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Daptomycin, an anti‐methicillin‐resistant Staphylococcus aureus drug, causes exposure‐dependent muscle toxicity and eosinophilic pneumonia. Although the area under the concentration‐time curve (AUC)‐guided dosing is crucial, an optimal blood sampling strategy is lacking. This study aimed to identify an optimal limited sampling strategy using Bayesian forecasting to rapidly achieve the target AUC. Two validated population pharmacokinetic models generated a virtual population of 1000 individuals (models 1 and 2 represent diverse patients and kidney transplant recipients, respectively). The AUC for each blood sample was assessed using the probability of achieving the estimated/reference AUC ratio on the second day (AUC24–48) and at the steady state (AUCss). In Model 1, Bayesian posterior probabilities for AUC24–48 increased from 50.7% (a priori) to 59.4% and for AUCss from 48.9% (a priori) to 61.9%, with one‐point Ctrough sampling at 24 h. With two‐point sampling at 7 and 24 h, the probabilities increased to 73.8% for AUC24–48 and 69.7% for AUCss. In Model 2, the probabilities for both AUC24–48 and AUCss with one‐point Ctrough or two‐point sampling incorporating Ctrough sampling increased compared to a priori probabilities. These results suggest that two‐point sampling incorporating Ctrough during initial dosing enhanced achieving the target AUC24–48 and AUCss rapidly. [ABSTRACT FROM AUTHOR]

Background: Daptomycin is a high‐use intravenous antimicrobial agent affording the convenience of once‐daily dosing. Prior studies suggest an opportunity to use a more operationally convenient fixed rather than weight‐based dosing but this approach has not been studied prospectively. Methods: This study quantified the probability of toxicity and efficacy end points by prospectively testing a fixed dose regimen of daptomycin (750 mg) in obese and non‐obese adults. At least, three daptomycin concentrations were measured at steady‐state for each patient. A population pharmacokinetic model was constructed to evaluate concentration‐time profiles and investigate covariates of daptomycin clearance. Simulations were performed to evaluate the probability of achieving efficacy (24‐h area under the curve (AUC0‐24) ≥ 666 mg∙h/L) and toxicity (minimum concentration (Cmin) ≥24.3 mg/L) targets for fixed (500–1000 mg) and weight‐based (6–12 mg/kg) daptomycin doses. Results: Thirty‐one patients (16 females, 15 males) with median (interquartile range (IQR)) age of 50 (30, 62) years and weight of 74 (54, 156) kg were included in the final analysis. Fixed dose daptomycin (750 mg) resulted in similar exposure across weights with a median (IQR) AUC0‐24 of 819 (499, 1501) mg∙h/L and 749 (606, 1265) mg∙h/L in patients weighing ≤74 kg and >74 kg, respectively. Overall, male sex and increased kidney function necessitate higher fixed and weight‐based doses to achieve efficacy. Creatine phosphokinase elevation was observed in two patients (6.5%) and predicted to be lower with fixed versus weight‐based regimens. Conclusions: Fixed daptomycin dosing adjusted for sex and kidney function is expected to improve the efficacy‐to‐toxicity ratio, transitions of care, and costs compared to weight‐based doses. However, no empiric dosing approach is predicted to achieve ≥90% efficacy while minimizing the risk of toxicity, so therapeutic drug monitoring should be considered on a patient‐specific basis. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Daptomycin is a last‐line antibiotic commonly used to treat vancomycin‐resistant Enterococci, but resistance evolves rapidly and further restricts already limited treatment options. While genetic determinants associated with clinical daptomycin resistance (DAPR) have been described, information on factors affecting the speed of DAPR acquisition is limited. The multiple peptide resistance factor (MprF), a phosphatidylglycerol‐modifying enzyme involved in cationic antimicrobial resistance, is linked to DAPR in pathogens such as methicillin‐resistant Staphylococcus aureus. Since Enterococcus faecalis encodes two paralogs of mprF and clinical DAPR mutations do not map to mprF, we hypothesized that functional redundancy between the paralogs prevents mprF‐mediated resistance and masks other evolutionary pathways to DAPR. Here, we performed in vitro evolution to DAPR in mprF mutant background. We discovered that the absence of mprF results in slowed DAPR evolution and is associated with inactivating mutations in ftsH, resulting in the depletion of the chaperone repressor HrcA. We also report that ftsH is essential in the parental, but not in the ΔmprF, strain where FtsH depletion results in growth impairment in the parental strain, a phenotype associated with reduced extracellular acidification and reduced ability for metabolic reduction. This presents FtsH and HrcA as enticing targets for developing anti‐resistance strategies. [ABSTRACT FROM AUTHOR]

Infections caused by Staphylococcus aureus, notably methicillin‐resistant S. aureus (MRSA), pose treatment challenges due to its ability to tolerate antibiotics and develop antibiotic resistance. The former, a mechanism independent of genetic changes, allows bacteria to withstand antibiotics by altering metabolic processes. Here, a potent methylazanediyl bisacetamide derivative, MB6, is described, which selectively targets MRSA membranes over mammalian membranes without observable resistance development. Although MB6 is effective against growing MRSA cells, its antimicrobial activity against MRSA persisters is limited. Nevertheless, MB6 significantly potentiates the bactericidal activity of gentamicin against MRSA persisters by facilitating gentamicin uptake. In addition, MB6 in combination with daptomycin exhibits enhanced anti‐persister activity through mutual reinforcement of their membrane‐disrupting activities. Crucially, the "triple" combination of MB6, gentamicin, and daptomycin exhibits a marked enhancement in the killing of MRSA persisters compared to individual components or any double combinations. These findings underscore the potential of MB6 to function as a potent and selective membrane‐active antimicrobial adjuvant to enhance the efficacy of existing antibiotics against persister cells. The molecular mechanisms of MB6 elucidated in this study provide valuable insights for designing anti‐persister adjuvants and for developing new antimicrobial combination strategies to overcome the current limitations of antibiotic treatments. [ABSTRACT FROM AUTHOR]

Background: Infection with vancomycin‐resistant Enterococcus (VRE) in liver transplant recipients (LTR) has been associated with extended hospital stays, increased readmission rates, graft failure, and death. A tailored perioperative surgical prophylaxis regimen targeting VRE may reduce postoperative infections in VRE‐colonized patients. This study investigated the outcomes of perioperative daptomycin in this patient population. Methods: This retrospective, single‐center cohort study included LTR ≥ 18 years old who were VRE‐colonized from June 2018 to November 2022. VRE colonization was identified by a VRE rectal swab screen or a positive VRE culture prior to transplant. Two groups were analyzed: daptomycin versus no daptomycin. All LTR received perioperative piperacillin‐tazobactam for 24 h. If VRE‐colonized, one dose of daptomycin (6 mg/kg) was given pre‐ and postoperatively. Demographics, clinical characteristics, risk factors for VRE infection, and daptomycin dose were collected. The primary outcome was VRE infection at 14 days and 90 days post‐transplant. Results: There were 36 VRE‐colonized LTR; 19 received daptomycin and 17 did not. Baseline characteristics and risk factors for VRE infection were similar between groups. More VRE infections occurred in the no daptomycin group within 14 days post‐transplant (24% vs. 0%, p =.04), but at 90 days posttransplant there was no significant difference (29% vs. 16%, p =.43). The average daptomycin dose was 7.1 mg/kg. Conclusion: Perioperative daptomycin reduced the rate of VRE infections in VRE‐colonized LTR within 14 days posttransplant but not at 90 days. Future studies should evaluate if higher doses and/or longer duration of perioperative daptomycin can reduce VRE infections beyond 14 days post‐transplant. [ABSTRACT FROM AUTHOR]

Key Clinical Message: Initial antibiotics for true Staphylococcus epidermidis bacteremia include vancomycin or linezolid, but if bacteremia persists, consideration should be made for salvage combination therapy regimes such as daptomycin with ceftaroline. [ABSTRACT FROM AUTHOR]

Streptomyces species have a complex life cycle and are the producers of ~70% of commercial antibiotics. Global regulators AfsR and AfsS are widespread among Streptomyces and have been identified as key activators of antibiotic production in several species. However, their roles as repressors of antibiotic production are unclear; in particular, nothing is known regarding the regulatory mechanism of AfsS, despite many decades of research, because it has no DNA‐binding domain. Here, we demonstrate that AfsR and AfsS negatively regulate avermectin production and morphological development in the industrially important species S. avermitilis. AfsR directly represses ave structural genes (aveA1, aveA4), cluster‐situated activator gene aveR, and eight key developmental genes, whereas it directly activates afsS, aco (for autoregulator avenolide biosynthesis), and avaR1 (encoding avenolide receptor). GST pull‐down, microscale thermophoresis, co‐immunoprecipitation, and chromatin immunoprecipitation‐quantitative PCR assays demonstrated that AfsS interacts with AfsR to co‐regulate target genes involved in avermectin production and development and that this interaction requires intact AfsS repeated sequences and enhances the binding affinity of AfsR to target promoters. AfsR/AfsS interaction also occurs in model species S. coelicolor and S. roseosporus (producer of daptomycin, a cyclic lipopeptide antibiotic widely used for the treatment of human infections), suggesting that such interaction is conserved in Streptomyces species. The master developmental repressor BldD acts as a direct activator of both afsR and afsS. Deletion of afsR or afsS strongly enhances avermectin production in wild‐type and industrial S. avermitilis strains. Our findings demonstrate novel regulatory roles and mechanisms of AfsR and AfsS in Streptomyces and facilitate methods for antibiotic overproduction. [ABSTRACT FROM AUTHOR]

Key Clinical Message: Daptomycin causes serious side effects like rhabdomyolysis at high doses. At lower doses it can cause isolated hyperkalemia without frank rhabdomyolysis. Checking BMP along with CK helps taking timely measures to prevent adverse consequences. Hyperkalemia is a common yet challenging clinical condition faced daily by physicians worldwide. Accurate etiology and timely management are paramount in correcting this preventable yet life‐threatening electrolyte imbalance. Very seldom has Daptomycin been implicated as a culprit for hyperkalemia. We present one such unique case where a low dose of Daptomycin led to hyperkalemia, and timely identification improved patient outcomes. We present a 69‐year‐old woman with multiple comorbidities admitted to the intensive care unit to manage diabetic ketoacidosis and sepsis. She developed acute kidney injury due to intravenous contrast, volume depletion, and obstructive uropathy. Interestingly although initially normokalemic, as her renal function started improving with sound urine output, she developed recurrent hyperkalemia, which required medical management. The etiology of hyperkalemia was initially unclear, but on closer review, it was discovered that Daptomycin was the potential culprit. Although case studies with high‐dose Daptomycin causing rhabdomyolysis and hyperkalemia have been reported, low‐dose Daptomycin causing hyperkalemia without rhabdomyolysis has never been reported, bringing forth the uniqueness of our article. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Aims: Standard doses of daptomycin at 4 and 6 mg/kg were used for the treatment of skin and soft tissue for infections and bacteraemia, respectively. However, increased doses of daptomycin are recommended for complicated infections by Gram-positive organisms. Methods: A systematic review was conducted using 4 databases. We compared treatment success between standard-dose (SD, 4–6 mg/kg) and high-dose (HD, >6 mg/kg) daptomycin in patients with all-cause bacteraemia, complicated bacteraemia, infective endocarditis, osteomyelitis and foreign body/prosthetic infection as the primary outcome. We also compared the success between SD and HD2 (≥8 mg/kg) daptomycin treatments in patients with these diseases as the secondary outcome. The incidence of creatine phosphokinase (CPK) elevation was evaluated as safety. Results: In patients with complicated bacteraemia and infective endocarditis, the treatment success was significantly lower in the SD group than in the HD group (odds ratio [OR] 0.48, 95% confidence interval [CI] 0.30–0.76 and OR 0.50, 95% CI 0.30–0.82) and HD2 group (OR 0.38, 95% CI 0.21–0.69 and OR 0.30, 95% CI 0.15–0.60), respectively. A significant difference was demonstrated only in the HD2 group in patients with bacteraemia, including simple infection. SD did not decrease the success rate for the treatment of osteomyelitis and foreign body/prosthetic infection. The incidence of elevated CPK was significantly lower in SD group than in HD group. Conclusion: SD daptomycin was associated with significantly lower treatment success than HD in patients with complicated bacteraemia/infective endocarditis. The CPK elevation should be considered in patients treated with high daptomycin doses. [ABSTRACT FROM AUTHOR]

The efficiency of drug biosynthesis depends on different transcriptional regulatory pathways in Streptomyces, and the protein degradation system adds another layer of complexity to the regulatory processes. AtrA, a transcriptional regulator in the A‐factor regulatory cascade, stimulates the production of daptomycin by binding to the dptE promoter in Streptomyces roseosporus. Using pull‐down assays, bacterial two‐hybrid system and knockout verification, we demonstrated that AtrA is a substrate for ClpP protease. Furthermore, we showed that ClpX is necessary for AtrA recognition and subsequent degradation. Bioinformatics analysis, truncating mutation, and overexpression proved that the AAA motifs of AtrA were essential for initial recognition in the degradation process. Finally, overexpression of mutated atrA (AAA‐QQQ) in S. roseosporus increased the yield of daptomycin by 225% in shake flask and by 164% in the 15 L bioreactor. Thus, improving the stability of key regulators is an effective method to promote the ability of antibiotic synthesis. [ABSTRACT FROM AUTHOR]

Study Objective: The preferred antibiotic salvage regimen for persistent methicillin‐resistant Staphylococcus aureus bacteremia (MRSAB) is unclear. We sought to evaluate the effectiveness and safety of vancomycin plus ceftaroline for persistent MRSAB. The primary outcome was time to MRSAB clearance post‐ceftaroline initiation. Secondary outcomes included microbiological cure, hospital length of stay, 90‐day readmission for MRSAB, 90‐day all‐cause mortality, MRSAB‐related mortality, and incidence of antibiotic‐associated adverse effects. Design: Single‐center, retrospective cohort study between January 1, 2016, and December 31, 2021. Setting: State University of New York Upstate University Hospital, a 748‐bed tertiary care, academic medical center in Syracuse, NY. Patients Adult patients were included if they had blood cultures positive for MRSA ≥72 h, received vancomycin monotherapy initially, and received vancomycin plus ceftaroline for ≥24 h. Patients were excluded if they received other anti‐MRSA antibiotics, were pregnant, or were incarcerated. Of the 178 patients identified, 30 unique patients were evaluated. Measurements and Main Results: Patients were medically complex with a median Pitt bacteremia score of 3, 63.3% (19/30) were admitted to the intensive care unit, and 66.7% (20/30) had infective endocarditis. Vancomycin‐associated acute kidney injury was observed in 10% (3/30) of patients, which resulted in dose adjustments. No patients experienced ceftaroline‐associated neutropenia or Clostridioides difficile infection, but 6.7% (2/30) developed a rash attributed to ceftaroline. Median time to MRSAB clearance post‐ceftaroline initiation was 2.6 days. Microbiologic cure occurred in nearly all patients 96.7% (29/30). Median hospital length of stay was 19.5 days, and 6.7% (2/30) of patients had 90‐day readmission for MRSAB. 90‐day all‐cause mortality and MRSAB‐related mortality occurred in 26.7% (8/30) and 13.3% (4/30) of patients, respectively. Conclusions: Vancomycin plus ceftaroline may represent an effective and well‐tolerated salvage regimen option for persistent MRSAB. [ABSTRACT FROM AUTHOR]

Daptomycin (DAP) is a cyclic lipopeptide antibiotic produced by Streptomyces roseosporus, and its biosynthesis is precisely regulated by a complex regulatory network. Although the biosynthetic pathway of DAP has been elucidated, the regulatory mechanism governing its biosynthesis at the transcriptional level is not yet fully understood. In the present study, a new transcriptional regulator, DhyR, was identified. A deletion mutant of dhyR was constructed using the CRISPR-Cas9 tool to elucidate the biological role of DhyR thanks to functional and transcriptomic analyses. The results demonstrated that DhyR positively regulates DAP biosynthesis in S. roseosporus. The in-frame deletion of the dhyR gene resulted in a significant downregulation of the transcription levels of all structural genes within the DAP biosynthetic gene cluster and a significant decrease in DAP yield. In contrast, overexpression of dhyR enhanced the transcription levels of the DAP biosynthetic gene cluster, leading to a 23% increase in DAP yield. Deletion of dhyR caused significant changes in the expression of multiple genes involved in carbohydrate metabolism, energy metabolism and amino acid metabolic pathways through transcriptome analysis. Especially, deletion of dhyR led to a significant downregulation of transcription levels of three DAP biosynthesis-associated genes, including atrA, depR1 and ssig-05090. In summary, DhyR positively regulates DAP biosynthesis in S. roseosporus by influencing the expression of the DAP gene cluster and modulating precursor flux. It functions as a pleiotropic regulator of primary and secondary metabolism in S. roseosporus., (© 2025 The Author(s). Microbial Biotechnology published by John Wiley & Sons Ltd.)

Herein, we report the synthesis and antibacterial evaluation of a series of daptomycin lactam‐based analogues. As compared with daptomycin, the daptomycin analogue with singly modified lactam has an eightfold increase in its minimum inhibitory concentration (MIC) against methicillin‐resistant Staphylococcus aureus. Incorporating effective modifications found in previous daptomycin structure–activity relationship studies to produce lactam‐based analogues with multiple modifications did not improve the antibacterial activity of the analogues. Instead, the antibacterial activity was greatly reduced when a rather rigid 4‐(phenylethynyl)benzoyl group replaced the flexible n‐decanoyl group. The fact that the lactam analogue with the 4‐(phenylethynyl)benzoyl group did not exhibit the antibacterial activity comparable to the two respective singly modified analogues showed that the inactivity was probably due to the deviation from the active conformation. This series of lactam analogues may generate insights on the importance of studying the active conformation of daptomycin and how the structural modifications affect the active conformation. [ABSTRACT FROM AUTHOR]

Herein, we report the synthesis of a daptomycin thiolactone analogue via the MeDbz‐linker based on resin self‐cleaving macrocyclization pathway. A detailed investigation of the reaction conditions is reported, including the variation of the cyclization buffer, temperature, concentration, and reaction time. Severe hydrolysis was observed under most of the conditions screened, presumably due to the low reactivity of (2R,3R)‐β‐methylcysteine (thioThr) used. Eventually, pyridine/acetic acid buffer was identified as the most viable solvent system to afford the hydrolysis‐free product. We perceive that this optimized protocol will enable the synthesis of other challenging thiolactone peptides, possibly those involving thioThr or penicillamine. [ABSTRACT FROM AUTHOR]

In a 2018 review of 196 case reports of drug-induced eosinophilic pneumonia, daptomycin was the leading cause.[2] Daptomycin-associated pulmonary toxicity has predominantly been described in hosts without underlying immunosuppression and is typically associated with eosinophilia.[[3], [5]] Although the use of daptomycin in the neutropenic and HCT patient population is now commonplace,[[6], [8]] there have been no published cases of daptomycin-associated pulmonary toxicity in this population. Additional research to clarify the pathophysiology of daptomycin-associated pulmonary toxicity is needed, as well as additional data on the safety and toxicity profile of daptomycin in HCT recipients. Daptomycin-associated pulmonary toxicity sans eosinophilia in a hematopoietic cell transplant recipient with profound leukopenia Keywords: daptomycin; eosinophilic pneumonia; hematopoietic stem cell transplant recipient; pulmonary toxicity EN daptomycin eosinophilic pneumonia hematopoietic stem cell transplant recipient pulmonary toxicity 1 3 3 06/19/23 20230601 NES 230601 To The Editor, A 44-year-old woman with relapsed high-risk myelodysplastic syndrome following allogeneic hematopoietic cell transplant (HCT) in October 2021, with subsequent transformation to acute myelogenous leukemia was admitted to the hospital for fever, hypotension, and dry cough. [Extracted from the article]

Aims: The present systematic review and meta‐analysis evaluated the incidence of elevated creatine phosphokinase (CPK) levels between daptomycin alone and concomitant daptomycin and statin use. Methods: We searched the PubMed, Web of Sciences, Cochrane Library and ClinicalTrials.gov databases. We analysed the incidence of elevated CPK between daptomycin alone and concomitant daptomycin and statins among studies defining CPK elevation as levels ≥ the upper limit of normal (ULN) or ≥5× ULN. We also analysed the incidence of rhabdomyolysis between the groups. We then calculated the odds ratios (ORs) and 95% confidence intervals (CIs) based on the included studies. Results: Comparing CPK elevation defined as CPK levels ≥ULN, a significantly higher incidence of CPK elevation was observed with concomitant daptomycin and statin use than with daptomycin alone (OR = 2.55, 95% CI 1.78–3.64, P <.00001, I2 = 0%). Likewise, when CPK elevation was defined as CPK levels ≥5× ULN, a significantly higher incidence of CPK elevation was detected with concomitant daptomycin and statin use than with daptomycin alone (OR = 1.89, 95% CI 1.06–3.35, P =.03, I2 = 48%). The incidence of rhabdomyolysis was significantly higher following concomitant daptomycin and statin use than with daptomycin alone (OR = 11.60, 95% CI 1.81–74.37, P =.01, I2 = 0%). Conclusion: The combined use of daptomycin and statins were significant risk factors for the incidence of CPK elevation defined as levels ≥ULN or ≥5× ULN and rhabdomyolysis. [ABSTRACT FROM AUTHOR]

Aims: Musculoskeletal toxicity is a typical side effect of daptomycin (DAP). However, the risk factors have not been well established. Here, we aimed to identify independent factors affecting DAP‐induced musculoskeletal toxicity using a combination of machine learning and conventional statistical methods. Methods: A population‐based, retrospective, observational cohort study was conducted using the Japanese electronic medical record database. Patients who received DAP between October 2011 and December 2020 were enrolled. Two definitions of musculoskeletal toxicity were employed: (1) elevation of creatine phosphokinase (CPK) value more than twice from baseline and >200 IU/L, and (2) >1000 IU/L. First, multiple logistic regression analyses (a conventional statistical method) were performed to identify independent factors affecting CPK elevation. Then, decision tree analyses, a machine learning method, were performed to detect combinations of factors that change CPK elevation risk. Results: Of the 2970 patients who received DAP, 706 were included. Elevation of CPK values >200 IU/L and >1000 IU/L occurred in 83 (11.8%) and 17 (2.41%) patients, respectively. In multiple logistic regression analysis, baseline CPK value and concomitant use of hydrophobic statins were commonly extracted as independent factors affecting each CPK elevation, but concomitant use of hydrophilic statins was not. In decision tree analysis, patients who received hydrophobic statins and had high baseline CPK values were classified into the high‐risk group. Conclusion: Our novel approach revealed new risk factors for CPK elevation. Our findings suggest that high‐risk patients require frequent CPK monitoring. [ABSTRACT FROM AUTHOR]

Daptomycin (dap) is an important antibiotic that interacts with the bacterial membrane lipid phosphatidylglycerol (PG) in a calcium‐dependent manner. The enantiomer of dap (ent‐dap) was synthesized and was found to be 85‐fold less active than dap against B. subtilis, indicating that dap interacts with a chiral target as part of its mechanism of action. Using liposomes containing enantiopure PG, we demonstrate that the binding of dap to PG, the structural transition that occurs upon dap binding to PG, and the subsequent oligomerization of dap, depends upon the configuration of PG, and that dap prefers the 1,2‐diacyl‐sn‐glycero‐3‐phospho‐1′‐sn‐glycerol stereoisomer (2R,2′S configuration). Ent‐dap has a lower affinity for 2R,2′S liposomes than dap and cannot oligomerize to the same extent as dap, which accounts for why ent‐dap is less active than dap. To our knowledge, this is the first example whereby the activity of an antibiotic depends upon the configuration of a lipid head group. [ABSTRACT FROM AUTHOR]

What is known and objective: The rhabditid nematode Strongyloides stercoralis is the major causative agent of disseminated strongyloidiasis (DS). In rare cases, DS has caused enterococcal meningitis. If DS‐associated vancomycin‐resistant Enterococcusfaecium (VRE) meningitis is suspected, combination antibiotic therapy should be considered. Case Summary: We present a case of a 61‐year‐old male who developed DS associated with vancomycin‐resistant and linezolid‐intermediate E. faecium meningitis after receiving corticosteroids. The VRE meningitis was treated with high‐dose daptomycin 12 mg/kg, linezolid, tigecycline and quinupristin/dalfopristin. Despite negative cultures, the patient expired. What is new and conclusion: In patients with DS‐associated VRE meningitis, early use of combination therapy may be warranted to improve patient outcomes. [ABSTRACT FROM AUTHOR]

BACKGROUND: Daptomycin is an effective clinical drug for treating Staphylococcus aureus bacteraemia. Daptomycin and its derivatives are essential resources for antimicrobial screening and drug development. The daptomycin nucleus is a critical intermediate for producing daptomycin and its derivatives; it is catalysed by deacylase from Actinoplanes utahensis. However, the yield of the daptomycin nucleus was low by the original strain. RESULTS: In this study, the deacylase gene was overexpressed in the heterologous hosts of three different Streptomyces strains, and the efficiency of recombinant Streptomyces coelicolor was higher than that of the other two strains. Daptomycin and its nucleus were isolated, their structures were identified by nuclear magnetic resonance (NMR) and liquid chromatography‐mass spectrometry (LC–MS), and its bioconversion was confirmed by high‐performance liquid chromatography (HPLC). The optimal conditions were a phosphate buffer with 0.2 mol L−1 KCl, pH 7.0, and temperature of 40 °C, with a reaction time >4 h; in these conditions, the bioconversion efficiency increased from 71.04% to 85.02%, which is an increase of 16.44%. In addition, daptomycin nucleus yield could reach 4.36 g L−1 when 8 g L−1 daptomycin was added to the 200 mL reaction system by recombinant S. coelicolor, and the yield was 1.23 g L−1 when 6 g L−1 of daptomycin was introduced into wild‐type strain in a preliminary study for further industrialization applications. CONCLUSION: These results are helpful for enhancing daptomycin nucleus production in recombinant Streptomyces. Our work could make it possible to commercialise the daptomycin nucleus‐overproducing stains and provide a library of chemical substances for antibacterial screening and drug development. © 2021 Society of Chemical Industry (SCI). [ABSTRACT FROM AUTHOR]

However, daptomycin users who also took statins had an even higher muscle toxicity than daptomycin users without statins (ROR, 3.44; 95% CI [1.40, 8.41]; I p i = .010; Table 1). Concomitant use of daptomycin and statins might be a high risk,3 although some reports have indicated no significant difference between concomitant statin use and muscle toxicity in daptomycin users.4,5 Therefore, the risk of muscle toxicity in daptomycin users remains controversial. Keywords: creatine phosphokinase; daptomycin; muscle toxicity; rhabdomyolysis; statin EN creatine phosphokinase daptomycin muscle toxicity rhabdomyolysis statin 268 272 5 08/19/21 20210901 NES 210901 Abbreviations BMI body mass index CKD chronic kidney disease CPK creatine phosphokinase DAP daptomycin JADER Japanese Adverse Drug Event Report MRSA methicillin-resistant Staphylococcus aureus INTRODUCTION AND BACKGROUND Daptomycin is an important antibiotic against most Gram-positive pathogens, including methicillin-resistant I Staphylococcus aureus i (MRSA), and is recommended as a first-line antibiotic in patients with bacteraemia, infective endocarditis and osteomyelitis.1 However, the use of daptomycin is associated with severe muscle toxicity, such as rhabdomyolysis,1,2 and these events can complicate treatment of infections and worsen patients' outcomes. DISCUSSION Our study showed that concomitant statin and daptomycin users had higher muscle toxicity than daptomycin users without statins, although we did not detect a signal of muscle toxicity in vancomycin users with or without statins. [Extracted from the article]

Streptococcus agalactiae, also known as Group B Streptococcus (GBS), is increasingly recognized as a major cause of soft tissue and invasive diseases in the elderly and diabetic populations. Antibiotics like penicillin are used with great frequency to treat these infections, although antimicrobial resistance is increasing among GBS strains and underlines a need for alternative methods not reliant on traditional antibiotics. GBS granadaene pigment is related to the hemolysin/cytolysin of GBS, which is critical for the pathogenesis of GBS diseases. Here, we show that photobleaching granadaene dampens the hemolytic activity of GBS. Furthermore, photobleaching of this antioxidant was found to increase GBS susceptibility to killing by reactive oxygen species like hydrogen peroxide. Treatment with light was also shown to affect GBS membrane permeability and contribute to increased susceptibility to the cell membrane‐targeting antibiotic daptomycin. Overall, our study demonstrates dual effects of photobleaching on the virulence and antimicrobial susceptibility of GBS and suggests a novel approach for the treatment of GBS infection. [ABSTRACT FROM AUTHOR]

What is known: Daptomycin is associated with a number of adverse effects including eosinophilic pneumonia, hypersensitivity reaction, myopathy, rhabdomyolysis, headache and transaminitis. The adverse effects of high‐dose daptomycin have not been fully evaluated in patients with end‐stage renal disease (ESRD). Objective: To determine the incidence and characteristics of significant adverse effects in patients receiving high‐dose daptomycin with severe renal dysfunction. Methods: A single‐centre, retrospective study was conducted to assess safety outcomes of high‐dose daptomycin in patients with an estimated creatinine clearance less than 30 mL/min. Adult patients aged 18 to 89 years admitted between 1 July 2015 and 1 July 2019 were eligible for inclusion. Patients must have received definitive daptomycin therapy with doses greater than or equal to 7.5 mg/kg based on actual body weight. The primary outcome was overall incidence of creatine phosphokinase (CK) elevation, myopathy and rhabdomyolysis. Results and discussion: A total of 74 patients who received daptomycin therapy were screened with 50 included in the study. The population was well distributed in terms of gender (48% male, n = 24) with a median age of 61 (IQR, 48‐67) years. The primary indication for daptomycin use was Gram‐positive bacteremia. The median daptomycin dose was 750 (IQR, 600‐875) mg, or 8.46 (IQR, 7.92‐9.96) mg/kg based on actual body weight, with a median patient weight of 81 (IQR, 65‐113) kg. The median duration of therapy was 27 (IQR, 14‐42) days. One patient experienced significant CK elevation while on daptomycin therapy with rhabdomyolysis; however, daptomycin was continued as there was an alternative explanation for an elevated CK. One patient experienced daptomycin discontinuation due to CK elevation without meeting the definition for significant CK elevation. What is new and conclusion: In a cohort of patients with severe renal dysfunction treated with daptomycin 7.5 mg/kg or greater, significant CK elevation on daptomycin therapy was infrequently observed. Future research should confirm these findings, with special consideration for higher mg/kg dosages and/or obese populations. [ABSTRACT FROM AUTHOR]

Summary: Daptomycin (DAP) is a novel microbial lipopeptide antibiotic synthesized by the DAP biosynthetic gene cluster dpt of Streptomyces roseosporus (S. roseosporus). DptP gene locates upstream of dpt and confers DAP resistance to Streptomyces ambofaciens (S. ambofaciens). So far, the biological functions of dptP gene for S. roseosporus growth are still completely uncovered. We performed label‐free quantification proteomic dissections with loss‐ and gain‐of‐function experiments to decipher dptP‐involved functions. Deletion of dptP gene activated energy metabolism and metabolism of secondary metabolites pathways and enhanced the transcription levels and protein abundance of key members of the dpt cluster. Whereas dptP deletion inhibited transport/signal transduction and drug resistance pathways and protein abundance of cell division‐relative proteins, subsequently decreased mycelia cell growth rate. S. roseosporus strain with dptP deletion was more sensitive to DAP treatment compared to the wild type. In contrast, overexpression of dptP gene decreased transcription levels of DAP biosynthetic genes and enhanced growth rate of Streptomcyes strain upon elevated culture temperature and DAP supplementation. Taken together, dptP gene contributes to Streptomcyes primary growth under elevated temperature and DAP treatment, whereas it plays negative roles on metabolism of secondary metabolites and transcription of DAP biosynthetic genes. [ABSTRACT FROM AUTHOR]

Daptomycin (DAP) is a calcium (Ca2+)‐dependent FDA‐approved antibiotic drug for the treatment of Gram‐positive infections. It possesses a complex pharmacophore hampering derivatization and/or synthesis of analogues. To mimic the Ca2+‐binding effect, we used a chemoenzymatic approach to modify the tryptophan (Trp) residue of DAP and synthesize kinetically characterized and structurally elucidated regiospecific Trp‐modified DAP analogues. We demonstrated that the modified DAPs are several times more active than the parent molecule against antibiotic‐susceptible and antibiotic‐resistant Gram‐positive bacteria. Strikingly, and in contrast to the parent molecule, the DAP derivatives do not rely on calcium or any additional elements for activity. [ABSTRACT FROM AUTHOR]

What is Known and Objective: Our previous report indicated that teicoplanin (TEIC) caused fewer adverse effects than vancomycin (VCM) in patients with febrile neutropenia (FN) receiving haematopoietic stem cell transplantation (HSCT). However, we observed breakthrough methicillin‐resistant‐Staphylococcus haemolyticus (MR‐S haemolyticus) infection during TEIC therapy in these patients. In this study, we sought to compare the incidence of breakthrough Gram‐positive cocci (GPC) infection during VCM and TEIC therapy in this population. Methods: A single‐centre, retrospective cohort study was conducted. Patients who had received HSCT and were administered VCM (n = 19) or TEIC (n = 38) for FN from 1 September 2011 to 31 August 2019 were enrolled. We compared the incidence of breakthrough GPC infection between the VCM and TEIC groups. Results: Breakthrough GPC infection during glycopeptide therapy in febrile neutropenic patients received HSCT was observed in three patients (7.9%) in the TEIC group but in none of patients (0%) in the VCM group. MR‐S haemolyticus with low glycopeptide susceptibility (TEIC MIC = 2‐8 μg/mL, VCM MIC = 2‐4 μg/mL) was isolated from blood cultures in all patients with breakthrough GPC infections. All breakthrough infections were cured by changing from TEIC to daptomycin (DAP). What is New and Conclusion: The incidence of breakthrough GPC infection during glycopeptide therapy in febrile neutropenic HSCT patients was higher in the TEIC group than in the VCM group. MR‐S haemolyticus with low glycopeptide susceptibility was isolated from all patients with breakthrough GPC infection and successfully treated with DAP. [ABSTRACT FROM AUTHOR]

Introduction : Observational and randomized controlled trials of the combination of vancomycin or daptomycin with a beta‐lactam (BL) in patients with methicillin‐resistant Staphylococcus aureus (MRSA) bacteremia have shown conflicting results on patient outcomes. Objectives : The primary purpose of this meta‐analysis was to compare clinical failure with the combination of vancomycin or daptomycin with a BL versus vancomycin or daptomycin monotherapy in MRSA bacteremia or endocarditis. Methods : A systematic literature search of PubMed, Embase, CINAHL, and meeting proceedings was conducted from inception through February 11, 2020, to identify relevant studies. The primary outcome was clinical failure and secondary outcomes were mortality, nephrotoxicity, and bacteremia. The meta‐analysis was performed using Comprehensive Meta Analysis (version 3.0) with a random effects model. Outcomes were reported as odds ratios (ORs) with corresponding 95% confidence intervals (CIs). Results : Nine studies of 1636 patients receiving vancomycin or daptomycin monotherapy versus the combination of vancomycin or daptomycin plus BL for MRSA bacteremia were included. Results showed combination therapy was associated with significantly lower clinical failure rates (OR 0.56, 95% CI 0.39–0.79, I2 = 26.22%, p=0.001). Improvement in clinical failure was driven by lower rates of bacteremia relapse and persistence. However, no difference was seen with mortality. Conclusions : Combination therapy with vancomycin or daptomycin plus BL for MRSA bacteremia showed lower clinical failure rates, however, no significant difference was seen in mortality. [ABSTRACT FROM AUTHOR]

Background: Vancomycin‐resistant Enterococcus (VRE)‐colonized liver transplantation (LT) recipients have increased post‐LT morbidity, mortality, and higher rates of VRE infections compared with their non‐colonized counterparts. Pre‐LT screening for VRE colonization and inclusion of daptomycin in the perioperative antibiotic prophylaxis regimen may mitigate this risk. Methods: We performed a retrospective chart review of liver transplant recipients aged ≥ 18 years between 2013 and August 2019 to identify pre‐LT VRE‐colonized recipients and whether they received daptomycin perioperative prophylaxis (DPP). Demographic and clinical characteristics, including risk factors for VRE infection, were collected. Outcomes measured were VRE‐related infection and all‐cause mortality within 90 days of LT. Results: Of the 27 VRE‐colonized liver transplant recipients within the study period, 25 received DPP. All recipients were admitted to the intensive care unit postoperatively, six (24%) required reoperation, fifteen (60%) required renal replacement therapy, and eight (32%) experienced postoperative hemorrhage within 90 days post‐transplant. Two recipients (8%) experienced acute cellular rejection, but no primary graft failure was seen within 90 days. Among those who received DPP, no infections related to VRE or death was seen within 90 days of LT. The two VRE‐colonized recipients who did not receive DPP both developed VRE bacteremia in the early post‐LT period. Conclusion: Despite having multiple risk factors for post‐LT VRE infection, VRE‐colonized recipients who received DPP did not develop VRE‐related infections in the first 90 days post‐LT. Our experience demonstrates that pre‐LT VRE screening and DPP may be associated with a reduction in VRE infection in the early post‐LT period, but this strategy warrants further evaluation in prospective studies. [ABSTRACT FROM AUTHOR]

The objective of this study was to evaluate the efficacy of various daptomycin dosing regimens against Staphylococcus aureus and Enterococcus faecium in pediatric patients with proven/suspected gram‐positive infection. Monte Carlo simulations (MCSs) were conducted using pharmacokinetic (PK) parameters and pharmacodynamic (PD) 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. According to the results of the MCSs, currently approved pediatric dosage regimens were sufficient against Staphylococcus aureus with MIC ≤ 0.5 μg/mL for all pediatric patients, but poor when MIC ≥ 1 μg/mL except for adolescents (12‐17 years) who need a dosage of ≥10 mg/kg/day at MIC = 1 μg/mL. For Enterococcus faecium with MIC ≤ 4 μg/mL, the recommended dosage of 8‐12 mg/kg/day in adults was enough for adolescents, but not subjected to younger pediatric patients. Furthermore, based on MIC distributions obtained from the European Committee on Antimicrobial Susceptibility Testing, the approved high‐dose regimen should be recommended for infants aged 3‐12 months, children (2‐11 years), and adolescents to achieve better clinical efficacy against methicillin‐resistant Staphylococcus aureus. In addition, the dosage of 8‐12 mg/kg/day was powerful against Enterococcus faecium for adolescents; however, only the highest dosage of 12 mg/kg/day was effective for infants aged 3‐12 months and children. All the simulated regimens were not optimal for infants aged 13‐24 months. These PK/PD‐based simulations rationalize and optimize the dosage regimens of daptomycin against Staphylococcus aureus and Enterococcus faecium in pediatric patients. [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]

Optimal antimicrobial therapy for Enterococcus faecium bloodstream infection (EFBSI) in the solid organ transplant (SOT) population is not well defined. The purpose of this study was to describe the pharmacotherapy and outcomes of EFBSI in SOT patients. This was a single‐center retrospective cohort of SOT patients with EFBSI from 2013 to 2019. Susceptibility testing was performed with Vitek® 2 or Etest. Estimates of optimal DAP pharmacokinetic/pharmacodynamic exposures (dose <10 mg/kg, fAUC/MIC >27.4) were made from previously established literature and equations. Fifty‐one unique cases were included in the analysis. The median age was 61 years and liver (64%), intestinal (19%), and kidney (12%) were the most common organs transplanted. Most patients had indwelling central lines (75%) at the time of bacteremia; intra‐abdominal abscesses/fluid collections were present in 44% of patients and 8% had endocarditis. Nineteen (37%) patients had polymicrobial infections. The most common definitive antimicrobial regimens were as follows: DAP plus beta‐lactam (46%), DAP monotherapy (18%), and LZD (25%). Of the 33 patients that received DAP, 21% of E faecium isolates developed DAP resistance. 30‐day mortality was 25% overall but higher in patients who received an initial DAP dose <10 mg/kg (43% vs 13%). Vancomycin‐resistance, severity of illness, neutropenia, and source control were also associated with mortality. Inadequate DAP dosing for EFBSI may be associated with mortality in the SOT population. Larger, controlled analyses are necessary to determine the impact of optimized pharmacodynamics in this population. [ABSTRACT FROM AUTHOR]

What is known and objective: Studies have demonstrated that ECMO leads to pharmacokinetic changes, with alterations in volume of distribution, clearance and drug sequestration by the circuit. We describe a successful dosing approach for daptomycin and micafungin for the treatment of VRE faecium bacteremia and C. glabrata fungemia in a patient receiving veno‐venous ECMO and CRRT. Case summary: We report a case of a patient with ARDS on veno‐venous ECMO complicated by VRE faecium bacteremia and C. glabrata fungemia. The patient was treated with daptomycin 10 mg/kg every 24 h and micafungin 150 mg every 24 h for 14 days. Key observations included the documented bacteremia and fungemia clearance without the need for ECMO circuit exchange. What is new and conclusion: This case report demonstrates successful bacteremia and fungemia clearance in an adult without the need for ECMO circuit exchange. It also highlights the need for more research to identify optimal antimicrobial dosing strategies in similar scenarios. [ABSTRACT FROM AUTHOR]

Vancomycin and daptomycin are often used in outpatient parenteral antimicrobial therapy for gram‐positive coverage. Vancomycin's narrow therapeutic window poses challenges. We retrospectively assessed acute kidney injury (AKI) and other adverse drug events in outpatient parenteral antimicrobial therapy patients receiving vancomycin or daptomycin at home after hospital discharge. Among 191 patients included, AKI was the most common adverse drug event. Early antibiotic discontinuation and AKI were more frequent in the vancomycin group. Vancomycin use (odds ratio [OR], 4.57; 95% confidence interval [CI], 1.02‐20.51); p = 0.04], female sex (OR, 3.28; 95%CI, 1.41‐7.67; P <.01), and longer hospitalization (OR, 1.06; 95%CI, 1.01‐1.11; P =.02] independently predicted moderate‐to‐severe AKI. In the vancomycin group, trough concentrations increased after discharge, and were higher in female compared to male patients, and in those who developed moderate‐to‐severe AKI compared to those who did not. Female sex (OR, 8.37; 95%CI, 2.35‐29.82; P <.01) and higher concentrations (OR, 1.12; 95%CI, 1.05‐1.19; P <.01) predicted moderate‐to‐severe AKI in patients receiving vancomycin. In conclusion, premature antibiotic discontinuations and nephrotoxicity are more frequent in patients treated at home with vancomycin compared to daptomycin. Among patients receiving vancomycin, plasma concentrations increased after hospital discharge and predicted moderate‐to‐severe AKI. Women had higher vancomycin concentrations and higher risk for AKI. [ABSTRACT FROM AUTHOR]

Methicillin‐resistant Staphylococcus aureus (MRSA) presents an increasing threat to public health, with antimicrobial resistance on the rise and infections endemic in the hospital setting. Despite a global research effort to understand and combat antimicrobial resistance, less work has focused on understanding the nuances in the immunopathogenesis of clinical strains. In particular, there is a surprising gap of knowledge in the literature pertaining to how clinical strains are recognized by dendritic cells (DCs). Here, we show that the activation of DCs is compromised in response to MRSA strains resistant to the last‐line antibiotic daptomycin. We found a significant reduction in the secretion of proinflammatory cytokines including tumor necrosis factor‐α, interleukin‐6, regulated upon activation, normal T cell expressed, and secreted and macrophage inflammatory protein‐1β, as well as decreased expression of CD80 by DCs responding to daptomycin‐resistant MRSA. We further demonstrate that this phenotype is coincident with the acquisition of specific point mutations in the cardiolipin synthase gene cls2, and, partly, in the bifunctional lysylphosphatidylglycerol flippase/synthetase gene mprF, which are genes that are often mutated in clinical daptomycin‐resistant strains. Therefore, throughout infection and antibiotic therapy, MRSA has the capacity to not only develop further antibiotic resistance, but also develop resistance to immunological recognition by DCs, because of single amino acid point mutations occurring under the selective pressures of both host immunity and antibiotic therapy. Understanding the diversity of clinical MRSA isolates and the nuances in their immune recognition will have important implications for future therapeutics and the treatment of these infections. [ABSTRACT FROM AUTHOR]

A de novo solid‐phase synthesis of the cyclic lipodepsipeptide daptomycin via Boc chemistry was achieved. The challenging ester bond formation between the nonproteinogenic amino acid kynurenine was achieved by esterification of a threonine residue with a protected tryptophan. Subsequent late‐stage on‐resin ozonolysis, inspired by the biomimetic pathway, afforded the kynurenine residue directly. Synthetic daptomycin possessed potent antimicrobial activity (MIC100=1.0 μg mL−1) against S. aureus, while five other daptomycin analogues containing (2R,3R)‐3‐methylglutamic acid, (2S,4S)‐4‐methylglutamic acid or canonical glutamic acid at position twelve prepared using this new methodology were all inactive, clearly establishing that the (2S,3R)‐3‐methylglutamic acid plays a key role in the antimicrobial activity of daptomycin. [ABSTRACT FROM AUTHOR]

Aims. To present a 60-year-old female patient who manifested clinical and radiological features of posterior reversible encephalopathy syndrome (PRES) following the administration of Daptomycin for glycopeptide-resistant Enterococcal urinary tract infection. Material. Case report. Method. Posterior reversible encephalopathy syndrome was diagnosed in our patient following the administration of Daptomycin based on clinical suspicion as well as brain CT and MRI imaging. Results. The temporal association between the initiation of Daptomycin and the onset of PRES is highly suggestive of causality, and this is further supported by clinical and radiological resolution after Daptomycin was withdrawn. Conclusion. This is the first report of Daptomycin-induced posterior reversible encephalopathy syndrome. [ABSTRACT FROM AUTHOR]

Summary: What is known and objective: Treatment of methicillin‐resistant Staphylococcus aureus (MRSA) bacteraemia is a long‐standing challenge to health care, often complicated by metastatic infections, treatment failure and mortality. When MRSA bacteraemia persists despite adequate initial treatment, current Infectious Diseases Society of America guidelines recommend evaluation and removal of possible sources of infection. In addition, a change in therapy may be considered. The objective of this review was to explore the therapeutic options for the treatment of persistent MRSA bacteraemia. Methods: A literature search of PubMed, MEDLINE and Google Scholar was performed using the following search terms: [methicillin‐resistant Staphylococcus aureus OR MRSA] AND [bacteraemia OR bloodstream infection] AND [persistent OR persistence OR refractory OR treatment failure OR salvage] AND treatment. We evaluated relevant, adult, English‐language, peer‐reviewed studies published between 1985 and May 2018. In vitro and animal studies were considered as supportive of in vivo data. Results and discussion: Randomized, controlled trials are lacking. However, case series and case reports support multiple treatment options including high‐dose daptomycin in combination with an antistaphylococcal β‐lactam, ceftaroline, trimethoprim‐sulfamethoxazole (TMP‐SMX) or fosfomycin; ceftaroline alone or in combination with vancomycin or TMP‐SMX; linezolid alone or in combination with a carbapenem, or telavancin. What is new and conclusion: Given the heterogeneity of the data, a preferred regimen has not emerged. Prescribers must take into consideration recent exposure, source control, and available synergy and clinical data. Further comparative trials are needed to establish a preferred regimen and the creation of a universal treatment algorithm. [ABSTRACT FROM AUTHOR]

Primary aim of this in vitro study was to test the efficacy of daptomycin to eradicate staphylococcal biofilms on various orthopedic implant materials. Secondary aim was to quantitatively estimate the formation of staphylococcal biofilm. We tested six clinically important biomaterials: Cobalt chrome, pure titanium, grid‐blasted titanium, porous plasma‐coated titanium with/without hydroxyapatite, and polyethylene. Biofilms of S. aureus and S. epidermidis were formed on the samples and thereafter exposed to daptomycin. Samples were subsequently sonicated in order to detect dislodged biofilm bacteria and transferred to a microcalorimeter for real‐time measurement of growth‐related heat flow. Minimal biofilm eradication concentration (MBEC) was determined as the lowest concentration of daptomycin required to eradicate biofilm bacteria on the sample. Median MBEC of S. aureus biofilm on smooth metallic surfaces was lower than the rough metallic surfaces. In experiments with S. epidermidis, no pattern was seen in relation to the surface roughness. Regarding the quantitative estimation of staphylococcal biofilm formation on the sample, we found a significantly higher amount of biofilm growth on the rough surfaces than the smooth samples and polyethylene. In conclusion, the presented study showed that daptomycin could eradicate S. aureus biofilm at lower concentrations on the smooth surfaces compared to the rough surfaces, as well as polyethylene. In experiments with daptomycin against S. epidermidis biofilms, no pattern was seen in relation to the surface roughness. Furthermore, we demonstrated a faster detection of staphylococcal heat flow due to higher biofilm quantity on the rough surfaces compared to smooth samples and polyethylene. © 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:2809–2816, 2018. This study of staphylococcal biofilm formation and eradication on various orthopedic implant materials showed that daptomycin could eradicate S. aureus biofilm at lower concentrations on the smooth surfaces compared to the rough surfaces, as well as polyethylene. In experiments with daptomycin against S. epidermidis biofilms, no pattern was seen in relation to the surface roughness. Furthermore, we demonstrated a faster detection of staphylococcal heat flow due to higher biofilm quantity on the rough surfaces compared to smooth samples and polyethylene. [ABSTRACT FROM AUTHOR]

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 (Cmax), minimum concentrations (Cmin), 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 Cmin 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, Cmax, and Cmin 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 Cmin 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. [ABSTRACT FROM AUTHOR]

Abstract: Background: Vancomycin‐resistant Enterococcus faecium (VRE) infections are common in liver transplant recipients (LTRs). Daptomycin (DAP) is an important treatment for such infections; however, DAP‐nonsusceptible VRE (DNS‐VRE) are increasingly frequent. The purpose of this study was to compare clinical characteristics and outcomes of LTRs with infections due to DNS‐VRE and DAP‐susceptible VRE (DS‐VRE). Methods: A single center, retrospective review of patients who underwent liver transplantation between January 1, 2010 and December 31, 2015 and developed infections due to DS‐VRE or DNS‐VRE post transplant was performed. Patients with DNS‐VRE and DS‐VRE infections were compared using univariate and logistic regression analysis. Results: Fourteen LTRs developed DNS‐VRE and 20 LTRs developed DS‐VRE infection post‐transplantation. No significant differences were observed in demographics, model for end‐stage liver disease (MELD) scores, causes of end‐stage liver disease, or rate of pre‐transplant perirectal VRE colonization between groups. Bleeding complications and renal replacement therapy were more common in the DNS‐VRE group than in the DS‐VRE group. The duration of transplant hospitalization and post‐transplant intensive care unit (ICU) admission was longer in the DNS‐VRE group than in the DS‐VRE group. The 30‐day and 6‐month mortality rate associated with DNS‐VRE infection was similar to that associated with DS‐VRE infection. Conclusions: Liver transplant recipients who develop DNS‐VRE infection have higher bleeding complications and longer, more complex hospitalizations compared to those who develop DS‐VRE infection post transplantation; however, mortality at 30 days and 6 months is not significantly worse. Further study is needed to determine optimal strategies for the prevention and treatment of DNS‐VRE infections in LTRs. [ABSTRACT FROM AUTHOR]

Study Objective: Current guidelines recommend higher daptomycin doses than the daptomycin label dose of 6 mg/kg for methicillin‐resistant Staphylococcus aureus (MRSA) bacteremia; however, the evidence supporting this recommendation is from in vitro and case series studies. This study evaluated the comparative effectiveness of the daptomycin label dose versus higher daptomycin doses in patients with MRSA bacteremia. Design: Retrospective national cohort study. Setting: Veterans Affairs medical centers. Patients: A total of 371 adults with MRSA bacteremia who were admitted between 2002 and 2015 and treated initially with vancomycin within 24 hours of initial culture collection and then switched to daptomycin therapy within 7 days; 138 patients (37.2%) received daptomycin doses higher than the daptomycin label dose (7 mg/kg or greater), and 233 (62.8%) received the daptomycin label dose (6 mg/kg). Measurements and Main Results: Clinical outcomes were compared among those who received the daptomycin label dose and those who received the higher dose using propensity score–matched Cox proportional hazards regression models. To identify dose partitioning associated with optimal survival, classification and regression tree (CART) analysis was used among patients, controlling for confounding with a 30‐day mortality disease risk score. Propensity score–matched 30‐day mortality was 8.6% (6/70 patients) among the higher dose group versus 18.6% (13/70 patients) among the label dose group (hazard ratio 0.31, 95% confidence interval 0.10–0.94). No significant differences were observed in inpatient mortality, length of stay, 30‐day readmission, or 30‐day S. aureus reinfection between groups. CART analysis resulted in doses of 7 mg/kg or greater providing benefit only among patients with higher (more than 51%) predicted probabilities of 30‐day mortality (p<0.001). Conclusion: To our knowledge, this is the first comparative effectiveness study of daptomycin doses in patients with MRSA bacteremia. Survival benefits were observed with doses higher than the daptomycin label dose (7 mg/kg or greater) for the treatment of MRSA bacteremia. These data suggest that higher doses than the daptomycin label dose may be preferred over the label dose for improving clinical outcomes in patients with MRSA bacteremia. [ABSTRACT FROM AUTHOR]

Background. Daptomycin is a cyclic lipopeptide antibiotic that provides great coverage for gram positive cocci. From the early years of daptomycin use, concerns were raised regarding the pulmonary side effects of daptomycin and potential development of acute eosinophilic pneumonia (AEP) secondary to daptomycin therapy. Discussion. AEP could be idiopathic or induced by drugs or toxins. It is a distinct entity from atopic diseases and autoimmune, parasitic, or fungal infections that can also cause pulmonary eosinophilia. Multiple medications are associated with acute eosinophilic pneumonia. Multiple cases of daptomycin-induced AEP have been reported in the literature. Diagnosis of AEP is based on clinical history, laboratory tests, and radiographic studies. Obtaining bronchoalveolar lavage or lung biopsy is needed to confirm the diagnosis. Timing of the drug use and clinical presentation is crucial in the diagnosis of drug-induced AEP. Discontinuation of the offending drug and systemic corticosteroids are the mainstay treatment with great outcomes and recovery. Conclusion. We present a case of AEP caused by daptomycin, with complete recovery after discontinuation of daptomycin and administration of steroids. The patient had AEP after almost 6 weeks of daptomycin therapy which has never been reported in literature and our patient achieved complete recovery with appropriate management. [ABSTRACT FROM AUTHOR]

Enterococcus species are the second most common cause of nosocomial infections in the United States and are particularly concerning in critically ill patients with preexisting comorbid conditions. Rising resistance to antimicrobials that were historically used as front-line agents for treatment of enterococcal infections, such as ampicillin, vancomycin, and aminoglycosides, further complicates the treatment of these infections. Of particular concern are Enterococcus faecium strains that are associated with the highest rate of vancomycin resistance. The introduction of antimicrobial agents with specific activity against vancomycin-resistant Enterococcus ( VRE) faecium including daptomycin, linezolid, quinupristin-dalfopristin, and tigecycline did not completely resolve this clinical dilemma. In this review, the mechanisms of action and resistance to currently available anti- VRE antimicrobial agents including newer agents such as oritavancin and dalbavancin will be presented. In addition, novel combination therapies including β-lactams and fosfomycin, and the promising results from in vitro , animal studies, and clinical experience in the treatment of VRE faecium will be discussed. [ABSTRACT FROM AUTHOR]

Daptomycin was the first approved drug from a new class of antimicrobials, the cyclic lipopeptides, and presents a broad spectrum of activity against a wide range of gram-positive bacteria. The daptomycin redox behaviour, by cyclic, differential pulse and square wave voltammetry, in a wide pH range, at a glassy carbon electrode, was investigated. The daptomycin oxidation was a two-step irreversible diffusion-controlled process and the diffusion coefficient DDPT = 2.32 × 10−5 cm2 s−1, was calculated. A detection limit LOD = 0.32 μM, was obtained. For the first time daptomycin, in fetal bovine serum biological fluid, using DP voltammetry, was determined. [ABSTRACT FROM AUTHOR]

Staphylococcus aureus is one of the most virulent Gram-positive organisms responsible for a multitude of infections, including bacteremia. Methicillin-resistant Staphylococcus aureus (MRSA) is of special concern in patients with bacteremia. Due to its associated poor clinical outcomes, morbidity, and mortality, the superlative salvage regimen for persistent MRSA bacteremia remains uncertain. An 85-year-old white female presented with persistent methicillin-resistant Staphylococcus aureus (MRSA) bacteremia. Empiric antibiotic therapy with linezolid was initiated prior to blood culture results. Once MRSA bacteremia was confirmed, alternative antibiotic therapy with daptomycin was initiated. Blood cultures remained positive for MRSA despite three days of daptomycin therapy after which ceftaroline was added to the antibiotic regimen. Blood cultures remained positive for MRSA despite seven days of combination therapy with daptomycin and ceftaroline. Salvage therapy was then initiated with daptomycin, linezolid, and meropenem. One day following initiation of salvage therapy, blood cultures revealed no bacterial growth for the remainder of the length of stay. This report supports the effectiveness of salvage therapy consisting of daptomycin, linezolid, and meropenem in patients with persistent MRSA bacteremia. [ABSTRACT FROM AUTHOR]

Limited data exist for appropriate drug dosing in obese children. This comprehensive review summarizes pharmacokinetic (PK) alterations that occur with age and obesity, and these effects on antimicrobial dosing. A thorough comparison of different measures of body weight and specific antimicrobial agents including cefazolin, cefepime, ceftazidime, daptomycin, doripenem, gentamicin, linezolid, meropenem, piperacillin-tazobactam, tobramycin, vancomycin, and voriconazole is presented. PubMed (1966-July 2015) and Cochrane Library searches were performed using these key terms: children, pharmacokinetic, obesity, overweight, body mass index, ideal body weight, lean body weight, body composition, and specific antimicrobial drugs. PK studies in obese children and, if necessary, data from adult studies were summarized. Knowledge of PK alterations stemming from physiologic changes that occur with age from the neonate to adolescent, as well as those that result from increased body fat, become an essential first step toward optimizing drug dosing in obese children. Excessive amounts of adipose tissue contribute significantly to body size, total body water content, and organ size and function that may modify drug distribution and clearance. PK studies that evaluated antimicrobial dosing primarily used total (or actual) body weight ( TBW) for loading doses and TBW or adjusted body weight for maintenance doses, depending on the drugs' properties and dosing units. PK studies in obese children are imperative to elucidate drug distribution, clearance, and, consequently, the dose required for effective therapy in these children. Future studies should evaluate the effects of both age and obesity on drug dosing because the incidence of obesity is increasing in pediatric patients. [ABSTRACT FROM AUTHOR]

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, Cmax and Cmin 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 AUC24-48h 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. [ABSTRACT FROM AUTHOR]

Introduction The management of gram-positive infections has been complicated in recent years by the emergence of antimicrobial resistance, leaving fewer options for therapy. Daptomycin is a lipopeptide antibiotic used for the systemic treatment of gram-positive infections. It has a distinct mechanism of action and a favorable side effect profile, and it requires once/day dosing. Unfortunately, there is a paucity of safety, efficacy, and pharmacokinetic data in neonatal and pediatric patients. The objective of this study was to review our experience with daptomycin use for the treatment of gram-positive infections in these patient populations. Methods We conducted a retrospective analysis of electronic medical records of hospitalized children who received daptomycin between October 2008 and June 2014 for the treatment of proven gram-positive infections. Results Of the 146 patients who received at least 3 days of daptomycin therapy, 109 patients had a proven gram-positive infection and were included for further analysis. Of the 109 patients, 71 were males (65%) and the median age was 12 years (range: 2.5 mo to 24 yrs). The median duration of therapy was 12 days (range: 3-121 days; mean = 16 days). Catheter-related bloodstream infections were the most common type of infections (n=81 patients) in those receiving daptomycin treatment. One hundred seven patients (98%) had documented improvement and resolution at the time of hospital discharge. One hundred four patients (95%) had a baseline creatine phosphokinase ( CPK) level obtained. Of these 104 patients, 48 (46%) had at least one follow-up CPK level after the start of therapy. Three patients' charts showed laboratory evidence of elevated CPK values. Conclusions The majority of patients demonstrated clinical improvement after receiving daptomycin as primary therapy for proven gram-positive infections. Larger randomized controlled trials focusing on safety and efficacy are necessary to assess these outcomes with daptomycin use in the pediatric population. [ABSTRACT FROM AUTHOR]