Clioquinol is a promising preventive morphological switching compound in the treatment of Candida infections linked to the use of intrauterine devices.

PURPOSE: Candida biofilm infections are frequently linked to the use of biomaterials and are of clinical significance because they are commonly resistant to antifungals. Clioquinol is an antiseptic drug and is effective against multidrug-resistant Candida. We investigated the effect of clioquinol and two other 8-hydroxyquinoline derivatives on Candida biofilm. METHODOLOGY: The ability to inhibit biofilm formation, inhibit preformed biofilm and remove established biofilms was evaluated using in vitro assays on microtitre plates. The action of clioquinol on biofilm in intrauterine devices (IUDs) was also investigated, describing the first protocol to quantify the inhibitory action of compounds on biofilms formed on IUDs. RESULTS: Clioquinol was found to be the most effective 8-hydroxyquinoline derivative among those tested. It prevented more than 90 % of biofilm formation, which can be attributed to blockade of hyphal development. Clioquinol also reduced the metabolic activity of sessile Candida but the susceptibility was lower compared to planktonic cells (0.031-0.5 µg ml-1 required to inhibit 50 % planktonic cells and 4-16 µg ml-1 to inhibit 50 % preformed biofilms). On the other hand, almost complete removal of biofilms was not achieved for the majority of the isolates. Candida spp. also showed the ability to form biofilm on copper IUD; clioquinol eradicated 80-100 % of these biofilms. CONCLUSION: Our results indicate a potential application in terms of biomaterials for 8-hydroxyquinoline derivatives. Clioquinol could be used as a coating to prevent morphological switching and thus prevent biofilm formation. Furthermore, clioquinol may have future applications in the treatment of Candida infections linked to the use of IUDs.

Antibiotic exposure as a risk factor for fluconazole-resistant Candida bloodstream infection.

Recent exposure to azoles is an important risk factor for infection with fluconazole-resistant Candida spp., but little is known about the role of antibacterial drug exposure in the emergence of drug-resistant Candida. We did a prospective nationwide surveillance study of candidemia in Israel and analyzed the propensity score-adjusted association between antifungal and antibacterial drug exposure and bloodstream infection with C. glabrata and fluconazole-resistant Candida isolates. Four hundred forty-four episodes of candidemia (450 Candida isolates, 69 [15%] C. glabrata isolates, and 38 [8.5%] fluconazole-resistant isolates) from 18 medical centers in Israel were included. C. glabrata bloodstream infection was strongly associated with recent metronidazole exposure (odds ratio [OR], 3.2; P < 0.001). Infection with a fluconazole-resistant isolate was associated with exposure to carbapenems, trimethoprim-sulfamethoxazole, clindamycin, and colistin (odds ratio, 2.8; P = 0.01). The inclusion of antibacterial drug exposure in a multivariable model significantly enhanced the model's predictive accuracy for fluconazole-resistant Candida bloodstream infection. Our findings may be relevant to the selection of empirical antifungal treatment and broaden the scope of antibiotic-associated collateral damage.

A rare case of Candida arthritis in a hemodialysis patient.

Patients on maintenance hemodialysis are particularly prone to opportunistic infections because of their increased exposure to antibiotics, frequent vascular access, and altered cellular immunity. This case report discusses a 63-year-old African American patient on maintenance hemodialysis who presented with acute painful swelling of her left knee and fever. She was diagnosed to have septic arthritis, candidemia, and arteriovenous (AV) graft infection caused by Candida albicans. The management included removal of the infected AV graft, intravenous fluconazole, and arthrotomy with lavage. The Candida infection subsided, but the patient continued to have knee swelling because of chronic synovitis. We believe that this is the first case of acute Candida septic arthritis in a patient with end-stage renal disease, where hematogenous spread was proven by positive C. albicans cultures from the blood, AV graft, and synovial fluid.

Antifungal prophylaxis in adult hematopoietic stem cell transplant recipients.

Invasive fungal infections (IFIs) are a frequent, costly and potentially life-threatening complication in hematopoietic stem cell transplant (HSCT) recipients. Most prevalent among the causative pathogens are Candida spp. and Aspergillus spp. Risk factors that further increase the risk of IFIs in this patient population include allogeneic transplant and acute graft versus host disease. Among strategies to improve outcomes is the administration of antifungal prophylaxis. However, optimal administration requires the identification of patients who are at the highest risk of developing a fungal infection, thus restricting concerns of drug cost, toxicity and resistance to those most likely to benefit. Currently, there are several antifungal agents recommended by the National Comprehensive Cancer Network for the prophylaxis of IFIs. These include fluconazole, itraconazole, voriconazole, posaconazole and micafungin. Fluconazole was widely considered the standard agent for prophylaxis in patients at lower risk of mold infections. New data support the efficacy of the newer triazole posaconazole and the echinocandin micafungin in this patient population..

Antifungal activity of the plant Dodonaea viscosa var. angustifolia on Candida albicans from HIV-infected patients.

THE AIM OF THIS STUDY: was to determine the minimum inhibitory concentration (MIC) and the time taken by Dodonaea viscosa var. angustifolia (PLE) a South African medicinal plant, chlorhexidine gluconate (CHX) and triclosan (TRN) to kill Candida albicans. 41 strains of Candida albicans were investigated, 20 from HIV-positive patients, 20 from HIV-negative subjects and Candida albicans ATCC 90028. The MICs of an acetone extract of PLE, CHX and TRN were measured using a microtitre double dilution technique, and the time taken to kill 99.5% of the strains was determined. The MICs of PLE, CHX and TRN were 6.25-25, 0.008-0.16 and 0.0022-0.009 mg/ml, respectively. PLE killed all the test strains within 30s and CHX 40% of the isolates from HIV-positive patients and 20% of strains from HIV-negative subjects in 1 min. During the same time TRN killed 55% and 35% of isolates from HIV-positive and HIV-negative patients. Dodonaea viscosa var. angustifolia has antifungal properties and is more effective than commercially available mouthrinses.

[Potential of anidulafungin in hematological patients]. / Potencial de anidulafungina en el paciente hematológico.

Until relatively recently, the treatment available for invasive fungal infections in hematological patients consisted of amphotericin B and azoles. Each of these groups had limitations and secondary effects. The echinocandins are a new class of antifungal agent that has shown promising results in the treatment of numerous invasive fungal infections. Anidulafungin is a new echinocandin that, in addition to showing potent in vitro activity against Aspergillus spp. and Candida spp. (including fluconazole- and amphotericin B-resistant microorganisms), also provides some advantages over other candins. In humans, these drugs are degraded through biotransformation rather than a metabolic process. No drug interactions have been found. In hematological patients, anidulafungin would play a "potential" role as empirical therapy in febrile neutropenia, as is the case of caspofungin. Given the epidemiology of Candida infection in these patients, anidulafungin could be used as initial therapy in candidemia before starting treatment with oral flucozanole, if indicated by the fungigram. This drug would also be indicated in the treatment of invasive Aspergillus spp. infections in patients with hepatic or renal insufficiency or in those taking concomitant medications. The available in vitro studies also suggest an important role for this drug in combinations of antifungal agents. Given the excellent safety profile and absence of interactions of anidulafungin, this drug will undoubtedly be of great utility in the management of difficult-to-treat mycotic infections in hematological patients.

Síndrome autoinmune poliglandular tipo II: reporte de un caso y revisión de la literatura / Autoinmune polyglandular syndrome type II: a case report and review of literature

El síndrome autoinmune poliglandular (SAP) corresponde a una infrecuente entidad clínica que se reconoce por el compromiso de dos o más glándulas endocrinas basados en mecanismos autoinmunes, siendo posible además la afectación de órganos no endocrinos por esta misma causa. Debido a esto último el término síndrome autoinmune "poliendocrino", antes utilizado frecuentemente, ya no es completamente aceptado para referirse a esta patología. Actualmente existen dos grupos clásicos (SAP tipo I y tipo II) los cuales se clasifican de acuerdo a la edad de presentación de la enfermedad, combinaciones características de órganos comprometidos y patrón hereditario, entre otros. Además se describen otros dos grupos de menor importancia clínica llamados SAP tipo III y IV. A continuación se presenta un caso clínico pediátrico de SAP tipo II diagnosticado en el Hospital Herminda Martín de Chillán y una revisión actualizada de la literatura correspondiente.

Systemic Candida infections in patients with leukemia: an overview of drug therapy.

Systemic fungal infections are becoming increasingly common in patients with hematologic malignancies receiving antineoplastic therapy. The presence of acute myeloid or acute lymphoid leukemia, plus the use of chemotherapy to totally ablate malignant bone marrow cells, puts patients in a protracted neutropenic state. During this profound and prolonged neutropenic phase, patients receive antibiotic therapy for suspected or identified bacterial infections. However, when fever or other signs of infection continue despite antibiotic therapy, patients frequently need to be treated for suspected or identified systemic fungal infections. These infections may occur in patients receiving either standard antileukemia therapy or research protocol therapy involving new drugs, new drug combinations, higher doses, or newer schedules of established drugs. After antifungal therapy is initiated, it may be continued postdischarge in outpatient or homecare settings. Therefore, becoming knowledgeable about antifungal therapy is important for all oncology nurses regardless of practice setting.

Clinical and mycological responses to fluconazole and fluconazole MIC in oropharyngeal candidiasis in HIV-infected patients.

INTRODUCTION: OPC is a common opportunistic infection in HIV-infected patients. Although some patients are asymptomatic, progression of the disease may occur leading to esophageal candidiasis. Fluconazole resistant candidiasis has been reported in several international studies. OBJECTIVES: This study aimed to test the MICs (minimal inhibitory concentrations) to fluconazole of Candida species isolated from mouthwash specimens of 54 HIV positive patients with oral candidiasis. Clinical and mycological responses to fluconazole were also assessed in 16 patients. MATERIAL AND METHOD: This was a prospective study. Mouthwash specimens were cultured on sabouraud dextrose agar twice. Candida species identification was performed and MICs for fluconazole were obtained using NCCLS guidelines. Clinical and mycological responses were assessed on day 14 and 42 in 16 patients who received a 14-day course of fluconazole. RESULTS: 48/54 patients (88.89%) were found to carry pure C. albicans. The other 6 patients (11.11%) had mixed Candida species on cultures. Among these 6 patients, 5 patients had mixed C. albicans and C. glabrata, and 1 patient had C. albicans and C. krusei. Fluconazole MICs of C. albicans, C. glabrata, and C. krusei ranged from 0.125-32 (median=0.250), 4-64 (median=2), and 8 g/L respectively. This study showed that the MICs to fluconazole of oropharyngeal Candida was a good predictor of the therapeutic responses.

Candida glabrata oropharyngeal candidiasis in patients receiving radiation treatment for head and neck cancer.

Candida glabrata colonization is common in patients receiving radiation treatment for head and neck cancer, but to our knowledge has never been described as the infecting organism with oropharyngeal candidiasis (OPC). This study presents the first three patients described with C. glabrata OPC in this patient population. Patient 1 developed C. glabrata OPC and required fluconazole, 800 mg/day, for clinical resolution. Antifungal susceptibility testing revealed a MIC of fluconazole of >64 microg/ml. Elapsed time from initial culturing to treatment decision was 7 days. Patients 2 and 3 developed C. glabrata OPC. They were patients in a study evaluating OPC infections, and cultures were taken immediately. CHROMagar Candida plates with 0, 8, and 16 microg of fluconazole/ml were employed for these cultures. Lavender colonies, consistent with C. glabrata, grew on the 0- and 8-microg plates but not on the 16-microg plate from patient 2 and grew on all three plates from patient 3. Based on these data, a fluconazole dose of 200 mg/day was chosen for patient 2 and a dose of 400 mg/day was chosen for patient 3, with clinical resolution in both. Elapsed time from initial culturing to treatment decision was 2 days. C. glabrata does cause OPC in head and neck radiation treatment patients, and the use of fluconazole-impregnated chromogenic agar may significantly reduce treatment decision time compared to that with conventional culturing and antifungal susceptibility testing.

Increased neutrophil motility by beta-glucan in the absence of chemoattractant.

Systemic candidasis is a life-threatening complication of antibiotic and immunosuppressive therapies and can alter host defense mechanisms through pathways that are poorly understood. Promotion of polymorphonuclear leukocyte (PMN) chemotaxis by beta-glucan towards fMLP or IL-8 gradients demonstrates a fundamental effect on host defenses by pathogenic fungi. The aim of the present study was to determine whether recognition of beta-glucan is sufficient to alter PMN motility in the absence of agonists of G-coupled protein chemotactic receptors. Present findings demonstrate a profound increase in PMN motility by beta-glucan supplementation of a fibronectin substratum in an underagarose migration assay. Motility on beta-glucan included a 3-fold increase in distance of migration, as well as a 5-fold increase in the number of PMNs recruited into the motile phase as compared to motility on fibronectin alone. This promotion of motility is determined by the beta2 integrin complement receptor 3 (CR3) (CD11b/CD18) rather than the beta1 integrin very late antigen 3 (VLA-3), which mediates chemotaxis on beta-glucan-supplemented matrix towards fMLP. PMN motility on beta-glucan-supplemented fibronectin was selectively decreased by inhibitors of pp60 src and ras, whereas motility was promoted by inhibition of p38-MAPK. No effect of these inhibitors was seen on PMNs migrating on fibronectin alone. Migration on beta-glucan-supplemented fibronectin, but not on fibronectin alone, was negatively regulated by protein kinase C (PKC) or cAMP activation. These findings indicate that beta-glucan is sufficient to alter the migratory capacity of PMN in the absence of costimulation by fMLP. Enhanced PMN migration on beta-glucan is mediated through specific integrins and second messenger pathways that are distinct from those utilized by PMNs migrating in the absence of beta-glucan.

Fungal colonization and invasive fungal infections following allogeneic BMT using metronidazole, ciprofloxacin and fluconazole or ciprofloxacin and fluconazole as intestinal decontamination.

Invasive fungal infections (IFI) are increasingly diagnosed in patients undergoing allogeneic BMT. We have previously shown that the addition of metronidazole to ciprofloxacin for gastrointestinal bacterial decontamination significantly reduces the incidence of grades II-IV aGVHD by reduction of the anaerobic intestinal bacterial flora. Here, we found that the combined use of ciprofloxacin, metronidazole and fluconazole as antifungal prophylaxis increased intestinal yeast colonization when compared to ciprofloxacin and fluconazole alone (P < 0.01). Based on the EORTC criteria, a total of 18 out of 134 study patients developed IFI: seven of 68 (10%) patients who received metronidazole compared to 11 of the 66 (17%) patients decontaminated without metronidazole developed IFI (log-rank P = 0.36). Lethal IFI occurred in two of seven patients receiving metronidazole and in four of 11 patients without anaerobic decontamination. In conclusion, bacterial intestinal decontamination using metronidazole as an antibiotic with activity against most anaerobic intestinal bacteria significantly increases the intestinal yeast burden without influencing the incidence of IFI in patients undergoing allogeneic BMT.

Multiple organ dysfunction syndrome induced by whole-body hyperthermia and polychemotherapy in a patient with disseminated leiomyosarcoma of the uterus.

OBJECTIVE: Whole-body hyperthermia (WBH) in combination with chemotherapy is a relatively new promising treatment modality for patients with cancer. The objective of this report is to present the development of an acute systemic inflammatory response syndrome (SIRS) with multiple organ dysfunction syndrome (MODS) following WBH in combination with chemotherapy. Although WBH can also induce cytokine production, MODS has not been described before in association with WBH. DESIGN: Case report. The patient was treated with WBH (core temperature 41.8 degrees C using a radiant heat device (Aquatherm) ) in combination with polychemotherapy (ifosfamide, carboplatin and etoposide (ICE) ) in the context of a clinical trial for metastatic sarcomas. SETTING: Department of medical oncology and intensive care unit of a university hospital. PATIENT: A 58-year-old Caucasian woman treated for disseminated leiomyosarcoma of the uterus, who developed SIRS with brain dysfunction, hypotension, respiratory failure and renal dysfunction following WBH/ICE. INTERVENTIONS: She was successfully treated in the intensive care unit by mechanical ventilation, inotropics and antibiotics. MEASUREMENTS AND RESULTS: There was a remarkable recovery within 2 days: she regained full conciousness, could be extubated, inotropic support was stopped and creatinine levels returned to pre-treatment levels. All cultures remained sterile. After almost complete recovery, 5 days later a second episode of fever during neutropenia occurred and, despite antibiotic treatment, she died of Bacteroides distasonis sepsis. CONCLUSION: WBH should be added as a new cause to the already known list of physical-chemical insults which can result in MODS.

Candida lambica polyarthritis in a patient with chronic alcoholism.

We describe a patient with an indolent polyarthritis over a period of several years caused by Candida lambica probably acquired from a contaminated wound. C. lambica has not been previously reported to cause infectious arthritis. Hematogenous spread was manifest by 4 separate sites of involvement. Chronic alcoholism was the only apparent risk factor for dissemination. The infection seems to be environmentally acquired.

Fungal prophylaxis by reduction of fungal colonization by oral administration of bovine anti-Candida antibodies in bone marrow transplant recipients.

Candida overgrowth and invasion constitute a serious threat with a high mortality in BMT recipients. Currently available topical antifungal prophylaxis is largely ineffective, and as resistance to existing, absorbable drugs for systemic use is rapidly developing, new forms of therapy are needed. We investigated the effect of oral treatment of BMT recipients with a bovine immunoglobulin product derived from animals immunized against several Candida species. The natural Candida colonization was first followed in 19 patients to establish the colonization pattern. Half of the patients were found to be colonized prior to transplantation and altogether 72% were colonized at some point during follow-up. Those with a high pre-transplant concentration of Candida in saliva (>100 CFU/ml) remained colonized throughout the BMT treatment period. The therapeutic effect was monitored in two other patient groups. The first group consisted of nine patients, where, due to a low number of primary colonized patients, response in colonized patients was suggestive of a therapeutic effect. In the second group, 10 patients with a high level of colonization (>100 CFU/ml) were given 10 g daily of the product in three divided doses. The results suggest a treatment-related reduction in Candida colonization in a majority (7/10) of patients and one patient became completely negative. As no adverse effects were noted, our findings encourage additional studies in immunocompromised, transplant patients.

Use of ciprofloxacin as a prophylactic agent in urinary tract infections in renal transplant recipients.

The most common form of bacterial infection in renal transplant recipients is urinary tract infection (UTI), and some studies have shown that prophylaxis can reduce this incidence. In the present investigation we evaluated 80 patients submitted to renal transplantation at the Renal Transplant Unit of the University Hospital of Ribeirao Preto, SP. The study was prospective, double blind and randomized. The patients were divided into two groups, one receiving placebo and the other ciprofloxacin at the dose of 250 mg twice a day for the first 10 d and 250 mg/d for 6 months after transplantation. Of the 41 patients who received ciprofloxacin 28 completed the study, and of the 39 patients who received placebo 30 completed the study. The largest number of UTI occurred in the placebo group, with a significant difference from the ciprofloxacin group during the first month after surgery (p < 0.05). In the group treated with ciprofloxacin, only 6/40 patients (15%) developed UTI, as opposed to 19/39 (48.7%) for the placebo group. The total number of infectious episodes was higher in the placebo group (26) than in the ciprofloxacin group (12). The medication was well tolerated throughout the study period.

The role of the gastrointestinal tract in hematogenous candidiasis: from the laboratory to the bedside.

The gastrointestinal (GI) tract is a frequent source of hematogenous candidiasis in humans. Animal models of GI and hematogenous candidiasis have provided insights into the nature of candidal infection of host mucosal tissue, mechanisms of fungal dissemination to body organs, and features of host response to candidal infections. Biological systems such as these that simulate human candidiasis can be used for testing novel antifungal drugs. We have focused on two murine models of candidiasis with similarities to this fungal disease in humans. The first model simulates a commensal association of Candida albicans with the GI tract of immunocompetent hosts; it has permitted studies of innate and immune cell response to long-term ( > 60 days) infection of the esophageal, gastric, and intestinal mucosa. The second model simulates candidal infection in granulocytopenic patients with invasive candidiasis that originated from sites of colonization in the gut. Both models are well suited for investigating new approaches to prevention and treatment of hematogenous candidiasis. A review of the data on the role of GI candidiasis in hematogenous candidal infections is presented.

Protection of C3H/HE J mice from development of Candida albicans infection by oral administration of Juzen-taiho-to and its component, Ginseng radix: possible roles of macrophages in the host defense mechanisms.

Protective effect of a Japanese traditional herbal medicine, Juzen-taiho-to (TJ-48), which was recently reported to augment host-mediated antifungal actions, in Candida albicans-infected mice was further studied. TJ-48, given orally once daily for 5 consecutive days in a dose of 2 g/kg after intravenous infection of C. albicans, prolonged survival period of infected mice of a C3H/He J strain which is characteristic of functional deficiency of macrophages, but did not that of infected mice of a C3H/He N strain with normal macrophage function. Peritoneal macrophages obtained from C3H/He J mice showed a moderate inhibitory activity against Candida growth in vitro. The anti-Candida activity of the macrophages was augmented by the addition of TJ-48 or some component extracts of TJ-48 to the incubation medium. Among such active component extracts is an extract of Ginseng radix which was demonstrated to enhance the anti-Candida activity of macrophages in vitro and to prolong the survival time of C. albicans-infected C3H/He J mice without effect on C3H/He N mice. On the base of these findings, the mechanisms underlying the protective action of TJ-48 against systemic Candida infection was discussed in relation with its possible activity to activate the macrophage function.