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Biomedical subjects

E M Bernard

Publications and source records attributed to E M Bernard.

At least 37 records · Page 2Linked to original sources
PubMed1990

Pharmacokinetics of aerosol amphotericin B in rats.

The distributions of amphotericin B (AmB) in tissue were compared after intraperitoneal or aerosol administration. Rats were sacrificed 24 h after receiving single or repeated daily doses; AmB concentrations in tissues were determined by high-performance liquid chromatography. After intraperitoneal doses of 4 mg/kg of body weight per day for 7 days, mean concentrations of AmB were 122.7, 55.2, and 4.31 micrograms/g in the spleen, liver, and lung, respectively. After aerosol doses (aero-AmB) of 1.6 mg/kg per day, the mean concentrations of AmB in the lung were 2.79 micrograms/g after a single dose and 9.88 micrograms/g after four doses, while the drug was undetectable (less than 0.1 micrograms/g) in serum, spleen, liver, kidney, and brain. The half-life of elimination of AmB from the lungs was 4.8 days according to serial sacrifices done after a single dose of 3.2 mg of aero-AmB per kg. Treatment with 60 mg of aero-AmB per kg was well tolerated and produced no histopathologic changes in the lungs. The aerosol route was much more efficient than the systemic route in delivering AmB to the lungs, and it limited the accumulation of AmB in other organs. Because AmB is eliminated slowly, infrequent dosing schedules can be used. These pharmacokinetic characteristics and its proven effectiveness in an animal model make aero-AmB a highly promising new method for the prevention of pulmonary aspergillosis. Aero-AmB should also be considered for use as an adjunct to intravenous AmB for treatment of fungal pneumonias.

Aerosols↗
PubMed1988

A new bioassay for terbinafine.

A simple, sensitive and specific agar diffusion bioassay for the antifungal agent terbinafine is described. Using a strain of Aspergillus flavus as the test organism, terbinafine at concentrations ranging from 0.2 microgram/ml to 6.4 micrograms/ml could be measured in serum.

Antifungal Agents↗
PubMed1988

Distribution of pentamidine in patients with AIDS.

We used a bioassay to measure pentamidine concentrations in autopsy specimens from 22 patients with AIDS. Patients received pentamidine isethionate (approximately 4 mg/kg per day) parenterally for Pneumocystis carinii pneumonia; one received monthly prophylaxis. We found that lung levels of 30 micrograms/g were achieved only after the fifth dose; tissue accumulation was usually greater in the liver, kidney, adrenal, and spleen than in the lung; detectable levels were present in some tissues as late as one year after the last dose; and low but detectable levels were present in the brain of six of 17 patients. Two patients had no detectable lung levels after two days of therapy; one had a level of 17.5 micrograms/g after four doses, and two had levels of 30 micrograms/g after five doses. A more rapid and effective method of delivery, such as aerosol, should achieve higher concentrations earlier. Because pentamidine persists in lung tissue over days to weeks, daily administration may not be necessary.

Acquired Immunodeficiency Syndrome↗
PubMed1988

Aerosol amphotericin B is effective for prophylaxis and therapy in a rat model of pulmonary aspergillosis.

Invasive pulmonary aspergillosis is a major life-threatening complication among transplant recipients and patients receiving cancer chemotherapy. In a rat model of progressive pulmonary aspergillosis that is characterized by hyphal bronchopneumonia, aerosol amphotericin B (aero-AmB; 1.6 mg/kg given 2 days before infection) significantly delayed mortality in rats compared with animals in a control group. The first death in the aero-AmB-treated group occurred on day 11, by which time seven of the eight control animals had died. The same dose of aero-AmB given as treatment (1.6 mg/kg given 24 h after infection and then daily for 6 days) was also effective. In this trial, eight of the ten animals treated with aero-AmB survived for 7 days, whereas only one of ten control animals survived. Colony counts in lung homogenates obtained 24 h after infection showed an 80-fold reduction in the number of viable spores in animals that had received 6.4-mg/kg doses of aero-AmB 2 days prior to infection. At 48 h after administering a single 1.6- or 3.2-mg/kg dose of aero-AmB, mean lung concentrations were 2.79 and 5.22 micrograms/g of tissue, respectively. We conclude, therefore, that aero-AmB kills inhaled spores and delays the progression of pulmonary aspergillosis by inhibiting mycelial proliferation.

Aerosols↗
PubMed1988

MIC and fungicidal activity of terbinafine against clinical isolates of Aspergillus spp.

Terbinafine and amphotericin B MICs for 90% of strains tested were 1.6 and 0.4 micrograms/ml against Aspergillus fumigatus (16 strains), 0.8 and 3.2 micrograms/ml against Aspergillus flavus (10 strains), and 0.4 and 1.6 micrograms/ml against Aspergillus niger (10 strains), respectively. For all species tested, the minimal inhibitory and fungicidal concentrations for 90% of strains of both drugs were identical and the inoculum size did not have a major effect on the results.

Amphotericin B↗
PubMed1985

Continuous high-grade mycobacterium avium-intracellulare bacteremia in patients with the acquired immune deficiency syndrome.

Serial quantitative blood cultures were performed before and during treatment in four patients with the acquired immune deficiency syndrome (AIDS) and Mycobacterium avium-intracellulare bacteremia. Initial colony counts were 350 to 28,000 cfu/ml, the counts declined substantially with treatment in two patients, and they declined modestly with treatment but rose when it was stopped in the other two. In one patient who was studied in detail, most of the circulating organisms were within the leukocytes, colony counts in blood subjected to lytic agents were 1.9- to 5.2-fold higher than in unlysed blood, and there were 10(5) to 10(6) times more organisms per gram in several tissue specimens obtained at autopsy than per milliliter of blood. It is concluded that continuous high-grade bacteremia is common in patients with AIDS and severe M. avium-intracellulare infections and that serial quantitative blood cultures provide a potential means for studying treatment in these patients.

Acquired Immunodeficiency Syndrome↗
PubMed1985

Humoral response to disseminated infection by Mycobacterium avium-Mycobacterium intracellulare in acquired immunodeficiency syndrome and hairy cell leukemia.

Antibody to Mycobacterium avium-Mycobacterium intracellulare antigen was measured by immunodiffusion, enzyme-linked immunosorbent assay (ELISA), and indirect immunofluorescence in sera from 30 patients with acquired immunodeficiency syndrome (AIDS), 10 patients with hairy cell leukemia, and 33 hospitalized and healthy controls. Ten patients with AIDS and three patients with hairy cell leukemia in the study population had disseminated M. avium-M. intracellulare infection. Patients with AIDS and disseminated infection had antimycobacterial antibody levels, demonstrated by ELISA, that did not differ significantly from those in uninfected patients with AIDS or controls. Infected patients with hairy cell leukemia had significantly higher levels of antimycobacterial antibody, demonstrated by ELISA, than did uninfected patients with hairy cell leukemia or controls (P less than .001). One patient with hairy cell leukemia, studied serially, showed a greater than 100-fold rise in antibody titer with the onset of infection. These results further demonstrate that AIDS involves a functional defect in humoral immunity, in addition to impairment of cellular immune function.

Acquired Immunodeficiency Syndrome↗
PubMed1985

Stereoisomeric configuration of arabinitol in serum, urine, and tissues in invasive candidiasis.

Because routine analytical methods cannot differentiate D- from L-arabinitol, a combined microbiological and gas chromatographic method was developed to study the stereoisomeric configuration of the arabinitol in humans and rats with invasive candidiasis. D-Arabinitol was defined as the difference between arabinitol concentrations measured with and without incubation with 5.0 X 10(5) blastospores of Candida tropicalis strain CT 12 at 37 C for 24 hr. The yeast consumed at least 95% of the D-arabinitol and none of the L-arabinitol added to normal serum and urine. D-Arabinitol as a fraction of D,L-arabinitol was 0.43 +/- 0.15 (mean +/- SD) in the urine of 10 normal humans, 0.82 +/- 0.12 in the serum or urine of five patients with cancer and invasive candidiasis (P less than .001), and 1.0 in the kidneys of rats with candidiasis. Because most or all of the excess arabinitol in body fluids or tissues in candidiasis was the D isomer, which is produced by fungal metabolism, stereospecific quantitation of arabinitol should improve the sensitivity of this approach to diagnosis of candidiasis.

Animals↗
PubMed1985

Use of a new bioassay to study pentamidine pharmacokinetics.

We developed a sensitive and specific agar-diffusion bioassay for pentamidine by using an amphotericin B-resistant isolate, Candida tropicalis ATCC 28707, as the test organism. We determined levels of pentamidine in serum of rats given intramuscular or intravenous injections and levels in serum, urine, and tissues of humans who had received the drug by slow intravenous infusion. Rats given intravenous pentamidine at a dose of 2 mg/kg had higher serum levels than those given intramuscular injection at a dose of 10 mg/kg; however, the drug was detectable in serum for 4 hr after intramuscular administration. The serum half-life in rats after intravenous injection was 2 min. Humans treated with 4 mg of pentamidine/kg by slow (1-2 hr) intravenous infusion had peak serum concentrations ranging from 0.5 to 3.4 micrograms/ml. The mean half-life of elimination from serum in humans was 17 +/- 4 min (n = 3). In two patients, studied after completion of therapy, urinary excretion rates declined with a half-life of five and nine days. In tissues obtained at autopsy from four patients who had received pentamidine, the drug was present in highest concentration in the spleen and liver, followed by kidneys, adrenals, and lungs.

Amidines↗
PubMed1985

Distribution and activity of amphotericin B in humans.

Concentrations of amphotericin B (AmB) in tissues obtained at autopsy from eight patients were measured by high-performance liquid chromatography (HPLC). The patients had received doses of 101-2,688 mg of antibiotic. Highest concentrations of the drug were found in the liver; in one patient the amount of AmB in the liver was 41% of the total dose. No evidence of metabolism of the drug was observed, and bioassay of ethanol extracts of tissue showed that the drug retained activity. Three of the patients had histologic evidence of aspergillar or candidal infection in tissues with concentrations of AmB ranging from 2.5 to 166 micrograms/g. With two patients, the concentrations of the drug in the tissues exceeded by greater than or equal to 10-fold the minimum inhibitory concentrations of the drug in isolates that had been obtained from the same tissues. Unknown factors present in tissues appear to limit the in vivo activity of AmB.

Amphotericin B↗
PubMed1985

Catheter-associated fungemia caused by Fusarium chlamydosporum in a patient with lymphocytic lymphoma.

A case of catheter-associated fungemia caused by Fusarium chlamydosporum is described in a patient with lymphocytic lymphoma. The fungus, which has been isolated from soil but not reported to cause human infection, characteristically produces microconidiophores that are polyphialides bearing microconidia that are spindle-shaped but never globose. Results of in vitro antimicrobial susceptibility tests depended on the test conditions used.

Adult↗
PubMed1985

Evaluation of the Quantum II yeast identification system.

We compared three methods for identifying clinical yeast isolates: Abbott Quantum II, API 20C, and a modified BBL Minitek system. The API 20C and modified Minitek systems agreed on the identification of 243 of 245 yeasts (99.2%). The Quantum II system correctly identified 197 (80.4%), incorrectly identified 19 (7.8%), and did not identify 29 (11.8%) of the yeasts. Most of the misidentifications with the Quantum II occurred because assimilation or biochemical results were false-positive. Sixteen different species of yeasts and 16 different Quantum II substrates contributed to the discrepancies. On retesting with the Quantum II, 31% of the discrepant strains were correctly identified, while the remaining 69% were incorrectly identified or were not identified. Erroneous biochemical and assimilation results were also noted with yeasts that were correctly identified by the Quantum II system.

Candida↗
PubMed1983

Serum arabinitol concentrations and arabinitol/creatinine ratios in invasive candidiasis.

Serum arabinitol concentrations and arabinitol/creatinine ratios were determined in 25 cancer patients with invasive candidiasis, 73 severely ill cancer patients who did not have invasive candidiasis, and 15 uninfected patients with chronic renal failure. Elevated arabinitol concentrations were found in patients with renal failure and invasive candidiasis. Serum arabinitol concentrations exceeded 1.19 micrograms/ml in 13 of 18 patients with invasive candidiasis who were studied when renal function was normal and in three of 52 control patients. Among patients with renal failure, 10 of 14 with invasive candidiasis but only four of 36 control patients had serum arabinitol concentrations of greater than 5.85 micrograms/ml. Serum arabinitol and creatinine concentrations were strongly correlated. The arabinitol/ creatinine ratio exceeded 1.5 in 16 of 25 patients with invasive candidiasis but in only three of 88 control patients. Increased serum arabinitol concentrations appear to reflect increased production of arabinitol by yeast in individuals with invasive candidiasis.

Candidiasis↗
PubMed1982

Synthesis of charged amphipathic nitroxide lipid spin labels and an example of their application in membrane studies.

The synthesis of a series of amphipathic nitroxide lipid spin labels is reported. Thus, 12-proxylhexadecanol has been converted into the versatile fatty acid spin label 14-proxylstearic acid. This substance was used to prepare 14-proxylstearyltrimethylammonium methanesulfonate, a positively charged label, and 14-proxylstearylmethyl phosphate sodium salt, a negatively charged label. Also prepared in the doxyl series were quaternary ammonium salts derived from 16-doxyl- and 7-doxylstearic acid. The positively charged and negatively charged proxyl labels were used in a preliminary experiment to investigate the role of charge in their interaction with reconstituted cytochrome oxidase. The average binding affinity of the negatively charged label is approximately 2-fold higher than that of the positively charged label at pH 7.4. At pH 5.5 the average relative affinity for negatively charged label is about 3.5-fold higher than that of positively charged label, suggesting that the ionizable group(s) on the protein can interact with the lipid headgroup.

Cyclic N-Oxides↗
PubMed1982

Increased arabinitol levels in experimental candidiasis in rats: arabinitol appearance rates, arabinitol/creatinine ratios, and severity of infection.

Renal colony counts, total arabinitol appearance, and the arabinitol/creatinine ratios in the serum and urine of rats with lethal candidiasis were measured. Total arabinitol appearance and the arabinitol/creatinine ratios increased significantly after infection. The serum arabinitol/creatinine ratio was high (2 SD above the mean value in normal animals) in five of six infected rats at 24 hr, in eight of eight at 48 hr, and in none of the control animals. The urinary arabinitol/creatinine ratio was high in 14 of 19 infected rats by 24 hr, in 11 of 11 by 48 hr, and in none of the control animals. Total arabinitol appearance and the arabinitol/creatinine ratios were highly correlated with renal colony counts. Arabinitol production in vitro was sufficient to account for the increased arabinitol appearance observed in vivo in 12 of 14 rats. Thus it is concluded that the excess arabinitol that appeared in vivo was produced by the infecting fungus and that arabinitol is a quantitative marker substance for candidiasis.

Animals↗
PubMed1982

The arabinitol appearance rate in laboratory animals and humans: estimation from the arabinitol/creatine ratio and relevance to the diagnosis of candidiasis.

The effects of renal function on serum concentrations of the candidal metabolite arabinitol were studied by examining the accumulation and elimination of arabinitol in animals and humans. Serum concentrations of arabinitol rose sharply and in direct proportion to creatine concentrations after nephrectomy in rats. The serum half-life of exogenous arabinitol was 20.8 hr in anephric rats but only 0.62 hr in sham-nephrectomized control animals. The mean +/- SD apparent space of distribution of arabinitol was 419 +/- 26 ml/kg. The fraction of exogenously administered arabinitol recovered in the urine was 0.73 +/- 0.13 in uremic rats, 0.85 +/- 0.28 in control rats, and 0.95 +/- 0.10 in normal dogs. The arabinitol/creatinine clearance ratio was 0.99 +/- 0.08 in normal dogs and 0.99 +/- 0.25 in 22 critically ill patients with cancer. Thus arabinitol is eliminated by nearly quantitative urinary excretion and its cleared at virtually the same rate as creatinine. Therefore, the rate of arabinitol appearance in the body from any source equals the urinary arabinitol excretion rate and is directly proportional to the concentration ratio of arabinitol to creatinine in serum or urine.

Animals↗
PubMed1982

Examination of Pseudomonas aeruginosa-gentamicin discrepancies encountered in an Autobac I-disk diffusion comparison.

Seven Pseudomonas aeruginosa strains found to be susceptible to gentamicin by the Autobac I system and resistant by the Bauer-Kirby disk diffusion method were tested for the presence of mixed populations of cells. Double zones of inhibition randomly appeared on gentamicin disk diffusion plates, and susceptible and resistant subpopulations were isolated from these plates. Growth kinetic studies of separated strains and mixed subpopulations indicated that the susceptible organisms grew rapidly and were read as susceptible at 5 h with the Autobac I system. Resistant organisms entered a sustained lag phase and did not achieve sufficient turbidity to be read as resistant with the Autobac I system before 6 h. Thus, a false reading of susceptible could be obtained with the Autobac I system, depending on the ratio of susceptible organisms to resistant organisms selected for testing. A mixed susceptible and resistant population could be recognized by extending the incubation time of the Autobac I cuvette or by using other susceptibility methods to test isolates with light-scattering indexes of less than 1.0.

Drug Resistance, Microbial↗