Correction to: Catheter retention as a consequence rather than a cause of unfavorable outcome in candidemia.

In the original publication the members of the FUNGINOS network were provided in such a way that they could not be indexed as collaborators on PubMed.

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.

Efficacy of anidulafungin in 539 patients with invasive candidiasis: a patient-level pooled analysis of six clinical trials.

Objectives: To evaluate the efficacy of anidulafungin for the treatment of candidaemia and invasive candidiasis in a large dataset, including patients with deep-seated tissue candidiasis, neutropenia and infection due to non- albicans Candida species. Methods: Data were pooled from six prospective, multicentre, multinational studies: four open-label, non-comparative studies of anidulafungin and two double-blind, double-dummy, randomized studies of anidulafungin versus caspofungin (clinical trial registrations: NCT00496197, NCT00548262, NCT00537329, NCT00689338, NCT00806351 and NCT00805740; ClinicalTrials.gov). In all studies, patients with culture-confirmed invasive candidiasis received a single intravenous (iv) loading dose of anidulafungin 200 mg on day 1, followed by 100 mg once-daily. Switch to oral fluconazole or voriconazole was permitted after 5-10 days of iv treatment in all studies except one. Antifungal treatment (iv plus oral therapy if applicable) was maintained for ≥14 days after the last positive Candida culture. The primary endpoint was successful global response at end of iv therapy (EOivT) in the modified ITT (mITT) population. Results: In total, 539 patients were included (mITT population). The most common baseline Candida species were Candida albicans (47.9%), Candida glabrata (21.0%), Candida tropicalis (13.7%), Candida parapsilosis (13.2%) and Candida krusei (3.5%). Median duration of anidulafungin iv treatment was 10.0 days. The global response success rate at EOivT was 76.4% (95% CI 72.9%-80.0%). All-cause mortality was 13.0% on day 14 and 19.1% on day 28. Adverse events (AEs) were consistent with the known AE profile for anidulafungin. Conclusions: These data demonstrate that anidulafungin is effective for treatment of candidaemia and invasive candidiasis in a broad patient population.

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.

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

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.

Pseudomonas aeruginosa serotypes in nosocomial pneumonia: prevalence and clinical outcomes.

INTRODUCTION: Pseudomonas aeruginosa frequently causes nosocomial pneumonia and is associated with poor outcome. The purpose of this study was to assess the prevalence and clinical outcome of nosocomial pneumonia caused by serotype-specific P. aeruginosa in critically ill patients under appropriate antimicrobial therapy management. METHODS: A retrospective, non-interventional epidemiological multicenter cohort study involving 143 patients with confirmed nosocomial pneumonia caused by P. aeruginosa. Patients were analyzed for a period of 30 days from time of nosocomial pneumonia onset. Fourteen patients fulfilling the same criteria from a phase IIa studyconducted at the same time/centers were included in the prevalence calculations but not in the clinical outcome analysis. RESULTS: The prevalence of serotypes was: O6 (29%), O11 (23%), O10 (10%), O2 (9%), and O1 (8%). Serotypes with a prevalence of less than 5% were found in 13% of patients, 8% were classified as not typeable. Across all serotypes, 19% mortality, 70% clinical resolution, 11% clinical continuation, and 5% clinical recurrence were recorded. Age and higher APACHE II (Acute Physiology and Chronic Health Evaluation II) were predictive risk factors associated with probability of death and lower clinical resolution for P. aeruginosa nosocomial pneumonia. Mortality tends to be higher with O1 (40%) and lower with O2 (0%); clinical resolution tends to be better with O2 (82%) compared to other serotypes. Persisting pneumonia with O6 and O11 was, respectively, 8% and 21%; clinical resolution with O6 and O11 was, respectively, 75% and 57%. CONCLUSIONS: In P. aeruginosa nosocomial pneumonia, the most prevalent serotypes were O6 and O11. Further studies including larger group sizes are needed to correlate clinical outcome with virulence factors of P. aeruginosa in patients with nosocomial pneumonia caused by various serotypes; and to compare O6 and O11, the two serotypes most frequently encountered in critically ill patients.

The safety and efficacy of high-dose daptomycin combined with rifampicin for the treatment of Gram-positive osteoarticular infections.

PURPOSE: Treatment of Gram-positive osteoarticular infections requires an adequate surgical approach combined with intensive antimicrobial therapy. The aim of this study was to evaluate the safety and efficacy of a combined regimen of high-dose daptomycin and rifampicin, in patients with various types of Gram-positive osteoarticular infections. METHODS: This single centre, non-comparative, prospective study evaluated the safety and efficacy of a combined regimen of intravenous daptomycin (8 mg/kg/day) and oral rifampicin (600 mg/day) in patients with Gram-positive osteoarticular infections, with a minimal follow-up of one year. Creatine phosphokinase, transaminases, bilirubinaemia, and serum creatinine, were measured at baseline and regular intervals. RESULTS: The median daily doses of daptomycin and rifampicin, administered for a median duration of 21 (range, 10-122) days to 16 patients (median age, 63.5 years; 11 males, five females) presenting with staphylococcal (n = 15) or streptococcal (n = 1) osteoarticular infections, were 8.15 (range, 6.6-8.9) mg/kg/day and 600 (range, 600-900) mg/day, respectively. The combined regimen of daptomycin and rifampicin was well tolerated by all except one patient, without requiring treatment adjustment or discontinuation. One patient developed allergic responses probably due to rifampicin after 42 days. Fifteen (94 %) patients showed favourable clinical and microbiological outcomes. CONCLUSIONS: The combined regimen of high-dose daptomycin and rifampicin was well tolerated and may provide a useful alternative to standard glycopeptide therapy for Gram-positive osteoarticular infections.

Short parenteral antibiotic treatment for adult septic arthritis after successful drainage.

OBJECTIVES: To assess the risk factors for recurrence of septic arthritis with an emphasis on the duration of antibiotic treatment, to gather data for a prospective study on an optimized antibiotic treatment in adults with septic arthritis. METHODS: This was a retrospective single-center study conducted for the period 1996-2008. RESULTS: A total of 169 episodes of septic arthritis in 157 adult patients (median age 63 years; 65 females) were included. In 21 episodes (21/169, 12%), arthritis recurred after the end of antibiotic treatment. Multivariate analysis showed that Gram-negative infection (odds ratio (OR) 5.9, 95% confidence interval (CI) 1.4-25.3), immune suppression (OR 5.3, 95% CI 1.3-22.0), and lack of surgical intervention were associated with recurrence. The size of the infected joint, the number of surgical drainages (OR 1.3, 95% CI 1.0-1.7), arthrotomy vs. arthroscopic drainage (OR 0.5, 95% CI 0.2-1.8), duration of antibiotic therapy (OR 1.0, 95% CI 0.95-1.05), and duration of intravenous antibiotic therapy (OR 1.0, 95% CI 1.0-1.0) were not. Seven days of intravenous therapy had the same success rate as 8-21 days (OR 0.4, 95% CI 0.1-1.7) and >21 days (OR 1.1, 95% CI 0.4-3.1). Fourteen days or less of total antibiotic treatment had the same outcome as 15-28 days (OR 0.4, 95% CI 0.1-2.3) or >28 days (OR 0.4, 95% CI 0.1-1.6). CONCLUSIONS: In this retrospective study of adults with septic arthritis, the duration of antibiotic therapy, or an early switch from intravenous to oral administration, did not statistically influence the risk of recurrence. Due to study limitations, the data cannot be used directly for antibiotic therapy recommendations for septic arthritis. Prospective randomized trials are warranted to optimize the antibiotic treatment of septic arthritis.

Pharmacokinetics and safety of panobacumab: specific adjunctive immunotherapy in critical patients with nosocomial Pseudomonas aeruginosa O11 pneumonia.

OBJECTIVES: Nosocomial Pseudomonas aeruginosa pneumonia remains a major concern in critically ill patients. We explored the potential impact of microorganism-targeted adjunctive immunotherapy in such patients. PATIENTS AND METHODS: This multicentre, open pilot Phase 2a clinical trial (NCT00851435) prospectively evaluated the safety, pharmacokinetics and potential efficacy of three doses of 1.2 mg/kg panobacumab, a fully human monoclonal anti-lipopolysaccharide IgM, given every 72 h in 18 patients developing nosocomial P. aeruginosa (serotype O11) pneumonia. RESULTS: Seventeen out of 18 patients were included in the pharmacokinetic analysis. In 13 patients receiving three doses, the maximal concentration after the third infusion was 33.9 ±â€Š8.0 µg/mL, total area under the serum concentration-time curve was 5397 ±â€Š1993 µg h/mL and elimination half-life was 102.3 ±â€Š47.8 h. Panobacumab was well tolerated, induced no immunogenicity and was detected in respiratory samples. In contrast to Acute Physiology and Chronic Health Evaluation II (APACHE II) prediction, all 13 patients receiving three doses survived, with a mean clinical resolution in 9.0 ±â€Š2.7 days. Two patients suffered a recurrence at days 17 and 20. CONCLUSIONS: These data suggest that panobacumab is safe, with a pharmacokinetic profile similar to that in healthy volunteers. It was associated with high clinical cure and survival rates in patients developing nosocomial P. aeruginosa O11 pneumonia. We concluded that these promising results warrant further trials.

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.

Respiratory viruses in HIV-infected patients with suspected respiratory opportunistic infection.

OBJECTIVE: To assess the incidence and epidemiological pattern of respiratory viruses in HIV-infected patients and to evaluate their potential clinical impact. DESIGN AND METHODS: A prospective population-based cohort study was conducted at three Swiss university hospitals. Study participants were HIV-infected patients who underwent a bronchoalveolar lavage to rule out an opportunistic event. All bronchoalveolar lavage specimens were screened using a set of real-time reverse transcriptase-polymerase chain reaction assays targeting 17 different respiratory viruses. RESULTS: Between November 2003 and November 2006, 59 bronchoalveolar episodes from 55 HIV-infected patients were analysed. Eleven of 59 episodes (18.6%) were positive for at least one respiratory virus. Coronavirus OC43 was identified in three cases (27.3%) followed by influenza A in two (18.2%). Parainfluenza virus (PIV) 2, PIV 3, PIV 4, bocavirus, human rhinovirus A and human metapneumovirus were each identified in one case (9%). In the majority of these cases (63.6%) no other concomitant microorganism was isolated. CONCLUSIONS: Clinical investigation of respiratory viral infections in HIV-infected patients should not be restricted to prototype viruses and also need to target all the different family of viruses as it seems likely that these viruses contribute to pulmonary complications and morbidity in this population.

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.

Invasive aspergillosis: is treatment with "inexpensive" amphotericin B cost saving if "expensive" voriconazole is only used on demand?

BACKGROUND: Voriconazole for the treatment of invasive aspergillosis (IA) shows superior clinical outcome and tolerability compared to conventional amphotericin B. However, the latter is often used as initial treatment due to lower drug acquisition costs. Therefore we performed a cost-effectiveness analysis. METHODS: A decision analytic model was designed to compare the cost-effectiveness of a regimen of voriconazole followed by conventional amphotericin B to a regimen of conventional amphotericin B followed by voriconazole. Patients initiated on treatment either completed initial therapy or switched to second line therapy due to toxicity or non-response. Probability of a switch was based on clinical trial data and local rates of renal toxicity. Resource use in the hospital was taken from the Global Comparative Aspergillosis (GCA) study. Costs were based on local drug acquisition costs, local cost estimates for hospitalisation and adjusted additional costs of amphotericin B-induced acute renal failure from the literature. Effectiveness was defined as survival at 12 weeks from the GCA study. An incremental cost-effectiveness ratio was estimated as the incremental cost per life saved comparing voriconazole to conventional amphotericin B. RESULTS: Based on this model, initial therapy of IA with voriconazole reduced total costs when compared to initial therapy with conventional amphotericin B (CHF 37 878/patient vs CHF 49 861/patient) and resulted in better survival at 12 weeks, making it the dominant treatment in terms of incremental cost-effectiveness. Results were most sensitive to alternative assumptions of the incidence of acute renal failure, but cost savings were sustained for voriconazole over a wide range of values. CONCLUSION: Considering that initial therapy with voriconazole is both cost-saving and results in better clinical outcomes, voriconazole is the dominant cost-effective option for initial therapy of IA, despite very low drug acquisition costs of conventional amphotericin B.

Chronic rhinoviral infection in lung transplant recipients.

RATIONALE: Lung transplant recipients are particularly at risk of complications from rhinovirus, the most frequent respiratory virus circulating in the community. OBJECTIVES: To determine whether lung transplant recipients can be chronically infected by rhinovirus and the potential clinical impact. METHODS: We first identified an index case, in which rhinovirus was isolated repeatedly, and conducted detailed molecular analysis to determine whether this was related to a unique strain or to re-infection episodes. Transbronchial biopsies were used to assess the presence of rhinovirus in the lung parenchyma. The incidence of chronic rhinoviral infections and potential clinical impact was assessed prospectively in a cohort of 68 lung transplant recipients during 19 mo by screening of bronchoalveolar lavages. MEASUREMENTS AND MAIN RESULTS: We describe 3 lung transplant recipients with graft dysfunctions in whom rhinovirus was identified by reverse transcriptase-polymerase chain reaction in upper and lower respiratory specimens over a 12-mo period. In two cases, rhinovirus was repeatedly isolated in culture. The persistence of a unique strain in each case was confirmed by sequence analysis of the 5'NCR and VP1 gene. In the index case, rhinovirus was detected in the lower respiratory parenchyma. In the cohort of lung transplant recipients, rhinoviral infections were documented in bronchoalveolar lavage specimens of 10 recipients, and 2 presented with a persistent infection. CONCLUSIONS: Rhinoviral infection can be persistent in lung transplant recipients with graft dysfunction, and the virus can be detected in the lung parenchyma. Given the potential clinical impact, chronic rhinoviral infection needs to be considered in lung transplant recipients.