Advances against aspergillosis.
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Antifungal Agents↗
Biomedical subjects
David A Stevens
Publications and source records attributed to David A Stevens.
Review of newer antifungal and immunomodulatory strategies for invasive aspergillosis.
The incidence of invasive aspergillosis is markedly increasing, and mortality remains dismal. Previously there were only 2 antifungals with activity against Aspergillus, but over the last few years there has been an explosion of newer agents and reformulations of older antifungals. Exploration has also begun with immunotherapy, with use of cytokines and granulocyte transfusions alone or in combination with antifungal therapy. This review will detail the available in vitro, in vivo, and clinical experience with the newer antifungal and immunomodulatory therapies in development for treatment of invasive aspergillosis.
Aminoglycosides↗
Combination and sequential antifungal therapy for invasive aspergillosis: review of published in vitro and in vivo interactions and 6281 clinical cases from 1966 to 2001.
The development of newer antifungal drugs is creating new potential combination therapies to combat the dismal mortality rate associated with invasive aspergillosis (IA). The efficacy of combination therapy for IA has not been established; sparse data on combination or sequential antifungal therapy depict interactions ranging from synergy to antagonism. We reviewed data from all published in vitro studies, animal model studies, and clinical reports and recent abstracts on combination and sequential antifungal therapy for IA from 1966-2001. Among cases of IA during 1966-2001, 249 were treated with 23 different antifungal combinations. Amphotericin B plus 5-fluorocytosine was the most commonly used (49% of cases), followed by amphotericin B plus itraconazole (16%) or plus rifampin (11%). Combination therapy resulted in improvement in 63% of patients, generally with amphotericin B plus 5-fluorocytosine or rifampin and indifference with amphotericin B plus itraconazole. In 27 in vitro reports, we found synergy (in 36% of reports), additivity (in 24%), indifference (in 28%), and antagonism (in 11%). Amphotericin B plus 5-fluorocytosine and amphotericin B plus rifampin showed generally positive interactions and amphotericin B plus itraconazole showed results that were largely indifferent. Eighteen animal model reports demonstrated synergy (in 14% of reports), additivity (in 20%), indifference (in 51%), and antagonism (in 14%). In general, amphotericin B plus 5-fluorocytosine, amphotericin B plus rifampin, and amphotericin B plus itraconazole showed indifferent results, whereas amphotericin B plus micafungin showed positive interactions. Thirty-four cases treated during 1990-2001 with sequential therapy, excluding amphotericin B followed by itraconazole, showed improvement in 68% of cases. Improvement was noted with amphotericin B or itraconazole followed by voriconazole but not with itraconazole followed by amphotericin B.
Amphotericin B↗
Allergic bronchopulmonary aspergillosis in cystic fibrosis--state of the art: Cystic Fibrosis Foundation Consensus Conference.
Because of the difficulties of recognizing allergic bronchopulmonary aspergillosis (ABPA) in the context of cystic fibrosis (because of overlapping clinical, radiographic, microbiologic, and immunologic features), advances in our understanding of the pathogenesis of allergic aspergillosis, new possibilities in therapy, and the need for agreed-upon definitions, an international consensus conference was convened. Areas addressed included fungal biology, immunopathogenesis, insights from animal models, diagnostic criteria, epidemiology, the use of new immunologic and genetic techniques in diagnosis, imaging modalities, pharmacology, and treatment approaches. Evidence from the existing literature was graded, and the consensus views were synthesized into this document and recirculated for affirmation. Virulence factors in Aspergillus that could aggravate these diseases, and particularly immunogenetic factors that could predispose persons to ABPA, were identified. New information has come from transgenic animals and recombinant fungal and host molecules. Diagnostic criteria that could provide a framework for monitoring were adopted, and helpful imaging features were identified. New possibilities in therapy produced plans for managing diverse clinical presentations.
Animals↗
Glycogen synthase kinase-3 inhibitors protect central neurons against excitotoxicity.
Protein kinase B (PKB, or Akt), a downstream effector of phosphatidylinositol 3-kinase (PI-3-K), can play a critical role in regulating neuronal survival. Among known targets of PKB, glycogen synthase kinase-3 (GSK-3) is inhibited by PKB-mediated phosphorylation. Recent studies implicate GSK-3 as a physiologically relevant principal regulatory target of the PI-3-K/PKB survival pathway. Here we show that SB-216763 and SB-415286, selective small molecule inhibitors of GSK-3, protected cultured rat cerebellar granule neurons and hippocampal neurons against excitotoxicity mediated by NMDA and non-NMDA receptor agonists. Treatment with SB-216763 and SB-415286 was optimal when initiated 6-7 days before excitotoxin exposure. As GSK-3 can modulate transcriptional events, these results may provide insight into the identification of new neuroprotective targets.
Aminophenols↗
Thyroid hormone activates fibroblast growth factor receptor-1 in bone.
Thyroid hormone (T3) and the T3 receptor (TR) alpha gene are essential for bone development whereas adult hyperthyroidism increases the risk of osteoporotic fracture. We isolated fibroblast growth factor receptor-1 (FGFR1) as a T3-target gene in osteoblasts by subtraction hybridization. FGFR1 mRNA was induced 2- to 3-fold in osteoblasts treated with T3 for 6-48 h, and FGFR1 protein was stimulated 2- to 4-fold. Induction of FGFR1 was independent of mRNA half-life and abolished by actinomycin D and cycloheximide, indicating the involvement of an intermediary protein. Fibroblast growth factor 2 (FGF2) stimulated MAPK in osteoblasts, and pretreatment with T3 for 6 h induced a more rapid response to FGF that was increased in magnitude by 2- to 3-fold. Similarly, T3 enhanced FGF2-activated autophosphorylation of FGFR1, but did not modify FGF2-induced phosphorylation of the docking protein FRS2. These effects were abolished by the FGFR-selective inhibitors PD166866 and PD161570. In situ hybridization analyses of TRalpha-knockout mice, which have impaired ossification and skeletal mineralization, revealed reduced FGFR1 mRNA expression in osteoblasts and osteocytes, whereas T3 failed to stimulate FGFR1 mRNA or enhance FGF2-activated MAPK signaling in TRalpha-null osteoblasts. These findings implicate FGFR1 signaling in T3-dependent bone development and the pathogenesis of skeletal disorders resulting from thyroid disease.
Animals↗
Caspofungin.
Caspofungin, the first inhibitor of fungal beta-1,3 glucan synthesis to receive approval by the United States Food and Drug Administration, is effective for the treatment of mucosal and invasive candidiasis and invasive aspergillosis. It is also active in vitro and in animal models against a number of other filamentous and dimorphic endemic fungi and in animal models of Pneumocystis carinii infection. In vitro studies and some animal studies almost always indicate an absence of antagonism when caspofungin is combined with azole or polyene antifungal agents. Caspofungin has an excellent safety profile. Caspofungin may prove to be useful in empirical therapy for suspected invasive fungal infections. Additional clinical trial data that expand our knowledge of the usefulness of caspofungin for these and other mycoses, including its administration in combination with other antifungal agents, is anticipated. Caspofungin is an important addition to the antifungal pharmacopoeia.
Anti-Bacterial Agents↗
Regulation by granulocyte-macrophage colony-stimulating factor and/or steroids given in vivo of proinflammatory cytokine and chemokine production by bronchoalveolar macrophages in response to Aspergillus conidia.
Production of the proinflammatory cytokines interleukin (IL)-1 alpha and tumor necrosis factor (TNF)-alpha and of the chemotactic chemokine macrophage inflammatory protein (MIP)-1 alpha by bronchoalveolar macrophages (BAMs) from mice in response to Aspergillus conidia was tested after in vivo administration of saline, dexamethasone, cortisone acetate, granulocyte-macrophage colony-stimulating factor (GM-CSF), or a combination. Dexamethasone suppressed production of IL-1 alpha, TNF-alpha, and MIP-1 alpha; GM-CSF reduced secretion slightly but antagonized dexamethasone suppression when the two were given in combination. Cortisone acetate gave results similar to dexamethasone, but cortisone acetate suppression of BAM responses lasted 7 days, > or = 4 days longer than dexamethasone suppression. The effect of GM-CSF on cortisone acetate suppression lasted at least 7 days. GM-CSF could promote resistance to conidia by maintaining proinflammatory responses.
Animals↗
A murine model of coccidioidal meningitis.
Coccidioidal meningitis is lethal in humans. A reproducible murine model was established by lumbar intrathecal injection of Coccidioides immitis arthroconidia. Cerebrospinal fluid (CSF) samples were obtained by cisternal puncture. Lethal infection developed in all mice given 10-60 colony-forming units (cfu). Lethargy, ataxia, or paralysis preceded death. Temporal studies after challenge with 27 cfu revealed positive brain (4/5 mice) and spinal cord (2/5 mice) cultures on day 3; CSF samples contained 688 leukocytes/mm(3) and 33 cfu/mL. The results of histopathologic analysis were unremarkable. By day 8, all mice were culture positive (5.0 log(10) cfu in brain tissue and 4.1 log(10) cfu in spinal cord tissue); CSF samples contained 4833 leukocytes/mm(3) and 3425 cfu/mL. Histopathologic examinations showed acute meningitis of the brain and spinal cord, some parenchymal invasion and abscesses, and meningeal arteritis. Groups of mice given ketoconazole had prolonged survival and suppressed lung disease; histopathologic examination demonstrated granulomatous meningitis, possibly a more chronic form. With the development of these models, studies of pathogenesis, host response, and therapy are possible.
Animals↗
Antifungal drug resistance.
The increasing incidence of invasive fungal infections is the result of many factors, including an increasing number of patients with severe immunosuppression. Although new drugs have been introduced to combat this problem, the development of resistance to antifungal drugs has become increasingly apparent, especially in patients who require long-term treatment or who are receiving antifungal prophylaxis, and there is growing awareness of shifts of flora to more-resistant species. The frequency, interpretation, and, in particular, mechanism of resistance to current classes of antifungal agents, particularly the azoles (where resistance has climbed most prominently) are discussed in this review.
Antifungal Agents↗
Coccidioidomycosis.
Coccidioides, a fungus, is endemic to specific parts of the Western Hemisphere. This article examines the prevalence, pathogenesis and host defense, clinical manifestations, diagnosis, and treatment of coccidioidomycosis.
AIDS-Related Opportunistic Infections↗
Management of varicella-vaccinated patients and employees exposed to varicella in the healthcare setting.
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Algorithms↗
Efficacy of amphotericin B or itraconazole in a murine model of central nervous system Aspergillus infection.
Given the greater than 90% lethality of clinical central nervous system (CNS) aspergillosis despite current therapies, there is a need for an animal model to study therapeutic strategies. We previously established a model of CNS aspergillosis by intracerebral infection and report here the results of treatment with the two therapies with the greatest clinical experience, i.e., treatments with amphotericin B (AMB) and itraconazole (ITZ). Mice were given cyclophosphamide to produce pancytopenia. AMB was given intraperitoneally (i.p.; 3 mg/kg of body weight) or intravenously (i.v.; 0.8 mg/kg) once daily. ITZ in cyclodextrin was given by gavage once daily at a dose of 100 mg/kg or twice daily at 50 mg/kg. Treatments were started at day 1 postinfection and given for 10 days. At day 15, survivors were euthanatized. Ninety percent of the mice given no treatment died by day 6, and 100% died by day 10. Mice treated with AMB either i.p. or i.v. had 40% survival. Mice treated with ITZ either once or twice per day had a median survival time of 10 days, compared with 4 days for control animals, but a survival rate of only 10%. AMB and ITZ prolonged survival (P, <0.0001 to <0.05) compared with controls. Brains from surviving mice had CFU of Aspergillus fumigatus. This model can be used to compare newer antifungals and to study combination therapy or immunotherapy to find better therapeutic alternatives.
Amphotericin B↗
Efficacy of micafungin alone or in combination against systemic murine aspergillosis.
We tested the efficacy of micafungin (FK) alone or in combination with other antifungals against systemic murine aspergillosis. FK alone at 10 mg/kg of body weight/dose prolonged survival (P = 0.01) and reduced CFU in the brain and kidney. Combination therapy that used suboptimal FK with amphotericin B or itraconazole prolonged survival. Although no survivors were free of infection, no antagonism was seen. Nikkomycin Z with FK showed significantly greater potency (P < 0.01) than either alone.
Amphotericin B↗
Levels of matrix metalloproteinase-9 within cerebrospinal fluid in a rabbit model of coccidioidal meningitis and vasculitis.
Matrix metalloproteinase (MMP)-9 is produced by the central nervous system and inflammatory cells in a variety of inflammatory conditions in both animals and humans. MMP-9 promotes inflammation, breakdown of the blood-brain barrier, and vasculitis. Because vasculitis is seen frequently in patients with coccidioidal meningitis (CM), this study evaluated the presence of MMP-9 within the cerebrospinal fluid (CSF) of rabbits infected intracisternally with Coccidioides immitis arthroconidia. Infected rabbits demonstrated systemic and neurological sequelae to infection, including CSF pleocytosis. Levels of MMP-9 within CSF were assayed by use of zymography and compared with MMP-2 levels, which served as an internal control. Elevated levels of MMP-9 were detectable by day 3, continued to increase through day 10, and declined by day 15 after infection. MMP-9 may contribute to inflammation and vasculitis in this animal model. Future work can focus on evaluation of MMP inhibitors, to gain a better perspective of the role of this MMP in CM.
Animals↗
Development of a murine model of cerebral aspergillosis.
Central nervous system (CNS) Aspergillus infection has a mortality rate in humans that approaches 95%. Because no animal models are available for studying this infection, we sought to develop a murine model of CNS aspergillosis. Inconsistent data were obtained for nonimmunosuppressed CD-1, C57BL/6, and DBA/2N mice after infection by midline intracranial injection of Aspergillus fumigatus. CD-1 mice given cyclophosphamide to produce immunosuppression had continuous pancytopenia. Dose-finding studies in CD-1 mice showed that infection with 5 x 106 conidia/mouse consistently caused 100% mortality by day 5-8; no mice died before day 3. Histologic examination of samples of brain tissue showed focal abscesses containing Aspergillus hyphae. Fungus burdens in brain were higher than those in other organs, although Aspergillus disseminated to the kidneys and the spleen. The model we established provides an opportunity to study immune responses to and therapeutic options for CNS disease in an immunologically defined, genetically manipulable, and inexpensive species.
Animals↗
Regulation of bronchoalveolar macrophage proinflammatory cytokine production by dexamethasone and granulocyte-macrophage colony-stimulating factor after stimulation by Aspergillus conidia or lipopolysaccharide.
There is substantial evidence that local production of proinflammatory cytokines are very important in host resistance to aspergillosis. Dexamethasone (DEX) down-regulates production of these cytokines by stimulated bronchoalveolar macrophages (BAM) and constitutes a risk factor for aspergillosis. Granulocyte-macrophage colony-stimulating factor (GM-CSF) antagonizes DEX suppression of antifungal activity by BAM. Here we investigated the possibility that GM-CSF could antagonize DEX down-regulation of interleukin (IL)-1alpha and tumour necrosis factor (TNF)-alpha production by stimulated BAM. Control BAM responded to increasing numbers of conidia of Aspergillus fumigatus with increasing production of IL-1 and TNF. DEX (10(-7)M) significantly suppressed IL-1 and TNF production by BAM+conidia. Although GM-CSF did not enhance IL-1 or TNF production by BAM+conidia, GM-CSF significantly antagonized DEX suppression of IL-1 cytokine production. For comparative purposes, lipopolysaccharide (LPS, 1 microg/ml) was used to stimulate BAM in experiments similar to the above. In contrast to the findings with conidia, GM-CSF enhanced the production of IL-1 (5-fold) and TNF (1.5-fold) by LPS treated BAM. DEX suppression of cytokine production by BAM+LPS was modestly but significantly antagonized by GM-CSF. Moreover, differences between regulation of IL-1 and TNF production by BAM+conidia or LPS and peritoneal macrophages (PM)+conidia or LPS were documented. Finally, the anti-inflammatory cytokine IL-10 was minimally produced by BAM + conidia or LPS, but IL-10 was produced by PM + conidia or LPS. In summary, these data indicate that the risk factor for aspergillosis associated with DEX could be lessened in the pulmonary compartment with GM-CSF. On the other hand, desired effects of DEX could be maintained in other compartments.
Animals↗
Protection of peritoneal macrophages by granulocyte/macrophage colony-stimulating factor (GM-CSF) against dexamethasone suppression of killing of Aspergillus, and the effect of human GM-CSF.
Murine peritoneal macrophages in vitro could kill Aspergillus fumigatus conidia, and this activity could be suppressed with dexamethasone. Treatment with granulocyte/macrophage colony-stimulating factor (GM-CSF) alone did not boost killing, but GM-CSF treatment concurrently with dexamethasone reversed the dexamethasone suppression. Both recombinant human and recombinant murine GM-CSF were equivalent in this activity, even though the human reagent reportedly does not stimulate differentiation of murine stem cells. Recombinant human GM-CSF could also reverse dexamethasone suppression of bronchoalveolar macrophage conidiacidal activity. Sequential studies with peritoneal macrophages indicated that recombinant human GM-CSF pretreatment also blocked dexamethasone suppression, but the GM-CSF treatment given after dexamethasone did not block the suppressive effect. Recombinant human GM-CSF did not boost spleen cell proliferation to a mitogenic stimulus, and did not reverse dexamethasone suppression of proliferation. These studies suggest GM-CSF treatment prior to and concurrent with steroid immunosuppression may ameliorate the steroid effect on tissue macrophage antifungal activity, but does not affect steroid suppression of T-cell immunity.
Animals↗