scholarly journals Fosfomycin Enhances the Activity of Daptomycin against Vancomycin-Resistant Enterococci in anIn VitroPharmacokinetic-Pharmacodynamic Model

2016 ◽  
Vol 60 (10) ◽  
pp. 5716-5723 ◽  
Author(s):  
Ashley D. Hall Snyder ◽  
Brian J. Werth ◽  
Poochit Nonejuie ◽  
John P. McRoberts ◽  
Joe Pogliano ◽  
...  
Keyword(s):  
Cell Surface ◽  
Surface Charge ◽  
Content Type ◽  
Cell Surface Charge ◽  
Resistant Strains ◽  
Vancomycin Resistant ◽  
High Doses ◽  
Zeta Potential Analysis

ABSTRACTDaptomycin (DAP) is being used more frequently to treat infections caused by vancomycin-resistant enterococcus (VRE). DAP tends to be less active against enterococci than staphylococci and may require high doses or combination therapy to be bactericidal. Fosfomycin (FOF) has activity against VRE and has demonstrated synergistic bactericidal activity with DAPin vitro. The objective of this study was to evaluate the activity of DAP alone and in combination with FOF against VRE in anin vitropharmacokinetic/pharmacodynamic (PK/PD) model. The activity of DAP at 8 and 12 mg/kg of body weight/day (DAP 8 and DAP 12, respectively) and FOF of 40 mg/kg intravenously every 8 h, alone and in combination, were evaluated against 2 vancomycin-resistantEnterococcus faeciumstrains (8019 and 5938) and 2 vancomycin-resistantE. faecalisstrains (V583 and R7302) in anin vitroPK/PD model over 72 h. Cell surface charge in the presence and absence of FOF was evaluated by zeta potential analysis. Daptomycin-boron-dipyrromethene (bodipy) binding was assessed by fluorescence microscopy. The addition of FOF to DAP 8 and DAP 12 resulted in significantly increased killing over DAP alone at 72 h for 8019, V583, and R7302 (P< 0.05). Therapeutic enhancement was observed with DAP 12 plus FOF against 8019, V583, and R7302. Cell surface charge became more negative after exposure to FOF by ∼2 to 8mV in all 4 strains. Daptomycin-bodipy binding increased by 2.6 times in the presence of fosfomycin (P< 0.0001). The combination of DAP plus FOF may provide improved killing against VRE (including DAP-resistant strains) through modulation of cell surface charge. Further studies to clarify the role of intravenous FOF are warranted.

scholarly journals Evolution of Daptomycin Resistance in Coagulase-Negative Staphylococci Involves Mutations of the Essential Two-Component Regulator WalKR

2019 ◽  
Vol 63 (3) ◽  
Author(s):  
Jhih-Hang Jiang ◽  
Carina Dexter ◽  
David R. Cameron ◽  
Ian R. Monk ◽  
Sarah L. Baines ◽  
...  
Keyword(s):  
Antimicrobial Resistance ◽  
Cell Surface ◽  
Surface Charge ◽  
Sequencing Analysis ◽  
Care Hospital ◽  
Coagulase Negative Staphylococci ◽  
Content Type ◽  
Staphylococcus Capitis ◽  
Cell Surface Charge ◽  
Two Component

ABSTRACTCoagulase-negative staphylococci (CoNS) represent one of the major causes of health care- and medical device-associated infections. Emerging antimicrobial resistance has complicated the treatment of systemic infections caused by CoNS. Here, we describe the prevalence of antimicrobial resistance in clinical CoNS strains from a tertiary care hospital over a 4-year period, and we observed a significant increase in resistance to daptomycin. Notably,Staphylococcus capitisaccounted for the majority of these daptomycin-resistant (DAP-R) CoNS. To further investigate the mechanisms of daptomycin resistance in CoNS, daptomycin-susceptible clinical strains ofS. capitisandStaphylococcus epidermidisunderwentin vitrodaptomycin exposure to generate DAP-R CoNS mutants. Unlike that seen withStaphylococcus aureus, alteration of cell surface charge was not observed in the DAP-R CoNS strains, but biofilm formation was compromised. Whole-genome sequencing analysis of the DAP-R CoNS strains identified single nucleotide polymorphisms (SNPs) inwalKR, the essential two-component regulatory system controlling cell wall biogenesis. PCR and sequencing ofwalKandwalRfrom 17 DAP-R CoNS clinical isolates identified seven nonsynonymous mutations. The results were confirmed by the recreation of thewalKSNP inS. epidermidis, which resulted in reduced susceptibility to daptomycin and vancomycin. This study highlights the significance of CoNS in evolving daptomycin resistance and showed thatwalKRis shared among the staphylococcal species and is involved in antibiotic resistance development. Notably, we did not observe mutations in genes responsible for phospholipid biosynthesis or an altered cell surface charge, suggesting that reduced daptomycin susceptibility in CoNS may emerge in a fashion distinct from that inS. aureus.

scholarly journals Role of Alanine Racemase Mutations in Mycobacterium tuberculosisd-Cycloserine Resistance

2017 ◽  
Vol 61 (12) ◽  
Author(s):  
Yoshio Nakatani ◽  
Helen K. Opel-Reading ◽  
Matthias Merker ◽  
Diana Machado ◽  
Sönke Andres ◽  
...  
Keyword(s):  
Alanine Racemase ◽  
Drug Resistant ◽  
Evolutionary Patterns ◽  
Content Type ◽  
Direct Measurements ◽  
Resistant Strains ◽  
Selection For ◽  
Drug Resistant Strains

ABSTRACT A screening of more than 1,500 drug-resistant strains of Mycobacterium tuberculosis revealed evolutionary patterns characteristic of positive selection for three alanine racemase (Alr) mutations. We investigated these mutations using molecular modeling, in vitro MIC testing, as well as direct measurements of enzymatic activity, which demonstrated that these mutations likely confer resistance to d-cycloserine.

scholarly journals 53 Nanoscale characterisation of the effect of OligoG treatment on bacterial cell-surface charge and aggregation in vitro

2012 ◽  
Vol 11 ◽  
pp. S69
Author(s):  
M. Pritchard ◽  
L. Powell ◽  
I. Doull ◽  
K.E. Hill ◽  
E. Onsøyen ◽  
...  
Keyword(s):  
Cell Surface ◽  
Surface Charge ◽  
Bacterial Cell ◽  
Bacterial Cell Surface ◽  
Cell Surface Charge

In vitro evaluation of a novel ketolide antimicrobial agent, RU-64004.

1997 ◽  
Vol 41 (2) ◽  
pp. 454-459 ◽  
Author(s):  
C Jamjian ◽  
D J Biedenbach ◽  
R N Jones
Keyword(s):  
Moraxella Catarrhalis ◽  
In Vitro Tests ◽  
In Vitro Activity ◽  
Gram Positive ◽  
Beta Hemolytic Streptococcus ◽  
Serious Infections ◽  
Resistant Strains ◽  
Vancomycin Resistant

Ketolides, a novel macrolide subclass, possess a mode of action that is similar to that of structurally related macrolide-lincosamide-streptogramin (MLS) compounds. By using reference in vitro tests, the in vitro activity of RU-64004 was compared to those of six other MLS compounds against more than 800 clinical pathogens, including 356 gram-positive organisms. The spectrum of activity of the ketolide was most similar to that of clindamycin versus staphylococci and streptococci and superior to those of all macrolides tested against oxacillin-resistant staphylococci and vancomycin-resistant (vanA, vanB, and vanC) enterococcal isolates. The activity of the ketolide was greater than those of the macrolides, azalides, or clindamycin tested against vancomycin-susceptible enterococci (MICs at which 90% of isolates are inhibited [MIC90S], 0.25 to 4 micrograms/ml), penicillin-resistant pneumococci (MIC90, 0.25 micrograms/ml), and most beta-hemolytic streptococci. All Streptococcus pneumoniae and beta-hemolytic streptococcus strain were inhibited by ketolide concentrations of < or = 0.25 micrograms/ml. Against 165 erythromycin-resistant strains, RU-64004 inhibited (MICs, < or = 0.5 micrograms/ml) approximately one-third of staphylococci, all streptococci, and slightly more than one-half of the enterococci. Quinupristin-dalfopristin (a streptogramin combination) was active against all tested isolates with the exception of non-Enterococcus faecium enterococci, against which the ketolide exhibited greater potency (MIC50S, 0.03 to 2 micrograms/ml). The ketolide was also active against Haemophilus influenzae (MIC90, 2 micrograms/ml), Moraxella catarrhalis (MIC90, 0.12 micrograms/ml), pathogenic Neisseria spp. (MIC90, 0.5 micrograms/ml), and many gram-positive anaerobes (MIC90, 0.5 micrograms/ml). RU-64004 may enhance the role of macrolide drugs in the treatment of some serious infections caused by MLS-resistant gram-positive organisms.

Modeling algal biofilms: Role of carbon, light, cell surface charge, and ionic species

1995 ◽  
Vol 67 (1) ◽  
pp. 87-94 ◽  
Author(s):  
Joseph R. V. Flora ◽  
Makram T. Suidan ◽  
Pratim Biswas ◽  
Gregory D. Sayles
Keyword(s):  
Cell Surface ◽  
Surface Charge ◽  
Ionic Species ◽  
Light Cell ◽  
Cell Surface Charge ◽  
Algal Biofilms

scholarly journals Verapamil Improves the Activity of Bedaquiline against Mycobacterium abscessus In Vitro and in Macrophages

2019 ◽  
Vol 63 (9) ◽  
Author(s):  
Albertus Viljoen ◽  
Clément Raynaud ◽  
Matt D. Johansen ◽  
Françoise Roquet-Banères ◽  
Jean-Louis Herrmann ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Adjunctive Therapy ◽  
Mycobacterium Abscessus ◽  
Pulmonary Infections ◽  
Content Type ◽  
Resistant Strains ◽  
High Doses ◽  
Clinical Potential

ABSTRACT Due to intrinsic multidrug resistance, pulmonary infections with Mycobacterium abscessus are extremely difficult to treat. Previously, we demonstrated that bedaquiline is highly effective against Mycobacterium abscessus both in vitro and in vivo. Here, we report that verapamil improves the efficacy of bedaquiline activity against M. abscessus clinical isolates and low-level resistant strains, both in vitro and in macrophages. Verapamil may have clinical potential as adjunctive therapy provided that sufficiently high doses can be safely achieved.

scholarly journals DaptomycinIn VitroActivity against Methicillin-Resistant Staphylococcus aureus Is Enhanced by d-Cycloserine in a Mechanism Associated with a Decrease in Cell Surface Charge

2013 ◽  
Vol 57 (9) ◽  
pp. 4537-4539 ◽  
Author(s):  
O. Gasch ◽  
S. K. Pillai ◽  
J. Dakos ◽  
S. Miyakis ◽  
R. C. Moellering ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Cell Surface ◽  
Surface Charge ◽  
Methicillin Resistant Staphylococcus Aureus ◽  
Binding Assays ◽  
Methicillin Resistant ◽  
Content Type ◽  
Killing Activity ◽  
Cell Surface Charge ◽  
Mrsa Strains

ABSTRACTThe killing activity of daptomycin against an isogenic pair of daptomycin-susceptible and daptomycin-nonsusceptible (DNS) methicillin-resistantStaphylococcus aureus(MRSA) strains was enhanced by the addition of certain cell wall agents at 1× MIC. However, when high inocula of the DNS strain were used, no significant killing was observed in our experiments. Cytochromecbinding assays revealedd-cycloserine as the only agent associated with a reduction in the cell surface charge for both strains at the concentrations used.

scholarly journals ACoccidioides posadasii CPS1Deletion Mutant Is Avirulent and Protects Mice from Lethal Infection

2016 ◽  
Vol 84 (10) ◽  
pp. 3007-3016 ◽  
Author(s):  
Hema P. Narra ◽  
Lisa F. Shubitz ◽  
M. Alejandra Mandel ◽  
Hien T. Trinh ◽  
Kurt Griffin ◽  
...  
Keyword(s):  
Homologous Gene ◽  
Coccidioides Posadasii ◽  
Content Type ◽  
Lethal Infection ◽  
High Doses ◽  
Regulatory Functions ◽  
High Degree ◽  
Promising Vaccine Candidate

TheCPS1gene was identified as a virulence factor in the maize pathogenCochliobolus heterostrophus. Hypothesizing that the homologous gene inCoccidioides posadasiicould be important for virulence, we created a Δcps1deletion mutant which was unable to cause disease in three strains of mice (C57BL/6, BALB/c, or the severely immunodeficient NOD-scid,γcnull[NSG]). Only a single colony was recovered from 1 of 60 C57BL/6 mice following intranasal infections of up to 4,400 spores. Following administration of very high doses (10,000 to 2.5 × 107spores) to NSG and BALB/c mice, spherules were observed in lung sections at time points from day 3 to day 10 postinfection, but nearly all appeared degraded with infrequent endosporulation. Although the role ofCPS1in virulence is not understood, phenotypic alterations and transcription differences of at least 33 genes in the Δcps1strain versusC. posadasiiis consistent with both metabolic and regulatory functions for the gene. Thein vitrophenotype of the Δcps1strain showed slower growth of mycelia with delayed and lower spore production thanC. posadasii, andin vitrospherules were smaller. Vaccination of C57BL/6 or BALB/c mice with live Δcps1spores either intranasally, intraperitoneally, or subcutaneously resulted in over 95% survival with mean residual lung fungal burdens of <1,000 CFU from an otherwise lethalC. posadasiiintranasal infection. Considering its apparently complete attenuation of virulence and the high degree of resistance toC. posadasiiinfection when used as a vaccine, the Δcps1strain is a promising vaccine candidate for preventing coccidioidomycosis in humans or other animals.

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