Therapeutic Drug Monitoring Of Amikacin Research Articles

Development and validation of LC-MS/MS method for the determination of amikacin in human plasma and its application in adult hospitalized patients in Yogyakarta Indonesia

Therapeutic drug monitoring (TDM) is critical to ensure the safe and effective administration of amikacin (AMK), which has a narrow therapeutic index. This study aimed to develop and validate an efficient and simple liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for determining AMK in human plasma and applying it to hospitalized patients. Before LC-MS/MS measurements, plasma samples were treated with an optimized protein precipitation method using methanol (MeOH). Optimum chromatographic conditions for determining AMK in human plasma include using a C8 column (5 μm, 100 × 4.6 mm) and gradient elution using ammonium formate-formic acid-H2O and formic acid-MeOH mixture as the mobile phase at a 0.5 ml/minute flow rate. The method has been validated following the European Medicines Agency guidelines and has met all validation requirements with excellent selectivity, an lowest limit of quantification value of 0.2 μg/ml, good accuracy and precision in the linear range of 0.2–25 μg/ml, good dilution integrity up to 20 dilution times, and stable under various conditions. The method has also successfully been applied for measuring AMK peak levels (Cmax) and trough levels (Cmin) in the plasma of adult inpatients at Dr. Sardjito Hospital Yogyakarta, Indonesia. The LC-MS/MS measurement can be completed in 7.5 minutes, and the method can be applied in the TDM of AMK.

Failure to predict amikacin elimination in critically ill patients with cancer based on the estimated glomerular filtration rate: applying PBPK approach in a therapeutic drug monitoring study.

The aim of this work was to integrate the Therapeutic Drug Monitoring (TDM) with the model-informed precision dosing (MIPD) approach, using Physiologically-based Pharmacokinetic/Pharmacodynamic (PBPK/PD) modelling and simulation, to explore the relationship between amikacin exposure and estimated glomerular filtration rate (GFR) in critically ill patients with cancer. In the TDM study, samples from 51 critically-ill patients with cancer treated with amikacin were analysed. Patients were stratified according to renal function based on GFR status. A full-body PBPK model with 12 organs model was developed using Simcyp V. 21, including steady-state volume of distribution of 0.21 L/kg and renal clearance of 6.9 L/h in healthy adults. PK parameters evaluated were within the 2-fold error range. During the validation step, predicted vs observed amikacin clearance values after single infusion dose in patients with normal renal function, mild and moderate renal impairment were 7.6 vs 8.1 L/h (7.5mg/kg dose); 3.8 vs 4.5 L/h (1500mg dose) and 2.2 vs 3.1 L/h (25mg/kg dose), respectively. However, predicted vs observed amikacin clearance after a single dose infusion of 1400mg in critically-ill patients with cancer were 1.46 vs 1.63 (P = 0.6406) L/h (severe), 2.83 vs 1.08 (P < 0.05) L/h (moderate), 4.23 vs 2.49 (P = 0.0625) L/h (mild) and 7.41 vs 3.36 (P < 0.05) L/h (normal renal function). This study demonstrated that estimated GFR did not predict amikacin elimination in critically-ill patients with cancer. Further studies are necessary to find amikacin PK covariates to optimize the pharmacotherapy in this population. Therefore, TDM of amikacin is imperative in cancer patients.

Therapeutic Drug Monitoring of Amikacin in Neutropenic Oncology Patients

Amikacin is the antibiotic of choice for the treatment of Gram-negative infections, namely, those in neutropenic oncology patients. No populational pharmacokinetic studies are currently available reporting amikacin pharmacokinetics in neutropenic oncology patients despite their specific pathophysiological features and treatments. A large-scale retrospective study was herein conducted to specifically investigate the effects that tumor diseases have on the pharmacokinetic parameters of amikacin and identify whether chemotherapy, the lag time between administration of chemotherapy and amikacin, age and renal function contribute to amikacin pharmacokinetics in neutropenic cancer patients. A total of 1180 pharmacokinetic analysis from 629 neutropenic patients were enrolled. The daily dose administered to oncology patients was higher than that administered to non-oncology patients (p < 0.0001). No statistical differences were found in amikacin concentrations, probably because drug clearance was increased in cancer patients (p < 0.0001). Chemotherapy influenced amikacin pharmacokinetics and drug clearance decreased as the lag time enhanced. The elderly group revealed no statistical differences between the doses administered to both the oncology groups, suggesting that the impact of ageing is stronger than chemotherapy. Our research suggests that cancer patients require higher initial doses of amikacin, as well as when chemotherapy is received less than 30 days before amikacin treatment has started.

A simple and rapid HPLC-MS/MS method for therapeutic drug monitoring of amikacin in dried matrix spots

Individualized treatment of amikacin under the guidance of therapeutic drug monitoring (TDM) is important to reduce the occurrence of toxicity and improve clinical efficacy. In the present study, we developed and validated a simple and high-throughput liquid chromatography-tandem mass spectrometry (LC-MS/MS) method to determine the concentration of amikacin in dried matrix spots (DMS) which the matrix is serum. DMS samples were obtained by spotting volumetric blood onto Whatman 903® cards. Samples were punched into 3 mm diameter discs and extracted with 0.2 % formic acid in water. The HILIC column (2.1 mm × 100 mm, 3.0 µm) under gradient elution was applied, and the analysis time was 3 min per injection. The mass spectrometry transitions were m/z 586.3 → 163.0 for amikacin and m/z 591.4 → 163.1 for D5-amikacin. Full validation was conducted for DMS method, and the method was applied for the amikacin TDM and compared with serum method. The linearity was ranged from 0.5 to 100 mg/L. Both within-run and between-run accuracy and precision of DMS ranged from 91.8 % to 109.6 % and 3.6 % to 14.2 %, respectively. The matrix effect was 100.5 %–106.5 % of DMS method. Amikacin remained stable in DMS for at least 6 days at room temperature, 16 days at 4 °C, 86 days at −20 °C and −70 °C. A good agreement between the DMS method and serum method has been shown in Bland-Altman plots and Passing-Bablok regression. All of the results demonstrated that the DMS methods can be a favorable replacement for amikacin TDM.

Therapeutic drug monitoring of Amikacin in hospitalized patients: A pilot study

BackgroundAmikacin, an aminoglycoside, is a widely used parenteral antibiotic. Therapeutic drug monitoring (TDM) is recommended for aminoglycosides to avoid toxicity. However, the lack of infrastructure at most places precludes it. This pilot and novel study attempt to estimate the real-world serum levels of Amikacin in hospitalised patients. MethodsThirty admitted patients, given Amikacin injections, were included in the study. In addition, 15 clinical specimens isolated with gram-negative bacteria were tested for minimum inhibitory concentration (MIC) value of Amikacin. Trough and peak serum levels of Amikacin were estimated by high-pressure liquid chromatography (HPLC). ResultsThe average MIC value of Amikacin estimated in our laboratory was 3.92 mcg/mL. Peak and trough serum levels of Amikacin ranged from 12.1 to 66.4 mcg/ml and 1.1 to 20.7 mcg/ml, respectively. More than 83% of our patients achieved peak Amikacin levels of 15 mcg/mL, and 37% had trough levels above 5 mcg/mL. These levels are desirable watersheds as per available literature. ConclusionTrough levels of Amikacin in all cases and a review of dosing according to MIC values are recommended to achieve drug safety and therapeutic efficacy.

Ion-Pairing Reagent Free Hydrophilic Interaction LC-MS/MS Method for Therapeutic Drug Monitoring of Amikacin in Neonates

Synthesis and Evaluation of new Ethyl N-[(Z)-(2-Oxo-5-Sulfamoyl-Indolin-3-Ylidene) Amino] Carbamate Derivatives for their Antimicrobial and Anti-inflammatory ActivitySrikanth Lingala, Kiran Samudrala, Raghunandan Nerella

A Simple and Rapid Hplc-Ms/Ms Method for Therapeutic Drug Monitoring of Amikacin in Dried Matrix Spots

A Simple and Rapid Hplc-Ms/Ms Method for Therapeutic Drug Monitoring of Amikacin in Dried Matrix Spots

Therapeutic drug monitoring of amikacin: quantification in plasma by liquid chromatography-tandem mass spectrometry and work experience of clinical pharmacists

ObjectivesAs part of the service provided by clinical pharmacists in our hospital, an assay for plasma amikacin quantification by liquid chromatography-tandem mass spectrometry (LC-MS/MS) has been established for clinical use...

Covariates of amikacin disposition in a large pediatric oncology cohort.

Amikacin pharmacokinetics (PK) in children display large variability due to maturational and disease-related covariates. The objective was to explore amikacin PK in a large pediatric oncology cohort, taking into account within-patient changes. Clinical data and amikacin therapeutic drug monitoring (TDM) observations were collected retrospectively from children with an oncology diagnosis receiving amikacin during febrile neutropenia. Individual amikacin PK parameters were calculated using a 1-compartment model with instantaneous input and first-order output. This approach was selected based on a pragmatic study design using TDM from routine clinical care, with availability of 2 TDM samples per treatment episode. To explore covariates of clearance (Cl) and volume of distribution (Vd), linear mixed models were used, modelling a random effect for patient to account for clustering due to repeated measurements. Based on 188 amikacin treatment episodes in 114 patients, median (interquartile range) amikacin Cl was 1.37 (1.05; 2.46) L/h and Vd 7.98 (5.66; 12.73) L. Height and creatinemia were significant covariates for Cl (marginal R2 71.1%), while weight, height, and creatinemia determined Vd (marginal R2 59.5%). We described extensive variability of amikacin PK in a large cohort of pediatric oncology patients, including within-patient changes across treatment episodes. Maturational covariates and creatinemia determined amikacin Cl and Vd, while primary non-maturational covariates were not significant. Our observations, based on combined clinical and PK data in children with oncology diagnoses, can be useful to feed dosing software programs to improve drug exposure in special populations.

Therapeutic monitoring of amikacin regimen-associated toxicity in febrile neutropenic pediatric cancer patients

Background Amikacin is used in the treatment of fever neutropenia (FN) in pediatric cancer patients. However it may be used once or twice daily, so the explanation of which regimen of amikacin (once or twice) is more effective and less toxic and how to detect renal toxicity early may help in a proper treatment of febrile neutropenia. Aim This study aimed to compare between once-daily versus twice-daily regimens of amikacin to know which regimen is most effective and less toxic. Patients and methods Venous blood from 40 pediatric patients with FN receiving 15 mg/kg amikacin intravenously either once a day (group I) or divided into two equal doses (group II) every 12 h by 30 min infusion. Amikacin was measured by means of homogeneous enzyme immunoassay for all patients. Renal function was assessed by measuring serum creatinine before and after the treatment. Results There were higher significant differences between once-daily versus twice-daily regimens of amikacin in the treatment of FN. The peak levels of amikacin were significantly higher in group I than those in group II (P = 0.001) and the duration of fever in group I was less than that in group II. Conclusion Therapeutic drug monitoring of amikacin should be done to detect its renal toxicity early and the administration of amikacin as a single daily dose may be associated with greater efficacy and less nephrotoxicity compared with that of amikacin administered as twice-daily dose.

Amikacin Pharmacokinetics To Optimize Dosing in Neonates with Perinatal Asphyxia Treated with Hypothermia

Aminoglycoside pharmacokinetics (PK) is expected to change in neonates with perinatal asphyxia treated with therapeutic hypothermia (PATH). Several amikacin dosing guidelines have been proposed for treating neonates with (suspected) septicemia; however, none provide adjustments for cases of PATH. Therefore, we aimed to quantify the differences in amikacin PK between neonates with and without PATH to propose suitable dosing recommendations. Based on amikacin therapeutic drug monitoring data collected retrospectively from neonates with PATH, combined with a published data set, we assessed the impact of PATH on amikacin PK by using population modeling. Monte Carlo and stochastic simulations were performed to establish amikacin exposures in neonates with PATH after dosing according to the current guidelines and according to proposed model-derived dosing guidelines. Amikacin clearance was decreased 40.6% in neonates with PATH, with no changes in volume of distribution. Simulations showed that increasing the dosing interval by 12 h results in a decrease in the percentage of neonates reaching toxic trough levels (>5 mg/liter), from 40 to 76% to 14 to 25%, while still reaching efficacy targets compared to the results of current dosing regimens. Based on this study, a 12-h increase in the amikacin dosing interval in neonates with PATH is proposed to correct for the reduced clearance, yielding safe and effective exposures. As amikacin is renally excreted, further studies into other renally excreted drugs may be required, as their clearance may also be impaired.

O-5 Amikacin disposition and dosing recommendations in neonates with perinatal asphyxia treated with therapeutic hypothermia (amicool study)

Background Aminoglycosides are administered to treat (suspected) neonatal sepsis. The pharmacokinetics (PK) of this antibiotic class are expected to be different in neonates with perinatal asphyxia (PA) treated with therapeutic hypothermia (TH). Effective exposure of the aminoglycoside amikacin in neonates is achieved using a prospectively validated population PK mod-el-derived dosing regimen.1 However, dosing adjust-ments in case of PA with TH are lacking. The aim of the current (AMICOOL) study was to further explore amikacin disposition in neonates by quantifying the impact of PA treated with TH on amikacin clearance and to provide dosing recommendations for this specific patient population. Methods Amikacin therapeutic drug monitoring data were retrospectively collected from term neonates with PA treated with TH and admitted to the neonatal inten-sive care units of VUmc Amsterdam and the University Hospitals Leuven between 2010–2015. Data were added to the original published amikacin population PK dataset.2 A data-driven covariate analysis was performed to assess the impact of PA treated with TH on amikacin clearance. Monte Carlo simulations facilitated the comparison of simulated amikacin exposures using the current dosing guidelines.1 and proposed dosing adaptations for PA treated with TH. We hereby aimed to achieve optimal amikacin trough ( 24 mg/L) levels. Stochastic simulations were used to investigate the differ-ences in exposure among typical neonates with PA and TH with varying birth weights (1965–4220 g). Results Data of 55 neonates with PA treated with TH were added to the original amikacin population PK dataset of 930 neonates.2 A 40.6% (RSE 9%) decrease in amikacin clearance for neonates with PA with TH was documented. Based on Monte Carlo simulations, the current dosing guidelines resulted in 40%–57% of neonates with PA and TH displaying amikacin trough concentrations above the toxic trough level (>5 mg/L), while an additional increase of the dosing interval with 12 hours decreased this percentage to 14%. Stochastic simulations showed that among typical neonates the percentage of patients with trough concentrations>5 mg/L ranges 14% to 25%. Conclusion In neonates with perinatal asphyxia treated with therapeutic hypothermia, amikacin clearance is reduced with 40.6%. Based on simulations, an additional prolongation of the dosing interval with 12 hours results in optimised amikacin exposure and reduces toxicity in this specific population. As a future perspective, the model-based dosing proposal needs prospective validation. Since amikacin can be used as a surrogate for glomerular filtration, clearance of other drugs using the same elimination route could also be reduced in case of perinatal asphyxia treated with therapeutic hypothermia and may require further dosing adaptations.

Amikacin use and therapeutic drug monitoring in adults: do dose regimens and drug exposures affect either outcome or adverse events? A systematic review.

The objectives of this study were to identify the amikacin dosage regimens and drug concentrations consistent with good outcomes and to determine the drug exposures related to nephrotoxicity and ototoxicity. A literature review was conducted in Medline, EMBASE and the Cochrane Central Register of Controlled Trials. Full journal articles reporting randomized controlled trials, controlled clinical trials, interrupted time series trials, and controlled before and after studies involving amikacin therapeutic drug monitoring (TDM) and dose adjustment were considered for inclusion. Seventeen studies for inclusion were identified, comprising 1677 participants. Amikacin doses ranged from 11 to 15 mg/kg/day with 13 studies using 15 mg/kg/day. Studies were generally designed to compare different aminoglycosides rather than to assess concentration-effect relationships. Only 11 papers presented data on target concentrations, rate of clinical cure and toxicity. Target peak concentrations ranged from 15 to 40 mg/L and target troughs were typically <10 or <5 mg/L. It was not clear whether these targets were achieved. Measured peaks averaged 28 mg/L for twice-daily dosing and 40-45 mg/L for once-daily dosing; troughs averaged 5 and 1-2 mg/L, respectively. Fifteen of the included studies reported rates of nephrotoxicity; auditory and vestibular toxicities were reported in 12 and 8 studies. This systematic review found little published evidence to support an optimal dosage regimen or TDM targets for amikacin therapy. The use of alternative approaches, such as consensus opinion and a review of current practice, will be required to develop guidelines to maximize therapeutic outcomes and minimize toxicity with amikacin.

Limited sampling strategies for therapeutic drug monitoring of amikacin and kanamycin in patients with multidrug-resistant tuberculosis

Amikacin and kanamycin are considered important and effective drugs in the treatment of multidrug-resistant tuberculosis (MDR-TB). Unfortunately, the incidence of toxicity is high and is related to elevated drug exposure. In order to achieve a balance between efficacy and toxicity, a population pharmacokinetic (PPK) model may help to optimise drug exposure. Patients with MDR-TB who had received amikacin or kanamycin as part of their treatment and who had routinely received therapeutic drug monitoring were evaluated. A PPK model was developed and subsequently validated. Using this model, a limited sampling model was developed. Eleven patients receiving amikacin and nine patients receiving kanamycin were included in this study. The median observed 24-h area under the concentration–time curve (AUC0–24h) was 77.2mgh/L [interquartile range (IQR) 64.7–96.2mgh/L] for amikacin and 64.1mgh/L (IQR 55.6–92.1mgh/L) for kanamycin. The PPK model was developed and validated using n−1 cross-validation. A robust population model was developed that is suitable for predicting the AUC0–24h of amikacin and kanamycin. This model, in combination with the limited sampling strategy developed, can be used in daily routine to guide dosing but also to assess AUC0–24h in phase 3 studies.

Design of a surface plasmon resonance immunoassay for therapeutic drug monitoring of amikacin

The therapeutic drug monitoring (TDM) of pharmaceutical drugs with narrow therapeutic ranges is of great importance in the clinical setting. It provides useful information towards the enhancement of drug therapies, aiding in dosage control and toxicity risk management. Amikacin is an aminoglycoside antibiotic commonly used in neonatal therapies that is indicated for TDM due to the toxicity risks inherent in its use. Current techniques for TDM such as high performance liquid chromatography (HPLC) and gas chromatography–mass spectrometry (GC–MS) are costly, time consuming, and cannot be performed at the site of action. Over the last decades, surface plasmon resonance (SPR) biosensors have become increasingly popular in clinical diagnostics due to their ability to detect biomolecular interactions in real-time.We present an SPR-based competitive immunoassay for the detection of the antibiotic amikacin, suitable for TDM in both adults and neonates. We have obtained high specificity and sensitivity levels with an IC50 value of 1.4ng/mL and a limit of detection of 0.13ng/mL, which comfortably comply with the drug's therapeutic range. Simple dilution of serum can therefore be sufficient to analyze low-volume real samples from neonates, increasing the potential of the methodology for TDM. Compared to current TDM conventional methods, this SPR-based immunoassay can provide advantages such as simplicity, potential portability, and label-free measurements with the possibility of high throughput. This work is the foundation towards the development of an integrated, simple use, highly sensitive, fast, and point-of-care sensing platform for the opportune TDM of antibiotics and other drugs in a clinical setting.

O-107 Prospective Validation Of A Model-based Dosing Regimen For Amikacin In Preterm And Term Neonates

<h3>Background and aims</h3> An essential step in drug dosing optimalisation is prospective validation of newly proposed dosing regimens. Based on a recently published population pharmacokinetic (PK) model, a neonatal amikacin dosing regimen was developed. The aim of the current study was to prospectively validate this model-derived dosing regimen. <h3>Methods</h3> Routine amikacin therapeutic drug monitoring (TDM) concentrations were prospectively collected. To test efficacy of the dosing regimen, early observed TDM results (i.e. prior to and 1 h after the second intravenous amikacin dose) reaching target concentrations (trough &lt;3 mg/L, peak &gt;24 mg/L) were defined. To test stability and accuracy of the model, all observed concentrations were compared with the predicted concentrations and a normalised prediction distribution error (NPDE) was performed. Monte Carlo simulations were used to evaluate amikacin exposure. <h3>Results</h3> In total, 1195 TDM results of 579 neonates [median gestational age 34 (range 24–41) weeks, postnatal age 2 (range 1–30) days] were included. Sixty percent of the early trough levels was below 3 mg/L, 90.4% of the peak levels reached 24 mg/L. Comparable parameter estimates were obtained between the final PK model and the prospective dataset. No trend was seen in the NPDE <i>versus</i> time and the NPDE <i>versus</i> predicted concentrations. Based on the Monte Carlo simulations, peak concentrations above 24 mg/L were reached in almost all patient subgroups. <h3>Conclusions</h3> After 14 years experience of amikacin dosing optimalisation in (pre)term neonates, a model-based dosing algorithm was prospectively validated confirming its efficacy, stability and accuracy over the entire neonatal population.

Therapeutic drug monitoring of amikacin in septic patients.

IntroductionUse of higher than standard doses of amikacin (AMK) has been proposed during sepsis, especially to treat less susceptible bacterial strains. However, few data are available on drug concentrations during prolonged therapy and on potential adverse events related to this strategy.MethodsSixty-three critically ill patients who required AMK administration for the treatment of severe infection were included in this study. After a loading dose (LD, 18 to 30 mg/kg), the daily regimen was adapted using therapeutic drug monitoring (TDM) of both peak (Cpeak) and trough (Cmin) concentrations. Target concentrations had to give a ratio of at least 8 between Cpeak and the minimal inhibitory concentration (MIC) of the isolated pathogen. A Cmin >5 mg/L was considered as potentially nephrotoxic. We recorded clinical and microbiological responses, the development of acute kidney injury (AKI) during therapy and ICU mortality.ResultsThe median AMK LD was 1500 (750 to 2400) mg, which resulted in a Cpeak/MIC ≥8 in 40 (63%) patients. Increasing the dose in the 23 patients with a Cpeak/MIC <8 resulted in optimal Cpeak/MIC in 15 of these patients (79%). In 23 patients (37%), Cmin was >5mg/L after the LD, notably in the presence of altered renal function at the onset of therapy, needing prolongation of drug administration. Overall, only 11 patients (17%) required no dose or interval adjustment during AMK therapy. Clinical cure (32/37 (86%) vs. 16/23 (70%), P = 0.18)) and microbiological eradication (29/35 (83%) vs. 14/23 (61%), P = 0.07) were higher in patients with an initial optimal Cpeak/MIC than in the other patients. The proportion of patients with clinical cure significantly improved as the Cpeak/MIC increased (P = 0.006). Also, increased time to optimal Cpeak was associated with worse microbiological and clinical results. AKI was identified in 15 patients (24%) during AMK therapy; 12 of these patients already had altered renal function before drug administration. Survivors (n = 47) had similar initial Cpeak/MIC ratios but lower Cmin values compared to nonsurvivors.ConclusionsTDM resulted in adjustment of AMK therapy in most of our septic patients. Early achievement of an optimal Cpeak/MIC ratio may have an impact on clinical and microbiological responses, but not on outcome. In patients with impaired renal function prior to treatment, AMK therapy may be associated with a further decline in renal function.

Quantification of Amikacin in Bronchial Epithelial Lining Fluid in Neonates

Amikacin efficacy is based on peak concentrations and the possibility of reaching therapeutic levels at the infection site. This study aimed to describe amikacin concentrations in the epithelial lining fluid (ELF) through bronchoalveolar lavage (BAL) in newborns. BAL fluid was collected in ventilated neonates treated with intravenous (i.v.) amikacin. Clinical characteristics, amikacin therapeutic drug monitoring serum concentrations, and the concentrations of urea in plasma were extracted from the individual patient files. Amikacin and urea BAL fluid concentrations were determined using liquid chromatography with pulsed electrochemical detection (LC-PED) and capillary electrophoresis with capacitively coupled contactless conductivity detection (CE-C(4)D), respectively. ELF amikacin concentrations were converted from BAL fluid concentrations through quantification of dilution (urea in plasma/urea in BAL fluid) during the BAL procedure. Twenty-two observations in 17 neonates (postmenstrual age, 31.9 [range, 25.1 to 41] weeks; postnatal age, 3.5 [range, 2 to 37] days) were collected. Median trough and peak amikacin serum concentrations were 2.1 (range, 1 to 7.1) mg/liter and 39.1 (range, 24.1 to 73.2) mg/liter; the median urea plasma concentration was 30 (8 to 90) mg/dl. The median amikacin concentration in ELF was 6.5 mg/liter, the minimum measured concentration was 1.5 mg/liter, and the maximum (peak) was 23 mg/liter. The highest measured ELF concentration was reached between 6 and 14.5 h after i.v. amikacin administration, and an estimated terminal elimination half-life was 8 to 10 h. The median and highest (peak) ELF amikacin concentrations observed in our study population were, respectively, 6.5 and 23 mg/liter. Despite the frequent use of amikacin in neonatal (pulmonary) infections, this is the first report of amikacin quantification in ELF in newborns.

Empirical models for dosage optimization of four β-lactams in critically ill septic patients based on therapeutic drug monitoring of amikacin

Objectives The study aims to develop empirical models able to predict the pharmacokinetics (PK) of four β-lactams using the amikacin (AMK) therapeutic drug monitoring (TDM), in order to optimize their dosage regimens. Design and methods 69 critically ill septic patients were included. All received a first dose of AMK combined with piperacillin/tazobactam, ceftazidime, cefepime or meropenem. A multivariate analysis was performed to predict the β-lactam PK using AMK PK parameters estimated from TDM and using pathophysiological variables. Results An optimal prediction model was identified for each PK parameter of each β-lactam. The best predictor of each model was one of the AMK PK parameters estimated from TDM. Other variables included colloid solution, renal and hepatic biomarkers, age and body weight. Conclusion PK of the four β-lactams could be easily and rapidly predicted in critically ill septic patients using the AMK TDM. These predictions could improve the β-lactam dosages in clinical practice.

Cerebrospinal Fluid Compartmental Pharmacokinetics of Amikacin in Neonates

To describe and investigate the covariate effects of cerebrospinal fluid (CSF) amikacin pharmacokinetics in neonates, CSF samples were prospectively collected from neonates in whom amikacin had been initiated before a diagnostic lumbar puncture was performed. CSF analysis (amikacin concentration, white blood count [WBC], glucose content, and protein concentration) and amikacin therapeutic drug monitoring results (peak and trough concentrations) in serum were recorded. Correlations (Spearman rank) between the CSF amikacin concentration and the CSF WBC and glucose and protein concentration were investigated. There were 44 CSF amikacin concentrations and 83 serum samples available from 43 neonates (mean postmenstrual age, 36 weeks [range, 26 to 41 weeks]; mean weight, 2.43 kg [range, 0.87 to 3.86 kg]). The median time interval between initiation of amikacin administration and CSF sampling was 25 h (range, 2.5 to 93.7 h). The median amikacin concentration in the CSF was 1.08 mg/liter (range, 0.34 to 2.65 mg/liter), and the mean trough and peak amikacin concentrations in serum were 3.8 +/- 2.5 mg/liter and 35.7 +/- 5.9 mg/liter, respectively. A correlation between CSF amikacin and CSF protein contents (P < 0.01, r = 0.41, 95% confidence interval = 0.13 to 0.63) but not between CSF WBC and CSF glucose was documented. A two-compartment (central and CSF) linear disposition model was used to estimate population pharmacokinetics. The half time for equilibration (T(eq)) between serum and CSF compartments was used as a measure of blood-brain barrier permeability. The T(eq) was 7.58 h (coefficient of variation [CV] = 49.1%) with a partition coefficient of 0.103 (CV = 26.4%). There was no relationship between the T(eq) and CSF WBC, CSF glucose content, or CSF protein content.