Development of high level daptomycin resistance (HLDR) in Abiotrophia and Granulicatella spp isolates from patients with infective endocarditis (IE).

2021 ◽  
Author(s):  
María A. Cañas ◽  
Adrian Téllez ◽  
Cristina García de la Mària ◽  
Anders Dahl ◽  
Javier García-González ◽  
...  
Keyword(s):  
Infective Endocarditis ◽  
Combination Therapy ◽  
Minimal Inhibitory Concentration ◽  
Inhibitory Concentration ◽  
Therapeutic Option ◽  
Combination Therapies ◽  
Viridans Streptococci ◽  
High Level ◽  
Time Kill

Abiotrophia and Granulicatella species are fastidious organisms, representing around 1%–3% of infective endocarditis (IE). Little is known about the optimal antibiotic treatment of these species, and daptomycin has been suggested as a therapeutic option. We describe the antimicrobial profile in Abiotrophia and Granulicatella IE isolates, investigate high-level daptomycin resistance (HLDR) development and evaluate daptomycin activity in combination therapy. In vitro studies with 16 IE strains (6 A. defectiva , 9 G. adiacens and 1 G. elegans ) were performed using microdilution to determine minimal inhibitory concentration (MIC) and time-kill methodology to evaluate combination therapy. Daptomycin non-susceptibility (DNS; MIC≥ 2 mg/L) and HLDR (MIC≥256 mg/L) were based on existing Clinical and Laboratory Standards (CLSI) breakpoints for viridans streptococci. All isolates were susceptible to vancomycin: G. adiacens was more susceptible to penicillin and ampicillin than A. defectiva (22% vs. 0%, and 67% vs. 33%) but less susceptible to ceftriaxone and daptomycin (56% vs. 83%, and 11% vs. 50%). HLDR developed in both A. defectiva (33%) and G. adiacens (78%) after 24h exposure to daptomycin. Combination therapy did not prevent the development of daptomycin resistance with ampicillin (2/3 strains), gentamicin (2/3 strains), ceftriaxone (2/3 strains) or ceftaroline (2/3 strains). Once developed, HLDR was stable for a prolonged time (>3 weeks) in G. adiacens , whereas in A. defectiva the HLDR it reversed to baseline MIC at day 10. This study is first to demonstrate rapid HLDR development in Abiotrophia and Granulicatella species in vitro . Resistance was stable, and most combination therapies did not prevent it.

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.

Emergence of ceftazidime/avibactam resistance in KPC-3-producing Klebsiella pneumoniae in vivo

2019 ◽  
Vol 74 (11) ◽  
pp. 3211-3216 ◽  
Author(s):  
Stephan Göttig ◽  
Denia Frank ◽  
Eleonora Mungo ◽  
Anika Nolte ◽  
Michael Hogardt ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Klebsiella Pneumoniae ◽  
Selection Pressure ◽  
Galleria Mellonella ◽  
Phenotypic Characterization ◽  
Infection Model ◽  
Development Of Resistance ◽  
Time Kill

Abstract Objectives The β-lactam/β-lactamase inhibitor combination ceftazidime/avibactam is active against KPC-producing Enterobacterales. Herein, we present molecular and phenotypic characterization of ceftazidime/avibactam resistance in KPC-3-producing Klebsiella pneumoniae that emerged in vivo and in vitro. Methods Sequence analysis of blaKPC-3 was performed from clinical and in vitro-generated ceftazidime/avibactam-resistant K. pneumoniae isolates. Time–kill kinetics and the Galleria mellonella infection model were applied to evaluate the activity of ceftazidime/avibactam and imipenem alone and in combination. Results The ceftazidime/avibactam-resistant clinical K. pneumoniae isolate revealed the amino acid change D179Y in KPC-3. Sixteen novel mutational changes in KPC-3 among in vitro-selected ceftazidime/avibactam-resistant isolates were described. Time–kill kinetics showed the emergence of a resistant subpopulation under selection pressure with either imipenem or ceftazidime/avibactam. However, combined selection pressure with imipenem plus ceftazidime/avibactam prevented the development of resistance and resulted in bactericidal activity. Concordantly, the G. mellonella infection model revealed that monotherapy with ceftazidime/avibactam is prone to select for resistance in vivo and that combination therapy with imipenem results in significantly better survival. Conclusions Ceftazidime/avibactam is a valuable antibiotic against MDR and carbapenem-resistant Enterobacterales. Based on time–kill kinetics as well as an in vivo infection model we postulate a combination therapy of ceftazidime/avibactam and imipenem as a strategy to prevent the development of ceftazidime/avibactam resistance in KPC-producing Enterobacterales in vivo.

scholarly journals In Vitro Synergy and In Vivo Activity of Tigecycline-Ciprofloxacin Combination Therapy against Vibrio vulnificus Sepsis

2019 ◽  
Vol 63 (10) ◽  
Author(s):  
Seong Eun Kim ◽  
Hee Kyung Kim ◽  
Su-Mi Choi ◽  
Yohan Yu ◽  
Uh Jin Kim ◽  
...  
Keyword(s):  
Survival Rate ◽  
Mortality Rate ◽  
Combination Therapy ◽  
Combination Treatment ◽  
Vibrio Vulnificus ◽  
Antibiotic Regimen ◽  
Content Type ◽  
Time Kill

ABSTRACT The mortality rate associated with Vibrio vulnificus sepsis remains high. An in vitro time-kill assay revealed synergism between tigecycline and ciprofloxacin. The survival rate was significantly higher in mice treated with tigecycline plus ciprofloxacin than in mice treated with cefotaxime plus minocycline. Thus, combination treatment with tigecycline-ciprofloxacin may be an effective novel antibiotic regimen for V. vulnificus sepsis.

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 Efficacy of Ampicillin plus Ceftriaxone in Treatment of Experimental Endocarditis Due to Enterococcus faecalis Strains Highly Resistant to Aminoglycosides

1999 ◽  
Vol 43 (3) ◽  
pp. 639-646 ◽  
Author(s):  
Joan Gavaldà ◽  
Carmen Torres ◽  
Carmen Tenorio ◽  
Pedro López ◽  
Myriam Zaragoza ◽  
...  
Keyword(s):  
Aortic Valve ◽  
Enterococcus Faecalis ◽  
Pharmacokinetic Parameters ◽  
Initial Inoculum ◽  
High Level ◽  
Time Kill ◽  
Disk Method ◽  
Level Resistance

The purpose of this work was to evaluate the in vitro possibilities of ampicillin-ceftriaxone combinations for 10 Enterococcus faecalis strains with high-level resistance to aminoglycosides (HLRAg) and to assess the efficacy of ampicillin plus ceftriaxone, both administered with humanlike pharmacokinetics, for the treatment of experimental endocarditis due to HLRAg E. faecalis. A reduction of 1 to 4 dilutions in MICs of ampicillin was obtained when ampicillin was combined with a fixed subinhibitory ceftriaxone concentration of 4 μg/ml. This potentiating effect was also observed by the double disk method with all 10 strains. Time-kill studies performed with 1 and 2 μg of ampicillin alone per ml or in combination with 5, 10, 20, 40, and 60 μg of ceftriaxone per ml showed a ≥2 log10 reduction in CFU per milliliter with respect to ampicillin alone and to the initial inoculum for all 10E. faecalis strains studied. This effect was obtained for seven strains with the combination of 2 μg of ampicillin per ml plus 10 μg of ceftriaxone per ml and for six strains with 5 μg of ceftriaxone per ml. Animals with catheter-induced endocarditis were infected intravenously with 108 CFU of E. faecalis V48 or 105 CFU of E. faecalisV45 and were treated for 3 days with humanlike pharmacokinetics of 2 g of ampicillin every 4 h, alone or combined with 2 g of ceftriaxone every 12 h. The levels in serum and the pharmacokinetic parameters of the humanlike pharmacokinetics of ampicillin or ceftriaxone in rabbits were similar to those found in humans treated with 2 g of ampicillin or ceftriaxone intravenously. Results of the therapy for experimental endocarditis caused by E. faecalis V48 or V45 showed that the residual bacterial titers in aortic valve vegetations were significantly lower in the animals treated with the combinations of ampicillin plus ceftriaxone than in those treated with ampicillin alone (P < 0.001). The combination of ampicillin and ceftriaxone showed in vitro and in vivo synergism against HLRAgE. faecalis.

scholarly journals Dalbavancin, Vancomycin and Daptomycin Alone and in Combination with Cefazolin against Resistant Phenotypes of Staphylococcus aureus in a Pharmacokinetic/Pharmacodynamic Model

Antibiotics ◽  
2020 ◽  
Vol 9 (10) ◽  
pp. 696 ◽  
Author(s):  
Jacinda C. Abdul-Mutakabbir ◽  
Razieh Kebriaei ◽  
Kyle C. Stamper ◽  
Zain Sheikh ◽  
Philip T. Maassen ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Bactericidal Activity ◽  
Inhibitory Concentration ◽  
Pharmacodynamic Model ◽  
In Vitro Tests ◽  
Beta Lactam ◽  
Fold Reduction ◽  
The One ◽  
Time Kill

The most efficacious antimicrobial therapy to aid in the successful elimination of resistant S. aureus infections is unknown. In this study, we evaluated varying phenotypes of S. aureus against dalbavancin (DAL), vancomycin (VAN), and daptomycin (DAP) alone and in combination with cefazolin (CFZ). The objective of this study was to observe whether there was a therapeutic improvement in adding a beta-lactam to a glycopeptide, lipopeptide, or a lipoglycopeptide. We completed a series of in vitro tests including minimum inhibitory concentration testing (MIC) of the antimicrobials in combination, time-kill analysis (TKA), and a 168 h (7-day) one-compartment pharmacokinetic/pharmacodynamic (PK/PD) model on two daptomycin non-susceptible (DNS), vancomycin intermediate S. aureus strains (VISA), D712 and 6913. Results from our MIC testing demonstrated a minimum 2-fold and a maximum 32-fold reduction in MIC values for DAL, VAN, and DAP in combination with CFZ, in contrast to either agent used alone. The TKAs completed on four strains paralleled the enhanced activity demonstrated via the combination MICs. In the one-compartment PK/PD models, the combination of DAP plus CFZ or VAN plus CFZ resulted in a significant (p < 0.001) improvement in bactericidal activity and overall reduction in CFU/ml over the 7-day period. While the addition of CFZ to DAL improved time to bactericidal activity, DAL alone demonstrated equal and more sustained overall activity compared to all other treatments. The use of DAL alone, with or without CFZ and the combinations of VAN or DAP with CFZ appear to result in increased bactericidal activity against various recalcitrant S. aureus phenotypes.

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 Fatty Acyl Benzamido Antibacterials Based on Inhibition of DnaK-catalyzed Protein Folding

2006 ◽  
Vol 282 (7) ◽  
pp. 4437-4446 ◽  
Author(s):  
Markus Liebscher ◽  
Günther Jahreis ◽  
Christian Lücke ◽  
Susanne Grabley ◽  
Satish Raina ◽  
...  
Keyword(s):  
Protein Folding ◽  
Minimal Inhibitory Concentration ◽  
Inhibitory Concentration ◽  
Acyl Chain ◽  
Fatty Acyl ◽  
Secondary Amide ◽  
Fatty Acyl Chain ◽  
Isomerase Activity

We have reported that the hsp70 chaperone DnaK from Escherichia coli might assist protein folding by catalyzing the cis/trans isomerization of secondary amide peptide bonds in unfolded or partially folded proteins. In this study a series of fatty acylated benzamido inhibitors of the cis/trans isomerase activity of DnaK was developed and tested for antibacterial effects in E. coli MC4100 cells. Nα-[Tetradecanoyl-(4-aminomethylbenzoyl)]-l-asparagine is the most effective antibacterial with a minimal inhibitory concentration of 100 ± 20 μg/ml. The compounds were shown to compete with fluorophore-labeled σ32-derived peptide for the peptide binding site of DnaK and to increase the fraction of aggregated proteins in heat-shocked bacteria. Despite its inability to serve as a folding helper in vivo a DnaK-inhibitor complex was still able to sequester an unfolded protein in vitro. Structure activity relationships revealed a distinct dependence of DnaK-assisted refolding of luciferase on the fatty acyl chain length, whereas the minimal inhibitory concentration was most sensitive to the structural nature of the benzamido core. We conclude that the isomerase activity of DnaK is a major survival factor in the heat shock response of bacteria and that small molecule inhibitors can lead to functional inactivation of DnaK and thus will display antibacterial activity.

scholarly journals In VitroPharmacodynamics of Vancomycin and Cefazolin Alone and in Combination against Methicillin-Resistant Staphylococcus aureus

2011 ◽  
Vol 56 (1) ◽  
pp. 202-207 ◽  
Author(s):  
Mao Hagihara ◽  
Dora E. Wiskirchen ◽  
Joseph L. Kuti ◽  
David P. Nicolau
Keyword(s):  
Staphylococcus Aureus ◽  
Combination Therapy ◽  
Synergistic Effects ◽  
Bacterial Density ◽  
Bacterial Killing ◽  
Methicillin Resistant ◽  
Content Type ◽  
Vancomycin Mics ◽  
Time Kill

ABSTRACTPrevious studies employing time-kill methods have observed synergistic effects against methicillin-resistantStaphylococcus aureus(MRSA) when a β-lactam is combined with vancomycin. However, these time-kill studies have neglected the importance of human-simulated exposures. We evaluated the effect of human simulated exposures of vancomycin at 1 g every 8 h (q8h) in combination with cefazolin at 1 g q8h against various MRSA isolates. Four clinical isolates (two MRSA isolates [vancomycin MICs, 0.5 and 2.0 μg/ml], a heterogeneous vancomycin-intermediateS. aureus[hVISA] isolate [MIC, 2.0 μg/ml], and a vancomycin-intermediateS. aureus[VISA] isolate [MIC, 8.0 μg/ml]) were evaluated in anin vitropharmacodynamic model with a starting inoculum of 106or 108CFU/ml. Bacterial density was measured over 48 to 72 h. Time-kill curves were constructed, and the area under the bacterial killing and regrowth curve (AUBC) was calculated. During 106CFU/ml studies, combination therapy achieved greater log10CFU/ml changes than vancomycin alone at 12 h (−4.31 ± 0.58 versus −2.80 ± 0.59,P< 0.001), but not at 48 h. Combination therapy significantly reduced the AUBC from 0 to 48 h (122 ± 14) compared with vancomycin alone (148 ± 22,P= 0.017). Similar results were observed during 108CFU/ml studies, where combination therapy achieved greater log10CFU/ml changes at 12 h than vancomycin alone (−4.00 ± 0.20 versus −1.10 ± 0.04,P< 0.001) and significantly reduced the AUBC (275 ± 30 versus 429 ± 37,P< 0.001) after 72 h of incubation. In this study, the combination of vancomycin and cefazolin at human-simulated exposures improved the rate of kill against these MRSA isolates and resulted in greater overall antibacterial effect, but no differences in bacterial density were observed by the end of the experiments.

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