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Biomedical subjects

D A Stevens

Publications and source records attributed to D A Stevens.

At least 19 recordsLinked to original sources
PubMed1995

Detection of bovine viral diarrhoea virus antigen and RNA in oviduct and granulosa cells of persistently infected cattle.

Large-scale in vitro bovine embryo production systems commonly use genital tracts obtained from an abattoir as a source of both cumulus-oocyte complexes and co-culture feeder cells. Tissues derived from this source may be contaminated with non-cytopathogenic bovine viral diarrhoea virus (BVDV) since, in several countries surveyed, approximately 1% of animals tested are persistently infected with this pathogen. Therefore, the use of such material in in vitro fertilization systems presents a potential risk for the transmission of BVDV to bovine embryos and via embryo transfer. This potential was investigated by obtaining oviduct epithelial cells and granulosa cells, which are commonly used as feeder cells, from cattle persistently infected with BVDV and examining them for the presence of BVD viral antigen (p80 non-structural protein and gp53 envelope glycoprotein) by indirect immunofluorescent histochemistry, and also viral RNA (encoding the p80 region) by in situ hybridization. In addition, titres of virus present in oviduct, ovary and blood were assayed by immunodetection on calf testis cell cultures. Luminal epithelial cells from the oviduct and primary cultures of granulosa cells and oviduct epithelial cells from such cattle were shown to contain both viral antigen and RNA. The susceptibility of both cell types to BVDV infection was further established by inoculating primary cell cultures of cells derived from cattle not infected with BVDV with a cloned isolate of non-cytopathogenic BVDV (Pe515). RNA encoding BVDV and the antigen were detected 12 h after inoculation.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Itraconazole therapy for blastomycosis and histoplasmosis. NIAID Mycoses Study Group.

OBJECTIVE: To assess the efficacy and toxicity of orally administered itraconazole in the treatment of nonmeningeal, nonlife-threatening forms of blastomycosis and histoplasmosis. DESIGN: Prospective, nonrandomized, open trial. SETTING: Multicenter trial at 14 university referral centers. PATIENTS: Eighty-five patients with culture or histopathologic evidence of blastomycosis (48 patients) or histoplasmosis (37 patients). Patients receiving other systemic antifungal therapy were excluded. INTERVENTIONS: Itraconazole was administered orally at doses of 200 to 400 mg/d. Patients in whom treatment was considered a success were treated for a median duration of 6.2 months (blastomycosis) and 9.0 months (histoplasmosis). Disease activity was assessed at baseline; drug efficacy and toxicity were evaluated at monthly intervals during therapy, and efficacy was evaluated at regular follow-up visits after completion of therapy. The median duration of posttreatment evaluation for successfully treated patients was 11.9 months (blastomycosis) and 12.1 months (histoplasmosis). MEASUREMENTS AND MAIN RESULTS: Among the 48 patients with blastomycosis, success was documented in 43 (90%). The success rate for patients treated for more than 2 months was 95% (38 of 40). Among the 37 patients with histoplasmosis, success was documented in 30 (81%). The success rate for patients treated for more than 2 months was 86% (30 of 35). All patients with histoplasmosis in whom treatment failed had chronic cavitary pulmonary disease. Toxicity was minor; only 25 (29%) patients experienced any side effects, and itraconazole toxicity necessitated stopping therapy in only 1 patient. CONCLUSIONS: Itraconazole is a highly effective therapy for nonmeningeal, nonlife-threatening blastomycosis and histoplasmosis. The drug is associated with minimal toxicity.

Adult↗
PubMed1992

Control of invasive pulmonary aspergillosis with oral itraconazole in a bone marrow transplant patient.

Pulmonary aspergillosis following bone marrow transplantation carries a mortality of 94%, irrespective of current treatment. We treated a patient who had acquired aspergillosis some 80 days after allogeneic bone marrow transplantation, with oral itraconazole, 600 mg daily. After initial deterioration, clinical and radiographic resolution occurred during 3 months of therapy despite severe graft-vs.-host and cytomegalovirus disease. Itraconazole should be considered for therapy of pulmonary aspergillosis in this and other immunocompromised settings.

Administration, Oral↗
PubMed1992

In vitro susceptibility and synergy studies of Aspergillus species to conventional and new agents.

In vitro susceptibility data using a macrodilution broth method on greater than 100 isolates of Aspergillus spp. are presented. For amphotericin B (Amp B) (n = 105), 67% had minimum inhibitory concentrations (MICs) less than or equal to 2 micrograms/ml, and 90% had MICs less than or equal to 4 micrograms/ml; for 5-fluorocytosine [flucytosine (5FC) (n = 60), 35% had MICs less than or equal to 12.5 micrograms/ml; for miconazole (MCL) (n = 18), 39% had MICs less than or equal to 5 micrograms/ml; for ketoconazole (KTZ) four (13%) of 32 isolates had an MIC less than or equal to 3.1 micrograms/ml; for itraconazole (ITZ) (n = 88), 97% had MICs less than or equal to 6.3 micrograms/ml; and for saperconazole (SAP) (n = 20), 90% had MICs less than or equal to 3.1 micrograms/ml. Of Amp B minimum fungicidal concentrations (MFCs) (n = 25), 76% were less than or equal to 4 micrograms/ml; 5% of ketoconazole (n = 20) and no flucytosine (n = 38) MFCs were less than or equal to 25 micrograms/ml; for itraconazole (n = 60), 70% had MFCs less than or equal to 6.3 micrograms/ml, and for saperconazole (n = 20), 75% had MFCs less than or equal to 3.1 micrograms/ml. Drug interaction studies were also performed. For Amp B and rifampin 36 (92%) of 39 showed synergy, for Amp B and flucytosine six (23%) of 26 showed synergy and another six (23%) showed antagonism; 13 (50%) were indifferent. In five Amp B-itraconazole combination studies, synergy and indifference were seen in two each and an additive effect was observed in one. The published literature on in vitro testing methodology and results for Aspergillus spp. is also reviewed, and recommendations for the clinical use of in vitro susceptibility testing are made.

Amphotericin B↗
PubMed1992

Quantitative preservation of viability of Aspergillus fumigatus.

Quantitative preservation of the viability of two isolates of Aspergillus fumigatus was studied over a 15-month period of storage. Significant loss of viability occurred in isolates preserved at -70 degrees C in both phosphate-buffered saline with Tween (PBST) and 0.1% gelatin, immediately, and between 6 and 15 months. Storage in 10% and 25% dimethyl sulphoxide at -70 degrees C was successful up to 8 weeks with gradual loss of viability later. PBST at 4 degrees C or room temperature, or 10% glycerol at -70 degrees C maintained 100% viability of the cultures up to 6 months and 15 months, respectively. To preserve 100% viability, long-term storage of A. fumigatus is best done in 10% glycerol in PBST at -70 degrees C compared with the other methods tested.

Aspergillus fumigatus↗
PubMed1992

A five-year study of needlestick injuries: significant reduction associated with communication, education, and convenient placement of sharps containers.

OBJECTIVE: To decrease the numbers of needlesticks among healthcare workers. DESIGN: All reported needlestick injuries at Santa Clara Valley Medical Center, San Jose, California, were reviewed, analyzed, and tabulated by the infection control department yearly from 1986 to 1990. SETTING: A 588-bed county teaching hospital in San Jose, California, affiliated with Stanford University. PARTICIPANTS: All employees of Santa Clara Valley Medical Center who reported needlestick injuries on injury report forms. INTERVENTIONS: From April to December 1987, more needle disposal containers were added to as many patient care areas and as close to the area of use as possible. Results of 1986, 1988, 1989, and 1990 analyses were communicated yearly to all personnel, extensive educational programs were conducted in 1987 and 1988, and educational efforts continued in 1989 and 1990. RESULTS: In 1986, there were 259 needlestick injuries at our institution, 22% (32) from recapping. After needle disposal containers were added to all patient care areas, needlestick injuries for 1988 totalled 143, a 45% decrease in the total needlestick injuries and a 53% decrease in recapping injuries. Communication of results to all areas of the hospital and educational activities were started in 1987 and continued through the next 3 years. In 1989, there were 135 needlestick injuries, a decrease of 6% from 1988; recapping injuries decreased 40% from 1988. In 1990, there were 104 needlestick injuries, a 23% decrease since 1989, and a 33% decrease in recapping injuries. The total number of needlestick injuries from 1986 to 1990 decreased by 60%, and those injuries from recapping decreased by 81% to 89%. CONCLUSIONS: We have continued to monitor needlestick injuries, communicate findings to all personnel, and include needlestick prevention in educational programs. We contend that more convenient placement of needle disposal containers, communication of findings, and education do decrease needlestick injuries in healthcare workers.

California↗
PubMed1992

Interaction of azoles with rifampin, phenytoin, and carbamazepine: in vitro and clinical observations.

Twelve patients receiving therapy with an azole agent (ketoconazole, itraconazole, and/or fluconazole) for systemic mycoses experienced drug interactions with rifampin, phenytoin, and/or carbamazepine resulting in substantial decreases in azole concentrations in serum. All four patients receiving azoles and concurrent phenytoin and/or carbamazepine failed to respond to treatment or suffered a relapse of their fungal infection. Four of five patients with cryptococcosis who received itraconazole and rifampin responded despite decreases in their serum itraconazole concentrations; synergy between itraconazole and rifampin was documented by in vitro analysis of inhibition and of killing of Cryptococcus neoformans isolates from all patients receiving this combination. In contrast, two patients with coccidioidomycosis failed to respond to itraconazole/rifampin. Moreover, two patients with cryptococcosis suffered a relapse or persistence of seborrheic dermatitis while receiving itraconazole/rifampin. The latter combination showed synergy in vitro in the inhibition of the mycelial phase of Coccidioides immitis and, to a lesser extent, of the pathogenic spherule phase of this fungus; synergy in the killing of C. immitis was not noted, nor was synergy seen against Malassezia furfur, the purported etiologic agent of seborrheic dermatitis. These findings illustrate several drug interactions that may affect clinical outcome and that must be considered in the management of antifungal therapy.

Adult↗
PubMed1992

Efficacies of amphotericin B lipid complex (ABLC) and conventional amphotericin B against murine coccidioidomycosis.

The comparative activities of two preparations of amphotericin B against Coccidioides immitis were investigated. These preparations were a deoxycholate suspension (conventional amphotericin B) and a lipid-based formulation, amphotericin B lipid complex (ABLC). In-vitro susceptibility testing demonstrated that the MICs of ABLC were < or = 0.25 mg/L and of conventional amphotericin B were 0.5 mg/L for C. immitis. However, conventional amphotericin B was at least four-fold more fungicidal, with a minimum fungicidal concentration of 4.0 vs > 16 mg/L for ABLC. The therapeutic efficacies were tested in murine models of acute systemic coccidioidomycosis. Female CD-1 mice were infected iv with C. immitis arthroconidia to establish high (> 50%) or low (< 50%) mortality models. Therapy with conventional amphotericin B or ABLC was given three times per week for two weeks starting three days post-infection. Controls received no therapy or drug-free diluent only. Survival was tallied up to 49 days post-infection and the fungal cfu counts in spleen, liver, and lungs of all survivors were determined. In the low mortality study all treated mice survived and all therapy regimens reduced infection in all organs. All mice given ABLC 6.6 or 13.2 mg/kg/dose and 80% given ABLC 16.5 mg/kg/dose, as well as 90% given conventional amphotericin B 0.66 mg/kg/dose were free of infection; all controls remained infected. In two high mortality studies, all mice given ABLC 0.66-20 mg/kg/dose or conventional amphotericin B 0.22 or 0.66 mg/kg/dose survived compared with 0-20% of controls. Thirty per cent of uninfected mice given ABLC 20 mg/kg/dose and 40% given conventional amphotericin B 2.0 mg/kg/dose died due to drug toxicity. Mice given ABLC or conventional amphotericin B had lower residual cfu counts of C. immitis in all organs than did controls. Sixty to one hundred per cent of mice given ABLC regimens > or = 6.6 mg/kg/dose were cured, whereas all controls and 50-60% of mice receiving the highest non-toxic conventional amphotericin B regimen (0.66 mg/kg/dose) remained infected. At equal non-toxic amphotericin B doses, conventional amphotericin B was more effective than ABLC in reducing cfu in infected organs.(ABSTRACT TRUNCATED AT 400 WORDS)

Amphotericin B↗
PubMed1992

Synergy of itraconazole with macrophages in killing Blastomyces dermatitidis.

We examined in vitro interaction between the azole antifungal agents itraconazole and ketoconazole and macrophages and their activities against Blastomyces dermatitidis. Fungistatic and fungicidal concentrations for B. dermatitidis in vitro were assessed in a microculture system in which fungistasis was measured as inhibition of multiplication and fungicidal activity was measured as reduction of inoculum CFU. Resident peritoneal murine macrophages, which surround but do not phagocytize the fungus, were not fungicidal for B. dermatitidis isolates but were fungistatic for some isolates studied. Synergy was demonstrated when fungistatic concentrations (e.g., 0.01 micrograms/ml) of itraconazole, which limited growth 55% compared with that of controls, were cocultured with macrophages; this resulted in fungicidal activity (85% killing) against B. dermatitidis (ATCC 26199) in 72-h assays. This synergy could occur even if itraconazole was added after the macrophages had surrounded the fungus. Ketoconazole at fungistatic concentrations did not act synergistically with macrophages to kill B. dermatitidis. Lymph node lymphocytes could not substitute for macrophages in synergy with itraconazole to kill B. dermatitidis. When B. dermatitidis was separated by a filter from macrophages in Transwell cultures, fungicidal synergy with itraconazole was less efficient. Pretreatment of B. dermatitidis with itraconazole for 24 h did not render the fungus susceptible to killing by macrophages in the absence of itraconazole, whereas pretreatment of nonfungistatic macrophages with itraconazole rendered them fungistatic in a dose-dependent manner. Three other isolates were killed by otherwise fungistatic concentrations of itraconazole when the isolates were cocultured with macrophages. These findings indicate that one basis for the efficacy of itraconazole versus ketoconazole in treating blastomycosis could be synergy of a fungistatic concentration of itraconazole with macrophages in killing of B. dermatitidis.

Animals↗
PubMed1992

Efficacy and safety of amphotericin B colloidal dispersion compared with those of amphotericin B deoxycholate suspension for treatment of disseminated murine cryptococcosis.

The efficacy and safety of amphotericin B colloidal dispersion (ABCD) were compared with those of amphotericin B deoxycholate suspension (ABDS) (Fungizone) in a murine model of disseminated cryptococcosis. Mice were treated intravenously with either ABDS at 0.2, 0.8, or 3.2 mg/kg of body weight per dose or ABCD at 0.8, 3.2, 6.4, 12.8, or 19.2 mg/kg dose three times per week for 2 weeks. Excluding mice treated with ABDS at 3.2 mg/kg, which was acutely lethal in 100% of mice, and ABCD at 19.2 mg/kg, which also resulted in two early deaths, the survival of ABCD- and ABDS-treated groups was prolonged over survival of controls (P < or = 0.05). Survival of ABCD (3.2 mg/kg)-treated mice was improved over that of ABDS (0.2 mg/kg)-treated mice (P < 0.05); however, comparisons of mice given all other dosages of ABCD with mice given sublethal dosages of ABDS did not demonstrate differences in survival. Comparative fungal burdens in organs showed a decrease in liver (P < 0.05) and spleen (P < 0.05) burdens for ABCD with the 19.2-mg/kg therapy versus those with ABDS with the 0.8-mg/kg therapy and liver burdens for ABCD with the 12.8-mg/kg therapy versus ABDS with the 0.8-mg/kg therapy (P < 0.05). There was no difference in organ burdens between therapy with ABCD at 0.8 mg/kg and ABDS at 0.8 mg/kg. These data show that the efficacy of ABCD is equal to that of ABDS on a milligram-per-kilogram basis for murine disseminated cryptococcosis. Because of its decreased toxicity, greater efficacy with ABCD could be achieved through doses fourfold higher than the 100% lethal dose for ABDS. Thus, ABCD shows promise as an effective but less toxic alternative to ABDS for the treatment of disseminated cryptococcosis.

Amphotericin B↗
PubMed1992

Effect of cyclodextrin on the pharmacology of antifungal oral azoles.

Concentrations of oral azoles in serum were compared in a single-dose pharmacologic study in mice. When hydroxypropyl-beta-cyclodextrin was used as a carrier and compared with a standard carrier, polyethylene glycol, drug concentrations determined by bioassay showed that the peak concentration and area under the concentration-time curve were greatly enhanced for itraconazole and saperconazole; moderately enhanced for ketoconazole; but negligibly affected for fluconazole, miconazole, and SCH 42427.

2-Hydroxypropyl-beta-cyclodextrin↗
PubMed1992

Comparison of antifungal activity of amphotericin B deoxycholate suspension with that of amphotericin B cholesteryl sulfate colloidal dispersion.

Complexing amphotericin B (AmB) with lipids or entrapping it in liposomes may increase its efficacy by reducing toxicity and affecting distribution. However, depending on the lipids involved, interference with antifungal activity has been shown. We compared the in vitro activity of AmB colloidal dispersion by cholesteryl sulfate (ABCD) to the standard AmB deoxycholate suspension (ABDS) against 41 isolates of 15 pathogenic species. Broth dilution MIC and minimum fungicidal concentration (MFC) ranges were similar, and the same number of isolates had lower MICs and MFCs with one drug as with the other. Differences between species were noted. In less than a third of comparisons, there were large (fourfold or more) decreases in ABCD activity relative to that of ABDS, and in approximately 1/10, there were large increases. Thus, ABCD complexing variably affects AmB activity. As ABCD pharmacokinetics and toxicology differ from those of ABDS, the significance of these results for in vivo activity needs to be determined.

Amphotericin B↗
PubMed1992

Fate of conidia of Paracoccidioides brasiliensis after ingestion by resident macrophages or cytokine-treated macrophages.

Conidia ingested by resident macrophages had an enhanced percentage of transformation to yeast cells compared with those in culture medium without macrophages. The yeast cells subsequently grew intracellularly by budding. Macrophages treated with cytokines from antigen-stimulated spleen cells from immunized mice significantly inhibited transformation of ingested conidia.

Animals↗
PubMed1992

US experience with itraconazole in Aspergillus, Cryptococcus and Histoplasma infections in the immunocompromised host.

Itraconazole has emerged as an important new oral agent in the treatment of systemic fungal infections. This paper summarizes the data available on its use in aspergillosis, cryptococcosis and histoplasmosis, compiled in the United States with particular attention to the immunocompromised host. Data have been accrued in open-label studies including 57 patients with cryptococcal disease where the overall response rate among patients with meningitis was 86%, and in 28 patients (8 with acquired immune deficiency syndrome (AIDS) or human immunodeficiency virus (HIV) infection) with invasive aspergillosis where the overall response rates were 80% in patients without AIDS and 86% in patients with AIDS. Data are summarized on 6 patients with allergic bronchopulmonary aspergillosis, 5 of whom demonstrated marked improvement on therapy, and 12 patients with histoplasmosis including 8 with AIDS, 11 of whom responded and 1 recrudesced on therapy. In summary, itraconazole showed activity in human studies of aspergillosis, cryptococcosis and histoplasmosis with minimal toxicity. Itraconazole offers a new oral alternative to conventional amphotericin B therapy in these infections. Comparative studies are needed to clarify its role.

Acquired Immunodeficiency Syndrome↗
PubMed1992

Encephalopathy and seizures induced by intravesical alum irrigations.

Hemorrhagic cystitis is a significant toxic effect of cyclophosphamide therapy. Continuous bladder irrigation of a 1% alum solution is a simple and generally safe method of chemical cautery to treat the bleeding urothelium. We report four cases of encephalopathy coincident with elevated aluminum levels as well as one patient who developed seizures while receiving continuous bladder irrigations with alum. All patients had significant renal insufficiency. We recommend the cautious use of alum irrigation in patients with renal impairment and monitoring of serum aluminum levels to prevent excessive accumulation and toxicity.

Administration, Intravesical↗
PubMed1992

Induction of stress protein synthesis in Histoplasma capsulatum by heat, low pH and hydrogen peroxide.

It is well known that some micro-organisms synthesize proteins when stressed by heat or other factors. The function of these proteins is not yet clear, but some of them are believed to be related to resistance against a hostile environment. Histoplasma capsulatum is an intracellular pathogenic fungus that multiplies inside macrophages and resists macrophage microbicidal mechanisms. To study the defense mechanisms of H. capsulatum and mimic the hostile environment the fungus may encounter during infection, we investigated protein synthesis by H. capsulatum (isolate G217B) when stressed by heat (40 degrees C), low pH (pH 4), or oxidative products (H2O2) using [35S]-methionine labelling. Analysis of cytosol proteins by SDS-PAGE and fluorography disclosed that H. capsulatum increased synthesis of six constitutive proteins and decreased synthesis of six proteins when stressed at 40 degrees C. When stressed by pH 4 or H2O2, H. capsulatum increased the synthesis of eight and five constitutive proteins, respectively, and decreased the synthesis of three proteins. Estimation of superoxide dismutase (SOD) and catalase enzymatic activity in cytosols from stressed H. capsulatum did not reveal an increase of these enzymatic activities compared to cytosols from non-stressed H. capsulatum. These results suggest that H. capsulatum increases the synthesis of some constitutive proteins when stressed by heat, low pH or H2O2, which might relate to pathogenicity, and are thus worthy of further study. These induced proteins are apparently different from SOD or catalase.

Catalase↗