Successful treatment of disseminated Trichosporon beigelii (cutaneum) infection with associated splenic involvement

Fungemia caused by Trichosporon beigelii (cutaneum) has been recently recognized as a fatal infection afflicting immunocompromised patients. The authors report the case of a leukemic patient who developed splenic infection from disseminated T. beigelii. Treatment with amphotericin B, 5-fluorocytosine, and splenectomy proved successful. The etiology of disseminated T. beigelii infection, visceral seeding, and combination antifungal therapy also are discussed.     

Paecilomyces variotii central nervous system infection in a patient with cancer

Paecilomyces variotii was isolated from two subsequent cerebrospinal fluid (CSF) specimens of a cancer patient. Identification was confirmed through beta-tubulin and rDNA ITS sequencing. MICs were determined for seven antifungal agents; the isolate was found to be susceptible to amphotericin B (AMB), itraconazole (ITZ), ketaconazole (KTZ) and 5-fluorocytosine (5FC) but resistant to fluconazole (FLZ) and miconazole (MCZ). Despite antimycotic therapy, the infection proved to be fatal.     

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.     

Trichosporon beigelii Infection in an Immunocompromised Host Trichosporon beigelii-Infektion bei einem abwehrgeschwächten Wirt

Summary: A case of Trichosporon beigelii infection in a patient with non-Hodgkins lymphoma that illustrates some of the associated diagnostic and chemotherapeutic problems, is described. Despite prolonged isolation of the yeast from blood cultures, the patient recovered from the infection after treatment with amphotericin B and flucytosine. Presenting features, diagnosis and monitoring of antifungal therapy in renal failure are discussed.
Zusammenfassung: An einer Trichosporon beigelii- Infektion bei einem Patienten mit Non-Hodgkin-Lymphom werden einige diagnostische und therapeutische Proble-me aufgezeigt. Trotz wiederholter Isolie-rung der Hefe aus Blutkulturen erholte sich der Patient unter einer Therapie mit Amphotericin B und Flucytosin. Symptomatik, Diagnose und das Vorgehen bei der antimy-kotischen Therapie unter Nierenversagen werden diskutiert.     

Favorable outcome of invasive aspergillosis in patients with acute leukemia

During a 2-year period, 15 of 110 patients (14%) admitted for intensive therapy of acute leukemia associated with prolonged deep granulocytopenia developed documented invasive aspergillosis (IA). Antemortem diagnosis was accomplished in 14, and 13 of 15 (87%) survived the infection. Because of the high success rate, we reviewed the courses of the 15 patients to assess factors associated with this favorable outcome. Eleven presented with pulmonary IA; early symptoms occurred at a mean 21.6 days of granulocytopenia (less than 100/muL) and included refractory fever in 14 and pulmonary signs or symptoms in 11. Primary necrotic chest wall lesions associated with Hickman catheters developed in four at a mean 11 days of granulocytopenia, followed by pulmonary involvement. All 15 patients had chest radiographs during granulocytopenia, with 14 (93%) demonstrating pulmonary infiltrates and/or nodules at a mean 20.6 days of aplasia. Nine patients had lung computerized tomography (CT) scans, revealing nodular infiltrates in one patient and a characteristic zone of low attenuation surrounding a mass-like infiltrate in seven other patients, which was found to be diagnostic of IA. Subsequent CT scans performed during and following bone marrow recovery showed progression to cavitation followed by either complete resolution or minimal pulmonary scarring. Eleven patients developed IA during empiric amphotericin B (Amp-B) therapy (0.5 mg/kg/d) for fever refractory to antibacterial antibiotics. Fourteen patients received high-dose Amp-B (1.0 to 1.5 mg/kg/d), which was started within a mean of 2.2 days of first clinical findings; 13 survived. Ten patients received 5-fluorocytosine in addition to high dose amp-B. Survival was similar regardless of presentation, as 91% with primary pulmonary IA and 75% presenting with chest wall lesions survived. All 13 surviving patients had complete granulocyte recovery at a mean 33.8 days. Nephrotoxicity (creatinine greater than 2.0 mg/dL) was observed in seven patients during therapy for IA, but was transient in all seven. We conclude IA can be successfully treated in the deeply granulocytopenic patient provided that it is recognized and treated early, and provided that antifungal therapy is aggressive and is continued until granulocyte recovery occurs.     

Combination therapy in a model of pulmonary aspergillosis

The current treatment for pulmonary aspergillosis, amphotericin B, is toxic and not always effective. This study was done to evaluate combinations of amphotericin B with other agents in an animal model of pulmonary aspergillosis. Sprague-Dawley rats were treated with cortisone acetate, infected intratracheally with 10(6) spores of Aspergillus fumigatus, and followed daily for survival. Mortality among controls started on day 2, and it was 80% by day seven, whereas therapy with amphotericin B resulted in survival of all animals. When given alone, ketoconazole, 5-fluorocytosine and rifampin did not improve survival. The combination of ketoconazole with amphotericin B resulted in complete antagonism. When animals received a combination of aerosol amphotericin B prophylaxis two days prior to infection followed by treatments with SCH39304 or itraconazole seven days after infection, survival rates were superior as compared to animals that had received aerosol prophylaxis only. The combinations of either 5-fluorocytosine or rifampin with amphotericin B were not better than amphotericin B alone. While combinations with 5-fluorocytosine or rifampin appear not to offer any advantage over therapy with amphotericin B alone, additional studies to further evaluate the role of azoles in combination therapy are needed.     

Candida antigen and antibody kinetics during antifungal therapy in non-neutropenic intensive care patients

The present study aimed at determining Candida antigen and antibody kinetics during antifungal therapy. 115 non-neutropenic patients with a stay of more than 5 days in an interdisciplinary intensive care unit during a period of 2 years were reviewed. Routinely measured Candida antigen and antibody titers were evaluated at the beginning and during antifungal therapy. In 67 patients serological data were evaluable in defined time slots. Under fluconazole therapy (FT) the median of Candida antigen (Ramco) was 1:4 and did not change significantly. Candida antibody level increased from 1:80 to 1:320. Initial titers between FT and amphotericin B/5-fluorocytosine therapy (AT) showed a significant difference. During AT antigen titers decreased from 1:8 to 1:4 while antibody titers kept constant at a level of 1:160.     

Effect of 5-Fluorocytosine and 5-Fluorouracil on Human and Rat Hepatic Cytochrome P 450 Die Wirkung von 5-Fluorcytosin und 5-Fluoruracil auf Leber-Cytochrom-P 450 in Mensch und Ratte

Hepatotoxicity is a well-known side effect of the antifungal drug 5-fluorocytosine. The underlying mechanisms of this toxicity are unknown. The present in vitro study was, therefore, designed to assess the influence of 5-fluorocytosine and 5-fluorouracil on the hepatic cytochrome P 450 concentration in human and rat liver microsomes. Incubation of human or rat hepatic microsomes for 1 h with 5-fluorocytosine up to 500 micrograms/ml or with 5-fluorouracil up to 200 micrograms/ml did not influence the cytochrome P 450 concentration. In comparison the amount of cytochrome P 450 in human liver, however, was lower than in rat liver microsomes and a more interindividual variation was observed.     

Antifungal susceptibility testing in chronically recurrent vaginal candidosis as basis for effective therapy

The chronically recidivist vulvo-vaginal candidiasis is one of the most stubborn problematic diagnosis in the dermatology and gynaecology ward. Prognosis and therapy are primarily determined by the causative micro-organism and the interaction of the fungal species with the currently available antifungal agents. Objective of the study was the investigation of vaginal yeast isolates from patients with chronically recidivist vaginal candidiasis against 8 antifungal agents with the aim of optimising the standard therapy with azole antifungal agents and assessment of alternative therapy schemes. 55 clinical isolates (Dermatology, Charité) of 40 patients were tested by microdilution according to DIN 58940-84. Species differentiation and identification was performed by Fourier-Transform Infrared Spectroscopy (FTIR). In the result Candida glabrata was the predominant causative agent for the recidivist vaginal candidiasis. MIC-mode values for C. glabrata were: fluconacole 32 micrograms/ml, itraconacole 1 microgram/ml, ketoconacole 1 microgram/ml, amphotericine B, voriconacole 0.03 microgram/ml, amphotericin B 0.5 microgram/ml, terbinafine 128 micrograms/ml, cicloproxolamine 4 micrograms/ml, 5-fluorocytosine 0.03 microgram/ml. Some strains of Patients with suboptimal introductory low doses of fluconacole showed increasing of MIC in course of therapy. Parallel resistance with itraconacole was observed in all these cases. Consecutively isolated strains could be clearly and reliably identified by FTIR. In conclusion of most importance is the initial dose adapatation of the drug used, e.g. for fluconacole 800/d p.o., when C. glabrata is the causative agent. Low dose fluconacole therapy is always unsuccessful in recurrent vaginal candidiasis and induces secondary resistance. Demonstrated high susceptibility of voriconacole, amphotericine B an 5-fluorocytosine particularly for C. glabrata may indicate of an anitmycotic therapy potential unconsidered regarding to dermatological indication up to now.     

Fungal infections in surgical patients

Deep fungal infection was diagnosed in 42 patients (a rate of four per 1000) treated during a one-year period between 1988 and 1989 at the Surgical Clinic in Würzburg. Most occurred in association with damage to intra-abdominal hollow organs. Diagnosis of deep fungal infections is difficult and only histological identification provides definite proof. However, often the decision to treat has to be made on the basis of the clinical picture and the physician's subjective assessment. Combination treatment with amphotericin B and 5-fluorocytosine is still the current recommendation but the introduction of the azole antifungal agents appears likely to bring about a change. A trial of fluconazole showed it to have clear advantages over combination treatment, being effective, well tolerated and easily administered.     

Can intravenous antifungal therapy be safely used in the outpatient parenteral antimicrobial therapy (OPAT) setting?

Outpatient parenteral antimicrobial therapy (OPAT) is an established treatment option for patients with a variety of infections who require a period of intravenous therapy, are clinically stable, and do not require continuous monitoring. Many patients with fungal infections require prolonged therapy due to resistance or intolerance to oral antifungal agents. Despite the widespread use of OPAT by infection specialists, antifungal agents appear infrequently used in this setting. We suggest that with appropriate patient selection, patients with fungal infections could successfully be treated on OPAT.     

Role of surveillance cultures in prevention and treatment of fungal infections

Fungal surveillance cultures have been studied as potential predictors of invasive or disseminated mycoses. Several studies have demonstrated that the presence of Candida tropicalis in mucosal surveillance cultures has a high predictive value for invasive fungal infection due to this pathogen in granulocytopenic patients. By comparison, surveillance cultures for Candida albicans have a poor positive predictive value for invasive fungal infection. The value of routine surveillance cultures of the nares for Aspergillus spp. has not been consistently confirmed. The use of surveillance cultures for less common fungal pathogens, such as Trichosporon beigelii, also remains unclear. Fungal surveillance cultures of the inanimate hospital environment have proven useful in identifying the source of conidia in well-defined clusters or outbreaks of nosocomial aspergillosis and other mycoses. As investigational tools, fungal surveillance cultures also may be useful for studying the effects of new antifungal agents on mucosal flora. Fungal surveillance cultures, especially for C. tropicalis and possibly Aspergillus spp. in high-risk populations, may be useful when a pathogen-directed approach to antifungal therapy is used. However, the time required, diagnostic limitations, and expense of routine mucosal fungal surveillance cultures must be balanced against the effect of this information on therapeutic decisions. Empirical antifungal therapy and early diagnostic approaches for high-risk patients may obviate the need for routine fungal surveillance cultures while decreasing the frequency of invasive mycoses.     

Candida colonization and systemic infection in neutropenic patients. A retrospective study

The results of surveillance cultures in 424 neutropenic patients with hematologic malignancies were analyzed to evaluate the relationship between colonization and infection by Candida species. Eighteen (32%) of 56 patients with multiple noncontiguous colonized sites developed proven (13 cases) or probable (five cases) systemic candidiasis, versus two patients with proven candidiasis (1.2%) of 170 with one colonized site (P less than 0.00000001), and one patient with proven candidiasis (0.5%) of 198 without any evidence of Candida colonization (P less than 0.00000001). Twenty-two patients with multiple colonized sites who developed a febrile episode resistant to antibiotics were treated with empiric amphotericin B. Nine of 11 given empiric amphotericin B within day 6 survived versus three of 11 receiving antifungal therapy after day 6 (P = 0.014). The above data seem to justify further prospective studies on Candida colonization as indication to early antifungal therapy in febrile neutropenic patients.     

Candida tropicalis Infections in Children with Leukemia

The Candida species account for approximately three-fourths of fungal infections in patients with cancer. Although Candida albicans is the most frequent cause, C. tropicalis is increasingly implicated as an important pathogen. Over a 12 year period 19 children treated for leukemia at our institution developed C. tropicalis infections. We describe their clinical presentation, extent of fungal infection, treatment, and outcome. Fungemia without meningitis in 11 children was treated successfully, whereas C. tropicalis meningitis in 7 children was uniformly fatal. An additional patient had unsuspected, widespread infection detected at autopsy. Multiple sites, including the cerebrospinal fluid yielded C. tropicalis. Previously reported risk factors including neutropenia, broad-spectrum antibiotic usage, corticosteroid therapy, and total parenteral nutrition were observed in our cases. A high index of suspicion and the early use of aggressive antifungal therapy are critical to the successful management of C. tropicalis infections in children with leukemia.     

The air crescent sign of invasive pulmonary mucormycosis in acute leukemia

An unusual radiographic sign of crescentic cavitation appeared in a case of invasive pulmonary mucormycosis complicating the treatment of a patient with acute myelogenous leukemia and having a normal admission chest radiograph. The first manifestation was a large, wedge-shaped pleural-based consolidation, which evolved about 10 days later into a fungus ball-like lesion, usually known as the air crescent sign. Amphotericin B and 5-fluorocytosine, which were initiated immediately after appearance of the sign, proved to be effective, probably in association with hematologic improvement. Transbronchial lung biopsy was not only helpful in establishing a definitive diagnosis, but also suggested that an intracavitary mass could have resulted from pulmonary infarction. This experience thus showed that the sign may appear in greater frequency in mucormycosis as well as in aspergillosis, and may be useful as a clinical index for initiating antifungal therapy in immunocompromised patients.     

Wechselwirkungen zwischen 5-Fluorcytosin und Polyen-Antibiotica bzw. Imidazol-Derivaten

Zusammenfassung: Mittels Warburg-Technik wurde an Myzeten (Saccharomyces cerevisiae und Candida albicans) untersucht, ob 5-Fluorcytosin die antimyzetische Aktivität von Polyen-Antibiotika (Amphotericin B und Nystatin) bzw. von Imidazol-Derivaten (Econazolnitrat und Ketoconazol) verstärkt, oder ob ein Antagonismus vorliegt.
Im Falle der Polyen-Antibiotica ließ sich ein statistisch signifikanter additiver Effekt mit 5-Fluorcytosin nach weisen. Bei den Imidazol-Derivaten hingegen fehlte jegliche additive Wirkung des 5-Fluorcytosins; eine wechselseitige Abschwächung war aber auch nicht nachzuweisen. Die Ergebnisse werden im Hinblick auf ihre klinisch therapeutische Bedeutung kurz diskutiert.
Summary: On resting yeasts (Candida albicans, Saccharomyces cerevisiae), investigations were carried out to find out whether there exist interactions between 5-fluorocytosine and polyene antibiotics, respectively imidazole derivatives. Among the polyenes, amphotericine B and nystatin, among the imidazoles, ketoconazole and econazole nitrate were tested.
With the polyene antibiotics, a significant additive action with 5-fluorocytosine could be demonstrated. Such additive effect lacked in the case of the imidazole antifungals. However, no decrease in activity could be shown neither.
For practical purposes in human systemic antifungal therapy, these results permit the simultaneous application of 5-fluorocytosine together with polyene antibiotics (amphotericine B deoxycholate) or imidazole derivatives (ketoconazole). In the first case, an additive therapeutic effect may be expected, in the latter case at least no interactions causing a decrease in antifungal activity will occur.     

Disseminated Visceral Fusariosis Treated with Amphotericin B-Phospholipid Complex

Fusariosis, a rare infectious disease of the immunocompromised host, is relatively resistant to amphotericin B (AmB) or other antifungal agents. We describe a 5-year follow-up of a 40 year old woman with T-type acute lymphoblastic leukemia who following chemotherapy developed prolonged high fever, chills, night sweats, and severe weakness. Liver function tests were impaired and abdominal computerized tomography (CT) showed multiple lesions in the liver and abnormal structure of the spleen. A laparotomy revealed multiple granulomas containing Fusarium sp. in the liver, and the spleen was heavily infiltrated by the same fungus. The patient failed to respond to the conventional AmB dosage form (Fungizone) even after a total dose of 3.0 g was given, and developed significant renal impairment. AmB was complexed (in a mole ratio of 1:16) with a mixture of the phospholipids dimyristoyl phosphatidylcholine and dimyristoyl phosphatidylglycerol (mixed in 7:3 mole ratio). The resulting drug complex, AmB-PLC, was then administered (1-4mg/kg/day, total dose 4.2 g) and subsequently the patient was cured of all symptoms of fusariosis. There were only mild side effects and no nephrotoxicity was evident. On the contrary, marked improvement of the renal function tests occurred during AmB-PLC treatment. Eight months later, she developed a spinal lesion with dense consistency in L₅ and S₁, and after receiving another course of AmB-PLC (3.1 g) she recovered completely. In a 2 year follow-up period the patient had no further relapse of the fungal disease. Subsequent chemotheraphy given for relapse of the leukemia was followed by a new fungal infection, which was treated with AmB-cholesteryl sulfate complex (Amphocil^TM)*. The patient received 13.0 g Amb as Amphocil and fully recovered from the fungal infection.

This case report suggests that when Fungizone is nephrotoxic and does not permit efficacious antifungal treatment, AmB complexed with suitable lipids may be safe efficacious therapy.     

Geotrichosis of oral mucosa

Summary. A livid, sharply defined enanthema of the oral mucosa with ulcerations on the soft palate in a patient presenting with de novo acute myeloid leukaemia with prolonged, therapy-induced granulocytopenia (lt 0.5 nl^-1 for 113 days!) was diagnosed as geotrichosis. Geotrichum capitatum was identified both in vivo and in vitro. Pneumonic infiltrates in the upper lobes of both lungs were treated with amphotericin B infusions. Healing of the aforementioned enanthema was only achieved after addition of 5-fluorocytosine to therapy. Susceptibility determinations with several Geotrichum capitatum isolates led to the conclusion that amphotericin B was unsuitable as a therapeutic agent in this case. 5-Fluorcytosine and itraconazole exhibited superior antifungal and antimycotic activity.
Zusammenfassung. Ein livides, scharf begrenztes Enanthem der Mundschleimhaut mit Ulzerationen am weichen Gaumen bei einer de novo akuten myeloischen Leukämie mit extrem langer, therapiebedingter Granulozytopenie (lt 0.5 nl^-1über 113 Tage!) wird als Geotrichose angesehen. Geotrichum capitatum wurde in vivo und in vitro nachgewiesen. Pneumonische Infiltrate in beiden Lungenoberlappen waren Anlaß zu einer Infusionstherapie mit Amphotericin B. Eine Abheilung des obengenannten Enanthems wurde allerdings erst nach Umstellung der Therapie auf 5–Fluorcytosin-Infusionen erzielt. Resistenzbestimmungen mit mehreren Isolaten hinterließen den Eindruck, daß Amphotericin B als Therapeutikum hier nicht geeignet war. 5–Fluorcytosin und Itraconazol zeigten einen besseren antimyzetischen Effekt und antimykotische Wirksamkeit.     

A rapid susceptibility testing method for yeasts to 5-fluorocytosine

A rapid method of susceptibility testing of yeasts to 5-fluorocytosine is demonstrated. The method is based on photometric determination of the optical density of yeast suspensions before and after incubation for 4 h in the presence of the antifungal. The method was evaluated with 50 Candida strains.     

Invasive Aspergillosis in Neutropenic Patients with Hematological Disorders

Between 1983-1988, 72 patients with acute leukemia and 4 with aplastic anemia were treated in the Hematology Unit of The Chaim Sheba Medical Center. Ten patients with acute leukemia developed invasive pulmonary aspergillosis and 2 with aplastic anemia developed invasive aspergillosis of the nose and paranasal sinuses. These infections were diagnosed during a period of profound neutropenia while these patients were receiving broad spectrum antibiotics. The diagnosis of pulmonary aspergillosis was based on positive sputum cultures in 4 cases and on the appearance of typical clinical and radiologic features in six. In 2 culture-positive and in one culture-negative patient, the diagnosis was confirmed at autopsy. Thus, the diagnosis was definitive in 5 patients and probable in the remaining five patients. The 5 patients who achieved remission responded to antifungal treatment and recovered, while of the 5 who eventually died from the fungal infection, 4 did not achieve remission, and one died while in complete remission. In the 2 patients with aplastic anemia, aspergillosis was detected in cultures from necrotic nasal tissue. Both patients remained neutropenic, failed to respond to antifungal treatment and died within a short time after diagnosis. From this experience it appears that invasive aspergillosis in neutropenic patients is potentially curable if treated early by amphotericin B, provided that the neutrophil count recovers.