Tobramycin Therapy Research Articles

Mutations Affecting Cellular Levels of Cobalamin (Vitamin B12) Confer Tolerance to Bactericidal Antibiotics in Burkholderia cenocepacia.

The Burkholderia cepacia complex (Bcc) consists of opportunistic pathogens known to cause pneumonia in immunocompromised individuals, especially those with cystic fibrosis. Treating Bcc pneumonia is challenging due to the pathogens' high multidrug resistance. Therefore, inhalation therapy with tobramycin powder, which can achieve high antibiotic concentrations in the lungs, is a promising treatment option. In this study, we investigated potential mechanisms that could compromise the effectiveness of tobramycin therapy. By selecting for B. cenocepacia survivors against tobramycin, we identified three spontaneous mutations that disrupt a gene encoding a key enzyme in the biosynthesis of cobalamin (Vitamin B12). This disruption may affect the production of succinyl-CoA by methylmalonyl-CoA mutase, which requires adenosylcobalamin as a cofactor. The depletion of cellular succinyl-CoA may impact the tricarboxylic acid (TCA) cycle, which becomes metabolically overloaded upon exposure to tobramycin. Consequently, the mutants exhibited significantly reduced reactive oxygen species (ROS) production. Both the wild-type and mutants showed tolerance to tobramycin and various other bactericidal antibiotics under microaerobic conditions. This suggests that compromised ROS-mediated killing, due to the impacted TCA cycle, underlies the mutants' tolerance to bactericidal antibiotics. The importance of ROS-mediated killing and the potential emergence of mutants that evade it through the depletion of cobalamin (Vitamin B12) provide valuable insights for developing strategies to enhance antibiotic treatments of Bcc pneumonia.

Does Sample Size, Sampling Strategy, or Handling of Concentrations Below the Lower Limit of Quantification Matter When Externally Evaluating Population Pharmacokinetic Models?

Precision dosing requires selecting the appropriate population pharmacokinetic model, which can be assessed through external evaluations (EEs). The lack of understanding of how different study design factors influence EE study outcomes makes it challenging to select the most suitable model for clinical use. This study aimed to evaluate the impact of sample size, sampling strategy, and handling of concentrations below thelowerlimit of quantification (BLQ) on the outcomes of EE for four population pharmacokinetic models using vancomycin and tobramycin as examples. Three virtual patient populations undergoing vancomycin or tobramycin therapy were simulated with varying sample size and sampling scenarios. The three approaches used to handle BLQ data were to (1) discard them, (2) impute them as LLOQ/2, or (3) use a likelihood-based approach. EEs were performed with NONMEM and R. Sample size did not have an important impact on the EE results for a given scenario. Increasing the number of samples per patient did not improve predictive performance for two out of the three evaluated models. Evaluating a model developed with rich sampling did not result in better performance than those developed with regular therapeutic drug monitoring. A likelihood-based method to handle BLQ samples impacted the outcomes of the EE with lower bias for predicted troughs. This study suggests that a large sample size may not be necessary for an EE study, and models selected based on TDM may be more generalizable. The study highlights the need for guidelines for EE of population pharmacokinetic models for clinical use.

Mutations in the efflux pump regulator MexZ shift tissue colonization by Pseudomonas aeruginosa to a state of antibiotic tolerance

Mutations in mexZ, encoding a negative regulator of the expression of the mexXY efflux pump genes, are frequently acquired by Pseudomonas aeruginosa at early stages of lung infection. Although traditionally related to resistance to the first-line drug tobramycin, mexZ mutations are associated with low-level aminoglycoside resistance when determined in the laboratory, suggesting that their selection during infection may not be necessarily, or only, related to tobramycin therapy. Here, we show that mexZ-mutated bacteria tend to accumulate inside the epithelial barrier of a human airway infection model, thus colonising the epithelium while being protected against diverse antibiotics. This phenotype is mediated by overexpression of lecA, a quorum sensing-controlled gene, encoding a lectin involved in P. aeruginosa tissue invasiveness. We find that lecA overexpression is caused by a disrupted equilibrium between the overproduced MexXY and another efflux pump, MexAB, which extrudes quorum sensing signals. Our results indicate that mexZ mutations affect the expression of quorum sensing-regulated pathways, thus promoting tissue invasiveness and protecting bacteria from the action of antibiotics within patients, something unnoticeable using standard laboratory tests.

Personalized tobramycin dosing in children with cystic fibrosis: a comparative clinical evaluation of log-linear and Bayesian methods.

Children with cystic fibrosis (CF) pulmonary exacerbations receive IV tobramycin therapy, with dosing guided by either log-linear regression (LLR) or Bayesian forecasting (BF). To compare clinical and performance outcomes for LLR and BF. A quasi-experimental intervention study was conducted at a tertiary children's hospital. Electronic medical records were extracted (from January 2015 to September 2021) to establish a database consisting of pre-intervention (LLR) and post-intervention (BF) patient admissions and relevant outcomes. All consecutive patients treated with IV tobramycin for CF pulmonary exacerbations guided by either LLR or BF were eligible. A total of 376 hospital admissions (LLR = 248, BF = 128) for CF pulmonary exacerbations were included. Patient demographics were similar between cohorts. There were no significant differences found in overall hospital length of stay, rates of re-admission within 1 month of discharge or change in forced expiratory volume in the first second (Δ FEV1) at the end of tobramycin treatment. Patients treated with LLR on average had twice the number of therapeutic drug monitoring (TDM) blood samples collected during a single hospital admission. The timeframe for blood sampling was more flexible with BF, with TDM samples collected up to 16 h post-tobramycin dose compared with 10 h for LLR. The tobramycin AUC0-24 target of ≥100 mg/L·h was more frequently attained using BF (72%; 92/128) compared with LLR (50%; 124/248) (P < 0.001). Incidence of acute kidney injury was rare in both groups. LLR and BF result in comparable clinical outcomes. However, BF can significantly reduce the number of blood collections required during each admission, improve dosing accuracy, and provide more reliable target concentration attainment in CF children.

Effectiveness of different eradication treatment protocols for new-onset Pseudomonas aeruginosa in children with cystic fibrosis.

While eradicating new-onset Pseudomonas aeruginosa in children with cystic fibrosis is an important issue, there is no clear evidence about the best treatment approach. This retrospective observational cohort study aims to compare the effectiveness of intravenous therapy versus inhalation with/without oral therapy in the eradication of new-onset P. aeruginosa, determine the factors affecting the treatment success and assess lung function at baseline and posttreatment. Of 399 children, 110 (140 episodes) with either the first P. aeruginosa isolation or a new isolation after at least 1 year free of infectionwere included. Different eradication regimens (intravenous therapy or inhaled tobramycin or inhaled tobramycin plus oral ciprofloxacin) were compared. Eradication success was accepted as remaining free of infection with a negative culture for 12 months. Demographic, clinical, and microbiological characteristics of children, effectiveness of different eradication strategies, time to a new P. aeruginosa isolation, and the relationship between lung function and the type of eradication regimen were determined. Of 140 episodes, intravenous therapy was administered in 53 and inhalation therapy (in combination with or without oral ciprofloxacin) in 87. Total success rate of eradication was 60.7%. Eradication was achieved in 56.6% of children with intravenous therapy, 59.7% with inhaled tobramycin therapy, and 72% with inhaled tobramycin plus oral ciprofloxacin therapy. Success rates of different eradication regimens did not differ significantly (p = 0.419). Lung function by the end of the first year was worse in the intravenous group compared to the inhalation group (p = 0.017 for forced expiratory volume in 1 s, p = 0.015 for forced vital capacity). No advantage of intravenous therapy was demonstrated compared to inhalation therapy in terms of eradication success.

Assessment of Detectable Serum Tobramycin Concentrations in Patients Receiving Inhaled Tobramycin for Ventilator-Associated Pneumonia.

Inhaled tobramycin can be used for empiric or definitive therapy of ventilator-associated pneumonia (VAP) in mechanically ventilated patients. This is believed to minimize systemic exposure and potential adverse drug toxicities including acute kidney injury (AKI). However, detectable serum tobramycin concentrations have been reported after inhaled tobramycin therapy with AKI. This retrospective, observational study evaluated mechanically ventilated adult subjects admitted to ICUs at a large, urban academic medical center that received empiric inhaled tobramycin for VAP. Subjects were separated into detectable (ie, ≥ 0.6 mg/L) or undetectable serum tobramycin concentration groups, and characteristics were compared. Independent predictors for detectable serum tobramycin concentration and new onset AKI during or within 48 h of therapy discontinuation were assessed. Fifty-nine inhaled tobramycin courses in 53 subjects were included in the analysis, of which 39 (66.1%) courses administered to 35 (66.0%) subjects had detectable serum tobramycin concentrations. Subjects with detectable serum tobramycin concentrations were older (57.1 y ± 11.4 vs 45.9 ±15.0, P = .004), had higher PEEP (9.2 cm H2O [7.0-11.0] vs 8.0 [5.6-8.9], P = .049), chronic kidney disease stage ≥ 2 (10 [29.4%] vs 0 [0%], P = .009), and higher serum creatinine before inhaled tobramycin therapy (1.26 mg/dL [0.84-2.18] vs 0.76 [0.47-1.28], P = .004). Age (odds ratio 1.09 [95% CI 1.02-1.16], P = .009) and PEEP (odds ratio 1.47 [95% CI 1.08-2.0], P =.01) were independent predictors for detectable serum tobramycin concentration. Thirty-seven subjects had no previous renal disease or injury, of which 9 (24.3%) developed an AKI. Sequential Organ Failure Assessment score (odds ratio 1.72 [95% CI 1.07-2.76], P = .03) was the only independent predictor for AKI. Detectable serum tobramycin concentrations were frequently observed in critically ill, mechanically ventilated subjects receiving empiric inhaled tobramycin for VAP. Subject age and PEEP were independent predictors for detectable serum tobramycin concentration. Serum monitoring and empiric dose reductions should be considered in older patients and those requiring higher PEEP.

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

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

Clinical and microbiological impact of inhaled tobramycin treatment on cystic fibrosis patients with Pseudomonas aeruginosa

Clinical and Microbiological Impact of Inhaled Tobramycin Treatment on Cystic Fibrosis Patients with Pseudomonas aeruginosa Francesca Dickhaus 1 , Mutasim Abu Hasan 2 , Elizabeth Tremblay 3 , Kenneth Klinker 4 , Kenneth Rand 5,6 Stacy G. Beal 5 1 University of Florida College of Medicine, Gainesville, Florida, USA 2 University of Florida College of Medicine, Department of Pediatrics, Pediatric Pulmonary and Allergy Division, Gainesville, Florida, USA 3 UF Health Shands Hospital, Department of Infection Control, Gainesville, Florida, USA 4 UF Health Shands Hospital, Department of Pharmacy Practice, Gainesville, Florida, USA 5 University of Florida College of Medicine, Department of Pathology, Immunology, and Laboratory Medicine, Gainesville, Florida, USA 6 University of Florida College of Medicine, Department of Internal Medicine, Division of Infectious Diseases and Global Medicine, Gainesville, Florida, USA ABSTRACT Objective: Patients’ with cystic fibrosis respiratory systems become colonized with pathogens as early as the first year of life. Some organisms are associated with a decline in pulmonary function and shortened survival, such as a mucoid strain of Pseudomonas aeruginosa (PA). Methods: We conducted a four year retrospective chart review study examining 158 pediatric and adult cystic fibrosis patients treated at an academic, tertiary care institution to compare patients treated by different antimicrobial regimens. Results: A higher proportion of mucoid PA study patients received alternate-monthly tobramycin therapy (83.3%), compared to those with non-mucoid PA (62.5%); although a large percentage of patients who had never had a mucoid PA infection were also receiving alternate-monthly tobramycin. Patients who had a mucoid PA infection had more hospitalizations and for longer periods of time than patients who had a non-mucoid PA infection; both mucoid and non-mucoid PA patients were hospitalized more often than patients who had never had a PA infection. We additionally found patients with mucoid PA infections to have strains that were either resistant or had intermediate resistance to tobramycin. Similar trends in resistance were not seen in patients who only received intermittent treatments with tobramycin. Conclusions Our findings on increased rates of infection with both Aspergillus (in the alternate-monthly inhaled tobramycin group) and NTM (in the overall patient population) comparative to international averages were also interesting, and open the doors to future research regarding CF patients with these infections. J Microbiol Infect Dis 2017; 7(4):178-185 Keywords: Cystic fibrosis, Pseudomonas, Tobramycin

Spatiotemporal pharmacodynamics of meropenem- and tobramycin-treated Pseudomonas aeruginosa biofilms

The selection and dose of antibiotic therapy for biofilm-related infections are based on traditional pharmacokinetic studies using planktonic bacteria. The objective of this study was to characterize the time course and spatial activity of human exposure levels of meropenem and tobramycin against Pseudomonas aeruginosa biofilms grown in an in vitro flow-chamber model. Pharmacokinetic profiles of meropenem and tobramycin used in human therapy were administered to GFP-labelled P. aeruginosa PAO1 grown in flow chambers for 24 or 72 h. Images were acquired using confocal laser scanning microscopy throughout antibiotic treatment. Bacterial biomass was measured using COMSTAT and pharmacokinetic/pharmacodynamic models were fitted using NONMEM7. Meropenem treatment resulted in more rapid and sustained killing of both the 24 and 72 h PAO1 biofilm compared with tobramycin. Biofilm regrowth after antibiotic treatment occurred fastest with tobramycin. Meropenem preferentially killed subpopulations within the mushroom cap of the biofilms, regardless of biofilm maturity. The spatial killing by tobramycin varied with biofilm maturity. A tobramycin-treated 24 h biofilm resulted in live and dead cells detaching from the biofilm, while treatment of a 72 h biofilm preferentially killed subpopulations on the periphery of the mushroom stalk. Regrowth occurred primarily on the mushroom caps. Combination meropenem and tobramycin therapy resulted in rapid and efficient killing of biofilm cells, with a spatial pattern similar to meropenem alone. Simulated human concentrations of meropenem and tobramycin in young and mature PAO1 biofilms exhibited differences in temporal and spatial patterns of killing and antibiotic tolerance development.

Urinary kidney injury biomarkers and tobramycin clearance among children and young adults with cystic fibrosis: a population pharmacokinetic analysis.

Tobramycin is frequently used for treatment of bronchopneumonia in patients with cystic fibrosis (CF). Variability in tobramycin clearance (CL) is high in this population with few reliable approaches to guide dosing. We sought to evaluate the pharmacokinetics of once-daily intravenous tobramycin in patients with CF and test the influence of covariates on tobramycin CL, including serum creatinine (SCr) and urinary biomarkers: neutrophil gelatinase-associated lipocalin (NGAL), retinol-binding protein (RBP) and kidney injury molecule-1 (KIM-1). This was a prospective, observational cohort study of children/young adults with CF receiving once-daily intravenous tobramycin from October 2012 to May 2014 at Cincinnati Children's Hospital Medical Center. Therapeutic drug monitoring data were prospectively obtained. Population pharmacokinetic analyses were performed using non-linear mixed-effects modelling. Thirty-seven patients (median age 15.3 years, IQR 12.7-19.5) received 62 tobramycin courses. A one-compartment model with allometrically scaled weight for tobramycin CL and volume of distribution (V) best described the data. Urinary NGAL was associated with tobramycin CL (P < 0.001), as was urinary RBP (P < 0.001). SCr, estimated glomerular filtration rate and urinary KIM-1 were not significant covariates. The population pharmacokinetic parameter estimates were CL = 8.60 L/h/70 kg (relative standard error 4.3%) and V = 31.3 L/70 kg (relative standard error 4.7%). We describe urinary biomarkers as predictors of tobramycin CL using a population pharmacokinetic modelling approach. Our findings suggest that patient weight and urinary NGAL or RBP could be used to individualize tobramycin therapy in patients with CF.

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.

The pharmacokinetics and toxicity of morning vs. evening tobramycin dosing for pulmonary exacerbations of cystic fibrosis: A randomised comparison

BackgroundCircadian variation in renal toxicity of aminoglycosides has been demonstrated in animal and human studies. People with CF are frequently prescribed aminoglycosides. Altered pharmacokinetics of aminoglycosides are predictive of toxicity. AimTo investigate whether the time of day of aminoglycoside administration modulates renal excretion of tobramycin and toxicity in children with CF. To determine whether circadian rhythms are disrupted in children with CF during hospital admission. MethodsChildren (age 5–18years) with CF scheduled for tobramycin therapy were randomly allocated to receive tobramycin at 0800 or 2000h. Serum tobramycin levels were drawn at 1h and between 3.5 and 5h post-infusion between days 5 and 9 of therapy. Melatonin levels were measured serially at intervals from 1800h in the evening until 1200h on the next day. Circadian rhythm was categorised as normal when dim light melatonin onset was demonstrated between 1800 and 2200h and/or peak melatonin levels were observed during the night. Weight and spirometry were measured at the start and end of the therapy. Urinary biomarkers of kidney toxicity (KIM1, NAG, NGAL, IL-18 and CysC) were assayed at the start and end of the course of tobramycin. ResultsEighteen children were recruited to the study. There were no differences in renal clearance between the morning and evening groups. The increase in urinary KIM-1 was greater in the evening dosage group compared to the morning group (mean difference, 0.73ng/mg; 95% CI, 0.14 to 1.32; p=0.018). There were no differences in the other urinary biomarkers. There was normal circadian rhythm in 7/11 participants (64%). ConclusionsRenal elimination of tobramycin was not affected by the time of day of administration. Urinary KIM-1 raises the possibility of greater nephrotoxicity with evening administration. Four children showed disturbed circadian rhythm and high melatonin levels (ClinicalTrials.gov NCT01207245).

トブラマイシン吸入療法で人工呼吸器離脱が可能となった難治性緑膿菌気道感染の1例

トブラマイシン吸入療法で人工呼吸器離脱が可能となった難治性緑膿菌気道感染の1例

Comparing dosage adjustment methods for once-daily tobramycin in paediatric and adolescent patients with cystic fibrosis.

Several dosage adjustment methods are currently available to individualize intravenous tobramycin dosing. This study compared different methods in terms of their recommendations for dosage adjustment, their estimation of patients' pharmacokinetic parameter values and their ability to predict subsequent observed tobramycin concentrations following once-daily tobramycin treatment in children and adolescents with cystic fibrosis. Retrospective data from 172 patients treated at the Royal Children's Hospital (Brisbane, QLD, Australia) were analysed. To be included in the analysis, each patient had to have at least one pair of tobramycin plasma concentration-time measurements recorded over a dosing interval. One or both of the concentrations in the paired set were applied in each of the following dosage adjustment methods: (i) the Therapeutic Guidelines Aminoglycoside nomogram; (ii) the Massie nomogram; (iii) log-linear regression analysis; and two Bayesian forecasting software programs: (iv) TCIWorks and (v) DoseMe. All methods were compared in regard to their recommendations for tobramycin dosage adjustment. The latter three methods were also examined in terms of estimated pharmacokinetic parameter values and their ability to predict subsequent observed tobramycin concentrations. The Therapeutic Guidelines nomogram recommended significantly greater mean doses for dosage adjustment (27.0 mg/kg) compared with all other methods (p ≤ 0.01), which gave similar mean dose recommendations (11.6-14.6 mg/kg); however, >20 % differences in doses on an individual level were seen on 20-35 % of occasions across all methods. The log-linear regression analysis method and the two Bayesian forecasting methods (TCIWorks and DoseMe) showed negligible bias but imprecision of around 20 % in predicting subsequent observed tobramycin concentrations. The Bayesian forecasting methods showed no significant difference in mean dose recommendations when using either one or two concentration measurements but increased imprecision in predicting subsequent observed tobramycin concentrations. The log-linear regression method and Massie nomogram are likely to be suitable alternative methods for tobramycin dosage adjustment when Bayesian forecasting software is unavailable. The Therapeutic Guidelines nomogram should not be used to aid dose adjustment of tobramycin therapy in children with cystic fibrosis.

Implant-associated infection after major orthopaedic surgery: biofilm production of staphylococci

Background:Aminoglycosides are commonly used in the treatment of infective endocarditis (IE). Because of it′s nephrotoxic potential it′s place in the treatment arsenal is currently being debated.What is the potential risk of giving short-term therapy ( 2500mg tobramycin implicated a decreased reversibility of eGFR during 1-year F/U. Concomitant vancomycin + tobramycin therapy caused a 19% loss in eGFR while no reduction followed sequential vancomycin + tobramycin therapy. Patients with an initial eGFR 2500mg tobramycin therapy caused a decreased reversibility during 1-year F/U, while short-term therapy<10 days had no impact on long-term kidney function.

Safety of inhaled (Tobi®) and intravenous tobramycin in young children with cystic fibrosis

BackgroundUse of inhaled tobramycin therapy for treatment of Pseudomonas aeruginosa infections in young children with cystic fibrosis (CF) is increasing. Safety data for pre-school children are sparse. MethodsThe aim of this study was to assess the safety of tobramycin solution for inhalation (TOBI®-TSI) administered twice daily for 2months/course concurrently to intravenous (IV) tobramycin during P. aeruginosa eradication therapy in children (0–5years). Audiological assessment and estimation of glomerular filtration rate (GFR) was measured prior to any exposure and end of the study. ResultsData were available from 142 patients who were either never exposed to aminoglycosides (n=39), exposed to IV aminoglycosides only (n=36) or exposed to IV+TSI (n=67). Median exposure to TSI was 113days [59, 119]. Comparison of effects on audiometry results and GFR, showed no detectable difference between the groups. ConclusionsUse of TSI and IV tobramycin in pre-school children with CF was not associated with detectable renal toxicity or ototoxicity.

Pharmacodynamic target attainment with high-dose extended-interval tobramycin therapy in patients with cystic fibrosis

Utilization of high-dose extended-interval aminoglycoside therapy (HEAT) in patients with cystic fibrosis (CF) is supported by primary literature and national guidelines. We sought to evaluate the effectiveness of a local aminoglycoside guideline to achieve pharmacodynamic goals in patients with CF that received ≧3 doses of HEAT from 2005 to 2011. Patients with renal dysfunction at baseline, status-post-lung transplant, or receiving inhaled tobramycin were excluded. In the 282 patient admissions, the average initial tobramycin dose was 10·3 mg/kg with an average initial peak of 21·5 mg/l. At least one dose titration was seen in 39% of patients. Patients who achieved the pharmacodynamic goal received a higher dose (10·4 mg/kg versus 9·7 mg/kg; P<0·001). A mean starting dose of tobramycin at 10·3 mg/kg every 24 hours achieved an average peak above goal. Higher initial dosing resulted in a higher likelihood of achieving the pharmacodynamic goal.

Effectiveness of inhaled tobramycin in eradicating Pseudomonas aeruginosa in children with cystic fibrosis

Inhaled tobramycin therapy has been shown to be efficacious in clinical trials for the eradication of initial Pseudomonas aeruginosa infection in children with cystic fibrosis (CF). However, the effectiveness of different regimens in eradicating P. aeruginosa and preventing the development of chronic infection in actual clinical settings has yet to be determined. This was an observational study of children (<18 years of age) with CF with incident P. aeruginosa infection from 2005-2012 based on data collected from the Toronto CF Database and medical charts. Patients who received inhaled tobramycin (80 mg/2 ml twice daily for 365 days) were compared to those who received tobramycin inhalation solution (TIS) (300 mg/5 ml twice daily for 28 days) with respect to eradication and development of chronic infection. We also examined the risk factors for recurrence of infection. During the study period, 65 patients were identified with incident P. aeruginosa, of which 7 (11%) failed eradication therapy. Eradication failure was similar between the two treatment groups. A total of 4 patients (6%) developed chronic P. aeruginosa infection in the 12 months following the end of therapy with no differences between treatment groups. Female gender, older age, pancreatic insufficiency, lower lung function and worse nutritional status were identified as risk factors for recurrence of P. aeruginosa infection. Both regimens of inhaled tobramycin have similar effectiveness in eradicating P. aeruginosa and preventing chronic P. aeruginosa infection in CF patients in clinical practice. Further work is needed, however, to identify patient characteristics and bacterial factors that play a role in eradication failure, in order to develop more effective antimicrobial rescue treatment strategies.

Tobramycin Disposition in the Rat Lung Following Airway Administration

A realistic ex vivo model, the isolated perfused rat lung (IPRL), was used to investigate tobramycin's pulmonary disposition at typical therapeutic concentrations. Different nominal doses were administered in aqueous solution to the airways alongside nonbinding absorption markers, fluorescein and mannitol. The mean fraction of each administered dose reaching the perfusate (Fp) was determined as a function of time following administration. Dynamic dialysis was also used to quantify the kinetics of tobramycin binding and/or tissue retention in the IPRL immediately after drug administration. Whereas the absorption markers fluorescein and mannitol both showed monoexponential dose-independent increases in Fp with time, tobramycin's pulmonary absorption into the perfusate was biexponential and dose-dependent due to tissue binding or retention. Best estimates for the first-order rate constants of tobramycin absorption appeared dose-independent (0.065-0.070 min(-1)), with values close to the mean for fluorescein (0.076 min(-1)). The rate constant for dissociation from IPRL tissue was also relatively constant (0.018-0.022 min(-1)), whereas that for association decreased from 0.16 to 0.07 min(-1) with increasing airway dose from 0.002 to 2 mg. Dynamic dialysis data from sliced IPRL tissue following identical airway administration were consistent with those from the intact IPRL, confirming tobramycin's "slow on, slow off" binding and sequestration by the rat lung. Overall, tobramycin absorption was fast following airway administration. However, dose- and concentration-dependent slow-onset tissue binding extended the duration of tobramycin's presence in the rat lung. These findings may explain, in part, the apparent success of inhaled tobramycin therapy when treating pulmonary infections.

P71 DAPTOMYCIN IN CARDIOVASCULAR IMPLANTABLE ELECTRONIC DEVICE (CIED) ENDOCARDITIS

tobramycin, 41% also received vancomycin. Kidney function was assessed by estimated glomerular filtration rate (eGFR), recorded prior to treatment, weekly during treatment, and 1 month, 3 months, and 1 year after IE treatment. Therewas ameandecrease of eGFR from88.4 to 78.0mL/min (−11.8%) from start of tobramycin treatment to 1 week post-treatment. The decrease was accentuated 1 month post-treatment (−12.4%). A gradual reversibility was recorded 3 months (−7.4%) and one year (−6.3%) post-treatment, respectively. Age, total dose of tobramycin, cardiac surgery, concomitant treatment with potential renal toxic drugs, concomitant vancomycin treatment, and elevated serum tobramycin concentrations were associated with accentuated in-hospital decrease in eGFR. Major risk factors for permanent decrease in kidney function were established after subgroup analyses of comparable groups. A total dose of >2500mg tobramycin implicated a decreased reversibility of eGFR during 1-year F/U. Concomitant vancomycin + tobramycin therapy caused a 19% loss in eGFR while no reduction followed sequential vancomycin + tobramycin therapy. Patients with an intial eGFR 2500mg tobramycin caused a decreased reversibility during 1-year F/U, while short-term therapy <10 days had no impact on long-term kidney function.