeks inhaled colistimethate sodium. Randomisation lists were generated by a statistician, who had no involvement in the trial, using a computer-generated list. Randomisation was stratified by centre and because of the nature of the interventions, blinding was not possible. Our primary outcome was eradication of P aeruginosa at 3 months and remaining free of infection to 15 months. Primary analysis used intention to treat (powered for superiority). Safety analysis included patients who received at least one dose of study drug. TORPEDO-CF was registered on the ISRCTN register, ISRCTN02734162, and EudraCT, 2009-012575-10. FINDINGS: Between Oct 5, 2010, and Jan 27, 2017, 286 patients were randomly assigned to treatment: 137 to intravenous antibiotics and 149 to oral antibiotics. 55 (44%) of 125 participants in the intravenous group and 68 (52%) of 130 participants in the oral group achieved the primary outcome. Participants randomly assigned to the intravenous group were less likely to achieve the primary outcome, although the difference between groups was not statistically significant (relative risk 0·84, 95% CI 0·65-1·09; p=0·18). 11 serious adverse events occurred in ten (8%) of 126 participants in the intravenous antibiotics group and 17 serious adverse events in 12 (8%) of 146 participants in the oral antibiotics group. INTERPRETATION: Compared with oral therapy, intravenous antibiotics did not achieve sustained eradication of P aeruginosa in a greater proportion of patients with cystic fibrosis and was more expensive. Although there were fewer hospitalisations in the intravenous group than the oral group during follow-up, this confers no advantage over oral treatment because intravenous eradication frequently requires hospitalisation. These results do not support the use of intravenous antibiotics to eradicate P aeruginosa in cystic fibrosis. FUNDING: National Institute for Health Research Health Technology Assessment Programme.

Health insurance and use of recommended routine care in adults with cystic fibrosis.

BACKGROUND: Low socioeconomic status is correlated with worse outcomes in patients with cystic fibrosis (CF). Whether insurance status impacts adherence to care in this population is unknown. METHODS: Patients ≥18 years old in the CF Foundation Patient Registry (2005-2013) were grouped based on reported annual insurance as private, public (Medicaid, Medicare or state medical assistance program), others or no insurance. Random effects logistic regression evaluated association between change in insurance status and annual use of recommended routine care. RESULTS: A total of 18 358 patients contributed 94 690 years of data to the analysis. In descriptive analysis, adherence to recommended routine care (≥4 clinic visits, ≥4 respiratory cultures and ≥2 pulmonary function tests per year) and recommended chronic medications for those with moderate to severe lung disease (dornase alfa and inhaled tobramycin or aztreonam if Pseudomoas aeruginosa in respiratory cultures) was most common in public insurance compared to other insurance types. In multivariable logistic regression, public insurance was associated with greater use of recommended care relative to private insurance (OR = 1.16; 95% confidence interval: 1.10-1.22; P < .001), while being uninsured was associated with lower odds of using recommended care (OR = 0.37; 95% confidence interval: 0.31-0.46; P < .001). CONCLUSIONS: For adults with CF in the United States, public insurance was associated with greater use of routine care than private coverage. Being uninsured was strongly associated with not using routine care. Further efforts to improve access to CF care should address the feasibility of universal and continuous insurance coverage in the CF population.

Economic Evaluation of Tobramycin Inhalation Powder for the Treatment of Chronic Pulmonary Pseudomonas aeruginosa Infection in Patients with Cystic Fibrosis.

BACKGROUND: Chronic lung infection with Pseudomonas aeruginosa occurs in approximately 50% of patients with cystic fibrosis (CF). This infection further compromises lung function, and significantly contributes to the increased healthcare costs. OBJECTIVES: Inhaled tobramycin, used to manage P. aeruginosa infection in CF patients, is available as powder (tobramycin inhalation powder, TIP) and solution (tobramycin inhalation solution, TIS). Evidence suggests increased adherence with the use of TIP over TIS. Hence, this analysis aimed to evaluate the potential pharmacoeconomic benefit of increased adherence with TIP over TIS in the US setting. METHODS: A patient-level simulation model was developed to compare TIP with TIS. Both costs and benefits were predicted over a 10-year time horizon from a payer's perspective, and were discounted annually at 3%. All costs were presented in 2016 US dollars. RESULTS: TIP was associated with greater quality-adjusted life-years (by 0.27) and lower total costs (by US$36,168) as compared with TIS over a 10-year time horizon. TIP-treated patients experienced a decreased mean number of exacerbations than TIS-treated patients (39.24 vs 50.20). Furthermore, administration of TIP via the T-326 Inhaler was associated with significant cost savings per patient, because of the nebulizer required for administering TIS (by US$1596) and exacerbation costs (by US$76,531). Probabilistic sensitivity analysis showed that TIP was dominant over TIS in 100% of the simulations. CONCLUSION: TIP is likely to be a more cost-effective treatment than TIS, and therefore may reduce the economic burden of CF.

Characteristics and clinical assessment of antibiotic delivery by chitosan sponge in the high-risk diabetic foot: a case series.

OBJECTIVE: The local delivery of antimicrobials is attractive for a number of reasons. Chitosan, a biodegradable polysaccharide sponge material, has been proposed as medium to deliver antibiotics directly to wounds. In this report we evaluate the safety and practicality of antimicrobial delivery via chitosan sponge. METHOD: We present the clinical course and systemic absorption characteristics of three cases of people with diabetic foot wounds treated with antibiotic soaked chitosan sponge (Sentrex BioSponge, Bionova Medical, Germantown, TN). The antibiotic sponge was made by reconstituting 1.2g tobramycin or 100mg doxycycline in 10-15ml saline and saturating the sponge with the solution. The sponge was then applied to the wounds. Serum levels of each respective antibiotic were evaluated after application. Additional in vitro studies were conducted evaluating elution of antibiotics from the chitosan sponge at established minimum inhibitory concentrations (MIC) for Staphylococcus aureus over 28 days. RESULTS: No patient experienced adverse local or systemic effects due to the sponge treatment. The measured serum levels applied antibiotics remained far less than established minimums after intravenous therapy. Each patient required further treatment, however local infection or contamination resolved during the course of their hospital stay after the chitosan/antibiotic application. CONCLUSION: The use of antibiotic-impregnated chitosan sponges appears a safe and effective mechanism of local delivery of antimicrobials in wounds. Future studies and clinical trials are ongoing to confirm these results and to guide clinical applications.

Surgical Site Infections following Spine Surgery for Non-idiopathic Scoliosis.

BACKGROUND: Surgical site infections (SSIs) following spine surgery in children and adolescents with nonidiopathic scoliosis are associated with increased morbidity and health care costs. Potentially modifiable risk factors for SSIs merit additional study in this population. METHODS: A single-center, retrospective cohort study was performed from August 2008 through December 2013 in children and adolescents undergoing surgery for nonidiopathic scoliosis to determine the trends in SSI rate and causative microorganisms. A standardized perioperative antimicrobial prophylaxis regimen was developed from September-October 2008. Potential risk factors for SSIs were assessed by multivariable analysis using Poisson regression models. Fusion procedures and growing construct procedures were analyzed separately. RESULTS: In all, 268 patients underwent 536 surgical procedures of whom 192 underwent 228 fusion procedures, 89 underwent 308 growing construct procedures, and 13 underwent both procedures during the study period. Twenty-one SSIs (3.9% of surgical procedures and 7.8% of patients) occurred within 90 days of surgery, 17 SSIs occurred after fusion procedures (4.5% of procedures and 8.9% of patients), and 4 SSIs occurred after growing construct procedures (1.3% of procedures and 4.5% of patients). There were 9 polymicrobial SSIs (42.9%). Of the 31 bacterial pathogens isolated, 48% were Gram-negative organisms. Among patients undergoing fusion procedures, SSIs were associated with underdosing of preoperative cefazolin [relative risk (RR)=4.99; 95% confidence interval (CI), 1.89-17.43; P=0.012] and tobramycin (RR=5.86; 95% CI, 1.90-18.06; P=0.002), underdosing of intraoperative (RR=5.65; 95% CI, 2.13-14.97; P=0.001) and postoperative (RR=3.86; 95% CI, 1.20-12.40; P=0.023) tobramycin, and any preoperative or intraoperative underdosing (RR=4.89; 95% CI, 1.70-14.12; P=0.003), after adjustment for duration of surgery. No factors were associated with SSIs in those undergoing growing construct procedures. During the study period, the SSIs rate declined (P<0.0001). CONCLUSIONS: Underdosing of tobramycin and preoperative cefazolin were associated with an increased SSI risk among patients undergoing fusion procedures. Future multicenter studies should further investigate the generalizability of these findings. LEVEL OF EVIDENCE: Level II-retrospective study.

Seguridad de tobramicina en polvo seco para inhalacion en pacientes con bronquiectasias no asociadas a fibrosis quistica colonizadas por pseudomona aeruginosa / Safety of tobramycin dry powder for inhalation in patients with bronchiectasis not associated with cystic fibrosis colonized by pseudomona aeruginosa

INTRODUCCIÓN: Antecedentes: El Instituto de Evaluación de Tecnologías en Salud e Investigación ha recibido la solicitud de evaluar la eficacia y seguridad de tobramicina en polvo seco para inhalación en pacientes con bronquiectasias no asociadas a fibrosis quística colonizada por Pseudomona Aeruginosa dentro del sistema de EsSalud, indicación actualmente no contemplada en el Petitorio Farmacológico de ESSALUD. Esta acción sigue lo estipulado en la Directiva N° 003-IETSI-ESSALUD-2016 y el objetivo final es determinar el estado del arte sobre la eficacia y seguridad de tobramicina en polvo seco para inhalación en el escenario específico descrito a continuación. Aspectos Generales: La bronquiectasia es una alteración anatómica acompañada de cambios histológicos. con dilataciones anormales e irreversibles de los bronquios. No es considerada como una enfermedad en sí misma. sino que es el resultado final de enfermedades o agresiones diferentes. Por lo general, surge como complicación de una patología de fondo, ya sea inflamatoria crónica o infecciosa. Existen reportes que evidencian un aumento en la prevalencia de las bronquiectasias. Así, Seitz et al. encontró que entre el 2000 al 2007 el número de los diagnósticos de bronquiectasias en Estados Unidos tuvo un aumento porcentual anual de 8,74%, con una prevalencia de periodo de 1,106 casos por 100,000. Además las bronquiectasias generan una importante carga para el sistema de salud. ya que se requieren largas estancias hospitalarias, consultas ambulatorias frecuentes y terapia médica extensa, solo en Estados unidos se encontró que significan $ 630 millones al año de gasto en salud. Tecnología Sanitaria de Interés: La Tobramicina es un antibacteriano aminoglucósido que actúa inhibiendo la síntesis proteica de las bacterias por unión a la unidad ribosomal 30S. Es bactericida a concentraciones iguales o ligeramente superiores a las concentraciones inhibitorias. Actualmente presenta dos presentaciones para inhalación, una solución para nebulización de 300 mg/ 5 ml y la tobramicina en polvo seco en capsulas de 28mg. La tobramicina en polvo para inhalación, está aprobada por la Agencia europea de medicamentos y por la FDA para el tratamiento supresor de las infecciones pulmonares crónicas debidas a Pseudomonas Aeruginosa en pacientes adultos y niños con fibrosis quística a partir de 6 años de edad. METODOLOGÍA: Estrategia de Búsqueda: Se realizó una búsqueda de la literatura con respecto a la eficacia y seguridad de tobramicina en polvo seco para inhalación para pacientes con bronquiectasis no asociadas a FQ colonizadas por PA en las bases de datos de MEDLINE, EMBASE, CENTRAL, DARE y TRIPDATABASE. Adicionalmente, se hizo una búsqueda dentro de la información generada por las principales agencias de tecnologías sanitarias que realizan revisiones sistemáticas (RS), evaluación de tecnologías sanitarias (ETS) y guías de práctica clínica (GPC). RESULTADOS: Sinopsis de la Evidencia: Se realizó la búsqueda bibliográfica y de evidencia científica que sustente el uso de Tobramicina polvo inhalatorio en el tratamiento de bronquiectasias no asociadas a fibrosis quística según la pregunta PICO establecida. Para el presente documento se seleccionó el siguiente cuerpo de evidencia que es resumido a continuación: Guías Clínicas: Se identificó una única guía consensuada de recomendaciones en el manejo de las bronquiectasias no asociadas a FQ colonizadas por PA, esta fue elaborada por la sociedad de tórax de Reino Unido. Evaluaciones de tecnología sanitaria: Se identificó una evaluación de la tecnología que puede ser considerada como evidencia indirecta ya que es realizada en población con FQ y es presentada como un reporte para la FDA por un comité revisor, esta fue descrita en detalle en la sección de tecnología sanitaria. Revisiones sistemáticas: No se encontraron revisiones sistemáticas. Ensayos clínicos: Un ensayo de fase uno es considerada la única evidencia directa para nuestra población y la tecnología de interés. CONCLUSIONES: El tratamiento antibiótico inhalatorio por periodos largos en pacientes con colonización por PA y sin FQ no está sólidamente respaldado y se requiere de maycr evidencia para recomendarlo. La Tobramicina en polvo seco es una opción terapéutica que en pacientes con FQ ha demostrado tener mayores riesgos que beneficios usado como tratamiento antibiótico de largo plazo en pacientes con FQ y no se tiene la suficiente evidencia para incluirlo como terapia inhalatoria en pacientes sin FQ con colonización por PA. El Instituto de Evaluación de Tecnologías en Salud e Investigación (JETS') no aprueba el uso de tobramicina inhalatoria en polvo según el esquema planteado en la pregunta PICO para pacientes adultos con diagnóstico de bronquiectasias colonizadas por PA en pacientes con bronquiectasias no asociadas a FQ. Dado que la evidencia que respalda el uso de antibióticos inhalatorios en pacientes con bronquiectasias no asociadas a FQ colonizadas por PA, es de muy baja calidad, se requiere estudios que evalúen de forma directa la eficacia y seguridad de los antibióticos inhalatorios en este grupo de pacientes.

Continuous alternating inhaled antibiotics for chronic pseudomonal infection in cystic fibrosis.

BACKGROUND: Inhaled antibiotics are standard of care for treating chronic pseudomonal respiratory infections in cystic fibrosis patients, initially approved for intermittent administration. However, use of continuous inhaled antibiotic regimens of differing combinations is growing. METHODS: This double-blind trial compared continuous alternating therapy (CAT) to an intermittent treatment regimen. Subjects were treated with 3cycles of 28-days inhaled aztreonam (AZLI) or placebo 3-times daily alternating with 28-days open-label tobramycin inhalation solution (TIS). RESULTS: 90 subjects were randomized over 18months. Study enrollment was limited, in part because of evolving practices by clinicians of adopting a CAT regimen in clinical practice; consequently the study was underpowered. AZLI/TIS treatment reduced exacerbation rates by 25.7% (p=0.25; primary endpoint) and rates of respiratory hospitalizations by 35.8% compared with placebo/TIS (p=0.14). AZLI/TIS CAT therapy was well tolerated. CONCLUSIONS: This trial illustrates challenges with studying treatment regimens in a constantly evolving CF care environment. Nonetheless, the results of this trial indicate that AZLI/TIS CAT is well tolerated and may provide additional clinical benefit in CF patients compared with intermittent use of TIS alone. Clinicaltrials.gov: NCT01641822.

Tobramicina inhalatoria en polvo versus tobramicina inhalatoria en solución en fibrosis quística / Tobramycin inhalation powder versus tobramycin inhalation solution for cystic fibrosis

INTRODUCCIÓN: La fibrosis quística (FQ) es una enfermedad genética autosómica recesiva causada por alteración del gen CFTR (del inglés Cystic Fibrosis Transmembrane Conductance Regulator), que afecta aproximadamente a 1 cada 2.000-3.000 nacidos en Europa y 1 cada 3.500 nacimientos en EE.UU. Esta alteración ocasiona disfunción en las glándulas exocrinas generando en vías respiratorias una intensa respuesta inflamatoria, mucosidad anormal, obstrucción y daño tisular, favoreciendo el crecimiento bacteriano. La Pseudomonas aeruginosa es uno de los principales patógenos colonizantes, y principal causa de morbimortalidad de esta patología, siendo muy importante su erradicación, para mejorar el pronóstico de la enfermedad. De las tres vías de administración de antibióticos (oral, inhalado y endovenoso), la administración inhalada representa una opción atractiva para el tratamiento de las infecciones pulmonares, dado que proporciona altas concentraciones locales y reduce la exposición sistémica. TECNOLOGÍA: La tobramicina es un antibiótico aminoglucósido de amplio espectro utilizado para el tratamiento de infección pulmonar crónica por Pseudomonas aeruginosa (Pa) en pacientes con FQ y una alternativa eficaz para su administración es la vía inhalatoria. Existen dos tipos de tobramicina inhalatoria: en solución (TIS); y en polvo (TIP). OBJETIVO: Evaluar la evidencia disponible acerca de la eficacia, seguridad y aspectos relacionados a las políticas de cobertura de la tobramicina inhalatoria en sus diferentes presentaciones para pacientes con fibrosis quística. MÉTODOS: Se realizó una búsqueda en las principales bases de datos bibliográficas (incluyendo Medline, Cochrane y CRD), en buscadores genéricos de Internet, agencias de evaluación de tecnologías sanitarias y financiadores de salud. Se priorizó la inclusión de revisiones sistemáticas, ensayos clínicos controlados aleatorizados (ECAs), evaluaciones de tecnologías sanitarias y económicas, guías de práctica clínica y políticas de cobertura de otros sistemas de salud cuando estaban disponibles. RESULTADOS: Se seleccionó una revisión sistemática (RS), un ECA, cinco políticas de cobertura y seis guías de práctica clínica. CONCLUSIONES: Evidencia de moderada calidad, compuesta por un único estudio comparativo entre las dos modalidades inhalatorias, no halló diferencias significativas en resultados clínicamente importantes entre tobramicina inhalatoria en solución y tobramicina inhalatoria en polvo. Las guías de práctica clínica y políticas de cobertura encontradas no consideran a la tobramicina inhalatoria en polvo como tratamiento de primera línea y en algunos casos la mencionan como una alternativa de tratamiento solo cuando se cumplen ciertas condiciones como intolerancia o falta de respuesta a colistina en solución, colistina en polvo, o tobramicina inhalatoria en solución; y bajo acuerdos de reducción de precio que hagan a la tobramicina inhalatoria en polvo más accesible.

INTRODUCTION: Cystic fibrosis (CF) is an autosomal recessive genetic disorder caused by a CFT (Cystic Fibrosis Transmembrane Conductance Regulator) gene disorder, affecting approximately 1 every 2,000-3,000 newborns in Europe and 1 every 3,500 newborns in the US. This disorder causes exocrine gland dysfunction, thus resulting in a significant inflammatory response in the airways, abnormal mucus, obstruction and tissue damage, favoring bacterial growth. Pseudomonas aeruginosa is one of the main colonizing pathogens and the most important cause of morbidity and mortality in this condition; therefore its eradication is very important to improve disease prognosis. Among the three routes of antibiotic administration (oral, inhalation and intravenous), inhalation is an attractive alternative for the treatment of lung infections, since it provides high local concentrations and it reduces systemic exposure. TECHNOLOGY: Tobramycin is a broad spectrum aminoglycoside antibiotic used for the treatment of Pseudomonas aeruginosa (Pa) chronic lung infection in patients with CF and an efficacious alternative for inhalation administration. There are two types of tobramycin for inhalation: solution (TIS) and powder (TIP). PURPOSE: To assess the available evidence on the efficacy, safety and coverage related aspects among different inhalation tobramycin formulations in patients with cystic fibrosis. METHODS: A bibliographic search was carried out on the main databases (such as MEDLINE, Cochrane and CRD), in general Internet engines, in health technology assessment agencies and health sponsors. Priority was given to the inclusion of systematic reviews; controlled, randomized clinical trials (RCTs); health technology assessments and economic evaluations; clinical practice guidelines and coverage policies of other health systems, when available. RESULTS: A systematic review (SR), one randomized clinical trial (RCT), five coverage policies and six clinical practice guidelines were chosen. CONCLUSIONS: There is moderate quality evidence, including a single study comparing both inhalation modes. No significant differences were found in clinically significant results between tobramycin inhalation solution and tobramycin inhalation powder. The clinical practice guidelines and coverage policies found do not consider tobramycin inhalation powder as a first line treatment and in some cases, they mention it as a treatment alternative only under certain conditions such as intolerance or no response to colistin solution, colistin powder or tobramycin inhalation solution; and with price reduction agreements that make tobramycin inhalation power more affordable.

Inhaled aztreonam lysine versus inhaled tobramycin in cystic fibrosis. An economic evaluation.

RATIONALE: Pseudomonas aeruginosa infection is a significant cause of morbidity and mortality in patients with cystic fibrosis and is associated with a high economic burden. A recently published comparator trial demonstrated that outcomes in patients with cystic fibrosis with chronic P. aeruginosa infections switched from tobramycin solution for inhalation to aztreonam lysine for inhalation were better than those of patients who continued on tobramycin. OBJECTIVES: To compare overall costs of treatment of chronic inhaled tobramycin and aztreonam lysine in patient with cystic fibrosis who have chronic Pseudomonas infection, taking differences in outcomes into account. METHODS: A cost-effectiveness analysis with a 3-year time horizon was performed to simulate the economic consequences of either treatment from the perspective of a third party payer in the United States. We extrapolated results from the comparator trial and used data regarding clinical outcomes, quality of life, and costs from published literature and proprietary databases. A Markov structure was used to consider transitions between health states, defined principally by levels of percent predicted of FEV1. Extensive scenario and probabilistic sensitivity analyses were performed. MEASUREMENTS AND MAIN RESULTS: Use of aztreonam lysine for inhalation was associated with an average cost saving of $41,947 per patient over 3 years, as well as greater quality-adjusted life-years and total life-years. Scenario analyses demonstrated that these findings were robust to changes in key assumptions. CONCLUSIONS: It appears, with high likelihood, that the use of aztreonam solution for inhalation is associated with cost savings, an increase in quality-adjusted life-years, and improved clinical outcomes among patients with extensive prior use of tobramycin solution for inhalation who are naive to inhaled aztreonam lysine.

Novel model-based dosing guidelines for gentamicin and tobramycin in preterm and term neonates.

OBJECTIVES: In the heterogeneous group of preterm and term neonates, gentamicin and tobramycin are mainly dosed according to empirical guidelines, after which therapeutic drug monitoring and subsequent dose adaptation are applied. In view of the variety of neonatal guidelines available, the purpose of this study was to evaluate target concentration attainment of these guidelines, and to propose a new model-based dosing guideline for these drugs in neonates. METHODS: Demographic characteristics of 1854 neonates (birth weight 390-5200 g, post-natal age 0-27 days) were extracted from earlier studies and sampled to obtain a test dataset of 5000 virtual patients. Monte Carlo simulations on the basis of validated models were undertaken to evaluate the attainment of target peak (5-12 mg/L) and trough (<0.5 mg/L) concentrations, and cumulative AUC, with the existing and proposed guidelines. RESULTS: Across the entire neonatal age and weight range, the Dutch National Formulary for Children, the British National Formulary for Children, Neofax and the Red Book resulted in adequate peak but elevated trough concentrations (63%-90% above target). The proposed dosing guideline (4.5 mg/kg gentamicin or 5.5 mg/kg tobramycin) with a dosing interval based on birth weight and post-natal age leads to adequate peak concentrations with only 33%-38% of the trough concentrations above target, and a constant AUC across weight and post-natal age. CONCLUSIONS: The proposed neonatal dosing guideline for gentamicin and tobramycin results in improved attainment of target concentrations and should be prospectively evaluated in clinical studies to evaluate the efficacy and safety of this treatment.

Assessment of aminoglycoside dosing and estimated glomerular filtration rate in determining gentamicin and tobramycin area under the curve and clearance.

BACKGROUND: Aminoglycoside clearance depends on kidney function, but the Australian Therapeutic Guidelines for antibiotics (version 14, 2010) recommend initial dosing based on weight without consideration of kidney function. Other guidelines that modify dosing based on kidney function estimates often use the Cockroft-Gault equation, but the role of the estimated glomerular filtration rate equations for this purpose is unclear. AIM: To determine the performance of current guideline dosing in achieving target area-under-the-curve and examine the relative precision of the estimated glomerular filtration rate equations compared with traditional Cockroft-Gault creatinine clearance in predicting aminoglycoside clearance. METHODS: We analysed 496 aminoglycoside treatment episodes involving 1377 infusions in adult patients. Conformity with antibiotic guideline dosing was achieved if the discrepancy between prescribed and recommended dose was less than 15%. Aminoglycoside clearance was determined from linear regression using a one compartment model with the Aminoglycoside Levels and Daily Dose Indicator programme. We assessed the precision of the Cockroft-Gault, Modification of Diet in renal Disease Study and Chronic Kidney Disease-Epidemiology Collaboration (CKD-EPI) equations in predicting aminoglycoside clearance by correlation and linear regression. RESULTS: Conformity with guideline dosing was not associated with achieving target area-under-the-curve. The CKD-EPI estimated glomerular filtration rate adjusted for body surface area showed the highest correlation (gentamicin, r = 0.66; tobramycin, r = 0.82) and best predictive model for aminoglycoside clearance. CONCLUSION: Current guideline dosing may be suboptimal for achieving target area-under-the-curve. The CKD-EPI equation adjusted for patient body surface area best predicts aminoglycoside clearance, and could be evaluated as a covariate in determining initial aminoglycoside dosing.

Dry powder inhalers in cystic fibrosis: same old drugs but different benefits?

PURPOSE OF REVIEW: Newer 'innovative' formulations of antibiotics for Pseudomonas aeruginosa lung infection in patients with cystic fibrosis include colistimethate sodium and tobramycin in the form of dry powders for inhalation (DPIs). Whilst these DPIs are anticipated to improve patient adherence because of increased convenience and ease of administration, questions remain concerning whether they are as clinically effective, safe and cost-effective as nebulized antibiotics. RECENT FINDINGS: This review describes the recent findings of a health technology assessment of the clinical effectiveness and cost-effectiveness of colistimethate sodium and tobramycin DPIs with regard to how innovative treatments may be judged to be incrementally better than existing treatments. The original assessment was undertaken to inform the National Institute for Health and Care Excellence's Technology Appraisal Programme to inform national clinical guidance on the use of these new treatments in the National Health Service. SUMMARY: Three trials were included in the systematic review. Issues surrounding the clinical effectiveness and cost-effectiveness of colistimethate sodium DPI and tobramycin DPI are discussed in light of the considerable uncertainties associated with the available evidence.

In vivo assessment of a multicomponent and nanostructural polymeric matrix as a delivery system for antimicrobials and bone morphogenetic protein-2 in a unicortical tibial defect in goats.

OBJECTIVE: To determine the response of cortical bone to a multicomponent and nanostructural polymeric matrix as a drug delivery system for enhancing bone healing. ANIMALS: 20 healthy adult crossbred goats. PROCEDURES: A 3.5-mm-diameter unicortical defect was created in each tibia (day 0), and goats (4 goats/group) were treated as follows: not treated (control group), grafted with the matrix, grafted with antimicrobial (tigecycline and tobramycin)-impregnated matrix, grafted with recombinant human bone morphogenetic protein type 2 (rhBMP-2)-impregnated matrix, or grafted with antimicrobial- and rhBMP-2-impregnated matrix. Elution kinetics of antimicrobials was monitored through plasma concentrations. Bone response was assessed with radiographic scoring (days 1 and 30) and dual-energy x-ray absorptiometry (days 1, 14, and 30). Goats were euthanized on day 30, and histomorphologic analysis was performed. Categorical variables were analyzed with a generalized linear model, and continuous variables were analyzed with an ANOVA. RESULTS: Plasma antimicrobial concentrations indicated continued release throughout the study. Radiography and dual-energy x-ray absorptiometry did not reveal significant differences among treatments on day 30. Periosteal reactions were significantly greater surrounding bone defects grafted with rhBMP-2-impregnated matrix than those not treated or grafted with matrix or with antimicrobial-impregnated matrix; periosteal reactions were similar in bone defects grafted with rhBMP-2-impregnated matrix and antimicrobial- and rhBMP-2-impregnated matrix. CONCLUSIONS AND CLINICAL RELEVANCE: The matrix served as an antimicrobial delivery system and stimulated bone proliferation when rhBMP-2 was present. Antimicrobial and rhBMP-2 can be used concurrently, but the presence of antimicrobials may affect the performance of rhBMP-2.

The economics of using prophylactic antibiotic-loaded bone cement in total knee replacement.

The rate of peri-prosthetic infection following total joint replacement continues to rise, and attempts to curb this trend have included the use of antibiotic-loaded bone cement at the time of primary surgery. We have investigated the clinical- and cost-effectiveness of the use of antibiotic-loaded cement for primary total knee replacement (TKR) by comparing the rate of infection in 3048 TKRs performed without loaded cement over a three-year period versus the incidence of infection after 4830 TKRs performed with tobramycin-loaded cement over a later period of time of a similar duration. In order to adjust for confounding factors, the rate of infection in 3347 and 4702 uncemented total hip replacements (THR) performed during the same time periods, respectively, was also examined. There were no significant differences in the characteristics of the patients in the different cohorts. The absolute rate of infection increased when antibiotic-loaded cement was used in TKR. However, this rate of increase was less than the rate of increase in infection following uncemented THR during the same period. If the rise in the rate of infection observed in THR were extrapolated to the TKR cohort, 18 additional cases of infection would have been expected to occur in the cohort receiving antibiotic-loaded cement, compared with the number observed. Depending on the type of antibiotic-loaded cement that is used, its cost in all primary TKRs ranges between USD $2112.72 and USD $112 606.67 per case of infection that is prevented.

Determination of tobramycin pharmacokinetics in burn patients to evaluate the potential utility of once-daily dosing in this population.

The objective was to determine the pharmacokinetics of tobramycin in critically ill adult burn patients and evaluate a variety of milligram per kilogram (mg/kg) total body weight (TBW) regimens to determine whether practical initial once-daily administration recommendations to attain desired plasma levels could be identified. A retrospective study was conducted in 58 eligible patients who received tobramycin and had at least one set of steady-state levels from which pharmacokinetic parameters could be determined using standard first-order pharmacokinetic equations. Classification and Regression Tree analysis was used to identify whether tobramycin clearance changed with time postburn. Monte Carlo Simulation was used to evaluate initial mg/kg TBW dosing regimens to determine whether a clinically useful once-daily tobramycin recommendation could be made. Tobramycin clearance was significantly greater for patients ≤45 days postburn vs patients >45 days postburn. Once-daily tobramycin dosing for patients ≤45 days postburn of 10 to 13 mg/kg TBW and for patients >45 days postburn of 8 to 10 mg/kg TBW provided levels similar to those known to be effective in nonburn injury patients. Once-daily tobramycin dosing recommendations for burn patients were determined. Variability in pharmacokinetics in this population and change in pharmacokinetics with time postburn injury necessitate monitoring of tobramycin levels to ensure targets are met and maintained.

The cost effectiveness of dry powder antibiotics for the treatment of Pseudomonas aeruginosa in patients with cystic fibrosis.

BACKGROUND: Cystic fibrosis (CF) affects over 9,000 people in the UK and limits life expectancy. CF patients are susceptible to lung infections, most commonly Pseudomonas aeruginosa. Once infection is established, patients require lifetime treatment using nebulised antibiotics. Newer dry powder formulations of antibiotics may reduce treatment burden and improve compliance. OBJECTIVE: Our objective was to evaluate the cost effectiveness of (i) colistimethate sodium dry powder for inhalation (DPI) and (ii) tobramycin DPI versus nebulised tobramycin for the treatment of chronic P. aeruginosa lung infection in patients with CF from the perspective of the National Health Service (NHS) and Personal Social Services (PSS). METHODS: We developed a state transition model based on transitions between three strata of lung function measured in terms of forced expiratory volume in 1 second (FEV1) % predicted. Additional health states representing post-lung transplantation and dead are also modelled. The model structure was informed by systematic reviews of evidence concerning the plausibility of potential relationships between intermediate endpoints and final outcomes. The model assumes that treatment impacts on FEV1 trajectory, which manifest as changes in health-related quality of life. No survival benefit is assumed due to the absence of robust quantifiable evidence. Model parameters were informed by patient-level and aggregate data from two randomised controlled trials together with the best available evidence from the literature. Resource use and costs associated with drug acquisition, the management of exacerbations and reduced nebuliser maintenance were drawn from reference sources and expert opinion. Costs were valued at 2011/2012 prices. Costs and health outcomes were discounted at a rate of 3.5 %. Simple and probabilistic sensitivity analyses were undertaken, including additional analyses of Patient Access Scheme (PAS) price discounts offered by the manufacturers of both DPI products. RESULTS: Colistimethate sodium DPI is expected to produce fewer quality-adjusted life-years (QALYs) than nebulised tobramycin. Based on its list price, colistimethate sodium DPI is expected to be dominated by nebulised tobramycin. When the PAS is incorporated, the incremental cost-effectiveness ratio (ICER) for colistimethate sodium DPI versus nebulised tobramycin is expected to be approximately £288,600 saved per QALY lost. Based on its current list price, the ICER for tobramycin DPI versus nebulised tobramycin is expected to be approximately £124,000 per QALY gained. When the proposed PAS is included, tobramycin DPI is expected to dominate nebulised tobramycin. CONCLUSIONS: Under their list prices, neither DPI product is likely to represent good value for money for the NHS given current cost-effectiveness thresholds. The PAS discounts have a significant impact upon the economic attractiveness of both DPI products compared against nebulised tobramycin. The clinical effectiveness and cost effectiveness of the DPIs against other nebulised antibiotics, such as aztreonam and inhaled colistimethate sodium, remains unclear.

Colistimethate sodium powder and tobramycin powder for inhalation for the treatment of chronic Pseudomonas aeruginosa lung infection in cystic fibrosis: systematic review and economic model.

BACKGROUND: Cystic fibrosis (CF) is an inherited condition characterised by the abnormal transport of chloride ions across transporting epithelia. This leads to the production of thick sticky mucus in the lungs, pancreas, liver, intestine and reproductive tract, and an increase in the salt content in sweat. Among other problems, people with CF experience recurrent respiratory infections and have difficulties digesting food. CF affects over 9000 individuals in the UK. CF shortens life expectancy and adversely affects quality of life. In 2010, CF was recorded as the cause of 103 deaths in England and Wales. OBJECTIVE: To evaluate the clinical effectiveness and cost-effectiveness of colistimethate sodium dry powder for inhalation (DPI) (Colobreathe(®), Forest Laboratories) and tobramycin DPI (TOBI Podhaler(®), Novartis Pharmaceuticals) for the treatment of Pseudomonas aeruginosa lung infection in CF. DATA SOURCES: Electronic databases were searched in February and March 2011 [MEDLINE, MEDLINE In-Process & Other Non-Indexed citations, EMBASE, The Cochrane Library databases, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Web of Science, Conference Proceedings Citation Index (CPCI) and Bioscience Information Service (BIOSIS) Previews]. Relevant databases were searched for ongoing and unpublished studies, and bibliographies of relevant systematic reviews and the manufacturers' submissions were also hand-searched. REVIEW METHODS: A systematic review of the clinical effectiveness and cost-effectiveness of colistimethate sodium DPI and tobramycin DPI for the treatment of chronic P. aeruginosa lung infection in CF was conducted. Existing economic evidence within the literature was reviewed and a de novo health economic model was also developed. RESULTS: Three randomised controlled trials (RCTs) were included in the clinical effectiveness review. Both colistimethate sodium DPI and tobramycin DPI were reported to be non-inferior to nebulised tobramycin for the outcome forced expiratory volume in first second percentage predicted (FEV1%). It was not possible to draw any firm conclusions as to the relative efficacy of colistimethate sodium DPI compared with tobramycin DPI. The economic analysis suggests that colistimethate sodium DPI produces fewer quality-adjusted life-years (QALYs) than nebulised tobramycin. Given the incremental discounted lifetime cost of tobramycin DPI compared with nebulised tobramycin, it highly unlikely that tobramycin DPI has an incremental cost-effectiveness ratio that is better than £30,000 per QALY gained. LIMITATION: The uncertainty surrounding the short-term evidence base inevitably results in uncertainty surrounding the long-term clinical effectiveness and cost-effectiveness of colistimethate sodium DPI. CONCLUSIONS: Both DPI formulations have been shown to be non-inferior to nebulised tobramycin as measured by FEV1%. The results of these trials should be interpreted with caution owing to the means by which the results were analysed, the length of follow-up, and concerns about the ability of FEV1% to accurately represent changes in lung health. Although the increase in QALYs is expected to be lower with colistimethate sodium DPI than with nebulised tobramycin, a price for this intervention had not been agreed at the time of the assessment. Depending on the price of colistimethate sodium DPI, this results either in a situation whereby colistimethate sodium DPI is dominated by nebulised tobramycin or in one whereby the incremental cost-effectiveness of nebulised tobramycin compared with colistimethate sodium DPI is in the range of £24,000-277,000 per QALY gained. The economic analysis also suggests that, given its price, it is unlikely that tobramycin DPI has a cost-effectiveness ratio of < £30,000 per QALY gained when compared with nebulised tobramycin. A RCT to assess the longer-term (≥ 12 months) efficacy of colistimethate sodium DPI and tobramycin DPI in comparison with nebulised treatments would be beneficial. Such a study should include the direct assessment of HRQoL using a relevant preference-based instrument. Future studies should ensure that the European Medicines Agency guidelines are adhered to. In addition, high-quality research concerning the relationship between forced expiratory volume in first second % (FEV1%) predicted or other measures of lung function and survival/health-related quality of life (HRQoL) would be useful. STUDY REGISTRATION: PROSPERO CRD42011001350. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Nebuliser systems for drug delivery in cystic fibrosis.

BACKGROUND: Nebuliser systems are used to deliver medications to control the symptoms and the progression of lung disease in people with cystic fibrosis. Many types of nebuliser systems are available for use with various medications; however, there has been no previous systematic review which has evaluated these systems. OBJECTIVES: To evaluate effectiveness, safety, burden of treatment and adherence to nebulised therapy using different nebuliser systems for people with cystic fibrosis. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register comprising references identified from comprehensive electronic database searches, handsearching of relevant journals and abstract books of conference proceedings. We searched the reference lists of each study for additional publications and approached the manufacturers of both nebuliser systems and nebulised medications for published and unpublished data. Date of the most recent search: 15 Oct 2012. SELECTION CRITERIA: Randomised controlled trials or quasi-randomised controlled trials comparing nebuliser systems including conventional nebulisers, vibrating mesh technology systems, adaptive aerosol delivery systems and ultrasonic nebuliser systems. DATA COLLECTION AND ANALYSIS: Two authors independently assessed studies for inclusion. They also independently extracted data and assessed the risk of bias. A third author assessed studies where agreement could not be reached. MAIN RESULTS: The search identified 40 studies with 20 of these (1936 participants) included in the review. These studies compared the delivery of tobramycin, colistin, dornase alfa, hypertonic sodium chloride and other solutions through the different nebuliser systems. This review demonstrates variability in the delivery of medication depending on the nebuliser system used. Conventional nebuliser systems providing higher flows, higher respirable fractions and smaller particles decrease treatment time, increase deposition and may be preferred by people with CF, as compared to conventional nebuliser systems providing lower flows, lower respirable fractions and larger particles. Nebulisers using adaptive aerosol delivery or vibrating mesh technology reduce treatment time to a far greater extent. Deposition (as a percentage of priming dose) is greater than conventional with adaptive aerosol delivery. Vibrating mesh technology systems may give greater deposition than conventional when measuring sputum levels, but lower deposition when measuring serum levels or using gamma scintigraphy. The available data indicate that these newer systems are safe when used with an appropriate priming dose, which may be different to the priming dose used for conventional systems. There is an indication that adherence is maintained or improved with systems which use these newer technologies, but also that some nebuliser systems using vibrating mesh technology may be subject to increased failures. AUTHORS' CONCLUSIONS: Clinicians should be aware of the variability in the performance of different nebuliser systems. Technologies such as adaptive aerosol delivery and vibrating mesh technology have advantages over conventional systems in terms of treatment time, deposition as a percentage of priming dose, patient preference and adherence. There is a need for long-term randomised controlled trials of these technologies to determine patient-focused outcomes (such as quality of life and burden of care), safe and effective dosing levels of medications and clinical outcomes (such as hospitalisations and need for antibiotics) and an economic evaluation of their use.

Timing of inhaled tobramycin affects assessment of intravenous tobramycin pharmacokinetic monitoring.

BACKGROUND: Aerosolized tobramycin inhalation solution (TIS) may be absorbed and result in measurable serum concentrations. We assessed the significance of TIS dosing in the latter portion of the IV dosing interval on the calculation of pharmacokinetic (PK) parameters and dosing. METHODS: Twenty adult CF patients admitted to the hospital for treatment of a pulmonary exacerbation were enrolled. PK parameters of tobramycin were calculated before and after introduction of TIS, which was given 5-9 h after the IV dose. RESULTS: Nine patients had a clinically significant change in tobramycin trough concentration. Fourteen patients had a reduced calculated elimination rate constant after TIS administration, which may be misinterpreted as a decreased clearance of IV tobramycin. CONCLUSION: Trough tobramycin concentrations were significantly influenced in some CF patients (45%), suggesting that timing of the inhaled dose should be considered when interpreting PK measures of IV tobramycin dosing.