amphotericin-b and Inflammation

Saksenaea vasiformis is an emerging human pathogen, belonging to the order Mucorales of the subphylum Mucormycotina, most often associated with rhino-cerebral, cutaneous and subcutaneous infections following trauma. A review of the published literature was attempted on the occasion of a cutaneous leg infection with favorable outcome in a young immunocompetent man after mild injury. The overall aim was the facilitation of the study and the integrated understanding of this kind of fungal infections.

Topics: Adult; Amphotericin B; Antifungal Agents; Debridement; Humans; Immunocompetence; Inflammation; Leg; Leg Injuries; Magnetic Resonance Imaging; Male; Mucorales; Mucormycosis

Severe asthma with fungal sensitisation and allergic bronchopulmonary aspergillosis encompass two closely related subgroups of patients with severe allergic asthma. Pulmonary disease is due to pronounced host inflammatory responses to noninvasive subclinical endobronchial infection with filamentous fungi, usually Aspergillus fumigatus. These patients usually do not achieve satisfactory disease control with conventional treatment of severe asthma, i.e. high-dose inhaled corticosteroids and long-acting bronchodilators. Although prolonged systemic corticosteroids are effective, they carry a substantial toxicity profile. Supplementary or alternative therapies have primarily focused on use of antifungal agents including oral triazoles and inhaled amphotericin B. Immunomodulation with omalizumab, a humanised anti-IgE monoclonal antibody, or "pulse" monthly high-dose intravenous corticosteroid, has also been employed. This article considers the experience with these approaches, with emphasis on recent clinical trials.

Topics: Adrenal Cortex Hormones; Amphotericin B; Antibodies, Anti-Idiotypic; Antibodies, Monoclonal; Antifungal Agents; Aspergillosis, Allergic Bronchopulmonary; Aspergillus fumigatus; Asthma; Clinical Trials as Topic; Humans; Inflammation; Triazoles

The chemotactic responses of leukocytes are initiated by the binding of chemoattractants to specific cell-surface receptors. At larger doses, chemoattractants stimulate other biologic activities in leukocytes, including the production of superoxide anions and the secretion of lysosomal enzymes. The tissue-destructive properties of inflammatory cells relate largely to these latter two biologic responses. It has recently been shown that the oligopeptide chemotactic factor receptor in human polymorphonuclear leukocyte membranes exists in high- and low-affinity states that are interconvertible and regulated by guanine nucleotides. In whole polymorphonuclear leukocytes, only one affinity of the receptor can be seen due to rapidly ongoing cellular processes. This affinity can be modified by agents that alter the physical state of the membrane and can be enhanced by aliphatic alcohols, agents that decrease membrane microviscosity. Under these conditions, the chemotactic responsiveness of polymorphonuclear leukocytes is enhanced, but lysosomal enzyme secretion and superoxide anion production are markedly depressed. Polyene antibiotics, which bind membrane cholesterol, decrease the affinity of the receptor. These agents also depress chemotaxis but enhance lysosomal enzyme secretion. These findings indicate that the transduction mechanisms for certain biologic responses initiated by chemoattractant receptors are heterogeneous. The particular transduction pathway initiated by chemotactic factors is reflected by the affinity state of the receptor. The higher affinity initiates chemotaxis whereas the lower affinity initiates lysosomal enzyme secretion and superoxide anion production. These findings suggest that pharmacologic agents may well be developed, which can selectively affect the specific functions of polymorphonuclear leukocytes in man. Anti-inflammatory agents that can decrease leukocyte lysosomal enzyme secretion and superoxide anion production, but not chemotaxis, may well be useful in the treatment of certain rheumatic diseases.

Topics: Amphotericin B; Chemotactic Factors; Chemotaxis, Leukocyte; Guanine Nucleotides; Humans; Inflammation; Membrane Fluidity; Models, Biological; Neutrophils; Oligopeptides; Phagocytes; Receptors, Cell Surface; Receptors, Formyl Peptide

It has been suggested that an exaggerated immune response to fungi is crucial in the pathogenesis of chronic rhinosinusitis (CRS). Based on this rationale, the use of topical antifungals (amphotericin B) has been advocated. Studies on its clinical effectiveness are, however, contradictory.. To examine the effect of nasal antifungal treatment on secreted mediators in samples of nasal lavage fluid from patients with CRS with or without nasal polyps (NP).. Part two of a prospective double-blind, placebo-controlled multicenter clinical trial investigating the effect of 13 weeks of treatment with amphotericin B or placebo on the levels of pro-inflammatory cytokines, chemokines and growth factors (i.e., IL-1beta, IL-1RA, IL-2, IL-2R, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12 (p40/p70 subunits), IL-13, IL-15, IL-17, TNF-alpha, IFN-alpha, IFN-gamma, G-CSF, GM-CSF, MIP-1alpha, MIP-1beta, IP-10, MIG, eotaxin, RANTES, MCP-1, MCP-2, MCP-3, VEGF, EGF, FGF-basic, HGF, Gro-alpha) and albumin via a fluorescent enzyme immunoassay in nasal lavage specimens of CRS patients with or without NP.. Topical amphotericin B had no significant effect on the level of any of the tested pro-inflammatory cytokines, chemokines, and growth factors in CRS nasal lavage samples. Treatment with placebo, however, increased the level of MIP-1alpha and MIP-1beta, which are mediators involved in wound healing.. Topical amphotericin B has no significant effect on activation markers of nasal inflammatory cells in chronic rhinosinusitis with or without nasal polyps.

Topics: Administration, Intranasal; Administration, Topical; Adult; Amphotericin B; Antifungal Agents; Chemokines; Chi-Square Distribution; Chronic Disease; Cytokines; Double-Blind Method; Female; Humans; Inflammation; Intercellular Signaling Peptides and Proteins; Male; Middle Aged; Nasal Lavage; Nasal Polyps; Prospective Studies; Rhinitis; Sinusitis; Statistics, Nonparametric; Treatment Outcome

Cryptococcal meningitis (CM) is a life-threatening disease that primarily affects patients with human immunodeficiency virus (HIV). Antifungal therapy with antiretroviral treatment (ART) usually leads to the clinical remission of CM; however, in some cases, these treatments exacerbate intracranial inflammation because of paradoxical inflammatory reaction or immune reconstitution inflammatory syndrome (IRIS). Here we report two CM cases that presented atypical clinical courses attributed to paradoxical inflammatory reactions. The first case was a 43-year-old man with headache and vertigo diagnosed with CM and HIV. The patient's CM not only was refractory to the antifungal combination therapy of liposomal amphotericin B (L-AMB) and fluconazole (FLCZ) but suddenly worsened because of a paradoxical inflammatory reaction after 18 days of treatment. He passed away from brain herniation on day 23. The second case was a 43-year-old man diagnosed with CM and HIV. After receiving antifungal therapy and ART, the patient's status was stable for more than 3 years with undetectable HIV-RNA. He suddenly presented with brain inflammation and was diagnosed with IRIS due to CM (CM-IRIS). His brain lesions were migratory and refractory to various antifungal therapies such as L-AMB, FLCZ, flucytosine, and intrathecal amphotericin B. Although the cryptococcal antigen in the patient's cerebrospinal fluid gradually diminished after continuous antifungal therapies, his cognitive function declined, and right hemiparesis persisted. These two cases of CM presented atypical clinical courses, presumably because of paradoxical inflammatory reactions. It should be noted that the onset of CM-IRIS may not necessarily depend on the timing of ART initiation.

Topics: Acquired Immunodeficiency Syndrome; Adult; AIDS-Related Opportunistic Infections; Anti-Retroviral Agents; Antifungal Agents; Fluconazole; HIV; HIV Infections; Humans; Immune Reconstitution Inflammatory Syndrome; Inflammation; Male; Meningitis, Cryptococcal

Alterations of the mycobiota composition associated with Crohn's disease (CD) are challenging to link to defining elements of pathophysiology, such as poor injury repair. Using culture-dependent and -independent methods, we discovered that

Topics: Amphotericin B; Animals; Anti-Bacterial Agents; Antifungal Agents; Chemokine CCL5; Colon; Crohn Disease; Debaryomyces; Female; Gastrointestinal Microbiome; Germ-Free Life; Humans; Ileum; Inflammation; Interferon Type I; Intestinal Mucosa; Macrophages; Male; Mice; Mice, Inbred C57BL

Type I interferons (IFNs) play critical roles in anti-viral and anti-tumor immunity. However, they also suppress protective immune responses in some infectious diseases. Here, we identify type I IFNs as major upstream regulators of CD4

Topics: Amphotericin B; Animals; CD4-Positive T-Lymphocytes; Cytokines; Dendritic Cells; Epitopes; Humans; Immunity; Inflammation; Interferon Type I; Interferon-gamma; Leishmaniasis, Visceral; Mice, Inbred C57BL; Nitriles; Parasites; Pyrazoles; Pyrimidines; Receptor, Interferon alpha-beta; Signal Transduction

The activation of proinflammatory cellular processes and signals such as those linked to NF-kB in macrophages are involved in the control of infection by Leishmania ssp. However, little is known about the influence of the drugs used in the treatment on the host cellular inflammatory signaling pathways. This study aimed to evaluate the effects of different drugs used in the treatment of leishmaniasis on inflammatory profile related to Toll-like receptors (TLRs) from L. amazonensis-infected macrophages. J774 macrophage-like cells were infected with the promastigote forms (5:1) and 24 hs incubated with Amphotericin B (AmB), Glucantime® (GLU) or Pentamidine (Pent). The following inflammatory pathways were evaluated: NF-κB p65, NF-κB p65 phosphorylated (Ser536), stress-activated protein kinase/c-Jun NH(2)-terminal kinase (SAPK/JNK) phosphorylated (Thr183/Tyr185), p38 mitogen activated protein kinase (MAPK p38) phosphorylated (Thr180/Tyr182), signal transducer and activator of transcription-3 (Stat3) phosphorylated (Tyr705) and inhibitor kappa B-α (IκB-α) phosphorylated (Ser32). In silico tests were performed to evaluate the molecular affinity between TLRs and antileishmanial drugs. Molecular docking showed that affinities varied significantly among the binders evaluated. The lowest affinity (-8.6 Kcal/Mol) was calculated for AmB in complex with TLR4. Pent showed higher values for TLR1, TLR2 and TLR3, while for TLR4 the affinity value was lower (5.5 Kcal/Mol). The values obtained for GLU were the highest for the set of binders tested. From the infected macrophages, treatments inhibited NF-kB p65 for GLU (65.44%), for Pent (46.43%) and for AmB (54.07%) compared to untreated infected macrophages. The activation of the signaling pathway of NF-kB, SAPK/JNK and IκB-α caused by AmB and Pent may potentiate the microbicidal mechanisms of the infected macrophages.

Topics: Amphotericin B; Animals; Antiprotozoal Agents; Cell Line; Inflammation; Leishmania; Leishmaniasis; Macrophages; Meglumine Antimoniate; Mice; Mitogen-Activated Protein Kinases; Molecular Docking Simulation; Pentamidine; Signal Transduction; Toll-Like Receptors; Transcription Factor RelA

Cryptococcosis is a subacute or chronic disease. For many years, amphotericin B has been used in severe fungal infections. Voriconazole is a triazole with high bioavailability, a large distribution volume, and excellent penetration of the central nervous system (CNS). The objective of this study was to evaluate the production of pro-inflammatory cytokines in the lungs during an experimental infection caused by C. neoformans in murine model (SCID) that was treated with amphotericin B and voriconazole. After intravenous inoculation with 3.0×10

Topics: Amphotericin B; Animals; Antifungal Agents; Cryptococcosis; Cryptococcus neoformans; Cytokines; Disease Models, Animal; Drug Therapy, Combination; Inflammation; Lung; Lung Diseases, Fungal; Mice; Severe Combined Immunodeficiency; Voriconazole

This study aimed at assessing the effectiveness and safety of repeated administrations of allogeneic bone marrow-derived mesenchymal stem cells (BM-MSCs) primed with tumor necrosis factor (TNF)-α and interferon-γ in an equine model of chemically-induced osteoarthritis. Arthritis was induced in both radio-carpal (RC)-joints by amphotericin-B in 18 ponies, divided into three groups depending on the treatment injected: MSC-naïve (n = 7), MSC-primed (n = 7) and control (n = 4). The study consisted of two phases and used one RC-joint of each animal in each phase, with four months time-lapse, in order to assess two end-points. Clinical, synovial, radiological and ultrasonographic follow-up was performed. At six months, animals were euthanized and both carpi were assessed by magnetic resonance imaging (MRI), gross anatomy, histopathology, histochemistry and gene expression.. Clinical and synovial inflammatory signs were quicker reduced in MSC-treated groups and repeated allogeneic administration did not produce adverse reactions, but MSC-primed group showed slight and transient local inflammation after second injection. Radiology and MRI did not show significant differences between treated and control groups, whereas ultrasonography suggested reduced synovial effusion in MSC-treated groups. Both MSC-treated groups showed enhanced cartilage gross appearance at two compared to six months (MSC-naïve, p < 0.05). Cartilage histopathology did not reveal differences but histochemistry suggested delayed progression of proteoglycan loss in MSC-treated groups. Synovium histopathology indicated decreased inflammation (p < 0.01) in MSC-primed and MSC-naïve at two and six months, respectively. At two months, cartilage from MSC-primed group significantly (p < 0.05) upregulated collagen type II (COL2A1) and transforming growth factor (TGF)-β1 and downregulated cyclooxygenase-2 and interleukin (IL)-1β. At six months, MSC-treatments significantly downregulated TNFα (p < 0.05), plus MSC-primed upregulated (p < 0.05) COL2A1, aggrecan, cartilage oligomeric protein, tissue inhibitor of metalloproteinases-2 and TGF-β1. In synovium, both MSC-treatments decreased (p < 0.01) matrix metalloproteinase-13 expression at two months and MSC-primed also downregulated TNFα (p < 0.05) and IL-1β (p < 0.01).. Both MSC-treatments provided beneficial effects, mostly observed at short-term. Despite no huge differences between MSC-treatments, the findings suggested enhanced anti-inflammatory and regulatory potential of MSC-primed. While further research is needed to better understand these effects and clarify immunogenicity implications, these findings contribute to enlarge the knowledge about MSC therapeutics and how they could be influenced.

Topics: Amphotericin B; Animals; Horse Diseases; Horses; Inflammation; Interferon-gamma; Male; Mesenchymal Stem Cell Transplantation; Osteoarthritis; Synovial Membrane; Tumor Necrosis Factor-alpha

Invasive fungal infection is a well-known cause of morbidity and mortality in immunocompromised patients. In this study we aimed to evaluate the hepatotoxicity induced by combined therapy of flucytosine and amphotericin B, at three different doses administered to mice for 14 days: 50 mg/kg flucytosine and 300 μg/kg amphotericin B; 100 mg/kg flucytosine and 600 μg/kg amphotericin B; 150 mg/kg flucytosine and 900 μg/kg amphotericin B. Liver injuries were evaluated by analysis of optic and electron microscopy samples, changes in TNF-α, IL-6, and NF-κB inflammation markers levels of expression, and evaluation of mRNA profiles. Histological and ultrastructural analysis revealed an increase in parenchymal and portal inflammation in mice and Kupffer cells activation. Combined antifungal treatment stimulated activation of an inflammatory pathway, demonstrated by a significant dose-dependent increase of TNF-α and IL-6 immunoreactivity, together with mRNA upregulation. Also, NF-κB was activated, as suggested by the high levels found in hepatic tissue and upregulation of target genes. Our results suggest that antifungal combined therapy exerts a synergistic inflammatory activation in a dose-dependent manner, through NF-κB pathway, which promotes an inflammatory cascade during inflammation. The use of combined antifungal therapy needs to be dose limiting due to the associated risk of liver injury, especially for those patients with hepatic dysfunction.

Topics: Amphotericin B; Animals; Antifungal Agents; Chemical and Drug Induced Liver Injury; Flucytosine; Fungi; Humans; Infections; Inflammation; Interleukin-6; Liver; Mice; NF-kappa B; Tumor Necrosis Factor-alpha

The incidence of secondary systemic fungal infections has sharply increased in bacterial septic patients. Antimycotics exhibit immunomodulatory properties, yet these effects are incompletely understood in secondary systemic fungal infections following bacterial sepsis. We investigated a model of systemic inflammation to determine whether antimycotics (liposomal amphotericin B (L-AMB), itraconazol (ITC), and anidulafungin (ANI)) modulate the gene and protein expression as well as the phagocytic activity of lipopolysaccharide (LPS)-stimulated human monocytes.. THP-1 monocytes were incubated with L-AMB, ITC or ANI and LPS. Gene expression levels of cytokines (TNF-, IL-1, IL-6, and IL-10) were measured after 2h, 6h, and 24h. Cytokine protein levels were evaluated after 24h and phagocytic activity was determined following co-incubation with Escherichia coli.. All antimycotics differentially modulated the gene and protein expression of cytokines in sepsis-like conditions. In the presence of LPS, we identified L-AMB as immunosuppressive, whereas ITC demonstrated pro-inflammatory properties. Both compounds induced remarkably less phagocytosis.. Our study suggests that antimycotics routinely used in septic patients alter the immune response in sepsis-like conditions by modulating cytokine gene and protein expression levels and phagocytic activity. Future treatment strategies should consider the immune status of the host and apply antimycotics accordingly in bacterial septic patients with secondary fungal infections.

Topics: Amphotericin B; Anidulafungin; Antifungal Agents; Cells, Cultured; Cytokines; Echinocandins; Gene Expression; Humans; Immunosuppressive Agents; Inflammation; Itraconazole; Monocytes; Phagocytosis; Sepsis

Acute kidney injury (AKI) following admission to hospital is associated with increased mortality, morbidity and length of stay. Factors that predispose patients to AKI frequently co-exist. The precise description of their representation in unselected admissions could help define mechanistic inter-relationships and optimise risk stratification strategies. Our aim was therefore to define precisely, using electronically available data, the variables that are associated with AKI.. A cohort study of 112,987 emergency admissions to an urban academic medical centre between 2006 and 2010 was performed. Post-admission AKI was defined using KDIGO aligned, proportionate changes in serum creatinine, denominated by the first measured. AKI correlated with co-morbidities, medications received and the C-reactive protein concentration (CRP).. The relationship between post-admission AKI and putative risk factors was defined in univariate and multivariate analyses. Inclusion of CRP in multivariate analyses significantly reduced the strength of association between some co-variables such as radiological contrast and gentamicin administration but not others.. The effect of CRP in these analyses supports the role of systemic inflammation in susceptibility to post-admission AKI. It accounts for the greater part of univariate associations between AKI and some nephrotoxic agents, placing the risk attributable to their use in context. Quantification of the systemic inflammatory response may have utility in AKI risk stratification, integrating various determinants of susceptibility.

Topics: Academic Medical Centers; Acute Kidney Injury; Adult; Aged; Aged, 80 and over; Amphotericin B; C-Reactive Protein; Comorbidity; Creatinine; Diabetes Mellitus; Emergencies; Female; Gentamicins; Hospitalization; Hospitals, Urban; Humans; Hypertension; Inflammation; Male; Middle Aged; Risk Assessment; Risk Factors

The purpose is to report an eye with endogenous Aspergillus flavus endophthalmitis that achieved a good visual outcome following early and aggressive management.. A 76-year-old male recently hospitalized for allergic Aspergillus pneumonitis after cleaning out a grain bin presented with reduced vision and anterior chamber and vitreous inflammation. The patient was treated with intravenous amphotericin and a pars plana vitrectomy with intravitreal amphotericin, and the vitreous biopsy sent for histopathological and microbial analysis.. A. flavus was isolated from the vitreous biopsy. Two weeks after vitrectomy, intravitreal amphotericin was again injected into the affected eye. The patient regained vision to 20/80 several months later, despite a moderate cataract.. Early treatment of A. flavus endophthalmitis with pars plana vitrectomy, intravitreal and systemic amphotericin can lead to good visual outcomes.

Topics: Aged; Amphotericin B; Anterior Chamber; Antifungal Agents; Aspergillosis; Aspergillus flavus; Endophthalmitis; Farmer's Lung; Humans; Inflammation; Injections, Intraocular; Injections, Intravenous; Male; Treatment Outcome; Vision, Low; Vision, Ocular; Visual Acuity; Vitrectomy; Vitreous Body

Topics: Administration, Topical; Amphotericin B; Biomarkers; Humans; Inflammation; Multicenter Studies as Topic; Randomized Controlled Trials as Topic; Sinusitis

A composition of amphotericin B and dialdehyde dextran was used for the therapy of male C57Bl/6 mice with systemic candidiasis. The composition was more effective than free amphotericin B. A decrease in the number and size of candidal granulomas in the lungs was more significant after therapy with the study composition (compared to free amphotericin B).

Topics: Amphotericin B; Animals; Antifungal Agents; Candidiasis; Dextrans; Granuloma; Inflammation; Lung Diseases, Fungal; Male; Mice; Mice, Inbred C57BL

Amphotericin B (AmB) is a polyene antibiotic and reported to have therapeutic effects on prion diseases, in which the microglial activation has been suggested to play important roles by proliferating and producing various factors such as nitric oxide, proinflammatory cytokines, and so on. However, the therapeutic mechanism of AmB on prion diseases remains elusive. In the present study, we investigated the effects of AmB on cellular functions of rat primary cultured microglia. We found that AmB, similarly as lipopolysaccharide (LPS), could activate microglia to produce nitric oxide via inducible nitric oxide synthase. Both AmB and LPS also induced mRNA expressions of interleukin-1beta, interleukin-6, and tumor necrosis factor-alpha in microglia. AmB also changed the expression levels of neurotrophic factors mRNAs. AmB and LPS significantly down-regulated the level of ciliary neurotrophic factor mRNA. However, AmB, but not LPS, significantly up-regulated the level of glial cell-line derived neurotrophic factor mRNA in microglia. In addition, brain-derived neurotrophic factor mRNA expression level was tending upward by treatment with AmB, but not with LPS. Taken together, these results suggest that AmB regulates the microglial activation in different manner from LPS and that microglia may participate in the therapeutic effects of AmB on prion diseases by controlling the expression and production of such mediators.

Topics: Amphotericin B; Animals; Antifungal Agents; Brain-Derived Neurotrophic Factor; Cell Survival; Cells, Cultured; Cytokines; Glial Cell Line-Derived Neurotrophic Factor; Gliosis; Inflammation; Interleukin-1beta; Interleukin-6; Microglia; Nerve Growth Factors; Neurotoxins; Nitric Oxide; Nitric Oxide Synthase; Prion Diseases; Rats; Rats, Wistar; RNA, Messenger; Tumor Necrosis Factor-alpha; Up-Regulation

We describe a case of sporotrichosis that disseminated to involve multiple nerves after initiation of immunosuppressive therapy and then precipitously worsened after withdrawal of therapy. This case illustrates that multiple mononeuropathies are not always caused by vasculitis, and a correct pathological diagnosis should be established before treatment. Based on clinical and pathological features, the mechanism of neuropathy may have been due to either direct nerve infection or a bystander effect of inflammatory/immune damage or, perhaps more likely, to both mechanisms.

Topics: Abscess; Amphotericin B; Anti-Bacterial Agents; Anti-Inflammatory Agents; Debridement; Dermatitis; Diagnostic Errors; Disease Progression; Forearm; Granulomatous Disease, Chronic; Humans; Immunosuppressive Agents; Inflammation; Male; Middle Aged; Muscle Weakness; Muscle, Skeletal; Pain; Peripheral Nerves; Peripheral Nervous System Diseases; Sporothrix; Sporotrichosis; Treatment Outcome; Wrist Joint

Topics: Amphotericin B; Anti-HIV Agents; HIV Infections; Humans; Inflammation; Leishmaniasis; Male; Middle Aged

Three lipid-based delivery systems (AmBisome, Amphocil, and Abelcet) for amphotericin B (AmB) have been marketed to overcome the disadvantages associated with the clinical use of AmB. However, to show their efficacy, they need to be administered at higher doses than the conventional dosage form, Fungizone. In this study, we compared LNS-AmB, our new low-dose therapeutic system for AmB using lipid nano-sphere (LNS), with these commercial formulations in terms of their pharmacokinetics and efficacy. The plasma AmB levels yielded by LNS-AmB after intravenous administration to rats were much higher than those yielded by Amphocil or Abelcet, and similar to those yielded by AmBisome, but in dogs LNS-AmB yielded plasma AmB concentrations about three times higher than did AmBisome. In a carrageenin-induced pleurisy model in rats, LNS-AmB yielded AmB levels in the pleural exudate over 20 times those yielded by Amphocil or Abelcet, and similar to those yielded by AmBisome. From these pharmacokinetic results, it is clear that Amphocil and Abelcet are based on a quite distinct drug-delivery concept from LNS-AmB. In a rat model of localized candidiasis, LNS-AmB significantly inhibited the growth of Candida albicans in the pouch, whereas AmBisome did not, even though the AmB concentrations in the pouch were similar. This difference in antifungal activity between LNS-AmB and AmBisome was also found in vitro. That is, the antifungal activity of LNS-AmB against C. albicans was similar to that of Fungizone and dimethyl sulfoxide-solubilized AmB, while AmBisome showed weaker antifungal activity than did other formulations. Based on these results, the release of AmB from AmBisome was judged to be slow and slight. In a mouse model of systemic candidiasis, LNS-AmB (1.0mg/kg) was much more effective than AmBisome (8.0mg/kg) or Fungizone (1.0mg/kg). These results suggest that LNS-AmB maintained the potent activity of AmB against fungal cells even though the AmB was incorporated into LNS particles. We conclude that LNS-AmB may offer an improved therapeutic profile at lower doses than Fungizone and commercial lipid-based formulations.

Topics: Amphotericin B; Animals; Antifungal Agents; Area Under Curve; Candida albicans; Carbon Isotopes; Carrageenan; Chemistry, Pharmaceutical; Colonic Pouches; Dogs; Dose-Response Relationship, Drug; Drug Carriers; Drug Evaluation, Preclinical; In Vitro Techniques; Inflammation; Lipids; Models, Animal; Nanotubes; Pleurisy; Radiochemistry; Rats; Species Specificity; Survival Rate

We report a case of noninvasive pulmonary disease due to Chrysosporium zonatum in an immunocompetent male. The fungus colonized an existing tuberculous cavity and was isolated from transbronchial lavage fluid and from a percutaneous aspiration specimen. The disease was accompanied by the unusual feature of an allergic reaction. The fungus ball was successfully treated by intracavitary administration of amphotericin B. C. zonatum is the anamorph of the heterothallic ascomycete Uncinocarpus orissi, and the identity of the case isolate was verified by formation of ascospores in mating tests with reference isolates.

Topics: Aged; Amphotericin B; Chrysosporium; Humans; Hypersensitivity; Inflammation; Lung; Lung Diseases, Fungal; Male; Microbial Sensitivity Tests

To understand whether the pseudo-allergic reactions to amphotericin B (AmB) administration are due to AmB or to the solubilizing vehicles, a study was designed to evaluate the effects of AmB, liposomal AmB, (L-AmB), AmB-deoxycholate micellar complex (AmB-DC) and deoxycholate (DC) on the responses of rat serosal mast cells (RSMC) and of human basophils (HB), in vitro.. Serosal mast cells were obtained by density gradient centrifugations from male Wistar albino rats. Partially purified HB were obtained from healthy donors. The cells were exposed to AmB, L-AmB, AmB-DC and DC. Histamine release was measured fluorometrically, and the release of lactic dehydrogenase (LDH) was measured spectrophotometrically. HB activation was evaluated cytofluorimetrically by CD63 expression.. AmB and L-AmB did not evoke histamine or LDH release from either RSMC or HB. CD63 expression was not induced in HB challenged with AmB and L-AMB. On the other hand, AmB-DC and DC produced a cytotoxic histamine release from both RSMC and HB, and a sustained increase of CD63 expression on HB.. Only AmB-DC was able to induce the release of inflammatory mediators from RSMC and HB. Conceivably, the cytotoxic effect is accounted for by the micellar complexes with DC, which has been confirmed as a powerful histamine releaser, and held responsible for the pseudo-allergic reactions after AmB-DC administration. The data lend support to a better safety profile of L-AmB.

Topics: Amphotericin B; Animals; Basophils; Centrifugation, Density Gradient; Deoxycholic Acid; Histamine Release; Humans; Immunoglobulin E; Inflammation; L-Lactate Dehydrogenase; Liposomes; Mast Cells; Phenotype; Rats

Topics: Amphotericin B; Cytokines; Gene Expression Regulation; Humans; Inflammation; Interleukin 1 Receptor Antagonist Protein; Interleukin-1; Sialoglycoproteins; Transcription, Genetic; Tumor Necrosis Factor-alpha

Amphotericin B is an antifungal drug associated with side effects such as fever and chills, symptoms which may be mediated by pro-inflammatory cytokines such as interleukin-1beta (IL-1beta) and tumour necrosis factor-alpha (TNFalpha). We assessed the capacity of amphotericin B to modulate production of these pro-inflammatory cytokines as well as the anti-inflammatory IL-1 receptor antagonist (IL-1ra), induced by LPS, heat-killed Candida albicans or Staphylococcus aureus. The results of the present study show that amphotericin B slightly increased the production of pro-inflammatory cytokines by human mononuclear cells (PBMC), whereas the production of the anti-inflammatory cytokine IL-1ra was significantly inhibited. This results in a shift towards pro-inflammatory cytokine production, as indicated by a decreased IL-1ra/IL-1beta ratio. Semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR) indicated that levels of IL-1beta and TNFalpha mRNA were increased. In conclusion, amphotericin B is able to cause a shift towards pro-inflammatory cytokine production by human PBMC. This may explain the side effects, such as fever and chills, observed after treatment of patients with amphotericin B.

Topics: Amphotericin B; Antifungal Agents; Candida albicans; Cytokines; Humans; In Vitro Techniques; Inflammation; Interleukin-1; Lipopolysaccharides; Neutrophil Activation; Neutrophils; RNA, Messenger; Staphylococcus aureus; Tumor Necrosis Factor-alpha

To assess the effects of antifungal therapy on the course of Candida albicans central nervous system infection and inflammation, we inoculated intracisternally 10(5) CFU of C. albicans into rabbits. Fluconazole (10 mg/kg of body weight) or amphotericin B (1 mg/kg) was infused intravenously daily for 14 days. Treatment was initiated 24 h or 5 days after infection. Cerebrospinal fluid (CSF) was repeatedly obtained to culture the organisms, assess the level of inflammation, and measure drug concentrations. Brain tissue was obtained at the end of therapy for culture, drug concentration determinations, and histopathology. The median number of days of treatment required to sterilize CSF cultures was 4 days for fluconazole therapy and 1 day for amphotericin B therapy (P = 0.037). There was a significant reduction in tumor necrosis factor alpha and leukocyte concentrations in the CSF of animals treated early versus those in untreated control animals (P < 0.05 and P < 0.001, respectively; analysis of variance). Compared with treated animals, a higher proportion of cultured CSF samples from untreated animals were positive for Candida (P < 0.001). A cultured brain sample from 1 of the 12 animals treated early with amphotericin B was positive for C. albicans (P < 0.01 versus controls); cultures of brain samples from 3 of 12 animals treated early with fluconazole were positive, whereas cultures of brain samples from 10 of 12 controls were positive (P < 0.05). The mean density of C. albicans was lower in the single culture-positive amphotericin B recipient (1 x 10(1) CFU/g of brain tissue) than in those treated with fluconazole (1 x 10(3) CFU/g) and in controls (8 x 10(4) CFU/g). In animals treated late, the density of C. albicans in the brain in relation to the number of days of therapy was significantly lower in amphotericin B recipients than in those treated with fluconazole (P < 0.01) and untreated controls (P < 0.01; analysis of covariance). By histopathology, a larger proportion of untreated animals compared with those treated early demonstrated features of severe infection such as perivasculitis, ventriculitis, and evidence of fungal organisms. Compared with amphotericin B-treated rabbits, those given fluconazole had a trend toward more severe pathologic lesions. Reduced susceptibility to both fluconazole and amphotericin B was observed in the C. albicans organisms isolated from the brain of one fluconazole-treated animal. These data suggest that amphotericin B

Topics: Amphotericin B; Animals; Antifungal Agents; Brain; Candida albicans; Candidiasis; Cytokines; Fluconazole; Inflammation; Interferons; Leukocyte Count; Male; Meningitis, Fungal; Microbial Sensitivity Tests; Rabbits; Tumor Necrosis Factor-alpha

Existing models of Candida albicans infection are semi-quantitative and do not allow continuous observations to be made on individual animals. We have used the inflammatory response in the footpad as an indirect measure of the number of yeast cells in a localised lesion. C. albicans infection of the footpad has been used in series of experiments in which changes in yeast-cell numbers in the local lesion have been compared with the degree of footpad oedema. Studies in animals treated with cyclophosphamide or amphotericin have confirmed that paw oedema parallels yeast-cell numbers in the local lesion. This quantitative approach will be helpful in the study of localised infection with C. albicans and other fungi and in the evaluation of antifungal agents.

Topics: Amphotericin B; Animals; Candida albicans; Candidiasis; Cyclophosphamide; Disease Models, Animal; Edema; Female; Foot; Inflammation; Male; Rats; Rats, Inbred Strains

Topics: Amphotericin B; Humans; Inflammation; Lenses, Intraocular; Orbital Diseases; Postoperative Complications; Vitrectomy

A case of bilateral necrotizing scleritis due to Aspergillus oryzae is reported. The patient was a former addict of intravenous narcotics treated five years previously for meningitis due to the same organism. A seeding focus in the thoracic spine was eventually found. The patient responded well to combined local and systemic therapy with amphotericin B, flucytosine, and natamycin. This represents, to the best of our knowledge, both the first reported case of ocular disease due to this species of Aspergillus and of isolated scleral, nonintraocular involvement in endogenous oculomycosis.

Topics: Adolescent; Adult; Amphotericin B; Aspergillosis; Aspergillus oryzae; Child; Cocaine; Eye Diseases; Female; Flucytosine; Heroin; Humans; Inflammation; Injections, Intravenous; Meningitis; Natamycin; Sclera; Substance-Related Disorders

Topics: Aged; Amphotericin B; Blindness; Eye Diseases; Female; Humans; Inflammation; Intraocular Pressure; Male; Mycoses; Peptic Ulcer; Postoperative Complications; Sudan; Visual Acuity

Topics: Amphotericin B; Animals; Cataract; Dose-Response Relationship, Drug; Female; Inflammation; Injections; Male; Necrosis; Rabbits; Retina; Retinal Detachment; Retinal Diseases; Retinal Hemorrhage; Time Factors; Vitreous Body

Topics: Amphotericin B; Candida albicans; Candidiasis; Child; Electroencephalography; Eye Diseases; Fever; Fundus Oculi; Humans; Inflammation; Injections, Intravenous; Male; Meningitis; Parenteral Nutrition; Visual Acuity

Topics: Adrenal Cortex Hormones; Amphotericin B; Biopsy; Blepharoptosis; Blindness; Brain Diseases; Child; Child, Preschool; Conjunctiva; Edema; Exophthalmos; Eye Diseases; Humans; Inflammation; Male; Mucormycosis; Paranasal Sinuses; Penicillins; Sinusitis