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.     

Use of the membrane filtration technique and Staib agar for the detection of Cryptococcus neoformans in the urine of AIDS patients--a contribution to diagnosis, therapy and pathogenesis of cryptococcosis

For the cultural control of Cryptococcus neoformans (Cr.n.), among the routinely examined standard specimens like CSF, sputum, blood, etc., urine earns special attention. The combination of membrane filtration technique (MFT) and Staib agar for the detection of Cr.n. from body fluids as described by Staib in 1963 was used for the cultural isolation of Cr.n. from urine of AIDS patients. In 3 examplary cases the diagnostic significance of this method could be demonstrated: The brown colour effect (BCE) of Cr.n. of a single CFU, as well as in colonies growing with a high density, was produced on average within 3-5 d/26 degrees C. The method was found to be useful for the evaluation of antimycotic therapy. One example of the survival of a few CFUs of Cr.n. under treatment with fluconazole as compared to the efficacy of therapy with amphotericin B + flucytosine, and one example of a re-emergence of Cr.n. in the urogenital tract after a too short duration of treatment with amphotericin B + flucytosine are shown. For the exclusion of the survival of single CFUs of Cr.n. in the urogenital tract of males, quantities up to 1 l of urine for the combination of MFT and Staib agar are proposed. As a secondary observation, it was found that this diagnostic combination in addition to its primary purpose, can serve to detect the metabolic end products of the human body present in urine which may influence capsule formation of Cr.n. neoformans.     

Cryptococcus neoformans in the Seminal Fluid of an AIDS Patient. A Contribution to the Clinical Course of Cryptococcosis: Cryptococcus neofomans im Sperma eines AIDS-Patienten. Ein Beitrag zum Minischen Verlauf der Cryptococcose

In a 33-year-old HIV-positive homosexual male suffering from unexplained headache, cryptococcosis was diagnosed in a progressive secondary stage. After treatment with the standard combination therapy of amphotericin B + flucytosine for 34 d, the patient was clinically symptom-free and discharged, upon his own request, from the hospital. He remained under ambulatory mycological control. After an interval of 65 d during which the urine had been free from Cryptococcus neoformans (Cr.n.), the fungus could not be isolated from urine but 3 X 10(5) CFUs/ml were found in the seminal fluid. Andrologically, teratospermia and hyposemia were present. There were no clinical signs in the genitourinary tract including the prostate. The significance of ecological niches for Cr.n. colonization of the genitourinary tract after antimycotic therapy is discussed. In such cases, in addition to cultural examination of urine for Cr.n. by the membrane filtration technique (MFT) and Staib agar, an additional cultural examination of seminal fluid is recommended. It is also proposed to pay more attention to Cr.n. in andrological examinations. Special regard should be given to a possible occurrence of Cr.n. in the seminal fluid of AIDS patients. In cytology of the seminal fluid, use of the Giemsa stain is unsuitable for the purpose of Cr.n. detection. For this reason, it should be supplemented by PAS staining.     

In vitro comparative evaluations of the postantifungal effect: synergistic interaction between flucytosine and fluconazole against Candida albicans

In vitro comparative evaluations were performed to study the efficacy of combinations of flucytosine and fluconazole in producing a postantifungal effect (PAFE) on Candida albicans. Initial studies were done to determine MIC, FIC (fractional inhibitory concentration) and optimal PAFE parameters. A turbidometric method was used to measure yeast cell growth following exposure to different concentrations of the two drugs for periods of 0.5, 1 or 2 h at temperatures of 30 degrees C and 37 degrees C. The PAFE was determined by the difference in time (h) required for growth of the control and test cultures to reach the 0.5 absorbance level following removal of the drug by dilution. Ten strains of C. albicans were then assayed (30 degrees C; 2 h exposure time) and a synergistic PAFE was evidenced with the two drugs at concentrations well below their individual MICs. PAFEs ranging from 3.8 to 10.5 h, which persisted for 1.2-2.5 h longer than those achieved with either agent separately, were evidenced when flucytosine and fluconazole were combined (flucytosine: fluconazole ratios of 1:16-1:32) at concentrations ranging from 0.024 to 0.098 micrograms ml-1 and 0.78 to 1.56 micrograms ml-1 respectively. The concentrations of each agent required to produce an optimal PAFE varied according to the C. albicans strain being assayed.     

Tracheobronchial aspergillosis in a patient with AIDS treated with aerosolized amphotericin B combined with itraconazole

Summary. The clinical features of a tracheobronchial infection due to Aspergillus flavus in an AIDS patient with a normal neutrophil count is described. Diagnosis was made by culture and microscopic examination of biopsies obtained from bronchial vegetations seen at bronchoscopy. Radiographic examination of the neck revealed the presence of large endoluminal fungal masses. Initially the patient was treated with a combination of itraconazole, flucytosine and aerosolized amphotericin B, then only with itraconazole plus aerosolized amphotericin B. A good therapeutic response was observed.
Zusammenfassung. Das klinische Bild einer tracheobronchialen Infektion, verursacht durch Aspergillus flavus bei einem AIDS-Patienten mit normaler Leukozytenzahl, wird vorgestellt. Die Diagnose wurde mikroskopisch und kulturell aus Biopsiematerial von Bronchialbelägen gestellt. Im Nacken-Röntgenbild waren endoluminale Pilzmassen nachweisbar. Der Patient wurde anfänglich mit einer Kombination von Itraconazol. Flucytosin und Amphotericin B-Aerosol behandelt, später nur mit Itraconazol und Amphotericin B-Aerosol. Der Patient sprach gut auf diese Therapie an.     

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.     

Candidosis of the urinary tract with padding phenomenon of the renal pelvises in an infant with obstructive uropathy

Summary. A male infant with obstructive uropathy developed yeast cell agglomerations which were detectable macroscopically and by imagegenerating techniques within both renal pelvises after Candida albicans infection of the urinary tract. Therapy with flucytosine induced excretion of 'fungal balls' via the urethra. Continuation of therapy with liposomal amphotericin B (AmBisome®) prevented a relapse after development of fungal resistance against flucytosine. Sonographically or radiographically detectable formation of 'concrements' within the urinary tract of patients with an immature or compromised immune system and additional features such as obstructive urinary tract should suggest a localized or systemic mycosis, particularly in the context of long-term antibiotic treatment.
Zusammenfassung. Bei einem Säugling mit obstruktiver Uropathie manifestierte sich eine Infektion der Harnwege durch Candida albicans , die zur Entwicklung von makroskopisch und durch bildgebende Verfahren nachweisbaren Hefezellag-glomerationen führte. Während einer Therapie mit Flucytosin kam es zur Ausscheidung von "Hefepilzbällen"über die Urethra. Durch Fortführung der Behandlung mit liposomalem Amphotericin B (AmBisome®) nach Resistenzentwicklung gegen Flucytosin wurde ein Rezidiv verhindert. Die sonografisch oder röntgenologisch nachweisbare Bildung von "Konkrementen" im Harntrakt von Patienten mit unreifem oder geschwächtem Immunsystem und eventuell zusätzlich vorhandenem locus minoris resistentiae in Gestalt einer Obstruktion der Harnwege sollte insbesondere im Zusammenhang mit langzeitigem Einsatz von Antibiotika an eine lokalisierte oder systemische Mykose denken lassen.     

Antifungal combination therapy in localized candidosis

A mouse model of localized candidosis in air-filled subcutaneous cysts imitating thrush has been developed. We have now tested various antifungal combinations in this animal model. Flucytosine (5-FC) + amphotericin B (Amph B) showed the highest efficacy, a clear additive or even synergistic effect was seen. The combination of 5-FC + imidazole or triazole derivative was less efficacious, an additive effect was rare. The combination of 5-FC + Amph B was also tested against Candida albicans strains showing various degrees of 5-FC-resistance. A significant reduction in 5-FC-resistant mutants was seen after the treatment with the combination.     

Persistence of Cryptococcus neoformans in seminal fluid and urine under itraconazole treatment. The urogenital tract (prostate) as a niche for Cryptococcus neoformans

The open questions of the persistence of Cryptococcus neoformans in the urogenital tract under antimycotic treatment can be examined under optimal mycological-diagnostic conditions only. The example of a case of cryptococcosis in an AIDS patient diagnosed and treated with itraconazole in the early secondary stage of cryptococcosis is used to discuss the problems of the persistence of Cr. neoformans involvement in the urogenital tract (prostate). Data from a ten-week follow-up study are presented and discussed. The observations made have shown that itraconazole is effective in all regions of the body, with the exception of the urogenital tract. In addition to clinical examinations, cases treated with itraconazole should be finally subjected to cultural examination of prostatic secretion and/or seminal fluid, to exclude the possible presence of a symptom-free involvement of the prostate by Cr. neoformans.