Genetic structure characteristics and treatment for Listeria monocytogenes infections

2020 ◽  
Author(s):  
Wei Yu ◽  
Yicheng Huang ◽  
Lihua Guo ◽  
Jiajie Zhang ◽  
Yaqiong Zhan ◽  
...  
Keyword(s):  
Listeria Monocytogenes ◽  
Therapeutic Option ◽  
Treatment Options ◽  
Bactericidal Effect ◽  
Bacterial Pathogenicity ◽  
Antibiotics Susceptibility ◽  
Susceptibility Tests ◽  
Time Kill ◽  
Sequence Types

Abstract Background: Invasive Listeria monocytogenes (Lm) carry a high mortality despite antibiotic treatment. The aim of this study was to investigate the mechanism of pathogenicity and resistance. In addition, the effect of existing treatment options against Lm were systematically evaluated as well. Methods: Three Lm isolates were collected and 15 antibiotics susceptibility tests were done. Subsequently, whole genome sequencing and bioinformatics analysis were performed. Furthermore, the effect of meropenem, linezolid, benzylpenicillin, vancomycin, trimethoprim/sulfamethoxazole were determined using the time-kill assay.Results: Two sequence types (STs) were identified for isolate 23949 (ST87), 26530 (ST3), 34096 (ST87), respectively. All isolates were resistant to fosfomycin and daptomycin. The resistant genes fosX, mprF, norB and vgaALC were identified in all isolates. Furthermore, 80 virulence genes were detected and 72 genes were found in all three isolates. There were 26 virulent genes associated with the structure, biosynthesis, motor switch of flagellum. And other virulent genes were involved in chemotaxis, protease, internalin and metabolism. It is of note that 8 genes (inlJ, llsB, llsD, llsG, llsH, llsP, llsX, llsY) were only found in 26530 isolated from cerebrospinal fluid (CSF), 7 of which were associated with haemolysin. Further in vitro time-kill assay found trimethoprim/sulfamethoxazole at serum or CSF concentrations had bactericidal effect (>3.5 log10 CFU/ml) against three tested Lm strains at 24 h. Conclusions: The involved virulence factors were mainly associated with bacterial pathogenicity. Notably, trimethoprim/sulfamethoxazole might be greater potential therapeutic option against Lm bloodstream infection or intracranial infection.

scholarly journals Analysis of genetic diversity and antibiotic options for clinical Listeria monocytogenes infections in China

2021 ◽  
Author(s):  
Wei Yu ◽  
Yicheng Huang ◽  
Chaoqun Ying ◽  
Yanzi Zhou ◽  
Li Zhang ◽  
...  
Keyword(s):  
Listeria Monocytogenes ◽  
Biofilm Formation ◽  
Virulence Genes ◽  
Genomic Island ◽  
Therapeutic Option ◽  
Treatment Options ◽  
Bactericidal Effect ◽  
Time Kill ◽  
Sequence Types

Abstract Background The aim of this study was to investigate the mechanism of Listeria monocytogenes (Lm) pathogenicity and resistance. In addition, the effect of existing treatment options against Lm were systematically evaluated. Methods Six Lm isolates were collected and antimicrobial susceptibility testing of 15 antibiotics were done. Subsequently, whole genome sequencing and bioinformatics analysis were performed. Biofilm formation was evaluated by crystal violet staining. Furthermore, the effect of meropenem, linezolid, penicillin, vancomycin, trimethoprim/sulfamethoxazole were determined using the time-kill assay. Results Four sequence types (STs) were identified (ST1, ST3, ST87, ST451). Multi-virulence-locus sequence typing (MVLST) results classified ST87 isolates into cluster. All isolates were resistant to fosfomycin and daptomycin with fosX and mprF. In addition, a total of 80 virulence genes were detected and 72 genes were found in all six isolates. Seven genes associated with haemolysin were found in 26530 and 115423. However, due to lack of one genomic island including virulence genes related to flagellar synthesis, isolate 115423 produced less biofilm than five other isolates. Even all isolates were susceptible to vancomycin, the in vitro time-kill assay showed vancomycin monotherapy resulted in less than 2 log10 CFU/mL compared with the initial count. Trimethoprim/sulfamethoxazole at serum or cerebrospinal fluid concentrations had bactericidal effect against tested Lm strains at 24 h. Conclusions ST87 clone was a typical prevalent ST in clinical Lm isolates in China. Trimethoprim/sulfamethoxazole might be greater potential therapeutic option against Lm infections.

scholarly journals Antimicrobial Properties of 8-Hydroxyserrulat-14-en-19-oic Acid for Treatment of Implant-Associated Infections

2012 ◽  
Vol 57 (1) ◽  
pp. 333-342 ◽  
Author(s):  
Justyna Nowakowska ◽  
Hans J. Griesser ◽  
Marcus Textor ◽  
Regine Landmann ◽  
Nina Khanna
Keyword(s):  
Structural Changes ◽  
Treatment Options ◽  
Antimicrobial Properties ◽  
Bactericidal Effect ◽  
Mouse Tissue ◽  
Logarithmic Phase ◽  
Content Type ◽  
Gram Positive Bacteria ◽  
Time Kill

ABSTRACTTreatment options are limited for implant-associated infections (IAI) that are mainly caused by biofilm-forming staphylococci. We report here on the activity of the serrulatane compound 8-hydroxyserrulat-14-en-19-oic acid (EN4), a diterpene isolated from the Australian plantEremophila neglecta. EN4 elicited antimicrobial activity toward various Gram-positive bacteria but not to Gram-negative bacteria. It showed a similar bactericidal effect against logarithmic-phase, stationary-phase, and adherentStaphylococcus epidermidis, as well as against methicillin-susceptible and methicillin-resistantS. aureuswith MICs of 25 to 50 μg/ml and MBCs of 50 to 100 μg/ml. The bactericidal activity of EN4 was similar againstS. epidermidisand its Δicamutant, which is unable to produce polysaccharide intercellular adhesin-mediated biofilm. In time-kill studies, EN4 exhibited a rapid and concentration-dependent killing of staphylococci, reducing bacterial counts by >3 log10CFU/ml within 5 min at concentrations of >50 μg/ml. Investigation of the mode of action of EN4 revealed membranolytic properties and a general inhibition of macromolecular biosynthesis, suggesting a multitarget activity.In vitro-tested cytotoxicity on eukaryotic cells was time and concentration dependent in the range of the MBCs. EN4 was then tested in a mouse tissue cage model, where it showed neither bactericidal nor cytotoxic effects, indicating an inhibition of its activity. Inhibition assays revealed that this was caused by interactions with albumin. Overall, these findings suggest that, upon structural changes, EN4 might be a promising pharmacophore for the development of new antimicrobials to treat IAI.

scholarly journals In Vitro Antimicrobial Activity of Fosfomycin, Rifampin, Vancomycin, Daptomycin Alone and in Combination Against Vancomycin-Resistant Enterococci

2021 ◽  
Author(s):  
Wei Yu ◽  
Yiheng Jiang ◽  
Hao Xu ◽  
Li Zhang ◽  
Xuehang Jin ◽  
...  
Keyword(s):  
Virulence Genes ◽  
Therapeutic Option ◽  
Bactericidal Effect ◽  
Resistance Determinant ◽  
Vancomycin Resistant Enterococci ◽  
Vancomycin Resistant ◽  
High Level ◽  
Time Kill ◽  
Level Resistance

Abstract OBJECTIVESThe emergence of vancomycin resistant enterococci (VRE) is shortening the choices for clinical anti-infective therapy. The aim of this study was to investigate the mechanism of vancomycin resistance and evaluate the effect of fosfomycin (FM), rifampin (RIF), vancomycin (VAN), linezolid (LNZ), daptomycin (DAP) alone or in combination against VRE.METHODSEight VRE isolates were collected. A total of 18 antibiotics susceptibility tests were further done for VRE. Whole genome sequencing and bioinformatics analysis were performed. The effect of FM, RIF, VNA, LNZ, DAP alone or in combination was determined using anti-biofilm testing and the time-kill assay.RESULTSAll isolates were susceptible to LNZ and DPA. The high-level resistance determinant of VAN in these strains was due to VanA-type cassette. MLST revealed two different STs for vancomycin-resistant Enterococcus faecium (VREm) and four different STs for vancomycin-resistant E. faecalis (VREs). Virulence genes in VREs were more than VREm, especially for 4942 isolated from blood. Gene acm and uppS were only identified in VREm, while virulence genes related to cytolysin were only found in E. faecalis. Further in vitro anti-biofilm testing and time-kill assay found FM (83 mg/L) combined with DAP (20.6 mg/L) and DAP monotherapy (47.1 mg/L) showed bactericidal effect against 8 tested VRE strains at 24h. CONCLUSIONSThe high-level resistance determinant of VAN in these strains was due to VanA-type cassette. FM combined with DAP might be greater potential therapeutic option against VRE.

scholarly journals Comparison of the In Vitro Efficacies of Moxifloxacin and Amoxicillin against Listeria monocytogenes

2008 ◽  
Vol 52 (5) ◽  
pp. 1697-1702 ◽  
Author(s):  
S. Grayo ◽  
O. Join-Lambert ◽  
M. C. Desroches ◽  
A. Le Monnier
Keyword(s):  
Listeria Monocytogenes ◽  
Bactericidal Effect ◽  
Cross Resistance ◽  
Resistant Bacteria ◽  
Gram Positive Bacteria ◽  
Severe Infections ◽  
Potential Alternative ◽  
Kill Curve ◽  
Time Kill

ABSTRACT Listeria monocytogenes is a facultative intracellular bacterium that causes severe infections associated with a high mortality rate. Moxifloxacin presents extended activity against gram-positive bacteria and has recently been suggested to be a potential alternative in the treatment of listeriosis. We evaluated the in vitro efficacy of moxifloxacin against L. monocytogenes using a combination of epidemiological and experimental approaches. The median MIC of moxifloxacin for a large collection of L. monocytogenes strains of various origins (human, food, and environment) was 0.5 μg/ml (MIC range, 0.064 to 1 μg/ml). No differences were observed, irrespective of the origin of the strains. Moreover, no cross-resistance with fluoroquinolones was detected in strains that have been reported to be resistant to ciprofloxacin. The in vitro activities of moxifloxacin and amoxicillin were compared by time-kill curve and inhibition of intracellular growth experiments by using a model of bone marrow-derived mouse macrophages infected by L. monocytogenes EGDe. Both moxifloxacin and amoxicillin were bactericidal in broth against extracellular forms of L. monocytogenes. However, moxifloxacin acted much more rapidly, beginning to exert its effects in the first 3 h and achieving complete broth sterilization within 24 h of incubation. Moxifloxacin has a rapid bactericidal effect against intracellular reservoirs of bacteria, whereas amoxicillin is only bacteriostatic and appears to prevent cellular lysis and the subsequent bacterial spreading to adjacent cells. No resistant bacteria were selected during the in vitro experiments. Taken together, our results suggest that moxifloxacin is an interesting alternative to the reference treatment, combining rapid and bactericidal activity, even against intracellular bacteria.

scholarly journals ZN148 Is a Modular Synthetic Metallo-β-Lactamase Inhibitor That Reverses Carbapenem Resistance in Gram-Negative Pathogens In Vivo

2020 ◽  
Vol 64 (6) ◽  
Author(s):  
Ørjan Samuelsen ◽  
Ove Alexander Høgmoen Åstrand ◽  
Christopher Fröhlich ◽  
Adam Heikal ◽  
Susann Skagseth ◽  
...  
Keyword(s):  
Active Site ◽  
Therapeutic Potential ◽  
Treatment Options ◽  
Carbapenem Resistance ◽  
Functional Space ◽  
Bactericidal Effect ◽  
Gram Negative ◽  
Content Type

ABSTRACT Carbapenem-resistant Gram-negative pathogens are a critical public health threat and there is an urgent need for new treatments. Carbapenemases (β-lactamases able to inactivate carbapenems) have been identified in both serine β-lactamase (SBL) and metallo-β-lactamase (MBL) families. The recent introduction of SBL carbapenemase inhibitors has provided alternative therapeutic options. Unfortunately, there are no approved inhibitors of MBL-mediated carbapenem-resistance and treatment options for infections caused by MBL-producing Gram-negatives are limited. Here, we present ZN148, a zinc-chelating MBL-inhibitor capable of restoring the bactericidal effect of meropenem and in vitro clinical susceptibility to carbapenems in >98% of a large international collection of MBL-producing clinical Enterobacterales strains (n = 234). Moreover, ZN148 was able to potentiate the effect of meropenem against NDM-1-producing Klebsiella pneumoniae in a murine neutropenic peritonitis model. ZN148 showed no inhibition of the human zinc-containing enzyme glyoxylase II at 500 μM, and no acute toxicity was observed in an in vivo mouse model with cumulative dosages up to 128 mg/kg. Biochemical analysis showed a time-dependent inhibition of MBLs by ZN148 and removal of zinc ions from the active site. Addition of exogenous zinc after ZN148 exposure only restored MBL activity by ∼30%, suggesting an irreversible mechanism of inhibition. Mass-spectrometry and molecular modeling indicated potential oxidation of the active site Cys221 residue. Overall, these results demonstrate the therapeutic potential of a ZN148-carbapenem combination against MBL-producing Gram-negative pathogens and that ZN148 is a highly promising MBL inhibitor that is capable of operating in a functional space not presently filled by any clinically approved compound.

In vitro effectiveness of biapenem against IMP-producing Enterobacteriaceae

2021 ◽  
Vol 70 (10) ◽  
Author(s):  
Kazuyoshi Gotoh ◽  
Makoto Miyoshi ◽  
I Putu Bayu Mayura ◽  
Koji Iio ◽  
Osamu Matsushita ◽  
...  
Keyword(s):  
Therapeutic Option ◽  
Small Data ◽  
Limited Data ◽  
Data Set ◽  
Content Type ◽  
Link Type ◽  
Almost All ◽  
New Treatments ◽  
Time Kill

The options available for treating infections with carbapenemase-producing Enterobacteriaceae (CPE) are limited; with the increasing threat of these infections, new treatments are urgently needed. Biapenem (BIPM) is a carbapenem, and limited data confirming its in vitro killing effect against CPE are available. In this study, we examined the minimum inhibitory concentrations (MICs) and minimum bactericidal concentrations (MBCs) of BIPM for 14 IMP-1-producing Enterobacteriaceae strains isolated from the Okayama region in Japan. The MICs against almost all the isolates were lower than 0.5 µg ml−1, indicating susceptibility to BIPM, while approximately half of the isolates were confirmed to be bacteriostatic to BIPM. However, initial killing to a 99.9 % reduction was observed in seven out of eight strains in a time–kill assay. Despite the small data set, we concluded that the in vitro efficacy of BIPM suggests that the drug could be a new therapeutic option against infection with IMP-producing CPE.

scholarly journals Semimechanistic Pharmacokinetic/Pharmacodynamic Modeling of Fosfomycin and Sulbactam Combination against Carbapenem-Resistant Acinetobacter baumannii

2021 ◽  
Vol 65 (5) ◽  
Author(s):  
Sazlyna Mohd Sazlly Lim ◽  
Aaron J. Heffernan ◽  
Jason A. Roberts ◽  
Fekade B. Sime
Keyword(s):  
Acinetobacter Baumannii ◽  
Treatment Options ◽  
Pharmacodynamic Modeling ◽  
Synergistic Activity ◽  
Bacterial Burden ◽  
Target Attainment ◽  
Content Type ◽  
Carbapenem Resistant ◽  
Time Kill

ABSTRACT Due to limited treatment options for carbapenem-resistant Acinetobacter baumannii (CR-AB) infections, antibiotic combinations are now considered potential treatments for CR-AB. This study aimed to explore the utility of fosfomycin-sulbactam combination (FOS/SUL) therapy against CR-AB isolates. Synergism of FOS/SUL against 50 clinical CR-AB isolates was screened using the checkerboard method. Thereafter, time-kill studies against two CR-AB isolates were performed. The time-kill data were described using a semimechanistic pharmacokinetic/pharmacodynamic (PK/PD) model. Monte Carlo simulations were then performed to estimate the probability of stasis, 1-log kill, and 2-log kill after 24 h of combination therapy. The FOS/SUL combination demonstrated a synergistic effect against 74% of isolates. No antagonism was observed. The MIC50 and MIC90 of FOS/SUL were decreased 4- to 8-fold, compared to the monotherapy MIC50 and MIC90. In the time-kill studies, the combination displayed bactericidal activity against both isolates and synergistic activity against one isolate at the highest clinically achievable concentrations. Our PK/PD model was able to describe the interaction between fosfomycin and sulbactam in vitro. Bacterial kill was mainly driven by sulbactam, with fosfomycin augmentation. FOS/SUL regimens that included sulbactam at 4 g every 8 h demonstrated a probability of target attainment of 1-log10 kill at 24 h of ∼69 to 76%, compared to ∼15 to 30% with monotherapy regimens at the highest doses. The reduction in the MIC values and the achievement of a moderate PTA of a 2-log10 reduction in bacterial burden demonstrated that FOS/SUL may potentially be effective against some CR-AB infections.

scholarly journals β-Phenylethylamine as a Natural Food Additive Shows Antimicrobial Activity against Listeria monocytogenes on Ready-to-Eat Foods

Foods ◽  
2020 ◽  
Vol 9 (10) ◽  
pp. 1363 ◽  
Author(s):  
Francis Muchaamba ◽  
Roger Stephan ◽  
Taurai Tasara
Keyword(s):  
Listeria Monocytogenes ◽  
Foodborne Pathogen ◽  
Bactericidal Effect ◽  
Model Systems ◽  
Natural Food ◽  
Smoked Salmon ◽  
Growth Inhibitory ◽  
Good Manufacturing Practices ◽  
Agar Media

Listeria monocytogenes is an important foodborne pathogen and a major cause of death associated with bacterial foodborne infections. Control of L. monocytogenes on most ready-to-eat (RTE) foods remains a challenge. The potential use of β-phenylethylamine (PEA) as an organic antimicrobial against L. monocytogenes was evaluated in an effort to develop a new intervention for its control. Using a collection of 62 clinical and food-related isolates we determined the minimum inhibitory concentration (MIC) of PEA against L. monocytogenes in different broth and agar media. Bologna type sausage (lyoner) and smoked salmon were used as food model systems to validate the in vitro findings. PEA had a growth inhibitory and bactericidal effect against L. monocytogenes both in in vitro experiments as well as on lyoner and smoked salmon. The MIC’s ranged from 8 to 12.5 mg/mL. Furthermore, PEA also inhibited L. monocytogenes biofilm formation. Based on good manufacturing practices as a prerequisite, the application of PEA to RTE products might be an additional hurdle to limit L. monocytogenes growth thereby increasing food safety.

scholarly journals Posaconazole against Candida glabrata Isolates with Various Susceptibilities to Fluconazole

2008 ◽  
Vol 52 (6) ◽  
pp. 1929-1933 ◽  
Author(s):  
Elisabetta Spreghini ◽  
Carmelo Massimo Maida ◽  
Serena Tomassetti ◽  
Fiorenza Orlando ◽  
Daniele Giannini ◽  
...  
Keyword(s):  
Experimental Model ◽  
Candida Glabrata ◽  
Therapeutic Option ◽  
Resistant Isolate ◽  
Dependent Manner ◽  
Fungal Burden ◽  
Systemic Infections ◽  
Time Kill ◽  
Dose Dependent

ABSTRACT We investigated the in vitro activities of posaconazole (POS), fluconazole (FLC), amphotericin B (AMB), and caspofungin (CAS) against four clinical isolates of Candida glabrata with various susceptibilities to FLC (FLC MICs ranging from 1.0 to >64 μg/ml). POS MICs ranged from ≤0.03 to 0.5 μg/ml; AMB MICs ranged from 0.25 to 2.0 μg/ml, while CAS MICs ranged from 0.03 to 0.25 μg/ml. When FLC MICs increased, so did POS MICs, although we did not observe any isolate with a POS MIC greater than 0.5 μg/ml. Time-kill experiments showed that POS, FLC, and CAS were fungistatic against all isolates, while AMB at eight times the MIC was fungicidal against three out of four isolates of C. glabrata tested. Then, we investigated the activity of POS in an experimental model of disseminated candidiasis using three different isolates of C. glabrata: one susceptible to FLC (S; FLC MICs ranging from 1.0 to 4.0 μg/ml; POS MIC of ≤0.03 μg/ml), one susceptible in a dose-dependent manner (SDD; FLC MICs ranging from 32 to 64 μg/ml; POS MICs ranging from 0.125 to 0.25 μg/ml), and another one resistant to FLC (R; FLC MIC of >64 μg/ml; POS MIC of 0.5 μg/ml). FLC significantly reduced the kidney burden of mice infected with the S strain (P = 0.0070) but not of those infected with the S-DD and R strains. POS was significantly effective against all three isolates at reducing the kidney fungal burden with respect to the controls (P ranging from 0.0003 to 0.029). In conclusion, our data suggest that POS may be a useful option in the management of systemic infections caused by C. glabrata. Additionally, the new triazole may be a therapeutic option in those cases where an FLC-resistant isolate is found to retain a relatively low POS MIC.

scholarly journals Time-kill curve analysis and pharmacodynamic functions for in vitro evaluation of antimicrobials againstNeisseria gonorrhoeae

2015 ◽  
Author(s):  
Sunniva Foerster ◽  
Magnus Unemo ◽  
Lucy J Hathaway ◽  
Nicola Low ◽  
Christian L Althaus
Keyword(s):  
Bactericidal Effect ◽  
World Health ◽  
Transmitted Infection ◽  
In Vitro Evaluation ◽  
Sexually Transmitted ◽  
Dosing Strategies ◽  
Kill Curve ◽  
Health Organization ◽  
Time Kill

Gonorrhea is a sexually transmitted infection caused by the Gram-negative bacteriumNeisseria gonorrhoeae. Resistance to first-line empirical monotherapy has emerged, so robust methods are needed to appropriately evaluate the activity of existing and novel antimicrobials against the bacterium. Pharmacodynamic functions, which describe the relationship between the concentration of antimicrobials and the bacterial net growth rate, provide more detailed information than the MIC only. In this study, a novel standardized in vitro time-kill curve assay was developed. The assay was validated using five World Health OrganizationN. gonorrhoeaereference strains and various concentrations of ciprofloxacin, and then the activity of nine antimicrobials with different target mechanisms were examined against a highly susceptible clinical wild type isolate (cultured in 1964). From the time-kill curves, the bacterial net growth rates at each antimicrobial concentration were estimated. Finally, a pharmacodynamic function was fitted to the data, resulting in four parameters that describe the pharmacodynamic properties of each antimicrobial. Ciprofloxacin resistance determinants shifted the pharmacodynamic MIC (zMIC) and attenuated the bactericidal effect at antimicrobial concentrations above the zMIC. Ciprofloxacin, spectinomycin and gentamicin had the strongest bactericidal effect during the first six hours of the assay. Only tetracycline and chloramphenicol showed a purely bacteriostatic effect. The pharmacodynamic functions differed between antimicrobials, showing that the effect of the drugs at concentrations below and above the MIC vary widely. In conclusion,N. gonorrhoeaetime-kill curve experiments analyzed with pharmacodynamic functions have potential for in vitro evaluation of new and existing antimicrobials and dosing strategies to treat gonorrhea.

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