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Background: Daptomycin is a cyclic lipopeptide antibiotic used to treat serious infectious endocarditis caused by Staphylococcus aureus . The pharmacodynamic parameter correlating best with efficacy is the ratio of the estimated area under the concentration (AUC 0-24 )-time curve to the minimum inhibitory concentration. The aim of the study is to develop a limited sampling strategy to estimate AUC 0-24 using a reduced number of samples., Methods: Sixty-eight daptomycin AUC 0-24 values were calculated for 50 White patients who underwent treatment for at least 5 consecutive days. Plasma concentrations were detected using a validated high-performance liquid chromatography-tandem mass spectrometry analytical method, with daptomycin-d5 as an internal standard. Multiple regression was used to evaluate the ability of 2 concentration-time points to predict the AUC 0-24 calculated from the entire pharmacokinetic profile. Prediction bias was calculated as the mean prediction error, whereas prediction precision was estimated as the mean absolute prediction error. The development and validation datasets comprised 40 and 10 randomly selected patients, respectively., Results: The AUC 0-24 (mg*h/L) was best estimated using the daptomycin trough concentration and plasma concentrations detected 2 hours after dosing. We calculated a mean prediction error of 1.6 (95% confidence interval, -10.7 to 10.9) and a mean absolute prediction error of 11.8 (95% confidence interval, 5.3-18.3), with 73% of prediction errors within ±15%., Conclusions: An equation was developed to estimate daptomycin exposure (AUC 0-24 ), offering clinical applicability and utility in generating personalized dosing regimens, especially for individuals at high risk of treatment failure or delayed response., Competing Interests: The authors declare no conflict of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Daptomycin is a concentration-dependent lipopeptide antibiotic for which exposure/effect relationships have been shown. Machine learning (ML) algorithms, developed to predict the individual exposure to drugs, have shown very good performances in comparison to maximum a posteriori Bayesian estimation (MAP-BE). The aim of this work was to predict the area under the blood concentration curve (AUC) of daptomycin from two samples and a few covariates using XGBoost ML algorithm trained on Monte Carlo simulations. Five thousand one hundred fifty patients were simulated from two literature population pharmacokinetics models. Data from the first model were split into a training set (75%) and a testing set (25%). Four ML algorithms were built to learn AUC based on daptomycin blood concentration samples at pre-dose and 1 h post-dose. The XGBoost model (best ML algorithm) with the lowest root mean square error (RMSE) in a 10-fold cross-validation experiment was evaluated in both the test set and the simulations from the second population pharmacokinetic model (validation). The ML model based on the two concentrations, the differences between these concentrations, and five other covariates (sex, weight, daptomycin dose, creatinine clearance, and body temperature) yielded very good AUC estimation in the test (relative bias/RMSE = 0.43/7.69%) and validation sets (relative bias/RMSE = 4.61/6.63%). The XGBoost ML model developed allowed accurate estimation of daptomycin AUC using C0, C1h, and a few covariates and could be used for exposure estimation and dose adjustment. This ML approach can facilitate the conduct of future therapeutic drug monitoring (TDM) studies., Competing Interests: The authors declare no conflict of interest.

Introduction: The pharmacokinetics (PK) of daptomycin has not been previously characterized in Japanese pediatric patients with complicated skin and soft tissue infections (cSSTI) or bacteremia. An aim of the study includes evaluation of PK of daptomycin in Japanese pediatric patients and an appropriateness of the age-specific, weight-based dosing regimens in Japanese pediatric patients based on PK comparison with Japanese adult patients., Methods: The phase 2 trial enrolled Japanese pediatric patients (age 1-17 years) with cSSTI (n = 14) or bacteremia (n = 4) caused by gram-positive cocci in order to evaluate safety, efficacy and PK. The Phase 3 trial in Japanese adult patients (SSTI n = 65, septicemia/right-sided infective endocarditis (RIE) n = 7) was referred to for PK comparison between adult and pediatric. Daptomycin concentrations in plasma were analyzed by reverse-phase high-performance liquid chromatography (HPLC). PK parameters were determined using non-compartmental analysis in Japanese pediatric and Japanese adult patients. The exposures in Japanese pediatric patients were graphically compared with those in Japanese adult patients. The relationship between daptomycin exposures and creatine phosphokinase (CPK) elevation was explored visually., Results: Following administration of the age-specific, weight-based dosing regimens, daptomycin exposures were overlapping across age groups in pediatric patients with cSSTI with similar observations based on clearance. The distribution of individual exposure in Japanese pediatric patients was overlapping with that in Japanese adult patients. No apparent relationship between daptomycin exposures and CPK elevation in Japanese pediatric patients was observed., Conclusions: The results suggested that the age-specific, weight-based dosing regimens are considered to be appropriate in Japanese pediatric patients., Competing Interests: Declaration of competing interest Rebecca E Wrishko is employee of Merck & Co., Inc., Rahway, NJ, USA, and all other authors are employees of MSD K.K. Employees may hold stock and/or stock options in the company., (Copyright © 2023 Japanese Society of Chemotherapy, Japanese Association for Infectious Diseases, and Japanese Society for Infection Prevention and Control. Published by Elsevier Ltd. All rights reserved.)

Purpose: This study evaluated the population pharmacokinetics of daptomycin in nonobese elderly patients with hypoalbuminemia and chronic kidney disease (CKD) using the glomerular filtration rate estimated from cystatin C (eGFRcys) and estimated its optimal dose., Methods: We performed population pharmacokinetic analysis of the unbound concentrations of daptomycin. The probability of target attainment of 90% for achieving an area under the concentration-time curve of unbound daptomycin at steady state/ minimum inhibitory concentration ratio of ≥66.6 was stochastically simulated., Results: In the population pharmacokinetic analysis of 25 patients aged ≥65 years, the two-compartment model using eGFRcys and age as covariates of clearance in central compartment of unbound daptomycin were optimal. The unbound fraction rate (fu) was 0.05-0.14. According to the Monte Carlo simulation, the optimal doses for patients with eGFRcys of 20-60 mL/min and aged 65-95 years were calculated as 200-500 mg q24h., Conclusion: These results suggest that establishing the dose using total concentrations may result in under- or overestimation caused by alterations in fu. The optimal dose for nonobese elderly patients with hypoalbuminemia and CKD depends on eGFRcys and age, and a standard dose may be insufficient for some patients.

Objectives: Critically ill patients in intensive care unit (ICU) are susceptible to infectious diseases, thus empirical therapy is recommended. However, the therapeutic effect in ICU patients is difficult to predict due to fluctuation in pharmacokinetics because of various factors. This problem can be solved by developing personalized medicine through therapeutic drug monitoring. However, when different measurement systems are used for various drugs, measurements are complicated and time consuming in clinical practice. In this study, we aimed to develop an assay using ultra-high performance liquid chromatography coupled with tandem mass spectrometry for simultaneous quantification of 12 antimicrobial agents commonly used in ICU: doripenem, meropenem, linezolid, tedizolid, daptomycin, ciprofloxacin, levofloxacin, pazufloxacin, fluconazole, voriconazole, voriconazole N-oxide which is a major metabolite of voriconazole, and posaconazole., Design & Methods: Plasma protein was precipitated by adding acetonitrile and 50% MeOH containing standard and labeled IS. The analytes were separated with an ACQUITY UHPLC CSH C18 column, under a gradient mobile phase consisting of water and acetonitrile containing 0.1% formic acid and 2 mM ammonium formate., Results: The method fulfilled the criteria of US Food and Drug Administration for assay validation. The recovery rate was more than 84.8%. Matrix effect ranged from 79.1% to 119.3%. All the calibration curves showed good linearity (back calculation of calibrators: relative error ≤ 15%) over wide concentration ranges, which allowed determination of C max and C trough . Clinical applicability of the novel method was confirmed., Conclusions: We have developed an assay for simultaneous quantification of 12 antimicrobial agents using a small sample volume of 50 μL with a short assay time of 7 min. Our novel method may contribute to simultaneous calculation of pharmacokinetic and pharmacodynamic parameters., (Copyright © 2021 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.)

A highly sensitive high-performance liquid chromatography method has been developed using the pre-column fluorescent derivatization of daptomycin (DAP) through cyclization of the amino group of ornithine with 2,3-naphthalenedialdehyde. With the proposed method, the limits of detection and quantification of DAP in murine serum were 8 and 3 nmol/L, respectively, and the calibration curve was linear across the examined dynamic range from 8 nmol/L to 1 μmol/L (n = 8, r = 0.9986). This method is suitable for animal experiments examining the side effects of DAP therapy using mice as a simple method with quantification to the order of 10 nmol/L.

Daptomycin, a cyclic lipopeptide antibiotic, has bactericidal activity against Gram-positive organisms and is especially effective against methicillin-resistant Staphylococcus aureus. Although daptomycin causes unique adverse drug reactions such as elevation of creatine phosphokinase or rhabdomyolysis, the detailed mechanisms underlying these adverse drug reactions in skeletal muscle are unclear. This study aimed to elucidate whether daptomycin causes direct skeletal muscle cell toxicity and investigate the relationship between daptomycin exposure and musculoskeletal toxicity. First, we evaluated the relationship between daptomycin exposure and skeletal muscle toxicity. Of the 38 patients who received daptomycin intravenously, an elevation in creatine phosphokinase levels was observed in five. The median plasma trough concentration of daptomycin in patients with elevated creatine phosphokinase levels was significantly higher than that in patients whose creatine phosphokinase levels were within the normal range, suggesting that increased exposure to daptomycin is related to elevation in creatine phosphokinase levels. In an in vitro study using human rhabdomyosarcoma cells, daptomycin reduced cell viability and increased membrane damage. These effects were more marked under hypoxic conditions. A necroptotic pathway seemed to be involved because phosphorylated mixed lineage kinase domain-like protein expression was enhanced following daptomycin exposure, which was significantly enhanced under hypoxic conditions. These findings indicate that daptomycin elicits cytotoxic effects against skeletal muscle cells via the necroptotic pathway, and the extent of toxicity is enhanced under hypoxic conditions.

During the lactation, the choice of a proper antibiotic is crucial since the drug can cross into breast milk causing toxicity to the infant. Therefore, an extraction protocol and LC/MS-MS method for the determination of daptomycin in human milk and plasma were developed, validated and applied to a case of a breastfeeding mother affected by a purulent acute soft skin infection treated with daptomycin. Because of daptomycin high protein binding and its high molecular weight, the optimisation of the extraction protocol and analytical conditions were deeply investigated, and several parameters were taken into account: in particular the type of extraction, internal standard, the type of organic modifier, pH of the aqueous solution, and gradient. The use of a protein precipitation protocol coupled to a C8-reverse phase LC-MS/MS allows for a reliable quantification of daptomycin in both plasma (in the range of 19-199 μg/mL) and breast milk (in the range of 0.12-0.32 μg/mL). The determination of milk/plasma (M/P) ratio, which ranged from 0.002 to 0.006, allowed to assess that daptomycin, effective for the mother, was contemporarily safe for the breastfed newborn., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Recently, several studies on pharmacokinetics parameters of daptomycin reported that plasma trough concentration was linked to efficacy and adverse effects, suggesting the usefulness of therapeutic drug monitoring. Although some methods for determining total daptomycin concentration using liquid chromatography coupled to tandem mass spectrometry were established previously, no sensitive quantification method for free drug concentration was established. In this study, we aimed to develop a quantitative method of measuring both total and free daptomycin concentrations using ultra-performance liquid chromatography coupled to tandem mass spectrometry (UPLC-MS/MS), by which both trough and maximum concentrations can be measured. Plasma samples were prepared by solid phase extraction. Free fractions were obtained by ultrafiltration. The assay fulfilled the requirements of US Food and Drug Administration and the European Medicines Agency for assay validation. The methods for total and free drug showed good fit over wide ranges of 0.5-200 and 0.04-40 μg/mL, with lower limits of quantitation of 0.5 and 0.04 μg/mL, respectively. Recovery rate of free daptomycin from ultrafiltration was approximately 100%. Extraction recovery rates of total and free drug measurements ranged from 57.1 to 67.4% and 54.6 to 62.3%, while matrix effect varied between 111.9 and 118.7% and 104.0 and 127.1%, respectively. The maximum and trough concentrations of total and free daptomycin in plasma from two patients in intensive care unit were successfully determined, demonstrating the feasibility of clinical application of the novel methods for determining plasma total and free daptomycin concentrations. In conclusion, we succeeded to develop a sensitive and selective method using UPLC-MS/MS for quantitative measurement of total and free daptomycin concentrations in plasma., (Copyright © 2018 Elsevier B.V. All rights reserved.)

The emergence of Acinetobacter baumannii with resistance to colistin (ABRC) led to the investigation of daptomycin as an adjunctive to colistin for these isolates. In this study, one ABRC carbapenemase-producing bloodstream isolate was examined. Minimum inhibitory concentrations (MICs) were >512, >512 and 8 µg/mL for imipenem, daptomycin and colistin, respectively. First, a 'humanised' model of the pharmacokinetics of daptomycin and colistin was developed in 18 male C57BL/6 mice. Then, 112 mice were infected by intraperitoneal injection of the ABRC isolate and were randomly assigned into four groups of once-daily treatment for 7 days: group A, controls treated with saline; group B, treated with 20 mg/kg colistin; group C, treated with 50 mg/kg daptomycin; and group D, treated with both agents. Survival was recorded for 7 days in ten mice per group. The remaining mice were sacrificed at regular time intervals following bacterial challenge and the bacterial outgrowth in the liver, lung and right kidney was determined. Mean serum concentrations of daptomycin at 15, 30 and 60 min post-dose were 121.8, 110.3 and 100.4 µg/mL, respectively. The respective concentrations of colistin were 13.9, 9.1 and 7.5 µg/mL. The 7-day mortality in groups A, B, C and D was 100%, 50%, 100% and 0%, respectively. Tissue outgrowth of the right kidney was significantly decreased in group D compared with group B after 72 h. Daptomycin used in combination with colistin leads to prolonged survival in an experimental infection by ABRC. Failure of colistin alone is probably related to rebound of tissue outgrowth., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Therapeutic drug monitoring (TDM) could optimise daptomycin use. However, no validated serum target levels have been established. This prospective study at a tertiary centre including hospitalised patients receiving daptomycin aimed to evaluate the adequacy of daptomycin doses in a real-life study, assess interpatient variability in serum levels, identify predictive factors for non-adequate serum levels and assess their clinical impact. Blood samples [trough (C min ) and peak (C max ) levels] were drawn ≥3 days post-treatment initiation. Serum daptomycin concentrations were determined by HPLC. Outcome was classified as: (i) favourable, if clinical improvement or cure occurred with no adverse events; or (ii) poor, in the case of no clinical response, recurrence, related mortality or if adverse events were detected. Sixty-three patients (63.5% male; median age 63.0 years) were included. The most common indications for daptomycin use were bacteraemia (46.0%), complicated skin and soft-tissue infection (30.2%) and endovascular infection (15.9%). The initial dosage was adequate in 43 patients (68.3%), low in 14 (22.2%) and high in 6 (9.5%). Large interindividual variability in serum levels was observed, with a median C min of 10.6 mg/L (range 1.3-44.7 mg/L) and median C max of 44.0 mg/L (range 3.0-93.7 mg/L). Multivariate analysis showed that C min < 3.18 mg/L was independently related to poor outcome (OR = 6.465, 95% CI 1.032-40.087; P = 0.046). High variability in daptomycin use and serum levels was detected. Specific serum targets were identified as risk factors for poor outcome. TDM might be useful to optimise daptomycin doses and to avoid therapeutic failure., (Copyright © 2018 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.)

We evaluated the effects of rifampin coadministration and MDR1 single nucleotide polymorphisms on the disposition of daptomycin in twelve healthy adults. There were no significant changes from baseline in the clearance (0.53 versus 0.55 liters/h, P =  1.00), volume of distribution (7.0 versus 7.2 liter, P =  0.62), or half-life (9.7 versus 9.6 h, P =  0.89) of daptomycin after exposure to rifampin. The tested MDR1 polymorphisms were not associated with significant differences in daptomycin disposition., (Copyright © 2018 American Society for Microbiology.)

Background: Daptomycin, a cyclic lipopeptide antibiotic, displays high plasma protein binding. This study developed the simple method of liquid chromatographic separation using a core-shell octadecylsilyl microparticulate coupled to tandem mass spectrometry for the quantitation of total and free daptomycin in human plasma., Methods: Free daptomycin in plasma was obtained by centrifugal ultrafiltration. Deproteinized plasma specimens were directly separated using a core-shell octadecylsilyl microparticulate with isocratic elution. The mass spectrometer was run in positive-ion electrospray ionization mode. This method was applied to the quantitation of plasma samples in patients treated with intravenous daptomycin., Results: Daptomycin and diazepam as an internal standard were eluted with a total run time of 10 minutes. The calibration curves of total and free daptomycin in human plasma were linear over the concentration ranges of 1-100 and 0.1-10 mcg/mL, respectively. The lower limits of quantitation of the total and free daptomycin in human plasma were 1.0 and 0.1 mcg/mL, respectively. Their extraction recovery rates in nonfiltrated and ultrafiltrated plasma samples were 106.1% and 98.2%, respectively. Total and free daptomycin did not exhibit any matrix effects in human plasma. The intraday and interday accuracies and imprecisions of total daptomycin were 88.7%-106.0% and 98.7%-105.9%, and within 4.1% and 10.4%, whereas those of free daptomycin were 86.8%-101.6% and 103.0%-107.8%, and within 14.6% and 14.6%, respectively. The plasma concentration ranges of total and free daptomycin in 15 infected patients were 3.01-34.1 and 0.39-3.64 mcg/mL, respectively. The plasma protein binding rate of daptomycin ranged from 80.8% to 94.9%., Conclusions: The present simple method with an acceptable analytical performance can be helpful for monitoring the pharmacokinetics of daptomycin in infected patients observed in clinical settings.

Objectives: To compare daptomycin exposures and predicted safety outcomes with a simulated weight-based and fixed dose in morbidly obese and nonobese subjects., Methods: We performed a nonparametric population pharmacokinetic analysis of daptomycin concentration-time data from a prior obese and nonobese kidney function-matched cohort of healthy adult volunteers. Monte Carlo simulations were performed to compare the maximum concentrations (C max ), minimum concentrations (C min ), and area under the curve (AUC) with the standard daptomycin 6 mg/kg/day dose or a 500-mg daily fixed dose in obese and nonobese subjects. The probability of exceeding a daptomycin C min target (24.3 mg/L or higher) associated with creatine phosphokinase (CPK) elevations was computed with the two regimens., Results: No significant differences were observed in clearance, volume of distribution at steady state, or terminal half-life between the morbidly obese and nonobese PK models. Daptomycin 6 mg/kg/day resulted in AUC, C max , and C min values that were ~2-fold higher in morbidly obese subjects relative to nonobese individuals. In contrast, fixed dosing (500 mg/day) resulted in relatively isometric exposures. The fraction of simulated morbidly obese subjects with a C min target associated with CPK elevations was 10.8% with 6 mg/kg/day and 2.0% at the 500 mg/day dosage., Conclusions: Weight-based maintenance dosing of daptomycin is less likely to yield bioequivalent exposures in morbidly obese subjects and provides credence for the evaluation of fixed maintenance doses across adult body size to improve safety., (© 2018 Pharmacotherapy Publications, Inc.)

A simple and precise ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was developed for the simultaneous analysis of five anti-infective agents used to treat severe infections [three antibiotics (daptomycin, moxifloxacin, ciprofloxacin) and two antifungals (isavuconazole, caspofungin)] in human plasma. Sample preparation was based on protein precipitation with ice cold methanol. All five agents were analyzed with the corresponding isotopically labeled internal standards. All analytes were detected in multiple reactions monitoring (MRM) using API 4000 triple-quadrupole mass spectrometer with electrospray (ESI) source operating in positive mode. The calibration curves were linear over the selected ranges (r > 0.99). The method is precise and accurate with a total run time of 5.5 min. Accuracy of all target analytes ranged between 95.9-116.6%, measured with an imprecision of less than 10.8%. The lower limit of quantification was 1.25 mg/L for caspofungin, 0.3125 mg/L for isavuconazole, 3.125 mg/L for daptomycin, 0.075 mg/L for ciprofloxacin, and 0.1875 mg/L for moxifloxacin. The successful application of the method in patient samples proved its suitability for the medical surveillance of antimicrobial therapy in intensive care units as well as to other pharmacokinetic studies., (Copyright © 2018. Published by Elsevier B.V.)

Daptomycin has shown activity against a wide range of Gram-positive bacteria; however, the approved dosages usually seem insufficient for critically ill patients. The aim of this study was to develop a population pharmacokinetic model for daptomycin in critically ill patients and to estimate the success of the therapy by applying pharmacokinetic/pharmacodynamic (PK/PD) criteria. Sixteen intensive care unit patients were included, four of whom underwent continuous renal replacement therapies (CRRT). Blood and, when necessary, effluent samples were drawn after daptomycin administration at previously defined time points. A population approach using NONMEM 7.3 was performed to analyse data. Monte Carlo simulations were executed to evaluate the suitability of different dosage regimens. The probabilities of achieving the PK/PD target value associated with treatment success (ratio of the area under the plasma concentration-time curve over 24 h divided by the minimum inhibitory concentration (AUC 24 /MIC ≥ 666)) and to reach daptomycin concentrations linked to toxicity (minimum concentration at steady-state (Cmin ss ) ≥ 24.3 mg/L) were calculated. The pharmacokinetics of daptomycin was best described by a one-compartment model. Elimination was conditioned by the creatinine clearance (Clcr) and also by the extra-corporeal clearance when patients were subjected to continuous renal replacement therapy (CRRT). The PK/PD analysis confirmed that 280- and 420-mg/d dosages would not be enough to achieve high probabilities of target attainment for MIC values ≥ 1 mg/L in patients with Clcr ≥ 60 mL/min or in subjects with lower Clcrs but receiving CRRT. In these patients, higher dosages (560-840 mg/d) should be needed. When treating infections due to MIC values ≥ 4 mg/L, even the highest dose would be insufficient., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Purpose: Persistent elevation of prothrombin time (PT) and International Normalized Ratio (INR) values in a patient receiving daptomycin is reported., Summary: A morbidly obese 51-year-old man was hospitalized for evaluation for surgical intervention for gallstone pancreatitis and biliary obstruction. Previously prescribed warfarin therapy was withheld due to suspected coagulopathy and an elevated INR (5.1), and warfarin reversal was initiated. After undergoing partial cholecystectomy on hospital day 6, the patient developed sepsis and was treated with i.v. meropenem and daptomycin for vancomycin-resistant Enterococcus infection. Warfarin therapy, which had been resumed after cholecystectomy, was again discontinued on hospital day 12. On the eighth day of daptomycin therapy, the INR remained elevated (2.6) even though the patient had no warfarin exposure for 9 days. On hospital day 21, thromboelastography (TEG) indicated normal whole blood coagulation. Other anticoagulation markers normalized, but the INR remained elevated until daptomycin was discontinued. Daptomycin has been shown to falsely prolong the INR when specific laboratory reagents are used for PT and INR testing, but the specific reagent used in this case has not been previously implicated., Conclusion: Daptomycin therapy appeared to cause a false and substantial INR elevation in a patient who had been receiving warfarin. Results of TEG suggested that the INR elevation was an artifact of a drug-laboratory interaction and did not represent an anticoagulated state. The patient's INR normalized after linezolid was substituted for daptomycin., (Copyright © 2018 by the American Society of Health-System Pharmacists, Inc. All rights reserved.)

Aim: The objective of this population pharmacokinetic (PK) analysis was to provide guidance for the dosing interval of daptomycin in patients undergoing continuous renal replacement therapy (CRRT)., Methods: A previously published population PK model for daptomycin was updated with data from patients undergoing continuous veno-venous haemodialysis (CVVHD; n = 9) and continuous veno-venous haemodiafiltration (CVVHDF; n = 8). Model-based simulations were performed to compare the 24 h AUC, C max and C min of daptomycin following various dosing regimens (4, 6, 8, 10, and 12 mg kg -1 every [Q] 24 h and Q48 h), with the safety and efficacy exposure references for Staphylococcus aureus bacteraemia/right-sided infective endocarditis., Results: The previously developed daptomycin structural population PK model could reasonably describe data from the patients on CRRT. The clearance in patients undergoing CVVHDF and CVVHD was estimated at 0.53 and 0.94 l h -1 , respectively, as compared with 0.75 l h -1 in patients with creatinine clearance (CrCl) ≥ 30 ml min -1 . Daptomycin Q24 h dosing in patients undergoing CRRT resulted in optimal exposure for efficacy, with AUC comparable to that in patients with CrCl ≥ 30 ml min -1 . In contrast, Q48 h dosing was associated with considerably lower AUC 24-48h in all patients for doses up to 12 mg kg -1 and is therefore inappropriate., Conclusions: Q24 h dosing of daptomycin up to 12 mg kg -1 provides comparable drug exposure in patients on CVVHD and in those with CrCl ≥ 30 ml min -1 . Daily daptomycin use up to 8 mg kg -1 doses are appropriate for patients on CVVHDF, but higher doses may increase the risk of toxicity., (© 2016 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

We report two cases of treatment failure in patients with osteoarticular infection associated with Staphylococcus aureus bacteremia and receiving daptomycin. Using a published population-pharmacokinetic model and daptomycin blood level in these patients, area under the curve (AUC) was calculated and compared to the pharmacological target. For the first patient, treated with 6 mg/kg every 48 hours due to acute renal failure and then every 24 hours, the AUC was 820 mg×h×L -1 , with a minimal concentration of 23.5 mg/L confirming the right dose adjustment and the absence of underdosing. The methicillin-resistant Staphylococcus aureus (MRSA) strain was still susceptible to daptomycin, but it was not sufficient to observe a favorable outcome. For the second patient, treated with 10 mg/kg/d, the steady state residual concentration was 10.4 mg/L, and the calculated AUC value was 550 mg×h×L -1 . AUC/MIC values evolved during treatment to be under the cut-off for bactericidal effects (> 800 hours), and the Staphylococcus aureus (SA) strain became daptomycin resistant. This study highlights the inter-individual pharmacokinetic variation leading sometimes to drug underdosing. Drug monitoring should be encouraged in order to avoid treatment failure.

Prothrombin time (PT) can reportedly be falsely prolonged by the antimicrobial drug daptomycin (DAP), and concomitant use of phosphatidylglycerol (PG). Although high doses of DAP (>6 mg/kg/day) are recommended for severe infection and result in a high blood concentration, the extent to which high blood concentrations of DAP interfere with PT, in the presence or absence of PG, has yet to be determined when using the HemosIL RecombiPlasTin 2G (Werfen Japan, Tokyo, Japan). We examined the effects of high doses of DAP on PT using this reagent. DAP (0-500 mg/L) was added to normal plasma and plasma with an already prolonged PT in the presence or absence of liposomal amphotericin B (L-AMB, 5-50 mg/L) or COATSOME EL-01 empty cationic liposomes (CS, 25-250 mg/L). Furthermore, we undertook a Monte Carlo simulation to calculate the probability of achieving DAP concentrations >100, >200 and >500 mg/L 0-48 hr after administering 6-12 mg/kg of DAP. Apparent PT increased with increasing DAP concentration, but neither L-AMB nor CS appeared to further elevate PT when co-administered with DAP. The probability of achieving DAP concentrations >100 and >200 mg/L increased with DAP dose. Higher doses of DAP than the approved dose caused false prolongation of PT. PT should be monitored carefully in patients taking high doses of DAP; ideally, PT should be measured at the trough blood concentration of DAP. Concomitant use of L-AMB and CS did not generally further elevate PT when co-administered with DAP., (© 2016 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).)

Purpose: To report a case of isolated daptomycin-induced acute liver injury without elevations in creatine kinase (CK) levels or kidney dysfunction., Summary: A 49-year-old female with a history of pancreatitis, lupus, diabetes, congestive heart failure, hypertension, and chronic pain syndrome presented to the emergency department with alteration in mental status and acute liver failure. The patient had been treated with daptomycin for methicillin-resistant Staphylococcus aureus (MRSA) endocarditis for 3 weeks. After ruling out other possible etiologies, daptomycin was suspected as a cause of acute liver failure. Her liver failure resolved gradually following withdrawal of daptomycin., Conclusion: Although hepatic abnormalities caused by daptomycin are rare, a handful of cases with daptomycin-induced liver injury have been reported in the literature. Of note, in most cases, patients on daptomycin therapy developed liver damage with elevations in CK levels. Our case report suggests possible severe liver injury associated with high-dose and long-term daptomycin treatment in the absence of rhabdomyolysis. Future research is warranted to further investigate the relationship between daptomycin use and liver injury, yet it is reasonable to monitor liver function tests at baseline and weekly thereafter along with CK levels, especially in patients requiring long-term daptomycin therapy., (© The Author(s) 2016.)

Methicillin-resistant Staphylococcus aureus infection is a serious clinical problem worldwide. Ceftaroline, daptomycin, linezolid in combination with rifampicin are particularly used in this indication. To allow monitoring of these antibiotics, an on-line solid phase extraction coupled to high-performance liquid chromatography-tandem mass spectrometry assay requiring a 100 μL aliquot of human plasma has been developed. Besides, significance of 25-O-desacetylrifampicin concentrations was evaluated. Sample pre-treatment is limited to protein precipitation with methanol. After centrifugation 10 μL of supernatant are injected into the chromatographic system, which consists of an on-line solid phase extraction followed by a separation on a phenyl-hexyl column and detected by a tandem mass spectrometer. Plasma drug concentrations were determined by multiple reaction monitoring in positive ion mode, and assay performance was evaluated. 25-O-Desacetylrifampicin activity, was compared to rifampicin using a microbiological method. Sample preparation using methanol precipitation followed by solid-phase extraction yielded good recovery and ionization efficiency, with chromatographic separation achieved within 3 min per sample. Within-run and between-run precisions ranged respectively from 1.22% to 9.35% and from 1.61% to 9.36%. Lower limits of quantification were 0.04 mg/L for linezolid, 0.1mg/L for rifampicin, 0.2mg/L for ceftaroline and 0.5mg/L for daptomycin. It appears that 25-O-desacetylrifampicin displays a substantial intrinsic bactericidal activity against S. aureus. This assay provides simple, rapid, sensitive and accurate quantification of the four antibiotic drugs and one metabolite and can be routinely used to monitor drug concentration in methicillin-resistant S. aureus infected patients., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Background: Daptomycin dose is adjusted to body weight and renal function and is usually not guided by therapeutic drug monitoring. Daptomycin plasma concentration measurement was established at our institution in January 2009 and is now increasingly being used. The aim of this study was to describe and characterize variability in daptomycin exposure during routine clinical therapy., Methods: We collected daptomycin plasma concentrations that were measured at our institution during the period January 2009-July 2012. Additional clinical and demographic data and their association with daptomycin exposure were tested by a multilevel linear regression analysis., Results: A total of 332 daptomycin plasma concentrations were determined in 86 patients. Sixty-six percent (n = 218) of all determinations were trough concentrations (Cmin), and 34% (n = 114) were peak concentrations (Cmax). Cmin ranged 2-68 mg/L (median, 16.7 mg/L), and Cmax 20-236 mg/L (median, 66.2 mg/L). A significant positive association of total dose, albumin, creatinine and a significant negative association of dose interval and intermittent hemodialysis with Cmin were found in the regression analysis. Total dose and intensive care unit (ICU) stay were significantly associated with Cmax (P < 0.05). However, only 28% (P < 0.005) of Cmin variability and 8% (P = 0.08) of Cmax variability were explained by the factors included in the analysis., Conclusions: Daptomycin plasma concentrations are often unpredictable as shown by highly variable drug exposure that is only partially explained by dose administered and underlying renal function.

Background: Daptomycin is approved for treatment of complicated skin/skin structure infections and Staphylococcus aureus bloodstream infections (bacteremia) in adults. This study was undertaken to determine the pharmacokinetics of daptomycin in pediatric patients 3-24 months of age with proven/suspected bacterial infection., Methods: In this phase 1, multicenter, open-label, noncomparative pharmacokinetic and safety study, patients were enrolled in 3 age groups: 3-6, 7-12 and 13-24 months. Intravenous daptomycin (single dose) was infused over 30 minutes at 6 mg/kg in subjects 13-24 months of age and at 4 mg/kg in the younger groups. Blood was collected for analysis of daptomycin concentrations., Results: Twenty-four subjects received daptomycin. Daptomycin exposures (area under the curve0-∞) in children 3-6 and 7-12 months of age receiving 4 mg/kg were similar (215 and 219 μg·h/mL, respectively). Children 13-24 months of age receiving a higher dose, 6 mg/kg, had higher exposures (282 μg·h/mL). Mean maximum plasma concentrations in the age groups were 38.7, 37.1 and 67.0 μg/mL, respectively. Daptomycin exposures based on mg/kg dosing were lower than previously reported for older children and adults, likely because of increased clearance and volume of distribution and decreased apparent elimination half-life. Single-dose daptomycin 4 and 6 mg/kg was well tolerated and was not associated with clinical or laboratory adverse events., Conclusions: To match known clinically and microbiologically effective exposures in adults, infants require higher mg/kg daptomycin doses. Daptomycin safety and efficacy have not been established in pediatric patients. Pediatric clinical trials are ongoing.

Daptomycin, a lipopeptide antibiotic with excellent activity against Gram-positive bacteria, is excreted primarily by the kidneys. Development of effective chromatographic methodologies for the determination of daptomycin in human specimens is necessary for clinical use. This study developed a simple and validated ultra-high-performance liquid chromatography method coupled to ultraviolet detection for determination of daptomycin in human plasma and urine. After the pretreatments involving protein precipitation, the supernatants were separated using a 2.3 µm particle size octadecylsilyl column, and the run time was 1 min. The calibration curves were linear over the concentration ranges of 2-200 mg/L for plasma and 25-300 mg/L for urine. Intra- and inter-assay precision and accuracy values of plasma were within 13.5 and 92-100% and within 10.7 and 100-107%, respectively. Those of urine were within 5.0 and 101-104% and within 3.7 and 100-101%, respectively. The validated method was applied to the determination of plasma and urine samples in patients receiving 4-6 mg/kg of intravenous daptomycin, resulting in sufficient sensitivity for evaluating the plasma exposure and urinary excretion. In conclusion, the present method with acceptable analytical performance can be helpful for evaluating the pharmacokinetic disposition of daptomycin in clinical settings., (Copyright © 2013 John Wiley & Sons, Ltd.)

Quantification of daptomycin in plasma samples may be useful in optimizing therapy especially in special patients' population. Nevertheless, therapeutic drug monitoring of daptomycin is still limited probably for the low number of laboratories which perform this analysis and for high shipment costs. We developed and validated a new UPLC-PDA method to quantify daptomycin in plasma and in dried plasma spots (DPS) collected on dried sample spots devices (DSSD). Daptomycin and quinoxaline, used as internal standard, were monitored at 262nm and 253nm, respectively. Daptomycin was extracted from plasma using acetonitrile and from DPS using an extraction solution (ethyl acetate-acetic acid-acetone-water; 50:20:20:10, v/v/v/v). Both assays were linear over the calibration range of 0.781 to 200μg/ml. Considering the method of extraction from plasma, mean intra and inter-day accuracy was -1.18% and -2.79%, respectively. Mean intra and inter-day precision was 7.91% and 9.22%, respectively. Regarding the extraction method from DPS, mean intra and inter-day accuracy was 2.21% and 2.41%, respectively. Mean intra and inter-day precision was 8.01% and 9.19%, respectively. Daptomycin in DPS was found to be stable for 7 days at room temperature (20-25°C) and for at least 30 days at 4°C. A statistically significant (p<0.001) linear correlation was found between daptomycin extracted from plasma and from DPS (r(2)=0.919). DPS represents a safe and cheap strategy to store and ship plasma samples. Thus, it is suited for pharmacokinetic studies and therapeutic drug monitoring of daptomycin in hospitals without a therapeutic drug monitoring laboratory., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Background: Higher daptomycin doses are advocated for select methicillin-resistant Staphylococcus aureus (MRSA)-related infections, but the probabilities of target attainment (PTA) and toxicity of these doses have not been characterized in critically ill patients., Methods: We evaluated the plasma pharmacokinetics (PK) and clinical outcomes of a cohort of critically ill patients treated with daptomycin 6-8 mg/kg/day for primarily Staphylococcus species-related infections. Daptomycin concentrations were measured intensively over the initial 96-hour dosing period. Data were modeled by population PK analyses, and Monte Carlo simulation was used to estimate the probabilities of effect and toxicity with standard and alternate dosing regimens., Results: Fifty patients with a mean (SD) age of 69.7 (12.2) years, weight 74.5 (20.3) kg, and creatinine clearance 56.8 (38.2) mL/minute were enrolled with measurements of 12 (2.2) daptomycin samples per patient. Significantly lower daptomycin exposures were observed despite comparable doses in a subset of patients (n = 13) with augmented clearance (CL). No covariates of CL were identified, but this subset was significantly more likely to be in severe sepsis or septic shock, have higher Sequential Organ Failure Assessment scores, and MRSA bacteremia. In-hospital mortality was significantly higher (30.7% vs 10.8%) in patients with augmented daptomycin CL. Use of an empiric fixed dose of 750 mg of daptomycin is predicted to achieve a comparable PTA with a lower probability of toxicity as compared to the use of 10 mg/kg in critically ill patients., Conclusions: A reappraisal of current daptomycin dosing recommendations is needed to improve the PTA and reduce toxicity among critically ill patients.

Antibiotic-resistant bacterial infection is one of the most serious clinical problems worldwide. Vancomycin, teicoplanin, daptomycin, and colistin are glycopeptide and lipopeptide antibiotics that are frequently used to treat multidrug-resistant bacterial infections. Therapeutic drug monitoring is recommended to ensure both safety and efficacy and to improve clinical outcomes. This study developed a fast, simple, and sensitive ultra-high-pressure liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method for the simultaneous determination of the concentrations of these four drugs in human plasma. The sample preparation process includes a simple protein denaturation step using acetonitrile, followed by an 11-fold dilution with 0.1% formic acid. Eight target peaks for the four drugs can be analyzed within 3 min using a Kinetex™ 2.6 μm C18 column. The mass spectrometry parameters were optimized, and two transitions for each target peak were used for multiple reaction monitoring, which provided high sensitivity and specificity. The UHPLC-MS/MS method was validated over clinical concentration ranges. The intra-day and inter-day precisions for the ratio of the peak area of each analyte to the peak area of the internal standard were all below 12.7 and 14.7% relative standard deviations, respectively. The accuracy at low, medium, and high concentrations of the eight target peaks was between 89.3 and 110.7%. The standard curves for the analytes were linear and had coefficients of determination higher than 0.997. The limits of detection were all below 70 ng mL(-1). The use of this method to analyze patient plasma samples confirmed that it is effective for the therapeutic drug monitoring of these four drugs and can be used to improve the therapeutic efficacy and safety of treatment with antibiotics., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Pharmacokinetic studies of daptomycin in septic patients indicate that pharmacokinetic parameters may be altered. The purpose of this clinical investigation is to determine the pharmacokinetics of daptomycin in a population of hospitalized patients with clinically significant gram-positive infections and receiving daptomycin. Daptomycin was measured using an isocratic HPLC technique. Thirty-five patients suffering from gram-positive severe infections and receiving daptomycin were included in the study. Patients were divided into two groups, depending on the dose of daptomycin received: group A, including 24 patients receiving 6 mg/kg/day daptomycin and group B, 11 patients receiving 8 mg/kg/day. Patients receiving a daptomycin dosage of 8 mg/kg/day had significantly higher values of mean C max and AUC0-24. Each group was further divided into three subgroups, according to the creatinine clearance (CrCl) values: (1) patients with a CrCl >80 ml/min, (2) patients with CrCl ranging between 80 and 40 ml/min, and (3) patients with CrCl <40 ml/min. Compared to patients with normal renal function, those with CrCl <40 ml/min had higher mean values of minimum concentration (C min) (p < 0.001), AUC0-24 (p = 0.03), and prolonged plasma half-time (p < 0.001). These differences were present both in patients receiving 6 and those with 8 mg/kg/day. However, in each of the three subgroups with different degrees of renal function a marked variability of pharmacokinetics parameters was observed. The factors associated with increased mortality were an infection acquired in the ICU, hypoalbuminemia, and AUC/MIC <666. The marked variability that characterizes daptomycin pharmacokinetics in these patients suggest the monitoring of the main pharmacokinetic parameters in this clinical setting.

Post-neurosurgical infection is a serious complication that occurs in approx. 4% of all patients undergoing neurosurgical procedures and is associated with high morbidity and mortality rates and prolonged length of intensive care unit (ICU) stay. Coagulase-negative staphylococci (CoNS), especially methicillin-resistant Staphylococcus epidermidis (MRSE), are the most frequent pathogens involved in CNS post-neurosurgical meningitis. Treatment is challenging especially in patients with meningitis due to multidrug- resistant (MDR) CONS. Herein, we report a unique case of post-neurosurgical meningitis due to MRSE resistant to linezolid (a molecular analysis revealed the presence of the mutation G2576T on domain V of the 23S rRNA gene) and with reduced susceptibility to glycopeptides, successfully treated with a combination of daptomycin at 10 mg/kg daily plus trimethoprim/sulfamethoxazole (TMP/SMX). This antibiotic combination showed an indifferent interaction in in vitro studies. Daptomycin serum and cerebrospinal fluid (CSF) concentrations, determined through blood and CSF samples drawn just prior to and 4 h after the third dose, were 18.9-0.78 and 51.65-3.1 mg/L, respectively. These values allowed us to approximate a 5-6% penetration rate of the drug through an inflamed blood-brain barrier. In conclusion, although further studies are needed, combination of high-dose daptomycin plus TMP/SMX is a reasonable option for treatment of meningitis caused by multidrug-resistant S. epidermidis., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Purpose: For critically ill patients undergoing continuous renal replacement therapy (CRRT), daptomycin dosing recommendations are scarce. We, therefore, retrospectively assessed routinely measured daptomycin plasma concentrations, daptomycin dose administered and microbiological data in 11 critically ill patients with Gram-positive infections that had received daptomycin once daily., Methods: The retrospective analysis included critically ill patients treated at the intensive care unit (ICU) who had daptomycin plasma concentrations measured., Results: Daptomycin dose ranged from 3 to 8 mg/kg/q24 h in patients undergoing CRRT (n = 7) and 6 to 10 mg/kg/q24 h in patients without CRRT (n = 4). Peak and trough concentrations showed a high intra- and inter-patient variability in both groups, independent of the dosage per kg body weight. No drug accumulation was detected in CRRT patients with once-daily daptomycin dosing. Causative pathogens were Enterococcus faecium (n = 6), coagulase-negative Staphylococcus (n = 2), Staphylococcus aureus (n = 2) and unknown in one patient. Microbiological eradication was successful in 8 of 11 patients. Two of three patients with unsuccessful microbiological eradication and fatal outcome had an Enterococcus faecium infection., Conclusion: In critically ill patients undergoing CRRT, daptomycin exposure with once-daily dosing was similar to ICU patients with normal renal function, but lower compared to healthy volunteers. Our data suggest that daptomycin once-daily dosing is appropriate in patients undergoing CRRT.

AFN-1252 is a novel inhibitor of FabI, an essential enzyme in fatty acid biosynthesis in Staphylococcus spp. AFN-1252 exhibits typical MIC(90) values of ≤0·015 μg/ml against diverse clinical isolates of S. aureus, oral absorption, long elimination half-live and efficacy in animal models. We now report high binding (∼95%) to serum proteins of mouse, rat, dog and humans, associated with an eight-fold increase in minimal inhibitory concentration (MIC) and which may be responsible for the long elimination half-lives on pharmacokinetic studies. Unlike daptomycin, AFN-1252 activity is not reduced in the presence of lung surfactant. AFN-1252 exhibits a short post-antibiotic effect of 1·1 hours against methicillin-susceptible S. aureus (MSSA) and methicillin-resistant S. aureus (MRSA) following a 4-hour exposure period. The AFN-1252 unique spectrum of activity is not compromised by interactions with major antibiotic classes, but demonstrates synergy with low concentrations of gentamicin against MSSA and MRSA. These studies support the continued investigation of AFN-1252 as a targeted therapeutic for staphylococcal infections.

The efficacy of daptomycin, imipenem, or rifampin with fosfomycin was evaluated and compared with that of daptomycin-rifampin in a tissue cage model infection caused by methicillin-resistant Staphylococcus aureus (MRSA). Strain HUSA 304 was used. The study yielded the following results for MICs (in μg/ml): fosfomycin, 4; daptomycin, 1; imipenem, 0.25; and rifampin, 0.03. The study yielded the following results for minimum bactericidal concentration (MBC) (in μg/ml): fosfomycin, 8; daptomycin, 4; imipenem, 32; and rifampin, 0.5. Daptomycin-rifampin was confirmed as the most effective therapy against MRSA foreign-body infections. Fosfomycin combinations with high doses of daptomycin and rifampin were efficacious alternative therapies in this setting. Fosfomycin-imipenem was relatively ineffective and did not protect against resistance.

Background: The optimal daptomycin dosing regimen for critically ill patients undergoing continuous renal replacement therapy (CRRT) has still to be established., Methods: Daptomycin pharmacokinetics was determined in 9 patients after administration of 6 mg/kg/day over 5 days., Results: At steady state, which was reached by day 3, the area under the curve over 24 h (AUC24h) was 667.4 ± 356.6 mg·h/l, and the maximum concentration (Cmax) was 66.9 ±25.3 mg/l. Mean CRRT clearance accounted for 48% (range 32-67%) of total clearance (mean 10.2 ml/min, range 6.1-18 ml/min). Significant correlations were observed between Cmax, minimum concentration (Cmin) and AUC24h (R(2) = 0.91, p < 0.001, and R(2) = 0.94, p < 0.001) and between albumin plasma concentration and free daptomycin (R(2) = 0.7, p = 0.009)., Conclusion: No significant accumulation occurred with a daily daptomycin dose of 6 mg/kg in patients undergoing CRRT with an effluent flow rate of >30 ml/kg/h. The quantification of trough concentrations (Cmin) appears to be a good surrogate to estimate AUC24h and to monitor daptomycin treatment in patients undergoing CRRT., (© 2013 S. Karger AG, Basel.)

Background: Daptomycin pharmacokinetics has not been extensively studied in patients undergoing continuous renal replacement therapy (CRRT)., Methods: The aim of the study was to collect pharmacokinetics and clinical data of patients undergoing CRRT and receiving daptomycin therapy. Daptomycin was measured using an isocratic high-performance liquid chromatography technique., Results: Three patients with bloodstream infection underwent CVVHD and three CVVHDF. CVVHDF patients had significantly lower mean AUC(0-24) and C(max) values. A significant decrease in plasma levels was observed in a CVVHDF patient using 'high cut-off' hemofilters., Conclusion: Increasing doses of daptomycin should be considered in critical patients, especially those undergoing CVVHDF.

Background: Limited data are available on the pharmacokinetics and optimal dosage of daptomycin, a lipopeptide compound possessing activity against Gram-positive bacteria, in the pediatric population, particularly in neonates and infants. We determined serum levels of daptomycin in hospitalized pediatric patients treated with various dosages of this agent., Methods: Blood samples were obtained from pediatric patients of all ages with normal renal function who had received daptomycin between May 2009 and December 2010. Serum levels prior ("trough") and 30 min after end of the infusion ("peak") were determined using an ultra-performance liquid chromatography-UV detection method., Results: A total of four daptomycin dosages and four patients were studied. Three patients were infants (gestational age: 29-38 weeks, age at sampling 26-65 days) and the fourth was a 7-year-old boy. A dosage of 6 mg/kg/12 h of daptomycin to the infants resulted in trough concentrations of <4-8.4 mg/l and peak concentrations of 10.9-17.7 mg/l. Comparable levels were observed after one of the infants received a dosage of 11 mg/kg/12 h, while a further dosage increase to 15 mg/kg/12 h yielded peak concentrations of 35.5 mg/l. The 7-year-old child received a daptomycin dosage of 12 mg/kg once daily; trough and peak levels were 4.2 and 103.4 mg/l, respectively., Conclusions: A dosage of daptomycin 6 mg/kg/12 h in small infants results in lower peak and similar trough concentrations compared with a dosage of 4 mg/kg/day administered to adults. This results suggests that daptomycin dosages of more than 6 mg/kg/12 h may be needed for this pediatric age group to achieve a similar drug exposure as adults.

Novel molecularly imprinted polymer (MIP)-coated fibers for solid-phase microextraction (SPME) fibers were prepared by using linezolid as the template molecule. The characteristics and application of these fibers were investigated. The polypyrrole, polythiophene, and poly(3-methylthiophene) coatings were prepared in the electrochemical polymerization way. The molecularly imprinted SPME coatings display a high selectivity toward linezolid. Molecularly imprinted coatings showed a stable and reproducible response without any influence of interferents commonly existing in biological samples. High-performance liquid chromatography with spectroscopic UV and mass spectrometry (MS) detectors were used for the determination of selected antibiotic drugs (linezolid, daptomycin, amoxicillin). The isolation and preconcentration of selected antibiotic drugs from new types of biological samples (acellular and protein-free simulated body fluid) and human plasma samples were performed. The SPME MIP-coated fibers are suitable for the selective extraction of antibiotic drugs in biological samples.

The therapeutic activity of ceftobiprole medocaril, the prodrug of ceftobiprole, was compared to that of vancomycin, daptomycin, and the combination of a subtherapeutic dose of ceftobiprole and vancomycin in a rat model of infective endocarditis due to methicillin-resistant Staphylococcus aureus (MRSA) (ATCC 43300) or glycopeptide-intermediate Staphylococcus aureus (GISA) (NRS4 and HIP 5836) strains. The minimum bactericidal concentrations of ceftobiprole, vancomycin, and daptomycin at bacterial cell densities similar to those encountered in the cardiac vegetation in the rat endocarditis model were 2, >64, and 8 μg/ml, respectively, for MRSA ATCC 43300 and 4, >64, and 8 μg/ml, respectively, for the GISA strain. Ceftobiprole medocaril administered in doses of 100 mg/kg of body weight given intravenously (i.v.) twice a day (BID) every 8 h (q8h) (equivalent to a human therapeutic dose of ceftobiprole [500 mg given three times a day [TID]) was the most effective monotherapy, eradicating nearly 5 log(10) CFU/g MRSA or 6 log(10) CFU/g GISA organisms from the cardiac vegetation and had the highest incidence of sterile vegetation compared to the other monotherapies in the endocarditis model. In in vitro time-kill studies, synergistic effects were observed with ceftobiprole and vancomycin on MRSA and GISA strains, and in vivo synergy was noted with combinations of subtherapeutic doses of these agents for the same strains. Additionally, sterile vegetations were achieved in 33 and 60%, respectively, of the animals infected with MRSA ATCC 43300 or GISA NRS4 receiving ceftobiprole-vancomycin combination therapy. In summary, ceftobiprole was efficacious both as monotherapy and in combination with vancomycin in treating MRSA and GISA infections in a rat infective endocarditis model and warrants further evaluation.

Background: Data comparing alternatives to vancomycin for the treatment of Staphylococcus aureus infections with vancomycin MIC >1 are lacking., Objective: We evaluated outcomes of S aureus infections based on whether daptomycin or vancomycin was used as initial therapy at a single institution, where the majority of S aureus infections had vancomycin MICs of 2 mg/L., Methods: A retrospective chart review was conducted at a 450-bed private acute care hospital. All patients >18 years of age who received initial vancomycin or daptomycin for at least 3 days to treat an S aureus infection between November 2006 and July 2008 were included. Patients with endocarditis, osteomyelitis, or a central nervous system infection and/or those being treated for an S aureus respiratory tract infection were excluded., Results: A total of 165 patients (median age 68 years, range 24-95 years; 56% male) were included: 57 (35%) received daptomycin and 108 (65%) received vancomycin; 78% had vancomycin MIC values of 2 mg/L. The median antibiotic-related length of stay was significantly shorter with daptomycin than with vancomycin (7.5 vs 10.0 days; P = 0.035). Relapse rates in the clinically evaluable population were 25% and 23% for daptomycin and vancomycin, respectively; for the subset with S aureus bacteremia with vancomycin MICs of 2 mg/L, rates were 0% (0/9 patients) and 26% (6/23 patients) for daptomycin and vancomycin, respectively (P = 0.089). Thirty-day all-cause mortality was 6% (10/165 patients) and did not differ significantly by treatment: 7% (4/57 patients) versus 6% (6/108 patients) for daptomycin and vancomycin, respectively (P = 0.708)., Conclusion: In this setting, in which the majority of S aureus infections had vancomycin MIC values of 2 mg/L, we found the median antibiotic-related length of stay to be significantly shorter with daptomycin than with vancomycin. Prospective studies are needed to determine whether daptomycin confers benefits over vancomycin in specific infection types under conditions that are unfavorable for vancomycin, such as higher vancomycin MICs., (Copyright © 2011 Elsevier HS Journals, Inc. All rights reserved.)

A rapid, simple and accurate analytical method based on ultra performance liquid chromatography (UPLC) combined with electrospray ionization (ESI) tandem mass spectrometry (MS/MS) on a hybrid q TOF instrument has been developed and fully validated for the quantification of daptomycin (DPT) in human plasma. The samples were analyzed after simple pretreatment involving protein precipitation, while chromatographic separation of DPT and the internal standard (reserpine) was achieved on an Acquity BEH C18 column (100 mm × 2.1 mm, 1.7 μm) using gradient elution with 0.1% aqueous formic acid (FA) and acetonitrile with 0.1% FA (with DPT eluting at 2.60 min). The method presented good fit (r>0.999) over the quantification range of 0.01-10 μg mL⁻¹ with the lower limit of quantitation (LLOQ) being 0.01 μg mL⁻¹ of human plasma for DPT. The intra- and inter-day precision, measured as % relative standard deviation, was less than 11% for DPT. The validation results showed that the developed method demonstrated adequate selectivity, sensitivity, precision and accuracy and therefore was successfully applied to the analysis of clinical samples following intravenous (iv) administration of 5.4 mg kg⁻¹ DPT to patients suffering from post-traumatic osteomyelitis induced by methicillin-resistant Staphylococcus aureus (MRSA). The developed methodology is the first report of an accurate mass tandem MS method for the analysis of this potent antibiotic in human plasma and can be used to further study pharmacokinetic, bioequivalence and even metabolic aspects related to this drug., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Objective: To describe a case of severe cellulitis, successfully treated with high-dose daptomycin plus continuous infusion meropenem, in a patient with morbid obesity and renal failure, in whom drug exposure over time was optimized by means of real-time therapeutic drug monitoring (TDM)., Case Summary: A 63-year-old man with morbid obesity (body mass index 81.6 kg/m²) and renal failure was admitted to the emergency department because of severe cellulitis. The patient had an admission Laboratory Risk Indicator for Necrotizing Fasciitis score of 9, and broad-spectrum antimicrobial therapy with daptomycin and meropenem was started. Because of rapidly changing renal function, dosage adjustments were guided by an intensive program of TDM (daptomycin ranging from 1200 mg every 48 hours over 30 minutes to 1200 mg every 36 hours over 30 minutes; meropenem ranging from 0.25 g every 8 hours over 6 hours to 500 mg every 4 hours by continuous infusion). Clinical response was observed within 72 hours. However, a sudden increase of serum creatine kinase (SCK) raised questions about the need for discontinuation of daptomycin. The drug concentrations were not toxic; therefore, we decided to continue therapy. Significant clinical improvement, with SCK normalization, was observed within a few days. Antimicrobial therapy was switched on day 29 to amoxicillin/clavulanate plus levofloxacin, and then discontinued at discharge on day 53., Discussion: High-dose daptomycin plus continuous infusion meropenem may ensure adequate empiric antimicrobial coverage in patients with possible early necrotizing fasciitis. However, in patients with morbid obesity and changing renal function, significant challenges may arise because of the hydrophilic nature of these drugs and the inaccuracy of standard methods of estimating renal function., Conclusions: Real-time TDM may represent an invaluable approach in optimizing drug exposure with high-dose daptomycin plus continuous infusion meropenem in patients with severe cellulitis, morbid obesity, and changing renal function.

Background and Objectives: This study sought to (1) characterize the pharmacokinetic (PK) profile of intravenous (i.v.) daptomycin among patients receiving continuous ambulatory peritoneal dialysis (CAPD); (2) identify optimal i.v. CAPD dosing schemes; and (3) determine extent of daptomycin penetration into the peritoneal space after i.v. administration., Design, Setting, Participants, & Measurements: A PK study was conducted among eight CAPD patients. Population PK modeling and Monte Carlo simulation (MCS) were used to identify CAPD dosing schemes providing efficacy and toxicity plasma profiles comparable with those obtained from MCS using the daptomycin population PK model derived from patients in the Staphylococcus aureus bacteremia-infective endocarditis (SAB-IE) study. The primary efficacy exposure target was the area under the curve (AUC). For toxicity, the goal was to identify CAPD dosing schemes that minimized plasma trough concentrations in excess of 24.3 mg/L. Finally, peritoneal cavity penetration was determined., Results: Administration of i.v. daptomycin 4 or 6 mg/kg, depending on indication, every 48 h was identified as the optimal CAPD dosing scheme. This regimen provided cumulative (AUC(0-48)) and daily partitioned (AUC(0-24 h) and AUC(24-48 h)) plasma AUC values similar to the SAB-IE or "typical patient" simulations. In addition, the proportion of patients likely to experience an elevated trough concentration in excess of 24.3 mg/L was similar between every 48 h CAPD dosing and the referent group. Penetration into the peritoneal cavity was 6% of plasma., Conclusions: Daptomycin 4 or 6 mg/kg, on the basis of indication, i.v. every 48 h was found to be the optimal i.v. CAPD dosing scheme., (Copyright © 2011 by the American Society of Nephrology)

In order to determine whether reduced susceptibility or tolerance to vancomycin in Staphylococcus aureus influences the activity of daptomycin by simulating serum concentrations in the first 24h of treatment in the presence of physiological concentrations of human albumin, a computerised pharmacodynamic simulation was performed using Mueller-Hinton broth with 4 g/dL human albumin concentrations. For daptomycin, the media was adjusted to physiological ionised calcium concentrations by adding 100 μg/mL Ca(2+). Protein binding was measured. Six S. aureus isolates were used, comprising one vancomycin-susceptible S. aureus (VSSA), three vancomycin-tolerant strains, one heteroresistant vancomycin-intermediate S. aureus (hVISA) and one homogeneous vancomycin-intermediate S. aureus (VISA). Minimum inhibitory concentrations (MICs) and minimum bactericidal concentrations (MBCs) of daptomycin increased eight times when determined in the presence of albumin (MIC(ALB) and MBC(ALB), respectively). Measured protein binding was 86.6% (C(max)) and 86.5% (C(min)) for daptomycin and 51.6% (C(max)) and 42.2% (C(min)) for vancomycin. Similar values were obtained for fAUC/MIC (where fAUC is the area under the concentration-time curve obtained with extrapolated concentrations using the highest protein binding rate experimentally obtained) and AUC/MIC(ALB) for each antibiotic. Daptomycin showed early (≤ 6 h) bactericidal activity [maximal effect (E(max)) >4 log(10) reductions in initial inocula] against all strains. Vancomycin produced an E(max) of 2.3 log(10) reductions at 8h against the VSSA and reductions ≤1.8 log(10) for the other strains in the 8-24h period. Pharmacodynamic parameters were fAUC/MBC from 8.0 to 15.6 (vancomycin) and from 56.0 to 111.6 (daptomycin) for tolerant strains, and fAUC/MIC of 126.8 and 63.3 for vancomycin and 222.6 and 113.2 for daptomycin against hVISA and VISA strains, respectively. Against the study strains (vancomycin-susceptible, -tolerant, heteroresistant or intermediate), daptomycin, in contrast to vancomycin, exhibited early bactericidal activity despite its high protein binding., (Copyright © 2011 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.)

Background: Daptomycin is a recently developed cyclic lipopeptide antibiotic active against most Gram-positive pathogens including vancomycin-resistant enterococci and methicillin-resistant Staphylococcus aureus. To optimize treatment efficacy and safety, especially in patients undergoing multiple drug regimens and/or co-morbidities, a specific liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed for the quantification of daptomycin in plasma., Methods: A C18 column was used for separation, with a mobile phase initially consisting of 0.1% formic acid, water, and acetonitrile (ACN) in a linear gradient from 20% to 70%. After protein precipitation with ACN, the clear upper layer was diluted in water:ACN (50:50, v/v) before injection. Detection was performed using an electrospray ionization technique. MS/MS transitions, monitored in the positive ion mode were m/z 811.1 → m/z 313.1 for daptomycin, and m/z 609.4 → m/z 194.9 for reserpine, used as internal standard., Results: Elution of daptomycin and reserpine occurred at 4.5 and 3.9 min, respectively. The method was validated over a range of concentrations from 1 mg/L to 120 mg/L. The assay met recommended acceptance criteria: coefficients of variation were <6.3% and <7.4%, and accuracies were between -5.9% and +11.2% and between -3.5% and +3.7%, for intra- and inter-day validations, respectively., Conclusions: This method appears well-adapted to routine hospital practice for therapeutic drug monitoring of daptomycin considering its time of analysis, range of concentrations measured, precision and accuracy.

Aims: The purpose of this study was to characterize the pharmacokinetics and tolerability of daptomycin in subjects undergoing hemodialysis (HD) or continuous ambulatory peritoneal dialysis (CAPD)., Method: 16 noninfected adults on stable dialysis regimens were enrolled. Daptomycin 6 mg/kg was administered after HD during a 48 h - 48 h - 72 h dialysis week or before a CAPD dwell time over a 48 h - 48 h - 48 h dialysis week. Pharmacokinetic parameters were described, and adverse events were monitored., Results: Daptomycin had mean half-lives in HD subjects of 28.0 and 35.9 h on Days 1 and 5, with corresponding values of 25.8 and 26.7 h in CAPD subjects. Steady state was reached by Day 5 in both groups. At steady state, HD subjects had a mean peak plasma concentration (Cmax) of 81.6 µg/ml and a mean trough concentration of 15.3 µg/ml (on Day 8). In CAPD subjects, Cmax was 93.9 µg/ml and the trough was 20.7 µg/ml (on Day 7). Adverse events were experienced by 71.4% and 66.7% of HD and CAPD subjects, respectively. Most of these were mild or moderate in intensity; however, 2 subjects experienced muscle spasms and mild creatine phosphokinase elevations although neither event was considered to be related to study drug., Conclusions: The pharmacokinetics of daptomycin 6 mg/kg support a dosing regimen of every 48 h in CAPD and thrice-weekly dosing in HD.

Study Objective: To determine whether daptomycin has the potential to be an effective alternative treatment to vancomycin for methicillin-resistant Staphylococcus aureus (MRSA) endogenous endophthalmitis by measuring daptomycin penetration into the vitreous humor., Design: Laboratory analysis of serum and intravitreal fluids to quantify the ratio between vitreous humor and serum daptomycin concentrations., Setting: Critical care unit in a university-affiliated tertiary care medical center., Patient: A 53-year-old woman treated with intravenous daptomycin for MRSA bacteremia, endophthalmitis, and pericarditis., Measurements and Main Results: After the first dose of intravenous daptomycin 10 mg/kg was administered to the patient, serum and intravitreal fluids were analyzed by using high-performance liquid chromatography to determine daptomycin concentrations; pericardial fluid was also analyzed to determine whether adequate levels were present in actively infected tissue. A vitreous concentration of approximately 28% of the serum concentration was achieved. Although therapeutic efficacy could not be assessed in the absence of intraocular cultures, the presence of adequate drug concentrations in the vitreous humor is promising. Ophthalmic infections caused by resistant isolates continue to increase, and effective alternatives to vancomycin, the standard of care, are needed. For endogenous endophthalmitis, these alternative therapies will need to reach therapeutic concentrations in the vitreous humor and adequately penetrate the terminal source of infection. In this analysis, the intravitreal concentration of daptomycin was comparable to concentrations previously reported with vancomycin; thus daptomcyin may be an attractive option when vancomycin therapy fails or is contraindicated. To our knowledge, this is the first report of intravitreal daptomycin concentrations measured in a patient receiving intravenous daptomycin., Conclusion: Adequate concentrations of daptomycin were achieved in the vitreous fluid after a single systemic dose of the drug. Daptomycin may be an effective alternative to vancomycin in patients with ophthalmic infections. Future clinical studies comparing daptomycin with vancomycin in this clinical setting are warranted.

Polythiophene (PTh) and polypyrrole (PPy) as sorbent phases for solid phase microextraction (SPME) were applied in order to extract the multi-resistant Staphylococcus aureus (MRSA) antibiotic drugs (linezolid and daptomycin) from whole blood followed by high performance liquid chromatography (HPLC) determination with UV detection. Relative standard deviations (RSDs) of in vitro and pseudo in vivo measurements performed in whole blood were in the range of 4.58-15.91% and 6.09-17.33% for linezolid and daptomycin, respectively. Determination coefficients (R(2)) were in range of 0.9884-0.9945 and 0.9807-0.9818 for linezolid and daptomycin, respectively. This study proved better adsorption capacity of PTh SPME coating compared to PPy coating for both, linezolid and daptomycin., (Copyright (c) 2010 Elsevier B.V. All rights reserved.)