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Biomedical subjects

D W Denning

Publications and source records attributed to D W Denning.

At least 145 records · Page 8Linked to original sources
PubMed1994

Administering amphotericin B--a practical approach.

Despite the introduction in recent years of novel antifungal agents, the potency and broad spectrum of activity of amphotericin B have ensured that it remains the treatment of choice for most deep-seated mycoses. However, this agent is not without significant toxicity, particularly in patients who are already seriously ill and/or who are receiving other potentially nephrotoxic drugs. We review the various routes by which amphotericin B can be administered, focusing mainly on the intravenous route. The use of more rapid infusion rates, lipid-complexed preparations, sodium supplementation in salt-depleted patients and strategies to reduce the incidence of infusion-related reactions and nephrotoxicity are also considered. Finally, detailed recommendations for the administration of amphotericin B are provided.

Amphotericin B↗
PubMed1994

High prevalence of antifungal resistance in Candida spp. from patients with AIDS.

Three hundred and forty-eight isolates of Candida spp. from patients treated at a regional infectious diseases unit for AIDS, immunocompromised patients admitted to the Hope Hospital and isolates referred from around the North West of England were tested for their in-vitro susceptibility to amphotericin B, fluconazole and flucytosine using standardized methods. Candida albicans comprised 73% of isolates, Candida glabrata 10% and Candida parapsilosis 7%. Ninety-six percent of isolates were susceptible to amphotericin B and resistance to > or = 12.5 mg/L fluconazole was found in 61 (17.5%) of the 348 isolates tested. Among isolates from patients with AIDS the incidence of fluconazole resistance was 33% whereas in other patients the incidence was only 11%. Flucytosine resistance was seen in only 12 (3.4%) isolates, 11 of which were C. albicans and in 6.5% of isolates from patients with AIDS. Resistance to fluconazole and flucytosine is now sufficiently prevalent among Candida spp. isolated from patients with AIDS to warrant routine susceptibility testing of yeast isolates.

AIDS-Related Opportunistic Infections↗
PubMed1994

Fluconazole-resistant candidosis in an HIV cohort.

OBJECTIVES: To report the occurrence of HIV-related mucosal candidosis that fails to respond to fluconazole, to establish the correlation between in vitro susceptibility testing and clinical failure, and to assess the efficacy of alternative treatments. DESIGN: Chart review of all patients with fluconazole failure and all patients with CD4 counts < 50 x 10(6)/l continuing to respond to fluconazole, and prospective in vitro susceptibility testing of Candida. SETTING: A regional treatment centre for HIV-infected individuals in north-west England. PATIENTS: A cohort of 155 HIV-positive individuals with CD4 counts < 300 x 10(6)/l cells. MAIN OUTCOME MEASURES: Clinical fluconazole failure was defined as symptomatic oropharyngeal or oesophageal candidosis despite fluconazole > or = 100 mg per day for 10 days. In vitro susceptibility to fluconazole was determined for Candida isolates. Cumulative 12-month fluconazole dose and time from first fluconazole therapy and prophylaxis were recorded. RESULTS: Nine (5.8%) patients meeting the definition of fluconazole failure were identified. In vitro susceptibility to fluconazole of temporally related oropharyngeal isolates was reduced in all cases. Intravenous amphotericin B was the only effective treatment for these patients when symptoms were severe suggesting azole cross-resistance. One patient, who had received alternative treatments for 9 months, reverted from in vitro and clinical fluconazole sensitivity but relapsed within 6 weeks of resuming fluconazole. The median fluconazole dose over the preceding 12 months for the eight adult cases was 386 mg weekly. The median dose for the same period was 79 mg weekly in 28 patients with CD4 counts < 50 x 10(6)/l but without fluconazole failure (difference, 307; 95% confidence interval, 199-514; P < 0.0001). CONCLUSION: A substantial problem of clinical fluconazole failure has developed among HIV-positive patients who have recurrent problematic mucosal candidosis.

AIDS-Related Opportunistic Infections↗
PubMed1994

Diagnosis of infections with Shiga-like toxin-producing Escherichia coli by use of enzyme-linked immunosorbent assays for Shiga-like toxins on cultured stool samples.

Shiga-like toxin-producing (SLT) Escherichia coli, particularly those belonging to serogroup O157, are responsible for haemorrhagic colitis, haemolytic uraemic syndrome and some cases of gastro-enteritis. The rapid and reliable diagnosis of all these infections is necessary for correct patient management and for epidemiological reasons, but is rarely possible with present methods. We compared the efficacy of two methods, (i) the culture of faeces in broth that contained mitomycin C followed by enzyme-linked immunosorbent assay (ELISA) for SLTs, and (ii) the culture of faeces on sorbitol MacConkey agar (SMA), in the detection of infections caused by SLT-producing E. coli. SLT-producing E. coli O157 strains were isolated on SMA from 42 of 475 faecal samples, but SLTs were detected by ELISA in culture supernates or lysates of 54 of 475 samples. SLT-producing E. coli strains were isolated subsequently from 11 of 12 ELISA-positive, SMA culture-negative samples by a colony blot technique. In four cases, SLT-producing E. coli of serogroups other than O157 were isolated and in seven cases E. coli O157 was isolated in small numbers. The ELISA is a rapid and sensitive technique for the diagnosis of SLT-producing E. coli infection, especially where low numbers of the organism are present in faeces and when the infection is caused by a serogroup other than O157.

Bacterial Toxins↗
PubMed1994

Oxygen requirements of Aspergillus species.

The growth of 24 Aspergillus isolates at low oxygen tensions was assessed. Isolates selected included A. fumigatus (10), A. terreus (6), A. niger (6), A. nidulans (1) and A. flavus (1). Three different agar media were used--potato dextrose agar (PDA), pH 5.6; brain heart infusion (BHI), pH 7.4; and a specially developed medium (Hall's) containing resazurin--with oxygen concentrations of 0, 0.025, 0.1, 0.5 and 2.5%. The CO2 concentration was 5%. Agar plates were inoculated with 2 x 10(7) conidia/ml, loaded into jars and flushed with a special gas mixture at 37 degrees C. The plates were inspected at intervals of 3, 5 and 10 days. On Hall's medium, none of the isolates grew at oxygen concentrations of 0 or 0.025%, but 21 (88%) of 24 grew at 0.1%. On PDA and BH1, all 14 isolates tested grew at oxygen concentrations of 0.5 and 2.5%. Three of these 14 conidiated on PDA at oxygen 0.5% and 12 of 14 conidiated on PDA at oxygen 2.5%. None grew without oxygen on these media. Thus, pathogenic Aspergillus spp. are capable of growth at low oxygen tensions, and this may have implications for pathogenicity and antifungal activity.

Anaerobiosis↗
PubMed1994

Hydrocortisone-enhanced growth of Aspergillus spp.: implications for pathogenesis.

Aspergillus fumigatus and Aspergillus flavus are the most common cause of invasive mould infections worldwide and carry a high mortality. Corticosteroid therapy and Cushing's disease are associated with an increase in invasive aspergillosis. Corticosteroids impair immune function in mammals and, specifically, the conidicidal activity of human macrophages, which was thought to be sufficient explanation for this increased risk. However, we have found a 30-40% increase in growth rate of A. fumigatus and A. flavus exposed to pharmacological doses of hydrocortisone (a human glucocorticoid), suggesting an alternative or additional mechanism for the association. No significant effect was observed with other human steroids such as testosterone, oestradiol or progesterone, though a smaller (21%) but significant growth rate increase was obtained with the fungal sterol ergosterol. The presence of a ligand/receptor system is therefore possible in pathogenic Aspergillus spp. Although corticosterone-binding proteins have been identified in some yeast species, a demonstrable physiological effect has been lacking. Interruption of the putative ligand/receptor interaction could have a major effect on the growth and pathogenicity of A. fumigatus, providing opportunities for the development of alternative therapeutic strategies to those currently available.

Aspergillosis↗
PubMed1994

Bioassay for serum itraconazole concentrations using hydroxyitraconazole standards.

Low concentrations of itraconazole in serum have been associated with therapeutic failure. Variable interpatient bioavailability and detrimental drug interactions with p450 enzyme-inducing agents are well documented. Thus, routine monitoring of serum itraconazole concentrations in patients with life-threatening mycoses is essential for patient care. Present high-performance liquid chromatography (HPLC) methods measure only concentrations of itraconazole and not its active metabolite hydroxyitraconazole. Bioassay methods using itraconazole standards overestimate concentrations in serum as measured by HPLC. We have developed a bioassay for total serum itraconazole and hydroxyitraconazole concentrations using hydroxyitraconazole standards. Itraconazole and hydroxyitraconazole concentrations in 40 clinical samples were assayed by HPLC. Total drug concentrations were measured in the same samples by bioassay with itraconazole or hydroxyitraconazole standards. The correlation of concentrations measured by the last bioassay method with HPLC determinations of both compounds was excellent (r = 0.98, slope = 0.5), with acceptable reproducibility. Small errors were seen at extremes of concentrations. The ratio of hydroxyitraconazole to itraconazole in serum varied from 0.76 to 3.2. The use of hydroxyitraconazole standards rather than itraconazole standards for determination of total itraconazole and hydroxyitraconazole concentrations in serum by bioassay gives accurate and reproducible results that correlate well with total itraconazole and hydroxyitraconazole concentrations as measured by HPLC. Our data show that although hydroxyitraconazole gives larger inhibition zones than itraconazole in bioassay standards, this is not true of patient samples, in which the two compounds make equivalent contributions.

Antifungal Agents↗
PubMed1993

Empiric amphotericin B therapy: the need for a reappraisal.

Neutropenic patients are at high risk of developing invasive fungal diseases. A number of studies, both randomized and historical, have demonstrated that empiric therapy with amphotericin B in neutropenic patients with fever, refractory to antibiotics, results in a decrease in the frequency and mortality of deep fungal infections. Recent years have seen a number of advances in the management of neutropenic patients. Reasonably effective antifungal prophylaxis now exists and in many centres forms part of the routine care of neutropenic patients. Other centres advocate the use of selective decontamination and/or protective isolation. Furthermore the duration of neutropenia can be reduced with the use of haematopoetic growth factors. The impact of empiric amphotericin B in patients already benefiting from such treatments has not been adequately studied. The optimum dose of empiric amphotericin B is not defined. The criteria for commencing amphotericin B therapy in febrile neutropenic patients must therefore be redefined on the basis of further studies carried out in the context of these developments. We offer an approach to the use of empiric amphotericin B based on risk factors and prophylaxis.

Amphotericin B↗
PubMed1993

In-vitro activity of the new triazole D0870 compared with amphotericin B and itraconazole against Aspergillus spp.

The in-vitro activity of D0870, a new triazole, was compared with amphotericin B (AMP B) and itraconazole (ITZ) against 40 Aspergillus isolates, which included 25 isolates of Aspergillus fumigatus, using a broth macro-dilution method at 37 degrees C. Minimum inhibitory concentration (MIC) and minimum fungicidal concentration (MFC) (killing of > or = 98%) were measured. For 40 isolates, geometric mean (GM) MIC values and ranges were D0870 10.55 and 2-32, ITZ 2.26 and 0.5-64, AMP B 2.42 and 1-64 mg/L. Differences in susceptibilities between species were apparent with Aspergillus flavus (n = 5) being the most susceptible to D0870 (GM 2.64, range 2-8 mg/L). MFC values were within one dilution of the MIC value for 90% of isolates (D0870 and ITZ) and 95% of isolates (AMP B). In reproducibility studies, seven, eight and four of eight isolates retested gave MIC results within one dilution for D0870, AMP B, and ITZ, respectively. Therefore, in-vitro mould testing with D0870 is feasible and reproducible with clear MIC and MFC end-points. D0870 is active against most Aspergillus spp., but at higher concentrations than either ITZ or AMP B.

Amphotericin B↗
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↗