scholarly journals Ceftaroline Restores Daptomycin Activity against Daptomycin-Nonsusceptible Vancomycin-Resistant Enterococcus faecium

2013 ◽  
Vol 58 (3) ◽  
pp. 1494-1500 ◽  
Author(s):  
George Sakoulas ◽  
Warren Rose ◽  
Poochit Nonejuie ◽  
Joshua Olson ◽  
Joseph Pogliano ◽  
...  
Keyword(s):  
Membrane Fluidity ◽  
Enterococcus Faecium ◽  
Surface Binding ◽  
Host Defense Peptides ◽  
Content Type ◽  
Invasive Infections ◽  
Vancomycin Resistant ◽  
Biophysical Changes

ABSTRACTDaptomycin-nonsusceptible vancomycin-resistantEnterococcus faecium(VRE) strains are a formidable emerging threat to patients with comorbidities, leaving few therapeutic options in cases of severe invasive infections. Using a previously characterized isogenic pair of VRE strains from the same patient differing in their daptomycin susceptibilities (Etest MICs of 0.38 mg/liter and 10 mg/liter), we examined the effect of ceftaroline, ceftriaxone, and ampicillin on membrane fluidity and susceptibility of VRE to surface binding and killing by daptomycin and human cathelicidin antimicrobial peptide LL37. Synergy was notedin vitrobetween daptomycin, ampicillin, and ceftaroline for the daptomycin-susceptible VRE strain, but only ceftaroline showed synergy against the daptomycin-nonsusceptible VRE strain (∼2 log10CFU reduction at 24 h). Ceftaroline cotreatment increased daptomycin surface binding with an associated increase in membrane fluidity and an increase in the net negative surface charge of the bacteria as evidenced by increased poly-l-lysine binding. Consistent with the observed biophysical changes, ceftaroline resulted in increased binding and killing of daptomycin-nonsusceptible VRE by human cathelicidin LL37. Using a pair of daptomycin-susceptible/nonsusceptible VRE strains, we noted that VRE is ceftaroline resistant, yet ceftaroline confers significant effects on growth rate as well as biophysical changes on the cell surface of VRE that can potentiate the activity of daptomycin and innate cationic host defense peptides, such as cathelicidin. Although limited to just 2 strains, these finding suggest that additionalin vivoandin vitrostudies need to be done to explore the possibility of using ceftaroline as adjunctive anti-VRE therapy.

scholarly journals The Fungal Cyp51-Specific Inhibitor VT-1598 DemonstratesIn VitroandIn VivoActivity againstCandida auris

2018 ◽  
Vol 63 (3) ◽  
Author(s):  
Nathan P. Wiederhold ◽  
Shawn R. Lockhart ◽  
Laura K. Najvar ◽  
Elizabeth L. Berkow ◽  
Rosie Jaramillo ◽  
...  
Keyword(s):  
Specific Inhibitor ◽  
Candida Auris ◽  
Once Daily ◽  
Content Type ◽  
Fungal Burden ◽  
Invasive Infections ◽  
Trough Concentrations ◽  
Dose Dependent

ABSTRACTCandida aurisis an emerging pathogen associated with significant mortality and often multidrug resistance. VT-1598, a tetrazole-based fungal CYP51-specific inhibitor, was evaluatedin vitroandin vivoagainstC. auris. Susceptibility testing was performed against 100 clinical isolates ofC. aurisby broth microdilution. Neutropenic mice were infected intravenously withC. auris, and treatment began 24 h postinoculation with a vehicle control, oral VT-1598 (5, 15, and 50 mg/kg of body weight once daily), oral fluconazole (20 mg/kg once daily), or intraperitoneal caspofungin (10 mg/kg once daily), which continued for 7 days. Fungal burden was assessed in the kidneys and brains on day 8 in the fungal burden arm and on the days the mice succumbed to infection or on day 21 in the survival arm. VT-1598 plasma trough concentrations were also assessed on day 8. VT-1598 demonstratedin vitroactivity againstC. auris, with a mode MIC of 0.25 μg/ml and MICs ranging from 0.03 to 8 μg/ml. Treatment with VT-1598 resulted in significant and dose-dependent improvements in survival (median survival, 15 and >21 days for VT-1598 at 15 and 50 mg/kg, respectively) and reductions in kidney and brain fungal burden (reductions of 1.88 to 3.61 log10CFU/g) compared to the control (5 days). The reductions in fungal burden correlated with plasma trough concentrations. Treatment with caspofungin, but not fluconazole, also resulted in significant improvements in survival and reductions in fungal burden compared to those with the control. These results suggest that VT-1598 may be a future option for the treatment of invasive infections caused byC. auris.

scholarly journals Genetic Basis forIn VitroandIn VivoResistance to Lincosamides, Streptogramins A, and Pleuromutilins (LSAP Phenotype) in Enterococcus faecium

2013 ◽  
Vol 57 (9) ◽  
pp. 4463-4469 ◽  
Author(s):  
Christophe Isnard ◽  
Brigitte Malbruny ◽  
Roland Leclercq ◽  
Vincent Cattoir
Keyword(s):  
Amino Acid ◽  
Molecular Mechanism ◽  
Enterococcus Faecium ◽  
Full Genome Sequence ◽  
Comparative Genomic ◽  
Content Type ◽  
Abc Protein

ABSTRACTAs opposed toEnterococcus faecalis, which is intrinsically resistant to lincosamides, streptogramins A, and pleuromutilins (LSAP phenotype) by production of the ABC protein Lsa(A),Enterococcus faeciumis naturally susceptible. Since this phenotype may be selected forin vivoby quinupristin-dalfopristin (Q-D), the aim of this study was to investigate the molecular mechanism of acquired LSAP resistance inE. faecium. Six LSAP-resistantin vitromutants ofE. faeciumHM1070 as well as three different pairs of clinical isolates (pre- and postexposure to Q-D) were studied. The full genome sequence of anin vitromutant (E. faeciumUCN90B) was determined by using 454 sequencing technology and was compared with that of the parental strain. Single-nucleotide replacement was carried out to confirm the role of this mutation. By comparative genomic analysis, a point mutation was found within a 1,503-bp gene coding for an ABC homologue showing 66% amino acid identity with Lsa(A). This mutation (C1349T) led to an amino acid substitution (Thr450Ile). An identical mutation was identified in allin vitroandin vivoresistant strains but was not present in susceptible strains. The wild-type allele was namedeat(A) (forEnterococcusABCtransporter), and its mutated allelic variant was namedeat(A)v. The introduction ofeat(A)vfrom UCN90B into HM1070 conferred the LSAP phenotype, whereas that ofeat(A) from HM1070 into UCN90B restored susceptibility entirely. This is the first description of the molecular mechanism of acquired LSAP resistance inE. faecium. Characterization of the biochemical mechanism of resistance and the physiological role of this ABC protein need further investigations.

scholarly journals Efficacy of Synthetic Peptides RP-1 and AA-RP-1 against Leishmania SpeciesIn VitroandIn Vivo

2011 ◽  
Vol 56 (2) ◽  
pp. 658-665 ◽  
Author(s):  
Marie Crisel B. Erfe ◽  
Consuelo V. David ◽  
Cher Huang ◽  
Victoria Lu ◽  
Ana Claudia Maretti-Mira ◽  
...  
Keyword(s):  
Intravenous Administration ◽  
Synthetic Peptides ◽  
Antileishmanial Activity ◽  
Host Defense Peptides ◽  
Content Type ◽  
Causative Agents ◽  
Antileishmanial Activities ◽  
Conventional Antibiotics

ABSTRACTHost defense peptides are naturally occurring molecules that play essential roles in innate immunity to infection. Based on prior structure-function knowledge, we tested two synthetic peptides (RP-1 and AA-RP-1) modeled on the conserved, microbicidal α-helical domain of mammalian CXCL4 platelet kinocidins. These peptides were evaluated for efficacy againstLeishmaniaspecies, the causative agents of the group of diseases known as leishmaniasis.In vitroantileishmanial activity was assessed against three distinctLeishmaniastrains by measuring proliferation, metabolic activity and parasite viability after exposure to various concentrations of peptides. We demonstrate that micromolar concentrations of RP-1 and AA-RP-1 caused dose-dependent growth inhibition ofLeishmaniapromastigotes. This antileishmanial activity correlated with rapid membrane disruption, as well as with a loss of mitochondrial transmembrane potential. In addition, RP-1 and AA-RP-1 demonstrated distinct and significantin vivoantileishmanial activities in a mouse model of experimental visceral leishmaniasis after intravenous administration. These results establish efficacy of RP-1 lineage synthetic peptides againstLeishmaniaspeciesin vitroand after intravenous administrationin vivoand provide further validation of proof of concept for the development of these and related systemic anti-infective peptides targeting pathogens that are resistant to conventional antibiotics.

scholarly journals β-Lactams Enhance Daptomycin Activity against Vancomycin-Resistant Enterococcus faecalis and Enterococcus faecium inIn VitroPharmacokinetic/Pharmacodynamic Models

2015 ◽  
Vol 59 (5) ◽  
pp. 2842-2848 ◽  
Author(s):  
Jordan R. Smith ◽  
Katie E. Barber ◽  
Animesh Raut ◽  
Michael J. Rybak
Keyword(s):  
Body Weight ◽  
Combination Therapy ◽  
Enterococcus Faecalis ◽  
Enterococcus Faecium ◽  
Single Agent ◽  
Vancomycin Resistant Enterococcus ◽  
Content Type ◽  
Vancomycin Resistant ◽  
Combination Regimens

ABSTRACTEnterococcus faecalisandEnterococcus faeciumare frequently resistant to vancomycin and β-lactams. In enterococcal infections with reduced glycopeptide susceptibility, combination therapy is often administered. Our objective was to conduct pharmacokinetic/pharmacodynamic (PK/PD) models to evaluate β-lactam synergy with daptomycin (DAP) against resistant enterococci. OneE. faecalisstrain (R6981) and twoE. faeciumstrains (R6370 and 8019) were evaluated. DAP MICs were obtained. All strains were evaluated for response to LL37, an antimicrobial peptide, in the presence and absence of ceftaroline (CPT), ertapenem (ERT), and ampicillin (AMP). After 96 h,in vitromodels were run simulating 10 mg DAP/kg body weight/day, 600 mg CPT every 8 h (q8h), 2 g AMP q4h, and 1 g ERT q24h, both alone and in combination against all strains. DAP MICs were 2, 4, and 4 μg/ml for strains R6981, R6370, and 8019, respectively. PK/PD models demonstrated bactericidal activity with DAP-CPT, DAP-AMP, and DAP-ERT combinations against strain 8019 (P< 0.001 and log10CFU/ml reduction of >2 compared to any single agent). Against strains R6981 and R6370, the DAP-AMP combination demonstrated enhancement against R6370 but not R6981, while the combinations of DAP-CPT and DAP-ERT were bactericidal, demonstrated enhancement, and were statistically superior to all other regimens at 96 h (P< 0.001) against both strains. CPT, ERT, and AMP similarly augmented LL37 killing against strain 8019. In strains R6981 and R6370, CPT and ERT aided LL37 more than AMP (P< 0.001). Compared to DAP alone, combination regimens provide better killing and prevent resistance. Clinical research involving DAP combinations is warranted.

scholarly journals Impact of Daptomycin Dose Exposure Alone or in Combination with β-Lactams or Rifampin against Vancomycin-Resistant Enterococci in an In Vitro Biofilm Model

2020 ◽  
Vol 64 (5) ◽  
Author(s):  
Seyedehameneh Jahanbakhsh ◽  
Nivedita B. Singh ◽  
Juwon Yim ◽  
Razieh Kebriaei ◽  
Jordan R. Smith ◽  
...  
Keyword(s):  
Bactericidal Activity ◽  
Enterococcus Faecium ◽  
Biofilm Reactor ◽  
Content Type ◽  
Biofilm Model ◽  
Vancomycin Resistant Enterococci ◽  
Dosing Regimens ◽  
Vancomycin Resistant ◽  
Reactor Models

ABSTRACT Enterococcus faecium strains are commonly resistant to vancomycin and β-lactams. In addition, E. faecium often causes biofilm-associated infections and these infections are difficult to treat. In this context, we investigated the activity of dosing regimens using daptomycin (DAP) (8, 10, 12, and 14 mg/kg of body weight/day) alone and in combination with ceftaroline (CPT), ampicillin (AMP), ertapenem (ERT), and rifampin (RIF) against 2 clinical strains of biofilm-producing vancomycin-resistant Enterococcus faecium (VREfm), namely, strains S447 and HOU503, in an in vitro biofilm model. HOU503 harbors common LiaS and LiaR substitutions, whereas S447 lacks mutations associated with the LiaFSR pathway. MIC results demonstrated that both strains were susceptible to DAP and resistant to CPT, AMP, ERT, and RIF. The 168-h pharmacokinetic/pharmacodynamic (PK/PD) CDC biofilm reactor models (simulating human antibiotic exposures) were used with titanium and polyurethane coupons to evaluate the efficacy of antibiotic combinations. DAP 12 and 14 achieved bactericidal activity against S447 but lacked such effect against HOU503. Addition of ERT and RIF enhanced DAP activity, allowing DAP 8 and 10 plus ERT or RIF to produce bactericidal activity against both strains at 168 h. While DAP 8 and 10 plus CPT improved killing, they did not reach bactericidal reduction against S447. Combination of AMP, CPT, ERT, or RIF resulted in enhanced and bactericidal activity for DAP against HOU503 at 168 h. Our data provide further support for the use of combinations of DAP with AMP, ERT, CPT, and RIF in infections caused by biofilm producing VREfm. Further research involving DAP combinations against biofilm-producing enterococci is warranted.

scholarly journals In Vitro and In Vivo Antibiotic Capacity of Two Host Defense Peptides

2020 ◽  
Vol 64 (7) ◽  
Author(s):  
Iván Arenas ◽  
Marco Antonio Ibarra ◽  
Felix L. Santana ◽  
Elba Villegas ◽  
Robert E. W. Hancock ◽  
...  
Keyword(s):  
Host Defense ◽  
Foot Ulcer ◽  
Diabetic Foot Ulcer ◽  
Immunomodulatory Activity ◽  
Host Defense Peptides ◽  
Content Type ◽  
Serovar Typhimurium ◽  
Infective Activity

ABSTRACT Two nonamidated host defense peptides named Pin2[G] and FA1 were evaluated against three types of pathogenic bacteria: two (Staphylococcus aureus UPD13 and Pseudomonas aeruginosa UPD3) isolated from diabetic foot ulcer patients, and another (Salmonella enterica serovar Typhimurium [ATCC 14028]) from a commercial collection. In vitro experiments showed that the antimicrobial performance of the synthetic peptides Pin2[G] and FA1 was modest, although FA1 was more effective than Pin2[G]. In contrast, Pin2[G] had superior in vivo anti-infective activity to FA1 in rabbit wound infections by the diabetic foot ulcer pathogens S. aureus UPD13 and P. aeruginosa UPD3. Indeed, Pin2[G] reduced bacterial colony counts of both S. aureus UPD13 and P. aeruginosa UPD3 by >100,000-fold after 48 to 72 h on skin wounds of infected rabbits, while in similar infected wounds, FA1 had no major effects at 72 to 96 h of treatment. Ceftriaxone was equally effective versus Pseudomonas but less effective versus S. aureus infections. Additionally, the two peptides were evaluated in mice against intragastrically inoculated S. enterica serovar Typhimurium (ATCC 14028). Only Pin2[G] at 0.56 mg/kg was effective in reducing systemic (liver) infection by >67-fold, equivalent to the effect of treatment with levofloxacin. Pin2[G] showed superior immunomodulatory activity in increasing chemokine production by a human bronchial cell line and suppressing polyinosinic-polycytidylic acid (poly[I:C])-induced proinflammatory IL-6 production. These data showed that the in vitro antimicrobial activity of these peptides was not correlated with their in vivo anti-infective activity and suggest that other factors such as immunomodulatory activity were more important.

scholarly journals In VitroCharacterization of PlySK1249, a Novel Phage Lysin, and Assessment of Its Antibacterial Activity in a Mouse Model of Streptococcus agalactiae Bacteremia

2013 ◽  
Vol 57 (12) ◽  
pp. 6276-6283 ◽  
Author(s):  
Frank Oechslin ◽  
Jean Daraspe ◽  
Marlyse Giddey ◽  
Philippe Moreillon ◽  
Grégory Resch
Keyword(s):  
Mouse Model ◽  
Streptococcus Agalactiae ◽  
Content Type ◽  
Cell Wall Binding ◽  
Gene Coding ◽  
Invasive Infections ◽  
Cell Wall Binding Domain ◽  
Bacterial Peptidoglycan

ABSTRACTBeta-hemolyticStreptococcus agalactiaeis the leading cause of bacteremia and invasive infections. These diseases are treated with β-lactams or macrolides, but the emergence of less susceptible and even fully resistant strains is a cause for concern. New bacteriophage lysins could be promising alternatives against such organisms. They hydrolyze the bacterial peptidoglycan at the end of the phage cycle, in order to release the phage progeny. By using a bioinformatic approach to screen several beta-hemolytic streptococci, a gene coding for a lysin was identified on a prophage carried byStreptococcus dysgalactiaesubsp.equisimilisSK1249. The gene product, named PlySK1249, harbored an original three-domain structure with a central cell wall-binding domain surrounded by an N-terminal amidase and a C-terminal CHAP domain. Purified PlySK1249 was highly lytic and bactericidal forS. dysgalactiae(2-log10CFU/ml decrease within 15 min). Moreover, it also efficiently killedS. agalactiae(1.5-log10CFU/ml decrease within 15 min) but not several streptococcal commensal species. We further investigated the activity of PlySK1249 in a mouse model ofS. agalactiaebacteremia. Eighty percent of the animals (n= 10) challenged intraperitoneally with 106CFU ofS. agalactiaedied within 72 h, whereas repeated injections of PlySK1249 (45 mg/kg 3 times within 24 h) significantly protected the mice (P< 0.01). Thus, PlySK1249, which was isolated fromS. dysgalactiae, demonstrated high cross-lytic activity againstS. agalactiaebothin vitroandin vivo. These encouraging results indicated that PlySK1249 might represent a good candidate to be developed as a new enzybiotic for the treatment of systemicS. agalactiaeinfections.

scholarly journals In Vitro and In Vivo Activities of a Novel Cephalosporin, BMS-247243, against Organisms other than Staphylococci

2002 ◽  
Vol 46 (4) ◽  
pp. 1108-1111 ◽  
Author(s):  
Junius Clark ◽  
Joan C. Fung-Tomc ◽  
Beatrice Minassian ◽  
Yuan-Hwang Tsai ◽  
Hyekyung Yang ◽  
...  
Keyword(s):  
Streptococcus Pneumoniae ◽  
Enterococcus Faecalis ◽  
Enterococcus Faecium ◽  
Gram Positive ◽  
Methicillin Resistant ◽  
Gram Positive Bacteria ◽  
Resistant Species ◽  
Vancomycin Resistant

ABSTRACT BMS-247243, a novel cephalosporin inhibitory for methicillin-resistant staphylococci, primarily has activity against gram-positive bacteria. The activities of BMS-247243, cefotaxime, and ceftriaxone against streptococci and Streptococcus pneumoniae were similar. BMS-247243 inhibits Enterococcus faecalis but not Enterococcus faecium. BMS-247243 also inhibits many inherently vancomycin-resistant species (Leuconstoc, Lactobacillus, Pediococcus) and anaerobic gram-positive bacteria.

scholarly journals Unexpected Cell Wall Alteration-Mediated Bactericidal Activity of the Antifungal Caspofungin against Vancomycin-Resistant Enterococcus faecium

2020 ◽  
Vol 64 (10) ◽  
Author(s):  
Christophe Isnard ◽  
Sara B. Hernandez ◽  
François Guérin ◽  
Fanny Joalland ◽  
Didier Goux ◽  
...  
Keyword(s):  
Cell Wall ◽  
Enterococcus Faecium ◽  
Opportunistic Pathogen ◽  
Glycerol Metabolism ◽  
Content Type ◽  
Mechanistic Pathway ◽  
Bacterial Cell Viability ◽  
Vancomycin Resistant ◽  
The Impact

ABSTRACT Enterococcus faecium has become a major opportunistic pathogen with the emergence of vancomycin-resistant enterococci (VRE). As part of the gut microbiota, they have to cope with numerous stresses, including effects of antibiotics and other xenobiotics, especially in patients hospitalized in intensive care units (ICUs) who receive many medications. The aim of this study was to investigate the impact of the most frequently prescribed xenobiotics for ICU patients on fitness, pathogenicity, and antimicrobial resistance of the vanB-positive E. faecium Aus0004 reference strain. Several phenotypic analyses were carried out, and we observed that caspofungin, an antifungal agent belonging to the family of echinocandins, had an important effect on E. faecium growth in vitro. We confirmed this effect by electron microscopy and peptidoglycan analysis and showed that, even at a subinhibitory concentration (1/4× MIC, 8 mg/liter), caspofungin had an impact on cell wall organization, especially with respect to the abundance of some muropeptide precursors. By transcriptome sequencing (RNA-seq), it was also shown that around 20% of the transcriptome was altered in the presence of caspofungin, with 321 and 259 significantly upregulated and downregulated genes, respectively. Since the fungal target of caspofungin (i.e., β-1,3-glucan synthase) was absent in bacteria, the mechanistic pathway of caspofungin activity was investigated. The repression of genes involved in the metabolism of pyruvate seemed to have a drastic impact on bacterial cell viability, while a decrease of glycerol metabolism could explain the conformational modifications of peptidoglycan. This is the first report of caspofungin antibacterial activity against E. faecium, highlighting the potential impact of nonantibiotic xenobiotics against bacterial pathogens.

scholarly journals Evaluation of Oritavancin Dosing Strategies against Vancomycin-Resistant Enterococcus faecium Isolates with or without Reduced Susceptibility to Daptomycin in an In Vitro Pharmacokinetic/Pharmacodynamic Model

2017 ◽  
Vol 62 (1) ◽  
Author(s):  
Adam Belley ◽  
Francis F. Arhin ◽  
Greg Moeck
Keyword(s):  
Enterococcus Faecium ◽  
Pharmacodynamic Model ◽  
Vancomycin Resistant Enterococcus ◽  
Content Type ◽  
Dosing Regimens ◽  
Dosing Strategies ◽  
Vancomycin Resistant ◽  
Lipopeptide Antibiotic ◽  
Long Acting

ABSTRACT The clinical development of nonsusceptibility to the lipopeptide antibiotic daptomycin remains a serious concern during therapy for infections caused by vancomycin-resistant Enterococcus faecium (VREfm). The long-acting lipoglycopeptide oritavancin exhibits potent in vitro activity against VREfm, although its safety and efficacy for treating clinical VREfm infections have not been established. In this study, novel dosing regimens of daptomycin and oritavancin were assessed against both VREfm and daptomycin-nonsusceptible VREfm isolates in an in vitro pharmacokinetic/pharmacodynamic model.

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