Experimentelle renale Infektionen der Maus mit Aspergillus fumigatus: Ein chemotherapeutisches Modell einer Organmykose: Experimental Renal Infection with Aspergillus fumigatus in Mice: A Chemotherapeutic Model of an Organic Mycosis

Zusammenfassung: Zur Prüfung von Antimykotika auf ihre Wirkung bei Infektionen von Mänsen mit Aspergillus fumigatus warden 10³ Sporen in eine Niere pro Tier inokuliert. Nach einer zweitägigen Behandlungsperiode erfolgte am dritten Versuchstag die Bestimmung der Keimdichte in den infizierten Nieren. Als Kriterium der Wirksamkeit diente die Reduktion an CFU im Vergleich zu unbehandelten Kontrollen.
In diesem Modell erwies sich Amphotericin B, BAY N 7133 sowie Itraconazol wirksam, 5-Fluorcytosm, Miconazol and Ketoconazol hatten in den untersuchten Dosierungen keinen Effekt.
Summary: For the evaluation of the antifungal activity of test compounds on marine aspergillosis, one kidney per animal was inoculated with 10³ spores. After a treatment period of two days the animals were killed three days p. i. to assess the fungal load in the infected kidneys. The efficacy was studied by the reduction of colony forming units in comparison with the untreated controls.
In this model amphotericin B, BAY N 7133 and itraconazole proved to be active whereas the applied doses of 5-fluorocytosine, miconazole and ketoconazole showed no activity.     

Poor efficacy of amphotericin B-based therapy in CNS aspergillosis

Recently, improved response and survival rates in patients treated with voriconazole and neurosurgery for central nervous system (CNS) aspergillosis have been reported. We assessed retrospectively the outcome in 17 patients with definite or probable CNS aspergillosis treated with amphotericin B alone (n = 15) or in combination with 5-fluorocytosine (n = 3) or itraconazole (n = 2). Four patients underwent neurosurgery. The mortality rate was 100% with a median survival of only 10 days (range: 3-60) after onset of first symptoms or first radiological evidence of CNS aspergillosis. In conclusion, treatment with amphotericin B and itraconazole has negligible efficacy in CNS aspergillosis.     

Case Report. Mycotic arteritis due to Aspergillus fumigatus in a diabetic with retrobulbar aspergillosis and mycotic meningitis

A 74-year-old man with diabetes mellitus type II, retinopathy and polyneuropathy suffered from exophthalmus, ptosis and diplopia. Magnetic resonance imaging and computer tomography showed a space-occupying process in the right orbital apex. An extranasal ethmoidectomy accompanied by an orbitotomia revealed the presence of septated hyphae. Aspergillus fumigatus was grown from the tissue. After surgical removal of the fungal masses, therapy with amphotericin B (1 mg kg(-1) body weight) plus itraconazole (Sempera, 200 mg per day) over 6 weeks was initiated. Five months later the patient's condition deteriorated again, with vomiting, nausea and pain behind the right eye plus increasing exophthalmus. Antifungal therapy was started again with amphotericin B and 5-fluorocytosine. Neutropenia did not occur. The patient became somnolent and deteriorated, a meningitis was suggested. Aspergillus antigen (titre 1:2, Pastorex) was detected in liquor. Anti-Aspergillus antibodies were not detectable. Both the right eye and retrobulbar fungal masses were eradicated by means of an exenteratio bulbi et orbitae. However, renal insufficiency and an apallic syndrome developed and the patient died. At autopsy, a mycotic aneurysm of the arteria carotis interna dextra was detected. The mycotic vasculitis of this aneurysm had caused a rupture of the blood vessel followed by a massive subarachnoidal haemorrhage. In addition, severe mycotic sphenoidal sinusitis and aspergillosis of the right orbit were seen, which had led to a bifrontal meningitis.     

Intracellular killing of Candida albicans by human neutrophils is potentiated by exposure to combinations of amphotericin B and 5-fluorocytosine

Combination treatment with amphotericin B and 5-fluorocytosine is synergistic and has become clinically useful in the treatment of various forms of systemic candidosis. The synergy between these two compounds may be explained in part by their combined effect on the interaction between fungal cells and host phagocytes. Pretreatment of Candida albicans for 2 h with either amphotericin B or 5-fluorocytosine or the two agents in combination did not inhibit or enhance phagocytosis by glass-adherent human neutrophils (P greater than 0.05). Intracellular killing of pretreated yeast cells was not influenced by antifungals alone (P greater than 0.05), but pretreatment of C. albicans with 5.0 mg l-1 amphotericin B + 10 l-1 5-fluorocytosine or 5.0 mg l-1 amphotericin B + 50 mg l-1 5-fluorocytosine significantly enhanced the ability of neutrophils to kill the number of viable yeast cells intracellularly (P less than 0.001).     

In vitro interactions between amphotericin B and other antifungal agents and rifampin against Fusarium spp.

Fusarium species are common hyaline soil saprophytes and plant pathogens that are opportunistic fungal pathogens of immunocompromised patients. The treatment for fusariosis remains uncertain with an unfavourable prognosis; new possibilities for treatment, such as various synergistic drug interactions, must be uncovered. In this study, we evaluated the in vitro interactions of amphotericin B with caspofungin, ketoconazole, 5‐flucytosine, itraconazole, miconazole, rifampin, fluconazole, terbinafine and voriconazole against isolates of Fusarium spp. using the chequerboard method with interactions evaluated by fractional inhibitory concentration indices. The highest percentages of synergistic interactions were observed for the combinations of amphotericin B and caspofungin (68.7%), amphotericin B and rifampin (68.7%), amphotericin B plus 5‐flucytosine (59.3%) and amphotericin B with voriconazole (37.5%). The pattern of susceptibility to antifungal agents among Fusarium species and their consequence on the effects of drug combinations are also discussed.     

Pulmonary Aspergillosis with Possible Cerebral Involvement in a Previously Healthy Pregnant Woman

Abstract

Invasive aspergillosis is observed mainly in immunodepressed patients. Here we report a case of pulmonary aspergillosis with CNS involvement in a pregnant woman without other known causes of immunodeficiency.

Case report: A 23-years old pregnant woman underwent a caesarean because of unexplained seizures. During the subsequent days worsening headache and a dete-riorating neurological status were reported suggesting meningitis. Stiffness, right sided hemiparesis and cranial nerve palsies were observed at admission. Radiological findings revealed lesions involving the right pulmonary apex, the right cerebellar hemisphere and the Pterygopalatina fossa. Microbiological studies revealed large colonies of Aspergillus fumigatus. A favorable outcome was observed after administration of liposomal amphotericin B and 5-fluorocytosine and, at improved conditions, when oral uptake of itraconazole was given.

The authors conclude that risk of infections sustained by fungal opportunistic agents during pregnancy must be considered. Sequential antifungal administration may be an efficient therapy able to shorten hospitalization.     

Successful treatment of cerebral aspergillosis by stereotactic operation and antifungal therapy

Summary. The following is a case report of a cerebral Aspergillus abscess in a male patient predisposed to this disease on account of many years of alcohol abuse. After timely identification of the pathogenic organism, the patient was cured by stereotactic operation in conjunction with antifungal therapy using amphotericin B and 5-fluorocytosine. The origin and the starting point of the infection remain obscure.
Zusammenfassung. Im folgenden wird ein Fall eines zerebralen Aspergillus -Abszesses bei einem durch langjährigen Alkoholabusus prädisponierten Patienten beschrieben. Er konnte durch stereotaktische Operation und antimykotische Therapie mit Amphotericin B und 5-Fluorcytosin nach rechtzeitigem Erregernachweis geheilt werden. Ursprung und Beginn der Infektion blieben unklar.     

In- Vitro Comparative Activity of Fluconazole and Other Antifungal Agents Against Blastoschizomyces capitatus

Summary

Blastoschizomyces caphatus represents an emerging fungal pathogen in acute leukemia patients. The susceptibility to amphotericin B, 5-fluorocytosine, ketoconazole and fluconazole of nine clinical isolates was evaluated. A specific medium (high resolution medium) was used for testing fluconazole. This agent and 5-fluorocytosine were at least four- to eightfold more active than amphotericin B and ketoconazole against all isolates but one.     

Sino-Orbital and Cerebral Aspergillosis: Cure with Medical Therapy/Sino-Orbital- und Zerebralaspergillose: Ausheilung durch medikamentöse Therapie

Summary: A patient with sino-orbital and cerebral aspergillosis was successfully treated medically without surgical debridement. Anti-fungal agents, including amphotericin B and flucytosine were given over a fifteen month period with improvement in symptoms, resolution of cerebral abscesses by CT scan, and disappearance of serum precipitins to Aspergillus fumigatus. Success was attributed to the long duration of therapy (received in part as an outpatient), the use of agents to which the organism was known to be susceptible, and the maintenance of therapeutic drug levels. Although surgery is important in the management of chronic sino-orbital and cerebral aspergillosis, in patients unable to undergo extensive debridement medical therapy given for extended periods of time may be successful in eradicating the infection.
Zusammenfassung: Eine Patientin mit einer Aspergillose der Nebenhöhlen, der Orbita und des Gehirns wurde erfolgreich medikamentös ohne chirurgisches Debridement behandelt. Antimykotika einschließlich Amphotericin B und Flucytosin wurden über einen Zeitraum von 15 Monaten verabreicht und führten zu einer Besserung der Symptomatik zu einer Rückbildung der computertomographisch erfaßbaren zerebralen Abszesse und zu einem Verschwinden der Serumpräzipitine gegen Aspergillus fumigatus. Der Erfolg wird der langen Dauer der antimykotischen Chemotherapie zugeschrieben (teilweise ambulant verabreicht), ferner der Anwendung von Präparaten mit ausgetesteter Suszeptibilität des Erregers und der Erzielung und Erhaltung therapeutisch wirksamer Antimykotika-Konzentrationen. Obgleich die Chirurgie in der Behandlung der Aspergillose der Nebenhöhlen, der Orbita und des Gehirns das Vorgehen der ersten Wahl ist, kann die medikamentöse Therapie bei Patienten, an denen ein extensives chirurgisches Debridement nicht möglich ist, bei Langzeitanwendung die Infektion zum Erlöschen bringen.     

Nebulized liposomal amphotericin B and combined systemic antifungal therapy for the treatment of severe pulmonary aspergillosis after allogeneic hematopoietic stem cell transplant for a fatal mitochondrial disorder

Nebulized liposomal amphotericin B (20-15 mg twice daily by nebulizer) was combined with high dose intravenous liposomal amphotericin B (10 mg/kg/day) and high dose caspofungin (100 mg/m(2)) for the treatment of severe, recurrent pulmonary aspergillosis following allogeneic hematopoietic stem cell transplantation from alternative donor in a patient with mitochondrial disease (Pearson's syndrome). This combined treatment was administered for 8 days. Nebulized liposomal amphotericin B was well tolerated. Since severe transplant complications developed, nebulized administration was withdrawn and intravenous doses of liposomal amphotericin B and caspofungin were tapered to usual schedules. Pulmonary aspergillosis responded well to 45 days of combined intravenous antifungal therapies which were maintained for 2 years with secondary prophylaxis, because of persistent immunosuppressive treatment.     

Itraconazole treatment of pulmonary aspergillosis in leukaemia patients during a nosocomial epidemic associated with indoor building renovation

During indoor building renovation a nosocomial epidemic of pulmonary aspergillosis occurred in a haematological ward, involving 10 patients with acute leukaemia undergoing intensive chemotherapy. Antifungal treatment included the combination of amphotericin B and 5-fluorocytosine during periods of granulocytopenia, followed by itraconazole after bone-marrow recovery. In five patients, lung aspergillomas disappeared completely, while significant improvement was observed in a further two patients. Itraconazole appeared to contribute significantly to the result, but the drug did not work during granulocytopenic episodes. Air analyses showed increased counts of fungal spores in ward locations with heavy traffic of patients and staff, suggesting the need to identify and avoid risk areas when placing patients undergoing intensive chemotherapy.     

Chemotherapie der Aspergillenkrankheiten der Lunge*

Zusammenfassung: Die hinsichtlich Aspergillose-Chemotherapie relevanten antimikrobiellen, tierexperimentellen und human-pharmakologischen Eigenschaften der heute verfügbaren systemischen Antimykotica Amphotericin B, Fluorzytosin, Miconazol und Ketoconazol werden aus der Literatur und aus eigenen Untersuchungen zusammengestellt. Sodann wird eine Bewertung der publizierten Erfahrungen versucht, die mit diesen Antimykotica bei invasiven Aspergillosen des Menschen bereits vorliegen. Es handelt sich um 96 bewertbare Anwendungen einer Mono- oder Kombinationstherapie bei 89 Patienten. Die z. Z. relativ günstigste und sicherste Bewertung resultiert für Amphotericin B und für die Kombination Amphotericin B plus Fluorzytosin: je ca. 50% Erfolge bei nicht weniger als 41 bzw. 23 Anwendungen. Die Kombination Amphotericin B plus Fluorzytosin wird aus folgenden Gründen bevorzugt: additive Wirkungen gegen Aspergillen in vitro und im Tierversuch; klinisch erwiesene Vorteile bei der Chemotherapie der Cryptococcose; Möglichkeit, die Dosis des relativ toxischen Amphotericins B herabzusetzen (ein geeignetes Dosierungsschema wird angegeben). Bei schwer neutropenischen Patienten kommt als Alternative die Kombination Amphotericin B plus Rifampicin in Frage. Ob auch das bronchopulmonale Aspergillom systemisch-antimykotisch behandelt werden soll, hängt davon ab, ob eine invasive Komponente vorliegt: Sekundäres Einwachsen des Pilzes durch die Wand der aufgrund eines nicht-mykotischen Prozesses (z. B. Tuberkulose) vorbestehenden Aspergillomhöhle, oder aber teilweises Zurückbleiben des Pilzes im Lungengewebe bei Entwicklung des Aspergilloms aus einer primär invasiven, einschmelzenden Aspergillose. Besonders für die zweite Möglichkeit werden aus der neueren Literatur Beispiele angeführt. Kurz erwähnt wird auch die lokale Chemotherapie des Aspergilloms (direkte Applikation eines Antimykoticums in die Aspergillom- oder Pleurahöhle), und es werden hierfür einige Dosierungsbeispiele zitiert. Summary: Of the available systemic antimycotic drags, amphotericin B, flucytosine, miconazole and ketoconazole, the antimicrobial and pharmacological data relevant to aspergillosis chemotherapy are collected from literature and our own experiments. An attempt is made to evaluate the published experience with the chemotherapy of human, invasive aspergillosis on the basis of the case reports on 89 patients receiving 96 treatment courses with any of the systemic antimycotics, alone or in combination. The relatively best usefulness is suggested, and is documented by a fair number of observations, for amphotericin B and for the combination amphotericin B plus flucytosine (approx. 50% of successes from 41 and 23 treatment courses, respectively). The combination amphotericin B plus flucytosine is preferred for the reasons that it showed additive effects on aspergilli in vitro and in vivo, proved advantageous in the chemotherapy of cryptococcosis, and may permit a reduced dosage of the relatively toxic amphotericin B (a suitable dosage schedule is indicated). In patients with grave neutropenia, the combination amphotericin B plus rifampicin may be used as an alternative. Whether bronchopulmonary aspergilloma may also deserve systemic treatment depends on whether there is evidence of an invasive component: (i) secondary growth of the fungus through the wall of the aspergilloma cavity which was of non-mycotic (e. g., tuberculotic) origin, or (ii) viable fungi still present in the lung tissue when aspergilloma is developing from invasive, cavitating aspergillosis. Particularly the latter possibility is exemplified by recent literature. Brief mention is also made of the local chemotherapy of aspergilloma (direct administration of an antimycotic into the aspergilloma or pleural cavity), and some dosage recommendations are cited.     

Does combination of lipid formulation of amphotericin B and echinocandins improve outcome of invasive aspergillosis in hematological malignancy patients?

BACKGROUND:

In vitro and in vivo studies suggested that combination of lipid formulation of amphotericin B (L‐AMB) and echinocandins may have a synergistic or additive effect against Aspergillus. Furthermore, clinical studies suggested that this combination may improve response of invasive aspergillosis (IA).

METHODS:

Between August 1993 and June 2008, the authors identified a total of 159 patients with hematological malignancies who received salvage therapy for IA, with L‐AMB alone, echinocandins alone, or a combination of L‐AMB and echinocandins. Clinical characteristics, response to salvage therapy, and death up to 12 weeks after initiation of salvage therapy were retrospectively determined for all patients.

RESULTS:

Seventy patients received salvage therapy with L‐AMB, 18 patients received echinocandins alone (89% of whom received caspofungin), and 71 patients received the combination therapy of amphotericin B and echinocandins (90% of who received caspofungin). The 3 salvage treatment groups were comparable in regard to clinical characteristics; graft versus host disease was more frequently encountered in the echinocandin group, whereas more patients in the L‐AMB and combination groups had neutropenia and received immunotherapy. The response to salvage therapy was better in the echinocandin group (9% L‐AMB, 28% echinocandins, and 21% for combination therapy). The 3 groups had a comparable rate of Aspergillus‐related death (58%‐64%) and overall mortality (61%‐67%).

CONCLUSIONS:

The combination of L‐AMB and echinocandins offered no advantage in terms of improving response or reducing mortality over either drug alone. Hence, this combination will only add to the cost of therapy without any improvement in outcome in patients with hematological malignancies. Cancer 2010. © 2010 American Cancer Society.     

Pulmonary aspergillosis with possible cerebral involvement in a previously healthy pregnant woman

Invasive aspergillosis is observed mainly in immunodepressed patients. Here we report a case of pulmonary aspergillosis with CNS involvement in a pregnant woman without other known causes of immunodeficiency. Case report: A 23-years old pregnant woman underwent a caesarean because of unexplained seizures. During the subsequent days worsening headache and a deteriorating neurological status were reported suggesting meningitis. Stiffness, right sided hemiparesis and cranial nerve palsies were observed at admission. Radiological findings revealed lesions involving the right pulmonary apex, the right cerebellar hemisphere and the Pterygopalatina fossa. Microbiological studies revealed large colonies of Aspergillus fumigatus. A favorable outcome was observed after administration of liposomal amphotericin B and 5-fluorocytosine and, at improved conditions, when oral uptake of itraconazole was given. The authors conclude that risk of infections sustained by fungal opportunistic agents during pregnancy must be considered. Sequential antifungal administration may be an efficient therapy able to shorten hospitalization.     

Nebulised liposomal amphotericin B for Aspergillus lung diseases: case series and literature review

Over the past 10 years the incidence of Aspergillus spp. has significantly increased, and it is now the most widespread air transmission fungal pathogen in developed countries. Whatever the clinical expression of the pulmonary disease and despite recent progress in antifungal drug therapy, morbidity and mortality related to aspergillosis lung disease still constitute a serious threat for immunosuppressed or mildly immunocompromised patients. Moreover, the treatments currently used have many limitations due to adverse effects and drug interactions. Finally, subjects exposed to azoles present an increased risk of Aspergillus‐resistant strain emergence. We have reported five cases with aspergillosis lung diseases that were either difficult to control or in which patients had a contra‐indication to triazole therapy, but which showed durable improvement following the administration of nebulised liposomal amphotericin B. Our alternative strategy could be of interest for patients with aspergillosis lung disease who otherwise cannot be conventionally treated by triazoles.     

A Pilot Study of Prophylactic Aerosolized Amphotericin B In Patients at Risk for Prolonged Neutropenia

Invasive aspergillosis continues to be a significant cause of morbidity and mortality in patients with prolonged neutropenia. We performed a phase I trial of escalating doses of aerosolized amphotericin B given by a face mask nebulizer system with a disposable bacterial exhale filter. Five, 10, 15, and 20 mg of drug were disolved in sterile water and inhaled over 10 to 15 minutes twice daily. Tolerance was studied in 26 patients (18 transplant recipients, and 8 leukemia patients). No side effects were observed at any dose level. Prophylactic treatment ended for 14 patients (54%) when intravenous (IV) amphotericin B was begun empirically for antifungal coverage following fevers. Eleven patients (43%) continued inhaled amphotericin B until blood counts recovered. One patient was taken off study when she developed cardiogenic pulmonary edema. No patient developed clinically suspicious or pathologically documented infection with invasive aspergillosis. Prophylactic aerosolized amphotericin B is well tolerated at 5, 10, 15, and 20 mg twice daily dosing. In addition, prophylactic aerosolized amphotericin B does not appear to sensitize patients to the subsequent use of IV amphotericin B. Although this study suggests that prophylactic inhaled amphotericin B is well tolerated and effective, a large scale controlled trial is needed.     

Efficacy of liposomal amphotericin B for prophylaxis of acute or reactivation models of invasive pulmonary aspergillosis

The efficacy of antifungal prophylaxis for prevention of invasive aspergillosis (IA) may depend on whether IA results from recent inhalation of spores or reactivation of latent colonisation. Compare the efficacy of liposomal amphotericin B (LAmB) for prophylaxis in acute and reactivation models of IA. In the acute model, mice immunosuppressed from day 0 were challenged at day 3 with an aerosol of Aspergillus fumigatus. LAmB (15 mg kg^?1) was administered at day 0 or at challenge. In the reactivation model, naïve mice exposed to A. fumigatus remained untreated until clearance of spores from the lungs, then immunosuppressed to induce reactivation. A single LAmB dose was administered at start of immunosuppression. In the acute model, a single administration of LAmB at start of immunosuppression was not effective, but an additional administration resulted in a significant decrease in lung fungal burden (P < 0.05 vs. controls). A significant prophylactic efficacy was observed when LAmB was administered once at challenge (P < 0.01). In the reactivation model, a single LAmB administration at start of immunosuppression significantly reduced both reactivation rate and fungal burden vs. controls (P < 0.01). Our results show that the conditions under which IA develop and timing of administration of LAmB were determinant variables for prophylactic efficacy.     

Early empiric antifungal therapy of infections in neutropenic patients comparing fluconazole with amphotericin B/flucytosine

We compared the efficacy and tolerability of fluconazole (FCA) with amphotericin B/flucytosine (ABF) in neutropenic patients with haematological malignancies. Antifungal therapy started on day 4 when fever was unresponsive to antibiotics or on day 1 together with the antibiotics, if there was evidence of mycosis. If patients did not respond to FCA after 7 days they switched to ABF. 98 patients, 51 FCA and 47 ABF were included in the study. Response to fever was achieved in 28/51 FCA patients and in another 16 after switching to ABF. So in overall 44/51 (86.2%) of the FCA and 37/47 (78.8%) of the ABF group defervescence was observed. 46 patients (21 FCA, 25 ABF) developed radiological signs of pneumonia. Resolution of infiltrates was achieved in 5/21 FCA and 20/25 ABF patients, and another 10 of 15 initially not responding patients showed regression when switched to ABF, 5 of these had highly suspected aspergillosis. Adverse events occurred in 19.6% of FCA and 97.9% of ABF patients. In conclusion fluconazole and amphotericin B/flucytosine seem to be equally effective. In view of its lower toxicity fluconazole may be preferred as first line empiric antifungal agent, but in case of nonresponse, pneumonia or aspergillosis it may be replaced by amphotericin B combined with flucytosine.     

Case report. Hepatic abscesses due to Aspergillus terreus in an immunodeficient child

We report the first case of hepatitis due to Aspergillus terreus in a 13-year-old boy with common variable immunodeficiency that occurred while the patient was receiving secondary prophylaxis with fluconazole after an episode of pulmonary candidosis. The infection subsided after the addition of itraconazole to the combination of liposomal amphotericin B and granulocyte-macrophage colony-stimulating factor that he was receiving.     

Oral, Topical and Parenteral Antifungal Treatment with Itraconazole in Normal and in Immunocompromised Animals

Summary: Itraconazole was dissolved in polyethylene glycol for oral and topical treatment and in hydroxypropyl-β-cyclo-dextrin for oral, topical or parenteral treatment.
Topical and oral treatment was successful in microsporosis, trichophytosis, skin-and vaginal candidosis, pityrosporosis and eye mycosis by Candida, Fusarium and Aspergillus . Vaginal candidosis could be cured with a one-day topical or oral treatment.
The same results could not be obtained with any of the reference compounds (griseofulvin, terbinafine, ketoconazole or fluconazole) on amg per kg body weight base, nor on a% concentration base. Antifungal levels were determined by bioassay: biologically active antifungal levels were present in plasma and vaginal fluid of rats, after one oral dose of 10mg.kg^-1, for at least 72 and 96 hours respectively. This was in good correlation with findings on prophylaxis of vaginal candidosis. Itraconazole was also successfully used, in normal animals and animals immunodepressed with various agents, in disseminated and systemic diseases: trichophytosis, sporotrichosis, histoplasmosis, candidosis, aspergillosis and cryptococcosis. Oral and parenteral treatment with itraconazole was compared in various models to oral and parenteral fluconazole and to parenteral amphotericin B. The outcome with itraconazole was better than with the other antifungals. Meningeal cryptococcosis responded very well to itraconazole. Combination therapy of itraconazole and fluconazole was not superior to treatment with itraconazole alone. No side-effects were observed in relation to itraconazole treatment.b