Cutaneous childhood sarcoidosis--a rare disease refractory to treatment.
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Adolescent↗
Biomedical subjects
D W Denning
Publications and source records attributed to D W Denning.
Infrared body temperature measurement of mice as an early predictor of death in experimental fungal infections.
Temperatures of mice were measured using an infrared high performance non-contact thermometer, after the device had been calibrated using implantable microchips containing temperature transponders. Mice were infected with three species of Candida (isolates) and the resultant disseminated infections monitored. Mouse temperatures could be reliably measured using the infrared device and this measurement caused little distress to the mice. We were further able to demonstrate that mice rarely recovered if their body temperature dropped below 33.3 degrees C (sensitivity 68%, specificity 97%). Adoption of a 33.3 degrees C endpoint in fungal sepsis experiments measured by infrared non-contact thermometer would significantly reduce the suffering in the terminal stages of this type of infection model.
Animals↗
Invasive infection due to penicillium species other than P. marneffei.
Infection caused by Penicillium spp. due to species other than P. marneffei is rare. We present three such cases of invasive disease. The first had chronic granulomatous disorder (CGD) with pulmonary infection caused by Penicillium spp. and he responded to amphotericin B therapy. Cases two and three were not known to be immunocompromised and both failed to respond to therapy. Case two had cerebral disease from an unknown source caused by P. chrysogenum. Case three probably acquired infection caused by P. decumbens peri-operatively and presented with paravertebral infection. The pertinent literature on invasive infections of Penicillium spp. other than P. marneffei is reviewed. From 1951 onwards, 31 reported cases of invasive disease included 12 cases of pulmonary infection (six in non-immunocompromised patients), four cases of prosthetic valve endocarditis, six cases of CAPD peritonitis, five cases of endophthalmitis, individual cases of fungemia and oesophagitis (both in AIDS), upper urinary tract infection and intracranial infection. Trauma, surgery or prosthetic material is commonly implicated in the non-pulmonary cases. Superficial infection (keratitis and otomycosis) is commonly caused by Penicillium spp. Allergic pulmonary disease, often occupational (such as various cheeseworkers' diseases), is also common. Optimal therapy for invasive infection is not established, but surgery may be advisable if possible. Amphotericin B may be the most effective antifungal drug.
AIDS-Related Opportunistic Infections↗
In vitro interaction of terbinafine with itraconazole, fluconazole, amphotericin B and 5-flucytosine against Aspergillus spp.
We investigated the in vitro interaction of terbinafine with itraconazole, fluconazole, amphotericin B and 5-flucytosine, against Aspergillus spp. We tested three isolates of Aspergillus fumigatus (one resistant to itraconazole), and two each of Aspergillus flavus, Aspergillus niger and Aspergillus terreus. We employed a broth microdilution-based method derived from an in vivo validated method capable of detecting itraconazole resistance in A. fumigatus. We studied the effect on the MICs by calculation of the fractional inhibitory concentration (FIC) and fractional fungicidal concentration (FFC) (99.99% kill). Itraconazole and terbinafine were synergic or additive in all strains (FIC = 0.15-1.0). Fluconazole and terbinafine were synergic with A. fumigatus, A. terreus and A. flavus (FIC = 0.3-0.5) and indifferent with A. niger (FIC = 2) isolates. Amphotericin B and terbinafine were mostly indifferent or antagonistic (FIC = 1.0-4.02). Flucytosine and terbinafine were usually indifferent or antagonistic (FIC = 0.63-8.5). FFCs were generally in accord with FICs. The use of terbinafine in combination therapy for Aspergillus infections with azoles seems promising, whereas terbinafine and amphotericin B or flucytosine in combination were less effective.
Amphotericin B↗
Azole cross-resistance in Aspergillus fumigatus.
We susceptibility tested 17 clinical isolates of Aspergillus fumigatus, for most of which MICs of itraconazole were elevated (MIC at which 50% of the isolates tested are inhibited, 16 microg/ml), against itraconazole, posaconazole, ravuconazole, and voriconazole. Posaconazole was the most active against itraconazole-susceptible isolates. A complex pattern of cross-resistance and hypersusceptibility was seen with voriconazole and ravuconazole, suggesting marked differences in activity and mechanisms of resistance.
Antifungal Agents↗
Defining opportunistic invasive fungal infections in immunocompromised patients with cancer and hematopoietic stem cell transplants: an international consensus.
During the past several decades, there has been a steady increase in the frequency of opportunistic invasive fungal infections (IFIs) in immunocompromised patients. However, there is substantial controversy concerning optimal diagnostic criteria for these IFIs. Therefore, members of the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group formed a consensus committee to develop standard definitions for IFIs for clinical research. On the basis of a review of literature and an international consensus, a set of research-oriented definitions for the IFIs most often seen and studied in immunocompromised patients with cancer is proposed. Three levels of probability are proposed: "proven," "probable," and "possible." The definitions are intended for use in the context of clinical and/or epidemiological research, not for clinical decision making.
Aspergillosis↗
Mannose-binding lectin gene polymorphisms as a susceptibility factor for chronic necrotizing pulmonary aspergillosis.
It was investigated whether a deficiency of mannose-binding lectin (MBL), which binds Aspergillus species avidly in vitro, could account for chronic necrotizing pulmonary aspergillosis (CNPA), which is seen most commonly in nonimmunocompromised patients. Blood samples were obtained from 11 patients (10 white) with CNPA and were compared with blood samples from 82 white control subjects. MBL haplotype profiles were determined by polymerase chain reaction, using sequence-specific primers and sequence-specific oligonucleotide probing techniques. Seven of the 10 white patients with CNPA had MBL haplotypes that encode for low levels of the protein, compared with 25.6% of the white control subjects (P=.004). Presence of the codon 52 mutation was particularly common in patients with CNPA (P=.015), which suggests a greater involvement of this mutation.
Alleles↗
A phase III study of recombinant human interferon gamma to prevent opportunistic infections in advanced HIV disease.
The efficacy and safety of recombinant human interferon gamma (rIFN-gamma) in the reduction of opportunistic disease in patients with advanced HIV-1 infection are assessed. A 12-month double-blind, placebo-controlled, multicenter, Phase III trial of rIFN-gamma in HIV-positive patients with CD4 < 100 x 10(9)/liter on stable antiretroviral therapy. Eighty-four patients were allocated treatment on a 1:1 basis to rIFN-gamma or placebo. Patients received rIFN-gamma 0.05 mg/m(2) or 0.9% saline subcutaneously three times weekly for 48 weeks (optional extension to 18 months). The primary end point was the incidence of opportunist infections (CDC categories B/C). Secondary end points included mortality, immunological, and virological parameters. Patients on placebo had a mean of 3.45 opportunist infections (OIs) in the first 48 weeks. Patients treated with rIFN-gamma had a mean of 1.71 OIs (p = 0.04). However, the model showed overdispersion and the inclusion of a dispersion factor raised the p value to 0.13. rIFN-gamma appeared to have a particular effect on the incidence of Candida, herpes simplex, and cytomegalovirus infections. Three-year survival in the rIFN-gamma arm was 28% compared to 18% in the placebo group (not significant). rIFN-gamma-associated side-effects of headache, fatigue, rigors, influenza-like symptoms, depression, myalgia, and granulocytopenia were reversible. There was no evidence for HIV activation. Although not significant, the trend towards decreased opportunistic infections and increased survival warrants consideration of further trials of rIFN-gamma. The study gives additional information on the safety profile of this cytokine.
AIDS-Related Opportunistic Infections↗
Need for alternative trial designs and evaluation strategies for therapeutic studies of invasive mycoses.
Studies of invasive fungal infections have been and remain difficult to implement. Randomized clinical trials of fungal infections are especially slow and expensive to perform because it is difficult to identify eligible patients in a timely fashion, to prove the presence of the fungal infection in an unequivocal fashion, and to evaluate outcome in a convincing fashion. Because of these challenges, licensing decisions for antifungal agents have to date depended heavily on historical control comparisons and secondary advantages of the new agent. Although the availability of newer and potentially more effective agents makes these approaches less desirable, the fundamental difficulties of trials of invasive fungal infections have not changed. Therefore, there is a need for alternative trial designs and evaluation strategies for therapeutic studies of invasive mycoses, and this article summarizes the possible strategies in this area.
Antifungal Agents↗
Increasing volume and changing characteristics of invasive pulmonary aspergillosis on sequential thoracic computed tomography scans in patients with neutropenia.
PURPOSE: In patients with neutropenia, thoracic computed tomography (CT) halo and air-crescent signs are recognized as major indicators of invasive pulmonary aspergillosis (IPA). Nevertheless, the exact timing of CT images is not well known. PATIENTS AND METHODS: Seventy-one thoracic CT scans were analyzed in 25 patients with neutropenia with surgically proven IPA. RESULTS: On the first day of IPA diagnosis with early CT scan (d0), a typical CT halo sign was observed in 24 of 25 patients. At that time, the median number of thoracic lesions was two (range, one to six), and pulmonary involvement was bilateral in 12 cases. The halo sign was present in 68%, 22%, and 19% of cases on d3, d7, and d14, respectively. Similarly, the air-crescent sign was seen in 8%, 28%, and 63% of cases on the same days. Otherwise, a nonspecific air-space consolidation aspect was seen in 31%, 50%, and 18% of cases on the same days. The analysis of calculated aspergillary volumes on CT showed that, despite antifungal treatment, the median volume of lesions increased four-fold from d0 to d7, whereas it remained stable from d7 to d14. Overall, 21 patients (84%) were cured by the medical-surgical approach. CONCLUSION: In patients with neutropenia, CT halo sign is a highly effective modality for IPA diagnosis. The duration of the halo sign is short, and it demonstrates the value of early CT. The increase of the aspergillosis size on CT in the first days after IPA diagnosis is not correlated with a pejorative immediate outcome when using a combined medical-surgical approach.
Adolescent↗
Muco-cutaneous retinoid-effects and facial erythema related to the novel triazole antifungal agent voriconazole.
Voriconazole is a new azole antifungal drug with activity against a wide range of systemic fungal pathogens, including Aspergillus spp. Five patients with chronic invasive aspergillosis were treated for 12-58 weeks with voriconazole, 200 mg twice daily and developed facial erythema and cheilitis. One who received 58 weeks of therapy also developed discoid lupus erythematosus-like lesions on both sides of her neck. Both erythema and cheilitis resolved after discontinuation of voriconazole. Serum retinoids were elevated in the three patients in whom they were measured. Voriconazole has the potential for retinoid-like side-effects and facial erythema.
Adult↗
Fungal infection of the diabetic foot: two distinct syndromes.
AIMS: Fungal infection of diabetic foot ulcers has not been described. We analysed the features of 17 patients with diabetic foot ulcers probably infected with fungi. METHODS: Seventeen patients were identified with clinically infected foot ulcers, (i) which had failed to heal despite prolonged antibiotic therapy and intensive podiatric care, (ii) from which Candida spp. was isolated or hyphae +/- yeasts were visualized in material from ulcers or surrounding skin. RESULTS: Multiple ulcers arising simultaneously were present in 10 patients (59%), preceded by blistering in seven cases. Single ulcers with markedly ulcerated margins were present in seven (41%) patients and were preceded by blisters in two. All 17 cases had neuropathy and 15 (88%) had severe peripheral vascular disease. All ulcers responded to antifungal therapy. CONCLUSIONS: Candida spp. is associated with two distinctive patterns of protracted ulceration in diabetic feet which improve following systemic antifungal therapy. Diabet. Med. 18, 567-572 (2001)
Adult↗
In vitro activity of a new echinocandin, LY303366, and comparison with fluconazole, flucytosine and amphotericin B against Candida species.
OBJECTIVE: To investigate the in vitro activity of LY303366 (LY) against Candida isolates comprising nine different species and comparison with fluconazole (FLU), flucytosine (5FC) and amphotericin B (AMB). METHODS: The method used was a microtitre modification of the NCCLS M27-A accepted standard using either RPMI-1640 with 2% glucose (5FC and FLU) or antibiotic medium 3 with 2% glucose (LY and AMB). The minimum inhibitory concentration (MIC) was the lowest drug concentration that reduced growth by 80% compared with the drug-free control. Minimum fungicidal concentrations (MFCs; 99% kill) were also determined for all isolates for LY and AMB. RESULTS: Overall, 58 of 105 (55.2%) isolates were resistant to FLU (MIC < or = 16 mg/L). There was no relationship between FLU and LY MICs for C. albicans or non-albicans species. For all isolates, geometric mean (GM) MIC values and ranges (in mg/L) were: LY 0.011 and < or = 0.001-16, FLU 8.72 and < or = 0.125- > 128, 5FC 0.393 and < or = 0.03- > 32, AMB 0.046 and 0.008-0.125. Differences in susceptibility to LY were seen: C. parapsilosis (n = 12, GM 0.4 and range 0.125-16) and C. guilliermondii (n = 8, GM 0.46 and range 0.25-1) were both found to be significantly less susceptible to LY than all other species (P < or = 0.05). For all isolates, geometric mean MFC values and ranges (in mg/L) were: LY 0.032 and 0.002-16, AMB 0.143 and 0.03-2. The MFC value was the same as or only one drug dilution higher than the MIC value for 69.5% and 48.6% of isolates tested for LY and AMB, respectively. Tolerance was described in 13.3% and 5.7% of isolates for LY and AMB, respectively. A reproducibility study performed on 20% of the isolates showed that 90.5%, 100%, 95.2% and 100% of isolates retested were the same or within one well of the original MIC value for LY, FLU, 5FC and AMB, respectively. CONCLUSIONS: LY303366 shows promising antifungal activity in vitro and warrants further in vivo investigation.
Amphotericin B↗
Treatment of Absidia corymbifera infection in mice with amphotericin B and itraconazole.
The activities of amphotericin B and itraconazole were studied in a temporarily neutropenic murine model of disseminated Absidia corymbifera infection, caused by two different strains. Amphotericin B MICs were 0.25 mg/L for both strains and itraconazole MICs were 1 and 2 mg/L. Amphotericin B was effective in vivo with both isolates. Itraconazole was less effective.
Absidia↗
Termination of development of D0870.
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Animals↗
Advances in invasive fungal infection and antifungal therapy: Introduction.
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Antifungal Agents↗
Chronic forms of pulmonary aspergillosis.
Aspergillus is a genus of fungi commonly found in all environments. Remarkably, only a few species cause disease and equally remarkably, those same species cause multiple diseases. In the lung, exposure to the fungus, the immunological status of the individual and the condition of the lung determine the pattern of disease. In asthmatic patients and those with cystic fibrosis, allergic bronchopulmonary aspergillosis (ABPA) is a complication that reduces pulmonary function and, in asthmatics, is substantially improved by itraconazole therapy. Patients with pre-existing lung cavities develop aspergillomas (fungal masses inside the cavity). Aspergillomas carry a 40% 5 years survival, and it not clear whether antifungal therapy is helpful. Similar in presentation to aspergilloma is chronic necrotizing pulmonary aspergillosis (CNPA). Development of new or expansion of existing pulmonary cavities with surrounding paracavitary shadowing is the hallmark of CNPA These two entities are probably a continuum of the same pathological process. Patients with CNPA respond to systemic antifungal therapy, but this may need to be lifelong. Surgery is appropriate for isolated aspergillomas, but not pleural or multicavity lesions. Aspergillus empyema is a complication of aspergilloma and CNPA, or surgery for these diseases and is slow to respond to treatment.
Antifungal Agents↗
Susceptibility testing of Aspergillus flavus: inoculum dependence with itraconazole and lack of correlation between susceptibility to amphotericin B in vitro and outcome in vivo.
We have attempted to validate in Aspergillus flavus the main in vitro methodologies that have been used to detect resistance in Aspergillus fumigatus. We developed a murine model with two A. flavus isolates, one that was apparently resistant in vitro to amphotericin B (AFL5) and another that was resistant to itraconazole (AFL8). No correlation was found for amphotericin B in AFL5, since the in vivo response was compatible with a susceptible isolate. Modification of the in vitro susceptibility test methodology for amphotericin B was unsuccessful. Although AFL8 was apparently resistant to itraconazole in vitro, it was found to be susceptible in vivo. Additional in vitro work has detected weaknesses in the in vitro susceptibility methodology validated for A. fumigatus when applied to A. flavus. The principal problems are that changes in the inoculum have a large effect on the MICs of itraconazole for some A. flavus strains and that a trailing end point and spore sediment often appear when an inoculum with a higher colony count is used. We propose a modified method using a final inoculum of 2.5 x 10(4) CFU per ml of RPMI 1640 medium with 2% glucose buffered to pH 7.0 in a microtiter format, incubated for 48 h with no growth end point. Validation of this methodology requires one or more itraconazole-resistant A. flavus isolates, which have yet to be identified.
Amphotericin B↗