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Biomedical subjects

D W Denning

Publications and source records attributed to D W Denning.

At least 73 records · Page 4Linked to original sources
PubMed1999

Assessment of therapeutic response of oropharyngeal and esophageal candidiasis in AIDS with use of a new clinical scoring system: studies with D0870.

We developed and compared five scoring systems designed to quantitate therapeutic response in cases of oropharyngeal candidiasis. We utilized prospectively collected data on 114 patients treated with several doses of the azole D0870. Patients were infected with fluconazole-susceptible (n = 49) or -resistant organisms (MIC, > or = 16 mg/mL; n = 61). Patients with fluconazole resistance had lower CD4+ cell counts at baseline; more symptoms (P = .0006); a higher frequency of dysgeusia (P = .004), dysphagia (P = .006), and throat pain (P = .0034); and greater oral coverage by plaques of Candida. There was no difference between the two groups in terms of colony-forming units, and any change did not correlate with response to therapy. Resolution of dysphagia (P < .01) and oral pain (P < .01) correlated well with response to therapy, unlike retrosternal pain and throat pain, which were also less frequent. Xerostomia, a "furry" taste, and dysgeusia were frequent nonspecific symptoms. Scoring system C, weighting resolution of a symptom higher than absence of a symptom at baseline, yielded the best correlation with global outcome (r = 0.86) and allows the quantitation of incomplete but clinically beneficial responses to therapy.

AIDS-Related Opportunistic Infections↗
PubMed1999

Endemic mycoses: a treatment update.

Endemic mycoses remain a major public health problem in several countries and they are becoming increasingly frequent with the spread of HIV infection. Amphotericin B remains the drug of choice during the acute stage of life-threatening endemic mycoses occurring in both immunocompetent and immunocompromised hosts. Ketoconazole is effective in non-AIDS patients with non-life-threatening histoplasmosis, blastomycosis, or paracoccidioidomycosis. Itraconazole is the treatment of choice for non-life-threatening Histoplasma capsulatum or Blastomyces dermatitidis infections occurring in immunocompetent individuals and is the most efficient secondary prophylaxis of histoplasmosis in AIDS patients. Itraconazole is also effective in lymphocutaneous and visceral sporotrichosis, in paracoccidioidomycosis, for Penicillum marneffei infection, and is an alternative to amphotericin B for Histoplasma duboisii infection. Coccidioidomycosis may be effectively treated with prolonged and sometimes life-long itraconazole or fluconazole therapy. Fluconazole has relatively poor efficacy against histoplasmosis, blastomycosis and sporotrichosis. New antifungal agents have been tested in vitro or in animal models and may soon be evaluated in clinical trials.

AIDS-Related Opportunistic Infections↗
PubMed1999

Aspergillus fumigatus catalases: cloning of an Aspergillus nidulans catalase B homologue and evidence for at least three catalases.

The presence of catalases in the water soluble fractions of three Aspergillus fumigatus strains was investigated using non-denaturing and denaturing polyacrylamide gel electrophoresis and Western analysis. Using non-denaturing polyacrylamide gel electrophoresis and staining for catalase activity, three separate catalases were identified. An A. fumigatus catalase gene (catB) was cloned from genomic DNA using the Aspergillus niger catR gene as a probe. Polyclonal antibodies were raised to a glutathione S-transferase-CatB fusion product expressed in Escherichia coli. Western analysis indicated that, under denaturing conditions, the polyclonal antibody recognised a 90-kDa band and under non-denaturing conditions, two separate bands were identified. These results indicate that A. fumigatus in addition to CatB, produces at least two other catalases, one of which is similar in size to CatB. The polyclonal antibody was also used to observe catalase expression in mice, experimentally infected with A. fumigatus. Staining was observed heterogeneously throughout the fungal hyphae. This result indicates that catalase is produced by A. fumigatus during invasive aspergillosis.

Animals↗
PubMed1999

Dose range evaluation of liposomal nystatin and comparisons with amphotericin B and amphotericin B lipid complex in temporarily neutropenic mice infected with an isolate of Aspergillus fumigatus with reduced susceptibility to amphotericin B.

Using an isolate of Aspergillus fumigatus that is less susceptible in vivo to amphotericin B than most other isolates, we compared different doses of liposomal nystatin (L-nystatin), liposomal amphotericin B (L-amphotericin), and amphotericin B lipid complex (ABLC) with amphotericin B deoxycholate. Four experiments with intravenously infected neutropenic mice were conducted. A dose of L-nystatin at 10 mg/kg of body weight was toxic (the mice had fits or respiratory arrest). The optimal dosage of L-nystatin was 5 mg/kg daily on days 1, 2, 4, and 7 (90% survival). This was superior to L-amphotericin (5 mg/kg [P = 0.24] and 1 mg/kg [P < 0.0001]), ABLC (5 mg/kg [P = 0.014] and 1 mg/kg [P < 0.0001]), and amphotericin B deoxycholate (5 mg/kg [P = 0.008]). In terms of liver and kidney cultures, L-nystatin (5 mg/kg) was superior to all other regimens (P = 0.0032 and <0.0001, respectively). Higher doses of L-amphotericin (25 and 50 mg/kg) in one earlier experiment were more effective (100% survival) than 1 mg of L-amphotericin per kg and amphotericin deoxycholate (5 mg/kg) in terms of mortality and both liver and kidney culture results and to L-amphotericin (5 mg/kg) in terms of liver and kidney culture results only. ABLC (25 mg/kg) given daily for 7 days was superior to ABLC (50 mg/kg [P = 0.03]) but not to ABLC at 5 mg/kg or amphotericin B deoxycholate in terms of mortality, although it was in terms of liver and kidney culture results. No dose-response for amphotericin B (5 and 1 mg/kg) was demonstrable. In conclusion, in this stringent model, high doses of L-amphotericin and ABLC could overcome reduced susceptibility to amphotericin B deoxycholate, but all were inferior to 5- to 10-fold lower doses of L-nystatin.

Amphotericin B↗
PubMed1999

Comparison of in vitro activity of liposomal nystatin against Aspergillus species with those of nystatin, amphotericin B (AB) deoxycholate, AB colloidal dispersion, liposomal AB, AB lipid complex, and itraconazole.

We compared the in vitro activity of liposomal nystatin (Nyotran) with those of other antifungal agents against 60 Aspergillus isolates. Twelve isolates were itraconazole resistant. For all isolates, geometric mean (GM) MICs (micrograms per milliliter) were 2.30 for liposomal nystatin, 0.58 for itraconazole, 0.86 for amphotericin B (AB) deoxycholate, 9.51 for nystatin, 2.07 for liposomal AB, 2.57 for AB lipid complex, and 0.86 for AB colloidal dispersion. Aspergillus terreus (GM, 8.72 micrograms/ml; range, 8 to 16 micrograms/ml) was significantly less susceptible to all of the polyene drugs than all other species (P = 0.0001).

Amphotericin B↗
PubMed1998

Influenza-like episodes in HIV-positive patients: the role of viral and 'atypical' infections.

OBJECTIVES: To document viral and 'atypical' infections in HIV-positive patients and association with influenza-like symptoms. PATIENTS AND METHODS: Monthly culture of urine, faeces and throat swabs in 63 HIV-positive patients (30 asymptomatic and 33 with AIDS-related complex/AIDS) over 5-27 months (with 1125 patient-months of follow-up), with further sample collections during influenza-like episodes. Standard viral detection methods were used. Throat swabs were assessed for Chlamydia sp. by culture and immunoblotting, and for Mycoplasma pneumoniae by polymerase chain reaction. RESULTS: Viruses were detected in 15 (50%) and M. pneumoniae in nine (30%) out of 30 HIV-positive patients during an influenza-like illness. A close temporal relationship with symptoms was observed in 12 (40%) patients: cytomegalovirus in six (20%), M. pneumoniae in three (10%), herpes simplex virus in three (10%), and enterovirus in one (4%). Influenza-like symptoms were more frequent in asymptomatic HIV infection than in AIDS-related complex/AIDS patients (actuarial risk at 1 year, 63 versus 26%; P=0.002), particularly in those with CD4 cell counts >300 x 10(6)/l at enrolment (P=0.002). At least 44% (four out of nine) M. pneumoniae infections were asymptomatic and 78% (seven out of nine) were associated with prolonged excretion (2-17 months). Chlamydia sp. were not detected. CONCLUSIONS: Influenza-like symptoms were more likely to be reported by HIV-positive patients at early stages of disease, possibly as a result of differences in immune responses to viral infection. There was a close association in 40% of cases between the development of symptoms and detection of cytomegalovirus, herpes simplex virus, enterovirus and M. pneumoniae (a previously unrecognized association).

AIDS-Related Opportunistic Infections↗
PubMed1998

Treatment of HIV-related fluconazole-resistant oral candidosis with D0870, a new triazole antifungal.

OBJECTIVES: To evaluate the efficacy and tolerance of D0870 in the treatment of HIV-related fluconazole-resistant oro-oesophageal candidosis. DESIGN: Multicentre open study. PATIENTS: HIV-seropositive patients with oro-oesophageal candidosis despite at least 7 days of treatment with fluconazole at doses of 100 mg per day or more. METHODS: Patients received an initial dose of D0870 (150 mg), then 25 mg per day for 6 days. Symptoms and signs of candidosis were compared at entry and on days 3 and 7 of treatment. At each visit, samples were taken for safety monitoring and for in vitro susceptibility testing of Candida isolates. Limited pharmacokinetic samples were taken on days 1 and 7. RESULTS: Of 26 evaluable patients, 16 showed partial improvement, nine showed no improvement, and only one had full clearance of thrush by day 7. In vitro testing of the cleared patient's isolate suggested that it was susceptible to fluconazole. Symptoms of dysphagia cleared in 14 and improved in five of the 22 patients with presumptive oesophageal involvement at entry. Pharmacokinetic measurement showed wide variability in maximum D0870 levels recorded on day 1 (range, 0.07-0.34 mg/l) and susceptibility testing of isolates also showed a range of minimal inhibitory concentration values to D0870 (range, < 0.06-8 mg/l; median, 0.25 mg/l). When these data were combined with clinical response there was a strong suggestion that lack of symptomatic improvement was related to low plasma D0870 levels or to the presence of less D0870-susceptible isolates. Six patients were noted to have a fall in haemoglobin, three of whom were receiving concomitant therapy known to suppress bone marrow. Three patients reported headaches as adverse events that were attributed to study medication, but D0870 was well tolerated overall. CONCLUSIONS: D0870 shows promise in the treatment of fluconazole-resistant oro-oesophageal candidosis and was well tolerated, although efficacy in this difficult-to-treat patient group was probably limited due to the inadequate plasma levels achieved in this pilot study with the low doses of D0870 administered.

AIDS-Related Opportunistic Infections↗
PubMed1998

An EORTC multicentre prospective survey of invasive aspergillosis in haematological patients: diagnosis and therapeutic outcome. EORTC Invasive Fungal Infections Cooperative Group.

OBJECTIVES: The EORTC Invasive Fungal Infections Cooperative Group (IFICG) conducted a prospective survey by questionnaire of all cases of invasive aspergillosis (IA) in cancer patients to ascertain current diagnostic and therapeutic approaches. METHODS: All members of the IFICG were asked prospectively to complete a detailed questionnaire for each IA case identified in their institution over a 12-month period. RESULTS: One hundred and thirty questionnaires were returned. All cases were independently evaluated (DWD & JC) and 123 were eligible. Cases came from 20 hospitals in eight countries and the number of cases per institution varied from 1-21. Acute myeloid leukaemia (AML) (60, 49%), acute lymphoblastic leukaemia (ALL) (21, 17%) and lymphoma (11, 9%) were the most frequent underlying diseases, and 16 (12%) patients had received an allogeneic bone marrow transplant. Pulmonary involvement was present in 87%, infection of sinuses/nose in 16% and brain in 8%. The chest radiograph was initially normal in 9% of those with primary pulmonary disease. The diagnosis was confirmed in 50%, probable in 31% and possible in 19%. The evidence for IA was on the basis of clinical and radiological features alone in 28%, with culture or histology in another 31% and 9%, respectively, and with both culture and histology in 29%. In three (2%) patients with diagnosis was based on culture or histology alone. Treatment was given to 120 patients (98%)-amphotericin B 75%, lipid-associated amphotericin B 36%, itraconazole 40%, flucytosine 12%, growth factors 33%, lobectomy 5%. At 3 months after diagnosis or first suspicion of IA, 44 (36%) patients were alive and 79 (64%) dead. Outcome was best in those with AML (30% death and 46% with a complete antifungal response or cure). Growth factors (mostly granulocyte colony stimulating factor) appeared not to influence outcome (P = 0.99). CONCLUSION: IA remains a considerable diagnostic and therapeutic challenge. No single diagnostic procedure was universally successful and a multifaceted approach including surgery is necessary. There was no discernable difference in outcome between initial therapy with amphotericin B, itraconazole or lipid-associated amphotericin B, although numbers are limited and the study was retrospective.

Adolescent↗
PubMed1998

Variation in morphotype, karyotype and DNA type of fluconazole resistant Candida albicans from an AIDS patient.

Azole-resistant oropharyngeal and oesophageal candidiasis is a recent phenomenon observed in patients with AIDS usually previously treated with fluconazole. Some variation has been observed in antifungal susceptibility testing among separate colonies of Candida albicans from the same patient. This raises the question of whether there are multiple clones present or simply phenotypic variation in expression of azole resistance. To address this question we took 18 isolates grown from multiple swabs taken before and after experimental azole therapy from a single HIV-positive individual with fluconazole-resistant oral candidiasis and compared morphotype, karyotype, PCR-based DNA typing and azole susceptibility. Ten of the isolates were from a single 2-day period. Amongst these 10 there were seven morphotypes, five karyotypes and four polymerase chain reaction (PCR) types. Three further morphotypes, one karyotype and two PCR types were found amongst the eight isolates obtained during the subsequent 4 months. Limited variation in susceptibility to two azoles--fluconazole and D0870--was also seen. This work emphasizes both the large genotype and phenotypic variability of C. albicans isolates in the mouth of AIDS patients with fluconazole resistance, and the difficulties in interpretation of present typing methods.

AIDS-Related Opportunistic Infections↗
PubMed1998

Skull base osteitis following fungal sinusitis.

Aspergillus sp. sinusitis is not uncommon in immunocompromised patients but is unusual in patients who are not immunocompromised. The disease may occur as a saprophytic condition, as an allergic sinusitis or as a potentially lethal invasive disease. The differentiation between non-invasive and invasive Aspergillus sp. sinusitis is crucial and this distinction is fully discussed. The treatment options are also considered. Invasive disease requires aggressive treatment with long-term antifungal agents in sufficient doses combined with wide surgical excision. We present a patient who presented with invasive Aspergillus fumigatus sinusitis and subsequently developed cranial neuropathies and skull base osteitis. She was initially treated with oral itraconazole (400 mg daily) for 18 months but due to lack of response this was changed to a new experimental oral azole (voriconazole) which was continued for a further 14 months. She has since remained well for the last five years.

Adult↗
PubMed1998

In-vitro activity of voriconazole against Aspergillus spp. and comparison with itraconazole and amphotericin B.

The in-vitro activity of the triazole antifungal agent voriconazole was compared with itraconazole and amphotericin B against 60 aspergillus isolates. Susceptibility tests were performed using two methods: a macrodilution and a microdulution method. For macrodilution methodology, geometric mean (GM) MIC values and ranges were 0.4 and 0.125-4 mg/L for voriconazole, 0.24 and 0.06-->16 mg/L for itraconazole, and 1.04 and 0.5-4 mg/L for amphotericin B. For the microdilution method, GM MICs and ranges were 0.66 and 0.125-2 mg/L for voriconazole, 0.27 and 0.06-->16 mg/L for itraconazole, and 1.62 and 0.25-32 mg/L for amphotericin B. In conclusion, voriconazole is active against Aspergillus spp. in vitro, and at similar concentrations to itraconazole.

Amphotericin B↗
PubMed1998

In-vitro activities of amphotericin B, itraconazole and voriconazole against 150 clinical and environmental Aspergillus fumigatus isolates.

The in-vitro activity of amphotericin B, itraconazole and voriconazole against 130 clinical and 20 environmental Aspergillus fumigatus isolates was tested with an agar dilution method using RPMI 1640 medium. Itraconazole-susceptible (AF71) and -resistant (AF90) isolates were included in each test and all isolates were tested in duplicate. Geometric mean MIC values (ranges) at 48 h and 72 h were, respectively, amphotericin B, 0.91 (0.25-2) and 1.50 (1-4) mg/L; itraconazole, 0.25 (0.06-1) and 0.48 (0.125-8) mg/L; and voriconazole, 0.56 (0.25-8) and 0.78 (0.25-8) mg/L. The reproducibility of the results was high for all drugs. In-vitro resistance of A. fumigatus to the tested antifungal agents was uncommon and the MICs of itraconazole were half those of voriconazole (P < 0.01).

Amphotericin B↗
PubMed1998

In vitro activity of the echinocandin antifungal agent LY303,366 in comparison with itraconazole and amphotericin B against Aspergillus spp.

LY303,366 (LY) is a novel derivative of the echinocandin class of antifungal agents. The in vitro activities of LY, itraconazole (ITZ), and amphotericin B (AMB) were assessed against 60 Aspergillus isolates, including 35 isolates of A. fumigatus, eight isolates of A. terreus, eight isolates of A. flavus, eight isolates of A. niger and one isolate of A. nidulans. Four A. fumigatus isolates were resistant to ITZ. Susceptibility testing for all drugs was performed with a broth microdilution procedure. LY was tested in two media: antibiotic medium 3 (AM3) and Casitone with 2% glucose (CAS) with an inoculum of 2 x 10(3) spores/ml. ITZ and AMB were tested in RPMI 1640 with 2% glucose with an inoculum of 1 x 10(6) spores/ml. All tests were incubated at 37 degrees C for 48 h. A novel end point was used to determine a minimal effective concentration (MEC) for LY, i. e., almost complete inhibition of growth save a few tiny spherical colonies attached to the microplate. MICs were measured for ITZ and AMB with a no-growth end point. Ranges and geometric mean (GM) MECs were from 0.0018 to >0.5 and 0.0039 mg/liter and from 0.0018 to >0.5 and 0.008 mg/liter for LY in AM3 and LY in CAS, respectively. Differences between species were apparent, with A. flavus being significantly less susceptible to LY than any other species tested with both media (P </= 0.05). Ranges and GM MICs were from 0.125 to >16 and 0.7 mg/liter for ITZ and from 0.25 to 16 and 1.78 mg/liter for AMB. Minimal fungicidal concentrations (MFCs) were also determined for all drugs. GM MFCs were 0.018, 0.09, 19.76, and 12.64 mg/liter for LY in AM3, LY in CAS, ITZ, and AMB, respectively. LY in AM3 and LY in CAS were fungicidal for 86.7 and 68% of isolates, respectively (98% killing). In comparison, ITZ and AMB were fungicidal for 35 and 70% of isolates, respectively (99.99% killing). A reproducibility study was performed on 20% of the isolates. For 12 isolates retested, the MEC or MIC was the same or was within 1 dilution of the original value for 11, 11, 10, and 9 isolates for LY in AM3, LY in CAS, ITZ, and AMB, respectively. In conclusion, LY seems to be a promising antifungal agent with excellent in vitro activity against Aspergillus spp.

Amphotericin B↗
PubMed1998

Efficacy of LY303366 against amphotericin B-susceptible and -resistant Aspergillus fumigatus in a murine model of invasive aspergillosis.

LY303366 is a novel antifungal echinocandin with excellent in vitro activity against Aspergillus spp. We compared four doses (1, 2.5, 10, and 25 mg/kg of body weight) of LY303366 with amphotericin B (0.5 to 5 mg/kg) in a temporarily neutropenic murine model of invasive aspergillosis against an amphotericin B-susceptible (AF210) and an amphotericin B-resistant (AF65) Aspergillus fumigatus isolate based on in vivo response. Mice were immunosuppressed with cyclophosphamide (200 mg/kg) and infected 3 days later. Treatment started 18 h after infection and lasted for 10 days. LY303366 was given once daily intravenously for 10 days, and amphotericin B (at 0.5, 2, and 5 mg/kg) was given once daily intraperitoneally for 10 days, or only on days 1, 2, 4, and 7 (at 5 mg/kg). Kidneys and lungs from survivors were cultured on day 11. Control mice in both experiments had 90 to 100% mortality. Amphotericin B at 0.5 mg/kg and LY303366 at 1 mg/kg yielded 10 to 20% survival rates for mice infected with either AF210 or AF65. Amphotericin B at 2 and 5 (both regimens) mg/kg yielded a 70 to 100% survival rate for mice infected with AF210 but a 10 to 30% survival rate for mice infected with AF65 (P = 0.01 to 0.04 compared with AF210). Against AF210 and AF65, LY303366 at 2.5, 10, and 25 mg/kg produced a survival rate of 70 to 80%, which was as effective as amphotericin B for AF210, but superior to amphotericin B for AF65 (P < 0.03 to 0.0006). For AF65, LY303366 at 10 and 25 mg/kg/day was superior to amphotericin B at 2 and 5 mg/kg/day in reducing tissue colony counts (P = 0.01 to 0.003), and for AF210, amphotericin B at 5 mg/kg/day and at 5 mg/kg in four doses was more effective than all four regimens of LY303366 in reducing renal culture counts (P = 0.01 to 0.0001). The present study shows, for the first time, that in vivo resistance of A. fumigatus to amphotericin B exists, although this could not be detected by in vitro susceptibility assays. Furthermore, LY303366 appears to be effective against amphotericin B-susceptible and -resistant A. fumigatus infection in this model and should be further evaluated clinically.

Amphotericin B↗
PubMed1998

Polar lipids of Aspergillus fumigatus, A. niger, A. nidulans, A. flavus and A. terreus.

Little is known of the phospholipid composition of Aspergillus species. The aim of this study was to determine individual phospholipid analogues in Aspergillus. Twenty-nine clinical and environmental isolates from five Aspergillus species were analysed. Fast atom bombardment mass spectrometric data were considered in two ranges, m/z 190-500 and m/z 500-1000, to facilitate the recognition of major fatty acyl groups and phospholipids. Quantitative comparison of major anions in both m/z ranges was undertaken. Confirmation of major phospholipid anions from eight representative isolates was achieved by tandem mass spectrometry. The major phospholipid families were phosphatidic acid (PA), phosphatidylethanolamine (PE), phosphatidylinositol (PI), and phosphatidylserine (PS). Anions were detected consistent with the presence of specific phospholipid moieties, such as palmitoyl-linolenoyl phosphatidic acid, palmitoyl-oleoylphosphatidylethenolamine, oleoyl-linoleoyl-phophatidylserine and palmitoyl-linoleoyl-phosphatidylinositol. It appears that there is some commonality of sn1 or sn2 fatty acyl substituents, frequently C18:2 at sn1 accompanied by C16:0 at sn2, with differing molecular weights being attributable to analogues with differing head groups. Differences in certain phospholipids (e.g. minor peak with m/z 933) were detected between A. fumigatus, A. nidulans and other species examined which could have diagnostic value.

Aspergillus↗
PubMed1998

Current trends in the detection of antigenaemia, metabolites and cell wall markers for the diagnosis and therapeutic monitoring of fungal infections.

There have been several recent developments in the diagnosis of fungal infections, including the production of novel antigen detection tests, the G-test, and assays for the detection of fungal metabolites. In this article we present an overview of these developments and examine the value of including these tests in clinical trials.

Antigens, Fungal↗