Voriconazole MICs are predictive for the outcome of experimental disseminated scedosporiosis.

Background: Scedosporiosis is associated with a mortality rate of up to 90% in patients suffering from disseminated infections. Recommended first-line treatment is voriconazole, but epidemiological cut-off values and clinical breakpoints have not been determined. Objectives: To correlate voriconazole treatment response in mice suffering from disseminated scedosporiosis with MIC values determined using CLSI broth microdilution, Etest (bioMérieux) and disc diffusion. Methods: Voriconazole MICs for 31 Scedosporium apiospermum strains were determined using CLSI broth microdilution, Etest and disc diffusion. Groups of mice were challenged intravenously with 1 out of 16 S. apiospermum strains (voriconazole CLSI broth microdilution MIC range: 0.125-8.0 mg/L) and treated with 40 mg/kg voriconazole orally by gavage once daily. Efficacy of voriconazole was evaluated by a statistically significant ( P < 0.05) reduction in fungal burden in brain. Results: A categorical agreement of 90.4% was reached for CLSI broth microdilution and disc diffusion and of 93.6% for CLSI broth microdilution and Etest. Correlation of CLSI MICs and in vivo outcome was good, as mice challenged with strains with an MIC ≤2 mg/L responded to voriconazole therapy in 92.3% and those challenged with strains with an MIC ≥4 mg/L responded to voriconazole therapy in 33.3%. Conclusions: CLSI broth microdilution and Etest deliver comparable results that enable a prediction of in vivo outcome. Our results suggest that voriconazole is able to reduce fungal burden in the brain of 92.3% of all mice challenged with strains with voriconazole CLSI MICs ≤2 mg/L, while mice challenged with strains with CLSI MICs ≥4 mg/L showed limited response to voriconazole treatment.

[The agent Latrodectus and canine paecilomycotic eclampsia as a laboratory model in the survey of treatment for mycoses and parasitic diseases].

The extragent used to prepare a Latrodectus mactans hydrocarbon extract is a multicomponent system composed of alkanes, alkenes, and arenes. More than 100 compounds were identified in the hydrocarbon extract (petroleum). The petroleum matrix of Latrodectus mactans was first obtained to manufacture homeopathic remedies. The authors could prepare the first Russian homeopathic medicine from Latrodectus mactans, which proved to be effective in treating canine eclampsia. Canine experiments provide a rationale for the authors' choice as the only homeopathic remedy among thousand known drugs to treat female eclampsia. It is Latrodectus mactans that is in the list of homeopathic medicines permitted for use in accordance with Order No. 335 (Supplement 2) of the Ministry of Health and Medical Industry of Russia, issued on November 29, 1995. It is manufactured from Latrodectus mactans living in the USA.

Evaluation of the safety and efficacy of liposomal amphotericin B (L-AMB) in children.

A multicenter, uncontrolled clinical study has been conducted to evaluate the safety, efficacy, and pharmacokinetics of liposomal amphotericin B (L-AMB) in children. In this article, the safety and efficacy of L-AMB are discussed. Subjects were diagnosed with invasive fungal infection (definitely diagnosed cases), possible fungal infection (clinically diagnosed cases), and febrile neutropenia with suspected fungal infection (febrile neutropenia cases). Of the 39 subjects treated with L-AMB, 18 received a definite (11) or clinical (7) diagnosis of invasive fungal infection. In these subjects, excluding one unevaluable subject, L-AMB was effective in nine out of 17 subjects(52.9%). Of 12 febrile neutropenia cases, improvement in clinical symptoms, etc., was observed for six but these were excluded from the efficacy analysis because they concomitantly used medications that may have affected efficacy. The causative fungus was identified in four out of 39 subjects and confirmed to be eliminated by treatment with L-AMB in one subject. Adverse events possibly related to L-AMB (adverse drug reactions) were reported in 36 out of 39 subjects (92.3%). The most commonad verse drug reaction was decreased potassium in 20 out of 39 subjects (51.3%), but all these subjects recovered with appropriate treatment, for example potassium supplementation.In a Japanese Phase II clinical study of adult patients, the incidence of adverse drug reactions was 95.3%(82/86 subjects) and the efficacy was 63.6% (42/66). Taken together, these data indicate that the safety and efficacy of L-AMB are almost the same in pediatric and adult patients.

[Amino acid exchange in paeci lomycosis-complicated echinococcosis].

The authors have detected atypical paecilomycosis-associated myocarditis with impaired amino acid exchange and pain syndrome for the first time. At first, pain occurs in the chest and radiates into the axilla, to the left arm to the finger tips, by paralyzing the arm. In some patients, pain manifests itself in both arms with radiation to the belly, by accompanying by fainting. The skin is wet, cold; the pulse is frequent and of poor volume and difficult-to-count. Heart pain spreads into the armpit and down the arm, by making the fingers numb. Attempts to use current analgesics (movalis, sirdalud, nimesil, morphine) in combination with fungicides (diflucan, mycosist, orungal) have failed to yield positive results. The homeopathic drug Latrodectus mactans, prepared from caracurt venom, in combination with the authors' designed diet and other homeopathic agents have relieved pain syndrome and normalized amino acid exchange, which offered possibilities for successful surgical treatment for echinococcosis with later recovery.

[Fungal blood stream infection, its pathogen and antifungal susceptibility in cancer patients].

It is important to correctly diagnose fungal bloodstream infection in cancer patients. Antifungal susceptibility testing (AST)supplies useful information for the management of invasive fungal infection. We analyzed fungi isolated from blood samples in Shizuoka Cancer Center over a period of 6 years, and detected 59 strains including yeast(57 isolates) and mold(Aspergillus fumigatus, Scedosporium sp). The clinical background was reviewed using the medical record. The major fungi isolated from blood were Candida albicans(39.0%), followed by C. glabrata(22.0%), C. parapsilosis (20.3%), and C. tropicalis(13.6%). AST was carried out for 32 strains out of 59, according to the National Committee of Clinical Laboratory Standards (NCCLS)M-27-A-2 method. Among 32 strains, 7 isolates were resistant to fluconazole and 8 to itraconazole. Through the research period, the distribution of MIC values for azole agents did not change widely; however, the values for micafungin increased between the former and latter periods. In order to estimate the efficacy of antifungal agents, it is thought that continuous monitoring and the establishment of a standard method to evaluate the sensitivity of antifungal drugs are necessary.

[Evaluation of beta-D-glucan density in blood after drinking an extraction element of Agaricus blazei murill].

beta-D-Glucan (beta-G) measurement in blood is useful for prompt diagnosis, selection of treatment and therapeutic evaluation for deep fungal infection. A patient with high beta-G blood was not improved by strong anti-fungal treatment in our hospital, and the beta-G levels in the blood fell immediately after discontinuing ingestion of the agaricus mushroom extracted element (sennseiro). To verify the elevation of beta-G concentration in the blood after intake of an agaricus mushroom extraction element, beta-G concentration in the blood was measured 4 days after 9 volunteers drank 2 g of agaricus mushroom extraction element, "SSG plus 35" twice a day for 3 days. A low value of beta-G in blood was detected in one person (11.1%), which demonstrated that beta-G concentration in the blood increased by oral ingestion of the agaricus element although the reason was unclear why it was detected in only one person. Taken together, when high beta-D-glucan is identified by uncertain cause or in spite of enough anti-fungal medication, it is necessary to confirm whether a patient has ingested health food containing an agaricus mushroom element or other fungus elements to avoid needless treatment with anti-fungal medicine.

Role of plasma lipids and lipoproteins in predicting amphotericin B-induced nephrotoxicity in pediatric oncology patients.

PURPOSE: The objective of this study was to determine if total plasma and lipoprotein cholesterol (C) and triglyceride (TG) concentrations could predict the degree of nephrotoxicity caused by the antifungal agent amphotericin B (AmpB); and to use the average amount of potassium supplementation received daily as a indicator of nephrotoxicity in pediatric oncology patients. PATIENTS AND METHODS: Plasma samples from 18 patients (ages < 17 years) who were receiving AmpB due to suspected or confirmed fungal infection at British Columbia Children's Hospital were analyzed for lipid concentrations. The high density lipoprotein (HDL) fractions were separated by precipitation; total (TOT) plasma and fraction C and TG concentrations were measured by enzymatic colorimetric assays; and low density lipoprotein (LDL) C levels were determined by Friedewald's formula. Changes in serum creatinine levels from baseline and amounts of potassium supplementation were used as indicators of nephrotoxicity; both were obtained from patients' medical charts. Pearson correlation coefficients (r) were determined and considered significant if P < 0.05. RESULTS: The total cumulative AmpB dose, adjusted for weight, does not seem to predict AmpB-induced nephrotoxicity. Positive but relatively weak correlations were found between total potassium supplementation and LDL C (r = 0.489, P < 0.02); and TOT C (r = 0.551, P < 0.01). In addition, a positive but relatively weak correlation between the average amount of potassium supplementation per day above baseline and HDL C (r = 0.407; P < 0.02) was observed. CONCLUSION: Differences in total plasma and LDL cholesterol concentrations may be used as predictors of AmpB-induced nephrotoxicity in pediatric oncology patients.

Ciprofloxacin plus piperacillin is an equally effective regimen for empiric therapy in febrile neutropenic patients compared with standard therapy.

The purpose of this study was to test the comparative efficacy and toxicity of empiric gentamicin and ciprofloxacin, in combination with piperacillin, in febrile patients with treatment-induced neutropenia. Fifty patients were prospectively randomized to receive piperacillin plus gentamicin (PG), and 46 were randomized to receive piperacillin plus ciprofloxacin (PC). The groups were similar in age, sex, diagnosis, duration of neutropenia, and incidence of positive cultures. The two antibiotic regimens were associated with comparable rates of defervescence in the patients with gram-positive bacteremia. In the patients with gram-negative bacteremia and those with negative cultures, however, defervescence was more prompt in the PC group. In particular, 27% of the culture-negative patients on PC, compared to only 5% of those on PG, defervesced within 72 hr (P = 0.015). Because of the more prompt defervescence in the PC group, amphotericin B was used less frequently; 78% of the patients on PG compared with only 56% of those on PC were started on amphotericin B (P = 0.025). PC is an effective alternative to the more traditional PG for treatment of febrile neutropenic hosts who have not been given prophylactic quinolones. More important, PC appears to hasten defervescence compared with PG, especially in culture-negative patients and those with gram-negative bacteremia, and may decrease the necessity of additional antimicrobial agents such as amphotericin B.

Bovine plasma vitamin A responses to selected nutrients, monensin, and endophytic fescue.

Previous research at this station adapted a maximal dose response (MDR) method of evaluating vitamin A status and utilization for use in beef cattle. This method was used in two experiments. In this first experiment, forty-eight crossbred steers (average weight, 284 kg) were fed diets supplemented with salt, monensin or both, and injected with vitamin E, zinc or selenium. Steers receiving monensin had higher (38.5 micrograms/dl, monensin; 31.0 micrograms/dl, controls) initial plasma concentrations of vitamin A (P = .14). However, monensin did not affect post-dosing (MDR) vitamin A concentrations. None of the other dietary treatments or injections affected either pre- or post-dosing concentrations of vitamin A in the plasma. In a second experiment 23 lactating multiparous beef cows (average weight, 500 kg) grazing either fungal endophyte-infected or endophyte-free tall fescue were used to assess possible influences of infected fescue upon vitamin A metabolism. Fungal endophyte infection did not affect either pre- (44.9 micrograms/dl, end-noninf.; 47.7 micrograms/dl, end-inf.) or post-dosing (57.2 micrograms/dl, end-noninf.; 59.3 micrograms/dl, end-inf.) vitamin A concentrations.

[Clinical evaluation of fluconazole in patients with mycotic infection].

Fluconazole, a triazole antifungal agent newly developed by Pfizer Inc.. was given orally to 4 patients with deep mycosis. Fluconazole was markedly effective against septicemia due to Candida and oral candidiasis accompanied with lingual ulcer in spite of seriousness of these underlying disease. In 2 patients with aspergilloma, eradication or contraction of fungus ball was observed and the drug was judged to be effective. In vitro MICs of fluconazole against clinically isolated Aspergillus spp. were much higher than its serum levels leaving a large discrepancy between in vitro activity and clinical efficacy. Although the dosage was 100-300 mg daily for 8 days to 6 months, neither adverse reactions nor laboratory parameter abnormalities were observed. The above results suggest that fluconazole is a useful agent in the treatment of fungal infections.

Malassezia fungemia in neonates and adults: complication of hyperalimentation.

Until recently, Malassezia furfur was thought to be a pathogen only in tinea versicolor. More recently, this lipophilic yeast has been recovered from sick neonates with catheter-related infections. Malassezia fungemia was studied in seven patients, and the salient features of this infection in patients described in the literature were reviewed. Major risk factors include prolonged hospitalization, the presence of central venous catheters, and the use of intravenous fat emulsions. It is difficult to identify specific manifestations of fungemia in these complex cases occurring in patients with severe underlying disease; however, neonates often present with the signs and symptoms of sepsis and thrombocytopenia, whereas fever may be the only manifestation in adults. Some patients are asymptomatic. When symptoms are present, they resolve upon removal of the colonized catheter. The role of the lipophilic nature of Malassezia in the pathogenesis of infection is apparent from the ability of intravenous fat emulsions to support the growth of the fungus in vitro. A special solid medium that can be used to determine the true prevalence of malassezia fungemia has been devised. M. furfur must be considered in the differential diagnosis of opportunistic infections in patients receiving central hyperalimentation and should be sought by the culture of blood on appropriate medium.