Tobramycin In Patients Research Articles

Comparing the Efficacy and Safety of Nebulized Gentamicin Plus Amikacin versus Tobramycin in Patients with Cystic Fibrosis.

Cystic fibrosis is an autosomal recessive disease that causes respiratory tract infection. These patients use nebulized antibiotics such as tobramycin and gentamicin plus amikacin. Due to the high price of tobramycin and the inaccessibility of this drug in Iran at different periods, we aimed to compare the efficacy and safety of nebulized plus amikacin and tobramycin in patients with cystic fibrosis. In this analytic cross-sectional study, data were collected from the records of all patients with cystic fibrosis. They were divided into two groups by their type of nebulized antibiotic. Group 1 included 41 patients who received 80 mg gentamicin and 500 mg amikacin as a nebulized antibiotic every other month, whereas, group 2 consisted of 9 patients who received 300 mg nebulized tobramycin. Collected data were pulmonary function parameters, body mass index, the frequency of hospitalization, infection progress, Shwachman-Kulczycki score, and renal complications. The data were compared in terms of efficacy and renal adverse effects by independent t-test and repeated measure ANOVA. A total of 50 cystic fibrosis patients were evaluated and there was no significant difference between group 1 and group 2 in terms of pulmonary function, frequency of hospitalizations, body mass index, Shwachman-Kulczycki score, infection progress, and renal complications. Notably, pulmonary function factors were reduced in both groups over time during their treatment. Nebulized tobramycin and gentamicin plus amikacin had similar efficacy against Pseudomonas aeruginosa in cystic fibrosis and had no serious renal complications.

A prospective phase IIA multicenter double-blinded randomized placebo-controlled clinical trial evaluating the efficacy and safety of inhaled Tobramycin in patients with ventilator-associated pneumonia (iToVAP)

ObjectiveTreatment of ventilated pneumonia is often unsuccessful, even when patients are treated according to current guidelines. Therefore, we aimed to investigate the efficacy of the adjunctive inhaled Tobramycin in patients with pneumonia caused by Gram-negative pathogens in addition to the standard systemic treatment. DesignProspective, multicenter, double-blinded, randomized, placebo-controlled clinical trial. Setting26 patients in medical and surgical ICUs. PatientsPatients with ventilator-associated pneumonia caused by Gram-negative pathogens. Measurement and main resultsFourteen patients were assigned to the Tobramycin Inhal group and 12 patients to the control group. The microbiological eradication of the Gram-negative pathogens was significantly higher in the intervention group than in the control group (p < 0.001). The probability of eradication was 100% in the intervention group [95% Confidence Interval: 0.78–1.0] and 25% in the control group [95% CI: 0.09–0.53]. The increased eradication frequency was not associated with increased patient survival. ConclusionInhaled aerosolized Tobramycin demonstrated clinically meaningful efficacy in patients with Gram-negative ventilator-associated pneumonia. The probability of eradication in the intervention group was 100%. However, the successful eradication was not associated with a reduction in systemic anti-infective therapy, a shorter ICU stay, or even a survival benefit. In the presence of multidrug-resistant Gram-negative pathogens that are sensitive only to colistin and/or aminoglycosides, supplemental inhaled therapy with nebulizers suitable for this purpose should be considered in addition to systemic antibiotic therapy.

Evaluation of Inhaled Tobramycin in Early Eradication of Pseudomonas aeruginosa in Infants With Cystic Fibrosis.

Early antibiotic therapy has the potential to eradicate initial Pseudomonas aeruginosa infection and postpone chronic infection. There are limited data evaluating the efficacy and safety of inhaled tobramycin in patients with cystic fibrosis (CF) who are younger than 1 year. The objective of this study was to evaluate the effectiveness of inhaled tobramycin in early eradication of P aeruginosa in infants with CF. This retrospective study evaluated patients with CF younger than 1 year with first time infection with P aeruginosa. The primary outcome was the frequency of P aeruginosa eradication. Secondary outcomes were sustained culture negativity at 12 and 18 months and safety assessments. Of 18 patients included in the study, 9 received inhaled tobramycin and an enteral fluoroquinolone and 9 received inhaled tobramycin alone. Microbiologic clearance of respiratory cultures was observed in 83% patients at end of therapy and 78% of patients at 1 month posttherapy. Eradication of P aeruginosa was observed in 56% of patients at 6 months posttreatment with sustained culture negativity observed in 39% of patients up to 18 months. Inhaled-tobramycin therapy is effective in early eradication of P aeruginosa infection and is well tolerated in infants younger than 1 year.

Monitoring of tobramycin serum concentrations in selected critically ill patients receiving selective decontamination of the digestive tract: a retrospective evaluation.

Selective decontamination of the digestive tract (SDD) is a strategy in mechanically ventilated patients to reduce mortality. Treatment consists of enterally administered non-absorbable antibiotics, i.e., tobramycin. However, most intensive care unit (ICU) patients with SDD appear to have detectable tobramycin serum concentrations. The Rijnstate Hospital implemented a protocol for therapeutic drug monitoring (TDM) of tobramycin in patients at risk. The aim of this study was to evaluate the necessity of TDM in these patients and to optimize the current protocol. This retrospective observational study included ICU patients with SDD treatment for ≥ 7days and renal failure. These patients were considered eligible for monitoring of tobramycin. Tobramycin serum concentrations, relevant laboratory parameters (i.e., renal function, lactate), and patient data were extracted from the National Intensive Care Evaluation database and the hospital electronic patient data system. In 23 subjects, a total of 43 tobramycin serum concentrations was determined. The median tobramycin serum concentration was 0.33 (IQR 0.17-0.49) mg/L of which 12 (27.9%) samples had concentrations < 0.2mg/L, 30 (69.8%) had concentrations 0.2-1.0mg/L and 1 (2.3%) had a toxic concentration > 1.0mg/L. In 3 (7.0%) cases, an intervention was conducted based on the tobramycin serum concentration. The majority (83.7%) of samples had detectable tobramycin serum concentrations. Monitoring of tobramycin serum concentrations can be considered necessary in patients at risk. However, the current protocol should be optimized to intercept patients more precise.

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.

Early administration of inhaled tobramycin in patients with severe multiple trauma

The aim of this study was to investigate efficacy and safety of early supplemental administration of inhaled tobramycin for prevention and treatment of hospital-acquired pneumonia (HAP) in patients with severe multiple trauma. Methods. Fifty four patients with severe multiple trauma were divided into 2 groups: the study group (n = 27) who took inhaled tobramycin added to systemic antibiotics and the control group (n = 27) who took standard systemic antibacterial treatment. Baselines characteristics did not differ between the groups. The patients' status was assessed daily using APACHE II and CPIS scales. Results. Frequency of HP in the study group was as twice as rare compared to the controls with correspondent reduction in days in ICU. The groups did not differ in mechanical ventilation parameters and frequency of sepsis. CPIS and APACHE II scores did not increase in the inhaled tobramycin group whereas CPIS total score increased and APACHE II score did not improve in the control group. To the 5 th day, significant between-group difference was found in CPIS (p = 0.0028) and APACHE-II (р = 0.0004). Conclusion. Early administration of inhaled tobramycin 600 mg daily added to the standard systemic antibacterial therapy is safe and effective in prevention and treatment of HAP in patients with severe multiple trauma. Such therapy decreased frequency of pulmonary infectious complications and significantly reduced duration of treatment in ICU.

Tobramycin exposure from active calcium sulfate bone graft substitute

BackgroundBone graft substitute such as calcium sulfate are frequently used as carrier material for local antimicrobial therapy in orthopedic surgery. This study aimed to assess the systemic absorption and disposition of tobramycin in patients treated with a tobramycin-laden bone graft substitute (Osteoset® T).MethodsNine blood samples were taken from 12 patients over 10 days after Osteoset® T surgical implantation. Tobramycin concentration was measured by fluorescence polarization. Population pharmacokinetic analysis was performed using NONMEM to assess the average value and variability (CV) of pharmacokinetic parameters. Bioavailability (F) was assessed by equating clearance (CL) with creatinine clearance (Cockcroft CLCr). Based on the final model, simulations with various doses and renal function levels were performed. (ClinicalTrials.gov number, NCT01938417).ResultsThe patients were 52 +/− 20 years old, their mean body weight was 73 +/− 17 kg and their mean CLCr was 119 +/− 55 mL/min. Either 10 g or 20 g Osteoset® T with 4% tobramycin sulfate was implanted in various sites. Concentration profiles remained low and consistent with absorption rate-limited first-order release, while showing important variability. With CL equated to CLCr, mean absorption rate constant (ka) was 0.06 h-1, F was 63% or 32% (CV 74%) for 10 and 20 g Osteoset® T respectively, and volume of distribution (V) was 16.6 L (CV 89%). Simulations predicted sustained high, potentially toxic concentrations with 10 g, 30 g and 50 g Osteoset® T for CLCr values below 10, 20 and 30 mL/min, respectively.ConclusionsOsteoset® T does not raise toxicity concerns in subjects without significant renal failure. The risk/benefit ratio might turn unfavorable in case of severe renal failure, even after standard dose implantation.

71 Pharmacokinetics of nasal administered tobramycin in patients with cystic fibrosis

Recent studies showed that the paranasal sinuses can constitute a niche for bacteria. To date no effective treatment for these bacteria is available. Off label administration of nasal antibiotics may be an option. However, first safety of this treatment has to be established. Objectives: With this pilot study in two patients the pharmacokinetic parameters of nasal administered tobramycin were investigated. Methods: In two hospitalised CF-patients, treated with intravenous tobramycin, after a wash-out period, 320 mg of tobramycin, dissolved in 200 ml isotonic saline, was administered to the nose using nasal lavage. Eleven venous blood samples were collected and with a Liquid Chromatography Tandem Mass Spectometer (LCMSMS) method, serum tobramycin concentrations were determined. Tobramycin pharmacokinetic parameters were calculated using the MW\Pharm software package. Systemic absorption was calculated by dividing AUC after nasal administration by AUC after intravenous administration corrected for the administered dose. Results: In patient 1, a female of 32 years old, the maximum concentration (Cmax) of tobramycin was 0.027 mg/L. This Cmax was reached 30 minutes after the nasal lavage with tobramycin (tmax). In total 0.20% (0.62 mg) of the tobramycin was systemically absorbed. In patient 2, a male of 36 years old, the Cmax was 0.029 mg/L. The tmax was 45 minutes and in total 0.16% (0.51 mg) of tobramycin was absorbed. Conclusion: Nasal lavage with 320 mg tobramycin did not result in toxic serum levels. The results of two patients showed a fast absorption of tobramycin and a slow elimination. Approximately 0.20% of the tobramycin was absorbed by the sinonasal mucosa.

Population Pharmacokinetics of Tobramycin in Patients With and Without Cystic Fibrosis

While several studies have examined the pharmacokinetics of tobramycin in patients with cystic fibrosis (CF), there is no consensus on whether they differ in patients with and without CF. The objectives of this study were to identify covariates which explain pharmacokinetic variability and to examine whether having the disease CF in itself alters these relationships and drug dose requirements. To investigate this issue, a population pharmacokinetic meta-analysis of data from eight centres was undertaken. NONMEM(®) 7.2 was used to analyse the data, which comprised 4,514 concentration-time measurements from 465 adults and children with CF and 1,095 concentration-time measurements from 267 adults and children without CF. Tobramycin disposition was well described by a two-compartment model with first-order elimination. Patient age, fat-free mass, serum creatinine concentration and sex were identified as significant covariates in the final model. Fat-free mass was superior to total bodyweight as a descriptor of clearance, volume of distribution of the central and peripheral compartments and inter-compartmental clearance. CF as an independent disease-specific factor had no significant influence on the pharmacokinetics of tobramycin at any stage during covariate model building. An optimal dose of 11 mg/kg every 24 h was defined for CF patients using a utility function approach. The pharmacokinetics of tobramycin do not differ significantly in CF patients compared with patients without CF when subject age, fat-free mass, sex and renal function are taken into consideration. Variations in tobramycin dosing between CF and non-CF patients should therefore reflect target concentrations or exposures based on differences in expected pathogen sensitivity and not the presence of CF.

Tobramycin pharmacokinetics in patients with cystic fibrosis before and after bilateral lung transplantation

To compare the pharmacokinetics (PK) of tobramycin in patients with cystic fibrosis (CF) before and after bilateral lung transplantation, in order to evaluate optimal dosing practices post transplant. Retrospective, single-center, chart review study, in which tobramycin concentrations from CF patients were used to calculate PK parameters, including elimination rate constant, half-life, volume of distribution (Vd), area under the curve (AUC), and clearance before and after lung transplantation. Medical school-affiliated teaching hospital. Eight patients with CF, who received a bilateral lung transplant from January 1, 2005 through August 1, 2009 (4 males, 4 females; mean age 26.3 years). None. Sixty-nine sets of pre- (n=52) and post transplant (n=17) tobramycin concentrations were available. PK parameters were significantly altered post transplant. Elimination rate constant decreased 38% from 0.26±0.1 to 0.16±0.1 h(-1) (P<0.001), with a related increase of 200% in half-life from 2.8±0.8 to 8.4±8.7 h (P<0.001). Clearance decreased 25% post transplant from 67.3±32.3 to 50.2±15.9 mL/min (P=0.04). No statistically significant change occurred in AUC or Vd after transplant, although a trend was seen toward increased Vd. Dosage requirements after transplantation were significantly lower, 10.7±2.5 and 7.6±1.6 mg/kg/day, pre and post transplant, respectively (P<0.001). Concentrations were also evaluated in 2 time periods: 0-3 weeks and ≥6 weeks post transplant, based on available data. Clearance and Vd ≥6 weeks post transplant did not significantly differ from pre-transplant values (P=0.28 and 0.54, respectively), suggesting that these changes may be temporary. The results suggest that tobramycin PK are altered in patients with CF after bilateral lung transplantation, although no clear trend was seen owing to inter-patient variability. We propose that PK parameters should be reassessed during each treatment course post transplant.

First experience of using nebulized tobramycin in patients with acute exacerbation of bronchiectasis

First experience of using nebulized tobramycin in patients with acute exacerbation of bronchiectasis.

Economic impact of tobramycin in patients with cystic fibrosis in a managed care population

Objective:Guidelines recommend chronic use of tobramycin solution for inhalation (TSI) for cystic fibrosis (CF) patients with moderate-to-severe lung disease and persistent airway Pseudomonas aeruginosa. This study evaluated the economic impact of TSI in managed care CF patients.Methods:Patients (0–64 years) with ≥2 CF medical claims between 01/01/04–03/31/09 were identified. For TSI users, the index date was the first TSI claim in the period; for non-users, a pseudo-index date was determined and randomly assigned by simulating the distribution of index dates of TSI users. Maximum sample size was obtained for patients with ≥3 months pre- and ≥12 months post-index eligibility. Users were categorized by number of TSI prescriptions filled during 12-month post-index period as low (1 fill), medium (2–3 fills) and high adherence (≥4 fills). Differences in per member per month (PMPM) costs pre-index to post-index were analyzed using paired t-tests.Results:A total of 388 TSI users (mean age 19 years, 48% female) and 444 non-users (mean age 30 years, 54% female) met study criteria. In users, total and CF-related PMPM costs decreased $959 (17%) and $113 (3%), respectively, after starting TSI. Among TSI users, CF-related inpatient PMPM costs decreased by $1171 (49%; p = 0.01), while CF-related prescription PMPM costs increased by $992 (p < 0.01). CF-related inpatient PMPM costs decreased by $381 (38%; p = 0.16) for low and $1425 (50%; p = 0.21) for medium users and decreased by $1829 (51%; p = 0.02) for high users.Limitations:Limitations include use of administrative claims data, small sample size due to disease rarity, random assignment of pseudo-index date to non-users and differences in baseline characteristics between TSI users and non-users.Conclusion:All-cause and CF-related PMPM medical costs significantly decreased after TSI initiation. Among TSI users, total healthcare costs decreased, although not significantly, due to PMPM increases in prescription costs. A trend towards greater decrease in inpatient PMPM costs was observed with increasing TSI adherence.

Deposição pulmonar de tobramicina inalatória antes e após fisioterapia respiratória e uso de salbutamol inalatório em pacientes com fibrose cística colonizados por Pseudomonas aeruginosa

To evaluate whether respiratory therapy followed by the use of inhaled albuterol modifies the pulmonary deposition of inhaled tobramycin in patients with cystic fibrosis (CF) and whether pulmonary deposition correlates with disease severity or genotype. A prospective study was carried out including patients with CF older than 6 years of age and colonized with Pseudomonas aeruginosa. Exclusion criteria were pulmonary exacerbation, changes in therapy between the study phases and FEV1 < 25%. All patients were submitted to pulmonary scintigraphy by means of a scintillation camera equipped with a low energy all purpose collimator in order to evaluate drug penetration following the administration of inhaled 99mTc-tobramycin, as well as to pulmonary perfusion with 99mTc-macroaggregated albumin (phase 1). One month later, the same procedure was performed following respiratory therapy and administration of inhaled albuterol (phase 2). We included 24 patients (12 males) aged 5-27 years (mean +/- SD: 12.85 +/- 6.64 years). The Shwachman score (SS) was excellent/good in 8 patients, moderate/fair in 16 and poor in 0. Genotyping revealed that 7 patients were DeltaF508 homozygotes, 13 were DeltaF508 heterozygotes; and 4 presented other mutations. In all patients, lung deposition of tobramycin decreased in phase 2, especially in those with moderate/fair SS (p = 0.017) and in heterozygotes (p = 0.043). The use of a respiratory therapy technique and the administration of inhaled albuterol immediately prior to the use of inhaled tobramycin decreased the pulmonary deposition of the latter in CF patients, and this reduction correlates with disease severity and genotype.

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.

Meropenem

Meropenem (Merrem, Meronem) is a broad-spectrum antibacterial agent of the carbapenem family, indicated as empirical therapy prior to the identification of causative organisms, or for disease caused by single or multiple susceptible bacteria in both adults and children with a broad range of serious infections. Meropenem is approved for use in complicated intra-abdominal infection (cIAI), complicated skin and skin structure infection (cSSSI) and bacterial meningitis (in paediatric patients aged > or = 3 months) in the US, and in most other countries for nosocomial pneumonia, cIAI, septicaemia, febrile neutropenia, cSSSI, bacterial meningitis, complicated urinary tract infection (UTI), obstetric and gynaecological infections, in cystic fibrosis patients with pulmonary exacerbations, and for the treatment of severe community-acquired pneumonia (CAP). Meropenem has a broad spectrum of in vitro activity against Gram-positive and Gram-negative pathogens, including extended-spectrum beta-lactamase (ESBL)- and AmpC-producing Enterobacteriaceae. It has similar efficacy to comparator antibacterial agents, including: imipenem/cilastatin in cIAI, cSSSI, febrile neutropenia, complicated UTI, obstetric or gynaecological infections and severe CAP; clindamycin plus tobramycin or gentamicin in cIAI or obstetric/gynaecological infections; cefotaxime plus metronidazole in cIAI; cefepime and ceftazidime plus amikacin in septicaemia or febrile neutropenia; and ceftazidime, clarithromycin plus ceftriaxone or amikacin in severe CAP. Meropenem has also shown similar efficacy to cefotaxime in paediatric and adult patients with bacterial meningitis, and to ceftazidime when both agents were administered with or without tobramycin in patients with cystic fibrosis experiencing acute pulmonary exacerbations. Meropenem showed greater efficacy than ceftazidime or piperacillin/tazobactam in febrile neutropenia, and greater efficacy than ceftazidime plus amikacin or tobramycin in patients with nosocomial pneumonia. Meropenem is well tolerated and has the advantage of being suitable for administration as an intravenous bolus or infusion. Its low propensity for inducing seizures means that it is suitable for treating bacterial meningitis and is the only carbapenem approved in this indication. Thus, meropenem continues to be an important option for the empirical treatment of serious bacterial infections in hospitalized patients.

Efficacy, Safety, and Local Pharmacokinetics of Highly Concentrated Nebulized Tobramycin in Patients with Cystic Fibrosis Colonized with Pseudomonas aeruginosa

Progressive respiratory failure due to Pseudomonas aeruginosa colonization is the most significant morbidity in patients with cystic fibrosis (CF). This trial was designed to investigate the efficacy and safety of a highly concentrated (300mg/4mL) tobramycin solution for inhalation (TSI) [Bramitob] in patients with CF and P. aeruginosa infection. Fifty-nine patients were randomized to receive a 4-week treatment with tobramycin or placebo administered twice daily via the Pari LC Plus nebulizer and Pari TurboBoy compressor, followed by a 4-week run-out phase. Pulmonary function (forced expiratory volume in 1 second [FEV(1)], forced vital capacity [FVC], and forced expiratory flow at the midportion of vital capacity [FEF(25-75%)]), P. aeruginosa susceptibility, microbiologic results, and in vitro minimum inhibitory concentration for 90% of strains (MIC(90)) were the efficacy outcome measures, while safety was monitored by the recording of adverse events, audiometry (bone conduction at 250-8,000Hz frequency), laboratory tests, physical examination and general health condition. The concentration of tobramycin attained in sputum was measured in a cohort of 21 patients. FEV(1) significantly increased from baseline in the tobramycin group compared with no change in the placebo group: the absolute difference between groups (intent-to-treat population) of predicted normal was 13.2% at week 2 (p = 0.002) and 13.3% at week 4 (p = 0.003). Significant differences in favor of the tobramycin group were also observed for FVC and FEF(25-75%). The microbiologic results at the end of the treatment period (P. aeruginosa-negative culture, persistence, superinfection) showed a significantly better outcome in the tobramycin group compared with placebo (p = 0.033). The effects of tobramycin on pulmonary function and microbiology were not maintained at the end of the run-out phase. Mean sputum concentrations of tobramycin after the first dose (695.6 +/- 817.0 microg/mL) were similar to those measured after the last dose (716.9 +/- 799 microg/mL) and were superior to the detected specific MIC(90). The proportion of patients with drug-related adverse events was lower in the tobramycin group and no signs of renal or auditory toxicity were observed. The 4-week administration of a highly concentrated TSI significantly improved pulmonary function and microbiologic outcome compared with placebo and was well tolerated. The results of this study should be confirmed in further long-term trials in larger populations.

Pharmacokinetic profile of once daily intravenous tobramycin in children with cystic fibrosis

Once-daily tobramycin in patients with cystic fibrosis (CF) is a more convenient dosing regimen than thrice daily dosing. There are limited data on the pharmacokinetic (PK) profile for once-daily tobramycin in patients with CF. The aim of this study was to define the PK parameters for once-daily tobramycin in children with CF and develop an algorithm for therapeutic drug monitoring dosing. CF patients admitted to hospital were commenced on once-daily intravenous tobramycin (12 mg/kg/day) and ticarcillin/clavulinic acid. Serum tobramycin levels were taken at 30 min, 2-4 h and 12 h post dose. Data points for the PK model included: age, sex, weight, tobramycin dose, time of tobramycin doses and levels, tobramycin levels. WinNonMix was used to obtain the PK parameters. Forty-four children with 86 admissions who were aged 9 months-20 years were included. A one-compartment intravenous infusion model with first order elimination kinetics produced the best model. Population parameters were: volume of distribution (V(d)) = 0.267 L/kg (95% confidence interval (CL) 0.260-0.272), clearance (CL) 0.103 L/kg/h (95% CI 0.098-0.107) and half-life (t(1/2)) 1.82 (95% CI 1.77-1.88) h. Once the population model was established post hoc analysis was used to calculate individual subject predictions. Plots of individual prediction curves agreed well with observed values. This study has established an algorithm for routine monitoring of once-daily tobramycin in children with CF. Satisfactory serum levels of tobramycin were obtained with a dose of 12 mg/kg/day and a regimen algorithm that uses only one measurement to monitor the plasma concentration is suggested.

183 Long-term administration of nebulised tobramycin in patients with Cystic Fibrosis

183 Long-term administration of nebulised tobramycin in patients with Cystic Fibrosis

Pharmacodynamics of tobramycin in patients with cystic fibrosis

Relationships between pharmacodynamic indices (PI), such as the area under the concentration–time curve (AUC)/MIC ratio and time > MIC ( T >MIC), and efficacy have been described for antimicrobial drugs. The use of these quantitative relationships may increase the power to demonstrate significant effects of drugs, obviating the need to include large numbers in comparative trials. Patients with cystic fibrosis (CF) hospitalized for treatment of an infectious exacerbation due to Pseudomonas aeruginosa were eligible for the study. They received tobramycin 3.3 mg/kg tid as initial therapy in combination with ticarcillin 125 mg/kg qid. Blood samples were drawn at t = 0–8 h after infusion. Pharmocokinetic parameters and PI were calculated for every individual and correlated to the relative improvement in forced expiratory volume during the first second (FEV1) and forced vital capacity (FVC) between pretreatment and days 9–11 as a measure of efficacy. The 3 PI fAUC/MIC, f Peak/MIC, and T >MIC of tobramycin showed a significant correlation with effect and was the highest for the fAUC/MIC relationships with FEV1 and FVC as determined both by the Emax model as well as Spearman correlations ( r = 0.77, P = 0.002 and 0.58, P = 0.036 for FEV1 and FVC). Pharmacokinetic parameters AUC and Peak as such showed no significant correlation with effect, nor did the MIC values. There is a significant relationship between PI of aminoglycosides and efficacy parameter (increase in FEV1 and FVC) in patients with CF. This study demonstrates the applicability of pharmacodynamic relationships in determining efficacy of antimicrobial therapy, by demonstrating a strong PI–effect relationship in a group of only 13 patients.

Vestibular Toxicity Due to Inhaled Tobramycin in a Patient With Renal Insufficiency

Inhaled tobramycin is being used increasingly in patients with cystic fibrosis and other forms of bronchiectasis for treatment of bronchial colonization with Pseudomonas aeruginosa. The goal of inhaled antibiotics is to provide maximal concentrations at the site of infection without risking systemic toxicity. We report an unusual case of reversible vestibular toxicity due to inhaled tobramycin in a patient with renal failure who was undergoing hemodialysis. Although systemic absorption after inhaled tobramycin is reportedly negligible, no recommendations have been published regarding monitoring of serum concentrations in patients receiving this form of therapy. We suggest that clinicians consider monitoring serum concentrations of tobramycin in patients at risk of renal toxicity and/or ototoxicity, such as those with predisposing renal or otologic compromise. Further studies in at-risk patients are needed to determine the optimal frequency and timing of such monitoring.