scholarly journals In Vivo Activities of Evernimicin (SCH 27899) against Vancomycin-Susceptible and Vancomycin-Resistant Enterococci in Experimental Endocarditis

2000 ◽  
Vol 44 (10) ◽  
pp. 2733-2739 ◽  
Author(s):  
Maria Souli ◽  
Claudie Thauvin-Eliopoulos ◽  
George M. Eliopoulos
Keyword(s):  
Continuous Infusion ◽  
Once Daily ◽  
Treatment Groups ◽  
Final Density ◽  
Vancomycin Resistant Enterococci ◽  
Potential Efficacy ◽  
Vancomycin Resistant ◽  
To Receive

ABSTRACT To assess the potential efficacy of evernimicin (SCH 27899) against serious enterococcal infections, we used a rat model of aortic valve endocarditis established with either a vancomycin-susceptibleEnterococcus faecalis or a vancomycin-resistantEnterococcus faecium strain. Animals infected with either one of the test strains were assigned to receive no treatment (controls) or 5-day therapy with one of the following regimens: evernimicin 60-mg/kg of body weight intravenous (i.v.) bolus once daily, 60-mg/kg i.v. bolus twice daily (b.i.d.), 60 mg/kg/day i.v. by continuous infusion, or 120 mg/kg/day i.v. by continuous infusion. These regimens were compared with vancomycin at 150 mg/kg/day. In animals infected with E. faecalis, evernimicin at 120 mg/kg/day by continuous infusion significantly reduced bacterial counts in vegetations (final density, 5.75 ± 3.38 log10CFU/g) compared with controls (8.51 ± 1.11 log10CFU/g). In animals infected with 0.5 ml of an 8 × 107-CFU/ml inoculum of the vancomycin-resistant E. faecium, both 60-mg/kg bolus once a day and b.i.d. dose regimens of evernimicin were very effective (viable counts, 3.45 ± 1.44 and 3.81 ± 1.98 log10 CFU/g, respectively). Vancomycin was unexpectedly active against infections induced with that inoculum. In animals infected with a 109-CFU/ml inoculum of the vancomycin-resistant E. faecium, the evernimicin 60-mg/kg i.v. bolus b.i.d. reduced viable counts in vegetations compared with controls (6.27 ± 1.63 versus 8.34 ± 0.91 log10 CFU/g; P < 0.05), whereas vancomycin was ineffective. Although resistant colonies could be selected in vitro, we were not able to identify evernimicin-resistant clones from cardiac vegetations. An unexplained observation from these experiments was the great variability in final bacterial densities within cardiac vegetations from animals in each of the evernimicin treatment groups.

scholarly journals In Vitro and In Vivo Activities of DA-7867, a New Oxazolidinone, against Aerobic Gram-Positive Bacteria

2005 ◽  
Vol 49 (6) ◽  
pp. 2498-2500 ◽  
Author(s):  
Eun Jeong Yoon ◽  
Yeong Woo Jo ◽  
Sung Hak Choi ◽  
Tae Ho Lee ◽  
Jae Keol Rhee ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Streptococcus Pneumoniae ◽  
Gram Positive ◽  
Methicillin Resistant ◽  
Gram Positive Bacteria ◽  
Vancomycin Resistant Enterococci ◽  
Infection Models ◽  
Vancomycin Resistant

ABSTRACT In vitro and in vivo activities of DA-7867 were assessed against methicillin-resistant Staphylococcus aureus, vancomycin-resistant enterococci, and penicillin-resistant Streptococcus pneumoniae. All isolates were inhibited by DA-7867 at ≤0.78 μg/ml, a four-times-lower concentration than that of inhibition by linezolid. For murine infection models, DA-7867 also exhibited greater efficacy than linezolid against all isolates tested.

scholarly journals Repurposing of the Fasciolicide Triclabendazole to Treat Infections Caused by Staphylococcus spp. and Vancomycin-Resistant Enterococci

2021 ◽  
Vol 9 (8) ◽  
pp. 1697
Author(s):  
Hongfei Pi ◽  
Abiodun D. Ogunniyi ◽  
Bhumi Savaliya ◽  
Hang Thi Nguyen ◽  
Stephen W. Page ◽  
...  
Keyword(s):  
Fasciola Hepatica ◽  
Bacterial Pathogens ◽  
Oral Treatment ◽  
Polymyxin B ◽  
Gram Negative Bacteria ◽  
Gram Negative ◽  
Vancomycin Resistant Enterococci ◽  
Vancomycin Resistant

One approach to combat the increasing incidence of multidrug-resistant (MDR) bacterial pathogens involves repurposing existing compounds with known safety and development pathways as new antibacterial classes with potentially novel mechanisms of action. Here, triclabendazole (TCBZ), a drug originally developed to treat Fasciola hepatica (liver fluke) in sheep and cattle, and later in humans, was evaluated as an antibacterial alone or in combination with sub-inhibitory concentrations of polymyxin B (PMB) against clinical isolates and reference strains of key Gram-positive and Gram-negative bacteria. We show for the first time that in vitro, TCBZ selectively kills methicillin-sensitive and methicillin-resistant Staphylococcus aureus and Staphylococcus pseudintermedius at a minimum inhibitory concentration (MIC) range of 2–4 µg/mL, and vancomycin-resistant enterococci at a MIC range of 4–8 µg/mL. TCBZ also inhibited key Gram-negative bacteria in the presence of sub-inhibitory concentrations of PMB, returning MIC90 values of 1 µg/mL for Escherichia coli, 8 µg/mL for Klebsiella pneumoniae, 2 µg/mL for Acinetobacter baumannii and 4 µg/mL for Pseudomonasaeruginosa. Interestingly, TCBZ was found to be bacteriostatic against intracellular S. aureus but bactericidal against intracellular S. pseudintermedius. Additionally, TCBZ’s favourable pharmacokinetic (PK) and pharmacodynamic (PD) profile was further explored by in vivo safety and efficacy studies using a bioluminescent mouse model of S. aureus sepsis. We show that repeated four-hourly oral treatment of mice with 50 mg/kg TCBZ after systemic S. aureus challenge resulted in a significant reduction in S. aureus populations in the blood to 18 h post-infection (compared to untreated mice) but did not clear the bacterial infection from the bloodstream, consistent with in vivo bacteriostatic activity. These results indicate that additional pharmaceutical development of TCBZ may enhance its PK/PD, allowing it to be an appropriate candidate for the treatment of serious MDR bacterial pathogens.

scholarly journals In vivo activity of human-simulated regimens of imipenem alone and in combination with relebactam against Pseudomonas aeruginosa in the murine thigh infection model

2020 ◽  
Author(s):  
Sergio Reyes ◽  
Kamilia Abdelraouf ◽  
David P Nicolau
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Clinical Utility ◽  
Infection Model ◽  
Treatment Groups ◽  
Log Reduction ◽  
Wide Range ◽  
To Receive ◽  
Inhibitor Combination

Abstract Background Imipenem/relebactam is a carbapenem/β-lactamase inhibitor combination with in vitro activity against Pseudomonas aeruginosa and Enterobacterales, including KPC producers. Objectives To provide translational data to support the clinical utility of the imipenem/relebactam 500/250 mg q6h regimen using a human-simulated regimen (HSR) of imipenem/relebactam, compared with imipenem alone, against a phenotypically and genotypically diverse population of P. aeruginosa. Methods Twenty-nine P. aeruginosa isolates, including KPC (n = 6), PDC (n = 9), PAO (n = 4), GES (n = 5) and VIM (n = 1) producers, were used for the in vivo efficacy studies. Neutropenic mice were thigh-inoculated and randomized to receive HSRs of either imipenem 500 mg q6h, imipenem 1 g q8h, imipenem/relebactam 500/250 mg q6h or saline. Results Twenty-seven of the 29 isolates examined were imipenem resistant, with 24/29 isolates showing imipenem MICs of ≥32 mg/L. The addition of relebactam decreased the MICs up to 64-fold; imipenem/relebactam MICs ranged from 0.25 to &gt;32 mg/L. Efficacies of the imipenem monotherapies and the imipenem/relebactam therapy were comparable for the two imipenem-susceptible organisms. Among the imipenem-resistant isolates, an increased mean growth was observed in the imipenem 500 mg q6h HSR and 1 g q8h HSR treatment groups of 1.31 ± 1.01 and 0.18 ± 1.67 log10 cfu/thigh, respectively. In contrast, a ≥2 log reduction in bacterial density was observed in 27/29 (93%) of the imipenem-resistant isolates subjected to imipenem/relebactam 500/250 mg q6h HSR. Conclusions The imipenem/relebactam 500/250 mg q6h HSR demonstrated superior in vivo activity compared with the conventionally employed imipenem regimens against MDR P. aeruginosa over a wide range of imipenem/relebactam MICs.

The Novel Potent Pan-Deacetylase (DAC) Inhibitor, Panobinostat (LBH589), Markedly Enhances the Anti-Myeloma Effects of Chemotherapy In Vitro and In Vivo.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2520-2520
Author(s):  
Richard A. Campbell ◽  
Eric Sanchez ◽  
Jeffrey Steinberg ◽  
Michael Share ◽  
Joseph Wang ◽  
...  
Keyword(s):  
Tumor Cell ◽  
Cell Lines ◽  
Low Dose ◽  
Liposomal Doxorubicin ◽  
Single Agent ◽  
Mouse Serum ◽  
Once Daily ◽  
Treatment Groups

Abstract Deacetylase (DAC) inhibitors represent a new class of anti-cancer therapeutics that inhibit DAC enzymes and have been shown to have multiple effects in tumor cell lines including decreased oncoprotein expression (Bcr-Abl, HER-2), decreased angiogenesis, induction of apoptosis, induction of cell-cycle arrest, and decreased tumor cell motility and invasion. Panobinostat (LBH589), a novel cinnamic hydroxamic acid analogue with potent histone DAC inhibitor activity, has recently been shown to have the potential to treat a wide range of solid and hematological malignancies including multiple myeloma (MM). In this study, we first evaluated the in vitro anti-MM effects of panobinostat alone and in combination with doxorubicin or melphalan using the MM cell lines RPMI8226, U266 and MM1S. Cells treated with the combinations of panobinostat + doxorubicin and panobinostat + melphalan showed marked synergistic anti-MM effects as determined by measuring proliferation with the MTS assay compared to treatment with single agent and untreated cells. Next, we evaluated the anti-MM effects of panobinostat alone and in these combinations in vivo using one of our SCID-hu mouse models of human MM, LAGλ-1. Each SCID mouse was implanted with a 2.0 - 4.0 mm3 LAGλ-1 into the left superficial gluteal muscle. In our panobinostat single agent study, tumors were allowed to grow for 7 days at which time human IgG levels were detectable in the mouse serum, and mice were blindly assigned into panobinostat treatment groups. Panobinostat was administered via intraperitoneal (i.p.) injection once daily five times per week at 5, 10 and 20 mg/kg. Control mice were given sterile normal saline as vehicle. Mice receiving panobinostat showed marked inhibition of tumor growth (10 mg/kg, P &lt; 0.003; 20 mg/kg, P &lt; 0.009) and reduction of paraprotein levels (10 mg/kg, P &lt; 0.0025; 20 mg/kg, P &lt; 0.015) compared to mice receiving vehicle. Next, we evaluated the combination of low-dose panobinostat (5 mg/kg) with low doses of either liposomal doxorubicin (1 mg/kg) or melphalan (3 mg/kg) i.p. in mice bearing LAGλ-1. Tumors were allowed to grow for 10 days at which time human IgG levels were detectable in the mouse serum, and mice were blindly assigned into treatment groups. Panobinostat was administered as above, and liposomal doxorubicin was injected once daily for three consecutive days weekly and melphalan once weekly. Mice treated with the combination of panobinostat + liposomal doxorubicin showed markedly smaller tumors and reduced hIgG levels compared to treatment with the DAC inhibitor alone, and treatment with liposomal doxorubicin as a single agent produced no anti-MM effects. Mice bearing LAGλ-1 treated with the combination of low-dose panobinostat + low-dose melphalan also showed markedly smaller tumors and decreased hIgG levels compared to treatment with panobinostat alone whereas mice receiving melphalan alone showed similar results to vehicle-treated animals. These promising results support the further clinical development of panobinostat and suggest that combining this DAC inhibitor with low-dose chemotherapy (liposomal doxorubicin or melphalan) may enhance the efficacy of this novel agent for the treatment of MM patients.

scholarly journals Pharmacodynamics of Telavancin (TD-6424), a Novel Bactericidal Agent, against Gram-Positive Bacteria

2004 ◽  
Vol 48 (8) ◽  
pp. 3043-3050 ◽  
Author(s):  
Sharath S. Hegde ◽  
Noe Reyes ◽  
Tania Wiens ◽  
Nicole Vanasse ◽  
Robert Skinner ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Gram Positive ◽  
Time Curve ◽  
Once Daily ◽  
Gram Positive Bacteria ◽  
Resistant Strains ◽  
Vancomycin Resistant ◽  
Dose Dependent

ABSTRACT Telavancin (TD-6424) is a novel lipoglycopeptide that produces rapid and concentration-dependent killing of clinically relevant gram-positive organisms in vitro. The present studies evaluated the in vivo pharmacodynamics of telavancin in the mouse neutropenic thigh (MNT) and mouse subcutaneous infection (MSI) animal models. Pharmacokinetic-pharmacodynamic studies in the MNT model demonstrated that the 24-h area under the concentration-time curve (AUC)/MIC ratio was the best predictor of efficacy. Telavancin produced dose-dependent reduction of thigh titers of several organisms, including methicillin-susceptible Staphylococcus aureus (MSSA) and methicillin-resistant Staphylococcus aureus (MRSA), penicillin-susceptible and -resistant strains of Streptococcus pneumoniae, and vancomycin-resistant Enterococcus faecalis. The 50% effective dose (ED50) estimates for telavancin ranged from 0.5 to 6.6 mg/kg of body weight (administered intravenously), and titers were reduced by up to 3 log10 CFU/g from pretreatment values. Against MRSA ATCC 33591, telavancin was 4- and 30-fold more potent (on an ED50 basis) than vancomycin and linezolid, respectively. Against MSSA ATCC 13709, telavancin was 16- and 40-fold more potent than vancomycin and nafcillin, respectively. Telavancin, vancomycin, and linezolid were all efficacious and more potent against MRSA ATCC 33591 in the MSI model compared to the MNT model. This deviation in potency was, however, disproportionately greater for vancomycin and linezolid than for telavancin, suggesting that activity of telavancin is less affected by the immune status. The findings of these studies collectively suggest that once-daily dosing of telavancin may provide an effective approach for the treatment of clinically relevant infections with gram-positive organisms.

scholarly journals Comparative in vitro activities of trovafloxacin (CP-99,219) against 445 gram-positive isolates from patients with endocarditis and those with other bloodstream infections.

1997 ◽  
Vol 41 (5) ◽  
pp. 1146-1149 ◽  
Author(s):  
H P Endtz ◽  
J W Mouton ◽  
J G den Hollander ◽  
N van den Braak ◽  
H A Verbrugh
Keyword(s):  
Antimicrobial Agents ◽  
Rank Order ◽  
Bloodstream Infections ◽  
In Vivo Studies ◽  
Gram Positive ◽  
Vancomycin Resistant Enterococci ◽  
Vancomycin Resistant ◽  
Viridans Group Streptococci

The in vitro activity of trovafloxacin (CP-99,219), a new fluoroquinolone, was compared with the in vitro activities of other commonly used quinolones and other antimicrobial agents against 445 gram-positive microorganisms isolated between 1986 and 1995 from patients with endocarditis and those with other bloodstream infections. The MICs at which 90% of the isolates are inhibited (MIC90) of trovafloxacin for methicillin-susceptible staphylococci, viridans group streptococci, and enterococci were 0.06, 0.25, and 0.5 mg/liter, respectively. The MIC90 of trovafloxacin for vancomycin-resistant enterococci as well as for methicillin-resistant Staphylococcus aureus and methicillin-susceptible and ciprofloxacin-resistant S. aureus, isolated from sources other than blood, was 1 mg/liter. For the quinolones the rank order of activity was trovafloxacin > sparfloxacin > ciprofloxacin = ofloxacin > pefloxacin. Depending on the species tested, trovafloxacin was 4- to 64-fold more active than ciprofloxacin. Further experimental and in vivo studies are warranted to evaluate the efficacy of trovafloxacin in the treatment of bacterial endocarditis and other infections caused by gram-positive organisms.

scholarly journals In vitro and in vivo activities of the carbonic anhydrase inhibitor, dorzolamide, against vancomycin-resistant enterococci

PeerJ ◽  
2021 ◽  
Vol 9 ◽  
pp. e11059
Author(s):  
Nader S. Abutaleb ◽  
Ahmed E.M. Elhassanny ◽  
Daniel P. Flaherty ◽  
Mohamed N. Seleem
Keyword(s):  
Carbonic Anhydrase ◽  
Bacterial Resistance ◽  
Additive Interaction ◽  
Drug Of Choice ◽  
Vancomycin Resistant Enterococci ◽  
Promising Treatment ◽  
Vancomycin Resistant ◽  
Healthcare Associated

Vancomycin-resistant enterococci (VRE) are a serious public health threat and a leading cause of healthcare-associated infections. Bacterial resistance to antibiotics recommended for the treatment of enterococcal infections complicates the management of these infections. Hence, there is a critical need for the discovery of new anti-VRE agents. We previously reported carbonic anhydrase inhibitors (CAIs) as new potent VRE inhibitors. In the present study, the activity of the CAI, dorzolamide was evaluated against VRE both in vitro and in vivo. Dorzolamide exhibited potent activity against a panel of clinical VRE isolates, with minimum inhibitory concentration (MIC) values ranging from 1 µg/mL to 8 µg/mL. A killing kinetics experiment determined that dorzolamide exhibited a bacteriostatic effect against VRE, which was similar to the drug of choice (linezolid). Dorzolamide interacted synergistically with gentamicin against four strains of VRE, and exhibited an additive interaction with gentamicin against six VRE strains, reducing gentamicin’s MIC by several folds. Moreover, dorzolamide outperformed linezolid in an in vivo VRE colonization reduction mouse model. Dorzolamide significantly reduced the VRE burden in fecal samples of mice by 2.9-log10 (99.9%) and 3.86-log10 (99.99%) after 3 and 5 days of treatment, respectively. Furthermore, dorzolamide reduced the VRE count in the cecal (1.74-log10 (98.2%) reduction) and ileal contents (1.5-log10 (96.3%)) of mice, which was superior to linezolid. Collectively, these results indicate that dorzolamide represents a promising treatment option that warrants consideration as a supplement to current therapeutics used for VRE infections.

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