scholarly journals A second generation fungerp analog SCY-247, shows potent in vivo activity in a murine model of hematogenously disseminated Candida albicans

2020 ◽  
pp. AAC.01989-20
Author(s):  
Sherman Chu ◽  
Lisa Long ◽  
Thomas S McCormick ◽  
Katyna Borroto-Esoda ◽  
Stephen Barat ◽  
...  
Keyword(s):  
Survival Rate ◽  
Murine Model ◽  
Second Generation ◽  
Fungal Infections ◽  
Plasma Concentrations ◽  
Survival Rates ◽  
Multidrug Resistant ◽  
Fungal Species ◽  
First Line Therapy

Echinocandins are a first-line therapy for Candida infections through their ability to inhibit the synthesis of polymer ß-(1,3)-D-glucan. However, there has been an emergence of multidrug-resistant fungal species necessitating the development of novel antifungal agents to combat invasive fungal infections. SCY-247, a second-generation glucan synthase inhibitor of the triterpenoid class (fungerps), is currently being developed as a potential therapy option. We determined the pharmacokinetics of SCY-247 following oral (gavage) administration in mice and evaluated the efficacy of SCY-247 in a murine model of hematogenously disseminated candidiasis caused by C. albicans. Plasma concentrations of SCY-247 were measurable through the last collected time point in all dose groups. Mean concentrations of SCY-247 increased with dose levels, with concentrations of SCY-247 higher after multiple doses compared to a single dose. Treatment with SCY-247 resulted in decreased fungal burden and improvement in survival rates against C. albicans disseminated infection. Treatment with 10 mg/kg SCY-247 showed a significant reduction in CFUs compared to the untreated control (3-log decrease on average) (P=0.008). Similarly, SCY-247 40 mg/kg demonstrated a statistically significant reduction in kidney CFUs compared to untreated mice (average log CFU ± SD of 2.38 ± 2.58 vs 6.26 ± 0.51; P=0.001). Mice treated with SCY-247 at 40 mg/kg exhibited a 100% survival rate at the end of the study, contrasted with 62.5% (5 of 8) survival rate in untreated mice. The results of this investigation indicate that SCY-247 is a promising novel anti-fungal agent with activity against Candida infections.

scholarly journals Efficacy of LY303366 against Amphotericin B-Susceptible and -Resistant Aspergillus fumigatus in a Murine Model of Invasive Aspergillosis

1998 ◽  
Vol 42 (4) ◽  
pp. 873-878 ◽  
Author(s):  
Paul E. Verweij ◽  
Karen L. Oakley ◽  
Jacqui Morrissey ◽  
Graham Morrissey ◽  
David W. Denning
Keyword(s):  
Survival Rate ◽  
Invasive Aspergillosis ◽  
Aspergillus Fumigatus ◽  
Amphotericin B ◽  
Murine Model ◽  
Survival Rates ◽  
In Vitro Susceptibility ◽  
Once Daily

ABSTRACT LY303366 is a novel antifungal echinocandin with excellent in vitro activity against Aspergillus spp. We compared four doses (1, 2.5, 10, and 25 mg/kg of body weight) of LY303366 with amphotericin B (0.5 to 5 mg/kg) in a temporarily neutropenic murine model of invasive aspergillosis against an amphotericin B-susceptible (AF210) and an amphotericin B-resistant (AF65) Aspergillus fumigatus isolate based on in vivo response. Mice were immunosuppressed with cyclophosphamide (200 mg/kg) and infected 3 days later. Treatment started 18 h after infection and lasted for 10 days. LY303366 was given once daily intravenously for 10 days, and amphotericin B (at 0.5, 2, and 5 mg/kg) was given once daily intraperitoneally for 10 days, or only on days 1, 2, 4, and 7 (at 5 mg/kg). Kidneys and lungs from survivors were cultured on day 11. Control mice in both experiments had 90 to 100% mortality. Amphotericin B at 0.5 mg/kg and LY303366 at 1 mg/kg yielded 10 to 20% survival rates for mice infected with either AF210 or AF65. Amphotericin B at 2 and 5 (both regimens) mg/kg yielded a 70 to 100% survival rate for mice infected with AF210 but a 10 to 30% survival rate for mice infected with AF65 (P = 0.01 to 0.04 compared with AF210). Against AF210 and AF65, LY303366 at 2.5, 10, and 25 mg/kg produced a survival rate of 70 to 80%, which was as effective as amphotericin B for AF210, but superior to amphotericin B for AF65 (P < 0.03 to 0.0006). For AF65, LY303366 at 10 and 25 mg/kg/day was superior to amphotericin B at 2 and 5 mg/kg/day in reducing tissue colony counts (P = 0.01 to 0.003), and for AF210, amphotericin B at 5 mg/kg/day and at 5 mg/kg in four doses was more effective than all four regimens of LY303366 in reducing renal culture counts (P = 0.01 to 0.0001). The present study shows, for the first time, that in vivo resistance of A. fumigatus to amphotericin B exists, although this could not be detected by in vitro susceptibility assays. Furthermore, LY303366 appears to be effective against amphotericin B-susceptible and -resistant A. fumigatus infection in this model and should be further evaluated clinically.

scholarly journals In vivo evaluation of a recombinant N-acylhomoserine lactonase formulated in a hydrogel using a murine model infected with MDR Pseudomonas aeruginosa clinical isolate, CCASUP2

AMB Express ◽  
2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Masarra M. Sakr ◽  
Walid F. Elkhatib ◽  
Khaled M. Aboshanab ◽  
Eman M. Mantawy ◽  
Mahmoud A. Yassien ◽  
...  
Keyword(s):  
Survival Rate ◽  
Murine Model ◽  
Histopathological Examination ◽  
Healing Process ◽  
Bacterial Count ◽  
Treated Group ◽  
Control Group ◽  
In Vivo Evaluation ◽  
Systemic Spread

AbstractFailure in the treatment of P. aeruginosa, due to its broad spectrum of resistance, has been associated with increased patient mortality. One alternative approach for infection control is quorum quenching which was found to decrease virulence of such pathogen. In this study, the efficiency of a recombinant Ahl-1 lactonase formulated as a hydrogel was investigated to control the infection of multidrug resistant (MDR) P. aeruginosa infected burn using a murine model. The recombinant N-acylhomoserine lactonase (Ahl-1) was formulated as a hydrogel. To test its ability to control the infection of MDR P. aeruginosa, a thermal injury model was used. Survival rate, and systemic spread of the infection were evaluated. Histopathological examination of the animal dorsal skin was also done for monitoring the healing and cellular changes at the site of infection. Survival rate in the treated group was 100% relative to 40% in the control group. A decrease of up to 3 logs of bacterial count in the blood samples of the treated animals relative to the control group and a decrease of up to 4 logs and 2.3 logs of bacteria in lung and liver samples, respectively were observed. Histopathological examination revealed more enhanced healing process in the treated group. Accordingly, by promoting healing of infected MDR P. aeruginosa burn and by reducing systemic spread of the infection as well as decreasing mortality rate, Ahl-1 hydrogel application is a promising strategy that can be used to combat and control P. aeruginosa burn infections.

scholarly journals In vivo Active Organometallic-containing Antimycotic Agents

2021 ◽  
Author(s):  
Riccardo Rubbiani ◽  
Tobias Weil ◽  
Noemi Tocci ◽  
Luciano Mastrobuoni ◽  
Severin Jeger ◽  
...  
Keyword(s):  
Fungal Infections ◽  
Care Home ◽  
Multidrug Resistant ◽  
Immunocompromised Patients ◽  
Fungal Strains ◽  
Global Problem

Fungal infections represent a global problem, notably for immunocompromised, patients in hospital, covid-19 patient wards and care home settings, and the ever-increasing emergence of multidrug resistant fungal strains is a...

Vancomycin enhances growth and virulence of Trichosporon spp. planktonic cells and biofilms

2021 ◽  
Author(s):  
Rossana de Aguiar Cordeiro ◽  
Bruno Nascimento da Silva ◽  
Ana Luiza Ribeiro de Aguiar ◽  
Livia Maria Galdino Pereira ◽  
Fernando Victor Monteiro Portela ◽  
...  
Keyword(s):  
Metabolic Activity ◽  
Fungal Infections ◽  
Tolerance Induction ◽  
Microscopic Analysis ◽  
Fungal Species ◽  
Planktonic Cells ◽  
Persister Cells ◽  
Candida Spp ◽  
Patients At Risk

Abstract Invasive fungal infections (IFIs) are important worldwide health problem, affecting the growing population of immunocompromised patients. Although the majority of IFIs are caused by Candida spp., other fungal species have been increasingly recognized as relevant opportunistic pathogens. Trichosporon spp. are members of skin and gut human microbiota. Since 1980’s, invasive trichosporonosis has been considered a significant cause of fungemia in patients with hematological malignancies. As prolonged antibiotic therapy is an important risk factor for IFIs, the present study investigated if vancomycin enhances growth and virulence of Trichosporon. Vancomycin was tested against T. inkin (n = 6) and T. asahii (n = 6) clinical strains. Planktonic cells were evaluated for their metabolic activity and virulence against Caenorhabditis elegans. Biofilms were evaluated for metabolic activity, biomass production, amphotericin B tolerance, induction of persister cells, and ultrastructure. Vancomycin stimulated planktonic growth of Trichosporon spp., increased tolerance to AMB, and potentiates virulence against C. elegans. Vancomycin stimulated growth (metabolic activity and biomass) of Trichosporon spp. biofilms during all stages of development. The antibiotic increased the number of persister cells inside Trichosporon biofilms. These cells showed higher tolerance to AMB than persister cells from VAN-free biofilms. Microscopic analysis showed that VAN increased production of extracellular matrix and cells in T. inkin and T. asahii biofilms. These results suggest that antibiotic exposure may have a direct impact on the pathophysiology of opportunistic trichosporonosis in patients at risk. Lay abstract This study showed that the vancomycin stimulated Trichosporon growth, induced morphological and physiological changes on their biofilms, and also enhanced their in vivo virulence. Although speculative, the stimulatory effect of vancomycin on fungal cells should be considered in a clinical scenario.

scholarly journals In vivo blockade of CD28/CTLA4: B7/BB1 interaction with CTLA4-Ig reduces lethal murine graft-versus-host disease across the major histocompatibility complex barrier in mice

Blood ◽  
1994 ◽  
Vol 83 (12) ◽  
pp. 3815-3825 ◽  
Author(s):  
BR Blazar ◽  
PA Taylor ◽  
PS Linsley ◽  
DA Vallera
Keyword(s):  
Major Histocompatibility Complex ◽  
Survival Rate ◽  
T Cell ◽  
Survival Rates ◽  
Actuarial Survival ◽  
Graft Versus Host ◽  
Histocompatibility Complex ◽  
Actuarial Survival Rate ◽  
Cell Repopulation

We tested whether the in vivo infusion of recombinant, soluble CTLA4 fused with Ig heavy chains, as a surrogate ligand used to block CD28/CTLA4 T-cell costimulation, could prevent efficient T-cell activation and thereby reduce graft-versus-host disease (GVHD). Lethally irradiated B10.BR recipients of major histocompatibility complex disparate C57BL/6 donor grafts received intraperitoneal injections of human CTLA4-Ig (hCTLA4-Ig) or murine CTLA4-Ig (mCTLA4-Ig) in various doses and schedules beginning on day -1 or day 0 of bone marrow transplantation (BMT). In all five experiments, recipients of CTLA4-Ig had a significantly higher actuarial survival rate compared to mice injected with an irrelevant antibody control (L6) or saline alone. Survival rates in recipients of hL6 or PBS were 0% at 29 to 45 days post-BMT. In recipients of CTLA4-Ig, survival rates were as high as 63% mice surviving 3 months post-BMT. However, protection was somewhat variable and recipients of CTLA4-Ig were not GVHD-free by body weight, clinical appearance, and histopathologic examination. There were no significant differences in the survival rates in comparing injection dose, injection duration, or species of CTLA4-Ig (hCTLA4-Ig v mCTLA4- Ig). Splenic and peripheral blood flow cytometry studies of long-term hCTLA4-Ig-injected survivors showed a significant peripheral B-cell and CD4+ T-cell lymphopenia, consistent with GVHD. A kinetic study of splenic reconstitution was performed in mice that received hCTLA4-Ig and showed that mature splenic localized CD8+ T-cell repopulation was not significantly different in recipients of hCTLA4-Ig compared with hL6, despite the significant increase in actuarial survival rate in that experiment. These data suggest that the beneficial effect of hCTLA4-Ig on survival is not mediated by interfering with mature donor- derived T-cell repopulation post-BMT. Neither hCTLA4-Ig nor mCTLA4-Ig interfered with hematopoietic recovery post-BMT. We conclude that CTLA4- Ig (most likely in combination with other agents) may represent an important new modality for GVHD prevention.

scholarly journals In Vitro and In Vivo Characterization of Tebipenem (TBP), an Orally Active Carbapenem, against Biothreat Pathogens

2021 ◽  
Author(s):  
Nicholas P. Clayton ◽  
Akash Jain ◽  
Stephanie A. Halasohoris ◽  
Lisa M. Pysz ◽  
Sanae Lembirik ◽  
...  
Keyword(s):  
Survival Rates ◽  
Multidrug Resistant ◽  
Positive Control ◽  
Vehicle Control ◽  
Control Group ◽  
Post Challenge ◽  
Vehicle Control Group ◽  
Tebipenem Pivoxil

Bacillus anthracis and Yersinia pestis, causative pathogens for anthrax and plague, respectively, along with Burkholderia mallei and B. pseudomallei are potential bioterrorism threats. Tebipenem pivoxil hydrobromide (TBP HBr, formerly SPR994), is an orally available prodrug of tebipenem, a carbapenem with activity versus multidrug-resistant (MDR) gram-negative pathogens, including quinolone-resistant and extended-spectrum-β-lactamase-producing Enterobacterales. We evaluated the in vitro activity and in vivo efficacy of tebipenem against biothreat pathogens. Tebipenem was active in vitro against 30-strain diversity sets of B. anthracis, Y. pestis, B. mallei, and B. pseudomallei with minimum inhibitory concentration (MIC) values of 0.001 – 0.008 μg/ml for B. anthracis, ≤0.0005 – 0.03 μg/ml for Y. pestis, 0.25 – 1 μg/ml for B. mallei, and 1 – 4 μg/ml for B. pseudomallei. In a B. anthracis murine model, all control animals died within 52 h post challenge. The survival rates in the groups treated with tebipenem were 75% and 73% when dosed at 12 h and 24 h post challenge, respectively. The survival rates in the positive control groups treated with ciprofloxacin were 75% and when dosed 12 h and 25% when dosed 24 h post challenge, respectively. Survival rates were significantly (p=0.0009) greater in tebipenem groups treated at 12 h and 24 h post challenge and in the ciprofloxacin group 12 h post-challenge vs. the vehicle-control group. For Y. pestis, survival rates for all animals in the tebipenem and ciprofloxacin groups were significantly (p<0.0001) greater than the vehicle-control group. These results support further development of tebipenem for treating biothreat pathogens.

scholarly journals Evaluation of the in vitro Activity and in vivo Efficacy of Anidulafungin-Loaded Human Serum Albumin Nanoparticles Against Candida albicans

2021 ◽  
Vol 12 ◽  
Author(s):  
Yu Zhang ◽  
Yan-Chao Liu ◽  
Si-Min Chen ◽  
Hui Zong ◽  
Wei-Tong Hou ◽  
...  
Keyword(s):  
Human Serum Albumin ◽  
Serum Albumin ◽  
Human Serum ◽  
Water Solubility ◽  
Fungal Infections ◽  
Antifungal Susceptibility ◽  
Fungal Species ◽  
Invasive Infection

Recent decades have seen a significant increase in invasive fungal infections, resulting in unacceptably high mortality rates. Anidulafungin (AN) is the newest echinocandin and appears to have several advantages over existing antifungals. However, its poor water solubility and burdensome route of administration (i.e., repeated, long-term intravenous infusions) have limited its practical use. The objective of this study was to develop anidulafungin-loaded Human Serum Albumin (HSA) nanoparticles (NP) so as to increase both its solubility and antifungal efficacy. HSA was reduced using SDS and DTT, allowing liberation of free thiols to form the intermolecular disulfide network and nanoassembly. Reduced HSA was then added to MES buffer (0.1 M, pH 4.8) and magnetically stirred at 350 rpm and 25°C with AN (m/m 50:1) for 2 h to form nanoparticles (AN NP). We next performed routine antifungal susceptibility testing of Candida strains (n = 31) using Clinical and Laboratory Standards Institute (CLSI) methodologies. Finally, the in vivo efficacy of both AN and AN NP was investigated in a murine model of invasive infection by one of the most common fungal species—C. albicans. The results indicated that our carrier formulations successfully improved the water solubility of AN and encapsulated AN, with the latter having a particle size of 29 ± 1.5 nm with Polymer dispersity index (PDI) equaling 0.173 ± 0.039. In vitro AN NP testing revealed a stronger effect against Candida species (n = 31), with Minimum Inhibitory Concentration (MIC) values 4- to 32-fold lower than AN alone. In mice infected with Candida and having invasive candidiasis, we found that AN NP prolonged survival time (P &lt; 0.005) and reduced fungal burden in kidneys compared to equivalent concentrations of free drug (P &lt; 0.0001). In conclusion, the anidulafungin nanoparticles developed here have the potential to improve drug administration and therapeutic outcomes for individuals suffering from fungal diseases.

scholarly journals Comparative resistance of Candida albicans clinical isolates to fluconazole and itraconazole in vitro and in vivo in a murine model.

1996 ◽  
Vol 40 (6) ◽  
pp. 1342-1345 ◽  
Author(s):  
A Valentin ◽  
R Le Guennec ◽  
E Rodriguez ◽  
J Reynes ◽  
M Mallie ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Murine Model ◽  
Survival Rates ◽  
Drug Regimen ◽  
Clinical Isolates ◽  
In Vitro Susceptibility ◽  
Microdilution Method ◽  
Broth Microdilution Method

Relationships between azole susceptibility and in vivo response to antifungal therapy in a murine model of candidiasis were investigated for Candida albicans isolates sampled from human immunodeficiency virus type 1-positive patients with oropharyngeal candidiasis. The susceptibilities of seven clinical isolates and two reference strains to fluconazole (FCZ) and itraconazole (ITZ) were determined in vitro by the broth microdilution method. Four isolates were resistant to FCZ and ITZ, two were susceptible to both azoles, and three were resistant to FCZ and susceptible to ITZ (dissociated resistance). CD1 mice were inoculated with each isolate and treated with either FCZ or ITZ (drug regimen, 5 mg/kg of body weight twice daily for 5 days). Quantitative cultures of kidneys were performed at the end of the treatment. On the other hand, the survival rates of the mice were followed daily. These two parameters were clearly correlated with in vitro susceptibility. Thus, the phenomenon of a dissociation of resistance to FCZ and ITZ may be found in vivo as well as in vitro.

scholarly journals Rhesus Theta Defensin 1 Promotes Long Term Survival in Systemic Candidiasis by Host Directed Mechanisms

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Virginia Basso ◽  
Dat Q. Tran ◽  
Justin B. Schaal ◽  
Patti Tran ◽  
Yoshihiro Eriguchi ◽  
...  
Keyword(s):  
Plasma Concentrations ◽  
Multidrug Resistant ◽  
Mouse Serum ◽  
Term Survival ◽  
Long Term Survival ◽  
Immunosuppressed Patients ◽  
Time Of Infection

AbstractInvasive candidiasis is an increasingly frequent cause of serious and often fatal infections in hospitalized and immunosuppressed patients. Mortality rates associated with these infections have risen sharply due to the emergence of multidrug resistant (MDR) strains of C. albicans and other Candida spp., highlighting the urgent need of new antifungal therapies. Rhesus theta (θ) defensin-1 (RTD-1), a natural macrocyclic antimicrobial peptide, was recently shown to be rapidly fungicidal against clinical isolates of MDR C. albicans in vitro. Here we found that RTD-1 was rapidly fungicidal against blastospores of fluconazole/caspofungin resistant C. albicans strains, and was active against established C. albicans biofilms in vitro. In vivo, systemic administration of RTD-1, initiated at the time of infection or 24 h post-infection, promoted long term survival in candidemic mice whether infected with drug-sensitive or MDR strains of C. albicans. RTD-1 induced an early (4 h post treatment) increase in neutrophils in naive and infected mice. In vivo efficacy was associated with fungal clearance, restoration of dysregulated inflammatory cytokines including TNF-α, IL-1β, IL-6, IL-10, and IL-17, and homeostatic reduction in numbers of circulating neutrophils and monocytes. Because these effects occurred using peptide doses that produced maximal plasma concentrations (Cmax) of less than 1% of RTD-1 levels required for in vitro antifungal activity in 50% mouse serum, while inducing a transient neutrophilia, we suggest that RTD-1 mediates its antifungal effects in vivo by host directed mechanisms rather than direct fungicidal activity. Results of this study suggest that θ-defensins represent a new class of host-directed compounds for treatment of disseminated candidiasis.

scholarly journals In vivo blockade of CD28/CTLA4: B7/BB1 interaction with CTLA4-Ig reduces lethal murine graft-versus-host disease across the major histocompatibility complex barrier in mice

Blood ◽  
1994 ◽  
Vol 83 (12) ◽  
pp. 3815-3825 ◽  
Author(s):  
BR Blazar ◽  
PA Taylor ◽  
PS Linsley ◽  
DA Vallera
Keyword(s):  
Major Histocompatibility Complex ◽  
Survival Rate ◽  
T Cell ◽  
Survival Rates ◽  
Actuarial Survival ◽  
Graft Versus Host ◽  
Histocompatibility Complex ◽  
Actuarial Survival Rate ◽  
Cell Repopulation

Abstract We tested whether the in vivo infusion of recombinant, soluble CTLA4 fused with Ig heavy chains, as a surrogate ligand used to block CD28/CTLA4 T-cell costimulation, could prevent efficient T-cell activation and thereby reduce graft-versus-host disease (GVHD). Lethally irradiated B10.BR recipients of major histocompatibility complex disparate C57BL/6 donor grafts received intraperitoneal injections of human CTLA4-Ig (hCTLA4-Ig) or murine CTLA4-Ig (mCTLA4-Ig) in various doses and schedules beginning on day -1 or day 0 of bone marrow transplantation (BMT). In all five experiments, recipients of CTLA4-Ig had a significantly higher actuarial survival rate compared to mice injected with an irrelevant antibody control (L6) or saline alone. Survival rates in recipients of hL6 or PBS were 0% at 29 to 45 days post-BMT. In recipients of CTLA4-Ig, survival rates were as high as 63% mice surviving 3 months post-BMT. However, protection was somewhat variable and recipients of CTLA4-Ig were not GVHD-free by body weight, clinical appearance, and histopathologic examination. There were no significant differences in the survival rates in comparing injection dose, injection duration, or species of CTLA4-Ig (hCTLA4-Ig v mCTLA4- Ig). Splenic and peripheral blood flow cytometry studies of long-term hCTLA4-Ig-injected survivors showed a significant peripheral B-cell and CD4+ T-cell lymphopenia, consistent with GVHD. A kinetic study of splenic reconstitution was performed in mice that received hCTLA4-Ig and showed that mature splenic localized CD8+ T-cell repopulation was not significantly different in recipients of hCTLA4-Ig compared with hL6, despite the significant increase in actuarial survival rate in that experiment. These data suggest that the beneficial effect of hCTLA4-Ig on survival is not mediated by interfering with mature donor- derived T-cell repopulation post-BMT. Neither hCTLA4-Ig nor mCTLA4-Ig interfered with hematopoietic recovery post-BMT. We conclude that CTLA4- Ig (most likely in combination with other agents) may represent an important new modality for GVHD prevention.

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