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Zoonoses and Public Health Feb 2015Daptomycin non-susceptible Enterococcus (DNSE) is an emerging clinical problem. Little is known about how de novo DNSE infections develop or the risk factors associated... (Review)
Review
Daptomycin non-susceptible Enterococcus (DNSE) is an emerging clinical problem. Little is known about how de novo DNSE infections develop or the risk factors associated with them. Determining risk factors associated with de novo DNSE infections will aid in understanding the mechanisms of daptomycin non-susceptibility. Humans in contact with animals worldwide are at risk of carriage of multidrug-resistant bacteria. Herein, I review the scientific evidence that supports the hypothesis that transport of daptomycin non-susceptibility genes between animals and humans may be a possible mechanism for development of de novo daptomycin non-susceptibility in enterococci.
Topics: Animals; Anti-Bacterial Agents; Daptomycin; Drug Resistance, Bacterial; Enterococcus; Feces; Gram-Positive Bacterial Infections; Humans; Risk Factors; Soil Microbiology; Zoonoses
PubMed: 24274811
DOI: 10.1111/zph.12091 -
Clinical Microbiology and Infection :... May 2005There is a clinical need for new treatment options for serious Gram-positive infections. Recently introduced agents such as the newer fluoroquinolones and the ketolide... (Review)
Review
There is a clinical need for new treatment options for serious Gram-positive infections. Recently introduced agents such as the newer fluoroquinolones and the ketolide telithromycin have limited use as they do not cover methicillin-resistant Staphylococcus aureus (MRSA) or glycopeptide-resistant enterococci (GRE). The clinical use of the streptogramin combination quinupristin/dalfopristin, which has activity against MRSA and vancomycin-resistant Enterococcus faecium, is limited because administration is via a slow infusion of a large volume. The oxazolidinone linezolid is active against MRSA and GRE but resistant organisms and treatment failures have been reported. A number of compounds currently in development show promise, the new glycopeptides oritavancin, dalbavancin and the glycolipodepsipeptide ramoplanin, as well as the new tetracyclines tigecycline and BAY73-7388. However, in some cases, there is concern that resistance may develop quickly to new compounds that are based on existing antimicrobial agents. Therefore daptomycin, a novel lipopeptide with a unique mode of action, is of particular interest. Daptomycin is active against MRSA (including vancomycin-resistant strains) and GRE. Daptomycin displays rapid concentration-dependent killing and is bactericidal even in the stationary phase of growth. Daptomycin-resistant strains are very difficult to generate in vitro. A dosage of 4 mg/kg intravenous once a day has been shown to be efficacious in two evaluator-blinded trials of complicated skin and soft tissue infections with clinical success rates similar for daptomycin and comparators (vancomycin or penicillinase-resistant penicillins). With its activity against key Gram-positive pathogens, including resistant strains, daptomycin has potential as a valuable addition to the available treatment options for serious Gram-positive infections.
Topics: Anti-Infective Agents; Daptomycin; Gram-Positive Bacterial Infections; Humans; Vancomycin Resistance
PubMed: 15900655
DOI: 10.1111/j.1469-0691.2005.01141.x -
Nefrologia : Publicacion Oficial de La... 2011
Topics: Anti-Bacterial Agents; Daptomycin; Humans; Infusions, Parenteral; Male; Middle Aged; Peritoneal Dialysis; Peritonitis; Staphylococcal Infections; Staphylococcus epidermidis
PubMed: 21629351
DOI: 10.3265/Nefrologia.pre2011.Mar.10806 -
Nature Communications Apr 2022Staphylococcus aureus frequently causes infections that are challenging to treat, leading to high rates of persistent and relapsing infection. Here, to understand how...
Staphylococcus aureus frequently causes infections that are challenging to treat, leading to high rates of persistent and relapsing infection. Here, to understand how the host environment influences treatment outcomes, we study the impact of human serum on staphylococcal antibiotic susceptibility. We show that serum triggers a high degree of tolerance to the lipopeptide antibiotic daptomycin and several other classes of antibiotic. Serum-induced daptomycin tolerance is due to two independent mechanisms. Firstly, the host defence peptide LL-37 induces tolerance by triggering the staphylococcal GraRS two-component system, leading to increased peptidoglycan accumulation. Secondly, GraRS-independent increases in membrane cardiolipin abundance are required for full tolerance. When both mechanisms are blocked, S. aureus incubated in serum is as susceptible to daptomycin as when grown in laboratory media. Our work demonstrates that host factors can significantly modulate antibiotic susceptibility via diverse mechanisms, and combination therapy may provide a way to mitigate this.
Topics: Anti-Bacterial Agents; Daptomycin; Humans; Microbial Sensitivity Tests; Staphylococcal Infections; Staphylococcus aureus
PubMed: 35440121
DOI: 10.1038/s41467-022-29717-3 -
Antimicrobial Agents and Chemotherapy Jun 2018We investigated whether the addition of fosfomycin or cloxacillin to daptomycin provides better outcomes in the treatment of methicillin-resistant (MRSA) experimental...
The Combination of Daptomycin and Fosfomycin Has Synergistic, Potent, and Rapid Bactericidal Activity against Methicillin-Resistant Staphylococcus aureus in a Rabbit Model of Experimental Endocarditis.
We investigated whether the addition of fosfomycin or cloxacillin to daptomycin provides better outcomes in the treatment of methicillin-resistant (MRSA) experimental aortic endocarditis in rabbits. Five MRSA strains were used to perform time-kill studies using standard (10) and high (10) inocula. Combined therapy was compared to daptomycin monotherapy treatment in the MRSA experimental endocarditis model. A human-like pharmacokinetics model was applied, and the equivalents of cloxacillin at 2 g/4 h, fosfomycin at 2 g/6 h, and daptomycin at 6 to 10 mg/kg/day were administered intravenously. A combination of daptomycin and either fosfomycin or cloxacillin was synergistic in the five strains tested at both inocula. A bactericidal effect was detected in four of five strains tested with both combinations. The MRSA-277 strain (vancomycin MIC, 2 μg/ml) was used for the experimental endocarditis model. Daptomycin plus fosfomycin significantly improved the efficacy of daptomycin monotherapy at 6 mg/kg/day in terms of both the proportion of sterile vegetations (100% versus 72%, = 0.046) and the decrease in the density of bacteria within the vegetations ( = 0.025). Daptomycin plus fosfomycin was as effective as daptomycin monotherapy at 10 mg/kg/day (100% versus 93%, = 1.00) and had activity similar to that of daptomycin plus cloxacillin when daptomycin was administered at 6 mg/kg/day (100% versus 88%, = 0.48). Daptomycin nonsusceptibility was not detected in any of the isolates recovered from vegetations. In conclusion, for the treatment of MRSA experimental endocarditis, the combination of daptomycin plus fosfomycin showed synergistic and bactericidal activity.
Topics: Animals; Anti-Bacterial Agents; Cloxacillin; Daptomycin; Drug Synergism; Endocarditis, Bacterial; Female; Fosfomycin; Humans; Methicillin-Resistant Staphylococcus aureus; Rabbits
PubMed: 29610194
DOI: 10.1128/AAC.02633-17 -
Langmuir : the ACS Journal of Surfaces... Nov 2017Daptomycin is an acidic, 13-amino acid, cyclic polypeptide that contains a number of nonproteinogenic residues and is modified at its N-terminus with a decanoyl chain....
Daptomycin is an acidic, 13-amino acid, cyclic polypeptide that contains a number of nonproteinogenic residues and is modified at its N-terminus with a decanoyl chain. It has been in clinical use since 2003 against selected drug-resistant Staphylococcus aureus and Enterococcus spp infections. In vitro, daptomycin is active against Gram-positive pathogens at low concentrations but its antibiotic activity depends critically on the presence of calcium ions. This dependence has been thought to arise from binding of one or two Ca ions to daptomycin as a required step in its interaction with the bacterial membrane. Here, we investigated the interaction of daptomycin with giant unilamellar vesicles (GUVs) composed 1-palmitoyl-2-oleoylphosphatidylcholine (POPC) and 1-palmitoyl-2-oleoylphosphatidylglycerol (POPG). We used fluorescence confocal microscopy to monitor binding of the peptide to GUVs and follow its effect on the membrane of the vesicle. We found that in the absence of POPG or Ca daptomycin does not bind measurably to the lipid membrane. In the presence of 20-30% PG in the membrane and 2 mM Ca, daptomycin induces the formation of membrane domains rich in acidic lipids. This effect is not induced by Ca alone. In addition, daptomycin causes GUV collapse, but it does not translocate across the membrane to the inside of intact POPC/POPG vesicles. We conclude that pore formation is probably not the mechanism by which the peptide functions. On the other hand, we found that daptomycin coclusters with the anionic phospholipid POPG and the fluorescent probes used, leading to extensive formation of daptomycin-POPG domains in the membrane.
Topics: Anti-Bacterial Agents; Daptomycin; Methicillin-Resistant Staphylococcus aureus; Phosphatidylglycerols; Unilamellar Liposomes
PubMed: 29130685
DOI: 10.1021/acs.langmuir.7b01841 -
WMJ : Official Publication of the State... Oct 2014Daptomycin is a cyclic lipopeptide antibiotic with activity against gram-positive organisms. With increasing use, acute eosinophilic pneumonia is a rare, but potentially...
INTRODUCTION
Daptomycin is a cyclic lipopeptide antibiotic with activity against gram-positive organisms. With increasing use, acute eosinophilic pneumonia is a rare, but potentially fatal adverse drug reaction that requires prompt recognition. The authors present a definite case of daptomycin-induced acute eosinophilic pneumonia.
CASE SUMMARY
A 61-year-old woman with poorly controlled type 2 diabetes who presented with bilateral foot pain was found to have bilateral calcaneal osteomyelitis. She was started on an antibiotic regimen that included daptomycin. Within 1 week, she developed fever, a dry cough, and shortness of breath and was treated for hospital-acquired pneumonia (HAP). Daptomycin was discontinued. Upon completion of therapy for HAP, the patient was subsequently restarted on daptomycin for continued therapy of bilateral calcaneal osteomyelitis. Within 48 hours of restarting daptomycin, the patient developed hypoxemic respiratory failure, bilateral pulmonary infiltrates, and peripheral eosinophilia. Bronchoscopic lavage revealed 30% eosinophils. Daptomycin-induced acute eosinophilic pneumonia was diagnosed. Daptomycin was discontinued, and the patient had complete resolution of symptoms, peripheral eosinophilia, and radiographic findings.
DISCUSSION
Daptomycin initially was approved for skin and soft tissue infections, but its utility has expanded to bacteremia and endocarditis. Daptomycin-induced acute eosinophilic pneumonia is rare. A recent Federal Drug Administration review identified a total of 58 cases of daptomycin-induced acute eosinophilic pneumonia. Of these, 38 were possible, 13 were probable, and 7 were definite. We believe this is the 8th definite case of daptomycin-induced acute eosinophilic pneumonia to be reported in the literature.
Topics: Acute Disease; Anti-Bacterial Agents; Daptomycin; Diagnosis, Differential; Female; Humans; Middle Aged; Osteomyelitis; Pulmonary Eosinophilia
PubMed: 25739164
DOI: No ID Found -
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 -
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 -
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