scholarly journals Efficacy of Omadacycline Against Multiresistant Enterococcus faecium Strains in a Mouse Peritonitis Model

2021 ◽  
Author(s):  
Kavindra V. Singh ◽  
Cesar A. Arias ◽  
Barbara E. Murray
Keyword(s):  
Enterococcus Faecium ◽  
Animal Survival ◽  
Peritonitis Model

Omadacycline (OMC) showed better in vitro potency than daptomycin (DAP) or vancomycin (VAN) against Van R , AMP R , DAP non-susceptible, linezolid R , cfr (B) + Enterococcus faecium strains. In a mouse peritonitis model, OMC also showed significantly better animal survival during and at the end of the study than DAP or VAN against these E. faecium strains. However, OMC, DAP and VAN showed comparable in vitro and in vivo efficacy against a non-VRE, tetracycline-resistant, DAP-susceptible, E. faecium strain.

scholarly journals Co-Administration of Fendiline Hydrochloride Enhances Chemotherapeutic Efficacy of Cisplatin in Neuroblastoma Treatment

Molecules ◽  
2020 ◽  
Vol 25 (22) ◽  
pp. 5234
Author(s):  
Antonella Brizzolara ◽  
Patrizia Garbati ◽  
Serena Vella ◽  
Matilde Calderoni ◽  
Alessandro Quattrone ◽  
...  
Keyword(s):  
Abc Transporters ◽  
Pharmacological Treatments ◽  
Growth Reduction ◽  
Rt Pcr ◽  
Animal Survival ◽  
Recent Treatment ◽  
In Vivo Effects ◽  
Novel Therapeutic

Despite significant improvement of neuroblastoma (NB) patients’ survival due to recent treatment advancements in recent years, NB is still associated with high mortality rate. In search of novel strategies to increase NB’s susceptibility to pharmacological treatments, we investigated the in vitro and in vivo effects of fendiline hydrochloride as an enhancer of cisplatin antitumor activity. To assess the modulation of fendiline treatment on cisplatin responses, we used in vitro (evaluating NB cell proliferation by XCELLigence technology and colony formation, and gene expression by RT-PCR) and in vivo (NB cell grafts in NOD-SCID mice) models of NB. NB cell treatment with fendiline induced the expression of the ncRNA NDM29, leading to cell differentiation and to the reduction of the expression of MDRs/ABC transporters linked to multidrug resistance. These events were correlated to higher NB cell susceptibility to cisplatin and, consequently, increased its cytotoxic potency. In vivo, this drug interaction causes an enhanced ability of cisplatin to induce apoptosis in NB masses, resulting in tumor growth reduction and prolonged animal survival rate. Thus, the administration of fendiline might be a possible novel therapeutic approach to increase cisplatin efficacy in aggressive and poorly responsive NB cases.

scholarly journals Activity of Tigecycline (GAR-936), a Novel Glycylcycline, against Enterococci in the Mouse Peritonitis Model

2003 ◽  
Vol 47 (2) ◽  
pp. 529-532 ◽  
Author(s):  
Esteban C. Nannini ◽  
Suresh R. Pai ◽  
Kavindra V. Singh ◽  
Barbara E. Murray
Keyword(s):  
Body Weight ◽  
Mouse Model ◽  
Protective Effect ◽  
Enterococcus Faecalis ◽  
Enterococcus Faecium ◽  
Tetracycline Resistance ◽  
Resistance Determinant ◽  
Subcutaneous Dose ◽  
Peritonitis Model

ABSTRACT A novel glycylcycline agent, tigecycline (GAR-936), was evaluated in vivo in the mouse model of peritonitis against three Enterococcus faecalis and four Enterococcus faecium isolates with different susceptibilities to vancomycin and tetracyclines, all of which were inhibited by ≤0.125 μg of tigecycline/ml. Using a single subcutaneous dose, tigecycline displayed a protective effect (50% protective dose, ≤5.7 mg/kg of body weight) against all strains tested, including two with Tn925 (from the Tn916 family), which contains the Tet(M) tetracycline resistance determinant, as well as VanA and VanB strains. As expected, tetracycline and minocycline were ineffective against the isolates carrying Tn925.

Activity of a novel dual PI3-kinase/mTOR inhibitor NVP-BEZ235 to enhance antitumor activities of gemcitabine and EMAP II in pancreatic cancer.

2011 ◽  
Vol 29 (4_suppl) ◽  
pp. 255-255
Author(s):  
N. Awasthi ◽  
P. L. Yen ◽  
M. A. Schwarz ◽  
R. Schwarz
Keyword(s):  
Pancreatic Cancer ◽  
Cell Proliferation ◽  
Antitumor Activity ◽  
Combination Therapy ◽  
Mtor Inhibitor ◽  
Single Agent ◽  
Percent Inhibition ◽  
Animal Survival

255 Background: Gemcitabine (Gem, G) has limited benefits as single agent or in combination for pancreatic ductal adenocarcinomas (PDACs). The phosphatidylinositol-3-kinase (PI3K)/AKT and mammalian target of rapamycin (mTOR) signaling pathways are frequently dysregulated in diverse human cancers including PDAC. NVP-BEZ235 (BEZ, B) is a novel dual PI3K/mTOR inhibitor that has been shown to have antitumor activity in multiple tumor types. Endothelial monocyte activating polypeptide II (EMAP, E) is an antiendothelial and antiangiogenic agent that enhances Gem and docetaxel activity in PDAC. We tested the combination benefits of BEZ and Gem in addition to EMAP in experimental PDAC. Methods: In vitro cell proliferation and protein expression were analyzed by WST-1 assay and Western blotting. In vivo animal survival experiments were performed in NOD-SCID PDAC xenografts. Results: Cultured cells of PDAC (AsPC-1), endothelial (HUVECs), and fibroblast origin (WI-38) all expressed AKT and mTOR protein. BEZ inhibited in vitro cell proliferation of AsPC-1 and HUVECs cells, with some additive effects in combination with Gem or EMAP, after 72 hours of incubation. In AsPC-1, treatment of BEZ (100 nM), Gem (100 nM) and EMAP (1 μM) caused 34, -7, -16, 62, 51, 3, and 59 percent inhibition in proliferation in the B, G, E, B+G, B+E, G+E and B+G+E groups. In HUVECs, percent inhibition in proliferation was 35, 33, 15, 55, 35, 31 and 53 in the B, G, E, B+G, B+E, G+E and B+G+E groups, respectively. Compared to controls (median survival: 16 days), an animal survival increase after BEZ and EMAP therapy alone (both 21 days) and Gem therapy alone (28 d) was observed. Further increases in survival occurred in combination therapy groups B+G (30 d, p=0.007), B+E (27 d, p=0.02), G+E (31 d, p=0.001) and B+G+E (33 d, p=0.004). Conclusions: Bez has experimental PDAC antitumor activity in vitro and in vivo that is further enhanced by combination of Gem and EMAP. These findings demonstrate advantages of combination therapy strategies targeting multiple pathways in pancreatic cancer treatment. No significant financial relationships to disclose.

scholarly journals Intra- and Extracellular Activities of Dicloxacillin against Staphylococcus aureus In Vivo and In Vitro

2010 ◽  
Vol 54 (6) ◽  
pp. 2391-2400 ◽  
Author(s):  
Anne Sandberg ◽  
Klaus Skovbo Jensen ◽  
Pierre Baudoux ◽  
Françoise Van Bambeke ◽  
Paul M. Tulkens ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Multiple Dosing ◽  
Time Curve ◽  
Highly Active ◽  
Intracellular Activities ◽  
Unit Reduction ◽  
Peritonitis Model ◽  
Extracellular Activity

ABSTRACT Antibiotic treatment of Staphylococcus aureus infections is often problematic due to the slow response and recurrences. The intracellular persistence of the staphylococci offers a plausible explanation for the treatment difficulties because of the impaired intracellular efficacies of the antibiotics. The intra- and extracellular time- and concentration-kill relationships were examined in vitro with THP-1 cells and in vivo by use of a mouse peritonitis model. The in vivo model was further used to estimate the most predictive pharmacokinetic/pharmacodynamic (PK/PD) indices (the ratio of the maximum concentration of drug in plasma/MIC, the ratio of the area under the concentration-time curve/MIC, or the cumulative percentage of a 24-h period that the free [f] drug concentration exceeded the MIC under steady-state pharmacokinetic conditions [fT MIC]) for dicloxacillin (DCX) intra- and extracellularly. In general, DCX was found to have similar intracellular activities, regardless of the model used. Both models showed (i) the relative maximal efficacy (1-log-unit reduction in the numbers of CFU) of DCX intracellularly and (ii) the equal relative potency of DCX intra- and extracellularly, with the MIC being a good indicator of the overall response in both situations. Discordant results, based on data obtained different times after dosing, were obtained from the two models when the extracellular activity of DCX was measured, in which the in vitro model showed a considerable reduction in the number of CFU from that in the original inoculum (3-log-unit decrease in the number of CFU after 24 h), whereas the extracellular CFU reduction achieved in vivo after 4 h did not exceed 1 log unit. Multiple dosing of DCX in vivo revealed increased extra- and intracellular efficacies (2.5 log and 2 log units of reduction in the numbers of CFU after 24 h, respectively), confirming that DCX is a highly active antistaphylococcal antibiotic. PK/PD analysis revealed that fT MIC is the index that is the most predictive of the outcome of infection both intra- and extracellularly.

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 Enhancing cytotoxic chemotherapy response through targeted BET bromodomain inhibition in preclinical pancreatic cancer models

2018 ◽  
Vol 1 (1) ◽  
Author(s):  
Sandeep Singh ◽  
Ross McCauley ◽  
Johann R. Schwarz ◽  
Roderich Schwarz ◽  
Niranjan Awasthi
Keyword(s):  
Cell Proliferation ◽  
Tumor Growth ◽  
Cytotoxic Chemotherapy ◽  
Ductal Adenocarcinoma ◽  
Chemotherapy Response ◽  
Standard Chemotherapy ◽  
Animal Survival ◽  
Bet Protein

Background and Hypothesis:   Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis and the standard of care regimen, nab-paclitaxel (NPT) plus gemcitabine (Gem), leads to a dismal 8.5 months median survival. Targeted inhibition of Bromodomain and Extra-Terminal (BET) protein is currently under investigation for several cancers. We hypothesize that BET protein pathway inhibition by iBet-762 will enhance cytotoxic chemotherapy response in PDAC.  Experimental Design:  In vitro cell proliferation assays were performed using WST-1 reagent. Protein expressions were determined by Western Blot analysis. In vivo animal survival and tumor growth experiments were performed in NOD-SCID mice.   Results:  Inhibition in cell proliferation in human PDAC cells at 1 µM concentration in NPT+Gem, iBET-762, and NPT+Gem+iBet762 was 64%, 27%, 76% in AsPC-1; 43%, 13%, 69% in Panc-1; and 42%, 51%, 75% in MIA PaCa cells. iBET-762 decreased oncogenic proteins c-Myc, [Symbol]-catenin, Vimentin, and P-AKT while apoptosis related proteins such as cleaved PARP-1 and cleaved caspase-3 and cell cycle inhibitors proteins P21 & P27 were increased. In a peritoneal dissemination model, median animal survival compared to control (21 days) was increased after therapy with NPT+Gem (33 days, a 57% increase), iBet-762 (30 days, a 43% increase) and NPT+Gem+iBET-762 (44 days, a 110% increase). Effect of iBET-762 in combination with chemotherapy on local tumor growth is currently underway.    Conclusion and Potential Impact:   These findings suggest that the effects of standard chemotherapy can be enhanced through specific inhibition of BET proteins activity, and supports the clinical application of iBET-762 in combination with standard chemotherapy in PDAC patients.

scholarly journals Αξιολόγηση της αποτελεσματικότητας της τιγεκυκλίνης σε πειραματικό μοντέλο εντεροκοκκίνης ενδοκαρδίτιδας

2013 ◽  
Author(s):  
Κωνσταντίνος Ποντίκης
Keyword(s):  
Enterococcus Faecium

Οι εντερόκοκκοι συγκαταλέγονται μεταξύ των συχνότερων αιτίων λοιμώδους ενδοκαρδίτιδας, τη στιγμή που θεραπευτικά προβλήματα ανακύπτουν από την εγγενή τους τάση να συσσωρεύουν μηχανισμούς αντοχής. Στη διδακτορική αυτή διατριβή αξιολογήθηκε η αποτελεσματικότητα της τιγεκυκλίνης, τόσο ως μονοθεραπεία, όσο και σε συνδυασμό με γενταμικίνη σε ζωικό πρότυπο ενδοκαρδίτιδας, σε κονίκλους,από στέλεχος Enterococcus faecium ανθεκτικό στη βανκομυκίνη και τη λινεζολίδη. Τα ζωικά πρότυπα στα οποία προκλήθηκε πειραματική λοιμώδης ενδοκαρδίτιδα τυχαιοποιήθηκαν σε 4 ομάδες: ομάδα ελέγχου (n=14), γενταμικίνη 6 mg/kg υποδορίως, άπαξ ημερησίως (n=15), τιγεκυκλίνη 4mg/kg ενδοφλεβίως, δις ημερησίως (n=15) και τιγεκυκλίνη σε συνδυασμό με γενταμικίνη στα προαναφερθέντα δοσολογικά σχήματα (n=15). Η διάρκεια της θεραπείας ήταν 5 ημέρες. Με σκοπό τον έλεγχο του ενδεχομένου υποτροπής της λοίμωξης μετά το τέλος της θεραπείας μελετήθηκαν άλλες δύο ομάδες, στις οποίες χορηγήθηκε τιγεκυκλίνη (n=13) ή συνδυασμός (n=12). Τα ζωικά αυτά πρότυπα θυσιάσθηκαν 5 ημέρες μετά το τέλος της αντιμικροβιακής θεραπείας. Όλα τα ζωικά πρότυπα υποβλήθηκαν σε νεκροτομή, και πραγματοποιήθηκε ποσοτική καλλιέργεια των αφαιρεθέντων εκβλαστήσεων, όπως επίσης και ιστικών τεμαχιδίων πνεύμονος, ήπατος, σπληνός και νεφρού.Η ελάχιστη ανασταλτική πυκνότητα της τιγεκυκλίνης του υπό μελέτη στελέχους ήταν 0,06 μg/ml.Χρησιμοποιώντας τη μέθοδο των καμπυλών θανάτωσης με την πάροδο του χρόνο, αναδείχθηκε η βακτηριοκτόνος της δράση. In vivo, παρατηρήθηκε στατιστικά σημαντική μείωση του βακτηριακού φορτίου των εκβλαστήσεων στα ζωικά πρότυπα που έλαβαν τιγεκυκλίνη, σε σύγκριση με την ομάδα ελέγχου και την ομάδα της γενταμικίνης (log10 cfu/g: 5,21 vs 8,02 και 8,12 αντίστοιχα, p<0.001). Η προσθήκη γενταμικίνης οδήγησε σε περαιτέρω, μη στατιστικά σημαντική, μείωση στον αριθμό των αποικιών (log10 cfu/g: 3,93,p=0.23 συγκριτικά με την ομάδα της τιγεκυκλίνης). Κανένα στέλεχος δεν ανέπτυξε in vivo αντοχή στην τιγεκυκλίνη. Ανάλογα αποτελέσματα παρατηρήθηκαν και στις ιστικές καλλιέργειες. Στις ομάδες ελέγχου υποτροπής, δεν παρατηρήθηκε αύξηση του βακτηριακού φορτίου.Συμπερασματικά, η τιγεκυκλίνη αποδείχθηκε αποτελεσματική στη μείωση του βακτηριακού φορτίου των εκβλαστήσεων και την αποστείρωση των περιφερικών ιστών, σε πειραματικό πρότυπο λοιμώδους ενδοκαρδίτιδας σε κονίκλους από στέλεχος E.faecium ανθεκτικό στη βανκομυκίνη και τη λινεζολίδη, ακόμη και πέντε ημέρες μετά τη διακοπή της θεραπείας. Δεν παρατηρήθηκε in vitro ή in vivo συνέργεια ή ανταγωνισμός με τη γενταμικίνη. Η τιγεκυκλίνη, θα μπορούσε να αποτελεί τμήμα ενός θεραπευτικούσυνδυασμού για την αντιμετώπιση της ανθρωπείου, πολυανθεκτικής, εντεροκοκκικής λοιμώδους ενδοκαρδίτιδας.

scholarly journals Intra- and Extracellular Activities of Dicloxacillin and Linezolid against a ClinicalStaphylococcus aureusStrain with a Small-Colony-Variant Phenotype in anIn VitroModel of THP-1 Macrophages and anIn VivoMouse Peritonitis Model

2011 ◽  
Vol 55 (4) ◽  
pp. 1443-1452 ◽  
Author(s):  
Anne Sandberg ◽  
Sandrine Lemaire ◽  
Françoise Van Bambeke ◽  
Paul M. Tulkens ◽  
Diarmaid Hughes ◽  
...  
Keyword(s):  
Cell Line ◽  
Recurrent Infection ◽  
Line Model ◽  
Small Colony Variant ◽  
Cell Line Model ◽  
Optimal Dosing ◽  
Small Colony ◽  
Peritonitis Model

ABSTRACTThe small-colony-variant (SCV) phenotype ofStaphylococcus aureushas been associated with difficult-to-treat infections, reduced antimicrobial susceptibility, and intracellular persistence. This study represents a detailed intra- and extracellular investigation of a clinical wild-type (WT)S. aureusstrain and its counterpart with an SCV phenotype bothin vitroandin vivo, using the THP-1 cell line model and the mouse peritonitis model, respectively. Bacteria of both phenotypes infected the mouse peritoneum intra- and extracellularly. The SCV phenotype was less virulent and showed distinct bacterial clearance, a reduced multiplication capacity, and a reduced internalization ability. However, some of the SCV-infected mice were still culture positive up to 96 h postinfection, and bacteria of this phenotype could spread to the mouse kidney and furthermore revert to the more virulent WT phenotype in both the mouse peritoneum and kidney. The SCV phenotype is therefore, despite reduced virulence, an important player inS. aureuspathogenesis. In the THP-1 cell line model, both dicloxacillin (DCX) and linezolid (LZD) reduced the intracellular inocula of bacteria of both phenotypes by approximately 1 to 1.5 log10in vitro, while DCX was considerably more effective against extracellular bacteria. In the mouse peritonitis model, DCX and LZD were also able to control both intra- and extracellular infections caused by either phenotype. Treatment with a single dose of DCX and LZD was, however, insufficient to clear the SCVs in the kidneys, and the risk of recurrent infection remained. This stresses the importance of an optimal dosing of the antibiotic when SCVs are present.

scholarly journals Broad-Spectrum β-Lactam Antibiotics for Treating Experimental Peritonitis in Mice Due to Klebsiella pneumoniae Producing the Carbapenemase OXA-48

2012 ◽  
Vol 56 (5) ◽  
pp. 2759-2760 ◽  
Author(s):  
Olivier Mimoz ◽  
Nicolas Grégoire ◽  
Laurent Poirel ◽  
Manuella Marliat ◽  
William Couet ◽  
...  
Keyword(s):  
Single Dose ◽  
Klebsiella Pneumoniae ◽  
Broad Spectrum ◽  
Content Type ◽  
Extended Spectrum ◽  
Experimental Peritonitis ◽  
Peritonitis Model

ABSTRACTA lethal peritonitis model was induced in mice with aKlebsiella pneumoniaeisolate producing the carbapenemase OXA-48. Administration of a single dose (up to 100 mg/kg) of the antibiotic piperacillin-tazobactam, imipenem-cilastatin, ertapenem, or cefotaxime had little or no impact on lethality. Ceftazidime had the highest efficacyin vivo, which mirrored itsin vitroactivity; this was not the case for carbapenems. Therefore, ceftazidime may be recommended for the treatment of infections due to OXA-48 producers if they do not coproduce an extended-spectrum β-lactamase or a plasmid-mediated AmpC cephalosporinase.

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