Population pharmacokinetics of daptomycin in critically ill patients receiving extracorporeal membrane oxygenation.

BACKGROUND: Daptomycin is widely used in critically ill patients for Gram-positive bacterial infections. Extracorporeal membrane oxygenation (ECMO) is increasingly used in this population and can potentially alter the pharmacokinetic (PK) behaviour of antibiotics. However, the effect of ECMO has not been evaluated in daptomycin. Our study aims to explore the effect of ECMO on daptomycin in critically ill patients through population pharmacokinetic (PopPK) analysis and to determine optimal dosage regimens based on both efficacy and safety considerations. METHODS: A prospective, open-label PK study was carried out in critically ill patients with or without ECMO. The total concentration of daptomycin was determined by UPLC-MS/MS. NONMEM was used for PopPK analysis and Monte Carlo simulations. RESULTS: Two hundred and ninety-three plasma samples were collected from 36 critically ill patients, 24 of whom received ECMO support. A two-compartment model with first-order elimination can best describe the PK of daptomycin. Creatinine clearance (CLCR) significantly affects the clearance of daptomycin while ECMO has no significant effect on the PK parameters. Monte Carlo simulations showed that, when the MICs for bacteria are  ≥1 mg/L, the currently recommended dosage regimen is insufficient for critically ill patients with CLCR > 30 mL/min. Our simulations suggest 10 mg/kg for patients with CLCR between 30 and 90 mL/min, and 12 mg/kg for patients with CLCR higher than 90 mL/min. CONCLUSIONS: This is the first PopPK model of daptomycin in ECMO patients. Optimal dosage regimens considering efficacy, safety, and pathogens were provided for critical patients based on pharmacokinetic-pharmacodynamic analysis.

Daptomycin Exposure Prediction With a Limited Sampling Strategy.

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.

A machine learning approach to predict daptomycin exposure from two concentrations based on Monte Carlo simulations.

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.

Daptomycin Dose Optimization in Pediatric Staphylococcus aureus Bacteremia: A Pharmacokinetic/Pharmacodynamic Investigation.

Daptomycin is an antibiotic with Gram-positive activity, including methicillin-resistant Staphylococcus aureus, for which optimal pediatric dosing is unknown. This study aimed to evaluate daptomycin exposures achieved with package label dosing and to identify dosing regimens necessary to enhance efficacy and minimize toxicity in children with S. aureus bacteremia. Monte Carlo simulations were performed to determine probability of target attainment (PTA) for six pediatric age cohorts. Area under the curve to minimum inhibitory concentration ratio (AUC0-24:MIC) ≥666 was used to determine the PTA for efficacy (PTAE). Minimum concentration (Cmin) ≥24.3 mg/L determined the PTA for toxicity (PTAT). Acceptable dosing regimens were those which achieved the combined target of ≥90% PTAE and ≤5% PTAT. Package label dosing of daptomycin yielded insufficient efficacy with only 26.3% PTAE in children 13-24 months, 39.5% PTAE in children 2-6 years, 30.1% PTAE in children 7-11 years, and 50.1% PTAE in adolescents ≥12 years. To achieve the combined efficacy and safety target, doses of 18-24 mg/kg in children 3-12 months, 20-24 mg/kg in children 13-24 months, 19-24 mg/kg in children 2-6 years, 17-19 mg/kg in children 7-11 years, and 10-14 mg/kg in adolescents ≥12 years are necessary. Package label dosing resulted in suboptimal exposure for the majority of pediatric patients in all age groups evaluated. If targeting validated efficacy and safety endpoints, daily daptomycin doses of at least 20 mg/kg in children ≤6 years, 17 mg/kg in children 7-11 years, and 10 mg/kg in adolescents ≥12 years are necessary. Clinical studies evaluating these higher doses are needed.

Comparison of the in vivo efficacy of ceftaroline fosamil, vancomycin and daptomycin in a murine model of methicillin-resistant Staphylococcus aureus bacteraemia.

The need for alternative drugs to treat methicillin-resistant Staphylococcus aureus (MRSA) bacteraemia has led to a focus on ceftaroline, for which clinical data remain scarce. Herein, the efficacy of ceftaroline fosamil for the treatment of experimental MRSA bacteraemia was compared with that of approved therapies. Five MRSA strains were tested in an immunocompetent BALB/c bacteraemia model. Serum pharmacokinetics of ceftaroline fosamil were determined using HPLC/MS Q-TOF. Two hours after infection with the MRSA strains, mice were administered 50 mg/kg of ceftaroline fosamil every 6 h, for 24 h. This regimen yielded a T>MIC of 61.5% for an MIC of 1 mg/L and proved efficacious against all strains, including an hVISA strain with non-susceptibility to daptomycin, as indicated by the reduction (mean ± s.d.) in log10 CFU/mL in blood of 2.34 ± 0.33 and log10 CFU/g in kidney of 2.08 ± 0.22. Similarly, treatment with daptomycin yielded a log reduction of 2.30 ± 0.60 in blood and 2.14 ± 0.31 in kidney. The decrease in bacterial density was less accentuated after treatment with vancomycin, which yielded 1.84 ± 0.73 and 1.95 ± 0.32 log reductions in blood and kidney, respectively. The results of the study showed that the efficacy of ceftaroline fosamil against MRSA bacteraemia in mice is not inferior to that of vancomycin and daptomycin, and indicated the potential use of ceftaroline fosamil against difficult-to-treat S. aureus bacteraemia. Considering these promising data, clinical trials should be conducted to ascertain the efficacy of the drug for treating bloodstream infections in humans.

Physiologically based pharmacokinetic modelling to inform combination dosing regimens of ceftaroline and daptomycin in special populations.

AIMS: The combination of daptomycin and ceftaroline used as salvage therapy is associated with higher survival and decreased clinical failure in complicated methicillin-resistant Staphylococcus aureus (MRSA) infections that are resistant to standard MRSA treatment. This study aimed to evaluate dosing regimens for coadministration of daptomycin and ceftaroline in special populations including paediatrics, renally impaired (RI), obese and geriatrics that generate sufficient coverage against daptomycin-resistant MRSA. METHODS: Physiologically based pharmacokinetic models were developed from pharmacokinetic studies of healthy adults, geriatric, paediatric, obese and RI patients. The predicted profiles were used to evaluate joint probability of target attainment (PTA), as well as tissue-to-plasma ratios. RESULTS: The adult dosing regimens of 6 mg/kg every (q)24h or q48h daptomycin and 300-600 mg q12h ceftaroline fosamil by RI categories achieved ≥90% joint PTA when the minimum inhibitory concentrations in the combination are at or below 1 and 4 µg/mL against MRSA. In paediatrics, wherein there is no recommended daptomycin dosing regimen for S. aureus bacteraemia, ≥90% joint PTA is achieved when the minimum inhibitory concentrations in the combination are up to 0.5 and 2 µg/mL for standard paediatric dosing regimens of 7 mg/kg q24h daptomycin and 12 mg/kg q8h ceftaroline fosamil. Model predicted tissue-to-plasma ratios of 0.3 and 0.7 in the skin and lung, respectively, for ceftaroline and 0.8 in the skin for daptomycin. CONCLUSION: Our work illustrates how physiologically based pharmacokinetic modelling can inform appropriate dosing of adult and paediatric patients and thereby enable prediction of target attainment in the patients during multitherapies.

Daptomycin for the treatment of acute bacterial meningitis: A narrative review.

BACKGROUND: There is growing interest in the utilization of daptomycin for the treatment of multi-drug-resistant, Gram-positive infections. Pharmacokinetic studies suggest that daptomycin could penetrate into the cerebrospinal fluid, albeit to a small extent. The objective of this review was to evaluate the available clinical evidence for the use of daptomycin in acute bacterial meningitis of both paediatric and adult patients. METHODS: Electronic databases were searched up to June 2022 for studies published on the topic. The inclusion criteria were met if the study reported the use of intravenous daptomycin (more than a single dose) for the treatment of diagnosed acute bacterial meningitis. RESULTS: In total, 21 case reports were identified that met the inclusion criteria. These suggest that daptomycin could be a safe and effective alternative to achieve clinical cure of meningitis. In these studies, daptomycin was used in the event of treatment failure, patient intolerance or bacterial resistance to first-line agents. CONCLUSIONS: Daptomycin has potential to be an alternative to standard care for meningitis caused by Gram-positive bacteria in the future. However, more robust research is required to establish an optimal dosing regimen, duration of therapy, and place in therapy for the management of meningitis.

Pharmacokinetics of intravenous daptomycin in Japanese pediatric patients: Pharmacokinetic comparisons supporting dosing recommendations in Japanese pediatric patients.

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.

Population Pharmacokinetic Model for Unbound Concentrations of Daptomycin in Patients with MRSA Including Patients Undergoing Hemodialysis.

BACKGROUND AND OBJECTIVE: Unbound daptomycin concentrations are responsible for pharmacologically beneficial and adverse effects, although most previous reports have been limited to the use of total concentrations. We developed a population pharmacokinetic model to predict both total and unbound daptomycin concentrations. METHODS: Clinical data were collected from 58 patients with methicillin-resistant Staphylococcus aureus including patients undergoing hemodialysis. A total of 339 serum total and 329 unbound daptomycin concentrations were used for model construction. RESULTS: Total and unbound daptomycin concentration was explained by a model that assumed first-order distribution with two compartments, and first-order elimination. Normal fat body mass was identified as covariates. Renal function was incorporated as a linear function of renal clearance and independent non-renal clearance. The unbound fraction was estimated to be 0.066 with a standard albumin of 45 g/L and standard creatinine clearance of 100 mL/min. Simulated unbound daptomycin concentration was compared with minimum inhibitory concentration as a measure of clinical effectiveness and exposure-level-related induction of creatine phosphokinase elevation. The recommended doses were 4 mg/kg for patients with severe renal function [creatinine clearance (CLcr) ≤ 30 mL/min] and 6 mg/kg for patients with mild to moderate renal function (CLcr > 30 and ≤ 60 mL/min). A simulation indicated that dose adjusted by body weight and renal function improved target attainment. CONCLUSIONS: This population pharmacokinetics model for unbound daptomycin could help clinicians to select the appropriate dose regimen for patients undergoing daptomycin treatment and reduce associated adverse effects.

A High Daptomycin Dose Is Associated with Better Bacterial Clearance in Infections Caused by Vancomycin-Resistant Enterococcus faecium Regardless of Daptomycin Minimum Inhibitory Concentration in a Rat Infective Endocarditis Model.

A high daptomycin dose has been suggested for treating vancomycin-resistant Enterococcus faecium (VREf) infections. However, even a 12 mg/kg daptomycin dose might be insufficient for treating VREf with high daptomycin minimum inhibitory concentrations (MICs). Additionally, animal pharmacodynamic and infection models to confirm the efficacy of 12 mg/kg daptomycin are lacking. Male Wistar rats were used for pharmacokinetic profiling and for the development of an infective endocarditis (IE) model. Daptomycin-susceptible dose-dependent VREf (DSE) (MIC of 0.5 mg/L) and daptomycin nonsusceptible VREf (DNSE) (MIC of 8 mg/L) were used for the IE models. The bacterial load of vegetation was the primary outcome and was evaluated after 3 days of daptomycin treatment. Daptomycin administered subcutaneously (s.c.) at 45 and 90 mg/kg, which corresponded to maximum serum concentrations (Cmax) of 122.6 mg/L and 178.5 mg/L, respectively, was equivalent to doses of 8 mg/kg and 12 mg/kg, respectively, in humans. The Cmax/MIC value was correlated with the bacterial load of vegetation after treatment (r = -0.88, P < 0.001). The 90 mg/kg s.c. group showed a significantly lower bacterial load of vegetation (log10 CFU/g) than the 45 mg/kg s.c. group against DSE (0 versus 4.75, P < 0.001) and DNSE (5.12 versus 6.98, P = 0.002). The 90 mg/kg s.c. group did not sterilize the vegetation against DNSE. Although the human equivalent dose of 12 mg/kg daptomycin was more effective than the smaller dose in reducing the bacterial load in DSE and DNSE IE, the dose could not sterilize the vegetation during a DNSE treatment. Further treatment strategies by which to manage severe VREf infections, especially at high daptomycin MICs, are urgently needed. IMPORTANCE Using a rat IE model with pharmacokinetic analysis, the treatment response of VREf IE was found to be daptomycin dose-dependent, presented as Cmax/MIC or as the 24 h area under the concentration-time curve (AUC0-24)/MIC. Daptomycin 90 mg/kg s.c. significantly reduced the bacterial load against DSE and DNSE. It also showed significant activity against DSE and DNSE, compared to 45 mg/kg s.c. Although daptomycin 90 mg/kg can eradicate the bacterial load after 3 days of treatment against DSE, eradication cannot be achieved with 90 mg/kg daptomycin against DNSE.

Ceftobiprole and daptomycin concentrations in valve tissue in a patient with mitralic native valve endocarditis.

Ceftobiprole (CFB), especially in combination, could be a promising alternative treatment for infective endocarditis. A main determinant of clinical response to antibiotic treatment is drug concentration at the infected site. Data on CFB and Daptomycin (DPT) heart valve penetration are lacking.Here we report a clinical case of CFB and DPT treatment combination for endocarditis. Then, we measured CFB and DPT concentrations in a native infected valve to verify their pharmacokinetic penetration and relationship with pharmacodynamic microbiological markers.The isolated microorganism was a MRSA with CFB and DPT MIC < 2 mg/L and <1 mg/L, respectively. The CFB and DPT plasma concentrations were 36.2 and 14.1 mg/L, respectively and the extrapolated concentration, based on each half-life, at the operatory time were 16.4 and 19.1 mg/L for CFB and DPT, respectively; the corresponding median CFB and DPT valve concentrations were 2.26 (IQR 2.14-2.69) and 12.9 µg/g (IQR 5.69-20.9), respectively; the estimated tissue/plasma ratios for CFB and DTP were 0.14 and 0.67, respectively.The association of CFB and DPT showed a good efficacy in this single endocarditis clinical case, confirmed by plasma and tissue PK/PD data.This report shows the first data on CFB valve tissue penetration, and it needs to be confirmed in other patient valve tissues. Moreover, relative studies of correlation with clinical efficacy are needed.

PK/PD modeling of daptomycin against MRSA and MRSE and Monte Carlo simulation for bacteremia treatment.

OBJECTIVES: The aim of this study was to investigate the effect of daptomycin against methicillin-resistant staphylococci (MRSA and MRSE) bacteremia using computer modeling. METHODS: A pharmacokinetic/pharmacodynamic (PK/PD) modeling strategy to explain the data from an in vitro dynamic model employing time-kill curves for MRSA and MRSE was proposed. Bacterial killing was followed over time by determining viable counts and the resulting time-kill data was analyzed. Monte Carlo simulations were performed using pharmacokinetic parameters and pharmacodynamic data to determine the probabilities of target attainment and cumulative fractions of response in terms of area under the concentration curve/minimum inhibition concentration (MIC) targets of daptomycin. Simulations were conducted to assess the reduction in the number of colony-forming units (CFU)/mL for 18 days of treatment with daptomycin at doses of 6, 8, and 10 mg/kg/24 h or 48 h with variations in creatinine clearance (CLCR): 15-29 mL/min/1.73 m2, 30-49 mL/min/1.73 m2, 50-100 mL/min/1.73 m2, as well as for defining the probability of reaching the target fAUC/MIC = 80 in the same dose and clearance range. A PK/PD model with saturation in the number of bacteria in vitro, growth delay, and bacterial death, as well as Hill's factor, was used to describe the data for both MRSA and MRSE. RESULTS: Monte Carlo simulations showed that for MRSA there was a reduction > 2 log CFU/mL with doses ≥ 6 mg/kg/day in 75th percentile of the simulated population after 18 days of treatment with daptomycin, whereas for MRSE this reduction was observed in 95th percentile of the population. CONCLUSIONS: The presented in vitro PK/PD model and associated modeling approach were able to characterize the time-kill kinetics of MRSA and MRSE. Our study based on PTAs suggests that doses ≥ 6 mg/kg/day of daptomycin should be used to treat bacteremia caused by MRSA and MRSE in patients with CLCR of 15-29 mL/min/1.73 m2. For patients with CLCR ≥ 50 mL/min/1.73 m2, it would be necessary to employ a dose of 10 mg/kg/day to treat complicated bacteremias.

Daptomycin Pharmacokinetics and Pharmacodynamics in Patients on Methadone Substitution Therapy.

BACKGROUND AND OBJECTIVE: When administered for severe infections in intravenous drug users (IDUs) at a daily dose of 6 mg/kg, daptomycin displayed abnormal pharmacokinetic parameters compared with those seen in healthy volunteers; specifically, decreased trough and maximum concentrations (Ctrough; Cmax) and increased clearance (CL). The objective of this study was to evaluate the pharmacokinetics and pharmacodynamics of daptomycin administered at a daily dosage of 12 mg/kg for Staphylococcus aureus infective endocarditis (IE) in patients concomitantly treated with methadone, and to compare the results with those published in the literature for healthy controls treated with the same daily dose. METHODS: Antibiotic treatment included daptomycin (12 mg/kg daily) in combination with an antistaphylococcal ß-lactam (cefazolin 2 g three times a day). The minimum inhibitory concentration (MIC) of Staphylococcus aureus isolated through blood cultures was used to calculate pharmacokinetic and pharmacodynamic parameters such as the ratio of the area under the concentration-time curve over 24 h to the MIC (AUC0-24/MIC) and Cmax/MIC. RESULTS: Five IDUs hospitalized for IE were enrolled. The mean measured daptomycin Cmax and Ctrough were 54.1 µg/mL (CV: 0.32) and 8.7 µg/mL (CV: 0.59), respectively; the mean calculated AUC0-24 was 742.7 µg × h/mL (CV: 0.31). The estimated average volume of distribution at the steady state (Vd,ss) and the half-life (t1/2) were 316.5 mL/kg (CV: 0.53) and 14.4 h (CV: 0.30), respectively. The mean daptomycin clearance from plasma normalized for body weight (CLwp) was 17.3 mL/(h × kg) (CV: 0.33). The calculated average Cmax and AUC0-24 (183.7 µg/mL and 1277.4 µg × h/mL, respectively) were lower than and statistically significantly different from (p < 0.001 and p = 0.001, respectively) those expected for healthy volunteers. CONCLUSIONS: Treatment of Staphylococcus aureus IE in IDUs on methadone treatment requires the use of high daptomycin daily doses in order to achieve satisfactory pharmacodynamic parameters. Close monitoring of the daptomycin plasma concentration is suggested.

Optimization of dosing regimens of vancomycin, teicoplanin, linezolid and daptomycin against methicillin-resistant Staphylococcus aureus in neutropenic patients with cancer by Monte Carlo simulations.

The objective of this study was to evaluate the efficacy of various dosing regimens of vancomycin, teicoplanin, linezolid and daptomycin against methicillin-resistant Staphylococcus aureus (MRSA) in neutropenic patients with cancer. Monte Carlo simulations were conducted using pharmacokinetic parameters and pharmacodynamic data to determine cumulative fraction of response (CFRs) in terms of area under the concentration-time curve/minimum inhibition concentration target. Currently clinical standard dosing regimens of vancomycin, teicoplanin, linezolid and daptomycin were insufficient to provide expected CFRs against MRSA for neutropenic patients with cancer. The high dosing regimens of vancomycin (3500 mg/d), teicoplanin (800 mg/d) and daptomycin (8 mg/kg/d) could provide CFRs of ≥ 80%, showing a higher treatment success. However, the majority of CFRs with linezolid simulated dosing regimens reached < 80% against MRSA. Therefore, a strategy of high dosages of vancomycin, teicoplanin and daptomycin may be needed to attain optimal therapeutic efficacy against MRSA in neutropenic patients with cancer.

Population Pharmacokinetic Analysis and Dosing Optimization Based on Unbound Daptomycin Concentration and Cystatin C in Nonobese Elderly Patients with Hypoalbuminemia and Chronic Kidney Disease.

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.

[Development of a Sensitive Enzyme-linked Immunosorbent Assay for Daptomycin].

Daptomycin (DAP) has a completely different mechanism of action compared with conventional drugs for methicillin-resistant Staphylococcus aureus (MRSA) and is widely used as the first-line drug for treatment of dermal soft tissue infection and sepsis caused by MRSA infection in clinical practice. However, DAP has serious side effects, including renal dysfunction and rhabdomyolysis, and thus therapeutic drug monitoring of DAP is recommended. The purpose of this study was to develop an enzyme-linked immunosorbent assay (ELISA) for DAP that is simpler and more sensitive compared with existing assay methods and can be used in pharmacokinetic studies. Anti-DAP antibody was obtained by immunizing mice with an antigen conjugated with mercaptosuccinyl bovine serum albumin using N-(4-maleimidobutyryloxy) succinimide as a heterobifunctional coupling agent. Enzyme labeling of DAP with horseradish peroxidase was performed using pyromellitic dianhydride. The generated antibody and enzyme conjugate were used to develop a highly sensitive and specific ELISA for DAP in human serum. This ELISA shows a linear range of detection from 0.3 to 72.9 ng/mL, and a limit of quantification of approximately 0.3 ng/mL. The developed ELISA should be a valuable tool for pharmacokinetic studies and therapeutic drug monitoring of DAP.

The Antibiotic Peptide Daptomycin Functions by Reorganizing the Membrane.

The mechanism of the antimicrobial peptide daptomycin is reviewed and discussed. Daptomycin is a last-resort antibiotic in current use against drug-resistant bacterial infections. Many models have been proposed for its function, most based on the observation that it increases membrane permeability and causes leakage of contents, such as ions and small molecules from bacterial cells and lipid vesicles. However, daptomycin is actually not efficient at permeabilizing or translocating across membranes, contrary to many well-known antimicrobial peptides. There is strong evidence that daptomycin binds preferentially to membranes in active division regions of bacterial cells and that it causes large membrane reorganization in terms of the distribution of lipids and proteins, both in cells and in model membranes. Those observations support the alternative hypothesis for the mechanism of daptomycin that its primary effect is in inducing membrane reorganization and that other events, such as increased membrane leakage and depolarization, are secondary consequences, not essential to its function.

Clinical Pharmacokinetics of Daptomycin.

Due to the low level of resistance observed with daptomycin, this antibiotic has an important place in the treatment of severe Gram-positive infections. It is the first-in-class of the group of calcium-dependent, membrane-binding lipopeptides, and is a cyclic peptide constituted of 13 amino acids and an n-decanoyl fatty acid chain. The antibacterial action of daptomycin requires its complexation with calcium. Daptomycin is not absorbed from the gastrointestinal tract and needs to be administered parenterally. The distribution of daptomycin is limited (volume of distribution of 0.1 L/kg in healthy volunteers) due to its negative charge at physiological pH and its high binding to plasma proteins (about 90%). Its elimination is mainly renal, with about 50% of the dose excreted unchanged in the urine, justifying dosage adjustment for patients with renal insufficiency. The pharmacokinetics of daptomycin are altered under certain pathophysiological conditions, resulting in high interindividual variability. As a result, therapeutic drug monitoring of daptomycin may be of interest for certain patients, such as intensive care unit patients, patients with renal or hepatic insufficiency, dialysis patients, obese patients, or children. A target for the ratio of the area under the curve to the minimum inhibitory concentration > 666 is usually recommended for clinical efficacy, whereas in order to limit the risk of undesirable muscular effects the residual concentration should not exceed 24.3 mg/L.

Treatment Considerations for CNS Infections Caused by Vancomycin-Resistant Enterococcus faecium: A Focused Review of Linezolid and Daptomycin.

OBJECTIVE: To review the current literature describing pharmacology, pharmacokinetics/pharmacodynamics (PK/PD), efficacy, and safety of linezolid and daptomycin for the treatment of central nervous system (CNS) infections caused by vancomycin-resistant Enterococcus (VRE) faecium. DATA SOURCES: A literature search of PubMed/MEDLINE databases was conducted (from 1950 to April 2020) utilizing the following key terms: vancomycin-resistant Enterococcus, VRE, meningitis, ventriculitis, CNS infection, daptomycin, and linezolid. STUDY SELECTION AND DATA EXTRACTION: All relevant studies and case reports describing the treatment of VRE faecium from the CNS with linezolid or daptomycin were included. DATA SYNTHESIS: A total of 17 reports describing 22 cases were identified. There were 15 of 19 cases involving linezolid that reported clinical cure, of which 53.3% were monotherapy. Only 5 of 9 cases involving intravenous (IV) daptomycin resulted in cure; all 4 cases reporting daptomycin administration via the intrathecal or intraventricular route achieved clearance from the cerebrospinal fluid (CSF). RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: The preferred treatment option for VRE faecium infections involving the CNS remains unclear. Supporting evidence through observational case reports have described varying outcomes with linezolid and daptomycin. This review compares reported outcomes between the 2 agents and provides a thorough discussion on drug- and patient-specific variables to consider. CONCLUSIONS: Linezolid monotherapy appears to be safe and effective for the treatment of susceptible-VRE faecium CNS infections, with consideration of therapeutic drug monitoring in special populations and with prolonged treatment duration. Daptomycin is an effective treatment option via intrathecal or intraventricular administration when neurosurgical access is available. The role of IV daptomycin remains inconclusive.

Daptomycin in the treatment of enterococcal bloodstream infections and endocarditis: a EUCAST position paper.

SCOPE: This position paper describes the view adopted by EUCAST on the role of daptomycin in the treatment of serious infections caused by Enterococcus species. BACKGROUND: High-dose daptomycin is considered effective in the treatment of enterococcal bloodstream infection (BSI) and endocarditis, although published clinical experience with the latter condition is limited. METHODS: EUCAST reviewed the available published data on pharmacokinetics-pharmacodynamics (PK-PD), resistance selection, clinical efficacy and safety for the use of 10-12 mg/kg/day of daptomycin for these conditions, noting that the doses licensed by the European Medicines Agency are only 4-6 mg/kg/day, and only for infections caused by Staphylococcus aureus. FINDINGS AND RECOMMENDATIONS: The PK-PD evidence shows that, even with doses of 10-12 mg/kg/day, it is not possible to treat infections caused by isolates at the upper end of the wild-type distributions of Enterococcus faecalis (with MICs of 4 mg/L) and E. faecium (with MICs of 4 or 8 mg/L). For this reason, and because there are ongoing issues with the reliability of laboratory testing, EUCAST lists daptomycin breakpoints for Enterococcus species as "IE"-insufficient evidence. EUCAST advises increased vigilance in the use of high-dose of daptomycin to treat enterococcal BSI and endocarditis. Additional PK-PD studies and prospective efficacy and safety studies of serious Enterococcal infections treated with high-dose daptomycin may permit the setting of breakpoints in the future.