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1.
Campoli P Al Abdallah Q Robitaille R Solis NV Fielhaber JA Kristof AS Laverdiere M Filler SG Sheppard DC 《Antimicrobial agents and chemotherapy》2011,55(12):5732-5739
Posaconazole prophylaxis has proven highly effective in preventing invasive fungal infections, despite relatively low serum concentrations. However, high tissue levels of this agent have been reported in treated patients. We therefore hypothesized that the intracellular levels of antifungal agents are an important factor in determining the success of fungal prophylaxis. To examine the effect of host cell-associated antifungals on the growth of medically important molds, we exposed cells to antifungal agents and removed the extracellular drug prior to infection. Epithelial cells loaded with posaconazole and its parent molecule itraconazole, but not other antifungals, were able to inhibit fungal growth for at least 48 h and were protected from damage caused by infection. Cell-associated posaconazole levels were 40- to 50-fold higher than extracellular levels, and the drug was predominantly detected in cellular membranes. Fungistatic levels of posaconazole persisted within epithelial cells for up to 48 h. Therefore, the concentration of posaconazole in mammalian host cell membranes mediates its efficacy in prophylactic regimens and likely explains the observed discrepancy between serum antifungal levels and efficacy. 相似文献
2.
Fedja Farowski Oliver A. Cornely J?rg J. Vehreschild Pia Hartmann Tim Bauer Angela Steinbach Maria J. G. T. Rüping Carsten Müller 《Antimicrobial agents and chemotherapy》2010,54(7):2928-2931
Therapeutic drug monitoring (TDM) of antifungal plasma concentrations is increasingly recommended. However, data on antifungal concentrations in the other compartments of the peripheral blood are limited. Hence, we collected 23 blood samples from 14 patients receiving posaconazole for prophylaxis of fungal infections. These samples were separated by double-discontinuous Ficoll-Hypaque density gradient centrifugation. The intracellular posaconazole concentrations of the obtained cells, i.e., the peripheral blood mononuclear cells (PBMCs), polymorphonuclear leukocytes (PMNs), and red blood cells (RBCs), were determined by liquid chromatography-tandem mass spectrometry. The intracellular concentrations of the PBMCs and PMNs were significantly higher than those of surrounding media (P < 0.001). The ratios between the intracellular and extracellular concentrations (C/E) were 22.5 ± 21.2, 7.66 ± 6.50, and 0.09 ± 0.05 for the PBMCs, PMNs, and RBCs, respectively. Posaconazole reaches high concentrations within human PBMCs and PMNs and is, to a lesser extent, present in RBCs. The high intracellular concentrations might contribute to posaconazole efficacy and distribution.Posaconazole is an orally administered broad-spectrum triazole antifungal which has recently been approved for prophylaxis and treatment of opportunistic invasive fungal infections in immunocompromised patients. Posaconazole exposure depends on prandial status and drug-drug interactions, leading to intra- and interindividual variability (7, 12). Depending on the dosing group, a 38 to 68% interindividual variability of the pharmacokinetic parameters has been observed (14). The clinical significance of this finding is currently unclear (15).The intestinal absorption is likely to be influenced by graft-versus-host disease and mucositis. Ullmann et al. also described a reduced bioavailability of posaconazole in neutropenic patients (16). Due to the extensive pharmacokinetic variability of posaconazole, therapeutic drug monitoring (TDM) has been discussed as a possible means of ensuring a sufficient exposure (9, 13). While TDM usually is performed by measurement of serum or plasma concentrations, little is known about the concentrations in other compartments of the peripheral blood, i.e., peripheral blood mononuclear cells (PBMCs), polymorphonuclear leukocytes (PMNs), and red blood cells (RBCs). PBMCs and PMNs are important pillars of host defense against invasive fungal diseases (IFD). Interactions with these cells might well influence the efficacy of antifungal drugs.In a recently published trial by Conte et al., a 33-fold increase of the maximum concentration (Cmax) and area under the concentration-time curve (AUC) of posaconazole in alveolar macrophages (AM) compared to those of plasma was shown (4). However, up to now, no data on the intracellular concentration of posaconazole in PBMCs, PMNs, and RBCs have been published.The aim of the present work was to determine the intracellular concentrations of posaconazole in different compartments of the peripheral blood using a previously published liquid chromatography-tandem mass spectrometric assay (6).In keeping with the established literature, we use the term “intracellular” throughout this article, although we are aware that the term “cell associated” may be more accurate. 相似文献
3.
Incompetence of Neutrophils to Invasive Group A streptococcus Is Attributed to Induction of Plural Virulence Factors by Dysfunction of a Regulator
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Manabu Ato Tadayoshi Ikebe Hiroki Kawabata Toshitada Takemori Haruo Watanabe 《PLoS Clinical Trials》2008,3(10)
Group A streptococcus (GAS) causes variety of diseases ranging from common pharyngitis to life-threatening severe invasive diseases, including necrotizing fasciitis and streptococcal toxic shock-like syndrome. The characteristic of invasive GAS infections has been thought to attribute to genetic changes in bacteria, however, no clear evidence has shown due to lack of an intriguingly study using serotype-matched isolates from clinical severe invasive GAS infections. In addition, rare outbreaks of invasive infections and their distinctive pathology in which infectious foci without neutrophil infiltration hypothesized us invasive GAS could evade host defense, especially neutrophil functions. Herein we report that a panel of serotype-matched GAS, which were clinically isolated from severe invasive but not from non-invaive infections, could abrogate functions of human polymorphnuclear neutrophils (PMN) in at least two independent ways; due to inducing necrosis to PMN by enhanced production of a pore-forming toxin streptolysin O (SLO) and due to impairment of PMN migration via digesting interleukin-8, a PMN attracting chemokine, by increased production of a serine protease ScpC. Expression of genes was upregulated by a loss of repressive function with the mutation of csrS gene in the all emm49 severe invasive GAS isolates. The csrS mutants from clinical severe invasive GAS isolates exhibited high mortality and disseminated infection with paucity of neutrophils, a characteristic pathology seen in human invasive GAS infection, in a mouse model. However, GAS which lack either SLO or ScpC exhibit much less mortality than the csrS-mutated parent invasive GAS isolate to the infected mice. These results suggest that the abilities of GAS to abrogate PMN functions can determine the onset and severity of invasive GAS infection. 相似文献
4.
Uptake and Intracellular Activity of Moxifloxacin in Human Neutrophils and Tissue-Cultured Epithelial Cells 总被引:6,自引:3,他引:3
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Alvaro Pascual Isabel García Sofía Ballesta Evelio J. Perea 《Antimicrobial agents and chemotherapy》1999,43(1):12-15
The penetration by moxifloxacin of human neutrophils (polymorphonuclear leukocytes [PMN]) and tissue-cultured epithelial cells (McCoy cells) was evaluated by a fluorometric assay. At extracellular concentrations of 5 mg/liter, the cellular-to-extracellular concentration ratios (C/E) of moxifloxacin in PMN and McCoy cells were 10.9 ± 1.0 and 8.7 ± 1.0, respectively (20 min; 37°C). The uptake of moxifloxacin by PMN was rapid, reversible, nonsaturable (at extracellular concentrations ranging from 1 to 50 μg/ml), and not affected by cell viability. The uptake of moxifloxacin was affected by external pH and the environmental temperature. The incubation of PMN in the presence of sodium fluoride, sodium cyanide, and carbonyl cyanide m-chlorophenylhydrazone significantly decreased the C/E of this agent. Neither PMN stimulation nor phagocytosis of opsonized Staphylococcus aureus significantly affected the uptake of moxifloxacin by human PMN. This agent, at concentrations of 0.5, 1, and 5 mg/liter, induced a significant reduction in the survival of intracellular S. aureus in human PMN. In summary, moxifloxacin reaches much higher intracellular concentrations within phagocytic and nonphagocytic cells than extracellular ones, remaining active inside the neutrophils. 相似文献
5.
Amanda Fortes Francisco Michael D. Lewis Shiromani Jayawardhana Martin C. Taylor Eric Chatelain John M. Kelly 《Antimicrobial agents and chemotherapy》2015,59(8):4653-4661
The antifungal drug posaconazole has shown significant activity against Trypanosoma cruzi
in vitro and in experimental murine models. Despite this, in a recent clinical trial it displayed limited curative potential. Drug testing is problematic in experimental Chagas disease because of difficulties in demonstrating sterile cure, particularly during the chronic stage of infection when parasite burden is extremely low and tissue distribution is ill defined. To better assess posaconazole efficacy against acute and chronic Chagas disease, we have exploited a highly sensitive bioluminescence imaging system which generates data with greater accuracy than other methods, including PCR-based approaches. Mice inoculated with bioluminescent T. cruzi were assessed by in vivo and ex vivo imaging, with cyclophosphamide-induced immunosuppression used to enhance the detection of relapse. Posaconazole was found to be significantly inferior to benznidazole as a treatment for both acute and chronic T. cruzi infections. Whereas 20 days treatment with benznidazole was 100% successful in achieving sterile cure, posaconazole failed in almost all cases. Treatment of chronic infections with posaconazole did however significantly reduce infection-induced splenomegaly, even in the absence of parasitological cure. The imaging-based screening system also revealed that adipose tissue is a major site of recrudescence in mice treated with posaconazole in the acute, but not the chronic stage of infection. This in vivo screening model for Chagas disease is predictive, reproducible and adaptable to diverse treatment schedules. It should provide greater assurance that drugs are not advanced prematurely into clinical trial. 相似文献
6.
Efficacy of Liposomal Amphotericin B and Posaconazole in Intratracheal Models of Murine Mucormycosis
Guanpingsheng Luo Teclegiorgis Gebremariam Hongkyu Lee Samuel W. French Nathan P. Wiederhold Thomas F. Patterson Scott G. Filler Ashraf S. Ibrahim 《Antimicrobial agents and chemotherapy》2013,57(7):3340-3347
Mucormycosis is a life-threatening fungal infection almost uniformly affecting diabetics in ketoacidosis or other forms of acidosis and/or immunocompromised patients. Inhalation of Mucorales spores provides the most common natural route of entry into the host. In this study, we developed an intratracheal instillation model of pulmonary mucormycosis that hematogenously disseminates into other organs using diabetic ketoacidotic (DKA) or cyclophosphamide-cortisone acetate-treated mice. Various degrees of lethality were achieved for the DKA or cyclophosphamide-cortisone acetate-treated mice when infected with different clinical isolates of Mucorales. In both DKA and cyclophosphamide-cortisone acetate models, liposomal amphotericin B (LAmB) or posaconazole (POS) treatments were effective in improving survival, reducing lungs and brain fungal burdens, and histologically resolving the infection compared with placebo. These models can be used to study mechanisms of infection, develop immunotherapeutic strategies, and evaluate drug efficacies against life-threatening Mucorales infections. 相似文献
7.
Katihuska Paredes Javier Capilla Emilio Mayayo Josep Guarro 《Antimicrobial agents and chemotherapy》2016,60(4):2063-2068
Scopulariopsis is an emerging opportunistic fungus characterized by its high resistance to antifungal therapies. We have developed a murine model of disseminated infection in immunosuppressed animals by intravenous inoculation of Scopulariopsis brevicaulis and Scopulariopsis brumptii, the most clinically relevant species, in order to evaluate their virulence and their responses to conventional antifungal treatments. Survival and tissue burden studies showed that S. brumptii was more virulent than S. brevicaulis. The three drugs tested, liposomal amphotericin B, posaconazole, and voriconazole, prolonged the survival of mice infected with S. brumptii, but none showed efficacy against S. brevicaulis. The different therapies were only able to modestly reduce the fungal burden of infected tissue; however, in general, despite the high serum levels reached, they showed poor efficacy in the treatment of the infection. Unfortunately, the most effective therapy for Scopulariopsis infections remains unresolved. 相似文献
8.
Nathan P. Wiederhold Laura K. Najvar Rosie Bocanegra John R. Graybill Thomas F. Patterson 《Antimicrobial agents and chemotherapy》2010,54(3):1055-1059
Invasive fusariosis is a highly aggressive fungal infection associated with high mortality in heavily immunocompromised patients. Although posaconazole is efficacious as salvage therapy against infections caused by Fusarium species, concerns remain regarding this agent in the setting of reduced potency. To evaluate the efficacy of posaconazole as treatment or prophylaxis against invasive fusariosis caused by Fusarium solani, we utilized a neutropenic murine model of disseminated disease. ICR mice were administered escalating doses of posaconazole (6.25, 12.5, 25, or 50 mg/kg of body weight twice daily [BID]) by oral gavage beginning 2 days prior to inoculation in the prophylaxis studies or beginning 12 h after inoculation as treatment. Therapy was continued until day 9 postinoculation, and animals were monitored off therapy until day 15 for survival. Fungal burden was assessed as CFU in the kidneys. A clear dose-response relationship was observed, as the highest dose of posaconazole (50 mg/kg) was the most effective in prolonging survival and reducing tissue fungal burden both as prophylaxis and as treatment. This dose response was associated with high posaconazole serum concentrations as measured by bioassay. However, the extent of efficacy was also dependent on the infecting inoculum, as greater increases in survival and reductions in fungal burden were observed with the lower inocula tested. In this model high dosages of posaconazole were effective as treatment and prophylaxis against disseminated fusariosis caused by F. solani.Fusarium species are among the leading causes of invasive mold infections among patients with hematologic malignancies and those undergoing hematopoietic stem cell transplantation (HSCT), with mortality exceeding 70% (1, 2, 15). Risk factors for disseminated infection include neutropenia, lymphopenia, graft-versus-host disease, corticosteroids, and immunosuppressive therapy (1, 2). In vitro studies have reported moderate to negligible activity of available antifungals against Fusarium, with amphotericin B and itraconazole having minimal activity (3, 8, 16). Reduced in vitro potency has also been reported for voriconazole and posaconazole when measured by standard microdilution methodology (3, 8, 16). However, both voriconazole and posaconazole have been shown to be effective in animal models of invasive fusariosis, including infections caused by isolates with reduced in vitro susceptibility (4, 10, 20).Modifications to testing parameters used in determining the in vitro activity (e.g., inoculum size and incubation period) may greatly affect the MIC against Fusarium isolates (8, 16). This suggests that the in vitro activity as measured by standard microdilution methodology may not be predictive of in vivo efficacy. Our objective was to assess the in vivo efficacy of posaconazole against disseminated fusariosis caused by Fusarium solani, both as treatment and as prophylaxis, and to compare this activity to the in vitro potency measured at 24 and 48 h against different starting inocula. In addition, posaconazole concentrations were measured in animals that were administered the same dosages used for treatment and prophylaxis. 相似文献
9.
Urshila Durani Pritish K. Tosh Jason N. Barreto Lynn L. Estes Paul J. Jannetto Aaron J. Tande 《Antimicrobial agents and chemotherapy》2015,59(8):4914-4918
While posaconazole prophylaxis decreases the risk of invasive fungal infection compared to fluconazole, low bioavailability of the oral-suspension formulation limits its efficacy. A new delayed-release tablet formulation demonstrated an improved pharmacokinetic profile in healthy volunteers. However, serum levels for the two formulations have not been compared in clinical practice. This study compared achievement of therapeutic posaconazole levels in patients taking the delayed-release tablet to those taking the oral suspension. This retrospective cohort study included 93 patients initiated on posaconazole between 2012 and 2014 and had at least one serum posaconazole level measured. The primary measure was the proportion of patients achieving an initial therapeutic level (>700 ng/ml). An initial therapeutic posaconazole level was seen in 29 of 32 (91%) patients receiving tablets and 37 of 61 (61%) patients receiving suspension (P = 0.003). Among patients with a steady-state level measured 5 to 14 days after initiation, a therapeutic level was observed in 18 of 20 (90%) patients receiving tablets and 25 of 43 (58%) patients receiving suspension (P = 0.01). In these patients, the median posaconazole level of the tablet cohort (1655 ng/ml) was twice that of the suspension cohort (798 ng/ml) (P = 0.004). In this cohort study, the improved bioavailability of delayed-release posaconazole tablets translates into a significantly higher proportion of patients achieving therapeutic serum levels than in the cohort receiving the oral suspension. The results of this study strongly support the use of delayed-release tablets over suspension in patients at risk for invasive fungal infection. 相似文献
10.
Russell E. Lewis Nathaniel D. Albert Dimitrios P. Kontoyiannis 《Antimicrobial agents and chemotherapy》2014,58(11):6767-6772
We used two established neutropenic murine models of pulmonary aspergillosis and mucormycosis to explore the association between the posaconazole area under the concentration-time curve (AUC)-to-MIC ratio (AUC/MIC) and treatment outcome. Posaconazole serum pharmacokinetics were verified in infected mice to ensure that the studied doses reflected human exposures with the oral suspension, delayed-release tablet, and intravenous formulations of posaconazole. Sinopulmonary infections were then induced in groups of neutropenic mice with Aspergillus fumigatus strain 293 (posaconazole MIC, 0.5 mg/liter) or Rhizopus oryzae strain 969 (posaconazole MIC, 2 mg/liter) and treated with escalating daily dosages of oral posaconazole, which was designed to achieve AUCs ranging from 1.10 to 392 mg · h/liter. After 5 days of treatment, lung fungal burden was analyzed by quantitative real-time PCR. The relationships of the total drug AUC/MIC and the treatment response were similar in both models, with 90% effective concentrations (EC90s) corresponding to an AUC/MIC threshold of 76 (95% confidence interval [CI], 46 to 102) for strain 293 versus 87 (95% CI, 66 to 101) for strain 969. Using a provisional AUC/MIC target of >100, these exposures correlated with minimum serum posaconazole concentrations (Cmins) of 1.25 mg/liter for strain 293 and 4.0 mg/liter for strain 969. The addition of deferasirox, but not liposomal amphotericin or caspofungin, improved the activity of a suboptimal posaconazole regimen (AUC/MIC, 33) in animals with pulmonary mucormycosis. However, no combination was as effective as the high-dose posaconazole monotherapy regimen (AUC/MIC, 184). Our analysis suggests that posaconazole pharmacodynamics are similar for A. fumigatus and R. oryzae when indexed to pathogen MICs. 相似文献
11.
Activity of posaconazole in the treatment of central nervous system fungal infections 总被引:6,自引:0,他引:6
Pitisuttithum P Negroni R Graybill JR Bustamante B Pappas P Chapman S Hare RS Hardalo CJ 《The Journal of antimicrobial chemotherapy》2005,56(4):745-755
OBJECTIVES: A multinational, multicentre, open-label clinical trial was conducted to evaluate the safety and efficacy of posaconazole, an extended-spectrum triazole antifungal agent, in subjects with invasive fungal infections who had refractory disease or who were intolerant of standard antifungal therapy. In this subanalysis, we report on those subjects in this trial who had a fungal infection that involved the CNS. METHODS: Subjects received posaconazole oral suspension 800 mg/day in divided doses for up to 1 year; however, subjects could receive additional therapy as part of a treatment-use extension protocol. A blinded, third-party data review committee determined subject eligibility and outcome. RESULTS: Of the 330 subjects who enrolled in the study, 53 had infections of the CNS, of which 39 were considered evaluable for efficacy. Most had refractory disease (37 of 39) and underlying HIV infection (29 of 39). Twenty-nine subjects had cryptococcal infections, and 10 had infections caused by other fungal pathogens [Aspergillus spp. (four), Pseudallescheria boydii (two), Coccidioides immitis (one), Histoplasma capsulatum (one), Ramichloridium mackenziei (one), and Apophysomyces elegans plus a Basidiomycetes sp. (one)]. Successful outcomes were observed in 14 of 29 (48%) subjects with cryptococcal meningitis and five of 10 (50%) subjects with CNS infections due to other fungal pathogens. Posaconazole was well tolerated. CONCLUSIONS: These data suggest that posaconazole, as an oral medication, has clinical activity against fungal infections of the CNS and may provide a valuable alternative to parenteral therapy in patients failing existing antifungal agents. 相似文献
12.
Jeane P. Hester Maria C. Dignani Elias J. Anaissie Hagop M. Kantarjian Susan O'brien Emil J Freireich 《Journal of clinical apheresis》1995,10(4):188-193
Fifteen patients with prolonged neutropenia (a median of 23 days with granulocyte [PMN] ≤ 500/μl) and established fungal infections that had not responded to adequate antifungal therapy were transfused with PMN concentrates collected from 35 cytokine-primed granulocyte colony-stimulating factor (GCSF) donors. Patients received a median of six transfusions. Leukocytosis and granulocytosis were observed within 24 hours of the first GCSF injection, which yielded concentrates averaging 55 × 109 white blood cells and 41 × 109 PMN. Data analysis suggested that response might be related to the duration of neutropenia and known infection, as patients given PMN tx earlier in the infectious course tended to have a better response. No significant toxicity was observed in donors. 相似文献
13.
Anthony Weinstock Natarajan Arumugam Abdulrahman I. Almansour Raju Suresh Kumar Shankar Thangamani 《RSC advances》2019,9(51):29909
Invasive fungal infections caused by Candida and Cryptococcus species lead to life threating infections in immunocompromised individuals. Furthermore, increasing incidence of fungal strains resistant to FDA-approved antifungal drugs along with the paucity of antifungal drugs warrants novel drugs to treat invasive fungal infections. In this study, we investigated the antifungal activity of a novel series of diazahexa/hepta cyclic cage-like compounds. Results indicate that compounds with unsubstituted and o-methyl substitution on aryl rings exhibit potent broad-spectrum antifungal activity against various fungal strains. In addition, these compounds showed significant inhibitory activity against Candida hyphae and biofilm formation. Collectively, results from this study indicate that these compounds are promising candidates to develop as novel antifungal drugs to treat drug-resistant fungal infections.The synthesized cage-like compounds has been investigated for their antifungal activity against Candida and Cryptococcus species. 相似文献
14.
《Diagnostic microbiology and infectious disease》2014,79(4):428-431
We have evaluated the efficacy of amphotericin B, posaconazole, and voriconazole in immunosuppressed murine models of disseminated infection by Curvularia spicifera and Curvularia hawaiiensis. The 3 antifungals improved survival of mice in comparison to controls; however, only the 2 azoles were able to reduce significantly the fungal load. 相似文献
15.
Antifungal therapy of experimental cerebral phaeohyphomycosis due to Cladophialophora bantiana
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Al-Abdely HM Najvar LK Bocanegra R Graybill JR 《Antimicrobial agents and chemotherapy》2005,49(5):1701-1707
Cladophialophora bantiana is associated with central nervous system infection and a poor outcome. C. bantiana tends to be resistant to amphotericin B. Accordingly, we evaluated amphotericin B and three triazoles--posaconazole, itraconazole, and fluconazole--for treatment of C. bantiana infection in mice. In immunosuppressed ICR mice infected intravenously, posaconazole, itraconazole, and amphotericin B prolonged survival. This improvement in survival corresponded with a reduction in brain fungal concentrations for mice which were given itraconazole and posaconazole, but not amphotericin B. In nonimmunosuppressed BALB/c mice infected intracerebrally, posaconazole showed dose-dependent responses in survival and reduction of brain tissue counts. These responses were observed for short, delayed, and prolonged therapy. Although posaconazole prolonged the survival of mice with reductions in brain fungal counts, it did not sterilize brain tissue with continuous therapy for 8 weeks. We concluded that posaconazole shows promise for the treatment of C. bantiana brain infections. 相似文献
16.
Geraldine Nouailles Anca Dorhoi Markus Koch Jens Zerrahn January Weiner rd Kellen C. Faé Frida Arrey Stefanie Kuhlmann Silke Bandermann Delia Loewe Hans-Joachim Mollenkopf Alexis Vogelzang Catherine Meyer-Schwesinger Hans-Willi Mittrücker Gayle McEwen Stefan H.E. Kaufmann 《The Journal of clinical investigation》2014,124(3):1268-1282
Successful host defense against numerous pulmonary infections depends on bacterial clearance by polymorphonuclear leukocytes (PMNs); however, excessive PMN accumulation can result in life-threatening lung injury. Local expression of CXC chemokines is critical for PMN recruitment. The impact of chemokine-dependent PMN recruitment during pulmonary Mycobacterium tuberculosis infection is not fully understood. Here, we analyzed expression of genes encoding CXC chemokines in M. tuberculosis–infected murine lung tissue and found that M. tuberculosis infection promotes upregulation of Cxcr2 and its ligand Cxcl5. To determine the contribution of CXCL5 in pulmonary PMN recruitment, we generated Cxcl5–/– mice and analyzed their immune response against M. tuberculosis. Both Cxcr2–/– mice and Cxcl5–/– mice, which are deficient for only one of numerous CXCR2 ligands, exhibited enhanced survival compared with that of WT mice following high-dose M. tuberculosis infection. The resistance of Cxcl5–/– mice to M. tuberculosis infection was not due to heightened M. tuberculosis clearance but was the result of impaired PMN recruitment, which reduced pulmonary inflammation. Lung epithelial cells were the main source of CXCL5 upon M. tuberculosis infection, and secretion of CXCL5 was reduced by blocking TLR2 signaling. Together, our data indicate that TLR2-induced epithelial-derived CXCL5 is critical for PMN-driven destructive inflammation in pulmonary tuberculosis. 相似文献
17.
BACKGROUND: The incidence of invasive fungal infections (IFIs) caused by opportunistic filamentous molds is increasing, along with emerging fungal resistance. Posaconazole, a structural analogue of itraconazole that was approved for marketing in the United States in 2006, appears to be a promising antifungal agent. OBJECTIVE: This article provides an overview of the pharmacology, efficacy, and tolerability of posaconazole when used for the prophylaxis and treatment of various common and rare fungal infections. METHODS: Relevant information was identified through a search of MEDLINE (1966-April 2007), International Pharmaceutical Abstracts (1970-April 2007), and abstracts of the Interscience Conference on Antimicrobial Agents and Chemotherapy using the terms posaconazole and SCH 56592. Additional resources were found by searching the reference lists of the identified articles and the US Food and Drug Administration Web site. RESULTS: Posaconazole is available as an oral suspension. It is highly distributed to various sites, including bone, the central nervous system, and eye tissue. Its Vd is 2447 L when administered in multiple daily doses (up to 800 mg/d) in the presence of a high-fat meal. Because it is excreted mostly as unchanged drug in the feces (77%), posaconazole can be administered to patients with poor renal function without any dose adjustment. Posaconazole has shown in vitro and in vivo activity against a wide variety of fungi, including those that are rare and relatively resistant. Two clinical trials have compared posaconazole with fluconazole or itraconazole for the prophylaxis of IFIs in immunocompromised patients. The first, a randomized, double-blind trial in 600 recipients of hematopoietic stem cell transplants, found that overall rates of IFI did not differ significantly between posaconazole and fluconazole (5% vs 9%, respectively). The other, a randomized, open-label trial in 602 neutropenic patients, reported significantly fewer IFIs in patients receiving posaconazole compared with those receiving fluconazole or itraconazole (>2% vs >8%, respectively; P = 0.001). An additional 2 trials have investigated posaconazole for the treatment of oropharyngeal candidiasis (OPC) in patients with HIV infection. A randomized, controlled, evaluator-blinded study in 350 HIV-infected patients with OPC found similar 14-day clinical success rates with posaconazole and fluconazole (91.7% and 92.5%, respectively; 95% CI, -6.6l to 5.04), whereas an open-label study in 176 HIV-infected patients with a history of refractory OPC reported a 28-day clinical success rate of 75%. Numerous small studies and case reports have described successful posaconazole treatment of zygomycosis, aspergillosis, fusariosis, endemic dimorphic fungal infection, and superficial and subcutaneous fungal infections that were refractory to conventional antifungal agents or in patients who were unable to tolerate these agents. Posaconazole has been well tolerated. The most common complaints have been gastrointestinal in nature, including nausea (7%-8%) and diarrhea (3%-11%), although these have rarely led to permanent discontinuation of therapy. Other common adverse effects have included vomiting (4%-7%), headache (2%-8%), and liver enzyme elevations (2%-3%). CONCLUSIONS: Posaconazole suspension administered at up to 800 mg/d is a reasonable alternative to conventional antifungal agents for the prevention and treatment of IFIs in high-risk populations. It may also be suitable in patients with infections caused by rare or relatively resistant fungi, and those who are unable to tolerate long-term therapy with other antifungal agents. 相似文献
18.
Seyedmojtaba Seyedmousavi Roger J. M. Brüggemann Willem J. G. Melchers Paul E. Verweij Johan W. Mouton 《Antimicrobial agents and chemotherapy》2014,58(5):2964-2967
Adequate penetration to the infection/colonization site is crucial to attain optimal efficacy of posaconazole against Aspergillus fumigatus diseases. We evaluated posaconazole exposure in pulmonary epithelial lining fluid (ELF) in a murine model of invasive pulmonary aspergillosis. The posaconazole exposure (area under the plasma concentration-time curve from time zero to 24 h postinfusion [AUC0–24]) in ELF was 20% to 31% of that in plasma for total drug after the third dose, and the relationship between plasma and ELF exposure was linear (r2 = 0.97, P = 0.016). 相似文献
19.
Expression of elastase on polymorphonuclear neutrophils in vitro and in vivo: identification of CD11b as ligand for the surface-bound elastase 总被引:1,自引:0,他引:1
Zimmermann F Lautenschläger K Heppert V Wentzensen A Hänsch GM Wagner C 《Shock (Augusta, Ga.)》2005,23(3):216-223
Elastase is a major serine protease of polymorphonuclear neutrophils (PMN). On activation of PMN, the preformed protein is mobilized from intracellular stores and, depending on the activating conditions, is either released into the supernatant or is bound to the cell surface. By a variety of methods, including uptake and crosslink studies, as well as confocal laser scan microscopy, we now provide evidence that elastase binds to the beta(2)-integrin CD11b and induces a conformational alteration of CD11b, apparent as expression of a neodeterminant. Similarly to the in vitro data, elastase surface expression and conformational alterations of CD11b were seen on PMN of patients with Staphylococcus aureus-induced localized infection, particularly on PMNs recovered from the infected site. The presence of elastase at the site of inflammation is in keeping with its presumed role in leukocyte trafficking and host defense. On the other hand, because of its potential for degrading extracellular matrix proteins, elastase could participate in localized tissue damage as it occurs in severe S. aureus infection. 相似文献
20.
Antineutrophil Cytoplasmic Autoantibodies Interact with Primary Granule Constituents on the Surface of Apoptotic Neutrophils in the Absence of Neutrophil Priming 总被引:12,自引:0,他引:12
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Hannah M. Gilligan Brunel Bredy Hugh R. Brady Marie-Jose Hbert Henry S. Slayter Yuhui Xu Joyce Rauch Michael A. Shia Jason S. Koh Jerrold S. Levine 《The Journal of experimental medicine》1996,184(6):2231-2242
The pathogenic role of antineutrophil cytoplasmic autoantibodies (ANCA) remains controversial because of the difficulty in explaining how extracellular ANCA can interact with intracellular primary granule constituents. It has been postulated that cytokine priming of neutrophils (PMN), as may occur during a prodromal infection, is an important trigger for mobilization of granules to the cell surface, where they may interact with ANCA. We show by electron microscopy that apoptosis of unprimed PMN is also associated with the translocation of cytoplasmic granules to the cell surface and alignment just beneath an intact cell membrane. Immunofluorescent microscopy and FACS® analysis demonstrate reactivity of ANCA-positive sera and antimyeloperoxidase antibodies with apoptotic PMN, but not with viable PMN. Moreover, we show that apoptotic PMN may be divided into two subsets, based on the presence or absence of granular translocation, and that surface immunogold labeling of myeloperoxidase occurs only in the subset of PMN showing translocation. These results provide a novel mechanism that is independent of priming, by which ANCA may gain access to PMN granule components during ANCA-associated vasculitis. 相似文献