amphotericin-b and galactomannan

Mucormycosis generally develops under immunocompromised conditions, including hematological malignancies and solid organ or hematopoietic stem cell transplantation. Although mucormycosis usually affects the lungs and paranasal sinuses, sporadic cases of invasive mucormycosis of the liver have been reported. We hereby report a patient with myelofibrosis who developed hepatic mucormycosis diagnosed by post-mortem examination. An extensive literature review identified 13 reported cases of hepatic mucormycosis, including ours, without lung involvement. Most of the underlying diseases or conditions were hematological malignancies and solid organ transplantation. Three cases had splenic lesions and four had gastrointestinal lesions, suggesting the possibility of translocation to the liver and/or spleen from the gastrointestinal tracts. Hepatic mucormycosis should be recognized as one of the presentations of invasive mucormycosis, especially when hepatic nodules are found in immunocompromised patients such as those with hematological malignancy or recipients of solid organ transplantation.

Topics: Aged; Amphotericin B; Antifungal Agents; Autopsy; Fatal Outcome; Ferritins; Galactose; Humans; Invasive Fungal Infections; Liver Diseases; Male; Mannans; Mucormycosis; Primary Myelofibrosis; Spleen

This review summarizes recent developments in the diagnosis and treatment of fungal pneumonia, with an emphasis on invasive pulmonary aspergillosis.. Improvements in nonculture-based fungal diagnostics, early implementation of pulmonary high resolution, or spiral computed tomography scanning and a recent expansion of the antifungal armamentarium have greatly improved the outcome of immunocompromised patients with invasive aspergillosis. However, the field is changing: new pathogens (such as Zygomycetes) are emerging, and novel risk groups (ICU patients in particular) are being identified.. Galactomannan antigen detection is a valuable tool for evaluating patients at risk for invasive aspergillosis (as a screening assay on serum samples from neutropenic patients or as a confirmatory assay on bronchoalveolar lavage fluid samples, in general), but should be used in conjunction with modern imaging techniques. beta-D-Glucan and PCR assays are still investigational. Voriconazole is the drug of choice for invasive aspergillosis, whereas liposomal amphotericin B at 3 mg/kg per day is the preferred alternative in case of contraindication, drug-related side-effects, or intolerance. Whenever possible, optimal antifungal therapy should be complemented by surgical debridement of necrotic tissue. The added value of combination therapy is still unproven. Therapeutic drug monitoring of mold-active azoles should be implemented in order to minimize toxicity and maximize efficacy. Lipid-based formulations of amphotericin B, and to a lesser extent voriconazole, are the drugs of choice for non-Aspergillus related fungal pneumonia. Although active in prophylaxis, the efficacy of posaconazole in confirmed infections remains controversial.

Topics: Amphotericin B; Antifungal Agents; Fungi; Galactose; Humans; Mannans; Mycoses; Pneumonia; Pulmonary Aspergillosis; Pyrimidines; Radiography, Thoracic; Triazoles; Voriconazole

An improved number of anti-fungal drugs are currently available for the treatment of invasive aspergillosis (IA). While serial galactomannan index (GMI) measurement can be used to monitor response to treatment, the extent to which different anti-fungal regimens can affect galactomannan levels is unknown. In 147 IA patients receiving either voriconazole (VCZ) or conventional amphotericin B (CAB) in a multicentre clinical trial, we performed post-hoc analyses of GMI trends in relation to outcomes. The generalized estimation equations approach was used to estimate changes in the effect size for GMI over time within patients. Patients who received VCZ primary therapy and had good treatment response 12 weeks later showed earlier decreases in GMI values at Week 1 and Week 2 (p = 0.001 and 0.046 respectively) as compared to patients who only received CAB. At end-of-randomized therapy (EORT), which was a pre-set secondary assessment point for all patients who switched from randomized primary (CAB or VCZ) to an alternative anti-fungal drug, treatment failure was associated with increasing GMI at Weeks 1 and 2 in CAB-primary treated patients (p = 0.022 and 0.046 respectively). These distinct trends highlight the variations in GMI kinetics with the use of different anti-fungal drugs and their implications in relation to IA treatment response.

Topics: Amphotericin B; Antifungal Agents; Aspergillosis; Biomarkers; Female; Fungal Polysaccharides; Galactose; Hematologic Neoplasms; Humans; Male; Mannans; Pyrimidines; Survival Analysis; Treatment Outcome; Triazoles; Voriconazole

Patients with neutropenic fever after 4-7 days of broad-spectrum antibiotics are given antifungals empirically. This strategy may lead to over-treatment.. Patients with hematological malignancies undergoing intensive chemotherapy or hematopoietic stem cell transplantation were randomized to two arms. Patients in the 'preemptive' arm had regular galactomannan (GM) assays, and received caspofungin, amphotericin or voriconazole (CAV) for persistent febrile neutropenia if they had two positive GM results, or a positive GM result and a computed tomography (CT) of the thorax suggestive of invasive pulmonary aspergillosis (IPA). Patients in the 'empirical' arm received CAV in accordance with established guidelines.. Of 27 episodes in the preemptive arm, two cases of IPA were picked up by monitoring. In six episodes, CAV was started despite persistently negative GM readings. One additional patient received CAV for a false-positive GM. Of 25 episodes in the empirical arm, CAV was started empirically in 10, one of whom had CT features of IPA. By intent-to-treat and evaluable-episode analyses, respectively, the preemptive approach saved 11% and 14% of patients from empirical antifungals. Twelve-week survival was 85.2% in the preemptive arm and 84% in the empirical arm.. A preemptive approach may reduce empirical antifungal use without compromising survival in persistently febrile neutropenic patients.

Topics: Adolescent; Adult; Aged; Amphotericin B; Antifungal Agents; Caspofungin; Drug Therapy, Combination; Echinocandins; Female; Fever; Galactose; Humans; Immunocompromised Host; Invasive Pulmonary Aspergillosis; Lipopeptides; Male; Mannans; Middle Aged; Mycoses; Neutropenia; Opportunistic Infections; Prospective Studies; Pyrimidines; Radiography, Thoracic; Risk Factors; Singapore; Tomography, X-Ray Computed; Treatment Outcome; Triazoles; Voriconazole

Invasive aspergillosis has become the leading cause of death after allogeneic hematopoietic stem cell transplantation. This is partially due to the lack of a prompt diagnosis. Recently the detection of Aspergillus galactomannan antigen by means an ELISA technique in serum has been described. The objective of this study was to validate its usefulness in the allogeneic hematopoietic stem cell transplantation setting.

Topics: Adolescent; Adult; Amphotericin B; Anemia, Aplastic; Antifungal Agents; Antigens, Fungal; Aspergillosis; Aspergillus; Biomarkers; Enzyme-Linked Immunosorbent Assay; False Negative Reactions; Female; Fungemia; Galactose; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Humans; Immunocompromised Host; Male; Mannans; Middle Aged; Predictive Value of Tests; Prospective Studies; Transplantation Conditioning; Transplantation, Homologous

Aspergillus infection is a well-known complication of severe influenza and severe acute respiratory syndrome coronavirus (SARS-CoV), and these infections have been related with significant morbidity and mortality even when appropriately diagnosed and treated. Recent studies have indicated that SARS-CoV-2 might increase the risk of invasive pulmonary aspergillosis (IPA). Here, we report the first case of Aspergillus ochraceus in a SARS-CoV-2 positive immunocompetent patient, which is complicated by pulmonary and brain infections. Proven IPA is supported by the positive Galactomannan test, culture-positive, and histopathological evidence. The patient did not respond to voriconazole, and liposomal amphotericin B was added to his anti-fungal regimen. Further studies are needed to evaluate the prevalence of IPA in immunocompetent patients infected with SARS-CoV-2. Consequently, testing for the incidence of Aspergillus species in lower respiratory secretions and Galactomannan test of COVID-19 patients with appropriate therapy and targeted anti-fungal therapy based on the primary clinical suspicion of IPA are highly recommended.

Topics: Adult; Amphotericin B; Antifungal Agents; Aspergillosis; Aspergillus ochraceus; Biomarkers; Brain Abscess; Bronchoalveolar Lavage Fluid; COVID-19; COVID-19 Nucleic Acid Testing; Fatal Outcome; Galactose; Humans; Immunocompetence; Invasive Fungal Infections; Lung Diseases, Fungal; Male; Mannans; SARS-CoV-2; Voriconazole

Eye damage during invasive aspergillosis is rarely described and biological diagnosis remains challenging. Here we report the case of a heart transplant recipient with ocular aspergillosis complicating disseminated aspergillosis. Although voriconazole was rapidly given, a decrease in visual acuity of the right eye was consistent with endophthalmitis, resulting in an emergency vitrectomy. The diagnosis was rapidly confirmed: laboratory results showed the presence of Aspergillus fumigatus in a vitreous sample. A series of systemic antifungal medications (liposomal amphotericin B, caspofungin, and voriconazole), several liposomal amphotericin B ocular injections, and pars plana vitrectomy resulted in a limited positive clinical outcome. Interestingly although standard mycological follow-up procedures were negative, Aspergillus antigen testing gave an index of 5.92 on vitreous humour, thus a new intraocular injection of liposomal amphotericin B was performed and voriconazole reinitiated. Ten other vitreous samples from patients without fungal infections were also tested, all showing indexes below 0.25. Although larger studies are needed, this case illustrates that galactomannan testing of vitreous humour could be useful for the diagnosis of fungal endophthalmitis if these data are confirmed in other patients, in particular, if standard mycology is negative and PCR is not available.

Topics: Adult; Amphotericin B; Antifungal Agents; Aspergillosis; Aspergillus fumigatus; Endophthalmitis; Eye Infections, Fungal; Female; Galactose; Humans; Male; Mannans; Middle Aged; Visual Acuity; Vitrectomy; Vitreous Body; Voriconazole

Topics: Adult; Amphotericin B; Antifungal Agents; Antigens, Fungal; Area Under Curve; Bronchoalveolar Lavage Fluid; Extracorporeal Membrane Oxygenation; Female; Galactose; Humans; Invasive Pulmonary Aspergillosis; Liposomes; Mannans; Respiratory Distress Syndrome

Delays in diagnosing pulmonary invasive aspergillosis (IA), a significant cause of morbidity and mortality among heart transplant recipients (HTRs), may impact on successful treatment. The appropriate screening strategy for IA in these patients remains undefined, particularly in the setting of nosocomial outbreaks. We describe our experience employing chest computed tomography (CT) scans as a screening method for IA. In addition, we comment on antimicrobial prophylaxis in HTRs in the setting of an outbreak.. Screening CT scans of the chest and serum galactomannan (GM) were performed in HTRs during an outbreak that followed the index case of IA. Abnormal CT findings prompted a diagnostic workup. Antimicrobial prophylaxis for new transplants recipients included intravenous micafungin while hospitalized, followed by outpatient inhaled amphotericin B for up to 3 months.. During a 10-month period, five cases of IA were identified among HTRs. Two additional asymptomatic patients were diagnosed with IA among 15 asymptomatic HTRs who underwent screening chest CT scans. Among the five cases of IA in HTRs, two of five (40%) had a partial response and the other three failed voriconazole therapy. Complete response to voriconazole therapy assessed at 12 weeks was achieved in these two asymptomatic HTRs diagnosed via screening CTs. Serum GM was positive only in one of the symptomatic cases. The negative predictive value of CT scans was 100% (95% confidence interval, 71.5%-100%).. In an outbreak setting, screening CT scans of the chest may aid in early detection of asymptomatic HTRs with IA and improve outcome.

Topics: Adult; Aged; Aged, 80 and over; Amphotericin B; Antibiotic Prophylaxis; Antifungal Agents; Asymptomatic Diseases; Cohort Studies; Disease Outbreaks; Echinocandins; Female; Galactose; Heart Transplantation; Hematologic Neoplasms; Humans; Invasive Pulmonary Aspergillosis; Lipopeptides; Male; Mannans; Mass Screening; Micafungin; Middle Aged; Retrospective Studies; Risk Factors; Tomography, X-Ray Computed; Transplant Recipients; Voriconazole

To identify the incidence, risk factors and impact on long-term survival of invasive pulmonary aspergillosis (IPA) and Aspergillus colonisation in patients receiving vv-extracorporeal membrane oxygenation (ECMO). A retrospective evaluation was performed of patients receiving vv-ECMO at a tertiary hospital in Manchester (UK) between January 2012 and December 2016. Data collected included epidemiological data, microbiological cultures, radiographic findings and outcomes. Cases were classified as proven IPA, putative IPA or Aspergillus colonisation according to a validated clinical algorithm. One hundred thirty-four patients were supported with vv-ECMO, median age of 45.5 years (range 16.4-73.4). Ten (7%) patients had putative IPA and nine (7%) had Aspergillus colonisation. Half of the patients with putative IPA lacked classical host risk factors for IPA. The median number of days on ECMO prior to Aspergillus isolation was 5 days. Immunosuppression and influenza A infection were significantly associated with developing IPA in a logistic regression model. Cox regression model demonstrates a three times greater hazard of death associated with IPA. Overall 6-month mortality rate was 38%. Patients with putative IPA and colonised patients had a 6-month mortality rate of 80 and 11%, respectively. Immunosuppression and influenza A infection are independent risk factors for IPA. IPA, but not Aspergillus colonisation, is associated with high long-term mortality in patients supported with vv-ECMO.

Topics: Adolescent; Adult; Aged; Amphotericin B; Antifungal Agents; Aspergillus; Critical Illness; Echinocandins; Extracorporeal Membrane Oxygenation; Female; Galactose; Humans; Immunocompromised Host; Influenza, Human; Invasive Pulmonary Aspergillosis; Lipopeptides; Male; Mannans; Micafungin; Middle Aged; Retrospective Studies; Risk Factors; Treatment Outcome; Voriconazole; Young Adult

Pseudallescheria boydii is a fungal organism known to affect immunocompromised patients. This organism is known to cause, in severe cases, invasive infection of various organs such as the central nervous, cardiovascular, and respiratory systems. We report an unusual case of pulmonary P. boydii pneumonia in an immunocompromised critically ill patient with a co-infection of Aspergillus fumigatus and Aspergillus terreus with ARDS. This case highlights the importance of a high index of suspicion for superimposed fungal infections in patients who are critically ill and immunocompromised. Uncommon fungal pathogens should be considered in the differential diagnosis of respiratory failure, especially if diagnostic markers such as galactomannan (from BAL and serum) or 1,3-beta-D-glucan are elevated. Further diagnostic interventions are warranted when insufficient clinical improvement is observed to prevent treatment failure and adverse outcomes.

Topics: Aged; Amphotericin B; Antifungal Agents; Aspergillosis; Aspergillus fumigatus; beta-Glucans; Clarithromycin; Coinfection; Critical Illness; Extracorporeal Membrane Oxygenation; Galactose; Hematopoietic Stem Cell Transplantation; Humans; Immunocompromised Host; Linezolid; Male; Mannans; Meropenem; Pneumonia; Pseudallescheria; Severe Acute Respiratory Syndrome; Thienamycins; Transplant Recipients; Voriconazole

Patients with persistent or recurrent neutropenic fevers at risk of invasive fungal disease (IFD) are treated empirically with antifungal therapy (AFT). Early treatment using a diagnostic-driven (DD) strategy may reduce clinical and economic burdens. We compared costs and outcomes of both strategies from a UK perspective.. An empirical strategy with conventional amphotericin B deoxycholate (C-AmB), liposomal amphotericin B (L-AmB), or caspofungin was compared with a DD strategy (initiated based on positive ELISA results for galactomannan antigen) and/or positive results for Aspergillus species on polymerase chain reaction assay) using C-AmB, voriconazole, or L-AmB in a decision-analytic model. Rates of IFD incidence, overall mortality, and IFD-related mortality in adults expected to be neutropenic for ≥10 days were obtained. The empirical strategy was assumed to identify 30% of IFD and targeted AFT to improve survival by a hazard ratio of 0.589. AFT-specific adverse events were obtained from a summary of product characteristics. Resource use was obtained, and costs were estimated by using standard UK costing sources. All costs are presented in 2012 British pounds sterling.. Total costs were 32% lower for the DD strategy (£1561.29) versus the empirical strategy (£2301.93) due to a reduced incidence of adverse events and decreased use of AFT. Administration of AFT was reduced by 41% (DD strategy, 74 of 1000; empirical strategy, 125 of 1000), with similar survival rates.. This study suggests that a DD strategy is likely to be cost-saving versus empirical treatment for immunocompromised patients with persistent or recurrent neutropenic fevers.

Topics: Amphotericin B; Antifungal Agents; Aspergillosis; Aspergillus; Caspofungin; Cost Savings; Decision Trees; Deoxycholic Acid; Drug Combinations; Echinocandins; Febrile Neutropenia; Galactose; Health Care Costs; Health Resources; Humans; Immunocompromised Host; Lipopeptides; Mannans; Survival Rate; Voriconazole

To investigate the invasive aspergillosis (IA) status in a surgical intensive care unit (SICU).. The clinical data including general state, operation, pathogenic microorganisms, infection position, clinical situation, treatment and prognosis of patients with IA admitted to the SICU of Peking University First Hospital from January 2004 to December 2013 were retrospectively analyzed.. 8 220 patients admitted to the SICU of Peking University First Hospital from January 2004 to December 2013 were enrolled. Of 8 220 patients, there were 29 cases experienced IA, with an incidence of 0.35%, and the incidence of hospital onset of IA infection was 0.27% (22/8 220). The incidence of hospital onset of IA infection was accounted for 6.98% (22/315) of the incidence of hospital onset of infection in SICU in the same period. Compared with 2004-2008, in 2009-2013, the incidence of hospital onset of infection was significantly decreased [3.19% (137/4 293) vs. 4.53% (178/3 927), χ² = 10.020, P=0.002], while the incidence of IA [0.56% (24/4 293) vs. 0.13% (5/3 927), χ² = 10.874, P=0.001], the incidence of hospital onset of IA infection [0.40% (17/4 293) vs. 0.13% (5/3 927), χ² = 5.556, P=0.019], and the percentage of incidence of hospital onset of IA infection according to the incidence of hospital onset of infection were increased by 5 years [12.40% (17/137) vs. 2.81% (5/178), χ² = 10.982, P=0.001]. Of 29 patients with IA, 25 cases had occurred after operation, and the majority of them were from the Department of General Surgery (13 cases), and followed by post-renal transplantation (6 cases) and post-thoracic surgery (3 cases). In the total submission of 155 specimens from 29 patients with IA, there were 17 strains isolated aspergillosis, among which included 2 strains of Aspergillus fumigatus, and 15 other un-subgrouped strains. The most common infection site was lower respiratory tract (23 cases, 79.31%). Sixteen patients were found with positive galactomannan (GM) test. In all the risk factors contributing to IA, the ratio of the long-term usage of broad-spectrum antibiotics over 4 days was the highest [36.25% (29/80)], which followed by the long-term use of hormone [18.75% (15/80)], complicated with acute kidney injury [18.75% (15/80)], liver injury [13.75% (11/80)], the long-term use of immunosuppressive orally [7.50% (6/18)], and complicated with neutropenia [5.00% (4/80)]. In 29 patients with IA, there were 28 patients received anti-fungal treatment except for 1 patient without treatment, and those were single use of itraconazole in 1 case, single use of echinocandins in 3 cases, single use of liposomal amphotericin B in 5 cases, 8 cases with voriconazole, single use of liposomal amphotericin B or echinocandins then replaced by voriconazole in 8 cases, and 3 cases of echinocandins therapy combined with voriconazole. Seventeen of 29 patients di. IA is an uncommon but increasing postoperative complication of patients in SICU in recent 5 years. The most common sites of IA were lower respiratory tract. The mortality of IA is very high. So clinicians should pay more attention to the careful monitor for IA.

Topics: Amphotericin B; Aspergillosis; Critical Care; Galactose; Humans; Incidence; Intensive Care Units; Mannans; Prognosis; Retrospective Studies; Risk Factors

Conventional MIC testing of amphotericin B results in narrow MIC ranges challenging the detection of resistant strains. In order to discern amphotericin B pharmacodynamics, the in vitro activity of amphotericin B was studied against Aspergillus isolates with the same MICs by using a new in vitro pharmacokinetic/pharmacodynamic (PK/PD) model that simulates amphotericin B human plasma levels. Clinical isolates of Aspergillus fumigatus, A. terreus, and A. flavus with the same Clinical and Laboratory Standards Institute modal MICs of 1 mg/liter were exposed to amphotericin B concentrations following the plasma concentration-time profile after single-bolus administration with C(max) values of 0.6, 1.2, 2.4, and 4.8 mg/liter. Fungal growth was monitored for up to 72 h based on galactomannan production. Complete growth inhibition was observed only against A. fumigatus with amphotericin B with a Cmax of ≥ 2.4 mg/liter. At the lower C(max) values 0.6 and 1.2 mg/liter, significant growth delays of 34 and 52 h were observed, respectively (P < 0.001). For A. flavus, there was no complete inhibition but a progressive growth delay of 1 to 50 h at an amphotericin B C(max) of 0.6 to 4.8 mg/liter (P < 0.001). For A. terreus, the growth delay was modest (up to 8 h) at all C(max)s (P < 0.05). The C(max) (95% confidence interval) associated with 50% activity for A. fumigatus was 0.60 (0.49 to 0.72) mg/liter, which was significantly lower than for A. flavus 3.06 (2.46 to 3.80) mg/liter and for A. terreus 7.90 (5.20 to 12.29) mg/liter (P < 0.001). A differential in vitro activity of amphotericin B was found among Aspergillus species despite the same MIC in the order A. fumigatus > A. flavus > A. terreus in the in vitro PK/PD model, possibly reflecting the different concentration- and time-dependent inhibitory/killing activities amphotericin B exerted against these species.

Topics: Amphotericin B; Antifungal Agents; Aspergillus flavus; Aspergillus fumigatus; Culture Media; Galactose; Humans; Mannans; Microbial Sensitivity Tests; Models, Biological; Time Factors

We evaluated the efficacy of voriconazole against nine strains of Aspergillus terreus with different MICs (0.12 to 4 μg/ml) by using a murine model. Markers of efficacy included survival, tissue burden, galactomannan antigenemia, and drug serum levels. Voriconazole was especially effective in prolonging survival and reducing the fungal load in infections by strains that showed MICs that were less than or equal to the epidemiological cutoff value (1 μg/ml). In vitro data might be useful for predicting the outcome of A. terreus infections.

Topics: Amphotericin B; Animals; Antifungal Agents; Aspergillosis; Aspergillus; Drug Resistance, Fungal; Galactose; Male; Mannans; Mice; Microbial Sensitivity Tests; Prognosis; Pyrimidines; Survival Analysis; Triazoles; Voriconazole

The purpose of this study was to investigate the performance of non-invasive diagnostic tests such as galactomannan enzyme immunoassay and quantitative PCR in the early diagnosis of invasive aspergillosis (IA), and how these tests are impacted upon by the use of different classes of antifungal agents in an in-vivo model of IA.. A standardised rat inhalation model of IA was used to examine the effects of an azole, posaconazole, a polyene, amphotericin B and an echinocandin caspofungin. Daily blood samples were collected for subsequent analysis using a commercially available galactomannan assay and an inhouse qPCR assay.. No significant differences were observed in the CE/g of Aspergillus fumigatus in the lungs of each group. qPCR was statistically more sensitive than galactomannan for both the early detection of infected controls (p=0.045) and for overall detection (p=0.018). However, antifungal treatment significantly reduced the overall sensitivity of qPCR (p=0.020); these effects were due to posaconazole and caspofungin. In the latter stages of infection (days 4 and 5) there were no significant differences in the numbers of infections detected by galactomannan and qPCR; however, the antifungal class used caused significant qualitative differences (p=0.041). Galactomannan showed improved detection in posaconazole-treated animals.. Previous exposure to antifungal therapy must be considered when interpreting either qPCR or galactomannan-based IA diagnostics as this study has shown that individual classes of antifungal agents impact upon the dynamics of antigen and DNA release into the circulation.

Topics: Amphotericin B; Animals; Antifungal Agents; Aspergillus fumigatus; Biomarkers; Caspofungin; Disease Models, Animal; DNA, Fungal; Early Diagnosis; Echinocandins; Galactose; Immunoenzyme Techniques; Invasive Pulmonary Aspergillosis; Lipopeptides; Mannans; Microbiological Techniques; Mycological Typing Techniques; Predictive Value of Tests; Rats; Real-Time Polymerase Chain Reaction; Time Factors; Triazoles

In conventional ΜΙC tests, fungi are exposed to constant drug concentrations, whereas in vivo, fungi are exposed to changing drug concentrations. Therefore, we developed a new in vitro pharmacokinetic/pharmacodynamic model where human plasma pharmacokinetics of standard doses of 1 mg/kg amphotericin B, 4 mg/kg voriconazole, and 1 mg/kg caspofungin were simulated and their pharmacodynamic characteristics were determined against three clinical isolates of Aspergillus fumigatus, Aspergillus flavus, and Aspergillus terreus with identical MICs (1 mg/liter for amphotericin B, 0.5 mg/liter for voriconazole) and minimum effective concentrations (0.5 mg/liter for caspofungin). This new model consists of an internal compartment (a 10-ml dialysis tube made out of a semipermeable cellulose membrane allowing the free diffusion of antifungals but not galactomannan) inoculated with Aspergillus conidia and placed inside an external compartment (a 700-ml glass beaker) whose content is diluted after the addition of antifungal drugs by a peristaltic pump at the same rate as the clearance of the antifungal drugs in human plasma. Fungal growth was assessed by galactomannan production. Despite demonstrating the same MICs, amphotericin B completely inhibited (100%) A. fumigatus but not A. flavus and A. terreus, whose growth was delayed for 7.53 and 22.8 h, respectively. Voriconazole partially inhibited A. fumigatus (49.5%) and Α. flavus (27.9%) but not Α. terreus; it delayed their growth by 3.99 h (A. fumigatus) and 5.37 h (Α. terreus). Caspofungin did not alter galactomannan production in all of the species but A. terreus. The new model simulated human pharmacokinetics of antifungal drugs and revealed important pharmacodynamic differences in their activity.

Topics: Amphotericin B; Antifungal Agents; Aspergillosis; Aspergillus; Aspergillus flavus; Aspergillus fumigatus; Caspofungin; Diffusion Chambers, Culture; Echinocandins; Galactose; Humans; Lipopeptides; Mannans; Microbial Sensitivity Tests; Pulsatile Flow; Pyrimidines; Species Specificity; Spores, Fungal; Triazoles; Voriconazole

Acute invasive pulmonary aspergillosis is a rapidly progressive and frequently lethal infection. Relatively little is known about early events in the pathogenesis and relationship between the cell wall biomarkers galactomannan and (1→3)-β-d-glucan. The consequences of delayed antifungal therapy are also poorly defined. A persistently neutropenic rabbit model of invasive pulmonary aspergillosis was used to describe the histopathology of early invasive pulmonary aspergillosis and the kinetics of galactomannan and (1→3)-β-d-glucan. The time course of both molecules was mathematically modeled by using a population methodology, and Monte Carlo simulations were performed. The effect of progressive delay in the administration of amphotericin B deoxycholate 1 mg/kg at 24, 48, 72, and 96 h postinoculation on fungal burden, lung weight, pulmonary infarct score, and survival was determined. Histopathology showed phagocytosis of conidia by pulmonary alveolar macrophages at 4 h postinoculation. At 12 to 24 h, there was a progressive focal inflammatory response with conidial germination and hyphal extension. Subsequently, hyphae invaded into the contiguous lung. Galactomannan and (1→3)-β-d-glucan had similar trajectories, and both exhibited considerable interindividual variability, which was reflected in Monte Carlo simulations. Concentrations of both molecules began to rise <24 h postinoculation before pulmonary hemorrhagic infarction was present. Delays of 72 and 96 h in the administration of amphotericin B resulted in fungal burdens and lung weights that were indistinguishable from those of controls, respectively. Galactomannan and (1→3)-β-d-glucan have similar kinetics and are comparable biomarkers of early invasive pulmonary aspergillosis. Antifungal treatment at ≥48 h postinoculation is associated with suboptimal therapeutic outcomes.

Topics: Amphotericin B; Animals; Antifungal Agents; Aspergillus fumigatus; beta-Glucans; Deoxycholic Acid; Drug Combinations; Galactose; Invasive Pulmonary Aspergillosis; Mannans; Proteoglycans; Rabbits

Antifungal monotherapy with polyenes, azoles or echinocandins is not always effective for invasive pulmonary aspergillosis (IPA). The main purpose of this study was to evaluate the efficacy of a combination of micafungin and amphotericin B for the primary treatment of IPA in an immunocompromised mouse model.. Female ICR mice were used in all experiments. An immunosuppressive state was induced in mice by an intraperitoneal injection of cyclophosphamide. Mice were intratracheally inoculated with Aspergillus fumigatus conidia, treated with micafungin, amphotericin B or both for 7 days, and were tested for their survival 20 days after the Aspergillus inoculation. Fungal burden in lungs, serum galactomannan index (GMI) and histopathology of lungs, spleen and kidneys were also evaluated.. Combination therapy with micafungin and amphotericin B gave excellent survival of infected mice compared with monotherapy with micafungin or amphotericin B alone. Combined therapy reduced the fungal burden in the lungs and the serum GM levels compared with monotherapy or untreated controls, resulting in a significant histological improvement with disappearance of fungi in the lungs.. These findings suggest that combination therapy with micafungin and amphotericin B is more effective compared with monotherapy with either of them alone for IPA treatment.

Topics: Amphotericin B; Animals; Antifungal Agents; Aspergillus fumigatus; Drug Therapy, Combination; Echinocandins; Female; Galactose; Immunocompromised Host; Invasive Pulmonary Aspergillosis; Kidney; Lipopeptides; Lung; Mannans; Micafungin; Mice; Mice, Inbred ICR; Spleen; Survival Analysis

The purpose of this study was to assess the antifungal activity, pharmacokinetics, and tissue distribution of amphotericin B (AmpB) following the administration of Abelcet and AmBisome alone and in combination with Caspofungin to rats infected with Aspergillus fumigatus. Aspergillus fumigatus inoculum (2.1-2.5 x 10(7) colony forming units [CFU]) was injected via the jugular vein; 48 h later male albino Sprague-Dawley rats (350-400 g) were administered either a single intravenous (i.v.) dose of Abelcet (5 mg AmpB/kg; n = 6), AmBisome (5 mg AmpB/kg; n = 6), Caspofungin (3 mg/kg; n = 5), Abelcet (5 mg AmpB/kg) plus Caspofungin (3 mg/kg) (n = 6), AmBisome (5 mg AmpB/kg) plus Caspofungin (3 mg/kg) (n = 7), or physiologic saline (non-treated controls; n = 6) once daily for 4 days. Antifungal activity was assessed by organ CFU concentrations and plasma galactomannan levels. Plasma and tissue samples were taken from each animal for AmpB pharmacokinetic analysis and tissue distribution determinations. Abelcet treatment significantly decreased total fungal CFU concentrations recovered in all the organs added together by 73% compared to non-treated controls. Ambisome treatment significantly decreased total fungal CFU concentrations recovered in all the organs added together by 69% compared to non-treated controls. Caspofungin treatment significantly decreased total fungal CFU concentrations recovered in all the organs added together by 80% compared to non-treated controls. Abelcet plus Caspofungin treatment significantly decreased total fungal CFU concentrations recovered in all the organs added together by 81% compared to non-treated controls. Ambisome plus Caspofungin treatment significantly decreased total fungal CFU concentrations recovered in all the organs added together by 98% compared to non-treated controls. Abelcet treatment significantly decreased plasma galactomannan levels by 50 and 75% 96 h following the initiation of treatment in the absence and presence of Caspofungin co-therapy, respectively. AmBisome treatment significantly decreased plasma galactomannan levels by 73 and 78% 96 h following the initiation of treatment in the absence and presence of Caspofungin co-therapy, respectively. Co-administration of Caspofungin with Abelcet and AmBisome did not significantly alter the plasma concentration-time profile, pharmacokinetic parameters, and tissue distribution of AmpB. Taken together, our findings suggest that an alternative mechanism, possibly at t

Topics: Amphotericin B; Animals; Antifungal Agents; Aspergillosis; Aspergillus fumigatus; Caspofungin; Colony Count, Microbial; Disease Models, Animal; Drug Administration Schedule; Drug Combinations; Drug Therapy, Combination; Echinocandins; Galactose; Injections, Intravenous; Lipopeptides; Male; Mannans; Peptides, Cyclic; Phosphatidylcholines; Phosphatidylglycerols; Rats; Rats, Sprague-Dawley; Tissue Distribution

A case of cerebral aspergillosis was diagnosed by the detection of Aspergillus flavus-specific DNA in brain biopsy and serum specimens. The diagnosis was also supported by detection of elevated levels of galactomannan and (1-->3)-beta-d-glucan in serum specimens. Despite the presence of dichotomously branched septate hyphae in brain biopsy, the culture remained negative. The inability to isolate the organism in culture suggested that combined therapy of AmBisome and caspofungin was fungicidal for the fungus in the brain abscess.

Topics: Amphotericin B; Antifungal Agents; Aspergillosis; Aspergillus flavus; beta-Glucans; Brain; Brain Diseases; Caspofungin; Diagnosis, Differential; DNA, Fungal; Echinocandins; Electrophoresis, Agar Gel; Galactose; Humans; Lipopeptides; Male; Mannans; Middle Aged; Peptides, Cyclic; Polymerase Chain Reaction

Little is known about the pathogenesis of invasive pulmonary aspergillosis and the relationship between the kinetics of diagnostic markers and the outcome of antifungal therapy.. An in vitro model of the human alveolus, consisting of a bilayer of human alveolar epithelial and endothelial cells, was developed. An Aspergillus fumigatus strain expressing green fluorescent protein was used. Invasion of the cell bilayer was studied using confocal and electron microscopy. The kinetics of culture, polymerase chain reaction, and galactomannan were determined. Galactomannan was used to measure the antifungal effect of macrophages and amphotericin B. A mathematical model was developed, and results were bridged to humans.. A. fumigatus penetrated the cellular bilayer 14-16 h after inoculation. Galactomannan levels were inextricably tied to fungal invasion and were a robust measure of the antifungal effect of macrophages and amphotericin B. Neither amphotericin nor macrophages alone was able to suppress the growth of A. fumigatus; rather, the combination was required. Monte Carlo simulations showed that human dosages of amphotericin B of at least 0.6 mg/kg were required to achieve adequate drug exposure.. This model provides a strategy by which relationships among pathogenesis, immunological effectors, and antifungal drug therapy for invasive pulmonary aspergillosis may be further understood.

Topics: Amphotericin B; Antifungal Agents; Arteries; Aspergillosis; Aspergillus fumigatus; Cell Line, Tumor; Endothelial Cells; Galactose; Humans; In Vitro Techniques; Kinetics; Lung; Lung Diseases, Fungal; Macrophages; Mannans; Models, Biological; Monte Carlo Method

The purpose of this study was to assess the antifungal activity of a new oral amphotericin B (AmpB) lipid-based formulation following administration to rats infected with Aspergillus fumigatus. Aspergillus fumigatus inoculum (2.1-2.5 x 10(7) colony forming units [CFU]) were injected via the jugular vein; 48h later male albino Sprague-Dawley rats (350-400 g) were administered either a single oral dose of AmpB incorporated into Peceol (50 mg AmpB/kg), physiologic saline (nontreated controls) or Peceol alone (vehicle control) once daily for 4 days. To assess antifungal activity Brain, Lung, Heart, Liver, Spleen and Kidney sections were homogenized with normal saline (1 mL/g of tissue) and a 0.1-mL aliquot was spread plated onto a Sabourand dextrose agar plate. The plates were incubated for 48 hr at 37 degrees C, at which time the number of fungal CFU were determined and corrected for tissue weight. In addition, plasma galactomannan antigen concentrations were determined. Data was reported as mean +/- standard error of the mean. The AmpB-Peceol oral formulation significantly decreased total fungal CFU concentrations recovered in all the organs added together, brain CFU concentrations, spleen CFU concentrations and plasma galactomannan antigen concentrations compared to baseline. No significant differences in lung, heart, liver and kidney CFU concentrations between treatment and control groups were observed. Peceol vehicle control did not exhibit any antifungal activity. These findings suggest that a new oral lipid-based formulation of AmpB incorporated into Peceol can significantly decrease brain and spleen CFU concentrations and plasma galactomannan antigen concentrations compared to non-treated controls.

Topics: Administration, Oral; Amphotericin B; Animals; Antifungal Agents; Antigens, Fungal; Aspergillosis; Aspergillus fumigatus; Brain; Galactose; Intestinal Absorption; Male; Mannans; Oleic Acids; Rats; Rats, Sprague-Dawley; Spleen; Stem Cells

Invasive pulmonary aspergillosis is increasing in incidence in immunosuppressed patients. Diagnosis of this infection is problematic, relying on clinical suspicion and computerized tomography of the thorax and sinuses. An assay capable of detecting the fungal cell wall component galactomannan (GM) as a sign of Aspergillus infection is in use in patients with hematological malignancies. The aim of this study was to investigate the release of GM during growth of two medically important species, Aspergillus fumigatus and Aspergillus terreus, in liquid medium, including interaction with fluconazole, amphotericin B, liposomal amphotericin B and itraconazole, as well as human monocytes. Our results showed that for both species, amphotericin B deoxycholate, liposomal amphotericin B and itraconazole reduced the concentrations of GM to very low levels at the lowest doses tested (1, 3 and 4 microg/L, respectively). High doses of fluconazole had negligible effect on GM release by A. terreus, as expected. However, fluconazole at 128 microg/L increased GM concentrations released by A. fumigatus without reduction in visible growth. Co-incubation with human monocytes had no significant effect on GM release. The effects of antifungal agents on GM release may have diagnostic implications.

Topics: Amphotericin B; Antifungal Agents; Aspergillus; Cells, Cultured; Coculture Techniques; Culture Media; Fluconazole; Galactose; Humans; Itraconazole; Mannans; Monocytes

In view of the poor therapy outcomes of invasive aspergillosis, the objective of this study was to evaluate the efficacy of combination treatment consisting of the polyene amphotericin-B-intralipid, the echinocandin caspofungin and granulocyte-colony stimulating factor (G-CSF) in experimental murine systemic aspergillosis. With inhibition of synthesis of 1,3-beta-d-glucan in the fungal cell wall by caspofungin and an effect on the cell membrane by amphotericin-B-intralipid, this treatment may result in a synergic effect against Aspergillus fumigatus. Addition of G-CSF may further contribute to therapy of aspergillosis.. ICR mice were immunosuppressed by intraperitoneal administration of cyclophosphamide. Three days later, the mice were inoculated intravenously (iv) with A. fumigatus conidia. Infection and treatment were evaluated during an observation period of 30 days in terms of mortality (survival rate and mean survival time) and morbidity (quantitative determination of fungal burden, histopathology, and detection of serum galactomannan).. Combination of caspofungin + G-CSF or addition of G-CSF to the combination of caspofungin + amphotericin-B-intralipid increased the survival rate of infected mice up to 78.9% and prolonged their mean survival time to 25 days. These combinations also resulted in a reduction in fungal burden in organs, and a decrease in serum galactomannan.. The successful results obtained in the experimental model may possibly open the way to more effective management of aspergillosis in humans.

Topics: Amphotericin B; Animals; Antifungal Agents; Aspergillosis; Aspergillus fumigatus; Caspofungin; Disease Models, Animal; Drug Synergism; Drug Therapy, Combination; Echinocandins; Female; Galactose; Granulocyte Colony-Stimulating Factor; Immunocompromised Host; Kidney; Lipopeptides; Liposomes; Lung; Mannans; Mice; Mice, Inbred ICR; Peptides, Cyclic; Polyenes; Survival Rate

Empirical antifungal therapy is the standard treatment for persistent or relapsing antibiotic-resistant neutropenic fever. However, overtreatment resulting in increased toxicity and treatment-related cost is a major shortcoming of such therapy. We assessed the feasibility of a "preemptive" approach based on the incorporation of sensitive, noninvasive diagnostic tests for consecutive high-risk neutropenic patients who had received fluconazole prophylaxis while avoiding empirical therapy.. A total of 136 treatment episodes for persons who were at risk of acquiring invasive fungal infection (IFI) were screened for the presence of galactomannan with an enzyme immunoassay. A diagnostic evaluation, which included thoracic computed tomography scanning (HRCT) and bronchoscopy with lavage, was performed on the basis of well-defined clinical, radiological, and microbiological criteria. Only seropositive patients and patients with a positive microbiological test result plus supportive radiological findings received liposomal amphotericin B.. Neutropenic fever developed in 117 episodes, of which at least 41 episodes (35%) satisfied existing criteria for empirical antifungal therapy. However, our protocol-driven preemptive approach reduced the rate of antifungal use for these episodes from 35% to 7.7% (a 78% reduction) and led to the early initiation of antifungal therapy in 10 episodes (7.3%) that were clinically not suspected of being IFI. No undetected cases of invasive aspergillosis were identified; 1 case of zygomycosis was missed. Breakthrough candidemia was diagnosed by conventional culture techniques and was treated successfully. With use of a preemptive approach, the 12-week survival rate for patients with IFI was 63.6% (it was 63.1% for those with invasive aspergillosis).. Preemptive therapy based on enzyme immunoassay and HRCT reduced the exposure to expensive and potentially toxic drugs and offered effective antifungal control, but it failed to detect non-Aspergillus IFI.

Topics: Adolescent; Adult; Aged; Algorithms; Amphotericin B; Antifungal Agents; Aspergillosis; Feasibility Studies; Female; Galactose; Humans; Lung Diseases, Fungal; Male; Mannans; Middle Aged; Mycoses; Neutropenia; Prospective Studies; Risk Factors; Tomography, X-Ray Computed

Ravuconazole is a new antifungal triazole with broad-spectrum activity and a long half-life in plasma. We studied the antifungal efficacy, safety, and pharmacokinetics of ravuconazole lysine phosphoester in escalating dosages for the treatment of invasive pulmonary aspergillosis due to Aspergillus fumigatus in persistently neutropenic rabbits. Treatment groups consisted of rabbits treated with ravuconazole at 2.5 (RVC2.5), 5 (RVC5), and 10 (RVC10) mg/kg of body weight/day, rabbits treated with amphotericin B (AMB) at 1 mg/kg/day, or untreated controls. There was a dose-dependent reduction of pulmonary residual fungal burden (CFU per gram) in RVC5-, RVC10-, and AMB-treated rabbits in comparison to untreated controls (P < 0.01, P < 0.001, and P < 0.01, respectively). These findings correlated with progressive galactomannan antigenemia in untreated controls and the RVC2.5-treated rabbits, a lower galactomannan index (GMI) in RVC5- and RVC10-treated rabbits, and a similarly low GMI in AMB-treated rabbits (P < 0.01). Rabbits treated with RVC5, RVC10, and AMB also showed a reduction of organism-mediated pulmonary injury, as measured by infarct scores and lung weights, in comparison to untreated controls (P < 0.001). These results were supported by decreased pulmonary infiltrates detected by computed tomography in RVC5- and RVC10-treated rabbits in comparison to untreated controls (P < 0.05). Survival throughout the entire study was achieved in 95% of RVC5-treated rabbits (P < 0.001), 85% of RVC10-treated rabbits (P < 0.001), and 50% of AMB-treated rabbits (P < 0.05) in comparison to none of the untreated controls. Ravuconazole showed linear plasma pharmacokinetics and a large volume of distribution while maintaining concentrations in plasma above the MIC throughout the dosing interval. There was no evidence of hepatotoxicity or nephrotoxicity among ravuconazole-treated animals. Intravenously administered ravuconazole lysine phosphoester showed dose-dependent efficacy and an excellent safety profile for the treatment of invasive pulmonary aspergillosis in persistently neutropenic rabbits.

Topics: Amphotericin B; Animals; Antifungal Agents; Aspergillosis, Allergic Bronchopulmonary; Aspergillus fumigatus; Dose-Response Relationship, Drug; Female; Galactose; Half-Life; Image Processing, Computer-Assisted; Immunosuppressive Agents; Injections, Intravenous; Lung; Mannans; Microbial Sensitivity Tests; Neutropenia; Rabbits; Survival Analysis; Tetrazolium Salts; Thiazoles; Tomography, X-Ray Computed; Triazoles

Topics: Acute Disease; Amphotericin B; Antifungal Agents; Aspergillosis; Bone Marrow Transplantation; Bronchoalveolar Lavage Fluid; Child; Enzyme-Linked Immunosorbent Assay; Fatal Outcome; Galactose; Humans; Leukemia, Myeloid; Lung Diseases, Fungal; Male; Mannans; Postoperative Complications

The kinetics of various parameters of fungal load and cytokines were investigated, in order to acquire insight into the pathogenesis of invasive pulmonary aspergillosis (IPA) during antifungal treatment with amphotericin B.. Neutropenic rats with left-sided IPA received either treatment with amphotericin B or remained untreated. At 0, 4, 8, 16, 24, 48, 72 and 120 h after fungal inoculation, the rats were dissected. The size of the macroscopic pulmonary lesions, the number of cfu and amounts of chitin were determined in the infected left lung. Galactomannan concentrations were measured both in the left lung and serum. The cytokines tumour necrosis factor (TNF)-alpha, interleukin (IL)-1beta, IL-6, interferon (IFN)-gamma, IL-4, IL-10, and the chemokines macrophage inflammatory protein (MIP)-2 and monocyte chemoattractant protein (MCP)-1 were determined quantitatively by ELISA in the infected left lung, uninfected right lung and serum.. Amphotericin B treatment of IPA resulted in changed aspect of pulmonary lesions and significantly reduced levels of left lung chitin (72 and 120 h), left lung galactomannan (72 and 120 h) and serum galactomannan (120 h), but not left lung cfu, compared with untreated infected rats. In addition, amphotericin B treatment resulted in a significant decrease in levels of left lung IL-6 (at 72 and 120 h), MIP-2 (at 120 h) and MCP-1 (at 120 h). No local or systemic increases in TNF-alpha, IL-1beta or IFN-gamma were observed during infection.. It is concluded that treatment with amphotericin B results in decreased fungal load in the infected lung. This reduction in fungal load probably results in a decreased local inflammatory response, as measured by decreased levels of IL-6, MIP-2 and MCP-1 in the infected lung.

Topics: Amphotericin B; Animals; Antifungal Agents; Aspergillosis, Allergic Bronchopulmonary; Chitin; Colony Count, Microbial; Cytokines; Enzyme-Linked Immunosorbent Assay; Female; Galactose; Kinetics; Lung; Mannans; Neutropenia; Rats; Survival Analysis

In common with a proportion of patients with invasive pulmonary aspergillosis (IPA), the efficacy of AmBisome treatment regimens in our rat model remains suboptimal. To investigate whether this might be the result of initially low antifungal activity of amphotericin B at the site of infection when administered in the liposomal form, Fungizone was added to AmBisome at the start of treatment. Groups of granulocytopenic rats with left-sided IPA received 10 day treatment regimens with either AmBisome 10 mg/kg/day (n = 25) or AmBisome 10 mg/kg/day combined with a single dose of Fungizone 1 mg/kg at day 1 (n = 27). Parameters of treatment response included survival, serum galactomannan (GM), size and quality of pulmonary macroscopic lesions, lung weight, viable fungal counts (cfu) and chitin content of the infected lung, and extra-pulmonary disseminated fungal infection. In a separate experiment the significance of early start of treatment to obtain therapeutic efficacy was investigated. Compared with untreated controls, both treatment regimens showed a significant increase in survival and change in parameters of fungal infection except left lung cfu. The combination treatment showed a significant increase in survival compared with AmBisome monotherapy (P = 0.02) and a significant decrease in left lung chitin content (P = 0.03). Differences in circulating GM concentrations between the two treatment regimes approached significance (P = 0.06). Delay in the start of treatment from 16 to 24 h after fungal inoculation resulted in a significant decrease in therapeutic efficacy (P = 0.02). It is concluded that the efficacy of AmBisome therapy can be enhanced by the addition of Fungizone at the start of treatment. This is probably a result of active amphotericin B being immediately available in the lung at the start of treatment.

Topics: Agranulocytosis; Amphotericin B; Animals; Antifungal Agents; Aspergillosis; Aspergillosis, Allergic Bronchopulmonary; Biomarkers; Chitin; Drug Therapy, Combination; Female; Galactose; Lung; Mannans; Rats; Survival Analysis; Time Factors

The performance of antibody detection, antigen detection, and Aspergillus genus-specific PCR for diagnosing Aspergillus meningitis was investigated with 26 cerebrospinal fluid (CSF) samples obtained from a single patient with proven infection caused by Aspergillus fumigatus. Immunoglobulin G antibodies directed against Aspergillus were not detected by enzyme-linked immunosorbent assay in CSF or serum. The antigen galactomannan was detected in the CSF 45 days before a culture became positive, and Aspergillus DNA was detected 4 days prior to culture. Decline of the galactomannan antigen titer in the CSF during treatment with intravenous and intraventricular amphotericin B and intravenous voriconazole corresponded with the clinical response to treatment.

Topics: Aged; Amphotericin B; Antibodies, Fungal; Antifungal Agents; Antigens, Fungal; Aspergillosis; Aspergillus fumigatus; DNA, Fungal; Drug Resistance, Microbial; Female; Galactose; Humans; Mannans; Meningitis, Fungal; Mycology; Polymerase Chain Reaction; Pyrimidines; Time Factors; Triazoles; Voriconazole

The G test containing factor G, fractioned from the Limulus lysate, was used to detect (1-3)-beta-D-glucan in a rat model of aspergillosis. Aspergillus fumigatus strain MF-13, 1 x 10(4) conidia, were inoculated transtracheally into rats treated with cortisone acetate (100 mg/kg) and fed a low-protein (8%) diet. Increased serum (1-3)-beta-D-glucan was found on the sixth day after inoculation in concentrations of 370 +/- 178 pg/ml (mean +/- SD) in untreated controls, and 154 +/- 43 pg/ml in rats treated with 0.5 mg/kg of amphotericin B. On day 11 (1-3)-beta-D-glucan concentrations were 2,590 +/- 2,940 pg/ml and 448 +/- 442 pg/ml, respectively. The elevation in levels of (1-3)-beta-D-glucan increased in correlation with the elevation of galactomannan antigen titers; (1-3)-beta-D-glucan is thus measurable during experimental aspergillosis in rats.

Topics: Amphotericin B; Animals; Aspergillosis; Aspergillus fumigatus; beta-Glucans; Disease Models, Animal; Galactose; Glucans; Horseshoe Crabs; Lung; Male; Mannans; Rats; Rats, Sprague-Dawley

A model of primary pulmonary aspergillosis in rabbits was developed to reproduce the persistent levels of profound granulocytopenia and the histopathologic features of bronchopneumonia, vascular invasion, and hemorrhagic infarction encountered in humans. D-mannitol was detectable in bronchoalveolar lavage fluid by gas-liquid chromatography/mass spectroscopy, and galactomannan was measurable in serum by latex agglutination immunoassay. A pharmacokinetically distinctive unilamellar vesicle formulation of liposomal amphotericin B, 5 mg/kg/day intravenously, compared with high-dose conventional desoxycholate amphotericin B, 1 mg/kg/day intravenously, was more effective in preventing nephrotoxicity, increasing survival, reducing the number of viable organisms, and decreasing tissue injury due to Aspergillus organisms. Thus, D-mannitol in lavage fluid and galactomannan in serum may be useful markers of pulmonary aspergillosis, and liposomal amphotericin B was significantly more effective and safer than desoxycholate amphotericin B for treatment of pulmonary aspergillosis in profoundly granulocytopenic rabbits.

Topics: Agranulocytosis; Amphotericin B; Animals; Antigens, Fungal; Aspergillosis; Aspergillus fumigatus; Biomarkers; Bronchoalveolar Lavage Fluid; Ergosterol; Galactose; Kidney Diseases; Life Tables; Liposomes; Lung Diseases; Mannans; Mannitol; Opportunistic Infections; Rabbits; Survival Analysis