Tobramycin Inhalation Solution Research Articles

A phase 4 multicentre, 2×2 factorial randomised, double-blind, placebo-controlled trial to investigate the efficacy and safety of tobramycin inhalation solution for Pseudomonas aeruginosa eradication in bronchiectasis: ERASE.

Chronic Pseudomonas aeruginosa (PA) infection significantly contributes to morbidity and mortality in bronchiectasis patients. Initiating antibiotics early may lead to the eradication of PA. Here we outline the design of a trial (ERASE; NCT06093191) assessing the efficacy and safety of inhaled tobramycin, alone or with oral ciprofloxacin, in bronchiectasis patients with a new isolation of PA. This multicentre, 2×2 factorial randomised, double-blind, placebo-controlled, parallel-group trial includes a 2-week screening period, a 12-week treatment phase (with a combination of ciprofloxacin or a placebo at initial 2 weeks) and a 24-week follow-up. 364 adults with bronchiectasis and a new PA isolation will be randomly assigned to one of four groups: placebo (inhaled saline and ciprofloxacin placebo twice daily), ciprofloxacin alone (750 mg ciprofloxacin and inhaled saline twice daily), inhaled tobramycin alone (inhaled 300 mg tobramycin and ciprofloxacin placebo twice daily) or a combination of both drugs (inhaled 300 mg tobramycin and 750 mg ciprofloxacin twice daily). The primary objective of this study is to assess the proportion of patients successfully eradicating PA in each group by the end of the study. Efficacy will be evaluated based on the eradication rate of PA at other time points (12, 24 and 36 weeks), the occurrence of exacerbations and hospitalisations, time to first pulmonary exacerbations, patient-reported outcomes, symptom measures, pulmonary function tests and the cost of hospitalisations. To date no randomised trial has evaluated the benefit of different PA eradication strategies in bronchiectasis patients. The ERASE trial will therefore generate crucial data to inform future clinical guidelines.

Chronic inhaled antibiotic therapy in people with cystic fibrosis with Pseudomonas aeruginosa infection in Germany

BackgroundSeveral clinical guidelines recommend chronic inhaled therapy for pwCF (people with cystic fibrosis) and chronic Pseudomonas aeruginosa infection of the lungs. MethodsTo demonstrate what kind of therapy regimens are used in Germany, we retrospectively analysed chronic inhaled antibiotic therapy within the cohort of the German CF Registry in 2020. For comparison we also analysed the use of inhaled antibiotics in pwCF with intermittent Pseudomonas or without Pseudomonas infection. ResultsA total of 1960 pwCF had chronic P. aeruginosa infection and were retrospectively evaluated. Almost 90% (n = 1751) received at least one inhaled antibiotic. The most commonly used inhaled antibiotic was colistin solution for inhalation (55.2%), followed by aztreonam solution for inhalation (32.6%) and tobramycin solution for Inhalation (30%). Almost 56% of adults and 44% of children alternated two antibiotics for inhalation. In children, alternating colistin + tobramycin was the most often used regimen. In adults, only 23% used colistin + tobramycin; there was a wide range of treatment regimens among adults using two inhaled antibiotics alternately. 2456 pwCF had no Pseudomonas infection, but almost 24% had a chronic inhaled antibiotic therapy, while 56% of 361 pwCF and intermittent chronic Pseudomonas infection had a chronic inhaled antibiotic therapy. ConclusionIn all three groups the most commonly used inhaled antibiotic was colistin solution for inhalation. Almost 56% of adults and 44% of children with chronic Pseudomonas infection alternated two antibiotics for inhalation. It will be interesting to see how the introduction of the highly effective modulator elexacaftor/tezacaftor/ivacaftor will change the use of inhaled antibiotics.

Efficacy of Antibiotic Eradication Therapy of Early Pseudomonas aeruginosa Infection in Children with Primary Ciliary Dyskinesia.

Rationale: Chronic infection with Pseudomonas aeruginosa (PsA) negatively impacts lung disease in patients with primary ciliary dyskinesia (PCD). There is currently limited evidence regarding the efficacy of PsA antibiotic eradication therapy (AET) in children with PCD. Objectives: To assess the effectiveness of AET of early PsA infection in children with PCD. Methods: This retrospective study included pediatric patients with a confirmed PCD diagnosis according to the American Thoracic Society guidelines at the Hospital for Sick Children between 2010 and 2022. Children with newly acquired PsA infection underwent AET using a stepwise protocol. The protocol included the following steps: step 1, 28 days of tobramycin inhalation solution (TIS); step 2, repeat TIS if culture positive after step 1; and step 3, 14 days of intravenous antibiotics followed by 28 days of TIS if culture positive after step 2. Step 3 was also used for patients who presented with pulmonary exacerbation symptoms. The main outcome was a PsA-negative culture result based on the microbiological results of the first culture after completion of each step of treatment. Results: During the study period, 31 children had a new PsA infection and underwent AET. Of the 27 children who had been asymptomatic at the time of the PsA infection, negative PsA culture results were achieved in 20 (74%) of 27, 1 (14%) of 7, and 5 (83%) of 6 after steps 1, 2, and 3 of AET, respectively. All four symptomatic patients who initially were treated with step 3 had successful clearance of PsA. The overall cumulative success rate of the protocol for negative culture results after AET was 97% (30 of 31). For patients in whom AET was successful, the probability of staying PsA free for at least 1 year was 70%. Conclusions: AET for early PsA infection is highly effective in PCD, with sustained efficacy in most individuals. These data suggest that AET should be considered in all children with PCD who have early PsA infection.

Effects of long-term tobramycin inhalation solution (TIS) once daily on exacerbation rate in patients with non-cystic fibrosis bronchiectasis

BackgroundUse of long-term tobramycin inhalation solution (TIS) has been shown beneficial in cystic fibrosis (CF) and earlier findings also suggest a benefit in non-CF bronchiectasis. We investigated the efficacy and safety of maintenance TIS once daily (OD) in frequent exacerbating bronchiectasis patients chronically infected by different pathogens sensitive for tobramycin.ObjectiveThe primary outcome was the frequency of exacerbations during the 12-month study period. Secondary outcomes were time to first exacerbation, change in lung function and quality of life (QoL), bacterial analysis and safety.Materials/patientsIn this multicenter RCT patients aged ≥ 18-year-old were included with confirmed bronchiectasis and ≥ 2 exacerbations in the preceding year. Patients were assigned (1:1) to receive TIS or placebo OD for 1-year.Results58 patients were included of which 52 were analyzed in the mITT analysis. TIS reduced exacerbation frequency with a RR of 0.74 (95% CI 0.49–1.14) (p = 0.15). Within the TIS population a decrease in number of exacerbations was found (2; p = 0.00), which was also seen in the placebo-treated patients (1.5; p = 0.00). In the TIS-treated patients the QoL improved (LRTI-VAS p = 0.02 Leicester Cough p = 0.02) without additional safety concerns. No differences were found for the other secondary outcomes.ConclusionLong-term TIS OD is a safe treatment modality and showed a non-significant reduced exacerbation frequency of 0.74 as compared to placebo in bronchiectasis patients chronically infected by tobramycin sensitive pathogens. TIS OD may be a potential therapeutic strategy in selected patients with bronchiectasis suffering from a high burden of disease.Trail registration number: The BATTLE study was registered at Clinical trials.gov number: NCT02657473. Date: 13 august 2016.

The BATTLE study: Effects of long-term tobramycin inhalation solution (TIS) once daily on exacerbation rate in patients with non-cystic fibrosis bronchiectasis. Study protocol of a double blind, randomized, placebo-controlled trial: study protocol

BackgroundPatients with bronchiectasis typically suffer from chronic symptoms such as a productive cough with or without exacerbations leading to hospitalization, causing reduced quality of life (QoL) and mortality. Long-term inhaled antibiotics to treat chronic bronchial infection is registered for use in cystic fibrosis (CF) bronchiectasis. However, in patients with non-CF bronchiectasis data on long-term antibiotics are limited. ObjectiveTo investigate the effectiveness of maintenance tobramycin inhalation solution (TIS) in bronchiectasis patients without cystic fibrosis. Study designThe BATTLE study is a randomized, double blind placebo controlled, multicenter study in the Netherlands performed in patients aged ≥18-year-old with confirmed bronchiectasis, at least two exacerbations in the preceding year, and minimal one positive sputum culture with gram negative pathogens or Staphylococcus aureus, sensitive to tobramycin in the preceding year and at baseline. Patients will be treated with TIS once daily (OD) or placebo (saline 0.9%) OD for 52 weeks followed by a run-out period of 4 weeks after the last dose. The primary outcome is the yearly rate of pulmonary exacerbations. Among secondary outcome parameters are time to exacerbation, lung function, QoL, microbiological evaluation and safety. DiscussionThe BATTLE study is designed to determine the efficacy and safety of maintenance TIS OD in bronchiectasis patients colonized by different pathogens and could lead to important new evidence for TIS therapy in this population.The BATTLE study is registered in Clinical trials.gov with registration number: NCT02657473.

A Double-Blind Randomized Placebo-Controlled Phase 3 Trial of Tobramycin Inhalation Solution in Adults With Bronchiectasis With Pseudomonas aeruginosa Infection

Few large-scale studies have demonstrated the efficacy of tobramycin nebulization in bronchiectasis. We evaluated the efficacy and safety of nebulized tobramycin inhalation solution (TIS) in adults with bronchiectasis with Pseudomonas aeruginosa infection. Can TIS effectively reduce sputum Paeruginosa density and improve the bronchiectasis-specific quality of life in patients with bronchiectasis with Paeruginosa infection? This was a phase 3, 16-week, multicenter, randomized, double-blind, placebo-controlled trial. Eligible adults with bronchiectasis were recruited from October 2018 to July 2021. On the basis of usual care, patients nebulized TIS (300mg/5mL twice daily) or normal saline (5mL twice daily) via vibrating-mesh nebulizer. Treatment consisted of two cycles, each consisting of 28days on-treatment and 28days off-treatment. The coprimary end points included changes from baseline in Paeruginosa density and Quality-of-Life Bronchiectasis Respiratory Symptoms score on day29. The modified intention-to-treat population consisted of 167 patients in the tobramycin group and 172 patients in the placebo group. Compared with placebo, TIS resulted in a significantly greater reduction in Paeruginosa density (adjusted mean difference, 1.74 log10 colony-forming units/g; 95%CI, 1.12-2.35; P< .001) and greater improvement in Quality-of-Life Bronchiectasis Respiratory Symptoms score (adjusted mean difference, 7.91; 95%CI, 5.72-10.11; P< .001) on day 29. Similar findings were observed on day 85. TIS resulted in a significant reduction in 24-h sputum volume and sputum purulence score on days 29, 57, and 85. More patients became culture negative for Paeruginosa in the tobramycin group than in the placebo group on day 29 (29.3%vs10.6%). The incidence of adverse events and serious adverse events were comparable between the two groups. TIS is an effective treatment option and has an acceptable safety profile in patients with bronchiectasis with Paeruginosa infection. ClinicalTrials.gov; No. NCT03715322; URL: www. gov.

317 A Rare Case of Acute Kidney Injury (AKI) Induced by Tobramycin Inhalation Solution (TIS) in a Lung Transplant Recipient

317 A Rare Case of Acute Kidney Injury (AKI) Induced by Tobramycin Inhalation Solution (TIS) in a Lung Transplant Recipient

Is it Worth Adding Systemic Antibiotics to Inhalational Tobramycin Therapy to Treat Pseudomonas Infections in Cystic Fibrosis?

Pseudomonas aeruginosa (PA), a gram-negative rod-shaped bacterium, is one of the most common pathogens causing colonization and infection of the respiratory tract and lungs in patients with cystic fibrosis (CF). Antibiotic therapy is the mainstay treatment for PA infection, and tobramycin is one of the widely used antibiotics in intravenous or inhalation form. This review aims to explore if there is any advantage of adding systemic antibiotics to tobramycin inhalation therapy by comparing the combination regimen to tobramycin inhalation monotherapy in CF patients with PA infection. We collected studies relevant to our review topic by doing a literature search on multiple databases. According to the currently available studies, the addition of oral antibiotics such as fluoroquinolones and azithromycin to tobramycin inhalation solution (TIS) provides no additional benefit in eradicating PA infection or producing clinical improvement in cystic fibrosis patients. However, adding intravenous antibiotics to TIS has not produced conclusive results and thus requires further research. We recommend conducting more randomized controlled trials comparing different treatment regimens, which may help discover the most beneficial treatment regimen with decreased systemic side effects.

Therapeutic Approach of Chronic Pseudomonas Infection in Cystic Fibrosis-A Network Meta-Analysis.

Pseudomonas infection is a major determinant of morbidity and mortality in cystic fibrosis (CF). Maintaining optimal lung function in CF patients carrying Pseudomonas remains a challenge. Our study aims to investigate the efficacy of antipseudomonal inhaled antibiotics in CF patients with chronic Pseudomonas infection. A Bayesian network meta-analysis of randomized controlled trials was conducted. The main outcomes were changes in: (a) forced respiratory volume (FEV1), (b) Pseudomonas aeruginosa sputum density, and (c) CF Questionnaire Revised Respiratory Symptom Score (CFQR-RSS) at 4 weeks follow-up. Eighteen trials which reported on treatment with aztreonam lysine, tobramycin, colistin, levofloxacin, fosfomycin/tobramycin, and amikacin in various dosages were eligible for inclusion. In terms of change in FEV1%, aztreonam lysine (t.i.d., 75 mg) with a 28-day run in the tobramycin phase, aztreonam lysine (b.i.d., 75 mg) with a 28-day run in the tobramycin phase had the highest probability of being the most effective treatment (SUCRAs were 77, 76%, respectively). Regarding change in Pseudomonas sputum density, aztreonam lysine (b.i.d., 75 mg) with a 28-day run in the tobramycin phase, aztreonam lysine (t.i.d., 75 mg) with a 28-day run in the tobramycin phase had the highest probability of being the most effective treatment (SUCRAs were 90, 86%, respectively). Regarding change in CFQR-RSS, aztreonam lysine (t.i.d., 75 mg) and aztreonam lysine (b.i.d., 75 mg) with a 28-day run in the tobramycin inhalation solution phase had the highest probability of being the most effective treatments (SUCRA:74% and 72%, respectively). Regarding changes in FEV1% and Pseudomonas sputum density, aztreonam lysine with a run in tobramycin phase may be the best treatment option in treating chronic Pseudomonas in CF. According to CFQR-RSS no significant differences were found. Given the limitations of the studies included, validation trials are called for.

Long-term amikacin liposome inhalation suspension in cystic fibrosis patients with chronic P. aeruginosa infection

Background. In CLEAR-108—a phase 3, randomised, open-label study—once-daily amikacin liposome inhalation suspension (ALIS) was noninferior to twice-daily tobramycin inhalation solution (TIS) in improving lung function in patients with cystic fibrosis (CF) and chronic Pseudomonas aeruginosa infection after 3 treatment cycles (28 days on/28 days off). The CLEAR-110 extension study (ClinicalTrials.gov: NCT01316276; EudraCT: 2011-000443-24) assessed long-term safety, tolerability, and efficacy of ALIS in eligible patients who completed CLEAR-108. Methods. Patients received once-daily ALIS 590 mg for 12 treatment cycles (96 weeks). Patients were grouped by prior treatment: the “prior-ALIS” cohort received ALIS in CLEAR-108, and the “ALIS-naive" cohort received TIS in CLEAR-108. Results. Overall, 206 patients (prior-ALIS, n=92; ALIS-naive, n=114) entered CLEAR-110 and received ≥1 dose of ALIS. Most patients (88.8%) experienced ≥1 treatment-emergent adverse event (TEAE) through day 672 (end of year 2). Most TEAEs (72.3%) were mild or moderate in severity. Severe TEAEs were reported in 31 patients (15.0%). Two life-threatening TEAEs (haemoptysis; intestinal obstruction) and 1 death (cardiac failure) were reported. Twenty-one patients (10.2%) discontinued treatment due to a TEAE (mostly infective pulmonary exacerbation of CF). Mean change from baseline in forced expiratory volume in 1 second percent predicted at day 672 was −3.1% (prior-ALIS, −4.0%; ALIS-naive, −2.3%). Mean change from baseline in sputum density of P. aeruginosa at day 672 was 0.02 (prior-ALIS, −0.16; ALIS-naive, 0.19) log CFU/g. Conclusions. Long-term treatment with ALIS was well tolerated with a favourable adverse event profile and demonstrated continued antibacterial activity in CF patients with chronic P. aeruginosa infection.

The Role of Suboptimal Concentrations of Nebulized Tobramycin in Driving Antimicrobial Resistance in Pseudomonas aeruginosa Isolates in Cystic Fibrosis.

Antimicrobial resistance in Pseudomonas aeruginosa may be driven by exposure to suboptimal concentrations of tobramycin antibiotic delivered by less efficient nebulizers. P. aeruginosa isolates (no. = 114; 32 first + 82 chronic) were challenged invitro employing extrapolated peak and trough concentrations of tobramycin inhalation solution (TIS), corresponding to 3 nebulizers: Pari LC Plus, Sidestream12NEB400, and MistyNeb2035G. Bacterial persistence and antibiotic susceptibility to tobramycin was determined following 4 TIS cycles: (i) 28 d ON, (ii) 28 d ON + 28 d OFF, (iii) 2 × 28 d ON, and (iv) 28 d ON + 28 d ON + 28 d OFF. All first isolates were eradicated at peak and trough concentrations except for the trough concentration corresponding to Sidestream 12NEB400 (bactericidal activity 87%). For chronic isolates, peak concentrations eradicated 88%, 90%, and 92%, and trough concentrations eradicated 43%, 62%, and 85%, with the Sidestream12NEB400, MistyNeb2035G, and Pari LC Plus nebulizers, respectively. A statistically significant increase in antibiotic resistance with sensitive, intermediate, and resistant P. aeruginosa was noted following cycles (i) through (iv) at trough concentrations with the Sidestream 12NEB400 and MistyNeb2035G nebulizers. There was a significant reduction in tobramycin resistance following a 28-d OFF cycle, and no difference was noted following 1 × 28 d ON versus 2 × 28 d ON cycles. Our results indicate that suboptimal concentrations of tobramycin drove increased antibiotic resistance, emulating standard cycles of ON/OFF inhaled therapy. This was evident at extrapolated tobramycin concentrations at trough levels corresponding to less efficient nebulizers by initially allowing for the survival of intermediate and resistant organisms, because nebulizer performance did not achieve critical antibiotic concentrations sufficient to eradicate the organism, and by allowing the development of resistance in those cells that were able to survive the initial tobramycin challenge. Transferred to clinical practice, for people with cystic fibrosis on TIS treatment, it is important that clinicians employ an efficient nebulizer that helps mitigate an upward drift in antibiotic resistance, thereby protecting the clinical value of TIS within treatment for cystic fibrosis.

Real World Experience of Pseudomonas aeruginosa Eradication at an Urban Pediatric Cystic Fibrosis Center.

Clinical practice guidelines for eradication of Pseudomonas aeruginosa (PA) in patients with cystic fibrosis (CF) have been established, but current studies have not assessed how these guidelines translate into clinical practice. This study aimed to characterize the real-world eradication strategies, eradication rates, and microbiologic outcomes of patients with first acquisition of PA at an urban pediatric CF center. The Cystic Fibrosis Foundation Patient Registry was used to identify patients with CF who received care between January 2014 and September 2018 and had PA isolated from an airway culture. Patients were included if they had a first positive PA culture or the first positive culture in 2 years. Data regarding patient demographics, timing and results of airway cultures, and treatment regimens were collected. Over a 3.75-year period, 75 patients had an initial positive culture for PA. Of those patients, 74 (98.7%) received eradication treatment. Tobramycin inhalation solution (TIS) monotherapy was the most common regimen prescribed (52.7%) followed by TIS plus an oral fluoroquinolone (28.4%) (TIS + FQ). Of those treated, 62 (83.8%) patients had eradication of PA at first follow-up culture (median, 58 days; IQR, 49-77 days). Eradication rates (84.6% vs 76.2%, p = 0.421) and times to recurrence (6.37 months vs 5.1 months, p = 0.726) were comparable between TIS and TIS + FQ cohorts. The eradication rate for PA in clinical practice is similar to that published in the literature. Consistent with published guidelines, these microbiologic outcomes do not support the addition of an oral FQ to TIS for initial PA eradication.

Effect of Inspiratory Maneuvers on Lung Deposition of Tobramycin Inhalation Powder: A Modeling Study.

Background: Tobramycin inhalation powder (TIP) and tobramycin inhalation solution (TIS) are considered equally effective for the treatment of chronic pulmonary Pseudomonas aeruginosa infection in cystic fibrosis (CF) patients. The impact of TIP inhalation maneuvers on distribution of tobramycin is unknown. We hypothesized that (1) fast TIP inhalations result in greater extrathoracic and reduced small airway concentrations compared with slow or uninstructed TIP inhalations; (2) slow TIP inhalations result in greater small airway concentrations than TIS inhalations. The aim of the study was to assess TIP and TIS deposition with computational fluid dynamics (CFD). Methods: Uninstructed, instructed fast, and instructed slow TIP inhalations of CF patients on maintenance TIP therapy, and inhalations during nebulization of saline with PARI LC Plus® were recorded at home. Drug deposition was determined using TIP and TIS aerosol characteristics together with CFD simulations based on airway geometries from chest computed tomography scans. The drug concentration was assessed in extrathoracic, central, large, and small airways. Results: Twelve patients aged 12-45 years were included, and 144 CFD simulations were performed. In all individual analyses, the tobramycin concentrations were well above the threshold for effective dose of 10 times minimal inhibitory concentration throughout the bronchial tree. Extrathoracic concentrations were comparable between fast and uninstructed TIP inhalations, while slow inhalations resulted in reduced extrathoracic concentrations compared with uninstructed TIP inhalations (p = 0.024). Small airway concentrations were comparable between fast and uninstructed TIP inhalations, while slow TIP inhalations resulted in greater small airway concentrations than uninstructed TIP inhalations (p < 0.001). Small airway concentrations of TIS were comparable with those of slow TIP inhalations (p = 0.065), but greater than those of fast and uninstructed TIP inhalations (p < 0.001). Conclusion: All TIS and TIP inhalation maneuvers resulted in high enough concentrations, however, inhaling TIS or inhaling TIP slowly results in the greatest small airway deposition.

Treatments for preventing recurrence of infection with Pseudomonas aeruginosa in people with cystic fibrosis.

Chronic infection with Pseudomonas aeruginosa (PA) in cystic fibrosis (CF) is a source of much morbidity and mortality. Eradication of early PA infection is possible, but can recur in many individuals. We sought to examine strategies to delay the time to PA recurrence in people with CF. To establish whether secondary prevention strategies, using antibiotics or other therapies, increase the chances of people with CF remaining free from PA infection following successful eradication therapy. We searched the Cochrane Cystic Fibrosis Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books. We also searched ongoing trials registries and the reference lists of relevant articles and reviews. Date of last search: 21 August 2019. Randomised controlled trials (and quasi-randomised trials where the risk of bias was low) comparing any treatment modality aimed at preventing recurrence of PA infection with placebo, standard therapy or any other treatment modality in people with CF who have undergone successful eradication of PA. Two review authors independently assessed trials for inclusion and risk of bias. Quality of the evidence was assessed using GRADE. Conflicts were resolved by discussion and the opinion of a third review author was sought where necessary. Only a subset of participants in the included trial were eligible, therefore individual participant data were requested and obtained from the trial investigators. We included one trial (n = 306) in the review; however, only 253 participants had undergone successful eradication of PA, so fulfilling the inclusion criteria for our review. Information presented relates only to the included subset of participants. The trial recruited children aged one to 12 years (mean (standard deviation (SD)) age of 5.8 (3.5) years), 129 participants (51.0%) were female and the median follow-up was 494 days. We compared cycled therapy with tobramycin inhalation solution (TIS), in which participants underwent 28 days of TIS every three months, with culture-based therapy, in which participants were only prescribed medication when a quarterly sputum sample was positive for PA. Reasons for downgrading the quality of the evidence included applicability (only included children), incomplete outcome data and a small number of participants. The time to next isolation of PA was probably shorter with cycled TIS therapy than with culture-based therapy, hazard ratio (HR) 2.04 days (95% confidence interval (CI) 1.28 to 3.26) (moderate-quality evidence). This is in contrast to the main publication of the only included trial, which examined rate of PA positivity rather than time to PA infection and included participants not eligible for inclusion in this review. At the end of the trial, there was no difference between the cycled and culture-based groups in the change from baseline in forced expiratory volume in one second (FEV1) L, mean difference (MD) 0.0 L (95% CI -0.09 to 0.09) or in FEV1 % predicted, MD 0.70% (95% CI -4.33 to 5.73) (both very low-quality evidence). There was no difference in the change from baseline for FVC between the groups. There was also no difference in the frequency of pulmonary exacerbations between groups, MD -0.18 (95% CI -0.51 to 0.14) (moderate-quality evidence). Similarly, there was no difference between groups in the risk of participants developing novel resistant bacteria, RR 1.00 (95% CI 0.67 to 1.5) (moderate-quality evidence). There were more severe adverse events in the cycled group, but the type of treatment probably makes little or no difference to the results, RR 0.65 (95% CI 0.39 to 1.11) (moderate-quality evidence). There was no difference between groups in the change in weight or height from baseline or in rates of adherence to tobramycin or all trial medicines. The included trial did not assess changes in quality of life, the time to chronic infection with PA or the cost-effectiveness of treatment. Cycled TIS therapy may be beneficial in prolonging the time to recurrence of PA after successful eradication, but further trials are required, specifically addressing this question and in both adults and children.

Amikacin liposome inhalation suspension for chronic Pseudomonas aeruginosa infection in cystic fibrosis

BackgroundShortcomings of inhaled antibiotic treatments for Pseudomonas aeruginosa infection in patients with cystic fibrosis (CF) include poor drug penetration, inactivation by sputum, poor efficiency due to protective biofilm, and short residence in the lung. MethodsEligible patients with forced expiratory volume in 1 s (FEV1) ≥25% of predicted value at screening and CF with chronic P. aeruginosa infection were randomly assigned to receive 3 treatment cycles (28 days on, 28 days off) of amikacin liposome inhalation suspension (ALIS, 590 mg QD) or tobramycin inhalation solution (TIS, 300 mg BID). The primary endpoint was noninferiority of ALIS vs TIS in change from baseline to day 168 in FEV1 (per-protocol population). Secondary endpoints included change in respiratory symptoms by Cystic Fibrosis Questionnaire-Revised (CFQ-R). ResultsThe study was conducted February 2012 to September 2013. ALIS was noninferior to TIS (95% CI, −4.95 to 2.34) for relative change in FEV1 (L) from baseline. The mean increases in CFQ-R score from baseline on the Respiratory Symptoms scale suggested clinically meaningful improvement in both arms at the end of treatment in cycle 1 and in the ALIS arm at the end of treatment in cycles 2 and 3; however, the changes were not statistically significant between the 2 treatment arms. Treatment-emergent adverse events (TEAEs) were reported in most patients (ALIS, 84.5%; TIS, 78.8%). Serious TEAEs occurred in 17.6% and 19.9% of patients, respectively; most were hospitalisations for infective pulmonary exacerbation of CF. ConclusionsCyclical dosing of once-daily ALIS was noninferior to cyclical twice-daily TIS in improving lung function.ClinicalTrials.gov Identifier: NCT01315678

Pharmacokinetics and safety of tobramycin nebulization with the I-neb and PARI-LC Plus in children with cystic fibrosis: A randomized, crossover study.

AimsWe aimed to compare the pharmacokinetics (PK) and safety profile of tobramycin inhalation solution (TIS) using the I‐neb device to the standard PARI‐LC Plus nebulizer in children with cystic fibrosis.MethodsA randomized, open‐label, crossover study was performed. In 2 separate study visits, blood samples from 22 children were collected following TIS nebulization with I‐neb (75 mg) and PARI‐LC Plus (300 mg). Study visits were separated by 1 month, in which 1 of the study nebulizers was used twice daily. Tobramycin PK for both nebulizers was established using measured tobramycin concentrations and Bayesian PK modelling software. Hearing and renal function tests were performed to test for aminoglycoside associated toxicity. In addition to standard estimated glomerular filtration rate values, biomarkers for tubular injury (KIM‐1 and NAG) were measured. Patient and nebulizer satisfaction were assessed.ResultsInhalations were well tolerated and serum trough concentrations below the predefined toxic limit were reached with no significant differences in PK parameters between nebulizers. Results of audiometry and estimated glomerular filtration rate revealed no abnormalities. However, increased urinary NAG/creatinine ratios at visit 2 for both nebulizers suggest TIS‐induced subclinical tubular kidney injury. Nebulization time was 50% shorter and patient satisfaction was significantly higher with the I‐neb.ConclusionsNebulization of 75 mg TIS with the I‐neb in children with cystic fibrosis resulted in comparable systemic exposure to 300 mg TIS with the PARI‐LC Plus and was well tolerated and preferred over the PARI‐LC Plus. Long‐term safety of TIS nebulization should be monitored clinically, especially regarding the effects on tubular kidney injury.

Azithromycin for Early Pseudomonas Infection in Cystic Fibrosis. The OPTIMIZE Randomized Trial.

New isolation of Pseudomonas aeruginosa (Pa) is generally treated with inhaled antipseudomonal antibiotics such as tobramycin inhalation solution (TIS). A therapeutic approach that complements traditional antimicrobial therapy by reducing the risk of pulmonary exacerbation and inflammation may ultimately prolong the time to Pa recurrence. To test the hypothesis that the addition of azithromycin to TIS in children with cystic fibrosis and early Pa decreases the risk of pulmonary exacerbation and prolongs the time to Pa recurrence. The OPTIMIZE (Optimizing Treatment for Early Pseudomonas aeruginosa Infection in Cystic Fibrosis) trial was a multicenter, double-blind, randomized, placebo-controlled, 18-month trial in children with CF, 6 months to 18 years of age, with early Pa. Azithromycin or placebo was given 3× weekly with standardized TIS. The primary endpoint was the time to pulmonary exacerbation requiring antibiotics and the secondary endpoint was the time to Pa recurrence, in addition to other clinical and safety outcomes. A total of 221 participants (111 placebo, 110 azithromycin) out of a planned 274 were enrolled. Enrollment was stopped early by the NHLBI because the trial had reached the prespecified interim boundary for efficacy. The risk of pulmonary exacerbation was reduced by 44% in the azithromycin group as compared with the placebo group (hazard ratio, 0.56; 95% confidence interval, 0.37-0.83; P = 0.004). Weight increased by 1.27 kg in the azithromycin group compared with the placebo group (95% confidence interval, 0.01-2.52; P = 0.046). No significant differences were seen in microbiological or other clinical or safety endpoints. Azithromycin was associated with a significant reduction in the risk of pulmonary exacerbation and a sustained improvement in weight, but had no impact on microbiological outcomes in children with early Pa. Clinical trial registered with clinicaltrials.gov (NCT02054156).

Eradication of early P. aeruginosa infection in children

ObjectiveAntibiotic eradication treatment is the standard-of-care for cystic fibrosis (CF) patients with early Pseudomonas aeruginosa (Pa)-infection; however, evidence from placebo-controlled trials is limited. MethodsThis double-blind, placebo-controlled trial randomised CF patients <7 years (N = 51) with early Pa-infection to tobramycin inhalation solution (TOBI 300 mg) or placebo (twice daily) for 28 days with an optional cross-over on Day 35. Primary endpoint was proportion of patients having throat swabs/sputum free of Pa on Day 29. ResultsOn Day 29, 84.6% patients in the TOBI versus 24.0% in the placebo group were Pa-free (p < 0.001). At the end of the cross-over period, 76.0% patients receiving TOBI in the initial 28 days were Pa-free compared to 47.8% receiving placebo initially. Adverse events were consistent with the TOBI safety profile with no differences between TOBI and placebo. ConclusionTOBI was effective in eradicating early Pa-infection with a favourable safety profile in young CF patients.Trial registration number: NCT01082367

Early detection using qPCR of Pseudomonas aeruginosa infection in children with cystic fibrosis undergoing eradication treatment

BackgroundInfection with Pseudomonas aeruginosa (Pa) with a chronic phenotype is associated with antibiotic eradication therapy (AET) failure. Our objective was to determine whether higher levels of Pa (detected using qPCR) prior to culture positivity were associated with AET failure in pediatric CF patients. MethodsPa-specific qPCR was performed on stored sputa prior to culture positivity in pediatric CF patients with new-onset culture-positive Pa infections undergoing AET with a 28-day course of tobramycin-inhaled solution (TIS). DNA concentrations were compared in patients in whom AET was successful (Eradicated) to those with persistently positive sputum cultures (Persistent). ResultsForty-seven patients were included. AET was successful in 32 cases (68%), but failed in 15 cases (32%). Median sputum Pa-specific DNA concentration preceding the positive sputum culture was 2.2 × 10−6 μg/mL in Eradicated cases compared to 3 × 10−5 μg/mL in Persistent cases (p = 0.14). There was no significant difference in DNA concentration in the last sputum sample prior to culture positivity, nor in maximal DNA values. There was also no difference in sputum Pa DNA concentrations in patients who had a mucoid (compared to non-mucoid) Pa infection. ConclusionsPediatric CF patients with new-onset Pa infections have detectable Pa-specific DNA in the year preceding a positive culture, however, there is no significant difference in Pa DNA concentrations between patients in whom AET is successful compared to those in whom it fails. Therefore, early molecular detection of Pa may not lead to improved eradication success rates.

Resource Use Evaluation of Tobramycin Formulations in a State Medicaid Program.

Patients with cystic fibrosis (CF) often suffer from chronic infection with Pseudomonas aeruginosa. For patients with CF, 6 years of age and older, with P aeruginosa persistently present in cultures of the airways, the Cystic Fibrosis Foundation recommends the chronic use of inhaled tobramycin to reduce exacerbations. To ease treatment burden, a new dry powder formulation was developed. The objective of this research was to compare resource utilization between tobramycin inhaled solution (TIS) and a new tobramycin dry powder (TIP) formulation in a state Medicaid program. Members that switched from TIS to TIP were matched to TIS-only beneficiaries via propensity score based on age, sex, race, and residence location. The outcomes (tobramycin reimbursement, inpatient hospital reimbursement, additional antibiotic therapy reimbursement, length of inpatient stays, odds of adherence, odds of inpatient hospital stay, and additional mean days of antibiotic therapy) were assessed by using multivariable regression and included baseline clinical surrogates. No difference was found between 54 matched members for tobramycin reimbursement, length of inpatient stays, odds of adherence, or odds of hospital stay. Cost of additional antibiotic therapy was higher for TIP (+$518, p < 0.001) and inpatient reimbursement was higher for TIS (+$503, p = 0.031). Additional mean days of antibiotic therapy were lower for TIP (8.6 vs. 10.1, p = 0.374), but was not statistically significant. In patients that switched from TIS to TIP, an increase in cost of additional antibiotic therapy was observed, while inpatient costs were lower. Research should be considered in larger populations to fully determine the impact of the new dry powder formulation on overall resource use and outcomes.