scholarly journals Repurposing of the Tamoxifen Metabolites to Combat Infections by Multidrug-Resistant Gram-Negative Bacilli

Antibiotics ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 336
Author(s):  
Andrea Miró-Canturri ◽  
Rafael Ayerbe-Algaba ◽  
Andrea Vila-Domínguez ◽  
Manuel E. Jiménez-Mejías ◽  
Jerónimo Pachón ◽  
...  
Keyword(s):  
Outer Membrane Proteins ◽  
Bacterial Load ◽  
Drug Repurposing ◽  
Multidrug Resistant ◽  
E Coli ◽  
Immune System Cell ◽  
Tamoxifen Metabolites ◽  
Potential Alternative ◽  
Immunocompetent Mice ◽  
Time Kill

The development of new strategic antimicrobial therapeutic approaches, such as drug repurposing, has become an urgent need. Previously, we reported that tamoxifen presents therapeutic efficacy against multidrug-resistant (MDR) Acinetobacter baumannii, Pseudomonas aeruginosa, and Escherichia coli in experimental infection models by modulating innate immune system cell traffic. The main objective of this study was to analyze the activity of N-desmethyltamoxifen, 4-hydroxytamoxifen, and endoxifen, three major metabolites of tamoxifen, against these pathogens. We showed that immunosuppressed mice infected with A. baumannii, P. aeruginosa, or E. coli in peritoneal sepsis models and treated with tamoxifen at 80 mg/kg/d for three days still reduced the bacterial load in tissues and blood. Moreover, it increased mice survival to 66.7% (for A. baumannii and E. coli) and 16.7% (for P. aeruginosa) when compared with immunocompetent mice. Further, susceptibility and time-kill assays showed that N-desmethyltamoxifen, 4-hydroxytamoxifen, and endoxifen exhibited minimum inhibitory concentration of the 90% of the isolates (MIC90) values of 16 mg/L, and were bactericidal against clinical isolates of A. baumannii and E. coli. This antimicrobial activity of tamoxifen metabolites paralleled an increased membrane permeability of A. baumannii and E. coli without affecting their outer membrane proteins profiles. Together, these data showed that tamoxifen metabolites presented antibacterial activity against MDR A. baumannii and E. coli, and may be a potential alternative for the treatment of infections caused by these two pathogens.

scholarly journals Pharmacokinetics and Time-Kill Study of Inhaled Antipseudomonal Bacteriophage Therapy in Mice

2020 ◽  
Vol 65 (1) ◽  
pp. e01470-20
Author(s):  
Michael Y. T. Chow ◽  
Rachel Yoon Kyung Chang ◽  
Mengyu Li ◽  
Yuncheng Wang ◽  
Yu Lin ◽  
...  
Keyword(s):  
Pulmonary Delivery ◽  
Lavage Fluid ◽  
Treated Group ◽  
Multidrug Resistant ◽  
Bacteriophage Therapy ◽  
Content Type ◽  
Optimal Dosing ◽  
Potential Alternative ◽  
Time Kill

ABSTRACTInhaled bacteriophage (phage) therapy is a potential alternative to conventional antibiotic therapy to combat multidrug-resistant (MDR) Pseudomonas aeruginosa infections. However, pharmacokinetics (PK) and pharmacodynamics (PD) of phages are fundamentally different from antibiotics and the lack of understanding potentially limits optimal dosing. The aim of this study was to investigate the in vivo PK and PD profiles of antipseudomonal phage PEV31 delivered by pulmonary route in immune-suppressed mice. BALB/c mice were administered phage PEV31 at doses of 107 and 109 PFU by the intratracheal route. Mice (n = 4) were sacrificed at 0, 1, 2, 4, 8, and 24 h posttreatment and various tissues (lungs, kidney, spleen, and liver), bronchoalveolar lavage fluid, and blood were collected for phage quantification. In a separate study combining phage with bacteria, mice (n = 4) were treated with PEV31 (109 PFU) or phosphate-buffered saline (PBS) at 2 h postinoculation with MDR P. aeruginosa. Infective PEV31 and bacteria were enumerated from the lungs. In the phage-only study, the PEV31 titer gradually decreased in the lungs over 24 h, with a half-life of approximately 8 h for both doses. In the presence of bacteria, in contrast, the PEV31 titer increased by almost 2-log10 in the lungs at 16 h. Furthermore, bacterial growth was suppressed in the PEV31-treated group, while the PBS-treated group showed exponential growth. Of the 10 colonies tested, four phage-resistant isolates were observed from the lung homogenates sampled at 24 h after phage treatment. These colonies had a different antibiogram to the parent bacteria. This study provides evidence that pulmonary delivery of phage PEV31 in mice can reduce the MDR bacterial burden.

scholarly journals Potential Tamoxifen Repurposing to Combat Infections by Multidrug-Resistant Gram-Negative Bacilli

2021 ◽  
Vol 14 (6) ◽  
pp. 507
Author(s):  
Andrea Miró-Canturri ◽  
Rafael Ayerbe-Algaba ◽  
Raquel del Toro ◽  
Manuel Enrique-Jiménez Mejías ◽  
Jerónimo Pachón ◽  
...  
Keyword(s):  
Bacterial Load ◽  
Multidrug Resistant ◽  
Experimental Models ◽  
Resistant Bacteria ◽  
Gram Negative ◽  
Inflammatory Monocytes ◽  
Chemotactic Protein ◽  
Extracellular Signal ◽  
Immune System Modulation ◽  
Immunocompetent Mice

The development of new strategic therapies for multidrug-resistant bacteria, like the use of non-antimicrobial approaches and/or drugs repurposed to be used as monotherapies or in combination with clinically relevant antibiotics, has become urgent. A therapeutic alternative for infections by multidrug-resistant Gram-negative bacilli (MDR-GNB) is immune system modulation to improve the infection clearance. We showed that immunocompetent mice pretreated with tamoxifen at 80 mg/kg/d for three days and infected with Acinetobacter baumannii, Pseudomonas aeruginosa, or Escherichia coli in peritoneal sepsis models showed reduced release of the monocyte chemotactic protein-1 (MCP-1) and its signaling pathway interleukin-18 (IL-18), and phosphorylated extracellular signal-regulated kinase 1/2 (ERK1/2). This reduction of MCP-1 induced the reduction of migration of inflammatory monocytes and neutrophils from the bone marrow to the blood. Indeed, pretreatment with tamoxifen in murine peritoneal sepsis models reduced the bacterial load in tissues and blood, and increased mice survival from 0% to 60–100%. Together, these data show that tamoxifen presents therapeutic efficacy against MDR A. baumannii, P. aeruginosa, and E. coli in experimental models of infection and may be a new candidate to be repurposed as a treatment for GNB infections.

scholarly journals Efficacy of the New Lantibiotic NAI-107 in Experimental Infections Induced by Multidrug-Resistant Gram-Positive Pathogens

2011 ◽  
Vol 55 (4) ◽  
pp. 1671-1676 ◽  
Author(s):  
Daniela Jabés ◽  
Cristina Brunati ◽  
GianPaolo Candiani ◽  
Simona Riva ◽  
Gabriella Romanó ◽  
...  
Keyword(s):  
Bactericidal Activity ◽  
Bacterial Load ◽  
Severe Infection ◽  
Multidrug Resistant ◽  
Minimal Bactericidal Concentration ◽  
Gram Positive ◽  
Immunocompetent Mice ◽  
Dose Proportional

ABSTRACTNAI-107 is a novel lantibiotic active against Gram-positive bacteria, including methicillin-resistantStaphylococcus aureus(MRSA), glycopeptide-intermediateS. aureus(GISA), and vancomycin-resistant enterococci (VRE). The aim of this study was to evaluate thein vivoefficacy of NAI-107 in animal models of severe infection. In acute lethal infections induced with a penicillin-intermediateStreptococcus pneumoniaestrain in immunocompetent mice, or with MRSA, GISA, and VRE strains in neutropenic mice, the 50% effective dose (ED50) values of NAI-107 were comparable or lower than those of reference compounds, irrespective of the strain and immune status (0.51 to 14.2 mg/kg of body weight for intravenous [i.v.] NAI-107, 5.1 to 22.4 for oral linezolid, and 22.4 for subcutaneous [s.c.] vancomycin). Inthe granuloma pouch model induced in rats with a MRSA strain, intravenous NAI-107 showed a dose-proportional bactericidal activity that, at a single 40-mg/kg dose, compared with 2 20-mg/kg doses at a 12-h or 24-h interval, caused a 3-log10-CFU/ml reduction of viable MRSA in exudates that persisted for more than 72 h. Rat endocarditis was induced with a MRSA strain and treated for five consecutive days. In a first experiment, using 5, 10, or 20 mg/kg/day, and in a second experiment, when 10 mg/kg at 12-h intervals was compared to 20 mg/kg/day, intravenous NAI-107 was effective in reducing the bacterial load in heart vegetations in a dose-proportional manner. Trough plasma levels, as determined on days 2 and 5, were several times higher than the NAI-107 minimal bactericidal concentration (MBC). NAI-107 binding to rat and human serum ranges between 93% and 98.6%. The rapid bactericidal activity of NAI-107 observedin vitrowas thus confirmed by the efficacy in several models of experimental infection induced by Gram-positive pathogens, supporting further investigation of the compound.

scholarly journals In Vitro Activity of Ceftaroline Alone and in Combination against Clinical Isolates of Resistant Gram-Negative Pathogens, Including β-Lactamase-Producing Enterobacteriaceae and Pseudomonas aeruginosa

2009 ◽  
Vol 53 (6) ◽  
pp. 2360-2366 ◽  
Author(s):  
Céline Vidaillac ◽  
Steve N. Leonard ◽  
Helio S. Sader ◽  
Ronald N. Jones ◽  
Michael J. Rybak
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Therapeutic Option ◽  
Multidrug Resistant ◽  
Vitro Activity ◽  
In Vitro Activity ◽  
Clinical Value ◽  
Gram Negative ◽  
E Coli ◽  
Time Kill

ABSTRACT Ceftaroline is a novel broad-spectrum cephalosporin that exhibits bactericidal activity against many gram-positive and -negative pathogens. However, the activity of ceftaroline cannot be solely relied upon for eradication of multidrug-resistant gram-negative isolates, such as Pseudomonas aeruginosa and extended-spectrum β-lactamase (ESBL)-producing Enterobacteriaceae, which represent a current clinical concern. As drug combinations might be beneficial by potential synergy, we evaluated the in vitro activity of ceftaroline combined with meropenem, aztreonam, cefepime, tazobactam, amikacin, levofloxacin, and tigecycline. Susceptibility testing was performed for 20 clinical P. aeruginosa isolates, 10 ESBL-producing Escherichia coli isolates, 10 ESBL-producing Klebsiella pneumoniae isolates, and 10 AmpC-derepressed Enterobacter cloacae isolates. Time-kill experiments were performed for 10 isolates using antimicrobials at one-fourth the MIC. Ceftaroline exhibited a MIC range of 0.125 to 1,024 μg/ml and was reduced 2- to 512-fold by combination with tazobactam (4 μg/ml) for ESBL-producing strains. In time-kill experiments, ceftaroline plus amikacin was synergistic against 90% of the isolates (and indifferent for one P. aeruginosa isolate). Ceftaroline plus tazobactam was indifferent for E. cloacae and P. aeruginosa strains but synergistic against 100% of E. coli and K. pneumoniae isolates. Combinations of ceftaroline plus meropenem or aztreonam were also synergistic for all E. coli and E. cloacae isolates, respectively, but indifferent against 90% of the other isolates. Finally, combinations of ceftaroline plus either tigecycline, levofloxacin, or cefepime were indifferent for 100% of the isolates. No antagonism was observed with any combination. Ceftaroline plus amikacin appeared as the most likely synergistic combination. This represents a promising therapeutic option, and further studies are warranted to elucidate the clinical value of ceftaroline combinations against resistant gram-negative pathogens.

Synergistic effect of antimicrobial peptide LL-37 and colistin combination against multidrug-resistant Escherichia coli isolates

2021 ◽  
Author(s):  
Gianluca Morroni ◽  
Laura Di Sante ◽  
Oriana Simonetti ◽  
Lucia Brescini ◽  
Wojciech Kamysz ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Synergistic Effect ◽  
Antimicrobial Peptide ◽  
Biofilm Formation ◽  
Multidrug Resistant ◽  
E Coli ◽  
Antibiotic Effect ◽  
Global Spread ◽  
Time Kill ◽  
Post Antibiotic Effect

Overview: The global spread of antibiotic resistance represents a serious threat for public health. Aim: We evaluated the efficacy of the antimicrobial peptide LL-37 as antimicrobial agent against multidrug-resistant Escherichia coli. Results: LL-37 showed good activity against mcr-1 carrying, extended spectrum β-lactamase- and carbapenemase-producing E. coli (minimum inhibitory concentration, MIC, from 16 to 64 mg/l). Checkerboard assays demonstrated synergistic effect of LL-37/colistin combination against all tested strains, further confirmed by time–kill and post antibiotic effect assays. MIC and sub-MIC concentrations of LL-37 were able to reduce biofilm formation. Conclusion: Our preliminary data indicated that LL-37/colistin combination was effective against multidrug resistant E. coli strains and suggested a new possible clinical application.

scholarly journals In Vitro Activities of Daptomycin, Vancomycin, Linezolid, and Quinupristin-Dalfopristin against Staphylococci and Enterococci, Including Vancomycin- Intermediate and -Resistant Strains

2000 ◽  
Vol 44 (4) ◽  
pp. 1062-1066 ◽  
Author(s):  
Michael J. Rybak ◽  
Ellie Hershberger ◽  
Tabitha Moldovan ◽  
Richard G. Grucz
Keyword(s):  
Multidrug Resistant ◽  
Gram Positive ◽  
Gram Positive Bacteria ◽  
Vancomycin Resistant Enterococci ◽  
Alternative Drug ◽  
Potential Alternative ◽  
Resistant Strains ◽  
Vancomycin Resistant ◽  
Time Kill

ABSTRACT The in vitro activity of daptomycin was compared with those of vancomycin, linezolid, and quinupristin-dalfopristin against a variety (n = 203) of gram-positive bacteria, including methicillin-resistant Staphylococcus aureus and S. epidermidis (MRSA and MRSE, respectively), vancomycin-resistant enterococci (VRE), and vancomycin-intermediate S. aureus(VISA). Overall, daptomycin was more active against all organisms tested, except Enterococcus faecium and VISA, against which its activity was similar to that of quinupristin-dalfopristin. In time-kill studies with MRSA, MRSE, VRE, and VISA, daptomycin demonstrated greater bactericidal activity than all other drugs tested, killing ≥3 log CFU/ml by 8 h. Daptomycin may be a potential alternative drug therapy for multidrug-resistant gram-positive organisms and warrants further investigation.

scholarly journals 1292. Evaluation of Synergy with Piperacillin/Tazobactam plus Meropenem Against Carbapenemase-Producing Klebsiella pneumoniae and Enterobacter cloacae Using ETEST

2021 ◽  
Vol 8 (Supplement_1) ◽  
pp. S735-S735
Author(s):  
Deborah S Ashcraft ◽  
Royanne H Vortisch ◽  
George A Pankey
Keyword(s):  
Treatment Options ◽  
Enterobacter Cloacae ◽  
Multidrug Resistant ◽  
Mean Value ◽  
In Vivo Studies ◽  
Healthcare Facilities ◽  
E Coli ◽  
Carbapenem Resistant ◽  
Time Kill

Abstract Background Carbapenem-resistant Enterobacterales are considered an urgent threat for patients in healthcare facilities, causing infections with significant morbidity and mortality. Most isolates are multidrug resistant with limited treatment options, so combination therapy is an alternative. Recently, synergy with piperacillin/tazobactam (P/T) + meropenem (MP) was demonstrated against 7/10 (70%) KPC-producing Escherichia coli and 9/10 (90%) OXA-48-producing K. pneumoniae using time-kill assay (Lawandi et al, 2021). The aim of the present study was to further evaluate the combination of P/T + MP against KPC-producing Enterobacter cloacae, in addition to OXA-producing K. pneumoniae using our rapid ETEST MIC:MIC synergy method. Methods 14 carbapenemase-producing isolates: 7 OXA-48-like K. pneumoniae (1 OXA-48, 4 OXA-181, 2 OXA-232) and 7 KPC-producing E. cloacae (1 KPC-2, 4 KPC-3, 1 KPC-4, 1 KPC-6) were obtained from the CDC and FDA Antibiotic Resistance Isolate Bank. ETEST MICs for P/T and MP and our ETEST synergy method were performed in triplicate for each isolate. The summation fractional inhibitory concentration was calculated, and the mean value was interpreted as: < 0.5 synergy; > 0.5-1 additivity; > 1-4 indifference; and > 4 antagonism. Results MICs (µg/mL) ranged: MP, 0.5 to > 32 (14% susceptible) and P/T, 96/4 to > 256/4 (all resistant). The combination of P/T + MP showed synergy (3) or additivity (2) against 5/7 (71%) OXA-producing K. pneumoniae and synergy (6) or additivity (1) against all 7 KPC-producing E. cloacae. No antagonism was detected. Conclusion Using our ETEST MIC:MIC method, the combination of P/T + MP demonstrated synergy or additivity in 5/7 OXA-producing K. pneumoniae and 7/7 KPC-producing E. cloacae, similar to previously published findings showing synergy in 7/10 KPC-producing E. coli and 9/10 OXA-48-producing K. pneumoniae using time-kill assay. Our ETEST synergy method is simple to use and should be evaluated more extensively. Regardless of the method used, results may or may not correlate in an in vivo setting. In vivo studies are needed. Disclosures All Authors: No reported disclosures

scholarly journals Repurposing of the tamoxifen metabolites to treat methicillin-resistant Staphylococcus epidermidis and vancomycin-resistant Enterococcus faecalis infections

2021 ◽  
Author(s):  
Andrea Miró Canturri ◽  
Andrea Vila-Domínguez ◽  
Rafael Ayerbe Algaba ◽  
Jerónimo Pachón ◽  
Manuel Enrique Jiménez-Mejías ◽  
...  
Keyword(s):  
Membrane Permeability ◽  
Bactericidal Activity ◽  
Staphylococcus Epidermidis ◽  
Multidrug Resistant ◽  
New Approach ◽  
Methicillin Resistant ◽  
Tamoxifen Metabolites ◽  
Vancomycin Resistant ◽  
Kill Curve ◽  
Time Kill

Repurposing drugs provides a new approach to the fight against multidrug-resistant (MDR) bacteria. We have reported that three major tamoxifen metabolites, N-desmethyltamoxifen (DTAM), 4-hydroxytamoxifen (HTAM) and endoxifen (ENDX), presented bactericidal activity against Acinetobacter baumannii and Escherichia coli. Here, we aimed to analyse the activity of a mixture of the three tamoxifen metabolites against methicillin-resistant Staphylococcus epidermidis (MRSE) and Enterococcus spp. MRSE (n=17) and Enterococcus spp. (E. faecalis n=8, and E. faecium n=10) strains were used. MIC of the mixture of DTAM, HTAM and ENDX, and vancomycin were determined by microdilution assay. The bactericidal activity of the three metabolites together and vancomycin against MRSE (SE385 and SE742) and vancomycin-resistant E. faecalis (EVR1 and EVR2) strains was determined by time-kill curve assays. Finally, changes in membrane permeability of SE742 and EVR1 strains were analyzed using fluorescence assays. MIC50 and MIC90 of tamoxifen metabolites were 1 mg/L for MRSE strains and 2 mg/L for Enterococcus spp. strains. In the time-killing assays, tamoxifen metabolites mixture showed bactericidal activity at 2x and 4xMIC for MRSE (SE385 and SE742) and E. faecalis (EVR1 and EVR2) strains. This antimicrobial activity of tamoxifen metabolites paralleled an increased membrane permeability of SE385 and EVR2 strains. Altogether, these results showed that tamoxifen metabolites presented antibacterial activity against MRSE and vancomycin-resistant E. faecalis, suggesting that tamoxifen metabolites might increase the arsenal of drugs treatment against these bacterial pathogens.

scholarly journals Lipid Nanoparticles Loaded with Farnesol or Geraniol to Enhance the Susceptibility of E. coli MCR-1 to Colistin

Pharmaceutics ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 1849
Author(s):  
Chantal Valcourt ◽  
Julien M. Buyck ◽  
Nicolas Grégoire ◽  
William Couet ◽  
Sandrine Marchand ◽  
...  
Keyword(s):  
Bactericidal Effect ◽  
Multidrug Resistant ◽  
Lipid Nanoparticles ◽  
Inner Membrane ◽  
E Coli ◽  
Water Dispersible ◽  
Human Red Blood Cells ◽  
Development Of Resistance ◽  
Terpene Alcohols ◽  
Time Kill

Resistance to colistin, one of the antibiotics of last resort against multidrug-resistant Gram-negative bacteria, is increasingly reported. Notably, MCR plasmids discovered in 2015 have now been reported worldwide in humans. To keep this antibiotic of last resort efficient, a way to tackle this mechanism seems essential. Terpene alcohols such as farnesol have been shown to improve the efficacy of some antibiotics. However, their high lipophilicity makes them difficult to use. This problem can be solved by encapsulating them in water-dispersible lipid nanoparticles (LNPs). The aim of this study was to discover, using checkerboard tests and time-kill curve experiments, an association between colistin and farnesol or geraniol loaded in LNPs, which would improve the efficacy of colistin against E. coli and, in particular, MCR-1 transconjugants. Then, the effect of the combination on E. coli inner membrane permeabilisation was evaluated using propidium iodide (PI) uptake and compared to human red blood cells plasma membrane permeabilisation. Both terpene alcohols were able to restore the susceptibility of E. coli J53 MCR-1 to colistin with the same efficacy (Emax = 16, i.e., colistin MIC was decreased from 8 to 0.5 mg/L). However, with an EC50 of 2.69 mg/L, farnesol was more potent than geraniol (EC50 = 39.49 mg/L). Time-kill studies showed a bactericidal effect on MCR-1 transconjugant 6 h after incubation, with no regrowth up to 30 h in the presence of 1 mg/L colistin (1/8 MIC) and 60 mg/L or 200 mg/L farnesol or geraniol, respectively. Colistin alone was more potent in increasing PI uptake rate in the susceptible strain (EC50 = 0.86 ± 0.08 mg/L) than in the MCR-1 one (EC50 = 7.38 ± 0.85 mg/L). Against the MCR-1 strain, farnesol-loaded LNP at 60 mg/L enhanced the colistin-induced inner membrane permeabilization effect up to 5-fold and also increased its potency as shown by the decrease in its EC50 from 7.38 ± 0.85 mg/L to 2.69 ± 0.25 mg/L. Importantly, no hemolysis was observed for LNPs loaded with farnesol or geraniol, alone or in combination with colistin, at the concentrations showing the maximum decrease in colistin MICs. The results presented here indicate that farnesol-loaded LNPs should be studied as combination therapy with colistin to prevent the development of resistance to this antibiotic of last resort.

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