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Complicated skin and soft tissue infections (cSSTIs) and bacteremia caused by Staphylococcus aureus , including methicillin-resistant S. aureus (MRSA), are common causes of infection for children worldwide. Here, the safety and efficacy of daptomycin in Japanese pediatric participants are reported. This open-label, single-arm phase 2 study (NCT03643952) enrolled Japanese pediatric participants (age 1–17 years) with cSSTI or bacteremia caused by gram-positive cocci. Participants received age-adjusted doses of intravenous daptomycin for 5 to up to 14 days (cSSTI) or 5 to up to 42 days (bacteremia). The primary objective was safety and tolerability; efficacy among participants with infections caused by MRSA was a secondary objective. A total of 18 participants (cSSTI, n = 14; bacteremia, n = 4) were enrolled across 12 study sites in Japan. The most common pathogen was S. aureus (15/18 [83.3%]), including methicillin-susceptible and -resistant isolates. Adverse events (AE) were reported in 42.9% (6/14) of participants with cSSTI and 100% (4/4) of participants with bacteremia. No deaths, serious AEs, discontinuations of study medication due to an AE, or events of clinical interest occurred in the study. In participants with infections caused by MRSA, 87.5% [7/8] achieved favorable clinical response at test of cure (TOC) visit (cSSTI, 85.7% [6/7]; bacteremia, 100% [1/1]). In this population, favorable microbiological response at TOC was achieved by 71.4% (5/7) of participants with cSSTI and 100% (1/1) of participants with bacteremia. Daptomycin was well tolerated, exhibited a favorable safety profile, and was effective for the treatment of cSSTI or bacteremia in Japanese children. [ABSTRACT FROM AUTHOR]

What is known and objective: Daptomycin‐induced creatinine phosphokinase (CPK) elevation is reported to be associated with its trough level (Ctrough; breakpoint of 24.3 μg/mL). However, even with high‐dose treatment (ie, > 8 mg/kg), the safety of daptomycin treatment is widely demonstrated with low or no significant incidence of CPK elevation or other adverse effects, despite the possibility of Ctrough above 24.3 μg/mL. Therefore, we questioned the clinical significance of Ctrough levels of 24.3 μg/mL. In this study, we retrospectively evaluated the significance of Ctrough in the clinical setting, in addition to completing a retrospective safety assessment of daptomycin utilizing electronic health records. Methods: Patients who had received daptomycin treatment for > 4 days from July 2011 to June 2015 were enrolled. Serum daptomycin levels, including Ctrough and peak (Cpeak), were measured by high‐performance liquid chromatography equipped with a photodiode array. To evaluate the safety, patients' characteristics and relevant laboratory test values were reviewed retrospectively using an electronic medical record system. Results and discussion: A total of 52 therapeutic cases for 46 patients were identified; of these, Ctrough and Cpeak levels were measured in 27 and 28 cases, respectively, and 6 patients received multiple courses of daptomycin treatment. The median age of the 52 patients was 68 years (range: 19‐88 years), and 14 patients initially had an estimated creatinine clearance of less than 30 mL/min. Seven cases indicated a Ctrough of above 24.3 μg/mL; however, none of these presented CPK elevation, which meets with the study definition for abnormality. Furthermore, of the two patients with abnormal CPK elevations, only one patient had a measured Ctrough (of 10.9 μg/mL). Their CPK abnormalities were temporal and did not result in treatment discontinuation. The other four patients discontinued daptomycin treatment due to suspicions of adverse effects. Of the discontinued patients, two had measured Ctrough levels; these were 8.6 and 8.1 μg/mL. All patients with abnormal CPK elevation or treatment discontinuation exhibited Ctrough levels lower than 24.3 μg/mL. In this study, two patients receiving high‐dose daptomycin (ie, 9.4 and 10.0 mg/kg) had observed Ctrough levels similar to patients who received doses of daptomycin < 9 mg/kg. What is new and conclusions: The safety of daptomycin treatment was suggested in this study. Ctrough level of 24.3 μg/mL was not suggested as a significant clinical index for the incidence of CPK elevation, adverse effects or treatment discontinuation. Thus, acceptable tolerability towards higher Ctrough levels than 24.3 μg/mL was also suggested, though further studies are required. On the other hand, low levels of daptomycin in blood were unexpectedly observed in two cases, despite the high‐dose treatments. Accordingly, the monitoring of serum daptomycin levels may also be useful to assess cases in which subtherapeutic levels were achieved. [ABSTRACT FROM AUTHOR]

The objective of this study was to explore the optimal dosage regimen of daptomycin and to determine the necessity and validity of a high-dose regimen from the perspectives of PK/PD parameters using Monte Carlo Simulation (MCS) and therapeutic drug monitoring (TDM) in a Japanese clinical setting. The volume of distribution (0.13 ± 0.012 L/kg) in this study was greater than that in healthy volunteers reported in Japan. The range of half-lives was between 8.9 and 34.9 h, which were gradually prolonged as creatinine clearance decreased. In MCS, the cumulative fractions of response (CFR) of the peak/MIC ≧ 60 and the AUC/MIC ≧ 666 at the 6 mg/kg q 24 h were 72.0% and 78.8% but at the 10 mg/kg q 24 h, the CFRs improved to both 99%. In TDM with 6 mg/kg q 24 h regimen, the patients who reached the peak and AUC target were 40% (2 out of 5 patients), respectively. The intraindividual variability in daptomycin PK may indicate the necessity of TDM and high-dose regimen, such as over 8 mg/kg, may be needed to ensure the effectiveness especially on Japanese patients with normal renal function. [ABSTRACT FROM AUTHOR]

Corynebacterium striatum , generally considered an opportunistic organism in humans, has recently been known to develop high-level daptomycin resistance (HLDR) shortly after drug exposure. To date, however, only several such clinical isolates have been described in the literature and clinical background of the resistant pathogen remains to be elucidated. Here, we report a case involving a C. striatum strain with HLDR harboring novel nucleotide mutations, together with a review of the relevant literature. To the best of our knowledge, this is the first well-investigated clinical report from Japan including a genetic investigation. Considering the rapid emergence of HLDR C. striatum in vitro experiment, there could be a number of underreporting cases. Scrupulous attention is required when administering daptomycin for the treatment of C. striatum infections, even if the organism has initially exhibited susceptibility. [ABSTRACT FROM AUTHOR]

Daptomycin is a lipopeptide antibiotic active against gram-positive organisms and recently approved for marketing in Japan. This study investigates the efficacy and safety of daptomycin in Japanese patients with skin and soft tissue infections (SSTIs) caused by methicillin-resistant Staphylococcus aureus (MRSA) for regulatory filing in Japan. Overall, 111 Japanese patients with SSTI were randomized in this open-label, randomized, active-comparator controlled, parallel-group, multicenter, phase III study. Patients received intravenous daptomycin 4 mg/kg once daily or vancomycin 1 g twice daily for 7-14 days. Efficacy was determined by a blinded Efficacy Adjudication Committee. Among patients with SSTIs caused by MRSA, 81.8 % (95 % CI, 69.1-90.9) of daptomycin recipients and 84.2 % (95 % CI, 60.4-96.6) of vancomycin recipients achieved a successful clinical response at the test-of-cure (TOC) visit. The microbiological success rate against MRSA at the TOC visit was 56.4 % (95 % CI, 42.3-69.7) with daptomycin and 47.4 % (95 % CI, 24.4-71.1) with vancomycin. Daptomycin was generally well tolerated; most adverse events were of mild to moderate severity. The measurement of daptomycin concentration in plasma revealed that patients with mild or moderate impaired renal function showed similar pharmacokinetics profiles to patients with normal renal function. Clinical and microbiological responses, stratified by baseline MRSA susceptibility, suggested that patients infected with MRSA of higher daptomycin MIC showed a trend of lower clinical success with a P value of 0.052 by Cochran-Armitage test. Daptomycin was clinically and microbiologically effective for the treatment of MRSA-associated SSTIs in Japanese patients. [ABSTRACT FROM AUTHOR]

Daptomycin is a lipoglycopeptide antibacterial drug that is rapidly bactericidal for methicillin-resistant Staphylococcus aureus (MRSA) infection and has antibiotic activity against a wide range of Gram-positive organisms. It has been approved by the Ministry of Health, Labor and Welfare in Japan for the treatment for bacteremia, right-sided endocarditis, and skin and skin-structure infections, such as necrotizing fasciitis, due to MRSA on the basis of a Phase III trial conducted in Japan since July, 2011. In Japanese Phase I and III trials, daptomycin therapy given at 4 mg/kg and 6 mg/kg once per day was well tolerated and effective as standard therapy for the treatment of acute bacterial skin and skin-structure infections and bacteremia caused by MRSA, but side effects remain to be evaluated in large-scale trials. [ABSTRACT FROM AUTHOR]

Under the Japanese health insurance system, medicines undergoing therapeutic drug monitoring (TDM) can be billed for medical fees if they meet the specified requirements. In Japan, TDM of vancomycin, teicoplanin, aminoglycosides, and voriconazole, which are used for the treatment of infectious diseases, is common practice. This means the levels of antibiotics are measured in-house using chromatography or other methods. In some facilities, the blood and/or tissue concentrations of other non-TDM drugs are measured by HPLC and are applied to treatment, which is necessary for personalized medicine. This review describes personalized medicine based on the use of chromatography as a result of the current situation in Japan.

The aim of this study was to confirm the daptomycin (DAP) susceptibility of bacteria isolated before the launch of DAP in Japan. DAP showed good activity against all 833 isolates (MIC 90 = 0.25–0.5 mg/L for staphylococci, 0.5–4 mg/L for enterococci, and 0.25–0.5 mg/L for streptococci). This is the first report of the in vitro activity of DAP against Gram-positive cocci, including methicillin-resistant Staphylococcus aureus and enterococci, isolated in Japan. [ABSTRACT FROM AUTHOR]

We previously reported the emergence and high prevalence of group B streptococci (GBS) with reduced penicillin susceptibility (PRGBS) clinical isolates in Japan. PRGBS tend to be non-susceptible to macrolides and fluoroquinolones. In our previous study, we found that the minimum inhibitory concentration (MIC) of daptomycin for one clinical isolate of GBS was above the susceptible breakpoint settled by the Clinical and Laboratory Standards Institute (CLSI). This suggests the possibility of the unrecognized spread of daptomycin-non-susceptible clinical GBS isolates in Japan. This study aimed to analyze the daptomycin susceptibility in 1,046 clinical GBS isolates that were recovered after the approval of daptomycin in Japan. MICs of daptomycin for the 1,046 clinical isolates were determined by the microdilution method recommended by the CLSI. The MIC range was 0.12-1 µg/mL, and the MIC 50 and MIC 90 were 0.5 µg/mL and 1 µg/mL, respectively. All the GBS isolates evaluated in this study were susceptible to daptomycin. Therefore, at present, daptomycin might be considered as a new option to treat GBS infections, especially multidrug-resistant PRGBS infections.

High doses of daptomycin (DAP) (>6 mg/kg/day) have been preliminarily recommended in recent practical guidelines for methicillin-resistant Staphylococcus aureus infection, to achieve better clinical effects. While such doses can elevate the plasma trough concentration (Cmin) of DAP, there is an associated risk of creatine phosphokinase (CPK) elevation warranting further investigation. In the current study relationships between DAP Cmin and CPK elevation were investigated, and optimal DAP doses were determined. Plasma DAP concentrations were measured in 20 patients. Logistic regression analysis was performed to assess relationships between DAP Cmin and CPK elevation, then a population pharmacokinetic model of DAP was developed. To determine an optimal DAP dose a Monte Carlo simulation (MCS) was performed to minimize the risk of CPK elevation and maximize the probability of successful treatment. In logistic regression analysis DAP Cmin was significantly associated with CPK elevation (odds ratio 1.21, p = 0.048). With respect to dose-dependent increases in the probability of CPK elevation and exposure to DAP, MCS estimated an optimal DAP dose of 4-6 mg/kg/day, corresponding to a minimum inhibitory concentration (MIC) of ≤0.5 μg/mL. For an MIC of 1 μg/mL, MCS estimated an optimal DAP dose of 10 mg/kg/day. However, the probability of CPK elevation associated with high doses of DAP was higher than that associated with the approved doses. In cases where high doses of DAP are administered, close CPK monitoring is required and therapeutic drug monitoring of DAP may be desirable., (Copyright © 2019 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Background: Daptomycin has been reported to cause artificial prolongation of prothrombin time (PT) by interacting with some test reagents of PT. This prolongation was particularly prominent with high concentrations of daptomycin in vitro. However, whether this prolongation is important in clinical settings and the optimal timing to assess PT remain unclear., Methods: A prospective clinical study was conducted with patients who received daptomycin for confirmed or suspected drug-resistant, gram-positive bacterial infection at a university hospital in Japan. PT at the peak and trough of daptomycin was tested using nine PT reagents. Linear regression analyses were used to examine the difference in daptomycin concentration and the relative change of PT-international normalized ratios (PT-INR)., Results: Thirty-five patients received daptomycin (6 mg/kg). The mean ± standard deviation of the trough and peak concentrations of daptomycin were 13.5 ± 6.3 and 55.1 ± 16.9 μg/mL, respectively. Twelve patients (34%) received warfarin. With five PT reagents, a significant proportion of participants experienced prolongation of PT-INR at the daptomycin peak concentration compared to the PT-INR at the trough, although the mean relative change was less than 10%. None of the participants clinically showed any signs of bleeding. A linear, dose-dependent prolongation of PT was observed for one reagent [unadjusted coefficient β 3.1 × 10 -3 /μg/mL; 95% confidence interval (CI) 2.3 × 10 -5 -6.3 × 10 -3 ; p = 0.048]. When patients were stratified based on warfarin use, this significant linear relationship was observed in warfarin users for two PT reagents (adjusted coefficient β, 6.4 × 10 -3 /μg/mL; 95% CI 3.5 × 10 -3 -9.3 × 10 -3 ; p < 0.001; and adjusted coefficient β, 8.3 × 10 -3 /μg/mL; 95% CI 4.4 × 10 -3 -1.2 × 10 -2 ; p < 0.001). In non-warfarin users, this linear relationship was not observed for any PT reagents., Conclusions: We found that a higher concentration of daptomycin could lead to artificial prolongation of PT-INR by interacting with some PT reagents. This change may not be clinically negligible, especially in warfarin users receiving a high dose of daptomycin. It may be better to measure PT at the trough rather than at the peak daptomycin concentration.

Unlabelled: This was a phase I double-blind, randomized, placebo-controlled, 2-period, single-dose, crossover study in healthy Japanese subjects to evaluate the safety, tolerability, and pharmacokinetics of a single bolus injection of daptomycin. Twenty healthy subjects were randomized; 16 received a single intravenous (IV) administration of 6 mg/kg of daptomycin and 4 received a single intravenous administration of placebo (0.9% sodium chloride) by either bolus injection (10 s) or infusion (30 min) following an overnight fast in Periods 1 or 2. There was a minimum 5-day washout period from the administration in Period 1 to the administration in Period 2. Administration of a single bolus injection of daptomycin 6 mg/kg was generally well tolerated. The geometric mean ratios (GMRs) (90% confidence intervals [CIs]) for AUC0-∞, AUC0-24 h, Cmax, and C24 h of daptomycin in plasma following bolus injection over 10 s relative to IV infusion over 30 min were 1.01 (1.00, 1.03), 1.02 (1.00, 1.03), 1.50 (1.41, 1.60) and 1.05 (1.02, 1.08), respectively. Because no existing studies of this nature were available, Cmax following daptomycin 6 mg/kg/10 s multiple-dose bolus injections was simulated. It was estimated at 178 μg/mL (upper limit) and was expected to be equal to or less than the confirmed Cmax in Japanese or non-Japanese healthy subjects following single- or multiple-dose IV infusion over 30 min. From the results of this study, daptomycin multiple-dose bolus injections over 10 s are expected well tolerated and to have similar Cmax values as IV infusion over 30 min, thus offering potential clinical benefit., Trial Registration: Because this was a phase I trial in healthy subjects, the trial was not registered., (Copyright © 2014 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)