Case report. Rhinocerebral zygomycosis

A case of rhinocerebral zygomycosis treated with liposomal amphotericin B is described.     

A probable cause of paradoxical thrombosis in zygomycosis

Invasive zygomycoses (syn. mucormycoses) are rather rare but life-threatening diseases which often take a peracute course. Particularly endangered are diabetics and patients suffering from siderophilia. Zygomycosis is regularly complicated by thrombosis and subsequent necrosis. Usually it evolves from sinusitis in a rhinocerebral form. With the use of a clinical isolate (Rhizopus microsporus) and sera of the same female survivor, we investigated possible sources of the typical blood clotting. The results suggest that coagulation is probably initiated in a bimodal manner by an extracellular serine proteinase of the fungus and by elastase from the patients' leukocytes. The former causes a partial hydrolysis of fibrinogen, while the latter activates coagulation factor XIII (fibrin stabilizing factor). Both proteinases were present in the patient at the site of infection, and in vitro they jointly bring about regular clotting of fibrinogen.     

Fluconazole in the treatment of pulmonary zygomycosis

Summary. Pulmonary zygomycosis is an aggressive, often terminal infection that may be found in patients who are immunocompromised as a result of cytotoxic chemotherapy. Conventional treatment is by surgical debridement augmented with high-dose intravenous amphotericin B, but even with such treatment the course is usually fulminant with a high mortality rate. Recent work has suggested that the new antifungal triazole, fluconazole, may be of benefit in treating zygomycete infection. The case of a 15-year-old boy who developed pulmonary zygomycosis while on chemotherapy for acute lymphoblastic leukaemia, and who survived for 11 months with oral fluconazole therapy alone, is suppotive of this proposal.
Zusammenfassung. Die pulmonale Zygomykose ist eine aggressive, oftmals terminale Infektion, die bei Patienten auftritt, die mit Chemotherapeutika behandelt werden und somit immunsupprimiert sind. Die herkömmliche Therapie schließt das chirurgische Debridement, verbunden mit hochdosierter intravenöser Gabe von Amphotericin, ein. Doch selbst mit dieser Therapie ist der klinische Verlauf fulminant und mit einer hohen Mortalität verknüpft. Das neue anti-mykotische Triazol Fluconazol wird seit einiger Zeit zur Behandlung von Infekdonen mit Zygomyzeten empfohlen.
Hier wird der Fall eines 15 Jahre alten Jungen beschrieben, der während einer Chemotherapie für akute lymphoblastische Leukämie eine pulmonale Zygomykose entwickelte und elf Monate überlebte, obwohl er lediglich mit oral verabreichtem Fluconazol behandelt wurde.     

Cerebral zygomycosis

Fifty-six patients with cerebral zygomycosis (mucormycosis) were seen during the period 1971-2001 in two tertiary care hospitals located in south India with tropical climate and catering to neurological diseases. Forty-four patients had rhinocerebral and twelve patients had isolated central nervous system (CNS) zygomycosis. Of these, ten were culture proven (Rhizopus oryzae in eight and Mucor in two); 30 were diagnosed as probable and 16 were diagnosed possible; mixed infections were seen in three patients. Diabetes mellitus was the predisposing condition in a majority (31/44) of patients with the rhinocerebral form of zygomycosis. The tissue obtained at biopsy/autopsy in either form showed necrotic/infarcted tissue with neutrophilic infiltration with broad non-septate hyphae showing irregular branching. The outcome was poor despite surgical excision and antifungal therapy. The high concentration of spores in a mouldy environment, the bird population and improper disposal of hospital waste may facilitate healthy hosts presenting with primary CNS disease.     

Estimation of renal function and its potential impact on carboplatin dosing in children with cancer

Renal function-based carboplatin dosing is used routinely in paediatric oncology clinical practice. It is important that accurate assessments of renal function are carried out consistently across clinical centres, a view supported by recently published British Nuclear Medicine Society (BNMS) guidelines for measuring glomerular filtration rate (GFR). These guidelines recommend the use of a radioisotope method for GFR determination, with between two and five blood samples taken starting 2 h after radioisotope injection and application of the Brochner-Mortensen (BM) correction factor. To study the likely impact of these guidelines, we have investigated current practices of measuring GFR in all 21 Children's Cancer and Leukaemia Group (CCLG) paediatric oncology centres in the United Kingdom. This information was used to evaluate the potential impact on renal function-based carboplatin dosing using raw 51Cr-EDTA clearance data from 337 GFR tests carried out in children with cancer. A questionnaire survey revealed that between two and four samples were taken after isotope administration, with BM and Chantler corrections used in 38% (8/21) and 28% (6/21) of centres, respectively. A change from Chantler to BM correction, based on the BNMS guidelines, would result in a > 10% decrease in carboplatin dose in at least 15% of patients and a > 25% decrease in 2% of patients. A greater proportion of patients would have an alteration in carboplatin dose when centres not using any correction factor implement the BM correction. The increase in estimated 51Cr-EDTA half-life observed by omitting the I h sample decreases carboplatin dose by > 10% in 23-52% of patients and by > 25% in 3% of patients. This study highlights current variations in renal function measurement between clinical centres and the potential impact on carboplatin dosing. A standard methodology for estimating GFR should be followed to achieve uniform dosing in children with cancer.     

Paediatric radiotherapy in Australia and New Zealand: An anachronism in 2003?

This report reviews the activities of the Paediatric Special Interest Group of the Royal Australian and New Zealand College of Radiologists in terms of its involvement with the Australian and New Zealand Children's Cancer Study Group and its research and educational activities. Examples of when and how radiotherapy is currently used in the management of paediatric malignancies are provided. Some thoughts for the future of both paediatric radiotherapy and our subspecialty are also presented.     

Cutaneous zygomycosis in immunocompetent patients in Mexico

Summary We report three cases of traumatic cutaneous zygomycosis related to soil‐contaminated skin lesions occurring after automobile accidents in individuals with no underlying disorders, which showed delayed development and diagnosis in comparison with typical zygomycosis cutaneous lesions.     

Adaptive dosing and platinum-DNA adduct formation in children receiving high-dose carboplatin for the treatment of solid tumours

A pharmacokinetic-pharmacodynamic study was carried out to investigate the feasibility and potential importance of therapeutic monitoring following high-dose carboplatin treatment in children. High-dose carboplatin was administered over 3 or 5 days, with the initial dose based on renal function, to achieve target area under the plasma concentration-time curve (AUC) values of 21 or 20 mg ml(-1).min, respectively. Dose adjustment was carried out based on observed individual daily AUC values, to obtain the defined target exposures. Platinum-DNA adduct levels were determined in peripheral blood leucocytes and toxicity data were obtained. Twenty-eight children were studied. Based on observed AUC values, carboplatin dose adjustment was performed in 75% (21 out of 28) patients. Therapeutic monitoring resulted in the achievement of carboplatin exposures within 80-126% of target AUC values, as compared to estimated exposures of 65-213% of target values without dose adjustment. The carboplatin AUC predicted with no dose modification was positively correlated with pretreatment glomerular filtration rate (GFR) values. Higher GFR values were observed in those patients who would have experienced AUC values >25% above the target AUC than those patients attaining AUC values >25% below the target AUC, following renal function-based dosing. Platinum-DNA adduct levels correlated with observed AUC values on day 1 of carboplatin and increased over a 5-day course of treatment. Real-time monitoring of carboplatin pharmacokinetics with adaptive dosing is both feasible and necessary for the attainment of consistent AUC values in children receiving high-dose carboplatin treatment. Pharmacodynamic data suggest a strong correlation between carboplatin pharmacokinetics and the drug-target interaction.     

Successful multimodal therapy of invasive pulmonary and central nervous system aspergillosis in a neutropenic surgical patient: case report and review of the literature

Invasive aspergillosis predominantly occurs in patients with impaired host defence and is often resistant to different therapeutically strategies. However, mortality significantly increases if the central nervous system is affected. In this report, we describe a case of successful treatment of invasive aspergillosis with cerebral involvement. The treatment consists of a medication of voriconazole and lipid-associated amphotericin B as well as a stereotactic neurosurgical procedure to drain an intracranial abscess.     

Candidosis, aspergillosis and zygomycosis in an oncology department

The incidence, aetiology and treatment of fungal infections in a 60-bed department of clinical oncology over 2 years is reported. During the second year, after the moving of the department from an old to a new building with an improved epidemiologic regimen, the incidence decreased rapidly, although the mortality due to systemic disseminated mycosis did not change.     

Improved outcome of zygomycosis in patients with hematological diseases?

Zygomycosis is an opportunistic fungal infection that is increasingly reported in hematological patients. We describe 2 cases of successfully treated rhino-cerebral zygomycosis and give an overview of 120 patients from the literature with underlying hematological or oncological disorders. These data document the improved survival in sinus (15/17 patients surviving) and cutaneous (6/9 patients surviving) disease. Hematological patients with pulmonary (9/30 patients surviving) or disseminated (4/38 patients surviving) zygomycosis still have a poor prognosis. The clinical course of sinus-orbital involvement (4/11 patients surviving) follows sinus-cerebral (2/3 patients surviving) or cerebral (3/6 patients surviving) disease. Besides deoxycholate amphotericin B (AmB) (24/62 patients surviving), patients seem to benefit from liposomal amphotericin B (L-AmB) (10/16 patients surviving) or sequential AmB/L-AmB treatment (6/8 patients surviving). Alternative treatment options lead only in a few patients to success.     

Primary zygomycosis of the pericardium in an immunocompetent host

The fungi in the order Mucorales commonly target immunocompromised hosts, especially diabetics and produce fulminating respiratory and/or central nervous system infections, which are often fatal. We report primary zygomycotic pericarditis accompanied by osteomyelitis of the sternum in an immunocompetent female: a rare site and a rare setting. The disease was clinically thought to be of tuberculous aetiology and had evaded diagnosis for a year.     

Rhinocerebral zygomycosis in a patient with acute lymphoblastic leukemia

We report a case of a 28-year-old man with acute lymphoblastic leukemia whodeveloped rhinocerebral zygomycosis during induction chemotherapy. Thislife-threatening fungal infection is an infrequent cause of neutropenic fever,and is occasionally found in patients with leukemia and lymphoma, or patientswith severely compromised defence mechanisms due to other diseases. Itis caused by moulds belonging to theMucoraceaefamily, and ischaracterized by local destruction of the affected organ. In our patient, theinfection spread from the paranasal sinuses to the right orbit, destroyedintraorbital structures and resulted in blindness within days. Biopsy from theright maxillary sinus was performed and mucormycosis was suspected throughmicroscopic examination. Culture of the resected specimen identifiedRhizopus arrhizusas the causing agent.Treatment of zygomycosis should consist of radical surgical debridement ofthe infected tissue, together with intensive broad-spectrum antimycotictherapy with amphotericin B. What could be learned from this case is, thataggressive approaches to identify the cause of infection is necessary, andthat aggressive treatment strategies are inevitable to overcome the infection.Furthermore, treatment of the underlying disease should be continued as soonas possible.     

Monitoring plasma voriconazole levels may be necessary to avoid subtherapeutic levels in hematopoietic stem cell transplant recipients

BACKGROUND: Low voriconazole levels have been associated with a higher failure rate in patients with confirmed fungal infections. METHODS: Steady-state plasma trough voriconazole levels were measured after at least 5 days of therapy in 87 patients with hematologic malignancies on 201 separate occasions (1-5 levels per patient; median, 2). Most patients (90%) had undergone allogeneic hematopoietic stem cell transplantation. The daily voriconazole dose, administered in 2 divided doses, was 200 mg (n = 4), 400 mg (n = 151), 500 mg (n = 20), 600 mg (n = 18), and 800 mg (n = 8); corresponding to 2.0-16.3 (median, 5.4) mg/kg. Plasma voriconazole levels were 0-12.5 microg/mL (median, 1.2). Voriconazole was undetectable (<0.2 mug/mL) in 15%. RESULTS: The correlation between dose and levels was weak (r = 0.14; P = .045). The median absolute daily drug dose (400 mg) was identical in groups of patients with levels of 0, 0.2 to 0.5, >0.5 to 2.0, >2.0 to 5.0, and >5.0. Whereas the daily drug dose in mg/kg was significantly higher when the levels were >5.0 microg/mL, there was no consistent relation between dose and level below that threshold. In adult patients getting standard doses of voriconazole orally, the drug levels are highly variable. Based on limited available data, between a quarter and two-thirds of these levels could potentially be associated with a lower likelihood of response or a higher likelihood of failure. CONCLUSIONS: Future voriconazole studies should incorporate prospective therapeutic drug monitoring and consideration should be given to checking levels in patients receiving the drug for confirmed, life-threatening fungal infections.     

A rescue therapy with a combination of caspofungin and liposomal amphotericin B or voriconazole in children with haematological malignancy and refractory invasive fungal infections

Combination treatment of paediatric invasive fungal infections (IFIs) has rarely been reported. A total of 17 children with 19 IFI episodes were enrolled in the study. The median age of the patients was 5.3 (range 0.5–17) years. IFI was classified as proven in 4, probable in 12 and possible in 3 episodes. These patients received empiric antifungal treatment, which consisted of liposomal amphotericin B (LAmB) monotherapy for a median duration of 12 days (range 3–69 days). All patients were refractory to LAmB; therefore, caspofungin was added to the therapy in 11 patients. In the remaining six patients, LAmB was ceased and a combination of caspofungin and voriconazole was started. Among the patients who received caspofungin + LAmB, four did not show favourable response and the combination was switched to caspofungin + voriconazole. The median (range) and total duration of the therapy were 7 (3–14) days and 91 patient days for LAmB + caspofungin combination and 49 (7–126) days and 516 patient days for caspofungin + voriconazole combination. We found a favourable response rate of 68.4% in 16 proven or probable IFI episodes. Twelve‐week survival rate of these patients was 75%. No serious side effect was observed among the patients. Our data suggest that combination antifungal therapy is safe and effective in children with haematological malignancies.     

Rhinocerebral zygomycosis caused by Saksenae vasiformis in a diabetic patient

We report a rare case of invasive rhinocerebral Saksenae vasiformis infection in a 71-year-old man with type 2 diabetes mellitus ketoacidosis. Combined histological and microbiological examination of two biopsy specimens taken at four days' intervals showed broad non-septate hyphae on direct smears of biopsies and necrosis and angioinvasion by hyphae were seen in the tissue. S. vasiformis was cultured from both biopsies. The patient had a fatal outcome even though partial debridement, liposomal amphotericin B treatment and control of diabetes were instituted. Permission for necropsy was denied. Clinical, epidemiological and pathological features of the case and manifestations of S. vasiformis infections are discussed. Most cases involve cutaneous sites and only two cases of rhinocerebral infections (both with fatal outcome) have been described. The present case is the third documented case of involvement of the sinuses and the second case of S. vasiformis infection documented in Europe.     

Changes in Candida albicans colonization and morphology under influence of voriconazole

The aim was the investigation of fungal colonization and morphological alterations under the influence of voriconazole in an in vitro system. Voriconazole stopped growth and colonization of Candida albicans (wild type SC5314) on cover slips in microtiter plates dependent on drug concentration, the time of Candida growth before the input of voriconazole and oxygen concentration. The direct microscopy by fluorescence staining with the optical brightener Blancophor showed short bizarrely deformed mycelia looking swollen. The colonization on cover glass was diminished. Microcolonies or starting of biofilm formation as in the control was not observed. The metabolic activity was demonstrated by vital staining with FUN 1 resulting in red fluorescent structures in the yeast forms and mycelia in the controls. Under voriconazole influence the remaining cells only showed a green or pale yellow fluorescence. Most of the cells lost their metabolic activity.