Tobramycin In Cystic Fibrosis Patients Research Articles

Comparison of the predictive value of area under the curve versus maximum serum concentration of intravenous tobramycin in cystic fibrosis patients treated for an acute pulmonary exacerbation.

The primary objective of this study was to compare the therapeutic predictive value of area under the curve (AUC24 ) versus maximum concentration (Cmax ) in cystic fibrosis (CF) patients receiving intravenous (IV) tobramycin for a Pseudomonas aeruginosa (PsA) acute pulmonary exacerbation (APE). Acute kidney injury (AKI) incidence and the relationship between time undetectable and efficacy were also assessed. A retrospective review was conducted in patients aged at least 1 month with a diagnosis of CF receiving IV tobramycin for treatment of a PsA APE and admitted to the University of Kentucky between August 2015 and August 2019. Patients were excluded if they had no growth of PsA on sputum culture or if two postdose tobramycin levels were not obtained following a dose adjustment of ≥20%. A total of 44 pediatric and 107 adult patient encounters met inclusion criteria. In patients with therapeutic success (n = 91), 75.8% had an AUC24 ≥80% and 80.3% had a Cmax ≥8 times the highest PsA minimal inhibitory concentration. There was a significant correlation between AUC24 and Cmax (r[149] = 0.727; p < 0.001). AKI incidence was significantly higher in patients receiving IV tobramycin dosed multiple times daily versus at least every 24 h (χ2 [1, 151] = 3.9; p = 0.047). The results of this study indicate that both AUC24 and Cmax serve as relatively accurate predictors of tobramycin efficacy. Additionally, given the significant increase in incidence of AKI, multidaily dosing of IV tobramycin should be avoided in pediatric and adult patients with CF.

Role of Tris-CaEDTA as an adjuvant with nebulised tobramycin in cystic fibrosis patients with Pseudomonas aeruginosa lung infections: A randomised controlled trial

BackgroundWe tested if disrupting iron utilisation by P. aeruginosa by adding the Tris-buffered chelating agent CaEDTA to nebulised tobramycin would enhance bacterial clearance and improve lung function in CF patients. MethodsIn this double-blind, randomised controlled trial, 26 episodes (25 patients) with P. aeruginosa infection admitted to two CF centres for treatment of an acute pulmonary exacerbation were randomly assigned to receive either 75 mg CaEDTA in Tris-buffered saline or placebo (Tris-buffered saline) nebulised in combination with 250 mg tobramycin twice daily for six weeks followed with four week safety follow-up. Primary endpoints were safety, tolerability, and bacterial density of P. aeruginosa. A secondary endpoint was lung function. ResultsThe study drug was well tolerated with adverse events comparable in both groups. The mean (SD) reduction in sputum P. aeruginosa count (log10 CFU/g) in the CaEDTA vs placebo group was 2·05 (2·57) vs 0·82 (2·71) at two weeks relative to admission (p = 0·39). The mean improvement in ppFEV1 was 16 vs 5 (p = 0·16); 11 vs 2 (p = 0·28); and 6 vs 2 percentage points (p = 0·47) at two, six, and ten weeks in CaEDTA and placebo groups, respectively. ConclusionsIn this pilot study in CF patients, an increase in the reduction of sputum density of P. aeruginosa and an increase in ppFEV1 was observed in the group of patients who received Tris-CaEDTA added to inhaled tobramycin compared to the group who received inhaled tobramycin alone, although these differences were not statistically significant. The treatment was also shown to be safe.

Сравнительная характеристика и особенности клинической картины заболевания взрослых больных муковисцидозом с хроническим инфицированием нижних дыхательных путей Pseudomonas aeruginosa и другой грамотрицательной неферментирующей флорой

Background: in Russia, the life expectancy of cystic fibrosis (CF) patients increased by 10 years in 2011–2017 being 55.49 years in 2017. However, the number of patients with the chronic infection caused by non-fermenting gram-negative bacilli (NFGNB), e.g., Burkholderia cepacia, Achromobacter spp. etc., increased as well. Aim: to evaluate the differences in the nutritional and functional status and the severity of mutations in CF patients with chronic Pseudomonas infection or NFGNB infection and to assess the sensitivity of P. aeruginosa to tobramycin in CF patients in the Northwest region of Russia. Patients and Methods: 31 patients with CF aged 18–43 years (18 men and 13 women) were examined. The duration of the study was 12 months. Spirometry, anthropometry, and sputum culture were performed. Results: P. aeruginosa alone was isolated in 18 patients (58%), Achromobacter spp. in 9 patients (29%), and Burkholderia spp. in 4 patients (13%). The patients were divided into two groups, i.e., patients with chronic Pseudomonas infection (group 1, n=18, 10 out of 18 patients with mucoid strains of P. aeruginosa) or chronic NFGNB infection (group 2, n=13). The median age and the mode age were 27 years and 27 years, respectively, in group 1 and 24 years and 22 years, respectively, in group 2. It was demonstrated that CF patients with chronic NFGNB infection are characterized by poorer nutritional status (p&lt;0.05) but similar functional status and the severity of CFTR gene mutation compared to CF patients with chronic Pseudomonas infection. It was also shown that Р. aeruginosa is highly sensitive to tobramycin (94.4%). Conclusions: in CF patients, chronic lower respiratory tract infections with Burkholderia cepacia and Achromobacter spp. account for 41.9% of gram-negative rod infections. Further studies and drug sensitivity monitoring are needed. KEYWORDS: cystic fibrosis, DNA test, chronic infection with Pseudomonas aeruginosa, Burkholderia cepacia, Achromobacter spp, non-fermenting gram-negative bacilli, CFTR mutation, nutritional status, pulmonary function tests, inhaled antibiotic therapy. FOR CITATION: Makhmutova V.R., Gembitskaya T.E., Chermenskiy A.G. et al. Comparative characteristics and clinical presentation of cystic fibrosis in adults with chronic lower respiratory tract infections with Pseudomonas aeruginosa and other non-fermenting gram-negative bacilli. Russian Medical Inquiry. 2020;4(4):186–191. DOI: 10.32364/2587-6821-2020-4-4-186-191.

Usage and monitoring of intravenous tobramycin in cystic fibrosis in Australia and the UK

AbstractAim: To characterise usage and monitoring of intravenous tobramycin in cystic fibrosis (CF) patients in Australia and the UK.Methods: An anonymous, online survey of healthcare professionals caring for CF patients was conducted. Survey questions were designed to obtain information on tobramycin dosing, therapeutic drug monitoring and toxicity monitoring.Results: The survey was sent to pharmacists and clinicians in 73 CF centres. Responses were received from 32 and 40 healthcare professionals, from Australia and the UK, respectively. Once‐daily dosing of tobramycin was the preferred administration regimen for 93.8 and 67.5% of participants in Australia and the UK, respectively. Among them 68.8% of Australian and 55% of UK participants initiated tobramycin therapy at a dose of 10 mg/kg/day or greater. Australian participants most commonly adjusted tobramycin dosage using log‐linear regression analysis (40.6%) or trough measurements (28.1%). UK participants most commonly adjusted tobramycin dosage using trough (55%) or peak and trough measurements (37.5%). In 90.6% of Australian and 95% of UK participants practices, serum creatinine was routinely monitored during admission. Standard pure tone audiometry was performed by 15.6% of Australian and 17.5% of UK participants and high‐frequency pure tone audiometry was performed by 15.6% of Australian and 10% of UK participants, once or twice a year.Conclusions: Many discrepancies exist between Australia and the UK and within each country with respect to monitoring of intravenous tobramycin in CF patients. Greater ototoxicity monitoring is likely necessary in both countries. Further education of health professionals about the existence of national guidelines and guidance on how they can be applied in practice is likely required.

Pharmacokinetics and safety of an 8 week continuous treatment with once-daily versus twice-daily inhalation of tobramycin in cystic fibrosis patients.

We evaluated the pharmacokinetics, safety and tolerability of two different continuous treatment regimens of tobramycin inhalation solution (TIS) in 29 cystic fibrosis (CF) patients chronically infected with Pseudomonas aeruginosa. In this randomized, multicentre, open-label, two-period crossover study, TIS (300 mg/5 mL) was administered via PARI eFlow(®) rapid once daily and twice daily each for 8 weeks. Serum pharmacokinetics of these two regimens was analysed. Tobramycin levels were determined before the morning dose and at 30, 60 and 90 min after the end of nebulization in the middle and at the end of each 8 week cycle. At these timepoints, trough and peak serum tobramycin concentrations (Cmax, mg/L) as well as the area under the curve for 0-90 min of tobramycin (AUC0-90min) were assessed in order to evaluate the risk of systemic toxicity. Safety parameters and forced expiratory volume in 1 s (FEV1) were assessed. For once-daily treatment, tobramycin levels were 10% higher after 8 weeks compared with 4 weeks (AUC0-90min ratio = 1.096, 90% CI = 0.860-1.396, P = 0.5237). For twice-daily treatment, tobramycin levels after 8 weeks showed a 40% decrease compared with 4 weeks (AUC0-90min ratio = 0.608, 90% CI = 0.461-0.802, P = 0.0055). The AUC0-90min ratio at 8 weeks (once daily versus twice daily) did not differ significantly (AUC0-90min ratio = 0.749, 90% CI = 0.514-1.092, P = 0.2009). The mean FEV1 did not differ markedly compared between treatment periods or with baseline. No audiological or nephrotoxic side effects were noted. Continuous treatment with TIS (once daily or twice daily) over 8 weeks appears to be safe and tolerable.

Efficacy and tolerability of a new nasal spray formulation containing hyaluronate and tobramycin in cystic fibrosis patients with bacterial rhinosinusitis

BackgroundChronic rhinosinusitis is common in cystic fibrosis (CF), as CFTR defects equally affect the airway and sinonasal mucosa. However, therapeutic strategies for CF-associated chronic rhinosinusitis lag behind current approaches for pulmonary disease. ObjectiveTo assess the tolerability and efficacy of a nasal spray formulation containing 0.2% sodium hyaluronate and 3% tobramycin compared to a control formulation containing 0.2% sodium hyaluronate alone in the treatment of bacterial rhinosinusitis in patients with CF. MethodsIn a double-blind controlled study, 27 patients with an established diagnosis of CF and a documented nasal infection with Pseudomonas aeruginosa and/or Staphylococcus aureus [22 males (81%), median age of 15years (range 5–26yrs)], were randomized to receive the nasal spray formulation containing hyaluronate and tobramycin (N=14) or hyaluronate alone (N=13) for 14days. Efficacy and local tolerability of the treatments were assessed by ear, nose and throat (ENT) examination and related symptoms. ResultsThe formulation containing hyaluronate and tobramycin was more effective than hyaluronate alone in improving the status of the nasal mucosa, in reducing the mucopurulent secretion at the level of the osteomeatal complex and in improving ENT symptoms (hyposmia/anosmia and headache/facial pain). The treatment was well tolerated without relevant side effects. ConclusionsThe present study suggests that the combination therapy with hyaluronate plus tobramycin was more effective than hyaluronate alone in the treatment of bacterial rhinosinusitis in CF. Trial registration number: EudraCT 2007-003628-39.

83* Sinonasal inhalation of tobramycin in cystic fibrosis patients with P. aeruginosa colonization of the upper airways – results of a multicentric placebo-controlled pilot study

83* Sinonasal inhalation of tobramycin in cystic fibrosis patients with P. aeruginosa colonization of the upper airways – results of a multicentric placebo-controlled pilot study

No hearing loss after repeated courses of tobramycin in cystic fibrosis patients

Conclusion: Our results indicate that repeated treatment courses with tobramycin 10 mg/kg (twice daily for 3 weeks) may be safely applied in cystic fibrosis (CF) patients with respect to ototoxicity. The risk of hearing loss in this patient group is less than expected, which could be explained by either unfavourable baseline audiometry or the use of unidentified protective medication, or both. However, due to large inter-individual variations, audiometry screening remains important with respect to the detection of individual outliers. Objectives: Tobramycin is frequently prescribed for CF patients. In this study, hearing loss due to cumulative tobramycin exposure in adult CF patients was investigated. Patients and methods: We retrospectively investigated 19 patients with both baseline and follow-up audiometry before and after repeated courses of intravenous tobramycin (10 mg/kg/day in twice daily administrations for 3 weeks). Pure tone audiometry was performed at 0.250–16 kHz. Results: After repeated courses of tobramycin (median 3, range 1–8), the mean increase per frequency was 2.1 dB (median 0.5 dB, SD 12.6) with large (inter-individual) variations (range –23.5 to 34.5 dB). The pure tone averages (PTA) at 1-2-4 kHz and 8-10-12 kHz increased 1.4 dBHL and 2.3 dBHL, respectively, but were neither statistically significant, nor correlated with the cumulative tobramycin exposure.

No hearing loss after repeated courses of tobramycin in cystic fibrosis patients

No hearing loss after repeated courses of tobramycin in cystic fibrosis patients

Vestibulotoxicity as a consequence of systemically administered tobramycin in cystic fibrosis patients

Conclusion. The reported prevalence of vestibulotoxicity (30.4%) in cystic fibrosis (CF) patients supports vestibulotoxicity screening in CF patients during or after tobramycin exposure. Prospective longitudinal investigation is required for a more specific evidence-based proposal. Objective. To investigate the prevalence of tobramycin-induced vestibulotoxicity in CF patients, as it had not been investigated before. Patients and methods. In this observational cohort study, 23 CF patient volunteers from the Haga Teaching Hospital Adult CF centre who had been exposed to at least one treatment with systemically administered tobramycin were included. Subjective feelings of dizziness were measured using validated questionnaires and vestibular symptoms were assessed by physical examination. Electronystagmography (ENG) with caloric irrigation was used as the gold standard. Results. Peripheral vestibular loss was found in seven patients (7/23 = 30.4%). Central vestibular loss was found in one patient. Analysis of the 19 completed questionnaires showed that 12 patients (12/19 = 63.2%) did not experience dizziness and 3 patients (3/19 = 15/8%) experienced specific vestibular symptoms. The results of the questionnaire could not predict the results of ENG with caloric irrigation. Physical examination showed no abnormalities in any patients. No age- or dose-related predictive factors were found.

A Pilot Study to Compare Tobramycin 80 mg Injectable Preparation wth 300 mg Solution for Inhalation in Cystic Fibrosis Patients

Inhaled tobramycin has been shown to improve lung function in cystic fibrosis (CF) patients chronically infected with Pseudomonas aeruginosa. However, to date no comparative data are available for different dose regimens used in clinical practice. To compare the clinical efficacy of the two most commonly used treatment regimens of inhaled tobramycin in patients with CF. In an open crossover study of CF patients, subjects were randomly allocated to receive either 80 mg tobramycin twice-daily continuous treatment or 300 mg tobramycin twice daily in cycles of 28 days on and 28 days off treatment. After three months, patients were switched to the alternative treatment regimen. A total of 32 patients with a mean (+/- SD) age of 18.5+/-8.6 years were included in the study. Compared with the treatment period using colistin, forced expiratory volume in 1 s decreased by -2.1+/-13.8% in the 80 mg tobramycin group and increased by +2.3+/-13.0% in the 300 mg group. Similar changes were observed in forced vital capacity (-2.5+/-12.9% in the 80 mg tobramycin group versus +2.5+/-9.6% in the 300 mg tobramycin group). Variability in responses was large but the differences were not statistically significant. Personal preference indicated that the majority of patients preferred the high-dose cycle compared with the lower dose continuous inhalation, but this was not linked to objective data on efficacy. The present trial fails to provide convincing evidence for superiority in efficacy of either of the two treatment regimens of inhaled tobramycin in CF patients.

387 Vestibulotoxicity as a consequence of systemically administered tobramycin in Cystic Fibrosis patients

387 Vestibulotoxicity as a consequence of systemically administered tobramycin in Cystic Fibrosis patients

Laboratory parameter profiles among patients with cystic fibrosis

Background Clinical trials in cystic fibrosis (CF) currently use laboratory-specific reference ranges to evaluate chemistry and hematology measurements. Laboratory-specific normal reference ranges may not accurately reflect what is abnormal but clinically insignificant among CF patients. Methods To address this concern, data from the Phase III trial of inhaled tobramycin in CF patients was used to describe the distribution and variability of laboratory parameters. The laboratory specimens were analyzed at a central laboratory after being obtained at baseline and throughout the 24-week trial. Results At the time of entry into the clinical trial, 91% (463 of 508) of patients had at least a single value outside the normal range. Liver function tests (AST, ALT) were above the normal range in 16% and 12% of the patients respectively, with 2.4% of patients having an AST > 2.0 times the upper limit of normal. Of the 243 patients on placebo, 242 (99.6%) had at least one laboratory parameter that changed from normal to abnormal during the 24-week follow-up period. Of those same placebo patients, 11.5% ( N = 28) had a laboratory parameter change from a Common Toxicity Criteria (CTC) grade 0 to grade 2 or higher during follow-up. Conclusions Patients with CF frequently have laboratory values outside the normal range and have significant longitudinal variability of laboratory values. Interpretation of adverse events in the clinical trial setting may be complicated by the underlying high rates of some laboratory abnormalities in the CF population. This data was presented in poster format at the American Thoracic Society International Conference, Atlanta, USA, 2002, appearing subsequently in the Conference proceedings [Goss CH, Mayer-Hamblett N, Yunker A, Waltz DA, Kronmal RA, Ramsey BW. Laboratory parameter profiles among patients with cystic fibrosis. Am J Rep Crit Care Med 2002;165(8):A283].

Absence of Cochleotoxicity Measured by Standard and High-Frequency Pure Tone Audiometry in a Trial of Once- versus Three-Times-Daily Tobramycin in Cystic Fibrosis Patients

We undertook assessment of hearing in patients with cystic fibrosis who were taking part in a large randomized controlled trial of once- versus three-times-daily tobramycin for pulmonary exacerbations of cystic fibrosis (the TOPIC study). All patients were eligible to have standard pure tone audiometry performed across the frequency range of 0.25 to 8 kHz. High-frequency pure tone audiometry over 10 to 16 kHz was also performed with a subset of patients. Audiometry was undertaken at the start of tobramycin treatment, at the end of a 14-day course of treatment, and at follow-up 6 to 8 weeks later. We enrolled 244 patients, of whom 219 (125 children and 94 adults) completed treatment. Nineteen patients were excluded from analysis due to abnormal baseline audiometry. Complete pre- and posttreatment standard audiological data were obtained for 168/219 patients. We found no significant differences in hearing thresholds when they were assessed at the baseline, at the end of treatment, and at follow-up 6 to 8 weeks later were compared. In addition, no significant differences in hearing thresholds were detected between treatment regimens. Similar results were obtained for the subset of 63/168 patients who underwent high-frequency audiometry. We conclude that for a single 14-day course of tobramycin treatment in patients with cystic fibrosis with no preexisiting auditory deficit, no measurable effect on hearing was apparent with either once- or three-times-daily treatment. Estimation of the cumulative cochleotoxic risk in cystic fibrosis patients due to repeated aminoglycoside therapy, as evidenced by the patients excluded from this study due to hearing loss, also requires further characterization.

The Effect of Intermittent Inhaled Tobramycin on Microbial Flora

Two randomized, controlled trials have compared inhaled tobramycin in cystic fibrosis patients who continued to receive standard care. Together, 520 patients were enrolled over a six-month period for 28-day cycles on and off study drug. When compared with placebo, intermittent inhaled tobramycin appeared to safely improve lung function, decrease …

Suggestions for the Optimization of the Initial Tobramycin Dose in Adolescent and Adult Patients with Cystic Fibrosis

Clinical pharmacokinetic data of intravenously administered tobramycin in 34 patients with cystic fibrosis (CF) were correlated with patient parameters. Patients began tobramycin therapy with 10 mg/kg/day in three divided doses. Peak and trough serum concentrations were measured. Tobramycin dose was adjusted to a 30 min postdose peak of 10 mg/L and a predose trough of 1 mg/L. Pharmacokinetic data were calculated according to a one-compartment open model and were correlated with clinical data. Tobramycin half-life and total body clearance did not correlate with age, actual body weight, lean body mass, height, or body surface area. Tobramycin volume of distribution correlated with actual body weight (p < 0.02), lean body mass (p < 0.002), height (p < 0.05), and body surface area (p < 0.01), but not with age. The required daily dose after adjustment to a peak serum concentration of 10 mg/L and a trough level of 1 mg/L correlated with lean body mass (p < 0.02) and body surface area (p < 0.05). Based on our findings, the initial daily dose of tobramycin in patients with CF should be calculated by lean body mass rather than actual body weight or body surface area. A formula is presented to calculate the initial daily dose of tobramycin in CF patients who have normal renal function. Monitoring of tobramycin serum levels remains, however, necessary.