Administration Of Amphotericin Research Articles

Routine versus selective antifungal administration for control of fungal infections in patients with cancer.

Systemic fungal infection is considered to be an important cause of morbidity and mortality in cancer patients, particularly those with neutropenia. Antifungal drugs are often given prophylactically, or empirically to patients with persistent fever. To assess whether commonly used antifungal drugs decrease mortality in cancer patients with neutropenia. We searched PubMed from 1966 to 7 July 2014 and the reference lists of identified articles. Randomised clinical trials of amphotericin B, fluconazole, ketoconazole, miconazole, itraconazole or voriconazole compared with placebo or no treatment in cancer patients with neutropenia. The two review authors independently assessed trial eligibility and risk of bias, and abstracted data. Thirty-two trials involving 4287 patients were included. Prophylactic or empirical treatment with amphotericin B significantly decreased total mortality (relative risk (RR) 0.69, 95% confidence interval (CI) 0.50 to 0.96), whereas the estimated RRs for fluconazole, ketoconazole, miconazole, and itraconazole were close to 1.00. No eligible trials were found with voriconazole. Amphotericin B and fluconazole decreased mortality ascribed to fungal infection (RR 0.45, 95% CI 0.26 to 0.76 and RR 0.42, 95% CI 0.24 to 0.73, respectively). The incidence of invasive fungal infection decreased significantly with administration of amphotericin B (RR 0.41, 95% CI 0.24 to 0.73), fluconazole (RR 0.39, 95% CI 0.27 to 0.57) and itraconazole (RR 0.53, 95% CI 0.29 to 0.97), but not with ketoconazole or miconazole. Effect estimates were similar for those 13 trials that had adequate allocation concealment and were blinded. The reporting of harms was far too variable from trial to trial to allow a meaningful overview. For the 2011 and 2014 updates no additional trials were identified for inclusion. Intravenous amphotericin B was the only antifungal agent that reduced total mortality. It should therefore be preferred when prophylactic or empirical antifungal therapy is introduced in cancer patients with neutropenia.

Pharmacokinetic profile of micafungin when co-administered with amphotericin B in healthy male subjects

Micafungin and amphotericin B are antifungal agents with potent activity against a broad spectrum of fungal spp., including Candida and Aspergillus. The objective of this study was to evaluate the potential pharmacokinetic (PK) interaction of the two drugs in healthy subjects. PK were evaluated in healthy adults in an open-label, phase I clinical trial, following separate treatments with micafungin (200 mg; days 1 - 5) and conventional amphotericin B (0.25 mg/kg; days 8 - 13) alone, and following co-administration of both drugs (days 14 - 18). In 20 male subjects, systemic exposure to micafungin (measured using peak plasma micafungin concentration (Cmax) and area under the plasma micafungin concentration-time curve (AUC0-τ)) were similar following coadministration of micafungin and amphotericin B (day 18; Cmax 19.1 μg/mL, AUC0-τ 232 μg×h/mL) compared with administration of micafungin alone (day 5; Cmax 18.7 μg/mL, AUC0-τ 236 μg×h/mL), suggesting that administration of amphotericin B does not affect the PK of micafungin. The exposure to amphotericin B was ~ 30% greater following co-administration of both drugs (day 18; Cmax 704 μg/mL, AUC0-τ 9157 μg×h/mL) than after administration of amphotericin B alone (day 13; Cmax 621 μg/mL, AUC0-τ 7023 μg×h/mL). Concurrent treatment with micafungin and amphotericin B was less well tolerated than when either agent was administered alone. PK and safety-related observations during co-administration of micafungin and amphotericin B were considered to be a consequence of accumulation of amphotericin B to a steady state, indicating that co-administration of the two drugs does not affect the PK of micafungin.

Mycotic Infections

Endemic mycoses are caused by fungi that share several important characteristics but differ greatly in other respects. They include histoplasmosis, blastomycosis, coccidioidomycosis, and sporotrichosis. Discussions on their epidemiology, pathogenesis, clinical presentation, diagnosis, differential diagnosis, treatment, and prognosis are included. A section on antifungal therapy is included, discussing the use of azoles and amphotericin B. Figures show photomicrographs of biopsy samples from patients with histoplasmosis, blastomycosis, and coccidioidomycosis. Tables list selected drugs that may interact with azoles to change serum levels and information on the administration of amphotericin B for treatment of endemic mycoses. This review contains 3 highly rendered figures, 3 tables, and 71 references.

Recurrences of Visceral Leishmaniasis Caused by Leishmania siamensis after Treatment with Amphotericin B in a Seronegative Child

We report the first case of visceral leishmaniasis caused by Leishmania siamensis in a seronegative child. She was treated with amphotericin B at 1 mg/kg/day for 3 weeks; however, recurrences occurred twice. The patient was cured after the administration of amphotericin B for 5 weeks and monthly prophylaxis for 6 months.

Pharmacokinetics of amphotericin B lipid complex in critically ill patients undergoing continuous venovenous haemodiafiltration

The objective of this study was to examine the effect of continuous venovenous haemodiafiltration (CVVHDF) on the pharmacokinetics of amphotericin B (AmB) in critically ill patients following administration of amphotericin B lipid complex (ABLC). Plasma and ultrafiltrate (UF) samples were collected from patients administered ABLC and either receiving or not receiving CVVHDF. Pharmacokinetic (PK) analysis was performed on eight profiles from patients receiving CVVHDF and six profiles from patients not receiving CVVHDF. For patients receiving CVVHDF, the following median PK data were calculated: area under the concentration–time curve (AUC)=13.9h·μg/mL, volume of distribution at steady state (Vss)=1476L and drug clearance (CL)=27.4L/h; for patients not receiving CVVHDF, the corresponding median PK data were 11.5hμg/mL, 2048L and 43.7L/h, respectively. The median half-lives calculated during the dosage interval (t1/2int) were 30.9h and 32.5h on and off CVVHDF, respectively, and the total range of t1/2int values was 15.6–180.4h. Observed median peak concentrations on Day 1 were 0.563μg/mL and 0.468μg/mL in patients on and off CVVHDF, respectively. From AmB present in the UF, clearance via CVVHDF contributed<1% of total plasma clearance. The AmB concentration–time profiles for patients administered ABLC on and off CVVHDF were compared and no statistically significant differences in AUC, CL, t1/2int and Vss were observed. In conclusion, CVVHDF had no clinically significant effect on the pharmacokinetics of AmB following administration of ABLC.

Treatment of Pythiosis in Equine Limbs Using Intravenous Regional Perfusion of Amphotericin B

To evaluate the effects of intravenous regional limb perfusion (IRLP) administration of amphotericin B in horses to treat pythiosis after surgical excision and thermocautery. Case series. Horses (n = 12) with Pythium insidiosum infection of the distal aspect of the thoracic or pelvic limbs. After surgical excision of granulation tissue and thermocautery, 50 mg amphotericin B was administered by IRLP through a catheter placed in a superficial vein of the affected limb next to the lesion after placing a tourniquet above the injection site. The lesions and locomotor system were evaluated before treatment and at 7, 14, 21, 28, 35, and 60 days. Ninety-two percent of horses treated with amphotericin B had complete lesion resolution 35 or 60 days after 1 or 2 IRLP treatments, respectively. IRLP induced limb edema and pain during regional palpation in 42%, and inflammation of the injection site in 33% of horses; however these signs resolved after 14 days. IRLP administration of amphotericin B was effective for treating pythiosis in equine limbs, resolving infection with manageable side effects.

Zygomycosis in Europe: analysis of 230 cases accrued by the registry of the European Confederation of Medical Mycology (ECMM) Working Group on Zygomycosis between 2005 and 2007

Zygomycosis is an important emerging fungal infection, associated with high morbidity and mortality. The Working Group on Zygomycosis of the European Confederation of Medical Mycology (ECMM) prospectively collected cases of proven and probable zygomycosis in 13 European countries occurring between 2005 and 2007. Cases were recorded by a standardized case report form, entered into an electronic database and analysed descriptively and by logistic regression analysis. During the study period, 230 cases fulfilled pre-set criteria for eligibility. The median age of the patients was 50 years (range, 1 month to 87 years); 60% were men. Underlying conditions included haematological malignancies (44%), trauma (15%), haematopoietic stem cell transplantation (9%) and diabetes mellitus (9%). The most common manifestations of zygomycosis were pulmonary (30%), rhinocerebral (27%), soft tissue (26%) and disseminated disease (15%). Diagnosis was made by both histology and culture in 108 cases (44%). Among 172 cases with cultures, Rhizopus spp. (34%), Mucor spp. (19%) and Lichtheimia (formerly Absidia) spp. (19%) were most commonly identified. Thirty-nine per cent of patients received amphotericin B formulations, 7% posaconazole and 21% received both agents; 15% of patients received no antifungal therapy. Total mortality in the entire cohort was 47%. On multivariate analysis, factors associated with survival were trauma as an underlying condition (p 0.019), treatment with amphotericin B (p 0.006) and surgery (p <0.001); factors associated with death were higher age (p 0.005) and the administration of caspofungin prior to diagnosis (p 0.011). In conclusion, zygomycosis remains a highly lethal disease. Administration of amphotericin B and surgery, where feasible, significantly improve survival.

The Initial 96 Hours of Invasive Pulmonary Aspergillosis: Histopathology, Comparative Kinetics of Galactomannan and (1→3)-β- d -Glucan, and Consequences of Delayed Antifungal Therapy

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.

Effect of Amphotericin B on Parasitemia and Survival of Plasmodium Berghei-infected Mice

Premature death of Plasmodium-infected erythrocytes is considered to favourably influence the clinical course of malaria. Amphotericin B has previously been shown to trigger suicidal erythrocyte death or eryptosis, which is characterized by cell membrane scrambling leading to phosphatidylserine exposure at the cell surface. Phosphatidylserine-exposing cells are rapidly cleared from circulating blood. The present study thus tested whether amphotericin B exerts a direct effect on Plasmodium falciparum and influences eryptosis of infected erythrocytes, parasitemia and host survival in murine malaria. To this end, human erythrocytes were infected in vitro with Plasmodium falciparum and mice were infected with Plasmodium berghei ANKA by in vivo intraperitoneal injection of parasitized murine erythrocytes (1x10⁶). Half of the infected mice received amphotericin B (1.5 mg/kg b.w. i.v.) from the 8^th day of infection. Amphotericin B (≧ 1 µM) compromised the intracellular development of the parasite in human erythrocytes as evident from in vitro growth and DNA amplification assays. Amphotericin B further augmented the eryptosis of infected human erythrocytes. The administration of amphotericin B to infected mice tended to delay the increase of parasitemia and significantly delayed host death. All nontreated mice died from malaria within 27 days. In contrast, some 50% of amphotericin B-treated mice survived for more than 27 days after infection. In conclusion, amphotericin B augmented the suicidal death of infected erythrocytes and delayed the lethal course of malaria in Plasmodium berghei infected mice.

High-dose caspofungin salvage in a very-low-birth-weight infant with refractory candidemia

Candidiasis is one of the most common causes of late-onset infection among very-low-birth-weight infants (VLBW) in most neonatal intensive care units and is associated with significant morbidity and mortality. Standard therapy consists of the administration of amphotericin B, amphotericin B complex, and fluconazole. In many cases, candidiasis is not easily eradicated, despite the administration of these drugs. We report our experience of the addition of high-dose caspofungin to the conventional antifungal drugs in a VLBW infant with refractory candidemia. (Korean J Pediatr 2010;53:239-243)

Amphotericin B Lozengers: Prophylaxis for Esophagitis in Thoracic Radiotherapy

Esophagitis is an important side effect in thoracic radiotherapy, no preventive drug therapy has been established yet. The aim of the present study was to prospectively evaluate the effectiveness of prophylactic antimycotic treatment with amphotericin B lozengers. 40 consecutive patients with high-dose thoracic radiotherapy for lung cancer were investigated in a nonrandomized study. 20 patients receiving a median maximal esophageal dose of 67 Gy (range 61-80 Gy) were treated with amphotericin B lozengers four times daily from day 8 to the end of radiotherapy. Another 20 patients with a lower median maximal esophageal dose of 60 Gy (range 51-67.5 Gy) constituted the control group. Length of the irradiated esophagus and dose-length indices were evaluated. Side effects were prospectively scored according to the RTOG/EORTC criteria. There was a trend toward higher esophageal volumes in the prophylaxis group; furthermore, patients in this group were older, had a worse median Karnofsky Index and had more often received induction chemotherapy. In the prophylaxis group, 15 patients remained free from esophagitis and five patients developed esophagitis grade 1. In the control group, four patients remained free from symptoms, 14 patients showed esophagitis grade 1 and two patients grade 2. The difference between the two groups was statistically significant (p < 0.05). The start of symptoms was delayed in the prophylaxis group in comparison to the control group: day 21 (median, range 14-44) and day 18 (median, range 10-32) respectively. Amphotericin B lozengers were tolerated without side effects by all patients. Prophylactic administration of amphotericin B lozengers seems to effectively prevent radiation-induced esophagitis.

Postoperative application of amphotericin B nasal spray in chronic rhinosinusitis with nasal polyposis, with a review of the antifungal therapy

Chronic rhinosinusitis (CRS) affects 1-4% of the adult population. The etiology of this multifactorial, chronic disease, which leads to a significant impairment of the quality of life, often accompanied by nasal polyposis, is not fully understood. In the past decade, it was presumed that the disease, which causes characteristic eosinophilic infiltration of the nasal mucosa, is triggered by an enhanced (but not classical allergic IgE-type) immune response against fungal organisms in the nasal mucus. If this supposition is correct, then it appears obvious that the administration of amphotericin B nasal spray in adequate concentration following endoscopic polypectomy should be advantageous for these patients, and might even reduce the number of recurrent cases. To check on this assumption, we conducted a prospective randomized placebo-controlled trial involving 33 patients, 30 of whom remained in the study throughout. Patients with nasal polyposis were operated on with an endoscopic technique between 1 November 2005 and 1 October 2006; group A (14 randomly selected patients) were treated with a nasal spray containing 5 mg/ml amphotericin B, while the placebo group B (16 randomly selected patients) received a nasal spray lacking amphotericin B. We evaluated our results with the aid of a modified Lund-Mackay CT score, the SNAQ-11 test (which assesses changes in the symptoms), a quality of life test and endoscopy. The SPSS 14.0 for Windows program was utilized to process the data of examinations performed preoperatively and 1 year postoperatively. The CT scores of the group A patients 1 year after the operation exhibited wide scattering, without signs of recovery. The CT scores of the group B patients indicated a slight improvement, though this did not prove significant relative to group A. Both the SNAQ-11 test and the quality of life test revealed a significant improvement in each group, but the degrees of change in these tests did not differ significantly between the two groups of patients. The endoscopic findings indicated a slight improvement to the advantage of the amphotericin B-treated group 12 months after the operation. These results lead to the conclusion that the administration of amphotericin B nasal spray to patients operated on for nasal polyposis does not give rise to a significant alteration in either CT score, clinical symptoms, or quality of life. The more favorable clinical aspects observed in the amphotericin B-treated group during the endoscopic follow-up did not correspond to an improvement in the symptoms. In connection with the conclusions drawn from this study, the authors discuss the controversial data available on the fungal etiology of CRS. They critically analyze the contradictory observations and conclusions of seven recent clinical studies.

Postoperative application of amphotericin B nasal spray in chronic rhinosinusitis with nasal polyposis. Can recidive polyposis be prevented?

Chronic rhinosinusitis affects 1-4% of the adult population. The aetiology of this multifactorial, chronic disease, which leads to a significant impairment of the quality of life, often accompanied by nasal polyposis, is not fully understood. In the past decade it was presumed that the disease, which causes characteristic eosinophilic infiltration of the nasal mucosa, is triggered by an enhanced (but not classical allergic IgE type) immune response. If this supposition is correct, then it appears obvious that the administration of amphotericin B nasal spray in adequate concentration following endoscopic polypectomy should be advantageous for these patients, and might even reduce the number of recurrent cases. To check on this assumption, the authors conducted a prospective randomized placebo-controlled trial involving 33 patients, 30 of whom remained in the study throughout. Patients with nasal polyposis were operated on with an endoscopic technique between 1 November 2005 and 1 October 2006; one group of them (group A, 14 randomly selected patients) was treated with a nasal spray containing 5 mg/ml amphotericin B, while the placebo group (group B, 16 randomly selected patients) received a nasal spray lacking amphotericin B. The results were evaluated with the aid of a modified Lund-Mackay CT score, the SNAQ-11 test (which evaluates changes in the symptoms), the life-quality test and endoscopy. The SPSS 14.0 for Windows program was utilized to process the data of examinations performed preoperatively and one year postoperatively. The CT scores of the group A patients exhibited wide scattering without signs of recovery one year after the operation. The CT scores of the group B patients indicated a slight improvement, though this did not prove significant in relation to group A. Both the SNAQ-11 test and the life-quality test revealed a significant improvement in each group, but the degrees of change in these tests did not significantly differ between the two groups of patients. The endoscopic findings indicated a slight improvement to the advantage of the amphotericin B-treated group 12 months after the operation. These results lead to the conclusion that the administration of amphotericin B nasal spray to patients operated on for nasal polyposis does not give rise to a significant alteration in CT scores, clinical symptoms, or quality of life. The more favourable clinical aspects observed in the amphotericin B-treated group during the endoscopic follow-up did not correspond to an improvement in the symptoms. In connection with the conclusions drawn from this study the authors discuss the available data on the fungal theory. They critically analyse the contradictory observations of 7 recent clinical studies.

Outcomes of Cryptococcal Meningitis in Uganda Before and After the Availability of Highly Active Antiretroviral Therapy

Cryptococcal meningitis (CM) is the proximate cause of death in 20%-30% of persons with acquired immunodeficiency syndrome in Africa. Two prospective, observational cohorts enrolled human immunodeficiency virus (HIV)-infected, antiretroviral-naive persons with CM in Kampala, Uganda. The first cohort was enrolled in 2001-2002 (n = 92), prior to the availability of highly active antiretroviral therapy (HAART), and the second was enrolled in 2006-2007 (n = 44), when HAART was available. Ugandans presented with prolonged CM symptoms (median duration, 14 days; interquartile range, 7-21 days). The 14-day survival rates were 49% in 2001-2002 and 80% in 2006 (P < .001). HAART was started 35 +/- 13 days after CM diagnosis and does not explain the improved 14-day survival rate in 2006. In 2006-2007, the survival rate continued to decrease after hospitalization, with only 55% surviving to initiate HAART as an outpatient. Probable cryptococcal-related immune reconstitution inflammatory syndrome occurred in 42% of patients, with 4 deaths. At 6 months after CM diagnosis, 18 persons (41%) were alive and receiving HAART in 2007. The median cerebral spinal fluid (CSF) opening pressure was 330 mm H(2)O; 81% of patients had elevated pressure (>200 mm H(2)O). Only 5 patients consented to therapeutic lumbar puncture. There was a trend for higher mortality for pressures >250 mm H(2)O (odds ratio [OR], 2.1; 95% confidence interval [CI], 0.9-5.2; P = .09). Initial CSF WBC counts of <5 cells/mL were associated with failure of CSF sterilization (OR, 17.3; 95% CI, 3.1-94.3; P < .001), and protein levels <35 mg/dL were associated with higher mortality (OR, 2.0; 95% CI, 1.2-3.3; P = .007). Significant CM-associated mortality persists, despite the administration of amphotericin B and HIV therapy, because of the high mortality rate before receipt of HAART and because of immune reconstitution inflammatory syndrome-related complications after HAART initiation. Approaches to increase acceptance of therapeutic lumbar punctures are needed.

Multifocal squamous cell carcinomas in an HIV-infected patient with a long-term voriconazole therapy

Multifocal squamous cell carcinomas in an HIV-infected patient with a long-term voriconazole therapy

Efficacy of intravenous itraconazole against invasive pulmonary aspergillosis in neutropenic mice

The efficacy of itraconazole (ITZ) solubilized in hydroxypropyl-beta-cyclodextrin (ITZ-IV) was examined in a murine model of invasive pulmonary aspergillosis (IPA). Immunosuppressed mice were infected by the intratracheal inoculation of Aspergillus fumigatus conidia (2 x 10(6) conidia/mouse). Their body weight rapidly decreased and they died within 6 days after infection. Intravenous administration of various doses of ITZ-IV was started 24 h after infection and was continued once a day for 4 days. ITZ-IV at daily doses of 10, 20, or 40 mg/kg was as effective as the intraperitoneal administration of amphotericin B (AMPH) at a dosage of 1 mg/kg daily in improving survival. ITZ-IV (20 mg/kg per day), as well as AMPH (1 mg/kg per day) significantly lowered the fungal burden in the pulmonary tissues. Histological improvement was seen within 2 days after the beginning of administration of ITZ-IV (20 mg/kg per day). In mice intravenously given a single dose of ITZ-IV (20 mg/kg), the blood level and pulmonary tissue level of ITZ plus its active metabolites, mainly hydroxyitraconazole (OH-ITZ), decreased gradually after the injection, but after 4 h their concentration was still between 1.4 microg/ml (ITZ) and 1.9 microg/ml (OH-ITZ), concentrations that were approximately 10 to 20 times greater than the minimum inhibitory concentration (MIC) of ITZ for challenging the strain of A. fumigatus (0.16 microg/ml). These results support the clinical usefulness of ITZ-IV for the treatment of IPA in immunocompromised patients.

Effect of neutropenia and treatment delay on the response to antifungal agents in experimental disseminated candidiasis.

Disseminated candidiasis is associated with a high rate of morbidity and mortality. The presence of neutrophils and the timely administration of antifungal agents are likely to be critical factors for a favorable therapeutic outcome of this syndrome. The effect of neutropenia on the temporal profile of the burden of Candida albicans in untreated mice and those treated with amphotericin B was determined using a pharmacodynamic model of disseminated candidiasis. A mathematical model was developed to describe the rate and extent of the C. albicans killing attributable to neutrophils and to amphotericin B. The consequences of a delay in the administration of amphotericin B, flucytosine, or micafungin were studied by defining dose-response relationships. Neutrophils caused a logarithmic decline in fungal burden in treated and untreated mice. The combination of amphotericin B and neutrophils resulted in a high rate of Candida killing and a sustained anti-C. albicans effect. In neutropenic mice, 5 mg/kg of body weight of amphotericin B was required to prevent progressive logarithmic growth. An increased delay in drug administration resulted in a reduction in the maximum effect to a point at which no drug effect could be observed. Neutrophils and the timely initiation of antifungal agents are critical determinants in the treatment of experimental disseminated candidiasis.

Coccidioidomycosis in Pregnancy: Case Report and Review of the Literature

Background Coccidioidomycosis is an uncommon fungal infection during pregnancy. We report a case and review the literature on coccidioidomycosis in pregnancy. Methods We searched MEDLINE (1966-2005), PubMed (1950-2005), Embase (1974-2005), the Cochrane Library, and the Index-Catalogue of the Library of the Surgeon-General’s Office United States Army (1880-1961) for cases of coccidioidomycosis occurring during pregnancy. We describe a woman with disseminated coccidioidomycosis during the last trimester of pregnancy with fungemia, respiratory failure, a miliary pattern on chest radiograph, and skin and bony involvement. Results We identified 80 additional cases of coccidioidomycosis occurring with pregnancy in the literature. The mean age of patients was 26 years (range 16-38 years). Disseminated disease was strongly associated with the trimester of pregnancy; 40% of the cases diagnosed before pregnancy, 50% of the cases diagnosed in the first trimester, 62% of the cases diagnosed in the second trimester, and 96% of the cases diagnosed in the third trimester had dissemination ( P < .001). In addition, African American women had a 13-fold increased risk of dissemination compared with white women ( P = .007). Conclusions Mortality rates have improved over time in association with the timely administration of antifungal therapy. Disseminated coccidioidomycosis may occur during pregnancy, especially during the third trimester. Improved maternal and fetal survival is associated with early disease recognition and administration of amphotericin B.

Toxicity, stability and pharmacokinetics of amphotericin B in immunomodulator tuftsin-bearing liposomes in a murine model

In the present study we evaluated the pharmacokinetics and toxicity of amphotericin B in immunomodulator tuftsin-loaded liposomes in a murine model. Stability of amphotericin B liposomes was tested by incubating one volume of liposomal formulations of amphotericin B with nine volumes of serum. The pharmacokinetics of amphotericin B in Candida albicans-infected mice treated with conventional and tuftsin-loaded amphotericin B liposomes was evaluated over a period of 24 h. In vitro toxicity of amphotericin B deoxycholate, as well as amphotericin B liposomes, was tested by incubation with human erythrocytes for 1 h at 37 degrees C. To assess amphotericin B-induced in vivo toxicity, BALB/c mice were injected with three doses of amphotericin B deoxycholate, as well as amphotericin B liposomal formulations on days 1, 2 and 3 post C. albicans infection. Blood from treated mice was taken by retro-orbital puncture to test renal function parameters such as serum creatinine and urea. In vitro stability studies revealed that tuftsin-bearing amphotericin B liposomes released only 11% of the total liposomal amphotericin B in the serum, while it was found to be 19% from identical tuftsin-free amphotericin B liposomes. Both tuftsin-loaded as well as tuftsin-free liposomal formulations of amphotericin B induced approximately 20% haemolysis of erythrocytes at a dose of 40 mg/L, while the same amount of drug in amphotericin B deoxycholate caused 100% lysis of the erythrocytes. Pharmacokinetic studies revealed that subsequent to administration of various formulations of amphotericin B, there was 32 mg/L amphotericin B in the systemic circulation of mice treated with tuftsin-bearing amphotericin B liposomes, while it was 25 mg/L for amphotericin B liposomes, 4 h post drug administration. In vivo toxicity studies demonstrated that the amphotericin B deoxycholate formulation induced elevations in serum creatinine (approximately 300% of control) and blood urea (approximately 380% of control) values, while these values were substantially less (blood urea approximately 150% of control and serum creatinine approximately 210% of control) in the animals treated with the tuftsin-loaded amphotericin B liposomal formulation. Further, the administration of amphotericin B deoxycholate (1 mg/kg) in BALB/c mice at a dose of 1 mg/kg body weight led to the accumulation of 18.6 +/- 5.25 g/kg (of amphotericin B) in kidneys. On the other hand, administration of liposomal amphotericin B and tuftsin-bearing liposomal amphotericin B at a dose of 5 mg/kg body weight resulted in accumulation of 8.8 +/- 2.0 and 4.0 +/- 1.6 g/kg of amphotericin B, respectively, in the kidneys of treated animals. Co-administration of immunomodulator tuftsin along with liposomal formulations of amphotericin B successfully minimizes toxicity, as well as other side effects of the drug. Interestingly, tuftsin also increased the stability of liposomal amphotericin B. Superior efficacy, reliable safety and favourable pharmacodynamics of tuftsin-loaded amphotericin B liposomes suggest their potential therapeutic value in the management of fungal infections.

Systemic fungemia and hepatic localizations ofFusarium solani in a liver transplanted patient: An emerging fungal agent

The incidence of invasive fungal infection is increasing especially in the field of transplantation, affecting as many as 50% of bone marrow transplant (BMT) patients with neutropenia and 5-20% of solid-organ transplant (SOT) recipients. Fusarium species are soil saprophytes and plant pathogens. They may cause superficial mycoses or important opportunistic infections in patients with bone marrow suppression and neutropenia, they have been rarely described in solid organ recipients, and up to now there have been no reports of such infection in isolated liver transplanted patients. We describe a case of disseminated Fusarium solani infection with hepatic localization in a liver transplanted patient that resolved with the administration of amphotericin B. Our observation confirms that Fusarium spp. are emerging pathogens that may most frequently affect not only BMT patients and patients with hematological malignancies, but also SOT patients. They may cause both localized and disseminated infection. In conclusion, Fusarium spp. etiology should be considered in the context of infectious diseases following liver transplantation.