Oropharyngeal candidiasis resistant to fluconazole in patients infected by HIV

Uncomplicated extracapsular cataract extraction (EC) followed by posterior chamber lens implantation (PCL) has been shown to cause long-term lowering of intraocular pressure (IOP) in most patients. Since it has been suggested that Neodymium: YAG (Nd:YAG) laser capsulotomy can provoke persistent glaucoma, we examined the hypothesis that Nd:YAG laser capsulotomy may lead to a permanent elevation of IOP. In a case-control study, we compared two groups of 75 normotensive patients, who were unilaterally pseudophakic after phacoemulsification (PE) + PCL. Patients in group 1 had undergone Nd:YAG capsulotomy at least 2 months prior to this study, while in group 2 the posterior capsule was intact. Both groups were selected at random. Prior to surgery, none of the patients had suffered from glaucoma. Goldmann applanation tonometry was performed in both eyes of each patient and from that the ratio of IOP(pseudophakic)/IOP(phakic) was calculated. The distribution of this ratio for the two groups was compared using the Wilcoxon signed-rank test. There were 52 female and 23 male patients in group 1 versus 56 female and 19 male patients in group 2. Their mean ages were 75 + or -11 (group 1) and 75 + or - 9 years (group 2). The mean interval after PE + PCL was 48 + or - 29 months for patients with Nd:YAG capsulotomy and 16 + or - 17 months for patients with intact posterior capsule. Since the Nd:YAG capsulotomy, 28 + or - 23 months had elapsed on average. The median ratio of IOP (pseudophakic)/IOP(phakic) was higher in the Nd:YAG capsulotomy group than in the group of patients with an intact posterior capsule (1.00 vs. 0.80; p < 0.0001). There was almost no percentile, for which the distribution curve of group 1 intersected the curve of group 2. The median IOP in pseudophakic eyes was 14 mm Hg in group 1 and 12 mm Hg in group 2 (p<0.0001). These results are in accordance with the hypothesis that Nd:YAG capsulotomy will raise IOP permanently in most patients. Therefore Nd:YAG capsulotomy may harbor the risk of glaucomatous optic nerve damage in the long run. Long-term follow-up seems advisable in order to prevent possible glaucoma damage.     

Comparison of therapeutic activity of fluconazole and itraconazole in the treatment of oesophageal candidiasis in AIDS patients: a double-blind, randomized, controlled clinical study

The aim of this study was to assess the role and therapeutic efficacy of two azole antifungal drugs, fluconazole and itraconazole, in the treatment of endoscopically-diagnosed Candida oesophagitis in patients with Acquired Immunodeficiency Syndrome (AIDS). The study considered 120 Human Immunodeficiency Virus (HIV)-positive patients (67 males and 53 females, mean age 27 +/- 5) at their first episode of oesophageal candidiasis diagnosed by endoscopy (Kodsi's grade II endoscopic classification). The patients were double-blindly randomized into 2 groups of 60 patients each according to the pharmacological therapy administered: a) the patients in the first group received fluconazole (100 mg b.i.d. per os); b) the patients in the second group received itraconazole (100 mg b.i.d. per os). In order to evaluate the efficacy of the pharmacological therapy, a clinical examination was performed every week up to the end of the follow-up period (2 months); endoscopic examination was performed at the end of pharmacological treatment (3 weeks). All patients selected for the study gave their informed consent. Complete remission of endoscopic lesions was observed in 45 patients (75%) in the fluconazole group and in 23 patients (38%) in the itraconazole group (p < 0.001); partial remission of endoscopic lesions was observed in 15 patients (25%) in the fluconazole group and in 28 patients (47%) in the itraconazole group (p < 0.05). No response was observed in 9 patients (15%) in the itraconazole group. Complete clinical remission was observed in 47 patients (78%) in the fluconazole group and in 44 patients (73%) in the itraconazole group (p = n.s.); partial clinical remission was observed in 13 patients (22%) in the fluconazole group and in 12 patients (20%) in the itraconazole group (p =- m.s.). No clinical response was observed in 4 patients (7%) in the itraconazole group. No side-effects worthy of note were observed in the patients of either treatment group. The results of this study demonstrated that fluconazole is associated with higher rates of endoscopic and clinical cure than itraconazole, with a statistically significant difference as regards endoscopic cure. Both drugs appear to be safe and well tolerated. Nevertheless, further controlled clinical investigations are needed to improve our knowledge of the therapeutic action of antifungal drugs in the treatment of Candida oesophagitis in HIV disease.     

Curative treatment with fluconazole in 5 cases of invasive candidiasis

BACKGROUND: Amphotericin B is the treatment of choice for invasive and disseminated Candida sp. infections. Fluconazole is an antifungal drug with less toxicity. Because of its pharmacokinetic properties, fluconazole can be specially useful in the treatment of invasive candidiasis. Although it is useful in several forms of candidiasis, its efficacy in deep-seated candidal infections is not totally proved due to the lack of comparative studies with amphotericin. In order to contribute new data about the usefulness of fluconazole in the treatment of invasive candidiasis, we report 5 patients which cured with this antifungal drug. METHODS: The clinical records of those patients with invasive candidiasis that cured with fluconazole were retrospectively reviewed. RESULTS: Fluconazole was used in 2 patients after detecting toxicity to amphotericin. Fluconazole was used from the beginning in the other 3 patients. None of the patients were neutropenic. All the patients cured without recurrence. CONCLUSIONS: In this series, the employment of fluconazole was a non-toxic and effective alternative to amphotericin B in nonneutropenic patients with invasive candidiasis.     

Candida infections in patients with acute leukemia: ineffectiveness of nystatin prophylaxis and relationship between oropharyngeal and systemic candidiasis

Ninety-three hospitalizations of 70 patients, who underwent induction chemotherapy for acute leukemia to determine the effectiveness of oral nystatin in preventing oropharyngeal and systemic candidiasis were reviewed. Sixty-two percent of patients who received prophylactic nystatin and 58% of patients who did not receive nystatin developed oropharyngeal candidiasis; 11% of patients who received prophylaxis and 21% of those who did not receive prophylaxis developed systemic candidiasis. The use of oral nystatin did not significantly diminish the risk of developing either type of Candida infection. Oropharyngeal candidiasis occurred more commonly in patients who had severe and prolonged leukopenia, had received more parenteral antibiotics, and had developed chemotherapy-induced mucositis. Systemic candidiasis developed almost exclusively in patients who had prior oropharyngeal candidiasis. Guidelines for the empiric use of amphotericin B in these patients are provided.     

A randomized comparison of fluconazole with amphotericin B as empiric anti-fungal agents in cancer patients with prolonged fever and neutropenia

The severity of heterochromia on sun-damaged skin is a good indicator for the risk of development of a skin cancer. Clinical photography under ultraviolet light allows to objectivate such a risk factor.     

Itraconazole oral solution versus clotrimazole troches for the treatment of oropharyngeal candidiasis in immunocompromised patients

The development of the nervous system appears to be under the control of multiple growth factors, neurotrophins and cytokines, which may be expressed either continuously or transiently throughout defined stages of cellular generation, proliferation or differentiation. Fibroblast growth factor (FGF) cytokines and their receptors are abundantly expressed in the embryonic nervous system but their localization at autonomic levels in the fetal spinal cord has not yet been detailed. Immunoreactivity to FGF-2, probably the best characterized member of the FGF family (FGF-1 to FGF-10) and of one of its high affinity receptors, FGFR-1, was found in autonomic neurons at embryonic day E14, the peak day of generation and proliferation in the common ventral motoneuron pool. It was also continuously present throughout the investigated subsequent stages (E15 to postnatal day P30). Immunogold electron microscopy revealed the cytoplasmic localization of FGF-2 and FGFR-1 in intermediolateral neurons, the major group of sympathetic preganglionic neurons in the spinal cord. In these neurons, immunocytochemistry from E14 onwards showed the co-distribution of both markers at the period of axonal outgrowth to peripheral targets, e.g. the adrenal medulla. Our findings suggest autocrine and/or paracrine actions of FGF-2 for sympathetic preganglionic development but do not support its role as a target-derived neurotrophic factor for autonomic neuron development.     

Efficacy of fluconazole in the treatment of upper gastrointestinal candidiasis in neutropenic patients with cancer: factors influencing the outcome

Fluconazole has proved to be effective in treating oropharyngeal and esophageal candidiasis in immunocompromised patients. However, sufficient data are lacking regarding the efficacy of this agent in neutropenic hosts. The aim of the present study was to determine the clinical and mycological efficacy of fluconazole and to define the factor(s) affecting the outcome of fluconazole therapy in severely neutropenic patients (peripheral neutrophil count, < 500/microL) with cancer who have oropharyngeal and/or esophageal candidiasis. One hundred eleven patients with 129 episodes of candidal infections were treated with intravenous and consequently oral fluconazole (200 mg/d and 100 mg/d, respectively). Overall clinical cure and mycological eradication rates were 82% and 56%, respectively. Persistent neutropenia (P < .01), infection with a non-albicans strain of Candida (P = .012), and administration of antifungal therapy during the second or a later neutropenic episode (P < .002) were independently associated with a worse outcome. We conclude that fluconazole is effective in the treatment of upper gastrointestinal candidiasis in neutropenic patients with cancer. Effective treatment of the underlying malignancy, with the resultant recovery from neutropenia, and the determination of the species of infecting Candida isolates are required for the prediction of the outcome of antifungal therapy.     

A reevaluation of nystatin in prophylaxis and treatment of oropharyngeal candidiasis

The incidence of oropharyngeal candidiasis is growing. The species of the genus Candida are extremely frequent among human colonizers. The changes in the yeast-human interaction by aging, debilitating, and immunosuppressive diseases, and the more aggressive medical interventions can explain this phenomenon. Antifungals are used both in prophylaxis and therapy, but the number of available agents remains scarce. Acquired resistance to the more commonly used antifungal agents, the azole compounds, is also an increasing threat, Policies for antifungal use should be established in order to maintain the therapeutic possibilities of the current compounds, The widespread use of systemic azoles, agents useful in deep mycosis, may increasingly exert a selective power for resistant variants. Superficial infections, such as oropharyngeal candidiasis, can be successfully controlled by nystatin, a classic polyene, which is very well tolerated and has very low rates of resistance. This review on the importance of oropharyngeal candidiasis emphasizes this therapeutic possibility, and is complemented by in vitro studies documenting the excellent activity of nystatin on both azole-susceptible and resistant strains.     

Options for the management of mucosal candidiasis in patients with AIDS and HIV infection

OBJECTIVE: To design a document model that provides reliable and efficient access to clinical information in patient reports for a broad range of clinical applications, and to implement an automated method using natural language processing that maps textual reports to a form consistent with the model. METHODS: A document model that encodes structured clinical information in patient reports while retaining the original contents was designed using the extensible markup language (XML), and a document type definition (DTD) was created. An existing natural language processor (NLP) was modified to generate output consistent with the model. Two hundred reports were processed using the modified NLP system, and the XML output that was generated was validated using an XML validating parser. RESULTS: The modified NLP system successfully processed all 200 reports. The output of one report was invalid, and 199 reports were valid XML forms consistent with the DTD. CONCLUSIONS: Natural language processing can be used to automatically create an enriched document that contains a structured component whose elements are linked to portions of the original textual report. This integrated document model provides a representation where documents containing specific information can be accurately and efficiently retrieved by querying the structured components. If manual review of the documents is desired, the salient information in the original reports can also be identified and highlighted. Using an XML model of tagging provides an additional benefit in that software tools that manipulate XML documents are readily available.     

Pharmacodynamics of fluconazole in a murine model of systemic candidiasis

In this study we defined the pharmacodynamic parameter that optimizes outcome in deep-seated Candida albicans infections treated with fluconazole. Using a murine model of systemic candidiasis, we conducted single-dose dose-ranging studies with fluconazole to determine the dosage of this drug that resulted in a 50% reduction in fungal densities (50% effective dose [ED50]) in kidneys versus the fungal densities in the kidneys of untreated controls. We found that the ED50 of fluconazole given intraperitoneally was 4.56 mg/kg of body weight/day (95% confidence interval, 3.60 to 5.53 mg/kg/day), and the dose-response relationship was best described by an inhibitory sigmoid maximal effect (Emax) curve. To define the pharmacodynamics of fluconazole, we gave dosages lower than, approximating, and higher than the ED50 of fluconazole (range, 3.5 to 5.5 mg/kg/day, equivalent to the ED16 to the ED75) to various groups of infected animals using three dose-fractionation schedules. For each total dose of fluconazole examined, the dose-fractionation schedules optimized the ratio of the area under the concentration-time curve (AUC) to the MIC (the AUC/MIC ratio), the ratio of the maximum concentration of drug in serum (Cmax) to the MIC, and the time that the drug remained above the MIC for the infecting C. albicans isolate. Similar reductions in fungal densities in kidneys were seen between groups that received the same total dose of fluconazole in one, two, or four equally divided doses. Thus, dose-fractionation studies demonstrated that the pharmacodynamic parameter of fluconazole that best predicted outcome was the AUC/MIC ratio.     

Weekly fluconazole for the prevention of mucosal candidiasis in women with HIV infection. A randomized, double-blind, placebo-controlled trial. Terry Beirn Community Programs for Clinical Research on AIDS

BACKGROUND: Candidiasis is a frequent complication of infection with the human immunodeficiency virus (HIV); however, few data exist about the natural history, prevention, and treatment of mucosal candidiasis in women. OBJECTIVE: To evaluate the safety and effectiveness of weekly fluconazole prophylaxis for mucosal candidiasis in women infected with HIV. DESIGN: Randomized, double-blind, placebo-controlled trial. SETTING: 14 sites participating in the Community Programs for Clinical Research on AIDS (CPCRA). PATIENTS: 323 women with HIV infection and CD4+ cell counts of 300 cells/mm3 or less. INTERVENTION: 200 mg of fluconazole per week or placebo. Open-label fluconazole for candidiasis prophylaxis was permitted after two oropharyngeal or vaginal episodes or one esophageal episode. MEASUREMENTS: Development of mucosal candidiasis, clinical and in vitro resistance of Candida species to fluconazole, survival, and adverse events. RESULTS: After a median follow-up of 29 months, 72 of 162 patients receiving fluconazole and 93 of 161 patients receiving placebo had at least one episode of candidiasis (relative risk [RR], 0.56 [95% Cl, 0.41 to 0.77); P < 0.001). Weekly fluconazole was effective in preventing oropharyngeal candidiasis (RR, 0.50 [Cl, 0.33 to 0.74]; P < 0.001) and vaginal candidiasis (RR, 0.64 [Cl, 0.40 to 1.00]; P = 0.05) but not esophageal candidiasis (RR, 0.91 [Cl, 0.48 to 1.72]; P > 0.2). Relative risks were similar for women who had a history of mucosal candidiasis (RR, 0.5 [Cl, 0.35 to 0.75]) and those who did not (RR, 0.69 [Cl, 0.35 to 1.34]). Absolute risk reduction for patients with a history of infection was 25.6 per 100 person-years, which is more than twice the reduction of 11.2 per 100 person-years seen in patients with no history of infection. This difference reflects the higher risk of patients who previously had an infection. Candida albicans was not usually resistant to fluconazole in vaginal specimens in clinical or in vitro settings; such resistance occurred in less than 5% of patients in each group. CONCLUSIONS: Weekly fluconazole (200 mg) seems to be safe and effective in preventing oropharyngeal and vaginal candidiasis. This regimen has a useful role in the management of HIV-infected women who are at risk for recurrent mucosal candidiasis.     

Vegetable versus animal protein diet in cirrhotic patients with chronic encephalopathy. A randomized cross-over comparison

In a randomized cross-over comparison, the effects of a mainly vegetable protein diet were compared with an animal protein diet in eight patients with cirrhosis and chronic permanent encephalopathy, under optimum lactulose therapy. After a run-in period, patients were fed two equi-caloric, equi-nitrogenous diets for 7 days (71 g total proteins), containing either 50 g protein of animal origin or 50 g vegetable proteins. In the last 3 days of each period, nitrogen balance was significantly better during the vegetable protein diet (+0.2 (SD 1.4) g vs. -1.7 (2.4); P < 0.01), the difference being entirely due to a reduced urinary nitrogen excretion. Average daytime integrated blood glucose was slightly higher during vegetable proteins, whereas insulin, plasma amino acids and ammonia were lower. The clinical grading of encephalopathy improved slightly on vegetable proteins, and psychometric tests improved significantly, but remained grossly abnormal. Compliance to dietary manipulation was good. The data prove that a mainly vegetable protein diet is worthwhile in cirrhotic patients with chronic encephalopathy under optimum lactulose therapy. Improved nitrogen balance may be related to more effective nitrogen use for protein synthesis, probably due to blunted hormonal response, and largely outweighs the effects on encephalopathy.     

Candidal meningitis in HIV-infected patients: treatment with fluconazole

Although mucocutaneous candidiasis is a common occurrence in HIV-infected patients, candidal meningitis is uncommon. We report 3 cases of candidal meningitis in HIV-positive patients, all intravenous drug abusers, and we discuss the clinical course and outcome, the treatment with fluconazole and possible prophylaxis.     

Pharmacokinetics of oral fluconazole in premature infants

Systemic infections with Candida albicans in neonates are a frequent and well recognized problem. The therapeutic gold standard in this situation is the combined intravenous antimycotic treatment with amphotericin B and flucytosine. Potential adverse effects of this regimen have encouraged the search for desirable alternatives. We report on the use of oral fluconazole in neonates with Candida albicans septicaemia. Three premature infants were treated with four courses of therapy. Pharmacokinetic studies were performed during each course. At oral doses of 4.5-6 mg/kg once a day, serum levels of fluconazole were within the therapeutic range during the entire dosage interval. Follow up showed microbiological and clinical cure in all patients with no side-effects. In one patient a dosage of 4 mg/kg per day lead to a microbiological relapse with sub-therapeutic serum levels. CONCLUSIONS: Oral fluconazole seems to be a safe and effective treatment for Candida albicans septicaemia even in premature infants.     

Clinical use of oral nystatin in the prevention of systemic candidosis in patients at particular risk

Systemic candidosis is currently a major concern among certain groups of patients at particular risk because of recent treatment modalities. To prevent spread of Candida albicans, in particular, from the orogastrointestinal tract antimycotic treatment would appear beneficial. So far, however, suitable drugs are rare. Polyenes, and in particular oral nystatin, are the main ones considered so far. More recently, the oral azoles have provided therapeutic alternatives. In this review the current role of nystatin and, in particular nystatin tablets, which are better accepted than suspensions at higher dose levels, is described, focusing on efficacy and safety as determined in controlled trials. Recent evidence suggests that oral application of nystatin tablets can be considered both efficacious and safe in the appropriate context. The relative potency of oral nystatin and systemic azoles, particularly ketoconazole and fluconazole, awaits final determination.     

Fluconazole-resistant recurrent oral candidiasis in human immunodeficiency virus-positive patients: persistence of Candida albicans strains with the same genotype

Thirty human immunodeficiency virus-positive patients carrying Candida albicans in their oropharynx were treated with fluconazole and were monitored for 90 to 570 days. Fluconazole-resistant C. albicans (MIC, > 32 micrograms/ml) appeared only in seven patients and only after 90 days of treatment corresponding to a total dose of more than 10 g. Resistance was not associated with resistance to other azole derivatives. Susceptible and resistant strains from each patient had the same genotype (as defined by electrophoretic karyotype and restriction fragment length polymorphism). Thus, the resistant strains were selected by the antimycotic treatment from the susceptible strain present in each case.     

Pretreatment with antithrombotic agents during radiofrequency catheter ablation: a randomized comparison of aspirin versus ticlopidine

OBJECTIVES: To compare the variations in intensive care (ICU) outcome in relation to variations in resources utilization and costs between a developed and a developing country with different medical and economical conditions. DESIGN AND SETTING: Prospective comparison between a 26-bed French ICU and an 8-bed Tunisian ICU, both in university hospitals. PATIENTS: Four hundred thirty and 534 consecutive admissions, respectively, in the French and Tunisian ICUs. MEASUREMENTS: We prospectively recorded demographic, physiologic, and treatment information for all patients, and collected data on the two ICU structures and facilities. Costs and ICU outcome were compared in the overall population, in three groups of severity indexes and among selected diagnostic groups. RESULTS: Tunisian patients were significantly younger, were in better health previously and were less severely ill at ICU admission (p < 0.01). French patients had a lower overall mortality rate (17.2 vs 22.5%; p < 0.01) and received more treatment (p < 0.01). In the low severity range, the outcome and costs were similar in the two countries. In the highest severity range, Tunisian and French patients had similar mortality rates, while the former received less therapy throughout their ICU stays (p < 0.05). Conversely, in the mid-range of severity, mortality was higher among Tunisian patients, and a difference in management was identified in COPD patients. CONCLUSION: Although the Tunisian ICU might appear more cost-effective than the French one in the highest severity group of patients, most of this difference appeared in relation to shorter lengths of ICU stay, and a poorer efficiency and cost-effectiveness was suggested in the mid-range severity group. Differences in economical constraints may partly explain differences in ICU performances. These results indicate where resource allocation could be directed to improve the efficiency of ICU care.     

Distinct patterns of gene expression associated with development of fluconazole resistance in serial candida albicans isolates from human immunodeficiency virus-infected patients with oropharyngeal candidiasis

Resistance to fluconazole is becoming an increasing problem in the management of oropharyngeal candidiasis in human immunodeficiency virus-infected patients. Strains obtained from five patients developed decreased fluconazole susceptibility over time. DNA strain typing confirmed the high degree of relatedness among isolates from one patient and the variability among isolates from different patients. Expression of genes involved in development of fluconazole resistance was monitored in each isolate using probes specific for ERG11 (lanosterol 14alpha-demethylase), MDR1 (a major facilitator), and CDR (ATP-binding cassette or ABC transporter) genes. Increased expression of CDR genes was detected in the series of isolates from two patients. Isolates from one of the two patients also demonstrated increased ERG11 expression, whereas isolates from the other patient did not. Increased levels of MDR1 mRNA correlated with increased resistance in sequential isolates from another patient. Initial overexpression of MDR1 with subsequent overexpression of CDR genes and a final isolate again overexpressing MDR1 were detected in serial isolates from another patient. In another patient, overexpression of these genes was not detected despite an eightfold increase in fluconazole MIC. In this patient, sequence data of the ERG11 gene revealed no point mutations associated with decreased susceptibility. Five different patterns of gene expression were observed in isolates recovered from five patients who developed resistance. Therefore, these experiments demonstrate that a variety of mechanisms or combinations of mechanisms are associated with the development of fluconazole drug resistance. Additional studies are needed to estimate the frequency and clinical impact of these mechanisms of resistance.