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Biomedical subjects

D W Denning

Publications and source records attributed to D W Denning.

At least 127 records · Page 7Linked to original sources
PubMed1995

Molecular typing of Aspergillus species.

In the last four years, several molecular typing methods have been applied to various Aspergillus species, primarily A. fumigatus and A. niger. Many 'clones' or DNA types exist in the environment and in patients. The most discriminatory methods appear to be restriction fragment length polymorphism analysis with or without specific probes and random amplification of polymorphic DNA analysis. Insufficient work on interlaboratory reproducibility has been done. Most patients are infected by single DNA types, although occasionally multiple isolates are detected. Little work has been done with regard to detailed hospital epidemiology using molecular typing methods.

Aspergillus↗
PubMed1995

Scedosporium prolificans, a multi-resistant fungus, from a U.K. AIDS patient.

We report the first isolation of Scedosporium prolificans (inflatum) in the U.K. The patient, with advanced AIDS and neutropenia, had respiratory tract colonisation over many months without invasive disease despite neutropenia, while on itraconazole therapy. The organism was resistant in vitro to all licensed systemic antifungal agents tested.

AIDS-Related Opportunistic Infections↗
PubMed1995

DNA typing of epidemiologically-related isolates of Aspergillus fumigatus.

Invasive aspergillosis is often nosocomially acquired and carries a high mortality. Molecular typing methods to discriminate isolates have now been developed. Using simple restriction endonuclease (Sal1 and Xho1) digestion of total genomic DNA, we have typed 25 epidemiologically-related isolates of A. fumigatus from six hospital episodes of invasive aspergillosis. Eight DNA types were found and in each case the DNA type matched precisely the epidemiological data. Thus DNA typing of A. fumigatus can provide the means to match isolates from linked sources and distinguish isolates from diverse origins.

Aspergillosis↗
PubMed1995

Aflatoxin and outcome from acute lower respiratory infection in children in The Philippines.

Aflatoxin is immunosuppressive in experimental conditions. This study addressed its potentially contributory role in the poor outcome of acute lower respiratory infections (ALRI) in children in The Philippines. The catchment area included peri-urban slums and middle-class housing. One hundred and fifteen children (mean age 2.1, range 0.08-12 years) were enrolled and their serum and urine obtained at presentation with ALRI. Aflatoxins in serum and aflatoxin metabolites in urine were measured by previously validated ELISA tests. Using the 1986 WHO criteria for the severity of ALRI, 31% had mild, 12% moderate, 49% severe and 8% severe complicated pneumonia. Eighty of 97 (82%) chest radiographs were abnormal. Ninety per cent of the children were below average weight for age, using Filipino standards, with a mean of 79% (range 27-157%). Thirteen (11%) children died. Aflatoxin in their serum, reflecting recent ingestion, was detected in 33%, with a mean positive value of 462 pg/ml. Aflatoxin metabolites (reflecting chronic ingestion) were detected in 64 of 65 urines collected, with a mean value of 0.1-4.77ng/ml. None of the children with detectable serum aflatoxin died. Anorexia and impaired consciousness were strongly associated with a poor outcome (prolonged fever or death). There was a strong association between undetectable serum aflatoxin concentrations and death (p = 0.004), perhaps reflecting anorexia. There was no relationship between the concentration of urinary aflatoxin metabolites and outcome. Serum was also obtained from 29 mothers on admission and none contained detectable aflatoxin. As virtually all the children had evidence of exposure to aflatoxin, a potentially immunosuppressive role in the context of pneumonia cannot be excluded.

Aflatoxins↗
PubMed1995

Aspergillus fungemia: report of two cases and review.

We present two cases of aspergillus infection confirmed by blood culture and review 30 other cases of genuine aspergillus fungemia and 34 cases of aspergillus pseudofungemia. Multiple different media and blood culture systems were used to isolated Aspergillus. The median time to positive blood culture was 8.5 days (range, 1-27 days) in the genuine cases. Genuine aspergillus fungemia was observed more often after cardiac surgery (n = 11 [34%]) or during neutropenia (n = 9 [28%]) than in other settings. In a recent series of fungemia during neutropenia, 7.6% of all episodes were due to Aspergillus. Other patients at risk for aspergillus fungemia were similar to those at risk for invasive aspergillosis, including patients with AIDS. Seven (44%) of 19 patients who were treated survived. In the group of patients with aspergillus pseudofungemia, there were no deaths, and cultures of additional specimens from the same patient were not positive. Criteria that may be applied to ascertain whether the isolation of Aspergillus from blood cultures is clinically significant are put forward.

Aged↗
PubMed1995

Antifungal drug susceptibility testing. Working Party of the British Society for Antimicrobial chemotherapy.

This article describes the current situation with regard to intrinsic and acquired resistance to antifungal compounds and progress with the development of standardized methods of susceptibility testing for amphotericin B, flucytosine, and the azoles. Recommendations for testing of isolates from patients destined to receive antifungal drug treatment, or in whom therapeutic failure or relapse is suspected, are presented.

Antifungal Agents↗
PubMed1995

In vitro activity of D0870 compared with those of other azoles against fluconazole-resistant Candida spp.

We compared the in vitro activity of a new triazole, D0870, with those of fluconazole, itraconazole, and ketoconazole against 41 clinical isolates of fluconazole-resistant Candida belonging to nine different species. The 50% inhibitory concentrations (IC50s) were determined by a microdilution method with morpholinopropanesulfonic acid (MOPS)-buffered RPMI medium and an inoculum of approximately 10(4) yeasts per ml. After incubation for 48 h at 37 degrees C the optical density at 550 nm was measured. The IC50 was the lowest drug concentration which reduced the optical density at 550 nm by > or = 50% compared with that for a drug-free control. D0870 had significant activity against many of the isolates. Its activity was comparable to that of ketoconazole, slightly superior to that of itraconazole, and markedly superior to that of fluconazole against Candida albicans. Against Candida glabrata, Candida krusei, and Candida inconspicua, it had activity similar to those of itraconazole and ketoconazole but had activity superior to that of fluconazole. D0870 IC50s for some isolates were increased. This may be due to cross-resistance mechanisms because the IC50s of both itraconazole and ketoconazole for these isolates were often high. When IC50s and IC80s were compared there was a marked organism and drug variation. With C. glabrata much higher endpoints for itraconazole were observed when an IC80 endpoint was used. For C. albicans there was also a significant shift upward in endpoints for itraconazole and ketoconazole. Values were changed little when IC50 and IC80 endpoints of D0870 were compared. For 35 of 41 isolates tested the D0870 IC50 was less than the 2.5-mg/liter breakpoint threshold proposed previously. Therefore, D0870 may be a useful agent for the therapy of infections caused by fluconazole-resistant Candida spp.

Antifungal Agents↗
PubMed1995

Efficacy of D0870 compared with those of itraconazole and amphotericin B in two murine models of invasive aspergillosis.

D0870 is a novel azole antifungal compound. It was compared with conventional amphotericin B and itraconazole therapy in two murine models of invasive aspergillosis, one a systemic nonimmunocompromised mouse model and the other a temporarily neutropenic mouse respiratory model. D0870 was given orally and achieved measurable concentrations in serum approximately proportional to the daily dose with accumulation over time if it was given twice daily. Amphotericin B at 3.3 mg/kg of body weight was given intraperitoneally for four to six doses, and itraconazole was given orally in a cyclodextrin suspension at 5 to 50 mg/kg daily or twice daily (BID). The duration of therapy varied from 7 to 14 days. In the nonimmunocompromised mouse model, D0870 at 25 mg/kg BID was slightly inferior to amphotericin B and itraconazole with regard to mortality, with a median survival of 20 days for the three groups (P = 0.03 compared with amphotericin B). However, D0870 at 25 mg/kg BID was inferior to amphotericin B (but not itraconazole) with respect to renal culture (P = 0.01) and brain culture (P = 0.0001) results. Only amphotericin B was statistically superior to controls with regard to mortality. In the neutropenic mouse respiratory model, D0870 at 50 mg/kg/day was superior to amphotericin B, itraconazole, and controls with regard to mortality. D0870 at both 25 and 50 mg/kg/day was statistically superior to controls with regard to lung culture results (P = 0.004 to 0.04). A second experiment with a higher inoculum showed that no drug regimen was effective in that model. In all models low doses and concentrations of D0870 in serum were ineffective. D0870 has some efficacy for the treatment of invasive aspergillosis when it is given at modest doses.

Amphotericin B↗
PubMed1994

NIAID Mycoses Study Group Multicenter Trial of Oral Itraconazole Therapy for Invasive Aspergillosis.

BACKGROUND: Invasive aspergillosis is the most common invasive mould infection and a major cause of mortality in immunocompromised patients. Response to amphotericin B, the only antifungal agent licensed in the United States for the treatment of aspergillosis, is suboptimal. METHODS: A multicenter open study with strict entry criteria for invasive aspergillosis evaluated oral itraconazole (600 mg/d for 4 days followed by 400 mg/d) in patients with various underlying conditions. Response was based on clinical and radiologic criteria plus microbiology, histopathology, and autopsy data. Responses were categorized as complete, partial, or stable. Failure was categorized as an itraconazole failure or overall failure. RESULTS: Our study population consisted of 76 evaluable patients. Therapy duration varied from 0.3 to 97 weeks (median 46). At the end of treatment, 30 (39%) patients had a complete or partial response, and 3 (4%) had a stable response, and in 20 patients (26%), the protocol therapy was discontinued early (at 0.6 to 54.3 weeks) because of a worsening clinical course or death due to aspergillosis (itraconazole failure). Twenty-three (30%) patients withdrew for other reasons including possible toxicity (7%) and death due to another cause but without resolution of aspergillosis (20%). Itraconazole failure rates varied widely according to site of disease and underlying disease group: 14% for pulmonary and tracheobronchial disease, 50% for sinus disease, 63% for central nervous system disease, and 44% for other sites; 7% in solid organ transplant, 29% in allogeneic bone marrow transplant patients, and 14% in those with prolonged granulocytopenia (median 19 days), 44% in AIDS patients, and 32% in other host groups. The relapse rates among those who completed therapy and those who discontinued early for possible toxicity were 12% and 40%, respectively; all were still immunosuppressed. CONCLUSION: Oral itraconazole is a useful alternative therapy for invasive aspergillosis with response rates apparently comparable to amphotericin B. Relapse in immunocompromised patients may be a problem. Controlled trials are necessary to fully assess the role of itraconazole in the treatment of invasive aspergillosis.

AIDS-Related Opportunistic Infections↗
PubMed1994

Treatment of invasive aspergillosis.

Invasive aspergillosis is generally a life-threatening invasive opportunistic mycosis affecting principally the upper and lower respiratory tract. Therapeutic response rates vary considerably from one host group to another with particularly high mortality rates in bone marrow transplant, liver transplant and patients with aplastic anaemia or AIDS. Only two drugs are useful for therapy, amphotericin and itraconazole. Recent advances in the formulation of amphoterin B (AmBisome and Amphocil) have resulted in intravenous preparations with lower toxicity, particularly nephrotoxicity, but it has yet to be shown that they have an increased therapeutic index for the treatment of invasive aspergillosis. Itraconazole can only be used orally and in some particularly high-risk or critically ill patients adequate serum concentrations cannot be achieved. The addition of flucytosine or rifampicin to amphotericin B therapy has, at best, only a marginal benefit. Surgery is essential for some manifestations of invasive aspergillosis. This article reviews therapeutic strategies including criteria for initiation of therapy, combination and sequential therapy, duration of therapy and secondary prophylaxis and indications for surgery in invasive aspergillosis.

AIDS-Related Opportunistic Infections↗
PubMed1994

An algorithmic approach to aspergillus sinusitis.

The effective management of paranasal sinus aspergillosis requires early diagnosis, histological classification, surgery and where appropriate, chemotherapy. Fungal sinusitis may be easily missed unless a high index of suspicion is maintained and specific culture and histology requested. The disease is classified into invasive and noninvasive types, each being divided into two subgroups: invasive aspergillosis may be either fulminant or indolent and noninvasive disease localized or allergic. The literature is reviewed and an algorithmic approach to aspergillus sinusitis proposed. The importance of histologically differentiating invasive from noninvasive aspergillosis prior to selecting the appropriate treatment options is stressed. CT scan should precede definitive surgery, and be used in follow-up. Close and prolonged follow-up is essential.

Algorithms↗
PubMed1994

Successful treatment of sinusitis caused by Cunninghamella bertholletiae.

Seventeen cases of infections due to Cunninghamella species have been reported worldwide in humans, and there have been only three survivors. We report a case of paranasal sinusitis due to Cunninghamella bertholletiae in an elderly patient who had diabetes mellitus and myelodysplasia. After receiving 7 weeks of therapy with deoxycholate amphotericin B (44 mg/kg or a total of 3 g) and rifampin, the patient was cured and did not have to undergo radical surgery.

Aged↗
PubMed1994

Invasive aspergillosis in patients with AIDS.

The prolonged survival of profoundly immunocompromised patients with AIDS has contributed to the increasing recognition of aspergillus infections as an emerging problem. Nevertheless, many of these infections continue to be diagnosed only at autopsy. In this article we review details of 293 reported cases. Invasive aspergillosis occurs in advanced AIDS and most commonly affects the lungs, although brain involvement has also been frequently reported. The diagnosis is often difficult to make while the patient is alive, although examination of specimens obtained via bronchoalveolar lavage, percutaneous needle aspiration, or biopsy is often successful. Biopsy of the affected organ along with histologic examination and culture may be necessary for diagnosis. The dismal prognosis of invasive aspergillosis in patients with AIDS can be improved only with earlier diagnosis of disease and the availability of more-effective antifungal regimens.

AIDS-Related Opportunistic Infections↗