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D W Denning

Publications and source records attributed to D W Denning.

At least 91 records · Page 5Linked to original sources
PubMed1997

Azole resistance in Candida.

Resistance of Candida to azoles is an increasing problem. Susceptibility testing of Candida against fluconazole and ketoconazole is now feasible and desirable. Good correlation of resistance in vitro with clinical failure of fluconazole therapy has now been shown in mucosal candidiasis. The relationship, if any, between resistance and clinical failure in the context of invasive candidiasis is not clear at present and additional correlative work needs to be done. Monitoring of resistance trends in Candida is clearly important now.

Antifungal Agents↗
PubMed1997

Guidelines for the investigation of invasive fungal infections in haematological malignancy and solid organ transplantation. British Society for Medical Mycology.

Invasive fungal infections are increasing in incidence and now affect as many as 50% of neutropenic/bone marrow transplant patients and 5 to 20% of solid organ transplant recipients. Unfortunately, many of the diagnostic tests available have a low sensitivity. The guidelines presented here have been produced by a working party of the British Society for Medical Mycology in an attempt to optimise the use of these tests. The yield of fungi from blood cultures can be increased by ensuring that at least 20 ml of blood are taken for aerobic culture, by using more than one method of blood culture, and by employing terminal subculture if continuous monitoring systems are used with a five-day incubation protocol. Skin lesions in febrile neutropenic patients should be biopsied and cultured for fungi. The detection of galactomannan in blood or urine is of value in diagnosing invasive aspergillosis only if tests are performed at least twice weekly in high-risk patients. Antigen detection tests for invasive candidiasis are less valuable. Computed tomography scanning is particularly valuable in diagnosing invasive pulmonary fungal infection when the chest radiograph is negative or shows only minimal changes. Bronchoalveolar lavage is most useful in patients with diffuse changes on computed tomography scan. The major advances in the diagnosis of invasive fungal infection in patients with haematological malignancy or solid organ transplantation have been in the use of imaging techniques, rather than in the development of new mycological methods in the routine laboratory.

Algorithms↗
PubMed1997

In-vitro activity of D0870, a new triazole antifungal drug, in comparison with fluconazole and itraconazole against Aspergillus fumigatus and Candida krusei.

The activity of the new triazole antifungal D0870 was compared with those of itraconazole and fluconazole against Candida krusei and Aspergillus fumigatus, two fungi showing inherent tolerance of fluconazole. The activity of D0870 resembled that of itraconazole against whole cells of C. krusei, but it was less effective against A. fumigatus. However, the effect on sterol biosynthesis, in terms of the sterol type accumulating and IC50 for in-vitro biosynthesis, appeared similar in both species. The superior antifungal effect of D0870 over fluconazole appeared related to better inhibition of ergosterol biosynthesis in A. fumigatus, but in C. krusei this did not account for the entire difference which may result mainly from reduced efflux of drug.

Antifungal Agents↗
PubMed1997

Amphotericin B resistance testing of Candida spp.: a comparison of methods.

Several methods of susceptibility testing were compared for their ability to detect amphotericin B resistance among yeast isolates, including isolates known to be amphotericin-B-resistant in an animal model. A microtitre MIC method using antibiotic medium no. 3 and Etest strips were able to discriminate susceptible and resistant isolates. A disc susceptibility test was also able to identify resistant isolates and this method may be suitable for routine use as a screening test. A survey of resistance in 644 clinical isolates showed that the incidence of elevated MICs (> or = 0.25 mg/L) was only 1.2%.

Amphotericin B↗
PubMed1997

Correlation between in-vitro susceptibility testing to itraconazole and in-vivo outcome of Aspergillus fumigatus infection.

Given the increased choice of therapeutic agents and the rising incidence of serious invasive disease, it is important that reliable in-vitro methods for detecting antifungal drug resistance in Aspergillus spp. are developed. Six clinical isolates of Aspergillus fumigatus, obtained from patients in whom the clinical outcome was known, were selected for study. Each was used to examine a range of parameters affecting agar dilution and broth microdilution susceptibility test results. The in-vitro results were compared with outcome in a neutropenic mouse model of invasive aspergillosis. Groups of animals were treated with itraconazole at 25 mg/kg and 75 mg/kg and survival rates and organ burdens were determined. Itraconazole was efficacious against four isolates (susceptible) but failed for two (resistant) in the animal model of infection. Both the resistant isolates had been obtained from patients receiving itraconazole treatment with good serum concentrations of the drug. Conditions for the agar dilution test which produced results that correlated best with our in-vivo observations included the use of RPMI agar with L-glutamine buffered to pH 7 with MOPS, inoculated with 10(6)-10(7) conidia/mL and incubated for 48-72 h at 28 or 35 degrees C with a no-growth endpoint. Optimal conditions for the broth microdilution method included the use of RPMI medium with L-glutamine and 2% glucose buffered to pH 7 with MOPS, an inoculum of 2 x 10(5) conidia in 200 microL incubated for 48 h at 35 degrees C with a growth (or trace) endpoint. The MICs for the susceptible isolates were 0.12-1.0 mg/L and > or = 16 mg/L for the resistant isolates. With careful selection and standardization of test conditions it is possible to generate reproducible in-vitro susceptibility data for Aspergillus spp. that will predict clinical outcome.

Animals↗
PubMed1997

A dose comparison study of a new triazole antifungal (D0870) in HIV-positive patients with oral candidiasis.

OBJECTIVE: This multicentre study evaluated the clinical efficacy and tolerability of D0870 in treating oropharyngeal candidiasis in HIV-positive patients who had no history of clinical resistance to fluconazole. METHODS: Three regimens were evaluated in two phases. In phase I a 50 mg initial dose was followed by 10 mg for 4 days (Group 1). In phase II a 100 mg initial dose was followed by 25 mg for 4 days (Group 2), or 10 mg for 5 days (Group 3). RESULTS: Clinical cure was obtained in 27 patients of a total of 35 (77%) and six other patients improved (17%). Two patients at the lowest dose failed and both had very low plasma concentration of D0870. No association was found between clinical outcome; minimum inhibitory concentration of D0870 pre-therapy for Candida albicans, maximum recorded plasma D0870 concentration, cfu of culture or CD4 cell count at entry. Overall, 37% of the patients experienced relapse during the 2 weeks post therapy. Tolerance was excellent. Mild adverse events possibly related to the study drug were recorded in five patients. CONCLUSION: D0870 demonstrates excellent efficacy at low doses in the treatment of HIV-related OPC and exhibits a favourable safety profile.

AIDS-Related Opportunistic Infections↗
PubMed1997

In vitro activity of SCH-56592 and comparison with activities of amphotericin B and itraconazole against Aspergillus spp.

In this study, we investigated the in vitro activity of SCH-56592 (SCH), a new triazole antifungal agent. We compared the activity of SCH with those of itraconazole (ITZ) and amphotericin B (AB) against 60 clinical isolates of Aspergillus spp. by using a microtiter format. Incubation was done at 37 degrees C for 48 h, and MIC endpoints (no growth) were read visually. The medium used for all of the drugs was RPMI 1640 buffered with morpholinepropanesulfonic acid (MOPS) and supplemented with 2% glucose. MICs and minimum fungicidal concentrations (MFCs; killing of > or = 99.99%) were measured for all isolates. The geometric mean (GM) MICs and ranges (in micrograms per milliliter) were as follows: SCH, 0.09 and < or = 0.01 to 1; ITZ, 0.25 and 0.06 to 32; AB, 1.46 and 0.25 to 32. Aspergillus terreus (n = 7) was markedly more susceptible to SCH (GM, 0.05 microg/ml) and ITZ (GM, 0.07 microg/ml) than to AB (GM, 8.8 microg/ml). For all isolates, the GM MFCs and ranges (in micrograms per milliliter) were as follows: SCH, 3.64 and 0.125 to 16; ITZ, 15.09 and 0.125 to 32; AB, 10.3 and 1 to 32. In the drug concentration range tested, 71, 32, and 64% of the isolates against which SCH, ITZ, and AB, respectively, were tested were killed. A reproducibility study was performed with 20% of the isolates; for 11 of the 12 isolates retested, the MIC was the same or within 1 well of the original MIC of each drug. Therefore, in vitro mould testing of SCH is feasible and reproducible. SCH was found to be very active against all species of Aspergillus and at lower concentrations than either ITZ or AB.

Amphotericin B↗
PubMed1997

Itraconazole resistance in Aspergillus fumigatus.

Invasive aspergillosis is an increasingly frequent opportunistic infection in immunocompromised patients. Only two agents, amphotericin B and itraconazole, are licensed for therapy. Itraconazole acts through inhibition of a P-450 enzyme undertaking sterol 14alpha demethylation. In vitro resistance in Aspergillus fumigatus to itraconazole correlated with in vivo outcome has not been previously described. For three isolates (AF72, AF90, and AF91) of A. fumigatus from two patients with invasive aspergillosis itraconazole MICs were elevated. A neutropenic murine model was used to establish the validity of the MICs. The isolates were typed by random amplification of polymorphic DNA. Analysis of sterols, inhibition of cell-free sterol biosynthesis from [14C] mevalonate, quantitation of P-450 content, and [3H]itraconazole concentration in mycelial pellets were used to determine the mechanisms of resistance. The MICs for the three resistant isolates were >16 microg/ml. In vitro resistance was confirmed in vivo for all three isolates. Molecular typing showed the isolates from the two patients to be genetically distinct. Compared to the susceptible isolate from patient 1, AF72 had a reduced ergosterol content, greater quantities of sterol intermediates, a similar susceptibility to itraconazole in cell-free ergosterol biosynthesis, and a reduced intracellular [3H]itraconazole concentration. In contrast, AF91 and AF92 had slightly higher ergosterol and lower intermediate sterol concentrations, fivefold increased resistance in cell-free systems to the effect of itraconazole on sterol 14alpha demethylation, and intracellular [3H] itraconazole concentrations found in susceptible isolates. Resistance to itraconazole in A. fumigatus is detectable in vitro and is present in wild-type isolates, and at least two mechanisms of resistance are responsible.

Adult↗
PubMed1997

Efficacy of SCH-56592 in a temporarily neutropenic murine model of invasive aspergillosis with an itraconazole-susceptible and an itraconazole-resistant isolate of Aspergillus fumigatus.

SCH-56592 (SCH) is a novel triazole antifungal agent with excellent in vitro activity against Aspergillus. We compared three doses (5, 10, and 25 mg/kg of body weight) of SCH with itraconazole (ITZ; 25 mg/kg) and amphotericin B (AB; 5 mg/kg) in a temporarily neutropenic murine model of disseminated aspergillosis (lungs and kidneys) against one ITZ-susceptible (AF71) and one ITZ-resistant (AF90) isolate of Aspergillus fumigatus. Treatment started 24 h after infection and lasted for 10 days. Dosing regimens for SCH were once daily for 10 days, those for ITZ were three times daily for 2 days and then twice daily for 3 to 10 days, and those for AB were once daily on days 1, 2, 4, and 7. Both isolates killed 90% of control mice. Kidneys and lungs from survivors were cultured on day 11. Against AF71, all three doses of SCH and ITZ yielded a 90 to 100% survival rate and AB yielded 40% survival (P < or = 0.01 to 0.0001 for all treatment groups compared with the controls). All three doses of SCH were superior to AB in cultures of lung and kidney tissue samples (P < or = 0.01 to 0.0002) and SCH at 25 mg/kg was superior to ITZ in cultures of kidneys (P = 0.01). Against AF90, the highest dose of SCH (25 mg/kg) resulted in a 100% survival rate, compared with 60 and 20% survival rates for the groups treated with SCH at 10 and 5 mg/kg, respectively. Treatment with ITZ yielded no survivors. AB therapy achieved a 50% survival rate. SCH at 25 mg/kg (P < 0.001), SCH at 10 mg/kg (P < or = 0.005), and AB (P < 0.05) were superior to ITZ in cultures of lungs and kidneys. There was a correlation between the MICs of SCH and quantitative organ culture results and between the minimum fungicidal concentration of AB with quantitative organ culture results. SCH appears to be a highly effective anti-Aspergillus compound in this model. There appears to be a degree of cross-resistance between itraconazole and SCH.

Animals↗
PubMed1997

Species differentiation by internally transcribed spacer PCR and HhaI digestion of fluconazole-resistant Candida krusei, Candida inconspicua, and Candida norvegensis strains.

PCR amplification of the regions containing the internally transcribed spacers and 5.8S rRNA gene of Candida krusei, C. inconspicua, and C. norvegensis yielded fragments of 510, 460, and 500 bp, respectively. HhaI digestion of these fragments yielded species-specific bands. Random amplification of polymorphic DNA with primer R108 showed interspecific discriminatory band patterns. Susceptibilities to fluconazole and amphotericin B were determined.

Antifungal Agents↗
PubMed1997

Atypical eumycetoma caused by Phialophora parasitica successfully treated with itraconazole and flucytosine.

Phialophora species are occasional pathogens causing subcutaneous and invasive disease. We report the first case of eumycetoma caused by P. parasitica in an otherwise healthy U.K. resident who visited India. She failed to respond to surgical excision and itraconazole, 400 mg daily, but responded to itraconazole, 400 mg daily, and flucytosine, 1 g three times daily, for 12 months. In vitro susceptibility testing predicted a response.

Adult↗
PubMed1996

Fungal infections: a survey of laboratory services for diagnosis and treatment.

A questionnaire on the services provided and the methods used for the diagnosis of fungal infections and for the support of antifungal chemotherapy was sent to members of the British Society for Medical Mycology (BSMM) and the British Society for Antimicrobial Chemotherapy (BSAC). Ninety-five responses from general microbiology laboratories in the United Kingdom were analysed, and we compared services provided by laboratories that serve a transplant unit with those offered by other laboratories. We estimate that about 150 cases of cryptococcosis, 500 to 600 of candidaemia, and 300 to 400 of invasive aspergillosis are identified by laboratories in the United Kingdom (UK) each year. The clinical laboratories are aware of the importance of fungal infection, but rely heavily on reference services. In some laboratories, however, the degree of investigation of specimens and the procedures in use are inadequate for diagnosing systemic mycoses and determining the susceptibility of isolates to antifungal agents. The balance between reference and local services requires attention and external quality assurance needs to be applied effectively. In addition, effective methods for the diagnosis of systemic mycoses, and reliable and practicable methods for determining the susceptibility of isolates to antifungal agents, are needed urgently.

Antifungal Agents↗