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Biomedical subjects

D W Denning

Publications and source records attributed to D W Denning.

At least 163 records · Page 9Linked to original sources
PubMed1992

Interaction of azoles with rifampin, phenytoin, and carbamazepine: in vitro and clinical observations.

Twelve patients receiving therapy with an azole agent (ketoconazole, itraconazole, and/or fluconazole) for systemic mycoses experienced drug interactions with rifampin, phenytoin, and/or carbamazepine resulting in substantial decreases in azole concentrations in serum. All four patients receiving azoles and concurrent phenytoin and/or carbamazepine failed to respond to treatment or suffered a relapse of their fungal infection. Four of five patients with cryptococcosis who received itraconazole and rifampin responded despite decreases in their serum itraconazole concentrations; synergy between itraconazole and rifampin was documented by in vitro analysis of inhibition and of killing of Cryptococcus neoformans isolates from all patients receiving this combination. In contrast, two patients with coccidioidomycosis failed to respond to itraconazole/rifampin. Moreover, two patients with cryptococcosis suffered a relapse or persistence of seborrheic dermatitis while receiving itraconazole/rifampin. The latter combination showed synergy in vitro in the inhibition of the mycelial phase of Coccidioides immitis and, to a lesser extent, of the pathogenic spherule phase of this fungus; synergy in the killing of C. immitis was not noted, nor was synergy seen against Malassezia furfur, the purported etiologic agent of seborrheic dermatitis. These findings illustrate several drug interactions that may affect clinical outcome and that must be considered in the management of antifungal therapy.

Adult↗
PubMed1992

Lack of vessel wall elastolysis in human invasive pulmonary aspergillosis.

In experimental studies, the apparent ability of Aspergillus fumigatus isolates to produce elastase in agar plates correlates with their ability to cause invasive pulmonary aspergillosis in mice pretreated with cortisone. Thus, elastase production may govern the pathogenicity of particular isolates. If this is so, then disruption of the elastic layers within blood vessel walls in invasive aspergillosis would be expected. To test this hypothesis, tissue blocks were prepared from nine patients with invasive pulmonary aspergillosis. Separate but immediately adjacent histological sections were stained by the Grocott and periodic acid-Schiff methods for fungal hyphae and by the elastic van Gieson technique for elastic tissue. Comparison of those segments of vessel walls infiltrated by hyphae with those not infiltrated by hyphae showed no overall loss of elastic tissue. Material from five of the cases was also stained with an unconventional combination of histochemical stains, allowing accurate identification of both fungal hyphae and elastic laminae in the same histological sections. The results showed no more disruption of elastic laminae than would be expected from simple physical displacement of elastic laminae. We conclude that if elastolysis contributes at all to invasion of vessel walls by aspergilli, then it seems to be very localized and/or transient.

Adult↗
PubMed1992

US experience with itraconazole in Aspergillus, Cryptococcus and Histoplasma infections in the immunocompromised host.

Itraconazole has emerged as an important new oral agent in the treatment of systemic fungal infections. This paper summarizes the data available on its use in aspergillosis, cryptococcosis and histoplasmosis, compiled in the United States with particular attention to the immunocompromised host. Data have been accrued in open-label studies including 57 patients with cryptococcal disease where the overall response rate among patients with meningitis was 86%, and in 28 patients (8 with acquired immune deficiency syndrome (AIDS) or human immunodeficiency virus (HIV) infection) with invasive aspergillosis where the overall response rates were 80% in patients without AIDS and 86% in patients with AIDS. Data are summarized on 6 patients with allergic bronchopulmonary aspergillosis, 5 of whom demonstrated marked improvement on therapy, and 12 patients with histoplasmosis including 8 with AIDS, 11 of whom responded and 1 recrudesced on therapy. In summary, itraconazole showed activity in human studies of aspergillosis, cryptococcosis and histoplasmosis with minimal toxicity. Itraconazole offers a new oral alternative to conventional amphotericin B therapy in these infections. Comparative studies are needed to clarify its role.

Acquired Immunodeficiency Syndrome↗
PubMed1992

Antifungal prophylaxis during neutropenia or allogeneic bone marrow transplantation: what is the state of the art? Ad HOC Working Group.

Neutropenia induced by intensive chemotherapy and allogeneic bone marrow transplantation are increasingly commonly complicated by fungal infections; thus prophylaxis may be justified. The authors surveyed the literature and culled their experience - few randomized trials have been done and definitions have often been poor. In prophylaxis of mucosal candidosis, miconazole and clotrimazole may both be more effective than placebo. Nystatin is ineffective and ketoconazole of medicine efficacy. Fluconazole is effective at 50 mg/day and 400 mg/day. Itraconazole and amphotericin B both need further evaluation. In prevention of systemic candidosis, oral nystatin prophylaxis, up to 4 X 10(6) U/day, is usually unsuccessful, though compliance is variable. Oral amphotericin B in low doses is ineffective, but 50 mg or more 4 times daily may prevent systemic candidosis, though compliance is variable. Oral ketoconazole, 400-600 mg/day, is possibly effective prophylaxis in neutropenia but not after bone marrow transplantation; liver function (often abnormal in these patients) is a problem, as is tolerability. Oral fluconazole is well tolerated, has reliable serum concentrations and is effective following bone marrow transplantation, but the optimum dose is uncertain. In bone marrow transplantation, intravenous amphotericin B, 0.1 mg/kg/day, appears to be effective; there are no data in neutropenia. Oral itraconazole (capsules, 200 mg/day) may be active; data are scanty. In prevention of invasive aspergillosis, itraconazole, 200 mg/day, is probably active, but only if adequate serum concentrations are achieved. New oral and intravenous itraconazole formulations in cyclodextrin may achieve more reliable serum concentrations. No oral drug provides effective prophylaxis against Torulopsis, Fusarium, Trichosporon, or Pseudallescheria.

Antifungal Agents↗
PubMed1991

Pulmonary aspergillosis in the acquired immunodeficiency syndrome.

BACKGROUND AND METHODS: Symptomatic pulmonary aspergillosis has rarely been reported in patients with the acquired immunodeficiency syndrome (AIDS). We describe the predisposing factors, the clinical and radiologic features, and the therapeutic outcomes in 13 patients with pulmonary aspergillosis, all of whom had human immunodeficiency virus (HIV) infection and 12 of whom had AIDS. RESULTS: Pulmonary aspergillosis was detected a median of 25 months after the diagnosis of AIDS, usually following corticosteroid use, neutropenia, pneumonia due to other pathogens, marijuana smoking, or the use of broad-spectrum antibiotics. Two major patterns of disease were observed: invasive aspergillosis (in 10 patients) and obstructing bronchial aspergillosis (in 3). Cough and fever, the most common symptoms, tended to be insidious in onset in patients with invasive disease (median duration, 1.3 months before diagnosis). Breathlessness, cough, and chest pain predominated in the three patients with obstructing bronchial aspergillosis, who coughed up fungal casts. Radiologic patterns included upper-lobe cavitary disease (sometimes mistaken for tuberculosis), nodules, pleural-based lesions, and diffuse infiltrates, usually of the lower lobe. Transbronchial biopsies were usually negative, but positive cultures were obtained from bronchoalveolar-lavage fluid or percutaneous aspirates. Dissemination to other organs occurred in at least two patients, and direct invasion of extrapulmonary sites was seen in two others. The results of treatment with amphotericin B, itraconazole, or both were variable. Ten of the patients died a median of 3 months after the diagnosis (range, 0 to 12 months). CONCLUSIONS: Pulmonary aspergillosis is a possible late complication of AIDS; if diagnosed early, it may be treated successfully.

Acquired Immunodeficiency Syndrome↗
PubMed1991

Elevated cerebrospinal fluid pressures in patients with cryptococcal meningitis and acquired immunodeficiency syndrome.

Increased intracranial pressure has been a noteworthy problem in some of our patients with cryptococcal meningitis and acquired immunodeficiency syndrome (AIDS), and this appears to be a feature observed in patients with cryptococcal meningitis reported in the literature. Whereas most attention of clinicians is presently focused on optimizing the antifungal regimen, so as to improve on high failure rates in cryptococcal meningitis in AIDS, little attention has been paid to the problem of intracranial hypertension. We argue that visual loss and some of the cases of death early after the onset of chemotherapy may be related to high cerebrospinal fluid (CSF) pressure, regardless of antifungal therapy. The possible pathophysiologic mechanisms are discussed, and we postulate that the mechanism is reduced CSF outflow possibly due to increased outflow resistance, not necessarily accompanied by prominent cerebral edema. Optimal therapy of this complication is not yet established, but some measures that may be helpful are ventricular shunting, frequent high-volume lumbar punctures, and possibly glucocorticoids.

Acquired Immunodeficiency Syndrome↗
PubMed1991

Epidemiology and pathogenesis of systemic fungal infections in the immunocompromised host.

The epidemiology and pathogenesis of invasive candidosis and aspergillosis, cryptococcal meningitis, mucormycosis and disseminated histoplasmosis are reviewed. Particular areas of growth of knowledge that are emphasized are the epidemiology of candidosis and aspergillosis, putative virulence factors in aspergillosis and the pathogenesis of cryptococcosis.

Animals↗
PubMed1991

Efficacy of cilofungin alone and in combination with amphotericin B in a murine model of disseminated aspergillosis.

Cilofungin, amphotericin B, and a combination of the two drugs were compared in a model of aspergillosis in immunocompetent mice in three experiments. Cilofungin was equivalent to amphotericin B in preventing death and eradicating cerebral aspergillosis, but it did not sterilize the kidneys. This is the first demonstration of the in vivo activity of cilofungin against any fungus other than Candida albicans. The mortality with combination therapy was higher than those with amphotericin B alone (P = 0.003) and cilofungin alone (P = 0.054), as was weight loss after infection, indicating antagonism between cilofungin and amphotericin B in this model. The mechanisms of action and antagonism remain to be explained.

Amphotericin B↗
PubMed1991

Performance of cryptococcus antigen latex agglutination kits on serum and cerebrospinal fluid specimens of AIDS patients before and after pronase treatment.

Cryptococcal antigen titers in 97 serum and 42 cerebrospinal fluid (CSF) specimens from 37 AIDS patients with culture-proven cryptococcal infection were determined with the Meridian kit (Meridian Diagnostics Inc., Cincinnati, Ohio) before and after treatment with pronase. The geometric mean titers before and after pronase treatment were 1:45 and 1:588 in serum and 1:97 and 1:79 in CSF, respectively. Only on serum (but not CSF) specimens after pronase treatment were (i) titers increased by 2 to 13 dilutions on 57% of the specimens, all of which had titers of less than or equal to 1:128 before pronase treatment, (ii) false-negative reactions on 27% of specimens before pronase treatment eliminated, all of which had titers from 1:4 to 1:4,096, (iii) prozone-like reactions (titer, less than or equal to 1:256) on 9% of the specimens before pronase treatment eliminated, and (iv) agglutination reactions on all specimens stronger and easier to interpret. Antifungal agents added to serum as well as freeze-thaw cycles did not change antigen titers in serum. After two separate tests, the same titers were obtained on 94% of 35 serum specimens that were treated with pronase and on 96% of 53 CSF specimens that were not treated with pronase. A total of 26 serum specimens and 28 CSF specimens from patients with no cryptococcal disease were negative before and after pronase treatment. The IBL kit (International Biological Labs Inc., Cranbury, N.J.) was compared with the Meridian kit on 41 serum specimens and 14 CSF specimens. Results from the two kits agreed on 54 and 68% of serum specimens and 86 and 93% of CSF specimens before and after pronase treatment, respectively. The IBL kit generally produced higher titers on specimens in disagreement and produced no prozone-like reactions. Routine pronase treatment of serum is recommended with the Meridian kit in order to eliminate false-negative and unclear agglutination reactions by producing a consistent interpretation of agglutination reactions. CSF specimens do not require pronase treatment. Titer results produced by the kits from the two different manufacturers varied considerably: the kits should not be used interchangeably for determining antigen titers in serum specimens.

Acquired Immunodeficiency Syndrome↗
PubMed1991

Ulcerative tracheobronchitis after lung transplantation. A new form of invasive aspergillosis.

Invasive aspergillosis is frequently a fatal disease in the setting of immunosuppression, including organ transplant recipients. The fungus usually affects lung parenchyma and may disseminate from there. We have recently noted tracheobronchitis in six patients with heart-lung and lung transplants, three of whom had deep mucosal ulceration and histologic evidence of invasive aspergillosis. This apparently new form of invasive disease is initially limited to the anastomosis site and large airways. Ulceration, necrosis, cartilage invasion, and formation of a pseudomembrane are the pathologic features. In two patients subsequent disseminated aspergillosis occurred with a fatal outcome. In the two single-lung recipients, disease was limited to the transplanted side emphasizing the importance of abnormal local defense mechanisms in the airways of lung transplant recipients. Routine bronchoscopic examination of the airways is important in early detection of this complication. Oral therapy with the new, antifungal agent itraconazole was successful in five of the six patients, with fatal relapse in one. A classification of the various forms of saprophytic, allergic, and invasive forms of aspergillus tracheobronchitis, to include this new entity, is proposed.

Adult↗
PubMed1991

Adjunctive therapy of allergic bronchopulmonary aspergillosis with itraconazole.

Itraconazole is a new orally active antifungal triazole with impressive activity against Aspergillus spp. Six patients with allergic bronchopulmonary aspergillosis (ABPA), aged 14 to 49 years, were treated with oral itraconazole (200 mg twice daily) for a mean of 3.9 months (range, one to six months; three patients continue on therapy). Two patients received two courses. Three patients had underlying cystic fibrosis, and three had severe asthma; four of the six required continuous high-dose systemic prednisone (mean, 43 mg/day; confidence interval [CI], 23 to 63 mg/day) at the start of therapy. In those treated for two months or longer, the mean total serum IgE level fell from 2,462 U/ml (CI, 752 to 4,202 U/ml) to 502 U/ml (CI, 123 to 880 U/ml) during each course, and the mean daily steroid dosage was decreased to a mean of 24 mg/day (CI, 11 to 37 mg/day). All patients experienced improvement in pulmonary function during the trial, with mean FEV, increasing from 1.43 to 1.77L/sec and mean FVC from 2.3 to 2.9 L in those treated for two months or longer. The mean steady-state serum concentration of itraconazole was 5.1 micrograms/ml (range, 1.8 micrograms/ml to 7.3 micrograms/ml); the patient with the lowest concentrations had the least significant clinical response. Cultures of sputum from two of three patients became negative for A fumigatus during therapy. No adverse clinical effects occurred except loss of libido in one patient. We conclude that oral itraconazole may be an effective adjunctive therapy in ABPA, possibly by clearing the airway of Aspergillus, and that randomized trials of this agent are warranted to better define its usefulness in this disorder.

Adolescent↗
PubMed1991

DNA fingerprinting of Aspergillus fumigatus isolates from patients with aspergilloma.

Fourteen sputum isolates of Aspergillus fumigatus from Glasgow, Scotland, including 12 isolates from patients with aspergilloma were DNA typed and compared to 31 previously typed isolates. Five isolates obtained over a period of 12 months from one aspergilloma patient were of four DNA types. Two isolates from another patient with aspergilloma were identical. One isolate each from five other aspergilloma patients showed five DNA types. Two DNA types, each shared by two aspergilloma isolates, were each identical to the DNA types from invasive aspergillosis isolates, one from Germany and one from the USA.

Animals↗
PubMed1990

Itraconazole therapy for chronic coccidioidal meningitis.

STUDY OBJECTIVE: To assess the efficacy of orally administered itraconazole in the treatment of coccidioidal meningitis. DESIGN: Prospective, nonrandomized open trial. SETTING: Multicenter trial at an urban county hospital, a university referral center, and referring institutions. PATIENTS: Ten patients with culture or serologic evidence of coccidioidal meningitis refractory to standard therapy. Patients receiving other systemic antifungal therapy were excluded. INTERVENTION: Itraconazole was administered orally at doses of 300 to 400 mg/d for a median duration of 10 months. Disease activity and drug efficacy were evaluated at initiation of therapy and at the most recent follow-up using a standardized scoring system. MEASUREMENTS AND MAIN RESULTS: Eight of ten patients are evaluable. Of five patients receiving itraconazole as sole therapy, four have responded. All three patients receiving intrathecal amphotericin B have had that therapy discontinued and have no evidence of active disease in the absence of intrathecal therapy. Toxicity has been minimal; one patient had mild nausea. CONCLUSIONS: Itraconazole shows impressive activity in this series of patients with refractory coccidioidal meningitis. Itraconazole in this and other fungal meningitides should be evaluated further.

Adolescent↗
PubMed1990

In vitro activity of saperconazole (R66 905) compared with amphotericin B and itraconazole against Aspergillus species.

Twenty isolates of aspergillus were tested against saperconazole and 16 of these against itraconazole and amphotericin B using a macrodilution broth method. For 18 (90%) of 20 isolates tested against saperconazole, MICs were less than or equal to 3.1 mg/l and for 15 (75%) of 20 isolates MFCs were less than or equal to 3.1 mg/l. For 9 (56%) of 16 isolates tested against itraconazole, MICs were less than or equal to 3.1 mg/l, and for 4 (33%) of 12 isolates MFCs were less than or equal to 3.1 mg/l. For all 16 isolates tested against amphotericin B MICs and MFCs were less than or equal to 4.0 mg/l; for 11 of 16 isolates MICs were less than or equal to 2.0 mg/l. Saperconazole appears to be highly active against Aspergillus spp. in vitro, with a bimodal distribution of MICs and MFCs.

Amphotericin B↗
PubMed1990

Itraconazole therapy for nonmeningeal coccidioidomycosis: clinical and laboratory observations.

Itraconazole, a new oral triazole antifungal agent, was administered in 75 courses to patients with chronic coccidioidomycosis at dosages of 50 to 400 mg/day for a median duration of 10 months. Assessment of efficacy was made with a standardized scoring system. Responses were seen in 42 of 58 assessable courses (72%). Nonresponse occurred exclusively in patients who had failed previous therapy and was most common in pulmonary disease. Toxicity was minimal at the doses studied. Pharmacokinetic analysis of itraconazole in serum at steady state showed negligible circadian variation; differences in serum concentrations among patients were large. Clinical isolates of Coccidioides immitis showed uniform in vitro susceptibility to itraconazole. Itraconazole shows impressive activity in this series of patients with refractory coccidioidomycosis. Further evaluation of itraconazole in this and in other systemic mycoses is in order.

Adolescent↗
PubMed1990

Itraconazole in opportunistic mycoses: cryptococcosis and aspergillosis.

Striking results were obtained with oral itraconazole therapy in two opportunistic mycoses. Of 28 patients with cryptococcal meningitis, 18 achieved complete responses, including 16 of 24 patients with acquired immunodeficiency syndrome. Other manifestations of cryptococcosis were similarly responsive. In aspergillosis 12 of 15 patients responded, including 8 of 10 immunocompromised hosts. These patients included those with invasive pulmonary disease (4/5), skeletal disease (2/2), pleural disease (1/2), and pericardial, sinus, mastoid, hepatosplenic, or nail disease (1/1). These results with itraconazole compare favorably to conventional (parenteral) therapy, and toxicity was minimal. This suggests that comparative trials are now in order.

Acquired Immunodeficiency Syndrome↗