Search

Enterococci have evolved resistance mechanisms to protect their cell envelopes against bacteriocins and host cationic antimicrobial peptides (CAMPs) produced in the gastrointestinal environment. Activation of the membrane stress response has also been tied to resistance to the lipopeptide antibiotic daptomycin. However, the actual effectors mediating resistance have not been elucidated. Here, we show that the MadRS (formerly YxdJK) membrane antimicrobial peptide defense system controls a network of genes, including a previously uncharacterized 3-gene operon (madEFG) that protects the Enterococcus faecalis cell envelope from antimicrobial peptides. Constitutive activation of the system confers protection against CAMPs and daptomycin in the absence of a functional LiaFSR system and leads to persistence of cardiac microlesions in vivo. Moreover, changes in the lipid cell membrane environment alter CAMP susceptibility and expression of the MadRS system. Thus, we provide a framework supporting a multilayered envelope defense mechanism for resistance and survival coupled to virulence., Competing Interests: Potential conflicts of interest. W. R. M. has received grant support from Merck; and royalties from UpToDate. C. A. A. has received royalties from UpToDate. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Purpose: This review explores the management of persistent methicillin-susceptible Staphylococcus aureus bacteremia (SAB), emphasizing the importance of timely intervention due to SAB's association with metastatic dissemination, relapse, and mortality., Summary: The literature analysis first delves into risk factors for persistent SAB, highlighting the need for effective treatment strategies. The subsequent focus is on combination strategies for persistent SAB. Daptomycin, ertapenem, ceftaroline, fosfomycin, rifampin, and gentamicin are explored as adjuncts to cefazolin or antistaphylococcal penicillins. Daptomycin combination therapy is assessed through in vivo and clinical studies, indicating potential benefits, especially with higher-risk sources of infection. Ertapenem combination therapy has been demonstrated to have a synergistic effect with cefazolin, presenting a viable salvage option. Rifampin's ability to penetrate biofilm is examined, with discussion of inconclusive evidence on mortality benefits. The review also considers stewardship implications, discussing concerns such as resistance emergence, adverse events, and increased costs associated with combination therapy. Mathematical models suggest combination therapy as an effective approach to prevent resistance. Adverse events vary with each combination, and duration of therapy remains diverse across studies in the absence of well-established dosing guidelines., Conclusion: The review provides a thorough exploration of the literature on treatment of persistent SAB, underscoring the need for evidence-based guidelines, further studies, and clinical judgment in tailoring treatment strategies. The multifaceted analysis contributes valuable insights for clinicians managing this challenging condition., (© American Society of Health-System Pharmacists 2024. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Objectives: This study investigated the efficacy of daptomycin against adherent Staphylococcus aureus (S. aureus), a common colonizer of medical devices that leads to severe infections. For the first time, we evaluated the bactericidal effects of daptomycin on S. aureus immediately after adhesion, mimicking early-stage contamination of biomaterials. Time-kill curve assay and confocal laser scanning microscopy (CLSM) were used to analyze the process dynamics. In addition, atomic force microscopy (AFM) and scanning electron microscopy (SEM) were employed to elucidate daptomycin-induced structural changes in the bacterial cell wall., Results Description: Daptomycin, at clinically relevant concentrations, rapidly eradicated adherent bacteria in the exponential growth phase, demonstrating an efficiency comparable to its action against planktonic cells. Prolonged exposure to the antibiotic caused marked alterations in the bacterial cell wall, including surface roughening and perforation, as revealed by multimodal imaging. However, daptomycin effectiveness diminished as biofilm formation progressed, underscoring the need for further exploration of optimized clinical strategies., Competing Interests: Ethics. Ethics approval and consent to participate: Not applicable. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Introduction: Corynebacterium species potentially develop high-level daptomycin resistance (HLDR) shortly after daptomycin (DAP) administration. We aimed to investigate the clinical and microbiological characteristics of HLDR Corynebacterium infections., Methods: We first presented a clinical case accompanied by the results of a comprehensive genetic analysis of the isolate, and then performed a systematic scoping review. Based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews, we searched for articles with related keywords, including "Corynebacterium", "Daptomycin", and "Resistance", in the MEDLINE and Web of Science databases from the database inception to October 25, 2024. Clinical case reports and research articles documenting the isolation of HLDR Corynebacterium species, defined by a minimum inhibitory concentration of DAP at ≥256 μg/mL, were deemed eligible for this review., Results: Of 80 articles screened, seven case reports detailing eight cases of HLDR Corynebacterium infections, as well as five research articles, were included. C. striatum was the most common species (7/9 cases, 77.8 %), and prosthetic device-associated infections accounted for 66.7 % of the cases. Duration of DAP administration before the emergence of HLDR isolates ranged from 5 days to 3 months; three-quarters of the cases developed within 17 days. Three HLDR isolates were genetically confirmed to have an alteration in pgsA2. The majority of the patients were treated with either glycopeptides or linezolid, with favorable outcomes. In vitro experiments confirmed that C. striatum strains acquire the HLDR phenotype at higher rates (71 %-100 %) within 24 h of incubation, compared to other Corynebacterium strains., Conclusion: DAP monotherapy, especially for prosthetic device-associated infections, can result in the development of HLDR Corynebacterium. Additional research is warranted to investigate the clinical implications of this potentially proliferating antimicrobial resistant pathogen., Competing Interests: Competing interests No authors have any competing interests in this case., (Copyright © 2024 Japanese Society of Chemotherapy, Japanese Association for Infectious Diseases, and Japanese Society for Infection Prevention and Control. Published by Elsevier Ltd. All rights reserved.)

Purpose: Monotherapy with vancomycin or daptomycin remains guideline-based care for methicillin-resistant Staphylococcus aureus bacteremia (MRSA-B) despite concerns regarding efficacy. Limited data support potential benefit of combination therapy with ceftaroline as initial therapy. We present an assessment of outcomes of patients initiated on early combination therapy for MRSA-B., Methods: This was a single-center, retrospective study of adult patients admitted with MRSA-B between July 1, 2017 and April 31, 2023. During this period, there was a change in institutional practice from routine administration of monotherapy to initial combination therapy for most patients with MRSA-B. Combination therapy included vancomycin or daptomycin plus ceftaroline within 72 h of index blood culture and monotherapy was vancomycin or daptomycin alone. The primary outcome was a composite of persistent bacteremia, 30-day all-cause mortality, and 30-day bacteremia recurrence. Time to microbiological cure and safety outcomes were assessed. All outcomes were assessed using propensity score-weighted logistic regression., Results: Of 213 patients included, 118 received monotherapy (115 vancomycin, 3 daptomycin) and 95 received combination therapy with ceftaroline (76 vancomycin, 19 daptomycin). The mean time from MRSA-positive molecular diagnostic blood culture result to combination therapy was 12.1 h. There was no difference between groups for the primary composite outcome (OR 1.58, 95% CI 0.60, 4.18). Time to microbiological cure was longer with combination therapy (mean difference 1.50 days, 95% CI 0.60, 2.41). Adverse event rates were similar in both groups., Conclusions: Early initiation of ceftaroline-based combination therapy did not improve outcomes for patients with MRSA-B in comparison to monotherapy therapy., Competing Interests: Declarations. Ethics approval and consent to participate: The research protocol received an Exempt approval by the Institutional Review Board (IRB) for Health Sciences Research at the University of Virginia. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Background: Daptomycin is a lipopeptide antibiotic with a broad spectrum of activity against gram-positive bacteria. Although information on daptomycin-induced adverse events can be found in clinical trials, data regarding the impact of age on these events are insufficient. Therefore, we evaluated whether age affects the occurrence of daptomycin-induced adverse events using adverse drug event reports in post-marketing stages provided by the U.S. Food and Drug Administration (FDA)., Methods: A total dataset of 7307 reports of patients treated with daptomycin in the FDA's Adverse Event Reporting System were analyzed. The patients were divided into seven age groups: 0-28 days, >28 days-23 months, 2-11 years, 12-17 years, 18-64 years, 65-80 years, and >80 years. A disproportionality analysis was conducted to calculate the reporting odds ratio, with a 95 % confidence interval. The univariate regression analysis was conducted using the percentage of each adverse event and age groups., Results: Compared with the number of reports aged 18-64 years, there were significantly increased reports of eosinophilic pneumonia in patients aged 65-80 years and >80 years, anaphylactic reaction and pseudomembranous colitis in patients aged 12-17 years, and acute renal failure in patients aged 65-80 years. The regression coefficient for the reporting proportion of eosinophilic pneumonia was significantly positive., Conclusions: Our findings revealed age-related trends in daptomycin-induced adverse events, supporting the idea that implementing age-dependent follow-up and supportive care helps in the continuation of daptomycin therapy., Competing Interests: Declaration of competing interest None of the authors have financial and non-financial competing interests., (Copyright © 2024 Japanese Society of Chemotherapy, Japanese Association for Infectious Diseases, and Japanese Society for Infection Prevention and Control. Published by Elsevier Ltd. All rights reserved.)

Introduction: Information on the clinical utility of daptomycin in patients with persistent bacteremia and daptomycin's pharmacokinetic data in pediatric patients has been sparse. In addition, reports on the experience of using daptomycin in children undergoing solid organ transplantation have been extremely limited. The authors describe a pediatric case of persistent bacteremia after solid organ transplantation successfully treated by daptomycin. Blood daptomycin concentrations were measured by liquid chromatography-mass spectrometry and pharmacokinetic analysis was performed. We also conducted a literature review on the use of daptomycin in children with persistent bacteremia., Case Report: An eight-year-old girl who underwent small bowel and liver transplantation experienced persistent bacteremia due to Staphylococcus epidermidis. The bacteremia persisted despite standard therapy; however, it finally resolved with the addition of daptomycin. The patient had renal dysfunction and the initial dosing resulted in excessive drug exposure. The dosage was adjusted based on the pharmacokinetic analysis. The dosage of administrated teicoplanin was also adjusted according to trough concentration values. In the literature review, we identified 12 cases of neonates and 24 cases of post-neonatal children with the experience of using daptomycin for persistent bacteremia; however, no solid organ transplant recipient was identified. Similar trends in blood concentrations and dose ratios of teicoplanin and daptomycin were observed over time., Discussion: More information is required regarding the clinical utility and pharmacokinetics of daptomycin in pediatric patients with persistent bacteremia. Referring to the exposure to renally excreted drugs that are routinely measured and pharmacokinetic analysis of daptomycin may be useful in optimizing the dose of daptomycin in special patient populations, including those with renal impairment., (Copyright © 2024 Japanese Society of Chemotherapy, Japanese Association for Infectious Diseases, and Japanese Society for Infection Prevention and Control. Published by Elsevier Ltd. All rights reserved.)

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 (AUC 24-48 ) and at the steady state (AUC ss ). In Model 1, Bayesian posterior probabilities for AUC 24-48 increased from 50.7% (a priori) to 59.4% and for AUC ss from 48.9% (a priori) to 61.9%, with one-point C trough sampling at 24 h. With two-point sampling at 7 and 24 h, the probabilities increased to 73.8% for AUC 24-48 and 69.7% for AUC ss . In Model 2, the probabilities for both AUC 24-48 and AUC ss with one-point C trough or two-point sampling incorporating C trough sampling increased compared to a priori probabilities. These results suggest that two-point sampling incorporating C trough during initial dosing enhanced achieving the target AUC 24-48 and AUC ss rapidly., (© 2024 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society). Published by John Wiley & Sons Ltd.)

Daptomycin is a common treatment for serious infections caused by gram-positive bacteria in adult patients; however, data regarding its safety and efficacy in the pediatric population are limited. This was a retrospective chart review of adverse reactions and treatment outcomes associated with daptomycin use in children <13 years old who received at least 1 dose of daptomycin. At least 1 dose of daptomycin was received by 147 patients. Seventy-two patients received daptomycin for 5 or more days. New-onset loose stools on daptomycin initiation were reported for 14 (9.5%) patients, elevations in creatine kinase in 3 (2%) patients, and elevated aspartate transaminase and alanine transaminase in 13 (8.8%) and 9 (6.1%) patients, respectively. Two patients (1.4%) had daptomycin discontinued due to specific concerns for adverse drug reactions. Daptomycin was found to be safe and effective in this pediatric cohort that included young children and infants with a variety of types and severities of infections., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Recently, a high-level daptomycin (DAP)-resistant Mammaliicoccus sciuri strain (TS92) was identified, which mediates a 33% decline of DAP when incubated in Mueller-Hinton (MH) medium. The genetic background of the DAP resistance in TS92 is a newly discovered two-gene operon, named drcAB, whose expression was reported to impair the structural integrity of DAP, eventually leading to its inactivation. Here, we set out to elucidate the chemical nature of drcAB -mediated DAP modification by applying a general unknown comparative screening (GUCS) approach in high-resolution mass spectrometry. DAP in MH medium was incubated with Staphylococcus aureu s strain RN4220&#95;P xyl/tet - drcAB, which carries the drcAB operon under control of an inducible promoter on a plasmid, and GUCS test and reference samples were obtained upon and without drcAB expression. A two-step process catalyzed by DrcAB was discovered, comprising a structural alteration of DAP. The mass spectrometric data indicate an N-substitution at the aniline moiety of kynurenine with dehydroalanine and, subsequently, a cleavage of the ester bond of the DAP core between kynurenine and threonine by means of water. The structures postulated were confirmed by comparison of in silico versus measured fragmentation patterns.

Purpose: Daptomycin-induced eosinophilic pneumonia (DIEP) is a rare yet severe adverse event that requires rapid recognition and management. Diagnosing a definite case is challenging and involves meeting the American Thoracic Society (ATS) criteria, although alternative criteria have been suggested. This study aims to conduct a systematic review of literature and includes a case series., Methods: Six cases of DIEP identified at Perugia Hospital, Perugia, Italy have been described. A systematic review was carried out adhering to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Statement guidelines., Results: a total of 74 cases of DIEP were analysed. Using ATS clinical criteria, 15 were classified as definite (20.3%), 54 as probable (73.0%), and 5 as possible (6.8%). Phillips criteria and the Lyon Algorithm identified 43/74 (58.2%) and 64/67 (95.5%) cases as definite, respectively. Bronchoalveolar lavage (BAL) was performed in 43 cases, revealing an average eosinophil count of 28.6% (SD 24.4). Radiological findings highlighted recurring features like bilateral opacities (68.1%), ground-glass opacities (41.7%), patchy infiltrates (30.6%), and peripheral predominance (19.4%). Upon suspicion, daptomycin was discontinued; 20 cases required no additional treatment, 38 received corticosteroids, and 12 received both corticosteroids and antibiotics. Recovery rates were high across all treatment types (≥ 73.7%). Most reports described rapid improvement post-withdrawal (within 96 h)., Conclusions: DIEP is a rare, fast-progressing condition where early diagnosis and prompt treatment are vital. Diagnosis relies on clinical, laboratory, and radiological evaluations. Stopping daptomycin is essential, with corticosteroids often necessary. Further research is needed to enhance diagnostic accuracy for this disease., Competing Interests: Declarations. Ethical statements: This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of Umbria Region (N. 1449/2023). Competing interests: the authors have no relevant financial or non-financial interests to disclose., (© 2024. The Author(s).)

Enterococcus faecalis and Enterococcus faecium are frequent causes of healthcare-associated infections. Antimicrobial-resistant enterococci pose a serious public health threat, particularly vancomycin-resistant enterococci (VRE), for which treatment options are limited. The Centers for Disease Control and Prevention's Division of Healthcare Quality Promotion Sentinel Surveillance system conducted surveillance from 2018 to 2019 to evaluate antimicrobial susceptibility profiles and molecular epidemiology of 205 E. faecalis and 180 E. faecium clinical isolates collected from nine geographically diverse sites in the United States. Whole genome sequencing revealed diverse genetic lineages, with no single sequence type accounting for more than 15% of E. faecalis or E. faecium . Phylogenetic analysis distinguished E. faecium from 19 E. lactis (previously known as E. faecium clade B). Resistance to vancomycin was 78.3% among E. faecium , 7.8% among E. faecalis , and did not occur among E. lactis isolates. Resistance to daptomycin and linezolid was rare: E. faecium (5.6%, 0.6%, respectively), E. faecalis (2%, 2%), and E. lactis (5.3%, 0%). All VRE harbored the vanA gene. Three of the seven isolates that were not susceptible to linezolid harbored optrA , one chromosomally located and two on linear plasmids that shared a conserved backbone with other multidrug-resistant conjugative linear plasmids. One of these isolates contained optrA and vanA co-localized on the linear plasmid. By screening all enterococci, 20% of E. faecium were predicted to harbor linear plasmids, whereas none were predicted among E. faecalis or E. lactis . Continued surveillance is needed to assess the future emergence and spread of antimicrobial resistance by linear plasmids and other mechanisms.IMPORTANCEThis work confirms prior reports of E. faecium showing higher levels of resistance to more antibiotics than E. faecalis and identifies that diverse sequence types are contributing to enterococcal infections in the United States. All VRE harbored the vanA gene. We present the first report of the linezolid resistance gene optrA on linear plasmids in the United States, one of which co-carried a vanA cassette. Additional studies integrating epidemiological, antimicrobial susceptibility, and genomic methods to characterize mechanisms of resistance, including the role of linear plasmids, will be critical to understanding the changing landscape of enterococci in the United States., Competing Interests: The authors declare no conflict of interest.

The bacterial pathogen Staphylococcus aureus responds to the host environment by synthesizing a thick peptidoglycan cell wall, which protects the bacterium from membrane-targeting antimicrobials and the immune response. However, the proteins required for this response were previously unknown. Here, we demonstrate by three independent approaches that the penicillin-binding protein PBP4 is crucial for serum-induced cell wall thickening. First, mutants lacking various non-essential cell wall synthesis enzymes were tested, revealing that a mutant lacking pbp4 was unable to generate a thick cell wall in serum. This resulted in reduced serum-induced tolerance of the pbp4 mutant toward the last resort antibiotic daptomycin relative to wild-type cells. Second, we found that serum-induced cell wall thickening occurred in each of a panel of 134 clinical bacteremia isolates, except for one strain with a naturally occurring mutation that results in an S140R substitution in the active site of PBP4. Finally, inhibition of PBP4 with cefoxitin prevented serum-induced cell wall thickening and the resulting antibiotic tolerance in the USA300 strain and clinical MRSA isolates. Together, this provides a rationale for combining daptomycin with cefoxitin, a PBP4 inhibitor, to potentially improve treatment outcomes for patients with invasive MRSA infections., Competing Interests: The authors declare no conflict of interest.

Methicillin-resistant Staphylococcus aureus (MRSA) is challenging to treat due to a lack of guidance for clinicians. The daptomycin and ceftaroline combination is promising for treating persistent MRSA bloodstream infections (BSIs). In this report, we present a case series of 7 patients who failed vancomycin and then were treated with daptomycin and ceftaroline for persistent MRSA BSIs. The median age (IQR) of the included patients was 59 (48-67), with 5 male and 2 female patients. Six patients (85.7%) had a clinical cure for their persistent BSIs. The median time (IQR) for sterilization of MRSA BSIs after initiation of daptomycin and ceftaroline combination was 2 days (1-3). Among the patients who had clinical cures, the median time for clinical cures (IQR) was 6 weeks (4.5-6 weeks). The combination of daptomycin and ceftaroline could be an excellent treatment option for persistent MRSA BSIs.

The lipopeptide antibiotic daptomycin exhibits bactericidal activity against Gram-positive bacteria by forming a complex with phosphatidylglycerol (PG) and lipid II in the cell membrane, causing membrane perforation. With the emergence of daptomycin-resistant bacteria, understanding the mechanisms of bacterial resistance to daptomycin has gained great importance. In this study, we aimed to identify the genetic factors contributing to daptomycin resistance in Bacillus subtilis , a model Gram-positive bacterium. Our findings demonstrated that overexpression of ugtP , which encodes diglucosyldiacylglycerol synthase, induces daptomycin resistance in B. subtilis . Specifically, overexpression of ugtP resulted in increased levels of diglucosyldiacylglycerol (Glc 2 DAG) and decreased levels of acidic phospholipids cardiolipin and PG, as well as the basic phospholipid lysylphosphatidylglycerol. However, ugtP overexpression did not alter the cell surface charge and the susceptibility to the cationic antimicrobial peptide nisin or the cationic surfactant hexadecyltrimethylammonium bromide. Furthermore, by serial passaging in the presence of daptomycin, we obtained daptomycin-resistant mutants carrying ugtP mutations. These mutants showed increased levels of Glc 2 DAG and a >4-fold increase in the minimum inhibitory concentration of daptomycin. These results suggest that increased Glc 2 DAG levels, driven by ugtP overexpression, modify the phospholipid composition and confer daptomycin resistance in B. subtilis without altering the cell surface charge of the bacteria.IMPORTANCEDaptomycin is one of the last-resort drugs for the treatment of methicillin-resistant Staphylococcus aureus infections, and the emergence of daptomycin-resistant bacteria has become a major concern. Understanding the mechanism of daptomycin resistance is important for establishing clinical countermeasures against daptomycin-resistant bacteria. In the present study, we found that overexpression of ugtP , which encodes diglucosyldiacylglycerol synthase, induces daptomycin resistance in B. subtilis , a model Gram-positive bacteria. The overexpression of UgtP increased diglucosyldiacylglycerol levels, resulting in altered phospholipid composition and daptomycin resistance. These findings are important for establishing clinical strategies against daptomycin-resistant bacteria, including their detection and management., Competing Interests: The authors declare no conflict of interest.

Background: Daptomycin non-susceptible Staphylococcus aureus (DNS) strains pose a serious clinical threat, yet their characteristics remain poorly understood., Methods: DNS derivatives were generated by exposing S. aureus strains to subinhibitory concentrations of daptomycin. Competition experiment and growth kinetics experiment were used to observe the growth of bacteria. Galleria mellonella larvae and mouse skin abscess models were used to observe the virulence of bacteria. Transmission electron microscopy (TEM), cytochrome C experiment and biofilm formation experiment were used to observe the drug resistance phenotype. And homologous recombination was used to study the role of mutations., Results: Phenotypic profiling of DNS strains revealed impaired growth, increased cell wall thickness, enhanced biofilm formation, reduced negative surface charge, and attenuated virulence compared to their wild-type strains. Whole genome sequencing identified mutations in mprF , cls2 , and saeR in DNS strains. Allelic replacement experiments validated the roles of MprF L341F and Cls2 F60S substitutions in augmenting daptomycin non-susceptibility in Newman. Deletion of saeR in the Newman MprFL341F strain and complementation of saeR in the Newman-DNS strain did not directly alter daptomycin susceptibility. However, the deletion of saeR was found to enhance competitive fitness under daptomycin pressure., Conclusion: This work validates adaptive laboratory evolution (ALE) for modeling clinical DNS strains and uncovers contributions of mprF , cls2 , and saeR mutations to the adaptation and resistance mechanisms of S. aureus against daptomycin. These findings enrich our understanding of how S. aureus acquired resistance to daptomycin, thus paving the way for the development of more effective treatment strategies and offering potential molecular markers for resistance surveillance., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Xu, Xiao, Zhao, Wang, Yu, Shang, Zhou, Wu, Guo and Yu.)

Purpose: Cardiac implantable electronic device (CIED) infections are increasingly common. Gram-positive bacteria such as coagulase negative staphylococci and Staphylococcus aureus are the most commonly involved pathogens. The aim of this study was to describe the characteristics and outcome of patients with CIED infections who underwent device removal and were empirically treated with high dose (8-12 mg/kg daily) daptomycin (DAP) in combination with ceftriaxone (CRO)., Methods: Retrospective, single center study including patients admitted at IRCCS San Raffaele Hospital (Milan, Italy), from June 2011 to June 2021, who underwent device removal for CIED infection and were empirically treated with DAP/CRO., Findings: Overall, 147 patients were included in this study. Median duration of therapy was 16 days (IQR 14-26). Empirical treatment with DAP/CRO was confirmed as definitive treatment in 140 patients (95.2%). In 7 (4.8%) patients DAP/CRO were discontinued according to the definite microbiological isolates: Corynebacterium spp. (4), Pseudomonas aeruginosa (2), Enterobacter cloacae (1). Ten patients (6.8%) underwent treatment simplification to narrow-spectrum antibiotics. One patient (0.6%) interrupted DAP-CRO due to pancytopenia. 6-month follow-up was available for 123/147 patients (83.7%): 9 patients recurred with a CIED infection (7.3%), and 9 died (7.3%)., Implications: In our 10-year experience, high-dose DAP in combination with CRO represented a good option for empirical therapy of CIED infections. DAP-CRO combination was safe and effective, showing no significant drug-related adverse events and low rates of 6-month recurrence and mortality., Competing Interests: Declaration of competing interest The authors have no relevant financial or non-financial interests to disclose., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: The increasing prevalence of methicillin-resistant Staphylococcus aureus (MRSA) strains resistant to non-beta-lactam antimicrobials poses a significant challenge in treating severe MRSA bloodstream infections. This study explores resistance development and mechanisms in MRSA isolates, especially after the first dalbavancin-resistant MRSA strain in our hospital in 2016., Methods: This study investigated 55 MRSA bloodstream isolates (02/2015-02/2021) from the University Hospital of the Medical University of Vienna, Austria. The MICs of dalbavancin, linezolid, and daptomycin were assessed. Two isolates (16-33 and 19-362) resistant to dalbavancin were analyzed via whole-genome sequencing, with morphology evaluated using transmission electron microscopy (TEM)., Results: S.aureus BSI strain 19-362 had two novel missense mutations (p.I515M and p.A606D) in the pbp2 gene. Isolate 16-33 had a 534 bp deletion in the DHH domain of GdpP and a SNV in pbp2 (p.G146R). Both strains had mutations in the rpoB gene, but at different positions. TEM revealed significantly thicker cell walls in 16-33 (p < 0.05) compared to 19-362 and dalbavancin-susceptible strains. None of the MRSA isolates showed resistance to linezolid or daptomycin., Conclusion: In light of increasing vancomycin resistance reports, continuous surveillance is essential to comprehend the molecular mechanisms of resistance in alternative MRSA treatment options. In this work, two novel missense mutations (p.I515M and p.A606D) in the pbp2 gene were newly identified as possible causes of dalbavancin resistance., (© 2024. The Author(s).)

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 (AUC 0-24 ) ≥ 666 mg∙h/L) and toxicity (minimum concentration (C min ) ≥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) AUC 0-24 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., (© 2024 Pharmacotherapy Publications, Inc.)

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 (AUC 0-24 :MIC) ≥666 was used to determine the PTA for efficacy (PTA E ). Minimum concentration (C min ) ≥24.3 mg/L determined the PTA for toxicity (PTA T ). Acceptable dosing regimens were those which achieved the combined target of ≥90% PTA E and ≤5% PTA T . Package label dosing of daptomycin yielded insufficient efficacy with only 26.3% PTA E in children 13-24 months, 39.5% PTA E in children 2-6 years, 30.1% PTA E in children 7-11 years, and 50.1% PTA E 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., (© 2024, The American College of Clinical Pharmacology.)

Purpose: Few studies describe the efficacy of antibiotic lock therapy (ALT) in long-term catheter-related bloodstream (CRBSI) infections. We applied local protocols combining Daptomycin (DPT) and Taurolidine ALT, associated with systemic antibiotic treatment (SAT), for conservative management of coagulase-negative Staphylococci (CoNS) CRBSI., Methods: Patients admitted for CoNS-associated CRBSI and treated with DPT and Taurolidine as ALT were retrospectively analyzed. Success was defined as catheter retention 30 days after ending treatment. Catheter removal within 30 days was considered as failure., Results: From April 2018 to September 2021, 22 subjects with CoNS-associated-CRBSI were included (95% with cancer, mean age 64 years, 59% male). Staphylococcus epidermidis was isolated in 82% of cases. Mean duration of DPT was 3.9 and 3 days as ALT and SAT, respectively. SAT also included Rifampin for 3 days. Taurolidine ALT was started on day 4 and was combined with oral SAT, that is, either Linezolid or Tedizolid. Mean duration of Taurolidine was 10.5 days, while total antibiotic treatment lasted 13.5 days. Clinical success and failure rates were 95% and 5%, respectively., Discussion: Short course DPT as ALT, combined with SAT and Taurolidine ALT, allowed high rates of conservative management of catheters in case of CoNS-associated-CRBSI., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Daptomycin is a membrane-targeting last-resort antimicrobial therapeutic for the treatment of infections caused by methicillin- and/or vancomycin-resistant Staphylococcus aureus . In the rare event of failed daptomycin therapy, the source of resistance is often attributable to mutations directly within the membrane phospholipid biosynthetic pathway of S. aureus or in the regulatory systems that control cell envelope response and membrane homeostasis. Here we describe the structural changes to the cell envelope in a daptomycin-resistant isolate of S. aureus strain N315 that has acquired mutations in the genes most commonly reported associated with daptomycin resistance: mprF , yycG , and pgsA . In addition to the decreased phosphatidylglycerol (PG) levels that are the hallmark of daptomycin resistance, the mutant with high-level daptomycin resistance had increased branched-chain fatty acids (BCFAs) in its membrane lipids, increased membrane fluidity, and increased cell wall thickness. However, the successful utilization of isotope-labeled straight-chain fatty acids (SCFAs) in lipid synthesis suggested that the aberrant BCFA:SCFA ratio arose from upstream alteration in fatty acid synthesis rather than a structural preference in PgsA. Transcriptomics studies revealed that expression of pyruvate dehydrogenase ( pdhB ) was suppressed in the daptomycin-resistant isolate, which is known to increase BCFA levels. While complementation with an additional copy of pdhB had no effect, complementation of the pgsA mutation resulted in increased PG formation, reduction in cell wall thickness, restoration of normal BCFA levels, and increased daptomycin susceptibility. Collectively, these results demonstrate that pgsA contributes to daptomycin resistance through its influence on membrane fluidity and cell wall thickness, in addition to phosphatidylglycerol levels., Importance: The cationic lipopeptide antimicrobial daptomycin has become an essential tool for combating infections with Staphylococcus aureus that display reduced susceptibility to β-lactams or vancomycin. Since daptomycin's activity is based on interaction with the negatively charged membrane of S. aureus , routes to daptomycin-resistance occur through mutations in the lipid biosynthetic pathway surrounding phosphatidylglycerols and the regulatory systems that control cell envelope homeostasis. Therefore, there are many avenues to achieve daptomycin resistance and several different, and sometimes contradictory, phenotypes of daptomycin-resistant S. aureus , including both increased and decreased cell wall thickness and membrane fluidity. This study is significant because it demonstrates the unexpected influence of a lipid biosynthesis gene, pgsA , on membrane fluidity and cell wall thickness in S. aureus with high-level daptomycin resistance., Competing Interests: The authors declare no conflict of interest.

Infections caused by methicillin-resistant Staphylococcus aureus (MRSA) are a leading cause of mortality worldwide. MRSA has acquired resistance to next-generation β-lactam antibiotics through the horizontal acquisition of the mecA resistance gene. Development of high resistance is, however, often associated with additional mutations in a set of chromosomal core genes, known as potentiators, which, through poorly described mechanisms, enhance resistance. The yjbH gene was recently identified as a hot spot for adaptive mutations during severe infections. Here, we show that inactivation of yjbH increased β-lactam MICs up to 16-fold and transformed MRSA cells with low levels of resistance to being homogenously highly resistant to β-lactams. The yjbH gene encodes an adaptor protein that targets the transcriptional stress regulator Spx for degradation by the ClpXP protease. Using CRISPR interference (CRISPRi) to knock down spx transcription, we unambiguously linked hyper-resistance to the accumulation of Spx. Spx was previously proposed to be essential; however, our data suggest that Spx is dispensable for growth at 37°C but becomes essential in the presence of antibiotics with various targets. On the other hand, high Spx levels bypassed the role of PBP4 in β-lactam resistance and broadly decreased MRSA susceptibility to compounds targeting the cell wall or the cell membrane, including vancomycin, daptomycin, and nisin. Strikingly, Spx potentiated resistance independently of its redox-sensing switch. Collectively, our study identifies a general stress pathway that, in addition to promoting the development of high-level, broad-spectrum β-lactam resistance, also decreases MRSA susceptibility to critical antibiotics of last resort., Competing Interests: The authors declare no conflict of interest.

Background: Antibiotic-containing carrier systems are one option that offers the advantage of releasing active ingredients over a longer period of time. In vitro sustained drug release from a carrier system consisting of microporous β-TCP ceramic and alginate has been reported in previous works. Alginate dialdehyde (ADA) gelatin gel showed both better mechanical properties when loaded into a β-TCP ceramic and higher biodegradability than pure alginate., Methods: Dual release of daptomycin and BMP-2 was measured on days 1, 2, 3, 6, 9, 14, 21, and 28 by HPLC and ELISA. After release, the microbial efficacy of the daptomycin was verified and the biocompatibility of the composite was tested in cell culture., Results: Daptomycin and the model compound FITC protein A (n = 30) were released from the composite over 28 days. A Daptomycin release above the minimum inhibitory concentration (MIC) by day 9 and a burst release of 71.7 ± 5.9% were observed in the loaded ceramics. Low concentrations of BMP-2 were released from the loaded ceramics over 28 days., (© 2024. The Author(s).)

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

Objectives: Daptomycin is one of the few last-line antimicrobials available for the treatment of multidrug-resistant Staphylococcus aureus infections. An increasing number of daptomycin non-susceptible S. aureus infections has been reported worldwide, including Australia. Resistance to daptomycin is multifactorial and involves chromosomal mutations in genes encoding proteins involved in cell membrane and cell wall synthesis., Methods: In this study, we performed broth microdilution (BMD) to determine the daptomycin minimum inhibitory concentration (MIC) of 66 clinical isolates of S. aureus previously reported as daptomycin non-susceptible by the VITEK Ⓡ 2. We used whole-genome sequencing to characterise the isolates and screened the genomes for mutations associated with daptomycin non-susceptibility., Results: Only 56 of the 66 isolates had a daptomycin MIC >1 mg/L by BMD. Although the 66 isolates were polyclonal, ST22 was the predominant sequence type and one-third of the isolates were multidrug resistant. Daptomycin non-susceptibility was primarily associated with MprF mutations-at least one MprF mutation was identified in the 66 isolates. Twelve previously reported MprF mutations associated with daptomycin non-susceptibility were identified in 83% of the isolates. Novel MprF mutations identified included P314A, P314F, P314T, S337T, L341V, F349del, and T423R., Conclusions: Daptomycin non-susceptible S. aureus causing infections in Australia are polyclonal and harbour MprF mutation(s). The identification of multidrug-resistant daptomycin non-susceptible S. aureus is a public health concern., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Daptomycin is one of the last therapeutic resources for multidrug-resistant gram-positive bacteria. Despite its structural similarities with glycopeptides, its mechanisms of action and resistance are different and in some respects are not completely understood. Mutations in several genes have been associated with daptomycin resistance, especially in mprF , walkR , rpoB and rpoC , but their role and importance remain to be elucidated. We have studied mutations in 11 genes, which have been previously associated with daptomycin non-susceptibility, in nine daptomycin-non-susceptible Staphylococcus aureus clinical isolates (daptomycin MIC: >1 mg/L). Susceptibility to daptomycin, vancomycin, linezolid, oxacillin, telavancin and dalbavancin was studied. walkR , agrA , cls1 , cls2 , fakA, pnpA , clpP , prs , rpoB , rpoC and mprF were amplified by PCR and sequenced. The sequences were compared with the S. aureus ATCC 25923 complete genome (GenBank gi: 685631213) by using BLAST ® software. We did not find any changes in walkR , pnpA , prs and clpP . All isolates excepting isolate MSa5 showed a high number of significant mutations (between 13 and 25 amino acid changes) in mprF . Most isolates also showed mutations in the rpo genes, the cls genes and fakA . Daptomycin non-susceptibility in S. aureus clinical isolates seems to be reached through different mutation combinations when compared to S. aureus ATCC 25293. Especially mprF and cls1 showed very high polymorphism in most isolates. Meanwhile, one isolate, MSa5, showed only single mutation in mprF (P314T).

Antibiotic resistance in Gram-positive pathogens is a relevant concern, particularly in the hospital setting. Several antibiotics are now available to treat these drug-resistant pathogens, such as daptomycin, dalbavancin, linezolid, tedizolid, ceftaroline, ceftobiprole, and fosfomycin. However, antibiotic resistance can also affect these newer molecules. Overall, this is not a frequent phenomenon, but it is a growing concern in some settings and can compromise the effectiveness of these molecules, leaving few therapeutic options. We reviewed the available evidence about the epidemiology of antibiotic resistance to these antibiotics and the main molecular mechanisms of resistance, particularly methicillin-resistant Sthaphylococcus aureus , methicillin-resistant coagulase-negative staphylococci, vancomycin-resistant Enterococcus faecium , and penicillin-resistant Streptococcus pneumoniae . We discussed the interpretation of susceptibility tests when minimum inhibitory concentrations are not available. We focused on the risk of the emergence of resistance during treatment, particularly for daptomycin and fosfomycin, and we discussed the strategies that can be implemented to reduce this phenomenon, which can lead to clinical failure despite appropriate antibiotic treatment. The judicious use of antibiotics, epidemiological surveillance, and infection control measures is essential to preserving the efficacy of these drugs., Competing Interests: The authors declare no conflict of interest.

As membrane-mediated antibiotic resistance continues to evolve in Gram-positive bacteria, the development of new approaches to elucidate the membrane properties involved in antibiotic resistance has become critical. Membrane vesicles (MVs) secreted by the cytoplasmic membrane of Gram-positive bacteria contain native components, preserving lipid and protein diversity, nucleic acids, and sometimes virulence factors. Thus, MV-derived membrane platforms present a great model for Gram-positive bacterial membranes. In this work, we report the development of a planar bacterial cytoplasmic membrane-based biosensor using MVs isolated from the Bacillus subtilis WT strain that can be coated on multiple surface types such as glass, quartz crystals, and polymeric electrodes, fostering the multimodal assessment of drug-membrane interactions. Retention of native membrane components such as lipoteichoic acids, lipids, and proteins is verified. This biosensor replicates known interaction patterns of the antimicrobial compound, daptomycin, with the Gram-positive bacterial membrane, establishing the applicability of this platform for carrying out biophysical characterization of the interactions of membrane-acting antibiotic compounds with the bacterial cytoplasmic membrane. We report changes in membrane viscoelasticity and permeability that correspond to partial membrane disruption when calcium ions are present with daptomycin but not when these ions are chelated. This biomembrane biosensing platform enables an assessment of membrane biophysical characteristics during exposure to antibiotic drug candidates to aid in identifying compounds that target membrane disruption as a mechanism of action.

Introduction: Acute eosinophilic pneumonia (AEP) is a rare respiratory condition caused by eosinophil accumulation in the pulmonary tissue that can be related to drug administration. Daptomycin, an antibiotic active against gram-positive bacteria, is one of the leading causes of AEP among drugs. In order to raise awareness of this rare syndrome, in our work we have described a case of an 82-year-old male with Enterococcus faecalis endocarditis treated with daptomycin, who developed a daptomycin-induced AEP. We have performed a systematic review of the literature for all similar reported cases., Methods: The systematic review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. To conduct the analysis, the terms "daptomycin AND eosinoph* AND pneum*" were entered into the databases Medline, CINAHL, and Embase on April 13, 2023. We considered all relevant records documenting AEP after daptomycin use. No restrictions in terms of year or language were made. A formal appraisal of observational studies was performed by Newcastle-Ottawa Scale. All results and data were reported by means of tables., Results: Our search identified 93 relevant records, published between 2007 and 2023. A total of 120 patients were considered. Patients who experienced AEP were mostly males (n = 88, 73.3%) with a mean age of 68.28 years (SD 11.54). Daptomycin was most frequently prescribed for osteoarticular infections (n = 75, 62.5%) and to treat gram-positive cocci infections. The most frequently isolated pathogen was methicillin-resistant Staphylococcus aureus. Daptomycin was mostly used with off-label indications (n = 89, 74%). Symptoms of AEP were usually reported after a mean of 21.75 days of treatment (range 3-84) and typically included fever, dyspnea, dry cough, and acute respiratory failure. Reported treatment strategies invariably included daptomycin withdrawal, respiratory support, and corticosteroid treatment. One hundred and sixteen patients fully recovered. A fatal outcome was described in 4 patients. Suggestive symptoms and imaging raised suspicion for AEP, confirmed with bronchoalveolar lavage in 57.5% of the cases., Discussion and Conclusions: Daptomycin-induced AEP is a rare but potentially fatal complication, mostly reported after long treatment with daptomycin. Clinicians should be aware of this syndrome, as it could be initially misdiagnosed for an acute infectious respiratory syndrome, resulting in a delay in its diagnosis and treatment. Furthermore, since the risk of developing AEP is increased by longer drug exposure, caution should be used when discussing the use of daptomycin in longer treatment regimens., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

Aim: To review preclinical and clinical data relevant to daptomycin lock therapy in catheter-related bloodstream infection (CRBSI). Methods: Systematic review in PubMed, Scopus and clinical trial registries. Results: Preclinical data demonstrate daptomycin lock solution stability and compatibility with heparin, good biofilm penetration, bactericidal activity against biofilm-embedded bacteria, and high efficacy in vitro and in animal catheter infection models. Clinical data remain limited (two case reports and five case series totaling n = 65 CRBSI episodes), albeit promising (successful catheter salvage in about 80% of cases). Conclusion: Despite theoretical advantages of daptomycin, clinical data remain scarce. Comparative studies versus alternative lock solutions are needed, as well as studies to define optimal daptomycin lock regimen (including optimal concentration, dwell time and lock duration).

This study is an economic analysis seeking to examine cost savings that may be accrued from usage of oral linezolid in place of OPAT IV daptomycin in patients requiring prolonged courses of IV or highly bioavailable oral antibiotic therapy. In order to do so we conducted a literature review to establish the scenarios in which the agents could be considered equivalent. We then, using a decision-tree model, conducted a cost analysis to establish differences in cost between the approaches. Under the model base-case, the total cost of treatment with OPAT daptomycin was €3,496.84 and the total cost of treatment with oral linezolid was €772.01. Therefore the oral linezolid strategy would be projected to save the Irish health service €2,724.83 per patient. These results were robust to one-way deterministic sensitivity analyses and probabilistic sensitivity analysis. Our study suggests that significant savings could be safely accrued in the management of these patients.

Biofilm-forming bacterial infections result in clinical failure, recurring infections, and high health care costs. The antibiotic concentrations needed to eradicate biofilm require further research. We aimed to model an in vitro prosthetic joint infection (PJI) to elucidate the activity of traditional systemic concentrations versus supratherapeutic concentrations to eradicate a Staphylococcus epidermidis biofilm PJI. We evaluated S. epidermidis high-biofilm-forming (ATCC 35984) and low-biofilm-forming (ATCC 12228) isolates in an in vitro pharmacodynamic biofilm reactor model with chromium cobalt coupons to simulate prosthetic joint infection. Vancomycin, daptomycin, levofloxacin, and minocycline were used alone and combined with rifampin to evaluate the effect of biofilm eradication. We simulated three exposures: (i) humanized systemic dosing alone, (ii) supratherapeutic doses (1,000× MIC), and (iii) and dosing in combination with rifampin. Resistance development was monitored throughout the study. Simulated humanized systemic doses of a lipoglycopeptide (daptomycin), a fluoroquinolone (levofloxacin), a tetracycline (minocycline), and a glycopeptide (vancomycin) alone failed to eradicate a formed S. epidermidis biofilm. Supratherapeutic doses of vancomycin (2,000 μg/mL) and minocycline (15 μg/mL) with or without rifampin (15 μg/mL) failed to eradicate biofilms. However, a levofloxacin supratherapeutic dose (125 μg/mL) with rifampin eradicated the high-biofilm-producing isolate by 48 h. Interestingly, supratherapeutic-dose exposures of daptomycin (500 μg/mL) alone eradicated high- and low-biofilm-forming isolates in established biofilms. The concentrations needed to eradicate biofilms on foreign materials are not obtained with systemic dosing regimens. The failure of systemic dosing regimens to eradicate biofilms validates clinical findings with recurring infections. The addition of rifampin to supratherapeutic dosing regimens does not result in synergy. Supratherapeutic daptomycin dosing may be effective at the site of action to eradicate biofilms. Further studies are needed., Competing Interests: The authors declare no conflict of interest.

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

Objective: To evaluate the cost-effectiveness of dalbavancin compared with standard of care (SoC) treatment as daptomycin or teicoplanin in patients with sternal wound infections (SWI)., Methods: Multicentre retrospective study of patients diagnosed with SWI from January 2016 to December 2019 at two cardiac surgery facilities treated with dalbavancin, teicoplanin or daptomycin. Patients with SWI treated with dalbavancin were compared with SoC to evaluate resolution of infection at 90 and 180 days from infection diagnosis, length of stay (LoS) and management costs., Results: 48 patients with SWI were enrolled, 25 (50%) male, median age 67 (60-73) years, Charlson index score 5 (4-7). Fifteen patients were treated with dalbavancin (31%) and 33 with SoC (69%): teicoplanin in 21 (63%), and daptomycin in 12 (37%). Staphylococcus species were the most frequent isolates (44, 92%), mostly (84%) resistant to methicillin. All patients were treated with surgical debridement followed by negative pressure wound therapy. Wound healing at day 90 and 180 was achieved in 46 (95.8%) and 34 (82.9%) of patients, respectively. A shorter length of hospitalization in patients treated with dalbavancin compared with SoC [12 (7-18) days vs 22 (12-36) days, p:0.009] was found. Treatment with dalbavancin resulted in total cost savings of €16 026 (95% CI 5976-26 076, P < 0.001). Savings were mainly related to the LoS that was significantly shorter in the dalbavancin group, generating significantly lower cost compared to SoC group., Conclusion: Dalbavancin treatment of sternal wound infections is effective and seems to reduce hospitalization length, leading to significantly lower costs., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Infections caused by vancomycin-resistant Enterococcus faecium (VREfm) are an important public health threat. VREfm isolates have become increasingly resistant to the front-line antibiotic daptomycin (DAP). As such, the use of DAP combination therapies with other antibiotics like fosfomycin (FOS) has received increased attention. Antibiotic combinations could extend the efficacy of currently available antibiotics and potentially delay the onset of further resistance. We investigated the potential for E. faecium HOU503, a clinical VREfm isolate that is DAP and FOS susceptible, to develop resistance to a DAP-FOS combination. Of particular interest was whether the genetic drivers for DAP-FOS resistance might be epistatic and, thus, potentially decrease the efficacy of a combinatorial approach in either inhibiting VREfm or in delaying the onset of resistance. We show that resistance to DAP-FOS could be achieved by independent mutations to proteins responsible for cell wall synthesis for FOS and in altering membrane dynamics for DAP. However, we did not observe genetic drivers that exhibited substantial cross-drug epistasis that could undermine the DAP-FOS combination. Of interest was that FOS resistance in HOU503 was largely mediated by changes in phosphoenolpyruvate (PEP) flux as a result of mutations in pyruvate kinase ( pyk ). Increasing PEP flux could be a readily accessible mechanism for FOS resistance in many pathogens. Importantly, we show that HOU503 was able to develop DAP resistance through a variety of biochemical mechanisms and was able to employ different adaptive strategies. Finally, we showed that the addition of FOS can prolong the efficacy of DAP and slow down DAP resistance in vitro .

Background: Corynebacterium striatum is a gram-positive facultative anaerobe found in the environment and human flora that has historically been considered a contaminant. More recently, Corynebacterium striatum has been implicated in human infections, including respiratory infections, endocarditis, and bone and joint infections, particularly those involving hardware or implanted devices., Case Presentation: A 65-year-old man presented for washout of his left total knee arthroplasty following a revision 20 days prior. The patient underwent debridement of his left total knee and revision of the left total femur arthroplasty. Daptomycin was initiated empirically due to a previous rash from vancomycin. Operative tissue cultures grew Staphylococcus haemolyticus, Staphylococcus epidermidis and Corynebacterium striatum. Given concern for daptomycin resistance and the reliability of vancomycin susceptibility, daptomycin was discontinued and vancomycin initiated following a graded challenge. Within a few days, the patient developed a diffuse, blanching, erythematous, maculopapular rash and daptomycin was restarted. Over the next 72 h, his rash progressed and he met criteria for drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome. Daptomycin was stopped and oral linezolid initiated; rash improved. C. striatum returned with susceptibility to gentamicin, linezolid, vancomycin and daptomycin. Due to concern for adverse effects on long-term linezolid, daptomycin was restarted and was tolerated for 20 days, at which point purulent drainage from incision increased. The patient underwent another arthroplasty revision and washout. Operative cultures from this surgery were again positive for C. striatum. Repeat C. striatum susceptibilities revealed resistance to daptomycin but retained susceptibility to linezolid. Daptomycin was again changed to linezolid. He completed six weeks of linezolid followed by linezolid 600 mg daily for suppression and ultimately opted for disarticulation., Conclusions: C. striatum has historically been regarded as a contaminant, particularly when grown in tissue culture in the setting of prosthetic joint infection. Based on the available literature and susceptibility patterns, the most appropriate first-line therapy is vancomycin or linezolid. Treatment with daptomycin should be avoided, even when isolates appear susceptible, due to the risk of development of high-level resistance (MIC > 256 µg/mL) and clinical failure., (© 2022. The Author(s).)

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.

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., (© 2021 Wiley-VCH GmbH.)

Although the measurement of aminoglycosides and glycopeptides in blood has been well established, it has become evident that therapeutic drug monitoring (TDM) should be extended to other antibiotics such as beta-lactams, daptomycin and linezolid. The use of a TDM guided approach allows reliable assessment of target concentration thus mitigating the risk for toxicity and preventing antibiotic resistance. This is especially relevant for the critically ill in intensive care. Herein we provide an overview on the different antibacterial antibiotics and their target pharmacokinetic/pharmacodynamic indexes in general as well as the importance for TDM of antibacterial antibiotics specifically. Analytical methods applicable to this approach in clinical laboratories are explored and highlighted., (Copyright © 2022 Elsevier Inc. All rights reserved.)

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

Objective: To evaluate evidence for high-dose daptomycin (doses ≥ 8 mg/kg/d)., Data Sources: A PubMed/MEDLINE literature search was performed (January 2000 to December 2020) using the search terms daptomycin, high dose , and dosing . Review article references and society guidelines were reviewed., Study Selection and Data Extraction: Clinical trials, observational studies, retrospective studies, meta-analyses, and systematic reviews reporting on high-dose daptomycin were included., Data Synthesis: Experimentally, daptomycin outperforms other antimicrobials for high inoculum and biofilm-associated infections. Clinically, high-dose daptomycin is supported as salvage and first-line therapy for endocarditis and bacteremia, primarily when caused by methicillin-resistant Staphylococcus aureus (when vancomycin minimum inhibitory concentration is >1 mg/L) and Enterococcus . High-dose daptomycin appears effective for osteomyelitis and central nervous system infections, although comparative studies are lacking. High dosing in renal replacement therapy requires considering clearance modality to achieve exposures like normal renal function. Weight-based dosing in obesity draws concern for elevated exposures, although high doses have not been evaluated kinetically in obesity. Some data show benefits of high doses in overweight populations. Burn patients clear daptomycin more rapidly, and high doses may only achieve drug exposures similar to standard doses (6 mg/kg)., Relevance to Patient Care and Clinical Practice: This review analyzes the efficacy and safety of high-dose daptomycin in serious gram-positive infections. Discussion of specific infectious etiologies and patient populations should encourage clinicians to evaluate their daptomycin dosing standards., Conclusions: The efficacy of high-dose daptomycin and limited safety concerns encourage clinicians to consider high-dose daptomycin more liberally in severe gram-positive infections.

Data demonstrating that antibiotics administered intraoperatively in patients with surgical revision for periprosthetic joint infection achieve concentrations exceeding minimal inhibitory concentrations of the identified bacteria at the surgical site when the new implant is inserted are lacking. We prospectively included patients with periprosthetic joint infection operated with one- or two-stage replacement during which cefepime (2g)-daptomycin (10mg/kg) combination was administered intravenously as intraoperative empirical antibiotic treatment. Three biopsies (two bones and one synovial membrane) were taken from each patient just before the insertion of the new implant. Eighteen adults of median age 68 years were included. Knee was involved in 10 patients (55.6%) and surgery consisted in one-/two-stage replacement in 11/7 patients. A tourniquet was used during the intervention in the 10 patients with knee prosthesis. Among 54 tissue samples, cefepime and daptomycin were detected respectively in 35 (64.8%) and 21 (38.9%) cases (P=0.01). A total of 17 bacteria dominated by staphylococci (n=14) were identified in 10 patients; tissue inhibitory quotient calculated in 51 samples was >1 in 22 cases (43.1%) for cefepime and in 16 cases (31.4%) for daptomycin. The proportion of tissue samples with detectable antibiotic was significantly higher in hip versus knee prosthesis (P=0.03). The present study suggests that intraoperative empirical administration of cefepime-daptomycin combination during septic prosthetic joint replacement results in a high proportion of tissue samples in which at least one of the two antibiotics was not detected or at a low concentration despite satisfactory concomitant blood serum concentrations., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Development of a simple method to enhance targeting and anti-tumor effect of the chemotherapeutic agents in vivo is a major problem. Amphipathic and natural daptomycin is biocompatible antibacterial polypeptide used in clinical practice. Herein, doxorubicin (DOX) was stabilized by zwitterionic daptomycin (Dap) micelles in aqueous solution to form a zwitterionic nanodrug (Dap-DOX micelles). The hydrodynamic size and zeta potential of Dap-DOX micelles were 85 nm and -10 mV, respectively. The study on the controlled release showed that more DOX molecules were released from Dap-DOX micelles at acidic condition of tumor tissue than that at neutral condition of normal tissue which was due to pH responsiveness of Dap-DOX micelles. Dap-DOX micelles exhibited good stability in fibrinogen solution. Moreover, MTT studies showed that Dap-DOX micelles had higher cytotoxicity than free DOX. Notably, the results of flow cytometry indicated that the average fluorescence intensity of Dap-DOX micelle-treated cells was higher than that of free DOX-treated cells, and acidic conditions were more favorable for Dap-DOX micelles than normal pH in cell uptake assay. More importantly, Dap-DOX micelles were biocompatible in vivo based on the changes of weight and blood indexes of mice. Dap-DOX micelles were selectively accumulated at tumor sites in vivo through EPR effect, which reduced the toxicity of free DOX and achieved excellent tumor inhibition effect. The tumor inhibition rate of Dap-DOX micelles reached 96%. Dap-DOX micelles also effectively inhibited the growth of bacterial. Taken together, Dap-based drug delivery systems are promising and effective in cancer therapy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

Streptococci still represent common etiologic agents of infective endocarditis (IE). Although renal failure is frequently reported as an aminoglycoside-associated adverse event, last international guidelines recommend a beta-lactam/gentamicin combination therapy. We retrospectively evaluated the use of daptomycin-based aminoglycoside-sparing combination therapy for the treatment of streptococcal IE in seven referral hospitals in Italy. Retrospective, multicenter, observational study. All patients with streptococcal IE admitted from 2016 to 2018 were enrolled. Mortality and incidence of acute kidney injury (AKI) were compared between Group A (standard of care, SoC) and Group B (daptomycin-based aminoglycoside-sparing combination therapy). Fifty-four patients were enrolled, 33 in Group A and 21 in Group B. Mortality was 2/33 (6%) in Group A and 0 in Group B ( p  = 0.681); AKI incidence was 8/33 (24%) in Group A and 0 in Group B ( p  = 0.04). Daptomycin-based aminoglycoside-sparing combination therapy appears to be promising for the treatment of streptococcal endocarditis because of similar efficacy compared with SoC and significantly reduced incidence of AKI.

Empyema is typically treated using pleural space drainage and systemic treatment with antimicrobials, and specific antimicrobial agents in the case of methicillin-resistant Staphylococcus aureus (MRSA) infections. A 57-year-old man underwent segmental resection of the left lung owing to multiple lung metastases and developed MRSA-related empyema postoperatively. Although the patient received chest drainage and linezolid, the inflammation caused by the infection persisted. Consequently, linezolid was replaced by daptomycin, and his empyema was accordingly resolved. Our findings indicate that daptomycin could be an effective treatment for postoperative MRSA-related empyema.

Introduction. Dalbavancin was approved in Europe in 2015 for skin and soft tissue infections. Hypothesis/Gap Statement. Data on methicillin-resistant coagulase-negative staphylococci (MR-CNS) dalbavancin susceptibility are scarce. Aim. To assess the susceptibility of MR-CNS to dalbavancin and other anti-staphylococcal agents. Methodology. A total of 443 MR-CNS clinical isolates from patients hospitalized in a Greek university hospital during a 2.5-year period (January 2018 to June 2020) were included. The MICs for vancomycin, teicoplanin, linezolid and daptomycin were investigated by Etest and the MIC for dalbavancin was determined according to European Committee on Antimicrobial Susceptibility Testing (EUCAST) guidelines in 196 isolates. The consumption of the aforementioned antimicrobials was calculated. Results. In total, 51 isolates were resistant to teicoplanin (11.5 %) and 211 (47.6 %) to linezolid; all were susceptible to vancomycin and daptomycin. Among 196 isolates tested, 32 (16.3 %) were resistant to dalbavancin. A significant increase of MIC during the study period was found for vancomycin, teicoplanin and daptomycin, while a decrease in linezolid's MIC was observed. Dalbavancin's MIC remained stable. No difference in consumption was observed among the studied anti-staphylococcal agents. Conclusion. An increase of vancomycin, teicoplanin and daptomycin MICs among MR-CNS was observed, whereas 47.6 % of isolates were non-susceptible to linezolid. Dalbavancin retains excellent potency against MR-CNS, even in the presence of non-susceptibility to other anti-staphylococcal antibiotics.