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Polish Journal of Microbiology Sep 2022Daptomycin is a cyclolipopeptide antibiotic produced by . It is widely used to treat drug-resistant bacterial infections; however, daptomycin yield in wild strains is...
Daptomycin is a cyclolipopeptide antibiotic produced by . It is widely used to treat drug-resistant bacterial infections; however, daptomycin yield in wild strains is very low. To improve the daptomycin production by the strain BNCC 342432, a modified method of ribosome engineering with superposition of streptomycin resistance was adopted in this study. The highest-yield mutant strain SR-2620 was obtained by increasing streptomycin resistance of BNCC 342432, and achieved daptomycin production of 38.5 mg/l in shake-flask fermentation, 1.79-fold higher than the parent strain and its heredity stability was stable. The morphological characteristics of the two strains were significantly different, and the 440 base G of the gene in the mutant strain was deleted, which resulted in a frameshift mutation. Our results demonstrate that gradually increasing strain resistance to streptomycin was an effective breeding method to improve daptomycin yield in .
Topics: Anti-Bacterial Agents; Daptomycin; Fermentation; Streptomycin
PubMed: 36185027
DOI: 10.33073/pjm-2022-041 -
Microbiology Spectrum Apr 2022Bacterial biofilms are difficult to eradicate and can complicate many infections by forming on tissues and medical devices. Phage+antibiotic combinations (PAC) may be...
Bacterial biofilms are difficult to eradicate and can complicate many infections by forming on tissues and medical devices. Phage+antibiotic combinations (PAC) may be more active on biofilms than either type of agent alone, but it is difficult to predict which PAC regimens will be reliably effective. To establish a method for screening PAC combinations against Staphylococcus aureus biofilms, we conducted biofilm time-kill analyses (TKA) using various combinations of phage Sb-1 with clinically relevant antibiotics. We determined the activity of PAC against biofilm versus planktonic bacteria and investigated the emergence of resistance during (24 h) exposure to PAC. As expected, fewer treatment regimens were effective against biofilm than planktonic bacteria. In experiments with isogenic strain pairs, we also saw less activity of PACs against DNS-VISA mutants versus their respective parentals. The most effective treatment against both biofilm and planktonic bacteria was the phage+daptomycin+ceftaroline regimen, which met our stringent definition of bactericidal activity (>3 log CFU/mL reduction). With the VISA-DNS strain 8015 and DNS strain 684, we detected anti-biofilm synergy between Sb-1 and DAP in the phage+daptomycin regimen (>2 log CFU/mL reduction versus best single agent). We did not observe any bacterial resensitization to antibiotics following treatment, but phage resistance was avoided after exposure to PAC regimens for all tested strains. The release of bacterial membrane vesicles tended to be either unaffected or reduced by the various treatment regimens. Interestingly, phage yields from certain biofilm experiments were greater than from similar planktonic experiments, suggesting that Sb-1 might be more efficiently propagated on biofilm. Biofilm-associated multidrug-resistant infections pose significant challenges for antibiotic therapy. The extracellular polymeric matrix of biofilms presents an impediment for antibiotic diffusion, facilitating the emergence of multidrug-resistant populations. Some bacteriophages (phages) can move across the biofilm matrix, degrade it, and support antibiotic penetration. However, little is known about how phages and their hosts interact in the biofilm environment or how different phage+antibiotic combinations (PACs) impact biofilms in comparison to the planktonic state of bacteria, though scattered data suggest that phage+antibiotic synergy occurs more readily under biofilm-like conditions. Our results demonstrated that phage Sb-1 can infect MRSA strains both in biofilm and planktonic states and suggested PAC regimens worthy of further investigation as adjuncts to antibiotics.
Topics: Anti-Bacterial Agents; Bacteriophages; Biofilms; Daptomycin; Methicillin-Resistant Staphylococcus aureus
PubMed: 35348366
DOI: 10.1128/spectrum.00411-22 -
Pharmacology 2008Daptomycin is the first approved member of a new class of antibiotics, namely the cyclic lipopeptides. Daptomycin has rapid bactericidal activity against Gram-positive... (Review)
Review
Daptomycin is the first approved member of a new class of antibiotics, namely the cyclic lipopeptides. Daptomycin has rapid bactericidal activity against Gram-positive pathogens. It acts by penetrating into the bacterial cell wall with consecutive formation of pores, loss of electrical membrane potential and inhibition of peptidoglycan synthesis. As the mode of action of daptomycin is 'concentration-dependent', the pharmacokinetic/pharmacodynamic indices that correlate best with its activity are the ratios of the peak concentration (C(max)) to minimum inhibitory concentration (MIC) or the area under the curve (24-hour AUC) to MIC. Daptomycin should be administered intravenously once daily, because adverse effects on skeletal muscle associated with an increase in plasma levels of creatine phosphokinase and myopathy were observed more frequently at shorter dosing intervals. Overall, the rate of adverse events during daptomycin therapy is comparable to that of other standard regimens. Daptomycin was shown to be not inferior to antimicrobial standard therapy and therefore was approved for complicated skin and skin structure infections at a dose of 4 mg/kg, for Staphylococcus aureus bacteremia and right-sided endocarditis at a dose of 6 mg/kg. Dosage regimens remain a matter of discussion, and an increase in the currently approved doses from 4-6 to 6-8 mg/kg per day for severe infections seems promising. Though not approved up to now, daptomycin appears to be a treatment alternative for Gram-positive bone and joint infections based on clinical observations. Large international studies showed high susceptibility of relevant Gram-positive pathogens to daptomycin, even in multidrug-resistant strains. Thus, treatment of infections caused by Gram-positive cocci resistant to other antimicrobial drugs is a potential indication of daptomycin. Since glycopeptides and daptomycin have the same target site, there appears to be a risk of reduced susceptibility to both drugs after consecutive use. Therefore, daptomycin should be used with caution for treatment of vancomycin-resistant isolates or after prior vancomycin (glycopeptide) therapy. This review describes the history, mechanism of action, susceptibility, recent discoveries and clinical experience regarding daptomycin, discussing its current role in the field of infectious diseases.
Topics: Animals; Anti-Bacterial Agents; Clinical Trials as Topic; Daptomycin; Drug Approval; Drug Resistance, Bacterial; Humans
PubMed: 17940348
DOI: 10.1159/000109868 -
Microbiology (Reading, England) Oct 2017Daptomycin is a lipopeptide antibiotic with activity against Gram-positive bacteria. We showed previously that Staphylococcus aureus can survive daptomycin exposure by...
Daptomycin is a lipopeptide antibiotic with activity against Gram-positive bacteria. We showed previously that Staphylococcus aureus can survive daptomycin exposure by releasing membrane phospholipids that inactivate the antibiotic. To determine whether other pathogens possess this defence mechanism, phospholipid release and daptomycin activity were measured after incubation of Staphylococcus epidermidis, group A or B streptococci, Streptococcus gordonii or Enterococcus faecalis with the antibiotic. All bacteria released phospholipids in response to daptomycin, which resulted in at least partial inactivation of the antibiotic. However, E. faecalis showed the highest levels of lipid release and daptomycin inactivation. As shown previously for S. aureus, phospholipid release by E. faecalis was inhibited by the lipid biosynthesis inhibitor platensimycin. In conclusion, several pathogenic Gram-positive bacteria, including E. faecalis, inactivate daptomycin by releasing phospholipids, which may contribute to the failure of daptomycin to resolve infections caused by these pathogens.
Topics: Anti-Bacterial Agents; Daptomycin; Enterococcus faecalis; Inactivation, Metabolic; Lipid Metabolism; Microbial Sensitivity Tests; Phospholipids; Staphylococcus aureus; Streptococcus; Time Factors
PubMed: 28942757
DOI: 10.1099/mic.0.000529 -
Biochimica Et Biophysica Acta Apr 2011Daptomycin is a lipopeptide antibiotic that kills Gram-positive bacteria by membrane depolarization. While it has long been assumed that the mode of action of daptomycin...
Daptomycin is a lipopeptide antibiotic that kills Gram-positive bacteria by membrane depolarization. While it has long been assumed that the mode of action of daptomycin involves the formation of membrane-associated oligomers, this has so far not been experimentally demonstrated. We here use FRET between native daptomycin and an NBD-labeled daptomycin derivative to show that such oligomerization indeed occurs. The oligomers are observed in the presence of calcium ions on membrane vesicles isolated from Bacillus subtilis, as well as on model membranes containing the negatively charged phospholipid phosphatidylglycerol. In contrast, oligomerization does not occur on membranes containing phosphatidylcholine only, nor in solution at micromolar daptomycin concentrations. The requirements for oligomerization of daptomycin resemble those previously reported for antibacterial activity, suggesting that oligomerization is necessary for the activity.
Topics: 4-Chloro-7-nitrobenzofurazan; Anti-Bacterial Agents; Bacillus subtilis; Calcium; Cell Membrane; Daptomycin; Dose-Response Relationship, Drug; Fluorescence Resonance Energy Transfer; Models, Chemical; Molecular Structure; Phosphatidylglycerols; Protein Multimerization; Unilamellar Liposomes
PubMed: 21223947
DOI: 10.1016/j.bbamem.2011.01.001 -
The Journal of Antimicrobial... Aug 2018Daptomycin non-susceptibility in Staphylococcus aureus can emerge via the accumulation of single or multiple mutations, each resulting in a slight increase in the...
OBJECTIVES
Daptomycin non-susceptibility in Staphylococcus aureus can emerge via the accumulation of single or multiple mutations, each resulting in a slight increase in the daptomycin MIC. The daptomycin-non-susceptible phenotype may include other features such as daptomycin tolerance. This study identifies S. aureus genomic regions that frequently develop mutations following prolonged daptomycin exposure but have not been previously associated with daptomycin non-susceptibility.
METHODS
Sequence variations in the same eight loci independently observed following 28 day parallel serial passages of S. aureus J01 in daptomycin were introduced in isolation into S. aureus J01. MICs were determined by microbroth dilution. Daptomycin killing and tolerance were determined by kill curve analysis.
RESULTS
Single mutations in snoF, hmp1, sspA, rimP, hepT, rsh, map1 and amaP had only a modest impact on the daptomycin MIC (≤2-fold). In contrast, individual mutation in several of these regions resulted in pronounced changes to daptomycin tolerance.
CONCLUSIONS
This study demonstrates that less characterized mutations in S. aureus following daptomycin exposure do not result in significant daptomycin susceptibility changes, but rather allow for enhanced survival characteristics during treatment. This sheds new light on genetic adaptations that may play a role in persistent infection. Further studies are needed to elucidate the prevalence of these mutations in clinical isolates.
Topics: Anti-Bacterial Agents; DNA Mutational Analysis; DNA, Bacterial; Daptomycin; Drug Resistance, Multiple, Bacterial; Genes, Bacterial; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Phenotype
PubMed: 29718242
DOI: 10.1093/jac/dky148 -
Emerging Infectious Diseases Jun 2016We investigated the prognostic role of high MICs for antistaphylococcal agents in patients with methicillin-sensitive Staphylococcus aureus catheter-related bloodstream...
We investigated the prognostic role of high MICs for antistaphylococcal agents in patients with methicillin-sensitive Staphylococcus aureus catheter-related bloodstream infection (MSSA CRBSI). We prospectively reviewed 83 episodes from 5 centers in Spain during April 2011-June 2014 that had optimized clinical management and analyzed the relationship between E-test MICs for vancomycin, daptomycin, oxacillin, and linezolid and development of complicated bacteremia by using multivariate analysis. Complicated MSSA CRBSI occurred in 26 (31.3%) patients; MICs for vancomycin and daptomycin were higher in these patients (optimal cutoff values for predictive accuracy = 1.5 μg/mL and 0.5 μg/mL). High MICs for vancomycin (hazard ratio 2.4, 95% CI 1.2-5.5) and daptomycin (hazard ratio 2.4, 95% CI 1.1-5.9) were independent risk factors for development of complicated MSSA CRBSI. Our data suggest that patients with MSSA CRBSI caused by strains that have high MICs for vancomycin or daptomycin are at increased risk for complications.
Topics: Anti-Bacterial Agents; Bacteremia; Catheter-Related Infections; Comorbidity; Daptomycin; Disease Management; Drug Resistance, Bacterial; Female; Humans; Kaplan-Meier Estimate; Male; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Middle Aged; Risk Factors; Spain; Staphylococcal Infections; Treatment Outcome; Vancomycin
PubMed: 27192097
DOI: 10.3201/eid2206.151709 -
Biochimica Et Biophysica Acta Oct 2014Daptomycin is a lipopeptide antibiotic that is used clinically to treat severe infections caused by Gram-positive bacteria. Its bactericidal action involves the...
Daptomycin is a lipopeptide antibiotic that is used clinically to treat severe infections caused by Gram-positive bacteria. Its bactericidal action involves the calcium-dependent binding to membranes containing phosphatidylglycerol, followed by the formation of membrane-associated oligomers. Bacterial cells exposed to daptomycin undergo membrane depolarization, suggesting the formation of channels or pores in the target membranes. We here used a liposome model to detect and characterize the permeability properties of the daptomycin pores. The pores are selective for cations, with permeabilities being highest for Na(+), K(+), and other alkali metal ions. The permeability is approximately twice lower for Mg(++), and lower again for the organic cations choline and hexamethonium. Anions are excluded, as is the zwitterion cysteine. These observations account for the observed depolarization of bacterial cells by daptomycin and suggest that under typical in vivo conditions depolarization is mainly due to sodium influx.
Topics: Bacteria; Cations; Cell Membrane; Cell Membrane Permeability; Daptomycin; Liposomes; Membrane Potentials; Metals; Models, Chemical
PubMed: 24857935
DOI: 10.1016/j.bbamem.2014.05.014 -
International Journal of Infectious... Aug 2019Daptomycin has shown clinical efficacy in diabetic foot infections (DFI). However, only limited data are available on its bone penetration in this particular population.... (Clinical Trial)
Clinical Trial
OBJECTIVES
Daptomycin has shown clinical efficacy in diabetic foot infections (DFI). However, only limited data are available on its bone penetration in this particular population. The aim of this study was to determine daptomycin bone concentrations in patients with DFI undergoing surgery after multiple daptomycin infusions and to determine bone daptomycin inhibitory quotients (IQs) for the predominant gram-positive species involved in DFI.
METHODS
Fourteen adult patients hospitalized with DFI treated with daptomycin and requiring surgical bone debridement and amputation were included in this single-centre prospective study. Daptomycin concentrations in serum and bone were determined by HPLC at steady state. Bone IQs were then calculated according to different minimum inhibitory concentrations (MICs; range 0.25-4mg/l) that are representative of the main MICs for Staphylococcus aureus, coagulase-negative staphylococci (CoNS), and Enterococcus sp populations.
RESULTS
Residual and peak concentrations varied from 4.5mg/l to 39.9mg/l and from 31.8mg/l to 110.9mg/l, respectively. Bone daptomycin concentrations at the moment of surgery varied from 1.2mg/l to 17mg/l. Up to a MIC of 1mg/l, which is the epidemiological cut-off value (ECOFF) and breakpoint value for S. aureus and CoNS, all bone daptomycin IQs were positive. The highest bone IQs were observed with Staphylococcus species. Calculated bone IQs for Enterococcus species were often weak at MIC values near the ECOFF.
CONCLUSIONS
Daptomycin penetrates bone well in patients treated for DFI. At an initially recommended dosage of 6mg/kg, bone concentrations are likely to be effective against staphylococcal infections and infections due to low-MIC Enterococcus.
Topics: Aged; Anti-Bacterial Agents; Bone and Bones; Daptomycin; Diabetic Foot; Enterococcus; Female; Foot Diseases; Gram-Positive Bacterial Infections; Humans; Male; Middle Aged; Prospective Studies; Staphylococcus; Staphylococcus aureus
PubMed: 31096056
DOI: 10.1016/j.ijid.2019.05.011 -
Expert Review of Anti-infective Therapy Mar 2023Methicillin-resistant and -susceptible (MRSA/MSSA) infections are a major global health-care problem. Bacteremia with exhibits high rates of morbidity and mortality...
INTRODUCTION
Methicillin-resistant and -susceptible (MRSA/MSSA) infections are a major global health-care problem. Bacteremia with exhibits high rates of morbidity and mortality and can cause complicated infections such as infective endocarditis (IE). The emerging resistance profile of is worrisome, and several international agencies have appealed for new treatment approaches to be developed.
AREAS COVERED
Daptomycin presents a rapid bactericidal effect against MRSA and has been considered at least as effective as vancomycin in treating MRSA bacteremia. However, therapy failure is often related to deep-seated infections, e.g. endocarditis, with high bacterial inocula and daptomycin regimens <10 mg/kg/day. Current antibiotic options for treating invasive infections have limitations in monotherapy. Daptomycin in combination with other antibiotics, e.g. fosfomycin, may be effective in improving clinical outcomes in patients with MRSA IE.
EXPERT OPINION
Exploring therapeutic combinations has shown fosfomycin to have a unique mechanism of action and to be the most effective option in preventing the onset of resistance to and optimizing the efficacy of daptomycin, suggesting the synergistic combination of fosfomycin with daptomycin is a useful alternative treatment option for MSSA or MRSA IE.
Topics: Humans; Daptomycin; Fosfomycin; Staphylococcus aureus; Anti-Bacterial Agents; Endocarditis, Bacterial; Staphylococcal Infections; Methicillin-Resistant Staphylococcus aureus; Endocarditis; Bacteremia; Microbial Sensitivity Tests
PubMed: 36744387
DOI: 10.1080/14787210.2023.2174969