Fluconazole non-susceptible breakthrough candidemia after prolonged low-dose prophylaxis: a prospective FUNGINOS study.

OBJECTIVES: Breakthrough candidemia (BTC) on fluconazole was associated with non-susceptible Candida spp. and increased mortality. This nationwide FUNGINOS study analyzed clinical and mycological BTC characteristics. METHODS: A 3-year prospective study was conducted in 567 consecutive candidemias. Species identification and antifungal susceptibility testing (CLSI) were performed in the FUNGINOS reference laboratory. Data were analyzed according to STROBE criteria. RESULTS: 43/576 (8%) BTC occurred: 37/43 (86%) on fluconazole (28 prophylaxis, median 200 mg/day). 21% BTC vs. 23% non-BTC presented severe sepsis/septic shock. Overall mortality was 34% vs. 32%. BTC was associated with gastrointestinal mucositis (multivariate OR 5.25, 95%CI 2.23-12.40, p < 0.001) and graft-versus-host-disease (6.25, 1.00-38.87, p = 0.05), immunosuppression (2.42, 1.03-5.68, p = 0.043), and parenteral nutrition (2.87, 1.44-5.71, p = 0.003). Non-albicans Candida were isolated in 58% BTC vs. 35% non-BTC (p = 0.005). 63% of 16 BTC occurring after 10-day fluconazole were non-susceptible (Candida glabrata, Candida krusei, Candida norvegensis) vs. 19% of 21 BTC (C. glabrata) following shorter exposure (7.10, 1.60-31.30, p = 0.007). Median fluconazole MIC was 4 mg/l vs. 0.25 mg/l (p < 0.001). Ten-day fluconazole exposure predicted non-susceptible BTC with 73% accuracy. CONCLUSIONS: Outcomes of BTC and non-BTC were similar. Fluconazole non-susceptible BTC occurred in three out of four cases after prolonged low-dose prophylaxis. This implies reassessment of prophylaxis duration and rapid de-escalation of empirical therapy in BTC after short fluconazole exposure.

Diferencias entre 2 electrocardiogramas sinusales como predictoras de fibrilación auricular: estudio de cohorte / Variations between 2 ECG as predictors of atrial fibrillation: Cohort study

Resumen Objetivo Evaluar la asociación entre las diferencias de mediciones de 2 ECG separados en el tiempo, con el desarrollo de fibrilación auricular (FA). Método Cohorte retrospectiva de 9,975 pacientes adultos, afiliados a la prepaga del Hospital Italiano de Buenos Aires, Argentina, con realización de al menos 2 ECG sinusales digitales entre 2006-2011. Se siguieron clínicamente para la detección de FA. Todas las mediciones electrocardiográficas y los deltas (diferencias entre los 2 ECG) fueron estandarizadas. Se estimaron los hazard ratio para desarrollo de FA, para cada delta de los distintos componentes electrocardiográficos utilizando un modelo de regresión de Cox. Resultados Durante una mediana de seguimiento de 3,5 años se detectaron 189 episodios de FA. El delta FC, delta intervalo ST y delta amplitud onda P se asociaron significativamente a FA. Ajustado por características clínicas y mediciones de ECG basal, el hazard ratio ajustado para FA fue 0.86 (IC95%: 0.75-0.98, p = 0.024) para delta FC; 1.12 (IC95%0.98-1.27, p = 0.082) para delta intervalo ST; y 1.21 (IC95%: 1.05-1.38, p = 0.006) para delta amplitud onda P. Conclusiones Las diferencias FC y amplitud onda P, entre mediciones de ECG, predicen FA en forma independiente de características clínicas y mediciones de ECG basal.

Abstract Objetive To evaluate the association between delta variations in the parameters of 2 sinusal ECG with atrial fibrillation (AF) onset. Method Retrospective cohort of 9,975 adult patients and members of the prepaid system at Hospital Italiano de Buenos Aires from Argentina, who had at least 2 sinusal ECG between 2006 and 2011. Population was followed up for detection of AF. All measurements and electrocardiographic deltas (differences between the 2 ECG) were standardized. Hazard ratio (HR) was estimated for the development of AF for each delta of the different ECG parameters using a Cox regression model. Results During a median follow up of 3.5 years, 189 patients (1.89%) developed AF. Heart rate delta, ST interval delta and P wave amplitude were predictors of AF. Hazard ratio Adjusted for clinical characteristics and ECGbasal values was 0,86 (CI95%: 0.75-0.98, p = 0.024) for heart rate delta, 1.12 (CI95%: 0.98-1.27, p = 0.082) for ST interval delta and 1.21 (CI95%: 1.05-1.38, p = 0.006) for P wave amplitude delta. Conclusion Differences of heart rate and P wave amplitude between ECG's measurements may predict AF, independently of clinical features and ECGbasal values.

Emerging invasive zygomycosis in a tertiary care center: epidemiology and associated risk factors.

OBJECTIVES: Invasive zygomycosis is a rare fungal opportunistic disease with a high morbidity and mortality rate, predominantly affecting immunosuppressed patients. Presented herein is our investigation of the epidemiological factors associated with an increasing incidence of the disease at the University of Geneva Hospitals, Geneva, Switzerland, over the past five years. METHODS: This was a retrospective study of the clinical charts and microbiology records of patients with a positive culture for zygomycetes, to evaluate predisposing factors and epidemiological characteristics. RESULTS: Three of 19 proven/probable invasive infections were diagnosed during 1989-2003, and 16 during 2003-2008. While the number of positive isolates for zygomycetes remained mainly stable, the ratio between invasive infections and colonized patients increased after the introduction of voriconazole and caspofungin in 2003 at our institution (p<0.001). All cases were unrelated and no nosocomial source of exposure or seasonal aggregation was identified. The increase in cases was coincident with an incremented use of voriconazole and caspofungin, and with an increased number of immunosuppressed patients, especially allogeneic bone marrow transplant recipients. CONCLUSIONS: Invasive zygomycosis is an emerging infection at our center and is probably related to an increase in immunosuppressed patients and the wide use of newer antifungals. Changes in antifungal drug prophylaxis and treatment prescription may help to control this emergence.

Report of a successful treatment of pulmonary Cunninghamella bertholletiae infection with liposomal amphotericin and posaconazole in a child with GvHD and review of the literature.

Zygomycosis is an emerging, opportunistic fungal infection particularly affecting immunocomprised patients. We report the case of a 10-year-old girl who developed pulmonary zygomycosis because of Cunninghamella bertholletiae 1 year after undergoing bone marrow transplantation complicated with severe cutaneous and digestive graft-versus-host disease. Treatment with surgery and liposomal amphotericin B followed by posaconazole successfully treated the infection.

Cladophialophora bantiana: a rare cause of fungal brain abscess. Clinical aspects and new therapeutic options.

Black molds or dematiaceous fungi are rare etiologic agents of intracerebral abscesses and such infections carry a high mortality of up to 70% despite combined surgical and antifungal therapy. While the growing use of immunosuppressive therapies and organ transplantation have caused an increase in the incidence of rare fungal cerebral infections, occurrence in immunocompetent hosts is also possible. We describe a 60-year-old female patient with a cerebral abscess caused by Cladophialophora bantiana. The case illustrates the clinical and radiological similarities between glioblastomas and brain abscesses and emphasizes the need to perform histological and microbiological studies prior to the initiation of any form of therapy. Long-term survival from cerebral black mold abscesses has been reported only when complete surgical resection was possible. The recommended antifungal treatment involves the use of amphotericin B combined with a triazole and, if possible, flucytosine. Highly-active new generation triazole antifungal compounds (voriconazole or posaconazole) are likely to offer improved survival rates for patients with rare mold infections. In particular, posaconazole could be a new therapeutic option given its better tolerance, lower toxicity and fewer drug-drug interactions. We discuss clinical, microbiological and practical pharmacological aspects and review current and evolving treatment options.

Immunomodulatory therapy in yeast infections.

Invasive yeast infections are a significant cause of morbidity and mortality in patients with defective immune response, such as those with cancer-related immunosuppression, organ transplantation or other immunodeficiencies, and neonates. Hospitalization in the intensive care unit may increase the risk for such infections. Despite the advent of new antifungal agents, the problem is escalating as the number of susceptible hosts increase and virulent, more resistant fungal strains emerge. Over the past few years, advances in immunology and molecular biology have greatly contributed to a better understanding of the pathogenesis of yeast infections. There is evidence that reconstitution of the host immune function is a major contributor to the resolution of yeast infections. Strategies aiming to increase the phagocyte number (e.g., granulocyte transfusions), to stimulate immune response (e.g., administration of hematopoietic growth factors and other proinflammatory cytokines) and to stimulate antigen-specific immunity (e.g., antibody therapy or vaccination) benefit patients at risk of, or suffering from, yeast infections. Further preclinical and clinical studies, as well as improving our understanding of immune system functions and dysfunctions, remain a future challenge.

Recurrent bacteremia with Helicobacter cinaedi: case report and review of the literature.

BACKGROUND: Helicobacter cinaedi is a rare pathogen in humans, occurring mostly in immuno-compromised patients, with a high potential for recurrence. We describe a case of a patient with lymphoma hospitalized for chemotherapy. CASE PRESENTATION: At admission, the patient presented with an indolent and non-prurigenic macular rash around her implantable venous access device. Gram staining of blood cultures revealed the presence of spiral-shaped gram-negative rods that could not be grown upon subculture. Helicobacter cinaedi was identified by PCR. No other symptoms or pathology were observed in a whole body CT scan. The implantable venous access device was removed and empiric therapy by ceftriaxone and gentamicin for 2 weeks was initiated, followed by peroral clarithromycin 2 x 500 mg/day and later by levofloxacin 2 x 500 mg/day for 7 weeks. Oncologic remission was achieved 3 months later. However, the patient was re-hospitalized 2 months later for fever, shivering, reappearance of the macular non-prurigenic rash, diarrhea, cough and asthenia. Blood cultures grew H. cinaedi. Multiple investigations could not identify the source. Empiric antibiotic therapy of ceftriaxone and doxycycline was started for 2 weeks with resolution of symptoms, followed by an oral combination of amoxicillin, metronidazole and doxycycline for 2 months; doxycycline was continued for another month. Bacteremia has not recurred for a period of 19 months. CONCLUSION: Although H. cinaedi is considered to be a low virulent bacteria, its potential to cause recurrent bacteremia should not be underestimated. H. cinaedi could have an endovascular source of infection and should be treated for an adequate duration with combined antibiotherapy.

Invasive candidiasis: comparison of management choices by infectious disease and critical care specialists.

OBJECTIVE: To compare the management of invasive candidiasis between infectious disease and critical care specialists. DESIGN AND SETTING: Clinical case scenarios of invasive candidiasis were presented during interactive sessions at national specialty meetings. Participants responded to questions using an anonymous electronic voting system. PATIENTS AND PARTICIPANTS: Sixty-five infectious disease and 51 critical care physicians in Switzerland. RESULTS: Critical care specialists were more likely to ask advice from a colleague with expertise in the field of fungal infections to treat Candida glabrata (19.5% vs. 3.5%) and C. krusei (36.4% vs. 3.3%) candidemia. Most participants reported that they would change or remove a central venous catheter in the presence of candidemia, but 77.1% of critical care specialists would start concomitant antifungal treatment, compared to only 50% of infectious disease specialists. Similarly, more critical care specialists would start antifungal prophylaxis when Candida spp. are isolated from the peritoneal fluid at time of surgery for peritonitis resulting from bowel perforation (22.2% vs. 7.2%). The two groups equally considered Candida spp. as pathogens in tertiary peritonitis, but critical care specialists would more frequently use amphotericin B than fluconazole, caspofungin, or voriconazole. In mechanically ventilated patients the isolation of 10(4) Candida spp. from a bronchoalveolar lavage was considered a colonizing organism by 94.9% of infectious disease, compared to 46.8% of critical care specialists, with a marked difference in the use of antifungal agents (5.1% vs. 51%). CONCLUSIONS: These data highlight differences between management approaches for candidiasis in two groups of specialists, particularly in the reported use of antifungals.

Fusarium peritonitis concomitant to kidney transplantation successfully managed with voriconazole: case report and review of the literature.

Fusarium infections in solid organ transplant recipients are often localized, occur later in the post-transplantation period, and have a better outcome than fusarial infections in patients with hematologic malignancies or bone marrow transplants. We report the first case of proven peritonitis caused by Fusarium species in a renal transplant recipient which is also the first successfully managed with voriconazole. We also review previously reported cases of fusarial infection in solid organ transplant recipients.

Respiratory viruses and severe lower respiratory tract complications in hospitalized patients.

BACKGROUND: Acute respiratory viral infections are generally self-limited in healthy subjects but can lead to severe complications in immunocompromised hosts. We report the clinical impact of acute lower respiratory tract viral infections in hospitalized patients. MATERIALS AND METHODS: Of 1,001 fiberoptic bronchoscopies performed during a period of 5 years, 33 BAL samples were positive for respiratory viruses by cell culture. The main diagnosis, length of hospitalization, response to initial treatment, and the mortality rate at 30 days were analyzed. Spirometry performed before and after infection was compared in lung transplant recipients. RESULTS: The following respiratory viruses were identified in 33 cases: influenza A or B (n = 13), parainfluenza virus 1-3 (n = 7), rhinovirus (n = 5), respiratory syncytial virus (n = 4), and adenovirus (n = 4). All cases were immunocompromised patients who acquired new respiratory symptoms and/or radiologic abnormalities suggesting a pulmonary infection. Twenty-five patients (74%) did not respond to initial broad-spectrum antibiotics, and 11 patients (33%) required intensive care for respiratory failure. The overall mortality rate at 1 month was 24%. In patients with a sole viral pathogen identified in their BAL, the mortality rate was 39%. In lung transplant recipients (n = 10), the mean FEV(1) decreased from 2.2 to 1.9 L/s before and during the infection episode, respectively (p < 0.01); 3 months later, 60% of the patients had still not completely recovered to baseline values. CONCLUSION: Respiratory viruses recovered in BAL samples of immunocompromised patients are associated with severe lower respiratory complications. In lung transplant recipients, we observed a persisting impairment of pulmonary function.

Inappropriate initial antimicrobial therapy and its effect on survival in a clinical trial of immunomodulating therapy for severe sepsis.

PURPOSE: To examine the effect of inappropriate initial antimicrobial therapy on the prognosis of patients with sepsis who were enrolled in a clinical trial of an immunomodulating agent conducted in 108 hospitals in North America and Europe. METHODS: We assessed initial antimicrobial choice and results of microbiologic cultures in 904 patients who had microbiologically confirmed severe sepsis or early septic shock. If a patient did not receive at least one antimicrobial agent to which the causative microorganisms were susceptible within 24 hours from the diagnosis of severe sepsis, then the initial antimicrobial treatment was considered to be inappropriate. A propensity score that adjusted for factors associated with inappropriate antimicrobial treatment was calculated and included in multivariable models to adjust for confounding. RESULTS: A total of 468 patients (52%) had documented bloodstream infection, and 211 patients (23%) received inappropriate initial antimicrobial therapy. Characteristics associated with inappropriate treatment were study enrollment in Europe, admission to surgery, nosocomial infection, infection with multiresistant microorganisms, and fungal or polymicrobial infection (all P <0.05). The 28-day mortality was 24% (168/693) for patients in the adequately treated group versus 39% (82/211) for patients receiving inappropriate initial antimicrobial therapy (P <0.001). After adjusting for comorbid conditions, severity of illness, site of infection, and the propensity score, inappropriate antimicrobial therapy was independently associated with increased mortality (odds ratio = 1.8; 95% confidence interval: 1.2 to 2.6). CONCLUSION: In a large cohort of patients with microbiologically confirmed severe sepsis, appropriate initial antimicrobial therapy was an important determinant of survival. New approaches aimed at improving detection and treatment of early sepsis are needed.

Anti-inflammatory response after infusion of p55 soluble tumor necrosis factor receptor fusion protein for severe sepsis.

OBJECTIVES: To investigate the effects of Lenercept , a recombinant soluble TNF receptor p55 fused to an immunoglobulin heavy chain IgG1, on the balance of pro- and anti-inflammatory mediators in sepsis. DESIGN: Post hoc analysis of a subgroup of patients enrolled in a multicenter phase III, prospective, double-blind, placebo-controlled, randomized study of Lenercept in severe sepsis. SETTING: Surgical and medical intensive care units, and postoperative recovery room of a tertiary care teaching hospital. PATIENTS: A total of 57 patients were enrolled in the multicenter study in our center. INTERVENTION: Septic patients were randomly assigned to receive either Lenercept 0.125 mg/kg or placebo. The patients were followed for up to 28 days after randomization. MEASUREMENTS AND MAIN RESULTS: Circulating levels of TNF-alpha, IL-6, TNFsR75 and IL-1Ra were measured before and after treatment. The two groups were comparable with regard to age, gender and diagnosis distribution. The total level of TNF-alpha increased significantly in treated patients, compared to patients receiving placebo. The levels of the other inflammatory mediators did not differ between the two groups CONCLUSIONS: Lenercept -treated patients experienced a protracted TNF-alpha half-life, leading to higher total TNF-alpha levels throughout the study. However, the treatment had no effects on anti-inflammatory mediators. Therefore, peripheral inflammatory processes might not have been significantly modified by the treatment. This might account for the lack of efficacy this treatment in septic patients

Secular trends of candidemia over 12 years in adult patients at a tertiary care hospital.

The incidence of fungal infections has been increasing for the last 3 decades, especially among neutropenic, cancer, and critically ill patients. These infections are associated with high mortality rates. We retrospectively reviewed medical charts of adult patients with fungemia from 1989 to 2000 at our institution. The characteristics of the population groups served by the hospital were described. Of 328 patients with fungemia, we reviewed 315 (96%) medical records, and focused on those with candidemia (n = 294). The species distribution in patients with candidemia showed that the most commonly identified species were Candida albicans (66%), followed by C. glabrata (17%), and C. parapsilosis (6%). The incidence of candidemia ranged from 0.2 to 0.46 per 10,000 patient-days with the highest incidence in 1993 and the lowest in 1997. Although most studies show an increased incidence of candidemia, we observed a reduction over the study period. Furthermore, we observed no shift from C. albicans to non-albicans Candida species despite a significant increase in the use of fluconazole. The overall mortality among patients with candidemia was 44%, with the highest rate in patients over 65 years (52%). Factors independently associated with higher mortality were patient age greater than 65 years, intensive care unit admission, and underlying cancer.