Fluconazole treatment of Candidal infections caused by non-Albicans Candida species

Fluconazole is an effective alternative to amphotericin B for the treatment of serious infections caused byCandida albicans. Through a literature survey of candidal infections caused by non-albicans Candida spp., 43 cases treated with fluconazole were found. The most common causative organisms wereCandida parapsilosis (14 patients),Candida glabrata (12 patients), andCandida tropicalis (11 patients). The dose of fluconazole varied from 50 to 400 mg daily. The median duration of treatment was 21 days. Overall efficacy was 77%. The efficacy against the various species was 93% forCandida parapsilosis, 50% forCandida glabrata, and 82% forCandida tropicalis. In conclusion, fluconazole is effective against the most commonnonalbicans Candida spp., although higher doses may be required for infections caused byCandida glabrata. Infections caused byCandida krusei should not be treated with fluconazole.     

Traitement antifongique des candidoses systémiques en réanimation

Hospital-acquired infections secondary to Candida have undergone a considerable recrudescence in the last decade. They still represent a substantial mortality rate, particularly in ICU patients. Their bad prognosis is mainly due to delay in treatment because of the difficulties involved in diagnosis. Clear indications for treatment resulting from an international consensus have not yet been established. The therapeutic regimen includes Amphotericin B, 5-fluorocytosin, azoles (fluconazole, itraconazole), and recently, new antifungals, mainly voriconazole and caspofungin. The use of amphotericin B is restricted because of its renal toxicity and the difficulty involved in its administration. Fluconazole use is still limited because of the possible development of fungal resistance especially in case of severe infection or of previous exposure to the drug. Indeed, the emergence of fluconazole resistance in Candida albicans as well as the frequency of other naturally resistant Candida species, such as Candida krusei, seems to have increased considerably since the introduction of fluconazole at the beginning of the 1990s'. However, since the appearance of new standardized and reasonably reliable methods to measure resistance, this worrisome rise in resistance seems to be the result of the absence of standard definition criteria rather than a microbiological cause. Furthermore, the interaction between the yeast and the host is so complex that the microbiological resistance has a low predictive value, if at all, for clinical resistance. Fluconazole should be the first choice for all patients without a documented or highly suspected resistance. Amphotericin B should be reserved for particular indications such us intracranial infections. The treatment should be adjusted according to the clinical evolution and the results of sensitivity tests.     

Fungemia at a tertiary care hospital: incidence,therapy, and distribution and antifungal susceptibility of causative species

The aim of this study was to review fungal bloodstream infections at a large tertiary care hospital to evaluate the incidence of fungemia and the distribution of causative species during the period 2001–2005. Another aim was to assess the extent of antifungal resistance. A review of all episodes of fungemia at the University Hospitals of Leuven (Belgium) was conducted between January 2001 and December 2005. For the first yeast isolate collected from each non-mould fungemic episode during a 1-year period (June 2004–June 2005), susceptibility to seven antifungal agents was determined using Sensititre YeastOne plates (Trek Diagnostic Systems, East Grinstead, UK), and the antifungal therapy was reviewed. The annual incidence of fungemia ranged between 1.30 and 1.68 episodes per 10,000 patient-days (on a total of 2,680,932 patient-days), with a decreasing trend observed over the 5-year study period. The most common species were Candida albicans (59%), Candida glabrata (22%), Candida parapsilosis (10%), and Candida tropicalis (4%). Overall, fluconazole resistance was rare (1.6%) and was detected only in C. glabrata and C. krusei. Voriconazole and caspofungin inhibited 100% of the isolates at a concentration of ≤1 μg/ml. Fluconazole was used to treat 75% of fungemic patients. Caspofungin was the second most commonly used antifungal agent (used to treat 11.7% of patients). The incidence of fungemia was higher than usually reported in other European countries. The low proportion of resistance supports the use of fluconazole as the treatment of first choice for candidemia in patients not previously exposed to this drug.     

A controlled trial of fluconazole to prevent fungal infections in patients undergoing bone marrow transplantation.

BACKGROUND AND METHODS. Superficial and systemic fungal infections are a major problem among severely immunocompromised patients who undergo bone marrow transplantation. We performed a double-blind, randomized, multicenter trial in which patients receiving bone marrow transplants were randomly assigned to receive placebo or fluconazole (400 mg daily). Fluconazole or placebo was administered prophylactically from the start of the conditioning regimen until the neutrophil count returned to 1000 per microliter, toxicity was suspected, or a systemic fungal infection was suspected or proved. RESULTS. By the end of the treatment period, 67.2 percent of the 177 patients assigned to placebo had a positive fungal culture of specimens from any site, as compared with 29.6 percent of the 179 patients assigned to fluconazole. Among these, superficial infections were diagnosed in 33.3 percent of the patients receiving placebo and in 8.4 percent of the patients receiving fluconazole (P less than 0.001). Systemic fungal infections occurred in 28 patients who received placebo as compared with 5 who received fluconazole (15.8 percent vs. 2.8 percent, P less than 0.001). Fluconazole prevented infection with all strains of candida except Candida krusei. Fluconazole was well tolerated, although patients who received it had a higher mean increase in alanine aminotransferase levels than patients who received placebo. Although there was no significant difference in overall mortality between the groups, fewer deaths were ascribed to acute systemic fungal infections in the group receiving fluconazole than in the group receiving placebo (1 of 179 vs. 10 of 177, P less than 0.001). CONCLUSIONS. Prophylactic administration of fluconazole to recipients of bone marrow transplants reduces the incidence of both systemic and superficial fungal infections.     

Treatment of oropharyngeal candidiasis in HIV-infected children with oral fluconazole

In an open, noncomparative, multicentre study the efficacy and safety of oral fluconazole was evaluated in the treatment of oropharyngeal candidiasis in children with HIV infection. Fifty-one children with a mean age of five years were enrolled. Oropharyngeal candidiasis was caused byCandida albicans in 28 cases (55 %). Fluconazole was given in a mean dosage of 3.4 mg/kg/d (range 2 to 5.6 mg/kg/d) for a mean duration of 12 days (range 6 to 28 days). By the end of treatment, 90 % of the children were clinically cured, 6 % had improved and 4 % failed to respond.Candida was eradicated in 82 % of the patients. Clinical failure occurred only in children given 3 mg/kg/d or less. Two and four weeks after therapy, clinical cure was confirmed in 88 % and 82 % of the children respectively as well as eradication in 76 % respectively. Six children experienced mild side effects (1 skin rash, 5 mild elevation of liver enzyme levels). The data show that fluconazole is safe and effective in treating oropharyngeal candidiasis in HIV-infected children.     

Fluconazole versus itraconazole for the prevention of fungal infections in haemato-oncology

AIMS: To compare the efficacy of and tolerance to oral fluconazole and intraconazole in preventing fungal infection in neutropenic patients with haematological malignancies. PATIENTS: 213 consecutive, afebrile adult patients treated with or without autologous stem cell transplantation for haematological malignancies. METHODS: A randomised, double blind, single centre study. Patients were randomly assigned to receive fluconazole 50 mg or itraconazole 100 mg, both twice daily in identical capsules. An intention to treat analysis was performed on 202 patients, 101 in each group. RESULTS: Microbiologically documented systemic fungal infections occurred in four patients in each group. Clinical fungal infection was thought to be present in seven recipients of fluconazole and four of itraconazole. In all 202 patients, 29 proceeded to intravenous amphotericin (amphotericin B), 16 in the fluconazole group and 13 in the itraconazole group. Superficial fungal infection was seen only in three non-compliant patients in the fluconazole group. All these infections were oral. No major differences were noted in the isolates of fungi in mouth washes and fecal samples. Overall mortality was 8.9% (18 deaths; seven in the fluconazole group, 11 in the itraconazole group). Mortality from microbiologically and clinically documented fungal infection was 4.5% (nine deaths; three in the fluconazole group, six in the itraconazole group). Median time to suspected or proven fungal infection was 16 days in both groups. None of these comparisons reached statistical significance (p < 0.05). No major clinical toxicity was noted and compliance was excellent. CONCLUSIONS: In neutropenic patients treated for haematological malignancies with or without autologous stem cell transplantation, fluconazole and itraconazole in low doses result in a similar low frequency of fungal disease. Fluconazole may be the preferable drug because of the smaller number of capsules and lack of need for timing relative to meals.     

Variable antifungal susceptibility of wild-typeCandida albicans phenotypes from neutropenic hosts

The aim of the present study was to investigate the relationship between phenotypes ofCandida albicans strains isolated from clinical specimens and susceptibility of the strains to two antifungal agents, itraconazole and fluconazole. Oropharyngeal, gastrointestinal tract, and urogenital tract specimens were collected from 131 neutropenic patients withCandida infection who had received no previous prophylactic treatment. The most frequent species isolated wasCandida albicans, followed byCandida glabrata,Candida tropicalis, Candida krusei, andCandida parapsilosis. Each of the 44Candida albicans strains recovered was found to express one of four phenotypes: smooth, irregular, fuzzy or stipple. Mean minimum inhibitory concentrations (MICs) of itraconazole and fluconazole as determined by the microdilution method and the E-test were consistently higher forCandida albicans strains expressing the stipple phenotype. The mean MICs for the four phenotypes of theCandida albicans strains ranged between 0.35 g/ml and 2.41 g/ml for itraconazole and 2.78 g/ml and 5.2 g/ml for fluconazole. Antifungal susceptibility of the stipple phenotype requires careful appraisal, especially in patients clinically unresponsive to azole chemotherapy or in cases of life-threatening, deepseatedCandida infections.     

Antifungal Prophylaxis in Severely Neutropenic Patients: How Much Fluconazole is Necessary?

Objectives: To evaluate the efficacy of low dose fluconazole treatment for the prevention of yeast colonization and infection in severely neutropenic patients.
Methods: An open randomized trial, comparing fluconazole (100 mg per day) with nystatin (800,000 IU per day), in a University Hospital setting.
Results: Antifungal prophylaxis was given during the period of neutropenia, defined as less than 500 polymorphonuclear cells (PMN)/mm³). Thirty-six patients were randomly assigned to fluconazole and 33 to nystatin treatment groups. New oropharyngeal colonizations were significantly reduced by fluconazole (P=0.005), and oropharyngeal infections occurred less frequently in the fluconazole group (3% versus 16%, P=0.07). Stool colonization was identical between both groups. Systemic fungal infections were rare; one fluconazole patient had pulmonary aspergillosis and one nystatin patient developped Candida pseudotropicalis fungemia. Empiric amphotericin B was given with the same frequency in both groups. No side effects were associated with fluconazole. However, the administration of nystatin became impossible for three patients because of vomiting and lack of compliance.
Conclusions: Fluconazole (100 mg per day) is more effective than nystatin for the prevention of oropharyngeal yeast colonization. Comparison with results in the literature suggests that a 100-mg dose of fluconazole has similar effects to 200 or 400 mg per day.     

Rapid Detection of Pathogenic Fungi from Clinical Specimens Using LightCycler Real-Time Fluorescence PCR

In the study presented here a LightCycler real-time PCR system was used for the diagnosis of fungal infections from clinical tissue samples. Nine specimens were investigated from six patients with suspected or proven invasive fungal infections. Seven of nine samples were positive in a broad-range fungal PCR assay. In four samples, Aspergillus fumigatus was detected both by a species-specific hybridization assay as well as by sequencing of amplification products. In addition, the broad-range fungal PCR assay and PCR sequencing detected and identified, respectively, the following organisms in the specimens noted: Candida albicans in a culture-negative liver biopsy, Histoplasma capsulatum in a bone marrow sample, and Conidiobolus coronatus in a facial soft tissue specimen. Real-time PCR is a promising tool for the diagnosis of invasive fungal infections in human tissue samples and offers some advantages over culture methods, such as rapid analysis and increased sensitivity.     

Fluconazole is removed by continuous venovenous hemofiltration in a liver transplant patient

Fluconazole is effective for the treatment of fungal infections. A continuous venovenous hemofiltration (CVVH) was necessary in a liver transplant patient with anuria. Fluconazole treatment was started after the diagnosis of systemic candidiasis. There was no adverse effect on liver function, and the immunosuppression with cyclosporine was not affected. It is shown for the first time that CVVH effectively removes fluconazole from the blood circulation by a clearance into the hemofiltrate of approximately 21 ml/min. These data suggest that the treatment of fungal infections with fluconazole does not necessitate a reduction of the dosage during CVVH.Abbreviations AUC area under the serum concentration-time curve - C _max maximum (peak) serum drug concentration - CL _CR creatinine clearance - CL _HF clearance into the hemofiltrate - CL _R renal clearance - CVVH continuous venovenous hemofiltration     

Evaluation of the susceptibility of pathogenicCandida species to fluconazole

A fluconazole 25 ug disk diffusion test was used to test 2230 consecutively isolatedCandida strains from 42 different hospital laboratories in 23 countries. Ninety seven percent of 1634Candida albicans isolates and 83.4% of 596 non-Candida albicans isolates were susceptible to fluconazole, applying the proposed breakpoints (26 mm for susceptible strains and 18–25 mm for dosedependent susceptible strains). This is the first hospital laboratory study to evaluate a large number and wide range of sequentialCandida isolates from patients with all types of hospital infections. The fluconazole disk diffusion test appears to be a low-cost, reproducible, and accurate means of assessing the in vitro susceptibility ofCandida isolates.     

Efficacy and safety of fluconazole in the treatment of systemic fungal infections in pediatric patients

In a non-comparative multicentre trial 51 patients aged 24 days to 17 years received treatment with intravenous or oral fluconazole for suspected systemic fungal infections. Twenty-seven patients had confirmed infections, 26 being confirmed mycologically and 1 histologically. All isolates wereCandida species. Of the 43 clinically assessed patients, 30 were considered cured, 7 improved and 6 experienced failure of therapy. Of 27 patients with confirmed fungal infections, 25 were assessed mycologically and all but one were considered cured. Of the six patients experiencing clinical failure, two had a confirmed infection and only one of these experienced mycological failure. This patient had a primary diagnosis of candidemia with persistence ofCandida albicans andCandida parapsilosis. All 51 patients were evaluable for safety. No treatment-related adverse events required termination of treatment. Treatment-related side effects (diarrhea, vomiting, deafness) were reported by three of 51 patients, three patients had laboratory test abnormalities possibly related to fluconazole treatment, including elevation of liver enzyme levels and of the eosinophil count. Results of this study confirm the efficacy and safety of fluconazole in the treatment of pediatric patients with severe fungal infection.K.W. Brammer, Pfizer Central Research, Sandwich, UK; R. Dopfer, University Children's Hospital, Tübingen, Germany; H.J. Schmitt, University Children's Hospital, Mainz, Germany; H. Gadner, A. Zoubek, St. Anna Kinderspital, Vienna, Austria; A. Robert, H. Rubie, Hôpital Purpan, Toulouse, France; H. Holzel, L.A. Bain, D.J. Macrae, The Hospitals for Sick Children, London, UK; P. Reinert, Centre Hospitalier Intercommunal, Creteil, France; J.P. Vannier, Hôpital Charles Nicolle, Rouen, France; C. Margueritte, Hôpital Saint Charles, Montpellier, France; J.B. Gouyon, Hôpital d'Enfants, Dijon, France; G. Paolucci, Policlinico Sant'Orsola, Bologna, Italy; N. Principi, Ospedale Luigi Sacco, Milan, Italy.     

Molecular Monitoring of Candida albicans Infections in Liver Transplant Recipients

This report describes the use of the 27A probe for the molecular monitoring of Candida albicans infections in liver transplant recipients. Nosocomial candidiasis is the major fungal infection in liver transplant recipients, with Candida albicans being the species most frequently isolated. The molecular epidemiology of Candida albicans infections has been widely investigated, but scant attention has been focused on monitoring the identity of infecting strains in individual patients over the entire course of their hospitalization. In the study presented here, a total of 179 Candida albicans isolates were collected from 10 liver transplant recipients during multiple surveillance cultures performed before and after liver transplantation and from three healthcare workers at the Transplant Unit of Ospedale di Cisanello, Pisa (Italy). Computer-aided analysis of the 27A-probed DNA fingerprints, used to compare the genetic relatedness of all the Candida albicans isolates, showed that most of the patients colonized with Candida albicans before transplantation harbored a unique Candida albicans genotype. This genotype persisted over the entire course of hospitalization and caused multiorgan failure in two patients, both of whom died from endogenously borne Candida albicans infections. Nosocomial acquisition of Candida albicans strains could be monitored in a timely manner in the other patients; for some of them, subsequent strain replacement was registered at different body sites during the post-transplant period. Neither cross-infection between patients nor transmission from healthcare workers to patients occurred in this hospital setting. These results indicate that the molecular monitoring of Candida albicans strains isolated from liver transplant recipients during their hospitalization may provide timely information about the identity of individual Candida albicans strains causing infections. Electronic Publication     

Mixed oropharyngeal candidiasis due toCandida albicans and non-albicans Candida strains in HIV-infected patients

In order to determine the clinical significance of mixed oropharyngeal candidiasis (Candida albicans plus a non-albicans strain ofCandida) in patients infected with HIV-1, a retrospective chart review was done in 12 HIV-1-infected patients with a clinical episode of oropharyngeal candidiasis, in whom a mixed culture ofCandida albicans (found to be fluconazole-sensitive) plus a non-albicans species ofCandida was obtained from their oral cavities. This group was compared with 26 HIV-positive patients (control group) with oropharyngeal candidiasis due toCandida albicans (found to be fluconazole-sensitive). Antifungal susceptibility testing was performed by a broth microdilution test with RPMI-2% glucose. A fungal strain was considered fluconazole-sensitive if its MIC was < 0.5 g/ml. Both the study and control groups had similar clinical and demographic characteristics. All the patients were severely immunocompromised, with a mean CD4+ lymphocyte count of 63/mm³ (95% Cl 41–84) and 80/mm³ (95% Cl 25–135) in the study and control groups, respectively. In the study group, seven patients hadCandida albicans andCandida krusei in their oral cavity, four hadCandida albicans andCandida glabrata, and one hadCandida albicans andCandida tropicalis. Antifungal therapy consisted of ketoconazole (5 patients in the study group, 14 in the control group) or fluconazole (7 patients in the study group, 12 in the control group); no statistically significant difference in clinical outcome was observed. Fungal strain persistence after therapy was frequently observed in both groups. It is concluded that non-albicans strains ofCandida, less sensitive to azole drugs than theirCandida albicans counterparts, are not clinically relevant in episodes of mixed oropharyngeal candidiasis in HIV-1-infected patients.     

In vitro activity of amphotericin B,flucytosine and fluconazole against yeasts causing bloodstream infections

The in vitro activity of amphotericin B, flucytosine and fluconazole against 95 yeasts causing fungemia in a single institution over the last eight years was determined by a broth macromethod recommended by the National Committee for Clinical Laboratory Standards. All strains were inhibited by amphotericin B concentrations of 1 µg/ml. With flucytosine in most species the MIC50 was between 0.12 and 0.25 µg/ml and the MIC90 was between 0.25 and 1 µg/ml. One exception with flucytosine wasCandida krusei, with an MIC50 and MIC90 of 16 µg/ml and 32 µg/ml, respectively. Overall, 12 % of the isolates needed at least 8 µg/ml of fluconazole to be inhibited. Fluconazole was very active againstCandida albicans, Candida tropicalis andCryptococcus neoformans, with MIC50 ranging from 0.12 to 0.5 µg/ml and MIC90 of 1 µg/ml, and somewhat less active againstCandida parapsilosis (MIC50 of 1 µg/ml and MIC90 of 4 µg/ml). Fluconazole exhibited poor in vitro activity againstCandida krusei (MIC50 and MIC90 of 64 µg/ml) andTorulopsis glabrata (MIC50 of 4 µg/ml and MIC90 of 16 µg/ml). High MICs of fluconazole were found for four strains ofCandida albicans, one with an MIC of 4 µg/ml and three (5.7 %) with MICs of 16 µg/ml. Previous exposure to fluconazole could be demonstrated in two of these strains. Further work must be done in order to determine appropriate breakpoints of antifungal agents, to assess the clinical relevance of azole resistance in yeasts causing bloodstream infections and to identify risk factors for infections with azole-resistant yeasts.     

Fluconazole treatment of children with severe fungal infections not treatable with conventional agents

Fluconazole was evaluated prospectively in 173 children aged between 4 months and 16 years in whom conventional antifungal therapy was ineffective or contraindicated. Children entered the study on an individual compassionate request basis for treatment of confirmed or presumed fungal infection or for prophylaxis of fungal infections. Sixty-two children had cancer, 40 had undergone transplantation, 14 had AIDS and 52 had other conditions. The mean fluconazole dosage was 3.4 mg/kg/day (range 0.16–11.1 mg/kg/day) and the mean duration of therapy was 36 days (range 1–340 days). Efficacy was evaluated in 63 children with confirmed fungal infection as documented by the presence of a fungal pathogen at baseline; clinical cure or improvement was achieved in 83 % (52/63), pathogen eradication in 73 % (43/59). All 173 children were assessed for safety. Related or possibly related adverse events occurred in 6 % (11/173) of patients; seven children were withdrawn from therapy because of adverse events. Results of this study demonstrate that the clinical efficacy and safety profile of fluconazole in the treatment of fungal infections in children are favorable, results being similar to those obtained in adults.     

Predictive value of surveillance cultures for systemic infection due toCandida species

Weekly fungal surveillance cultures (1,542 cultures) of urine (475), stool (520) and oropharyngeal (547) specimens from 111 patients on the bone marrow transplant and hematologic malignancy services were analyzed. Forty-three percent of the patients were colonized by Candida albicans and 10.8 % by Candida tropicalis. There were 22 proven systemic fungal infections, ten due to Candida albicans,eight to Candida tropicalis,one each to Candida pseudotropicalis and Torulopsis glabrata,and two to Aspergillus species. Positive surveillance cultures for Candida tropicalis were highly predictive of systemic infection. The finding of two or more positive cultures yielded high positive predictive values (100%) as a function of body site. Positive surveillance cultures for Candida albicans were not predictive of disease but negative cultures for Candida albicans and Candida tropicalis had a high negative predictive value (95–99 %). Surveillance culture data for specific Candida species may aid in diagnostic and therapeutic decision making.     

Comparing the Profile of Respiratory Fungal Pathogens amongst Immunocompetent and Immunocompromised Hosts,their Susceptibility Pattern and Correlation of Various Opportunistic Respiratory Fungal Infections and their Progression in Relation to the CD4+T-cell Counts

Introduction: Invasive fungal infections are increasingly common in the nosocomial setting. Materials and Methods: The patients were divided into two groups immunocompetent and immunocompromised that is, patients with significant neutropenia <500 neutrophils/μl for longer than 10 days. microscopy, culture, identification of isolates were done and some specilised tests on serum and BAL for antigen detection were performed. Results: Majority of the patients were young adult males in this study. A higher prevalence of 26.7% was seen in immunocompromised patients. Amongst yeasts, Candida albicans was the predominant species followed by the National AIDS Control that is, Candida glabrata, Candida dubliniensis, Candida parapsilosis and Candida tropicalis in the same order. Amongst moulds, Aspergillus fumigatus was the most common species followed by Aspergillus flavus and Aspergillus niger. Mucor and Penicillium marneffei were seen in a lower prevalence. By Broth microdilution method, isolates of Candida spp. were most sensitive to caspofungin, amphotericin B, ketoconazole and fluconazole in the same order. Isolates of Aspergillus spp. were most sensitive to caspofungin, amphotericin B and itraconazole in the same order. By disc diffusion method, resistance to fluconazole was observed in 6.9% isolates of C. albicans. 50% of C. dubliniensis and 20% of C. glabrata showed resistance to fluconazole. A total mortality of 27.7% was observed during this study. This was distributed as 24.1%, 26.7%, 50%, 50%, 100% and 0% among by patients of candidiasis, aspergillosis, cryptococcosis, pneumocystosis, mucormycosis and penicilliosis. Fifteen per cent were lost to follow-up. Conclusion: Patterns of invasive fungal infections are changing in many ways. In the midst of these evolving trends, IFI of the respiratory tractcontinue to remain important causes of morbidity and mortality. Diagnostic tools can be adequately used only if the treating physician is aware of the propensity of patients to acquire a fungal infection. Thus, continuous awareness and education is crucial for successful management of patients. Judicious use of antifungal medications as prophylactic measures must be employed, particularly in the critically ill and patients of HIV.     

Treatment of orogastrointestinal candidosis in SCID mice with fluconazole alone or in combination with recombinant granulocyte colony-stimulating factor or interferon-gamma.

Mucosal candidosis is common in acquired immune deficiency syndrome (AIDS) patients, where there is extensive mucosal involvement, but rarely dissemination. To mimic this disease, SCID mice were inoculated orally with Candida albicans, which could be recovered from standardized tissue samples of the esophagus, stomach, small intestine and caecum of all mice. Treatment with fluconazole at 5 or 10 mg kg(-1) per day were equivalent to each other and efficacious in reducing the fungal burden from all four tissues compared with no treatment or lower doses of fluconazole (P < 0.01-0.001). Fluconazole at 5 or 10 mg kg(-1) reduced fungal burden in the stomach by about 200 or 580-fold, respectively, and by approximately 25-fold in the other tissues, with 80 or 100% of mice cleared of esophageal infection, and 40 or 80% cleared of infection in the small intestine, respectively; the same doses cleared < or =20% of stomach infection and none of caecal infection. Treatment with recombinant human granulocyte colony-stimulating factor (G-CSF) up to 500 microg kg(-1) per day or 10(5) U of murine interferon-gamma (IFN-gamma) alone was ineffective, nor were combinations with a suboptimal dose fluconazole synergistic. Overall, fluconazole had dose-responsive efficacy, whereas neither G-CSF nor IFN-gamma alone or in combination with fluconazole improved efficacy. These studies demonstrate the utility of this model for examining antifungal efficacy in a situation that mimics clinical disease in AIDS patients.     

Fungal Peritonitis in Patients on Continuous Ambulatory Peritoneal Dialysis

 The purpose of this study was to analyze the microbiological and clinical features of fungal peritonitis in patients with endstage renal failure treated with continuous ambulatory peritoneal dialysis (CAPD). The diagnosis of peritonitis was based on abdominal discomfort or pain, cloudy peritoneal effluent with an elevated leukocyte count and isolation of fungi from the peritoneal effluent. Amphotericin B, flucytosine, ketoconazole, miconazole and more recently fluconazole were used for antifungal therapy. From 1983 to 1997 13 patients experienced 14 episodes of fungal peritonitis, comprising 3.1% of all episodes of peritonitis in the dialysis centre. Isolates from the peritoneal effluent comprised Candida tropicalis in two cases, Candida parapsilosis in two cases, Candida albicans in one case, Candida lusitaniae in one case,Cephalosporium spp. in three cases, Aspergillus fumigatus in two cases, and an Aspergillus sp., a Trichoderma sp. and a yeast in one case each. In eight cases bacterial infection shortly before the episode of fungal peritonitis was documented. In 12 (86%) cases the peritoneal catheter had to be removed. Four patients died during the treatment, and one patient died 2 months after the end of treatment due to intra-abdominal bleeding from peritoneal adhesions. Only two patients continued CAPD later; the other patients were switched to hemodialysis. It is concluded that fungal peritonitis is a rare but serious complication in CAPD patients with high rates of morbidity, mortality and drop-out from the CAPD programme (85%). The most frequent isolates were Candida spp. A predisposing factor for fungal peritonitis could be a recent bacterial infection treated with antibiotics. Early peritoneal catheter removal is recommended.