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Development of zinc bioavailability and toxicity for the springtail Folsomia candida in an experimentally contaminated field plot.

The influence of outdoor exposure conditions and ageing of contamination on the toxicity of zinc was investigated for the springtail Folsomia candida to evaluate the validity of a standardised soil toxicity test. In three successive years, animals were incubated in an experimentally contaminated field plot. During the first months after construction of the test field, total zine concentrations of the soil decreased rapidly due to leaching of excess zinc with rainwater, while increased sorption of the remaining residues resulted in a reduced bioavailability of the metal. Although variation between replicates was substantial, the EC50s for the effect of zinc on reproduction of F. candida determined in the field experiments differed by less than a factor of two from effect concentrations obtained in laboratory tests in which the same soil was used. Expression of the EC50s on the basis of water soluble zinc allowed for a comparison with effect concentrations estimated for other soil types. EC50s were comparable with literature data, which indicates that bioavailability of zinc is the main factor determining toxicity for F. candida. It is concluded that laboratory based toxicity data are suitable to predict effects of zinc for F. candida under outdoor conditions, provided that the bioavailability of zinc is determined accurately using water soluble concentrations.

Journal Article↗

[Ophtalmoscopic examination in critically ill non-neutropenic patients: Candida endophtalmitis].

Invasive Candida (IC) infection is the most common cause of endogenous endophthalmitis. Ocular candidiasis develops within three days and at least two weeks of fungemia. There are two characteristic ocular signs: Candida chorioretinitis defined as retina and choroid lesions without vitreal involvement, and Candida endophthalmitis defined as chorioretinitis with extension into the vitreous with characteristic fluffy balls. The most common initial visual symptoms are blurred vision and floaters. Amphotericin B, fluconazole and voriconazole are effective in the treatment of chorioretinitis; however, when vitreous is involved vitrectomy seems necessary. Early antifungal systemic treatment at first evidence of infection in patients at risk of IC, appears to decrease dramatically the incidence of endogenous fungal endophthalmitis, probably healing minimal chorioretinal infections. Routine ophthalmoscopic examination seems of little value in patients with positive blood culture, with early implementation of antifungal treatment, without symptoms of ocular infection and without impairment of the level of consciousness during the episode. However, periodic ophthalmoscopic examination should be performed in children with candidemia and critically ill patients with documented deep Candida infection.

Candidiasis↗

A randomized trial of amorolfine 5% solution nail lacquer in association with itraconazole pulse therapy compared with itraconazole alone in the treatment of Candida fingernail onychomycosis.

BACKGROUND: Treatment failures and relapses are not uncommon in onychomycosis. Therefore, it is worthwhile to consider the combination of systemic and topical antifungals to improve the cure rates further and to reduce the duration of systemic treatment. OBJECTIVES: To evaluate and compare itraconazole pulse therapy combined with amorolfine with itraconazole alone in the treatment of Candida fingernail onychomycosis. METHODS: Ninety patients with moderate to severe Candida fingernail onychomycosis were randomized into two treatment groups of 45 subjects each. Group 1 received itraconazole pulse therapy for 2 months and applied amorolfine 5% solution nail lacquer for 6 months, while group 2 received monotherapy with three pulses of itraconazole. The primary efficacy criterion was the result of mycological examination at 3 months. The secondary criterion was the combined mycological and clinical response at 9 months. A pharmacoeconomic analysis was also performed to compare the cost-effectiveness of combined therapy vs. monotherapy. RESULTS: Eighty-five patients were analysed (73 women and 12 men, mean +/- SD age 44.2 +/- 12.9 years). Patients had a mean +/- SD of 3.64 +/- 2.0 nails involved and 228.6 +/- 148.0 mm2 of their nail surface diseased. The mean duration of onychomycosis was 11 months. Paronychial involvement was evident in 71 patients. C. albicans was isolated in 85 cases, C. parapsilosis in three and other Candida species in two cases. Side-effects were uncommon and in only one case led to withdrawal. At the 3-month visit, mycological cure was seen in 32 (74%) of 43 patients in group 1 and in 25 (60%) of 42 patients in group 2. At the 9-month visit, a global cure was seen in 40 patients (93%) in group 1 and in 34 patients (81%) in group 2. Statistical analysis showed no statistically significant difference (P > 0.1) between the two treatment groups. The cost per cure ratio was 1.63 and 1.70euro for groups 1 and 2, respectively. CONCLUSIONS: The combination of amorolfine and oral itraconazole, which interfere with different steps of ergosterol synthesis, exhibited substantial synergy. Compared with oral itraconazole alone, the combination achieved greater mycological cure and increased total cure rate. However, no statistically significant difference was documented for this number of observations. Combination treatment with amorolfine and two pulses of itraconazole is at least as safe and effective as three pulses of itraconazole, with a lower cost per patient. In our opinion, the addition of amorolfine to oral itraconazole pulse therapy is of value in the treatment of moderate to severe Candida fingernail onychomycosis.

Administration, Cutaneous↗

Itraconazole pulse therapy for the treatment of Candida onychomycosis.

In this open label, multicentre trial, 44 patients with clinical and mycological evidence of Candida onychomycosis were treated with itraconazole pulse therapy. Onychomycosis of the toes alone and concomitant disease involving the fingers and toes was treated with three pulses, and onychomycosis of the fingers alone with two pulses. Final evaluation for patients with finger and toe onychomycosis was at 6-9 months and 9-12 months, respectively. There were 29 patients with toe onychomycosis (C. albicans, 27; C. glabrata, one; Candida species, one), 12 patients with finger onychomycosis (C. albicans, two; C. glabrata, one) and three patients had combined toe and finger onychomycosis (C. albicans, two; C. guillermondii, one). In the patients with toe onychomycosis mycological cure was observed in 29 of 32 patients (90.6%). There was complete cure [mycological cure (negative culture and KOH at endpoint evaluation) with clinical cure] or marked improvement (mycological cure with 75% or greater decrease in area of involvement of target nail compared with pretherapy) in 24 of 32 patients (75.0%). All 12 patients with finger onychomycosis alone due to Candida species achieved a mycological cure (100%). In this group of patients complete cure or marked improvement was observed in 11 of 12 patients (91.7%). Itraconazole pulse therapy was well tolerated and no serious adverse events were reported in the patients treated with this triazole. In conclusion, itraconazole pulse therapy is an effective and safe treatment for both finger and toe onychomycosis associated with Candida.

Adult↗

Staged reimplantation of total knee arthroplasty after Candida infection.

Prosthetic joint infection with Candida is uncommon. Only 28 cases have been reported in the English literature. Successful reimplantation after eradication of Candida infection has been reported in 3 hip joints and only 1 knee. We present the case of a 68-year-old woman with chronic Candida parapsilosis infection of a prosthetic knee joint. Removal of the prosthesis, thorough débridement, and antifungal therapy treated the infection successfully. Antifungal therapy included 6 weeks of parenteral administration of fluconazole followed by 4 weeks of oral fluconazole. The involved knee joint was reimplanted 3 months after initial treatment. The prosthetic joint was pain free and functioned satisfactorily during the ensuing 4 years. No recurrence of infection was noted. The principle in treating Candida prosthetic infection generally has been the same as that of bacterial prosthetic infection. In chronic cases, removal of implants, thorough débridement, and effective antifungal therapy are mandatory for the eradication of infection. Reimplantation of the prosthesis can be performed successfully in a staged surgical procedure with the interval between the 2 stages shortened to 3 months.

Aged↗

[Bilateral candida endophthalmitis in 2 i. v. drug-dependent patients with oral L-methadone substitution].

BACKGROUND: Controlled therapy programs for former i.v. heroin abusers supervised by physicians offer levomethadone (L-Polamidon) as an oral substitute for heroin to allow social stabilisation of the addict. As well they reduce the risk of bloodborne infections (e.g. HIV and hepatitis) by giving up "needle sharing". Assuming that i.v. drug abuse is one of the major risk factors for Candida endophthalmitis in young, otherwise healthy patients, in case of strict oral substitution no onset of Candida endophthalmitis should be expected. CASE REPORT: The clinical courses of two HIV-negative and primarily i.v. heroin addicted young male white patients are presented. While participating in an exclusively controlled, oral program of methadone substitution for several months, both patients developed bilateral Candida endophthalmitis. CONCLUSION: A persisting i.v. abuse, either of heroin or of L-methadone, parallel to the supposingly strict orally applied substituting drug L-methadone has definitely to be suspected leading to the Candida endophthalmitis.

Administration, Oral↗

A new problem-solving indwelling voice prosthesis, eliminating the need for frequent Candida- and "underpressure"-related replacements: Provox ActiValve.

OBJECTIVES: To develop and clinically assess a new prosthesis for voice rehabilitation after total laryngectomy that solves the problem of frequent Candida- and "underpressure"-related replacements. MATERIAL AND METHODS: We designed a voice prosthesis with a new valve mechanism, applying Candida-resistant fluoroplastic (Teflon-like) material for the valve and valve seat and magnets to generate an active closing force, preventing inadvertent opening of the valve during swallowing or deep inhalation. Several prototypes were tested in 13 laryngectomized patients and, subsequently, the final design was assessed in a prospective clinical trial in a cohort of 18 patients with a short device lifetime of their standard indwelling voice prosthesis (mean 30 days). RESULTS: Prototype testing and the long-term clinical trial confirmed that the new valve material remained free of Candida growth and that the use of magnets can prevent inadvertent opening of the valve during swallowing and/or deep inhalation. This resulted in a highly significant increase in device lifetime in the 18 laryngectomized patients in the prospective trial (14-fold increase on average, range 3-39-fold; p < 0.001). Lubrication with special medical-grade fluoridated silicone oil is favorable in patients who experience possible adhesion of the valve to the valve seat. CONCLUSIONS: This new voice prosthesis, the Provox ActiValve, represents a solution for patients who have the problem of requiring very frequent voice prosthesis replacements due to excessive Candida growth and/or inadvertent opening of the valve by swallowing and inhalation-related underpressure in the esophagus.

Adult↗

Oesophageal defensin expression during Candida infection and reflux disease.

OBJECTIVE: Alpha (alpha-) and beta (beta-) defensins are major constituents of the innate defence system, providing rapid antimicrobial action. The expression of alpha- and beta-defensins in the oesophagus and stomach by quantitative, real-time, polymerase chain reaction (PCR) in healthy individuals was studied to define the influence of oesophageal Candida infection on their expression in comparison to oesophageal reflux disease. MATERIAL AND METHODS: Biopsy samples were taken from the upper gastrointestinal tract, mRNA was extracted, reverse transcribed into cDNA and real-time reverse transcription PCR (RT-PCR) analysis measuring transcript number of a-defensins and ss-defensins performed. Standard curves allowed quantification of gene copies per weight of mRNA. RESULTS: hBD-1, hBD-2 and hBD-3 had their highest expression levels in the oesophagus with factor 3 to 5 lower in the stomach. Candida oesophagitis resulted in massive up-regulation of hBD-2 (800-fold), while hBD-1 and hBD-3 expression were slightly increased. In addition, expression of HNP 1-3 was detected, indicating infiltration of neutrophil granulocytes. In reflux disease, an up-regulation of hBD-2 (20-fold) and hBD-3 (50-fold) could also be observed, while hBD-1, hBD-4 and HD5 remained unaffected. Cytokine expression of interleukin-1beta, interleukin-6 and interleukin-8 were increased in both groups, while interleukin-10 expression was elevated only in reflux lesions. CONCLUSIONS: Candida colonization induced a high expression of antimicrobial peptides. In oesophageal reflux disease, induction of defensin expression could also be observed but to a lower degree. Therefore, up-regulation of defensins might protect against invasive candidiasis and keep the Candida infection limited to the mucosal surface.

Adult↗

Multiple experimental designs to evaluate the role of T-cell-mediated immunity against experimental vaginal Candida albicans infection.

Studies to date suggest a limited protective role for Candida-specific Th1-type cell-mediated immunity (CMI) against Candida albicans vaginitis, despite protection against other mucosal Candida infections. Recent evidence suggests this may be due to immunoregulatory mechanisms that inhibit a more profound CMI response against C. albicans vaginal infections. The present study was designed to conduct an evaluation of the protective role of CMI against experimental C. albicans vaginitis using multiple approaches, including the use of T-cell-immunodeficient (SCID, Nude) and knockout (CD4) mice and several immunization designs in immunocompetent mice. Results showed, with few exceptions, that most T-cell-immunodeficient or knockout mice had a vaginal fungal burden similar to that of wild-type strains throughout the observation period. In addition, no correlation was observed between vaginal T-helper and proinflammatory cytokines and fungal burden, suggesting a generalized state of immunoregulation. Evaluation of the effects of various immunization designs that included different Candida antigens, routes of delivery and strains of mice yielded no protection against vaginal candidiasis. These studies provide further evidence of a lack of a protective role of T cells against C. albicans vaginitis, and continue to support the concept of immunoregulation against vaginal CMI responses.

Animals↗

Treatment of Candida infections with amphotericin B lipid complex.

The efficacy and renal safety of amphotericin B lipid complex (ABLC) were assessed in >900 patients with candidiasis. Overall, a favorable clinical response (cured or improved) was observed in 61% of patients infected with Candida species only, in 62% of patients infected with C. albicans, and in 61% of patients infected with a non-albicans Candida species. Clinical responses were similar in patients infected with invasive C. albicans and non-albicans Candida species (63% and 62%, respectively). Similarly, response rates of 60% and 59% were observed in patients infected with noninvasive C. albicans and non-albicans Candida species, respectively. Compared with patients who received lower doses of ABLC, patients who required higher doses of ABLC because of more-virulent infections did not demonstrate significant renal impairment, as assessed by end-of-therapy changes in serum creatinine level from baseline (median, 0.1 mg/dL; range, -3.9 to 2.4 mg/dL), incidence of serum creatinine doubling (16%), and need for new dialysis (7%). These data indicate the safety and efficacy of ABLC in treating candidiasis.

Adolescent↗

Candida and Aspergillus infections in immunocompromised patients: an overview.

Infection is a major cause of morbidity and mortality in granulocytopenic patients. With the increasing use of aggressive chemotherapy causing prolonged granulocytopenia in patients with cancer, the risk of disseminated fungal infection has increased. Although Candida and Aspergillus species are known to be the most common fungal pathogens responsible for disseminated infection, diagnosis of such infection may be difficult. The use of empiric amphotericin B for presumed disseminated candida infection may reduce morbidity caused by this fungal pathogen; moreover, amphotericin B remains the agent of choice for established candida infection, although fluconazole shows promise. The addition of flucytosine may enhance the efficacy of amphotericin B against Candida. Aspergillus infection is more difficult to treat. Early recognition of invasive aspergillosis and use of high-dose amphotericin B (1.0-1.5 mg/[kg.d]) alone or in combination with flucytosine may reduce associated mortality. More active, less toxic antifungal agents are needed to improve the efficacy of treatment and prophylaxis of disseminated fungal infection.

Agranulocytosis↗

Meningitis caused by Candida species: an emerging problem in neurosurgical patients.

Three cases of candida meningitis were encountered in a 3-year period in our hospital; all occurred in neurosurgical patients. We describe these three cases and review the 15 cases of neurosurgery-related candida meningitis previously reported in the English-language literature. Data regarding these 18 patients formed the basis for our review. Most patients with candida meningitis had recently received antibacterial agents, and it is notable that 50% of patients suffered from antecedent bacterial meningitis. The CSF analysis revealed neutrophilic pleocytosis that was indistinguishable from that of bacterial meningitis. The overall mortality was 11%. Administration of amphotericin B combined with flucytosine appeared to be the best therapeutic approach for candida meningitis.

Adult↗

Candida prosthetic valve endocarditis: prospective study of six cases and review of the literature.

Candida prosthetic valve endocarditis (PVE) is a rare entity; however, its incidence is expected to increase given the recent increase in incidence of nosocomial bloodstream candida infection. This report reviews six cases of candida PVE studied prospectively plus 12 cases previously reported in the literature. Transesophageal echocardiography was more sensitive than transthoracic echocardiography in detecting vegetations. Valvular replacement combined with antifungal therapy has been the standard treatment. However, successful therapy with long-term administration of oral fluconazole has been reported for five patients. The mortality due to candida PVE was high, especially when PVE was complicated by congestive heart failure and persistent fungemia. For uncomplicated PVE, the mortality rate for patients receiving antifungal therapy alone (40%) was no worse than for those receiving combined medical and surgical therapy (33%).

Adult↗

Candida antigen latex test for detection of invasive candidiasis in immunocompromised patients.

Candida antigen latex agglutination testing was performed twice weekly during 217 admissions of 200 patients undergoing intensive chemotherapy alone or supported by autologous or allogeneic bone marrow transplantation. Eleven patients developed invasive candidiasis, three of whom survived; 6 (54.5%) of the 11 had positive Candida antigens. In 206 admissions, invasive candidiasis could not be documented. Of the 60 patients who died, 41 underwent autopsy examination, and 29 (71%) had positive Candida antigens. The latex test was also positive in 30 (20.5%) of the survivors and 10 (53%) of the unautopsied patients. Serum creatinine levels were greater than 2 mg/dL in 61% and 13% of patients with positive and negative Candida antigens, respectively (P less than .0001). For patients in whom the presence or absence of invasive candidiasis could be unequivocally demonstrated, the sensitivity, specificity, and positive and negative predictive values of the latex test at a titer of 1:4 were 54.5%, 29%, 17%, and 70.5%, respectively, suggesting that the latex test should not be used to diagnose invasive candidiasis in immunocompromised patients.

Amphotericin B↗

Randomized trial of fluconazole versus nystatin for the prophylaxis of Candida infection following liver transplantation.

A prospective, randomized, multicenter study addressed the safety and efficacy of fluconazole therapy in 143 liver transplant patients. Seventy-six patients received daily oral fluconazole (100 mg), and 67 received nystatin (4 X 10(6) U) during the first 28 days after transplantation. Candida colonization occurred in 25% and 53% of patients in the fluconazole and nystatin groups, respectively (P = .04), and 13% and 34% of patients in the respective groups had Candida infections (P = .022). Of these patients, 10.5% in the fluconazole group and 25.3% in the nystatin group had superficial candidal infections (P = .024). Invasive candidiasis developed in 2 patients in the fluconazole group (2.6%) and 6 in the nystatin group (9.0%) (P = .12). There was no increased hepatotoxicity, cyclosporine interaction, or emergence of clinically relevant resistant Candida strains attributable to fluconazole. Thus, oral fluconazole (100 mg) is safe and reduces Candida colonization and infection after liver transplantation.

Adult↗

Candida septic thrombosis of the great central veins associated with central catheters. Clinical features and management.

Candida septic thrombosis of the great central veins is rarely diagnosed during life, and reports of survival with this condition are exceedingly rare. Eight patients with Candida septic thrombosis of the central veins, with six survivors, are reported. Seven of eight patients had multiple organ system failure following surgery or trauma. All patients had received broad spectrum antibiotics and total parenteral nutrition via a central catheter. Every patient showed features of venous thrombosis with localizing extremity edema and high grade candidemia. Intensive amphotericin B therapy (mean daily dose: 0.7 mg/kg) in all patients, combined with 5-fluorocytosine in five cases, resulted in cure and long-term survival in six patients who received 1600 to 3435 mg (mean: 26 mg/kg) total dose. None of these patients developed renal failure, while four showed improving renal function during treatment. In contrast to Candida endocarditis, septic central vein thrombosis caused by Candida appears to be curable medically in the majority of cases with intensive amphotericin B therapy (total dose: greater than or equal to 22 mg/kg), combined when feasible with 5-fluorocytosine.

Adult↗

Biofilm formation in infectious crystalline keratopathy due to Candida albicans.

Infectious crystalline keratopathy (ICK) is an uncommon, indolent corneal infection in which the slow clinical course contrasts with the rapid laboratory growth and microbiological sensitivities of the infecting organism. This prospective study aimed to determine whether biofilm production was the cause of this disparity. A case of failed medical management of ICK in a patient with Stevens-Johnson syndrome is presented. A penetrating keratoplasty yielded corneal tissue that was freshly fixed for electron microscopy using 0.05% ruthenium red and 2.5% gluteraldehyde. Candida albicans was grown from 3/3 broths, and fungi with morphology consistent with Candida were seen on histological examination. Electron microscopy revealed microorganisms morphologically typical of Candida surrounded by a polysaccharide-rich glycocalyx consistent with a biofilm. We concluded that Candida albicans is capable of producing a biofilm and is a known cause of ICK. This case is supportive evidence that biofilm production is associated with cases of ICK and may explain the chronic, pauciinflammatory features of ICK and its relative resistance to antibiotic treatment.

Biofilms↗

Candida fungemia in neonates treated with fluconazole: report of forty cases, including eight with meningitis.

PURPOSE OF THE STUDY: To assess efficacy and safety of fluconazole in neonates with Candida fungemia. STUDY DESIGN: Multicenter prospective protocol of all fungemias appearing between January 1, 1993, and December 31, 1997, in four major university hospitals. RESULTS: Forty neonates, 28 of them with very low birth weight (<1500 g; 30.5 median gestation week), with documented Candida albicans fungemia were treated with intravenous fluconazole in a daily dosage of 6 mg/kg once daily for 6 to 48 days. Thirty-four received fluconazole as monotherapy and 6 received it in combination with amphotericin B. Thirty-two (80%) were cured; 4 of them relapsed despite at least 14 days of therapy, but they were ultimately cured without sequelae. Eight other neonates died, 4 because of fungal infection and 4 because of prematurity or hemorrhage or lung failure, with fungemia (20% overall and 10% attributable mortality). Two neonates had elevated liver enzymes during fluconazole therapy and 2 others had elevated serum creatinine during fluconazole monotherapy. In none of them did these abnormalities necessitate discontinuation of antifungal therapy. In 8 neonates fungal meningitis developed as a complication of fungemia. All but 3 fungemias were C. albicans; 3 were Candida parapsilosis. CONCLUSIONS: Fluconazole was safe and effective antifungal therapy even in complicated or Candida fungemia in neonates and in infants with very low birth weight.

Antifungal Agents↗