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BioMed Research International 2019Daptomycin (DAP), a cyclic lipopeptide produced by , is a novel antibiotic to clinically treat various Gram-positive pathogenic bacteria-induced infections. Although DAP... (Review)
Review
Daptomycin (DAP), a cyclic lipopeptide produced by , is a novel antibiotic to clinically treat various Gram-positive pathogenic bacteria-induced infections. Although DAP has a strong broad-spectrum bactericidal effect, recently rare bacterial antibiotic resistance against DAP gradually arises. The review is to summarize the normal indications of DAP, its off-label usage against several clinical pathogen infections, the unique antibacterial mechanisms of DAP, and the combination of antibiotic therapies for highly DAP-resistant pathogens. More noticeably, rising evidences demonstrate that DAP has new potential activity of anticancer and immunomodulatory effects. So far the multifunctional pharmaceutical effects of DAP deserve to be further explored for future clinical applications.
Topics: Animals; Anti-Bacterial Agents; Antineoplastic Agents; Daptomycin; Drug Resistance, Bacterial; Drug Synergism; Humans; Microbial Sensitivity Tests
PubMed: 31263709
DOI: 10.1155/2019/8609218 -
Antimicrobial Agents and Chemotherapy Jan 2022Enterococcus faecium is a significant multidrug-resistant pathogen. Bacteriophage cocktails are being proposed to complement antibiotic therapy. After a screen of 8 E....
Enterococcus faecium is a significant multidrug-resistant pathogen. Bacteriophage cocktails are being proposed to complement antibiotic therapy. After a screen of 8 E. faecium strains against 4 phages, 2 phages (113 and 9184) with the broadest host ranges were chosen for further experiments. Transmission electron microscopy, whole-genome sequencing, comparative genome analyses, and time-kill analyses were performed. Daptomycin (DAP) plus the phage cocktail (113 [myophage] and 9184 [siphopage]) showed bactericidal activity in most regimens, while DAP addition prevented phage 9184 resistance against daptomycin-nonsusceptible E. faecium.
Topics: Anti-Bacterial Agents; Bacteriophages; Daptomycin; Enterococcus faecium; Microbial Sensitivity Tests
PubMed: 34723631
DOI: 10.1128/AAC.01623-21 -
Journal of Infection and Chemotherapy :... Jun 2013Daptomycin is a lipopeptide antibiotic active against gram-positive organisms and recently approved for marketing in Japan. This study investigates the efficacy and... (Randomized Controlled Trial)
Randomized Controlled Trial
Daptomycin is a lipopeptide antibiotic active against gram-positive organisms and recently approved for marketing in Japan. This study investigates the efficacy and safety of daptomycin in Japanese patients with skin and soft tissue infections (SSTIs) caused by methicillin-resistant Staphylococcus aureus (MRSA) for regulatory filing in Japan. Overall, 111 Japanese patients with SSTI were randomized in this open-label, randomized, active-comparator controlled, parallel-group, multicenter, phase III study. Patients received intravenous daptomycin 4 mg/kg once daily or vancomycin 1 g twice daily for 7-14 days. Efficacy was determined by a blinded Efficacy Adjudication Committee. Among patients with SSTIs caused by MRSA, 81.8 % (95 % CI, 69.1-90.9) of daptomycin recipients and 84.2 % (95 % CI, 60.4-96.6) of vancomycin recipients achieved a successful clinical response at the test-of-cure (TOC) visit. The microbiological success rate against MRSA at the TOC visit was 56.4 % (95 % CI, 42.3-69.7) with daptomycin and 47.4 % (95 % CI, 24.4-71.1) with vancomycin. Daptomycin was generally well tolerated; most adverse events were of mild to moderate severity. The measurement of daptomycin concentration in plasma revealed that patients with mild or moderate impaired renal function showed similar pharmacokinetics profiles to patients with normal renal function. Clinical and microbiological responses, stratified by baseline MRSA susceptibility, suggested that patients infected with MRSA of higher daptomycin MIC showed a trend of lower clinical success with a P value of 0.052 by Cochran-Armitage test. Daptomycin was clinically and microbiologically effective for the treatment of MRSA-associated SSTIs in Japanese patients.
Topics: Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Creatinine; Daptomycin; Female; Humans; Kidney Function Tests; Male; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Middle Aged; Soft Tissue Infections; Staphylococcal Skin Infections; Vancomycin
PubMed: 23085743
DOI: 10.1007/s10156-012-0501-9 -
Scientific Reports Dec 2019Staphylococcus epidermidis infections are a common occurrence in hospitals, particularly in catheter-related bloodstream and surgical site infections and infective...
Staphylococcus epidermidis infections are a common occurrence in hospitals, particularly in catheter-related bloodstream and surgical site infections and infective endocarditis. Higher daptomycin minimum inhibitory concentration (MIC) values may be associated with daptomycin treatment failure among patients with S. epidermidis infections. We therefore conducted a retrospective cohort study to determine the predictive value of daptomycin susceptibility. A retrospective study was undertaken in 1,337 patients with S. epidermidis infections. Data were collected from 1 January 2013 to 31 December 2016 at Ehime University Hospital, and included the following clinicopathological factors for evaluation: age, sex, resistance to vancomycin or teicoplanin, and history of antimicrobial therapy. Multiple analysis was performed using logistic regression to identify factors that independently and significantly affected the daptomycin resistance. Daptomycin-resistant S. epidermidis was identified in 38 (2.8%) patients. According to the multiple analysis, only higher MIC values (≥16 mg/L) for teicoplanin (P < 0.0001) were independently associated with an increased risk of developing daptomycin resistance. In conclusion, higher teicoplanin MIC values may predict resistance to daptomycin treatment in S. epidermidis infections.
Topics: Aged; Anti-Bacterial Agents; Catheter-Related Infections; Daptomycin; Dose-Response Relationship, Drug; Drug Resistance, Bacterial; Endocarditis, Bacterial; Female; Humans; Male; Microbial Sensitivity Tests; Middle Aged; Predictive Value of Tests; Retrospective Studies; Staphylococcal Infections; Staphylococcus epidermidis; Surgical Wound Infection; Teicoplanin; Treatment Failure
PubMed: 31811214
DOI: 10.1038/s41598-019-55149-z -
Journal of Global Antimicrobial... Jun 2020A systematic review and meta-analysis were conducted to re-assess the efficacy and safety of daptomycin compared with linezolid treatment for vancomycin-resistant... (Meta-Analysis)
Meta-Analysis
Efficacy and safety of daptomycin versus linezolid treatment in patients with vancomycin-resistant enterococcal bacteraemia: An updated systematic review and meta-analysis.
OBJECTIVES
A systematic review and meta-analysis were conducted to re-assess the efficacy and safety of daptomycin compared with linezolid treatment for vancomycin-resistant enterococcal (VRE) bacteraemia and to explore whether high-dose daptomycin is beneficial.
METHODS
PubMed, EMBASE, the Cochrane Library, and meeting abstracts were searched from inception to February 2019. Studies evaluating daptomycin and linezolid treatment for VRE bacteraemia were included.
RESULTS
Twenty-two observational studies were identified. A non-significant higher mortality (OR 1.27; 95% CI 0.99-1.63) and significantly lower risk of thrombocytopenia (OR 0.78; 95% CI 0.61-0.99) were found with daptomycin compared with linezolid treatment. Clinical response (OR 0.88; 95% CI 0.59-1.33), microbiological cure (OR 0.82; 95% CI 0.53-1.28), recurrence of bacteraemia (OR 0.96; 95% CI 0.70-1.32), and risk of creatine kinase elevation (OR 0.82; 95% CI 0.46-1.47) were similar for the two agents. In the subgroup analysis of studies focusing on high-dose daptomycin treatment, similar mortality was observed (OR 0.92; 95% CI 0.46-1.84). Moreover, patients receiving daptomycin tended to show a higher clinical response (OR 1.61; 95% CI 0.37-7.09) and microbiological cure (OR 2.09; 95% CI 0.43-10.1) and a lower risk of bacteraemia relapse (OR 0.47; 95% CI 0.15-1.45), although the difference was not significant.
CONCLUSIONS
Compared with linezolid treatment, daptomycin treatment showed comparable clinical and microbiological outcomes but a lower incidence of thrombocytopenia. Because of the dose-dependent effect that was observed, high-dose daptomycin should be considered for patients with VRE bacteraemia.
Topics: Anti-Bacterial Agents; Bacteremia; Daptomycin; Humans; Linezolid; Vancomycin
PubMed: 31629937
DOI: 10.1016/j.jgar.2019.10.008 -
Journal of Clinical Microbiology Mar 2021Members of the genus are increasingly recognized as pathobionts and can be very resistant to antimicrobial agents. Previous studies have demonstrated that can rapidly...
Members of the genus are increasingly recognized as pathobionts and can be very resistant to antimicrobial agents. Previous studies have demonstrated that can rapidly develop high-level daptomycin resistance (HLDR) (MIC, ≥256 μg/ml). Here, we conducted a multicenter study to assay for this phenotype in diverse species. clinical isolates ( = 157) from four medical centers were evaluated. MIC values to daptomycin, vancomycin, and telavancin were determined before and after overnight exposure to daptomycin to identify isolates able to rapidly develop daptomycin nonsusceptibility. To investigate assay reproducibility, 18 isolates were evaluated at three study sites. In addition, the stability of daptomycin nonsusceptibility was tested using repeated subculture without selective pressure. The impact of different medium brands was also investigated. Daptomycin nonsusceptibility emerged in 12 of 23 species evaluated in this study (, , , , , , , , , , , and ) and was detected in 50 of 157 (31.8%) isolates tested. All isolates displayed low (susceptible) MIC values to vancomycin and telavancin before and after daptomycin exposure. Repeated subculture demonstrated that 2 of 9 isolates (22.2%) exhibiting HLDR reverted to a susceptible phenotype. Of 30 isolates tested on three medium brands, 13 (43.3%) had differences in daptomycin MIC values between brands. Multiple species can rapidly develop daptomycin nonsusceptibility, including HLDR, after a short daptomycin exposure period.
Topics: Anti-Bacterial Agents; Corynebacterium; Daptomycin; Microbial Sensitivity Tests; Reproducibility of Results
PubMed: 33472898
DOI: 10.1128/JCM.02052-20 -
Journal of Infection and Chemotherapy :... Mar 2022Complicated skin and soft tissue infections (cSSTIs) and bacteremia caused by Staphylococcus aureus, including methicillin-resistant S. aureus (MRSA), are common causes...
INTRODUCTION
Complicated skin and soft tissue infections (cSSTIs) and bacteremia caused by Staphylococcus aureus, including methicillin-resistant S. aureus (MRSA), are common causes of infection for children worldwide. Here, the safety and efficacy of daptomycin in Japanese pediatric participants are reported.
METHODS
This open-label, single-arm phase 2 study (NCT03643952) enrolled Japanese pediatric participants (age 1-17 years) with cSSTI or bacteremia caused by gram-positive cocci. Participants received age-adjusted doses of intravenous daptomycin for 5 to up to 14 days (cSSTI) or 5 to up to 42 days (bacteremia). The primary objective was safety and tolerability; efficacy among participants with infections caused by MRSA was a secondary objective.
RESULTS
A total of 18 participants (cSSTI, n = 14; bacteremia, n = 4) were enrolled across 12 study sites in Japan. The most common pathogen was S. aureus (15/18 [83.3%]), including methicillin-susceptible and -resistant isolates. Adverse events (AE) were reported in 42.9% (6/14) of participants with cSSTI and 100% (4/4) of participants with bacteremia. No deaths, serious AEs, discontinuations of study medication due to an AE, or events of clinical interest occurred in the study. In participants with infections caused by MRSA, 87.5% [7/8] achieved favorable clinical response at test of cure (TOC) visit (cSSTI, 85.7% [6/7]; bacteremia, 100% [1/1]). In this population, favorable microbiological response at TOC was achieved by 71.4% (5/7) of participants with cSSTI and 100% (1/1) of participants with bacteremia.
CONCLUSIONS
Daptomycin was well tolerated, exhibited a favorable safety profile, and was effective for the treatment of cSSTI or bacteremia in Japanese children.
Topics: Adolescent; Anti-Bacterial Agents; Bacteremia; Child; Child, Preschool; Daptomycin; Gram-Positive Cocci; Humans; Infant; Japan; Methicillin-Resistant Staphylococcus aureus; Soft Tissue Infections; Staphylococcal Infections; Staphylococcus aureus; Treatment Outcome
PubMed: 34920946
DOI: 10.1016/j.jiac.2021.11.019 -
Antimicrobial Agents and Chemotherapy Sep 2009The findings of clinical and in vitro research support the theory that infective endocarditis (IE)-causing bacteria form biofilms and that biofilms negatively affect...
Activities of daptomycin and vancomycin alone and in combination with rifampin and gentamicin against biofilm-forming methicillin-resistant Staphylococcus aureus isolates in an experimental model of endocarditis.
The findings of clinical and in vitro research support the theory that infective endocarditis (IE)-causing bacteria form biofilms and that biofilms negatively affect treatment outcomes. The purpose of the present study was to quantify the biofilm formation of methicillin (meticillin)-resistant Staphylococcus aureus (MRSA) isolates obtained from patients with IE and to evaluate the in vitro activities of daptomycin and vancomycin alone and in combination with rifampin (rifampicin) or gentamicin while monitoring the isolates for the development of resistance. A high-inoculum, stationary-phase infection model of IE was used to simulate the pharmacokinetics in humans of daptomycin at 6 mg/kg of body weight/day, vancomycin at 1.25 g every 12 h (q12h) alone and in combination with rifampin at 300 mg every 8 h, and gentamicin at 1.3 mg/kg q12h. Two randomly selected clinical MRSA isolates were obtained from patients with IE; both MRSA isolates quantitatively produced biofilms. The time to bactericidal activity in the presence of daptomycin was isolate dependent but was achieved by 24 h for both MRSA isolates. Vancomycin did not achieve bactericidal activity throughout the experiment. At 24, 48, and 72 h, daptomycin-containing regimens had significantly more activity (greater declines in the mean number of CFU/g) than any of the vancomycin-containing regimens (P = 0.03). Rifampin and gentamicin antagonized or delayed the bactericidal activity of daptomycin (against MRSA B346846 for rifampin and against both isolates for gentamicin) in the first 24 h. Increases in the daptomycin and vancomycin MICs were not observed. We conclude that in an IE model of biofilm-forming MRSA, daptomycin monotherapy has better in vitro activity than daptomycin in combination with rifampin or gentamicin or any vancomycin-containing regimen studied within the first 24 h. Further investigations are needed to understand the initial delay in bactericidal activity observed when gentamicin or rifampin is combined with daptomycin.
Topics: Anti-Bacterial Agents; Biofilms; Daptomycin; Endocarditis; Gentamicins; Humans; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Rifampin; Vancomycin
PubMed: 19564363
DOI: 10.1128/AAC.00134-09 -
Journal of Global Antimicrobial... Mar 2022Over the past decade, daptomycin treatment of methicillin-resistant Staphylococcus aureus (MRSA) infections has led to the emergence of daptomycin nonsusceptible...
OBJECTIVES
Over the past decade, daptomycin treatment of methicillin-resistant Staphylococcus aureus (MRSA) infections has led to the emergence of daptomycin nonsusceptible (DAP-NS) MRSA strains and a subsequent interest in combinatorial antibiotic therapies. We investigated the phenotypic and genetic changes associated with the seesaw effect, which describes the correlation between daptomycin resistance and increased β-lactam susceptibility in DAP-NS MRSA and the reverse phenomenon of DAP-NS strains acquiring renewed susceptibility to daptomycin after β-lactam exposure.
METHODS
A continuous bioreactor model was used to study the effects of incremental doses of daptomycin followed by oxacillin on MRSA strain N315. Minimum inhibitory concentrations for daptomycin and oxacillin were determined for the bioreactor-derived samples. Transmission electron microscopy and cytochrome C binding assays were used to measure cell wall thickness and cell membrane charge, respectively, in the bioreactor-derived samples. Whole-genome sequencing was used to identify mutations associated with the seesaw effect.
RESULTS
Although daptomycin resistance conferred enhanced susceptibility to oxacillin, oxacillin treatment of DAP-NS strains was accompanied by a lowered minimum inhibitory concentration for daptomycin. Additionally, there was a reduction in relative positive cell surface charge and cell wall thickness. However, the mutations acquired in our DAP-NS populations were not accompanied by additional genomic changes after treatment with oxacillin, implicating alternative mechanisms for the seesaw effect.
CONCLUSION
In this study, we successfully produced and characterized the seesaw effect in MRSA strain N315 in a unique bioreactor model.
Topics: Bioreactors; Daptomycin; Methicillin-Resistant Staphylococcus aureus; Oxacillin; beta-Lactams
PubMed: 35085792
DOI: 10.1016/j.jgar.2022.01.013 -
Applied Microbiology and Biotechnology Sep 2020Daptomycin is a last resort antibiotic for the treatment of infections caused by many Gram-positive bacterial strains, including vancomycin-resistant Enterococcus (VRE)...
Daptomycin is a last resort antibiotic for the treatment of infections caused by many Gram-positive bacterial strains, including vancomycin-resistant Enterococcus (VRE) and methicillin- and vancomycin-resistant Staphylococcus aureus (MRSA and VRSA). However, the emergence of daptomycin-resistant strains of S. aureus and Enterococcus in recent years has renewed interest in synthesizing daptomycin analogs to overcome resistance mechanisms. Within this context, three aromatic prenyltransferases have been shown to accept daptomycin as a substrate, and the resulting prenylated analog was shown to be more potent against Gram-positive strains than the parent compound. Consequently, utilizing prenyltransferases to derivatize daptomycin offered an attractive alternative to traditional synthetic approaches, especially given the molecule's structural complexity. Herein, we report exploiting the ability of prenyltransferase CdpNPT to synthesize alkyl-diversified daptomycin analogs in combination with a library of synthetic non-native alkyl-pyrophosphates. The results revealed that CdpNPT can transfer a variety of alkyl groups onto daptomycin's tryptophan residue using the corresponding alkyl-pyrophosphates, while subsequent scaled-up reactions suggested that the enzyme can alkylate the N1, C2, C5, and C6 positions of the indole ring. In vitro antibacterial activity assays using 16 daptomycin analogs revealed that some of the analogs displayed 2-80-fold improvements in potency against MRSA, VRE, and daptomycin-resistant strains of S. aureus and Enterococcus faecalis. Thus, along with the new potent analogs, these findings have established that the regio-chemistry of alkyl substitution on the tryptophan residue can modulate daptomycin's potency. With additional protein engineering to improve the regio-selectivity, the described method has the potential to become a powerful tool for diversifying complex indole-containing molecules. KEY POINTS: • CdpNPT displays impressive donor promiscuity with daptomycin as the acceptor. • CdpNPT catalyzes N1-, C2-, C5-, and C6-alkylation on daptomycin's tryptophan residue. • Differential alkylation of daptomycin's tryptophan residue modulates its activity.
Topics: Anti-Bacterial Agents; Daptomycin; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Staphylococcus aureus; Vancomycin
PubMed: 32725322
DOI: 10.1007/s00253-020-10790-x