Necessity of Tobramycin trough Levels in Once Daily Iv-Treatment in Patients with Cystic Fibrosis.

BACKGROUND: Once daily intravenous (iv) treatment with tobramycin for Pseudomonas aeruginosa infection in patients with cystic fibrosis (pwCF) is frequently monitored by measuring tobramycin trough levels (TLs). Although the necessity of these TLs is recently questioned in pwCF without renal impairment, no study has evaluated this so far. The aim of this observational study was to evaluate the frequency of increased tobramycin TLs in pwCF treated with a once daily tobramycin dosing protocol. METHODS: Patient records of all consecutive once daily iv tobramycin courses in 35 pwCF between 07/2009 and 07/2019 were analyzed for tobramycin level, renal function, co-medication and comorbidity. RESULTS: Eight elevated TLs (2.9% of 278 courses) were recorded in four patients, two with normal renal function. One of these resolved without adjustment of tobramycin dosages suggesting a test timing or laboratory error. In the other patient the elevated tobramycin level decreased after tobramycin dosage adjustment. Six of the elevated levels occurred in two patients with chronic renal failure. In 15 other patients with reduced glomerular filtration rate (GFR) (36 courses) but normal range creatinine no case of elevated tobramycin trough levels was detected. Neither cumulative tobramycin dosages nor concomitant diabetes or nutritional status were risk factors for elevated TLs. CONCLUSION: Our data show that elevated tobramycin TLs are rare but cannot be excluded, so determination of tobramycin TLs is still recommended for safety.

Incorporating Fullerenes in Nanoscale Metal-Organic Matrixes: An Ultrasensitive Platform for Impedimetric Aptasensing of Tobramycin.

The rational design and preparation of available fullerene@metal-organic matrix hybrid materials are of profound significance in electrochemical biosensing applications due to their unique photoelectric properties. In this work, C60@UiO-66-NH2 nanocomposites serve as greatly promising materials to modify electrodes and fix aptamers, resulting in a remarkable electrochemical aptasensor for impedimetric sensing of tobramycin (TOB). Nanoscale composites have preferable electroactivity and small particle size with more exposed functional sites, such as Zr(IV) and -NH2, to immobilize aptamers for enhanced detection performance. As we know, most of the electrochemical impedance aptasensors require a long time to complete the detection process, but this prepared biosensor shows the rapid quantitative identification of target TOB within 4 min. This work expands the synthesis of functional fullerene@metal-organic matrix hybrid materials in electrochemical biosensing applications.

Intra-articular administration of vancomycin and tobramycin during primary cementless total knee arthroplasty : determination of intra-articular and serum elution profiles.

AIMS: Intra-articular administration of antibiotics during primary total knee arthroplasty (TKA) may represent a safe, cost-effective strategy to reduce the risk of acute periprosthetic joint infection (PJI). Vancomycin with an aminoglycoside provides antimicrobial cover for most organisms isolated from acute PJI after TKA. However, the intra-articular doses required to achieve sustained therapeutic intra-articular levels while remaining below toxic serum levels is unknown. The purpose of this study is to determine the intra-articular and serum levels of vancomycin and tobramycin over the first 24 hours postoperatively after intra-articular administration in primary cementless TKA. METHODS: A prospective cohort study was performed. Patients were excluded if they had poor renal function, known allergic reaction to vancomycin or tobramycin, received intravenous vancomycin, or were scheduled for same-day discharge. All patients received 600 mg tobramycin and 1 g of vancomycin powder suspended in 25 cc of normal saline and injected into the joint after closure of the arthrotomy. Serum from peripheral venous blood and drain fluid samples were collected at one, four, and 24 hours postoperatively. All concentrations are reported in µg per ml. RESULTS: A total of 22 patients were included in final analysis. At one, four, and 24 hours postoperatively, mean (95% confidence interval (CI)) serum concentrations were 2.4 (0.7 to 4.1), 5.0 (3.1 to 6.9), and 4.8 (2.8 to 6.9) for vancomycin and 4.9 (3.4 to 6.3), 7.0 (5.8 to 8.2), and 1.3 (0.8 to 1.8) for tobramycin; intra-articular concentrations were 1,900.6 (1,492.5 to 2,308.8), 717.9 (485.5 to 950.3), and 162.2 (20.5 to 304.0) for vancomycin and 2,105.3 (1,389.9 to 2,820.6), 403.2 (266.6 to 539.7), and 98.8 (0 to 206.5) for tobramycin. CONCLUSION: Intra-articular administration of 1 g of vancomycin and 600 mg of tobramycin as a solution after closure of the arthrotomy in primary cementless TKA achieves therapeutic intra-articular concentrations over the first 24 hours postoperatively and does not reach sustained toxic levels in peripheral blood. Cite this article: Bone Joint J 2021;103-B(11):1702-1708.

Comparative lung distribution of radiolabeled tobramycin between nebulized and intravenous administration in a mechanically-ventilated ovine model, an observational study.

BACKGROUND: Ventilator-associated pneumonia is common and is treated using nebulized antibiotics. Although adequate pulmonary biodistribution is important for antibiotic effect, there is a lack of data for both intravenous (IV) and nebulized antibiotic administration during mechanical ventilation. OBJECTIVE: To describe the comparative pulmonary regional distribution of IV and nebulized technetium-99m-labeled tobramycin (99mTc-tobramycin) 400 mg in a mechanically-ventilated ovine model. METHODS: The study was performed in a mechanically-ventilated ovine model. 99mTc-tobramycin 400 mg was obtained using a radiolabeling process. Computed tomography (CT) was performed. Ten sheep were given 99mTc-tobramycin 400 mg via either an IV (five sheep) or nebulized (five sheep) route. Planar images (dorsal, ventral, left lateral and right lateral) were obtained using a gamma camera. Blood samples were obtained every 15 min for 1 h (4 time points) and lung, liver, both kidney, and urine samples were obtained post-mortem. RESULTS: Ten sheep were anesthetized and mechanically ventilated. Whole-lung deposition of nebulized 99mTc-tobramycin 400 mg was significantly lower than with IV (8.8% vs. 57.1%, P<0.001). For both administration routes, there was significantly lower deposition in upper lung zones compared with the rest of the lungs. Dorsal deposition was significantly higher with nebulized 99mTc-tobramycin 400 mg compared with IV (68.9% vs. 58.9%, P=0.003). Lung concentrations of 99mTc-tobramycin were higher with IV compared with nebulized administration. There were significantly higher concentrations of 99mTc-tobramycin in blood, liver and urine with IV administration compared with nebulized. CONCLUSIONS: Nebulization resulted in lower whole and regional lung deposition of 99mTc-tobramycin compared with IV administration and appeared to be associated with low blood and extra-pulmonary organ concentrations.

Subsecond-Resolved Molecular Measurements Using Electrochemical Phase Interrogation of Aptamer-Based Sensors.

Recent years have seen the development of a number of biosensor architectures that rely on target binding-induced changes in the rate of electron transfer from an electrode-bound receptor. Most often, the interrogation of these sensors has relied on voltammetric methods, such as square-wave voltammetry, which limit their time resolution to a few seconds. Here, we describe the use of an impedance-based approach, which we have termed electrochemical phase interrogation, as a means of collecting high time resolution measurements with sensors in this class. Specifically, using changes in the electrochemical phase to monitor target binding in an electrochemical-aptamer based (EAB) sensor, we achieve subsecond temporal resolution and multihour stability in measurements performed directly in undiluted whole blood. Electrochemical phase interrogation also offers improved insights into EAB sensors' signaling mechanism. By modeling the interfacial resistance and capacitance using equivalent circuits, we find that the only parameter that is altered by target binding is the charge-transfer resistance. This confirms previous claims that binding-induced changes in electron-transfer kinetics drive signaling in this class of sensors. Considering that a wide range of electrochemical biosensor architectures rely on this signaling mechanism, we believe that electrochemical phase interrogation may prove generalizable toward subsecond measurements of molecular targets.

Area under the curve achievement of once daily tobramycin in children with cystic fibrosis during clinical care.

BACKGROUND: The area under the concentration-time curve over 24 hours (AUC24 ) is frequently utilized to monitor tobramycin exposure in children with cystic fibrosis (CF). An understanding of exposure target achievement during clinical implementation of an AUC24 based approach in children is limited. METHODS: A retrospective chart review was performed in children with CF treated with once daily tobramycin and drug concentration monitoring at a pediatric CF center. During clinical care AUC24 was estimated using a traditional log-linear regression approach (LLR). AUC24 was also estimated retrospectively using a pharmacokinetic model-based Bayesian forecasting approach (BF). AUC24 achievement after both approaches were compared. RESULTS: In 77 treatment courses (mean age, 12.7 ± 5.0 years), a target AUC24 100 to 125 mg h/L was achieved after starting dose in 21 (27%) and after initial dose adjustment in 35 (45%). In the first 7 days of treatment, 24 (32%) required ≥3 dose adjustments, and the mean number of drug concentrations measured was 7.1 ± 3.2. Examination of a BF approach demonstrated adequate prediction of measured tobramycin concentrations (median bias -2.1% [95% CI -3.1 to -1.4]; median precision 7.6% [95% CI, 7.1%-8.2%]). AUC24 estimates utilizing the BF approach were higher than the LLR approach with a mean difference of 6.4 mg h/L (95% CI, 4.8 to 8.0 mg h/L). CONCLUSIONS: Achievement of a narrow AUC24 target is challenging during clinical care, and dose individualization is needed in most children with CF. Implementing a BF approach for estimating AUC24 in children with CF is supported.

Elution Profiles of Synthetic CaSO4 Hemihydrate Beads Loaded with Vancomycin and Tobramycin.

BACKGROUNDS AND OBJECTIVES: The use of local antibiotic delivery vehicles is common in the management of biofilm-related infections as they provide high concentrations of local antibiotics while simultaneously avoiding complications from systemic toxicity. We present a 100% pure synthetic calcium sulfate hemi-hydrate mixed with 240 mg tobramycin and 500 mg vancomycin per 10 cc mixture for use in revision surgeries of periprosthetic joint infections (PJIs). The purified carrier demonstrates bioabsorbablity, promotion of bone growth, a physiologically favorable pH, and hydrophilicity. These unique properties may alleviate persistent postoperative wound drainage seen in patients with PJI. Our questions consist of two parts: (1) does the novel calcium sulfate carrier provide therapeutic concentrations of antibiotic locally that can kill biofilm related infections? (2) Are serum concentrations of antibiotic significant to cause concern for systemic toxicity? METHODS: To address these questions, we assayed the elution of antibiotic concentrations obtained from surgical drains and serum among 50 patients in the first 5 postoperative days. RESULTS: The elution of vancomycin and tobramycin was greatest on day 1 compared with those concentrations obtained on days 2, 3, 4, and 5; serum concentrations were largely undetectable. Our findings demonstrate that this calcium sulfate preparation provides therapeutic delivery of vancomycin and tobramycin locally at log 2-3 above the minimum inhibitory concentration (MIC), while avoiding toxic serum concentrations. CONCLUSIONS: When used in one-stage revision arthroplasties, the bioabsorbable, purified carrier delivers high concentrations of antibiotic while avoiding systemic toxicity.

Evaluation of Assays to Measure Aminoglycosides in Serum: Comparison of Accuracy and Precision Based on External Quality Assessment.

BACKGROUND: Aminoglycosides require highly accurate therapeutic drug monitoring owing to their narrow therapeutic windows and toxic side effects. Therapeutic drug monitoring varies in different laboratories, and this difference is mainly due to the use of different analytical techniques. This study aimed to compare the accuracy and precision of immunoassays for the measurement of gentamicin, tobramycin, and amikacin in serum. METHODS: Human plasma samples were spiked with known concentrations of amikacin, gentamicin, and tobramycin and dispatched to laboratories worldwide. The percentage deviation and coefficient of variation were calculated to compare the accuracy and precision among immunoassays and among antibiotics. RESULTS: We analyzed 273, 534, and 207 amikacin, gentamicin, and tobramycin measurement results, obtained satisfactory rates of 83.9%, 86.3%, and 93.7%, and coefficients of variation ranging from 1.1% to 15.6%, 2.9% to 25.2%, and 1.8% to 27.0%, respectively. The percentage deviation ranged from -7.5% to 6.6%, -20.8% to 18.7%, and -33.2% to 41.5% for amikacin, gentamicin, and tobramycin, respectively. Significant differences were observed in accuracy and precision among assays for all antibiotics. CONCLUSIONS: This study demonstrated high variations in results obtained from antibiotic assays conducted at different laboratories worldwide.

Development and validation of LC-MS/MS methods to measure tobramycin and lincomycin in plasma, microdialysis fluid and urine: application to a pilot pharmacokinetic research study.

Background The aim of our work was to develop and validate a hydrophilic interaction liquid chromatography-electrospray ionization-tandem mass spectrometry (HILIC-ESI-MS/MS) methods for the quantification of tobramycin (TMC) and lincomycin (LMC)in plasma, microdialysis fluid and urine. Methods Protein precipitation was used to extract TMC and LMC from plasma, while microdialysis fluid and urine sample were diluted prior to instrumental analysis. Mobile phase A consisted of 2 mM ammonium acetate in 10% acetonitrile with 0.2% formic acid (v/v) and mobile phase B consisted of 2 mM ammonium acetate in 90% acetonitrile with 0.2% formic acid (v/v). Gradient separation (80%-10% of mobile phase B) for TMC was done using a SeQuant zic-HILIC analytical guard column. While separation of LMC was performed using gradient elution (100%-40% of mobile phase B) on a SeQuant zic-HILIC analytical column equipped with a SeQuant zic-HILIC guard column. Vancomycin (VCM) was used as an internal standard. A quadratic calibration was obtained over the concentration range for plasma of 0.1-20 mg/L for TMC and 0.05-20 mg/L for LMC, for microdialysis fluid of 0.1-20 mg/L for both TMC and LMC, and 1-100 mg/L for urine for both TMC and LMC. Results For TMS and LMC, validation testing for matrix effects, precision and accuracy, specificity and stability were all within acceptance criteria of ±15%. Conclusions The methods described here meet validation acceptance criteria and were suitable for application in a pilot pharmacokinetic research study performed in a sheep model.

PHARMECMO: Therapeutic drug monitoring and adequacy of current dosing regimens of antibiotics in patients on Extracorporeal Life Support.

INTRODUCTION: Optimisation of antibiotic therapy for extracorporeal membrane oxygenation (ECMO) patients remains a pharmacological challenge. The objective of this study was to observe the plasma concentrations of commonly used antibiotics in intensive care for patients treated with extracorporeal membrane oxygenation. PATIENTS AND METHODS: The PHARMECMO study was a pilot, prospective study, conducted in a cardiac surgery intensive care unit. Every adult patient under ECMO support, with known or suspected sepsis and receiving antibiotic therapy, was eligible for inclusion. Plasma concentrations of antibiotics were determined by a combination of liquid chromatography and mass spectrometry. RESULTS: Forty-four eligible patients were enrolled for 68 inclusions on a twelve-month period. For the association piperacillin-tazobactam (n=19), 68.7% of CT50 and 93.7% of Cmin reached the pharmacokinetic goals defined (64 mg.L-1 for CT50 and 16 mg.L-1 for Cmin). For cefotaxime (n=12), the pharmacokinetic goals (4 mg.L-1 for CT50 and 1 mg.L-1 for Cmin) were achieved in 100% of the cases for CT50 and in 81.8% of the cases for Cmin. Regarding imipenem (n=10), the pharmacokinetic goals were 16 mg.L-1 for CT50 and 4 mg.L-1 for Cmin. Only one CT50 was above 16 mg.L-1. For Cmin, 60% of the doses did not reach the target concentration. In our 10 patients, only one patient was considered as reaching the pharmacokinetic goals. Finally, for amikacin (n=6), four Cmax (66.7%) were infra-therapeutics for a target between 60 and 80 mg.L-1. CONCLUSION: These preliminary results suggest that therapeutic drug monitoring could optimise the achievement of pharmacokinetic objectives associated with an effective antibiotic therapy. For most patients, the recommended doses of imipenem and amikacin did not achieve the pK targets.

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

INTRODUCTION: 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. METHODS: This retrospective observational study included ICU patients with SDD treatment for ≥ 7 days 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. RESULTS: 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 < 0.2 mg/L, 30 (69.8%) had concentrations 0.2-1.0 mg/L and 1 (2.3%) had a toxic concentration > 1.0 mg/L. In 3 (7.0%) cases, an intervention was conducted based on the tobramycin serum concentration. CONCLUSION: 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.

Bimetallic cerium/copper organic framework-derived cerium and copper oxides embedded by mesoporous carbon: Label-free aptasensor for ultrasensitive tobramycin detection.

We reported a novel bimetallic cerium/copper-based metal organic framework (Ce/Cu-MOF) and its derivatives pyrolyzed at different temperatures, followed by exploiting them as the scaffold of electrochemical aptamer sensors for extremely sensitive detection of trace tobramycin (TOB) in human serum and milk. After the calcination at high temperature, the meal coordination centers (Ce and Cu) were transferred to metal oxides containing various chemical valences, such as Ce(III), Ce(IV), Cu(II) and Cu(0), which were embedded within the mesoporous carbon network originated from the organic ligands (represented by CeO2/CuOx@mC). Owning to the strong synergistic effect among the metal oxides, mesoporous carbon, and small cavities and open channels of MOF, the as-prepared CeO2/CuOx@mC nanocomposites not only possess good electrochemical activity but also exhibit strong bioaffinity toward the aptamer strands. By comparing the electrochemical biosensing peroformances using on the Ce/Cu-MOF- and the series of CeO2/CuOx@mC-based aptasensors, the constructed CeO2/CuOx@mC900-based (calcinated at 900 °C) aptasensor exhibits an extremely low detection limit of 2.0 fg mL-1 within a broad linear TOB concentration range from 0.01 pg mL-1 to 10 ng mg L-1. It demonstrates that the proposed aptasensor is substantially superior to those previously reported in the literature, along with high selectivity, good stability and reproducibility, and acceptable applicability in human serum and milk. Thereby, the newly fabricated aptasensing approach based on bimetallic CeO2/CuOx@mC has a considerable potential for the quantitative detection of antibiotics in the food safety and biomedical field.

Breaking the Vicious Cycle of Antibiotic Killing and Regrowth of Biofilm-Residing Pseudomonas aeruginosa.

Biofilm-residing bacteria embedded in an extracellular matrix are protected from diverse physicochemical insults. In addition to the general recalcitrance of biofilm bacteria, high bacterial loads in biofilm-associated infections significantly diminish the efficacy of antimicrobials due to a low per-cell antibiotic concentration. Accordingly, present antimicrobial treatment protocols that have been established to serve the eradication of acute infections fail to clear biofilm-associated chronic infections. In the present study, we applied automated confocal microscopy on Pseudomonas aeruginosa to monitor dynamic killing of biofilm-grown bacteria by tobramycin and colistin in real time. We revealed that the time required for surviving bacteria to repopulate the biofilm could be taken as a measure for effectiveness of the antimicrobial treatment. It depends on the (i) nature and concentration of the antibiotic, (ii) duration of antibiotic treatment, (iii) application as monotherapy or combination therapy, and (iv) interval of drug administration. The vicious cycle of killing and repopulation of biofilm bacteria could also be broken in an in vivo model system by applying successive antibiotic dosages at intervals that do not allow full reconstitution of the biofilm communities. Treatment regimens that consider the important aspects of antimicrobial killing kinetics bear the potential to improve control of biofilm regrowth. This is an important and underestimated factor that is bound to ensure sustainable treatment success of chronic infections.

Comparison against current standards of a DNA aptamer for the label-free quantification of tobramycin in human sera employed for therapeutic drug monitoring.

The use of DNA aptamers in biosensors for the quantification of pharmaceuticals in the clinics would help to overcome the limitations of antibody-based detection for small molecules. The interest for such systems is proven by the ever-increasing number of aptamer-based solutions for analytics proposed in the literature as proof-of-concept demonstrators. Despite such diversity, these platforms often lack a comparative assessment of their performances against the current standard of practice in the clinics when using real samples. We employed an aptamer against tobramycin discovered in our laboratory to quantify through surface plasmon resonance the concentration of the antibiotic in clinical samples obtained from patients treated with tobramycin and undergoing therapeutic drug monitoring. We then compared the performances of our detection strategy against the current standard of practice. Our results show how, using adequate calibration and matrix complexity reduction, DNA aptamer-based direct assays can assess clinically relevant concentrations of small molecules in patient serum and with good correlation to current standards used in the clinics.

Monitoring of tobramycin in human plasma via mixed matrix membrane extraction prior to capillary electrophoresis with contactless conductivity detection.

A sample pre-treatment method based on a dynamic mixed matrix membrane tip extraction followed by capillary electrophoresis with contactless conductivity detection (CE-C4D) was evaluated for the determination of tobramycin in human plasma. The extraction tip device consisted of a cellulose triacetate membrane tip wall immobilised with 15% (w/w) of hydrophilic lipophilic balance (HLB) nanoparticles as adsorbent. The extraction was performed dynamically by withdrawing/dispensing the plasma sample through the tip device followed by desorption into 20 µL of acidified aqueous solution at pH 3 prior to the CE-C4D analysis. Under the optimum conditions, the detection limit of the method for tobramycin was 10 ng/mL, with intraday and interday repeatability RSDs of 3.5% and 4.5%, respectively. Relative recoveries in spiked human plasma were 99.6%-99.9%. The developed approach was successfully demonstrated for the quantification of tobramycin in human plasma samples.

Therapeutic antibiotic serum concentrations by two blood collection methods within the pediatric patient: A comparative effectiveness trial.

Repeated venipunctures and fingersticks to confirm serum drug concentrations cause pain and dissatisfaction for pediatric patients and their families. In many organizations, the standard of care to obtain therapeutic serum drug concentrations by peripheral venipuncture or capillary fingerstick, even when the patient has an existing peripheral intravenous catheter (PIV) or central venous catheter (CVC). The primary objective of this study was to assess agreement between serum tobramycin/vancomycin concentrations collected from a CVC or PIV, versus venipuncture or fingerstick. Among hospitalized pediatric patients (age 3 months to 22 years), 36 paired blood samples were collected. Serum trough vancomycin and random tobramycin concentrations were compared between peripheral intravenous or CVC samples, and venipuncture or fingerstick samples within the same patient. A strict sampling protocol for obtaining the samples was followed, that included collection of the CVC/PIV sample before the venipuncture or fingerstick, less than 2 min between collections of samples from the different sites, and a strict volume-based flush and waste protocol. Concordant correlation coefficients demonstrated substantial agreement between CVC/PIV and venipuncture/fingerstick concentrations for vancomycin (n = 17) and tobramycin (n = 19) (Rc = 0.982 for both). Bland-Altman analyses demonstrated good overall between-method agreement within subjects and minimal bias. Consequently, using a lumen volume-based flush and waste protocol, children with indwelling catheters may not require additional venipunctures and/or fingersticks for confirmation of drug concentrations while hospitalized, improving the quality of care and patient satisfaction.

Subsecond-Resolved Molecular Measurements in the Living Body Using Chronoamperometrically Interrogated Aptamer-Based Sensors.

Electrochemical, aptamer-based (E-AB) sensors support the continuous, real-time measurement of specific small molecules directly in situ in the living body over the course of many hours. They achieve this by employing binding-induced conformational changes to alter electron transfer from a redox-reporter-modified, electrode-attached aptamer. Previously we have used voltammetry (cyclic, alternating current, and square wave) to monitor this binding-induced change in transfer kinetics indirectly. Here, however, we demonstrate the potential advantages of employing chronoamperometry to measure the change in kinetics directly. In this approach target concentration is reported via changes in the lifetime of the exponential current decay seen when the sensor is subjected to a potential step. Because the lifetime of this decay is independent of its amplitude (e.g., insensitive to variations in the number of aptamer probes on the electrode), chronoamperometrically interrogated E-AB sensors are calibration-free and resistant to drift. Chronoamperometric measurements can also be performed in a few hundred milliseconds, improving the previous few-second time resolution of E-AB sensing by an order of magnitude. To illustrate the potential value of the approach we demonstrate here the calibration-free measurement of the drug tobramycin in situ in the living body with 300 ms time resolution and unprecedented, few-percent precision in the determination of its pharmacokinetic phases.

Evaluation of Tobramycin Exposure Predictions in Three Bayesian Forecasting Programmes Compared with Current Clinical Practice in Children and Adults with Cystic Fibrosis.

BACKGROUND AND OBJECTIVES: Bayesian forecasting (BF) methods for tobramycin dose individualisation has not seen widespread clinical adoption, despite being endorsed by clinical practice guidelines. Several freeware and commercial programmes using BF methods are available to support personalised dosing. This study evaluated exposure estimates, dose recommendations, and predictive performance compared with current clinical practice. METHODS: Data from 105 patients (50 adults and 55 children) with cystic fibrosis who received intravenous tobramycin treatment and had paired concentration-time measurements were analysed using (1) log-linear regression analysis, and (2) three BF programmes: TDMx, InsightRX, and DoseMe. Exposure estimates and dose recommendations were compared using the Wilcoxon signed-rank test and Bland-Altman analysis. Predictive performance of BF programmes was compared based on bias and imprecision. RESULTS: Median estimated tobramycin exposure with current clinical practice was significantly lower (87.8 vs. 92.5, 94.0 and 90.3 mg h l-1; p ≤ 0.01), hence median subsequent dose recommendations were significantly higher (10.1 vs. 9.4, 9.4 and 9.2 mg kg-1; p ≤ 0.01) compared with BF programmes. Furthermore, median relative dose-adjustment differences were higher in adults (> 10%) compared with children (4.4-7.8%), and differences in individual dose recommendations were > 20% on 19.1-27.4% of occasions. BF programmes showed low bias (< 7%) and imprecision (< 20%), and none of the programmes made consistently significantly different recommendations compared with each other. CONCLUSIONS: On average, the predictions made by the BF programmes were similar, however substantial individual differences were observed for some patients. This suggests the need for detailed investigations of true tobramycin exposure.

Detectable Concentrations of Inhaled Tobramycin in Critically Ill Children Without Cystic Fibrosis: Should Routine Monitoring Be Recommended?

OBJECTIVES: To determine the percentage of detectable tobramycin troughs and acute kidney injury in critically ill children without cystic fibrosis on inhaled therapy. DESIGN: Historic cohort. SETTING: Academic hospital. PATIENTS: Forty children less than 18 years receiving inhaled tobramycin across 6.5 years. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The primary objective was to determine the percentage of detectable tobramycin troughs greater than or equal to 0.5 µg/mL. Secondary objectives included a comparison of acute kidney injury in children with and without detectable troughs. Twenty-two (55%) had trough concentrations obtained. Ten of these (45.5%) had detectable concentrations, with a median of 0.85 µg/mL (interquartile range, 0.5-2.0). There was no statistical significance between the detectable and nondetectable groups in age, gender, and method of administration. However, patients in the detectable group tended to be younger than nondetectable group and more likely to have a tracheotomy. There was a clinically significant decrease in estimated glomerular filtration rate in the detectable trough group. CONCLUSIONS: Detectable troughs were noted in almost half of patients with concentrations obtained. A clinically significant decrease in estimated glomerular filtration rate was noted in patients with detectable concentrations. Continued work should be directed to better understand outcomes and monitoring in children requiring inhaled tobramycin.

Nano into Micro Formulations of Tobramycin for the Treatment of Pseudomonas aeruginosa Infections in Cystic Fibrosis.

Here, nano into micro formulations (NiMs) of tobramycin for the treatment of Pseudomonas aeruginosa airway infections in cystic fibrosis (CF) are described. NiMs were produced by spray drying a solution containing polymers or sugars and a nanometric polyanion-tobramcyin complex (PTC), able to achieve a prolonged antibiotic release. NiMs properties were compared to TOBIPodhaler(Novartis), the only one commercially available dry powder inhalatory formulation based on porous microparticles. Produced NiMs showed adequate characteristics for pulmonary administration, as spherical shape, micrometric size, and high cytocompatibility toward human bronchial epithelial cells. Contrarily to TOBIPodhaler, some of produced NiMs, thanks to their specific chemical composition, are able to facilitate the drug diffusion through the mucus secretion, achieving, at the same time, a sustained tobramycin delivery. Moreover, NiMs showed pronounced antimicrobial activity against P. aeruginosa pathogens and their biofilm, if compared to free tobramycin and TOBIPodhaler, demonstrating the potential of obtained formulations as drug delivery systems for the treatment of pulmonary infections in CF patients.