scholarly journals Chitinase Induction Prior to Caspofungin Treatment of Experimental Invasive Aspergillosis in Neutropenic Rats Does Not Enhance Survival

2017 ◽  
Vol 62 (1) ◽  
Author(s):  
Jeannine M. Refos ◽  
Alieke G. Vonk ◽  
Marian T. ten Kate ◽  
Henri A. Verbrugh ◽  
Irma A. J. M. Bakker-Woudenberg ◽  
...  
Keyword(s):  
Antifungal Activity ◽  
Invasive Aspergillosis ◽  
Invasive Pulmonary Aspergillosis ◽  
Left Lung ◽  
Chitinase Activity ◽  
Pulmonary Aspergillosis ◽  
Content Type ◽  
Acidic Mammalian Chitinase ◽  
Phosphate Buffered Saline

ABSTRACT Host chitinases, chitotriosidase and acidic mammalian chitinase (AMCase), improved the antifungal activity of caspofungin (CAS) against Aspergillus fumigatus in vitro. These chitinases are not constitutively expressed in the lung. Here, we investigated whether chitosan derivatives were able to induce chitinase activity in the lungs of neutropenic rats and, if so, whether these chitinases were able to prolong survival of rats with invasive pulmonary aspergillosis (IPA) or of rats with IPA and treated with CAS. An oligosaccharide-lactate chitosan (OLC) derivative was instilled in the left lung of neutropenic rats to induce chitotriosidase and AMCase activities. Rats instilled with OLC or with phosphate-buffered saline (PBS) were subsequently infected with A. fumigatus and then treated with suboptimal doses of CAS. Survival, histopathology, and galactomannan indexes were determined. Instillation of OLC resulted in chitotriosidase and AMCase activities. However, instillation of OLC did not prolong rat survival when rats were subsequently challenged with A. fumigatus. In 5 of 7 rats instilled with OLC, the fungal foci in the lungs were smaller than those in rats instilled with PBS. Instillation of OLC did not significantly enhance the survival of neutropenic rats challenged with A. fumigatus and treated with a suboptimal dosage of CAS. Chitotriosidase and AMCase activities can be induced with OLC, but the presence of active chitinases in the lung did not prevent the development of IPA or significantly enhance the therapeutic outcome of CAS treatment.

scholarly journals Efficacy of Ambruticin Analogs in a Murine Model of Invasive Pulmonary Aspergillosis

2006 ◽  
Vol 50 (10) ◽  
pp. 3464-3466 ◽  
Author(s):  
Lisa Y. Chiang ◽  
Daniele E. Ejzykowicz ◽  
Zong-Qiang Tian ◽  
Leonard Katz ◽  
Scott G. Filler
Keyword(s):  
Antifungal Activity ◽  
Mouse Model ◽  
Invasive Aspergillosis ◽  
Murine Model ◽  
Antifungal Agents ◽  
Invasive Pulmonary Aspergillosis ◽  
Vehicle Control ◽  
Pulmonary Aspergillosis

ABSTRACT Ambruticins are a family of polyketides. The antifungal activity of an ambruticin, KOSN-2079, was tested in the mouse model of invasive aspergillosis. KOSN-2079 significantly reduced pulmonary fungal burdens and improved survival over that with the vehicle control. These results support the continued development of ambruticins as antifungal agents.

scholarly journals Host Biomarkers of Invasive Pulmonary Aspergillosis To Monitor Therapeutic Response

2014 ◽  
Vol 58 (6) ◽  
pp. 3373-3378 ◽  
Author(s):  
Mila Krel ◽  
Vidmantas Petraitis ◽  
Ruta Petraitiene ◽  
Mohit Raja Jain ◽  
Yanan Zhao ◽  
...  
Keyword(s):  
Therapeutic Response ◽  
Invasive Pulmonary Aspergillosis ◽  
Rabbit Model ◽  
Time Of Flight ◽  
Lavage Fluid ◽  
Host Protein ◽  
Enzyme Linked Immunosorbent Assay ◽  
Pulmonary Aspergillosis ◽  
Content Type

ABSTRACTInvasive pulmonary aspergillosis (IPA) is a life-threatening disease of immunocompromised patients that requires aggressive therapy. Detection of the disease and monitoring of the therapeutic response during IPA are complex, and current molecular diagnostics are not suitably robust. Here, we explored proteomic profiles of bronchoalveolar lavage fluid (BALF) specimens from a persistently neutropenic rabbit model of IPA. Three experimental arms, uninfected control animals, infected untreated animals, and animals infected and treated with ravuconazole/amphotericin B, were studied. Total proteins were evaluated by two-dimensional (2D) gel electrophoresis, followed by matrix-assisted laser desorption ionization–time of flight/time of flight (MALDI-TOF/TOF) mass spectrometry (MS) and quantified by enzyme-linked immunosorbent assay (ELISA). Host-derived proteins haptoglobin (Hp), C-reactive protein (CRP), and annexin A1 (Anx A1) were prominently found in BALF during the IPA infection and showed significant changes in response to antifungal therapy (P< 0.0001). In serum, differences in Hp (P= 0.0001) between infected and treated rabbits were observed. Preliminaryin vitrostudies revealed thatAspergillus fumigatus-secreted proteases may contribute to the cleavage of Anx A1 during IPA. In summary, host protein biomarkers Hp, CRP, and Anx A1 may have value in monitoring therapeutic response to antifungal agents in IPA patients with confirmed disease.

scholarly journals APX001 Is Effective in the Treatment of Murine Invasive Pulmonary Aspergillosis

2018 ◽  
Vol 63 (2) ◽  
pp. e01713-18 ◽  
Author(s):  
Teclegiorgis Gebremariam ◽  
Sondus Alkhazraji ◽  
Abdullah Alqarihi ◽  
Heewon H. Jeon ◽  
Yiyou Gu ◽  
...  
Keyword(s):  
Fungal Infections ◽  
Histopathological Examination ◽  
Invasive Pulmonary Aspergillosis ◽  
Human Pharmacokinetics ◽  
Immunosuppressed Patient ◽  
Cytochrome P450 Enzymes ◽  
Pulmonary Aspergillosis ◽  
Minimum Effective Concentration ◽  
Content Type

ABSTRACTInvasive pulmonary aspergillosis (IPA) due toAspergillus fumigatusis a serious fungal infection in the immunosuppressed patient population. Despite the introduction of new antifungal agents, mortality rates remain high, and new treatments are needed. The novel antifungal APX001A targets the conserved Gwt1 enzyme required for the localization of glycosylphosphatidylinositol-anchored mannoproteins in fungi. We evaluated thein vitroactivity of APX001A againstA. fumigatusand thein vivoactivity of its prodrug APX001 in an immunosuppressed mouse model of IPA. APX001A inhibited the growth ofA. fumigatuswith a minimum effective concentration of 0.03 μg/ml. The use of 50 mg/kg 1-aminobenzotriazole (ABT), a suicide inhibitor of cytochrome P450 enzymes, enhanced APX001A exposures (area under the time-concentration curve [AUC]) 16- to 18-fold and enhanced serum half-life from ∼1 to 9 h, more closely mimicking human pharmacokinetics. We evaluated the efficacy of APX001 (with ABT) in treating murine IPA compared to posaconazole treatment. Treatment of mice with 78 mg/kg once daily (QD), 78 mg/kg twice daily, or 104 mg/kg QD APX001 significantly enhanced the median survival time and prolonged day 21 postinfection overall survival compared to the placebo. Furthermore, administration of APX001 resulted in a significant reduction in lung fungal burden (4.2 to 7.6 log10conidial equivalents/g of tissue) versus the untreated control and resolved the infection, as judged by histopathological examination. The observed survival and tissue clearance were comparable to a clinically relevant posaconazole dose. These results warrant the continued development of APX001 as a broad-spectrum, first-in-class treatment of invasive fungal infections.

scholarly journals Posaconazole Prophylaxis in Experimental Azole-Resistant Invasive Pulmonary Aspergillosis

2014 ◽  
Vol 59 (3) ◽  
pp. 1487-1494 ◽  
Author(s):  
Seyedmojtaba Seyedmousavi ◽  
Johan W. Mouton ◽  
Willem J. G. Melchers ◽  
Paul E. Verweij
Keyword(s):  
Invasive Aspergillosis ◽  
Aspergillus Fumigatus ◽  
Murine Model ◽  
Pulmonary Infection ◽  
Invasive Pulmonary Aspergillosis ◽  
Clinical Isolates ◽  
Wild Type ◽  
Breakthrough Infection ◽  
Pulmonary Aspergillosis ◽  
Content Type

ABSTRACTWe investigated the efficacy of posaconazole prophylaxis in preventing invasive aspergillosis due to azole-resistantAspergillus fumigatusisolates. Using a neutropenic murine model of pulmonary infection, posaconazole prophylaxis was evaluated using three isogenic clinical isolates, with posaconazole MICs of 0.063 mg/liter (wild type), 0.5 mg/liter (F219I mutation), and 16 mg/liter. A fourth isolate harboring TR34/L98H (MIC of 0.5 mg/liter) was also tested. Posaconazole prophylaxis was effective inA. fumigatuswith posaconazole MICs of ≤0.5 mg/liter, where 100% survival was reached. However, breakthrough infection was observed in mice infected with the isolate for which the posaconazole MIC was >16 mg/liter.

scholarly journals APX001 Pharmacokinetic/Pharmacodynamic Target Determination againstAspergillus fumigatusin anIn VivoModel of Invasive Pulmonary Aspergillosis

2019 ◽  
Vol 63 (4) ◽  
Author(s):  
Miao Zhao ◽  
Alexander J. Lepak ◽  
Karen Marchillo ◽  
Jamie Vanhecker ◽  
Hiram Sanchez ◽  
...  
Keyword(s):  
Invasive Pulmonary Aspergillosis ◽  
Dose Fractionation ◽  
Coefficient Of Determination ◽  
Dose Selection ◽  
Pulmonary Aspergillosis ◽  
Time Curve ◽  
Minimum Effective Concentration ◽  
Content Type

ABSTRACTAPX001, the prodrug of APX001A, is a first-in-class antifungal agent that has a potent activity againstAspergillus fumigatus. The goal of current study was to determine the pharmacodynamic (PD) index and target of APX001 in an immunocompromised murine model of invasive pulmonary aspergillosis against 6 A. fumigatusisolates. Minimum effective concentration (MEC) values ranged from 0.03 to 0.06 mg/liter. Dose fractionation was performed against isolate AF293 using total doses of APX001 ranging from 81 to 768 mg/kg of body weight/day fractionated into every 3-, 6-, and 8-h regimens over a 96-h treatment duration. Efficacy was assessed byA. fumigatusquantitative PCR (qPCR) of conidial equivalents from lung homogenates. Nonlinear regression analysis using the Hill equation demonstrated that the 24-h area under the concentration-time curve (AUC)/MEC ratio was the pharmacokinetic (PK)/PD index that best correlated with efficacy (coefficient of determination [R2] = 0.79). Treatment studies with the remaining strains utilized regimens of 40 to 1,536 mg/kg of APX001 administered every 3 h for a 96-h duration. Exposure-response relationships for all strains were similar, and the median free drug AUC/MEC PK/PD targets for stasis and 1-log-kill endpoints were 47.6 and 89.4, respectively. The present studies demonstratedin vitroandin vivoAPX001A/APX001 potency againstA. fumigatus. These results have potential relevance for clinical dose selection and evaluation of susceptibility breakpoints.

scholarly journals Combination of Voriconazole and Anidulafungin for Treatment of Triazole-Resistant Aspergillus fumigatus in anIn VitroModel of Invasive Pulmonary Aspergillosis

2012 ◽  
Vol 56 (10) ◽  
pp. 5180-5185 ◽  
Author(s):  
Adam R. Jeans ◽  
Susan J. Howard ◽  
Zaid Al-Nakeeb ◽  
Joanne Goodwin ◽  
Lea Gregson ◽  
...  
Keyword(s):  
High Performance ◽  
Molecular Mechanisms ◽  
Invasive Pulmonary Aspergillosis ◽  
Fungal Growth ◽  
Pulmonary Aspergillosis ◽  
Antifungal Effect ◽  
Content Type ◽  
Exposure Response ◽  
Relationship Of

ABSTRACTVoriconazole is a first-line agent for the treatment of invasive pulmonary aspergillosis. Isolates with elevated voriconazole MICs are increasingly being seen, and the optimal treatment regimen is not defined. We investigated whether the combination of voriconazole with anidulafungin may be beneficial for the treatment ofA. fumigatusstrains with elevated voriconazole MICs. We used anin vitromodel of the human alveolus to define the exposure-response relationships for a wild-type strain (voriconazole MIC, 0.5 mg/liter) and strains with defined molecular mechanisms of triazole resistance (MICs, 4 to 16 mg/liter). All strains had anidulafungin minimum effective concentrations (MECs) of 0.0078 mg/liter. Exposure-response relationships were estimated using galactomannan as a biomarker. Concentrations of voriconazole and anidulafungin were measured using high-performance liquid chromatography (HPLC). The interaction of voriconazole and anidulafungin was described using the Greco model. Fungal growth was progressively inhibited with higher drug exposures of voriconazole. Strains with elevated voriconazole MICs required proportionally greater voriconazole exposures to achieve a comparable antifungal effect. Galactomannan concentrations were only marginally reduced by anidulafungin monotherapy. An additive effect between voriconazole and anidulafungin was apparent. In conclusion, the addition of anidulafungin does not markedly alter the exposure-response relationship of voriconazole. A rise in serum galactomannan during combination therapy with voriconazole and anidulafungin should be interpreted as treatment failure and not attributed to a paradoxical reaction related to echinocandin treatment.

scholarly journals Comparison of Borate Bioactive Glass and Calcium Sulfate as Implants for the Local Delivery of Teicoplanin in the Treatment of Methicillin-Resistant Staphylococcus aureus-Induced Osteomyelitis in a Rabbit Model

2015 ◽  
Vol 59 (12) ◽  
pp. 7571-7580 ◽  
Author(s):  
Wei-Tao Jia ◽  
Qiang Fu ◽  
Wen-Hai Huang ◽  
Chang-Qing Zhang ◽  
Mohamed N. Rahaman
Keyword(s):  
Staphylococcus Aureus ◽  
Bioactive Glass ◽  
Calcium Sulfate ◽  
Rabbit Model ◽  
Local Delivery ◽  
Methicillin Resistant ◽  
Content Type ◽  
Borate Bioactive Glass ◽  
Phosphate Buffered Saline

ABSTRACTThere is growing interest in biomaterials that can cure bone infection and also regenerate bone. In this study, two groups of implants composed of 10% (wt/wt) teicoplanin (TEC)-loaded borate bioactive glass (designated TBG) or calcium sulfate (TCS) were created and evaluated for their ability to release TECin vitroand to cure methicillin-resistantStaphylococcus aureus(MRSA)-induced osteomyelitis in a rabbit model. When immersed in phosphate-buffered saline (PBS), both groups of implants provided a sustained release of TEC at a therapeutic level for up to 3 to 4 weeks while they were gradually degraded and converted to hydroxyapatite. The TBG implants showed a longer duration of TEC release and better retention of strength as a function of immersion time in PBS. Infected rabbit tibiae were treated by debridement, followed by implantation of TBG or TCS pellets or intravenous injection with TEC, or were left untreated. Evaluation at 6 weeks postimplantation showed that the animals implanted with TBG or TCS pellets had significantly lower radiological and histological scores, lower rates of MRSA-positive cultures, and lower bacterial loads than those preoperatively and those of animals treated intravenously. The level of bone regeneration was also higher in the defects treated with the TBG pellets. The results showed that local TEC delivery was more effective than intravenous administration for the treatment of MRSA-induced osteomyelitis. Borate glass has the advantages of better mechanical strength, more desirable kinetics of release of TEC, and a higher osteogenic capacity and thus could be an effective alternative to calcium sulfate for local delivery of TEC.

scholarly journals Complete Genome Sequence of Lanthionine-Producing Lactobacillus brevis Strain 100D8, Generated by PacBio Sequencing

2018 ◽  
Vol 7 (14) ◽  
Author(s):  
Min-Jung Kim ◽  
Hye Sun Kim ◽  
Sam Churl Kim ◽  
Youn-Sig Kwak
Keyword(s):  
Antifungal Activity ◽  
Genome Sequence ◽  
Complete Genome Sequence ◽  
Complete Genome ◽  
Lactobacillus Brevis ◽  
Pacbio Sequencing ◽  
Circular Chromosome ◽  
Coding Sequences ◽  
Content Type

Lactobacillus brevis strain 100D8 was isolated from rye silage and showed rapid acidification ability in vitro and antifungal activity against mycotoxin-producing fungi. We report here the complete genome sequence of L. brevis strain 100D8, which has a circular chromosome (2,351,988 bp, 2,304 coding sequences [CDSs]) and three plasmids (45,061 bp, 57 CDSs; 40,740 bp, 40 CDSs; and 39,943 bp, 57 CDSs).

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