Patricia Muñóz

Invasive fungal diseases are important causes of morbidity and mortality. Clarity and uniformity in defining these infections are important factors in improving the quality of clinical studies. A standard set of definitions strengthens the consistency and reproducibility of such studies.After the introduction of the original European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group definitions, advances in diagnostic technology and the recognition of areas in need of improvement led to a revision of this document. The revision process started with a meeting of participants in 2003, to decide on the process and to draft the proposal. This was followed by several rounds of consultation until a final draft was approved in 2005. This was made available for 6 months to allow public comment, and then the manuscript was prepared and approved.The revised definitions retain the original classifications of "proven," "probable," and "possible" invasive fungal disease, but the definition of "probable" has been expanded, whereas the scope of the category "possible" has been diminished. The category of proven invasive fungal disease can apply to any patient, regardless of whether the patient is immunocompromised, whereas the probable and possible categories are proposed for immunocompromised patients only.These revised definitions of invasive fungal disease are intended to advance clinical and epidemiological research and may serve as a useful model for defining other infections in high-risk patients.

The European Society for Clinical Microbiology and Infectious Diseases, the European Confederation of Medical Mycology and the European Respiratory Society Joint Clinical Guidelines focus on diagnosis and management of aspergillosis. Of the numerous recommendations, a few are summarized here. Chest computed tomography as well as bronchoscopy with bronchoalveolar lavage (BAL) in patients with suspicion of pulmonary invasive aspergillosis (IA) are strongly recommended. For diagnosis, direct microscopy, preferably using optical brighteners, histopathology and culture are strongly recommended. Serum and BAL galactomannan measures are recommended as markers for the diagnosis of IA. PCR should be considered in conjunction with other diagnostic tests. Pathogen identification to species complex level is strongly recommended for all clinically relevant Aspergillus isolates; antifungal susceptibility testing should be performed in patients with invasive disease in regions with resistance found in contemporary surveillance programmes. Isavuconazole and voriconazole are the preferred agents for first-line treatment of pulmonary IA, whereas liposomal amphotericin B is moderately supported. Combinations of antifungals as primary treatment options are not recommended. Therapeutic drug monitoring is strongly recommended for patients receiving posaconazole suspension or any form of voriconazole for IA treatment, and in refractory disease, where a personalized approach considering reversal of predisposing factors, switching drug class and surgical intervention is also strongly recommended. Primary prophylaxis with posaconazole is strongly recommended in patients with acute myelogenous leukaemia or myelodysplastic syndrome receiving induction chemotherapy. Secondary prophylaxis is strongly recommended in high-risk patients. We strongly recommend treatment duration based on clinical improvement, degree of immunosuppression and response on imaging.

Prosthetic valve endocarditis (PVE) is associated with significant mortality and morbidity. The contemporary clinical profile and outcome of PVE are not well defined.To describe the prevalence, clinical characteristics, and outcome of PVE, with attention to health care-associated infection, and to determine prognostic factors associated with in-hospital mortality.Prospective, observational cohort study conducted at 61 medical centers in 28 countries, including 556 patients with definite PVE as defined by Duke University diagnostic criteria who were enrolled in the International Collaboration on Endocarditis-Prospective Cohort Study from June 2000 to August 2005.In-hospital mortality.Definite PVE was present in 556 (20.1%) of 2670 patients with infective endocarditis. Staphylococcus aureus was the most common causative organism (128 patients [23.0%]), followed by coagulase-negative staphylococci (94 patients [16.9%]). Health care-associated PVE was present in 203 (36.5%) of the overall cohort. Seventy-one percent of health care-associated PVE occurred within the first year of valve implantation, and the majority of cases were diagnosed after the early (60-day) period. Surgery was performed in 272 (48.9%) patients during the index hospitalization. In-hospital death occurred in 127 (22.8%) patients and was predicted by older age, health care-associated infection (62/203 [30.5%]; adjusted odds ratio [OR], 1.62; 95% confidence interval [CI], 1.08-2.44; P = .02), S aureus infection (44/128 [34.4%]; adjusted OR, 1.73; 95% CI, 1.01-2.95; P = .05), and complications of PVE, including heart failure (60/183 [32.8%]; adjusted OR, 2.33; 95% CI, 1.62-3.34; P<.001), stroke (34/101 [33.7%]; adjusted OR, 2.25; 95% CI, 1.25-4.03; P = .007), intracardiac abscess (47/144 [32.6%]; adjusted OR, 1.86; 95% CI, 1.10-3.15; P = .02), and persistent bacteremia (27/49 [55.1%]; adjusted OR, 4.29; 95% CI, 1.99-9.22; P<.001).Prosthetic valve endocarditis accounts for a high percentage of all cases of infective endocarditis in many regions of the world. Staphylococcus aureus is now the leading cause of PVE. Health care-associated infection significantly influences the clinical characteristics and outcome of PVE. Complications of PVE strongly predict in-hospital mortality, which remains high despite prompt diagnosis and the frequent use of surgical intervention.

These European Society for Clinical Microbiology and Infectious Diseases and European Confederation of Medical Mycology Joint Clinical Guidelines focus on the diagnosis and management of mucormycosis. Only a few of the numerous recommendations can be summarized here. To diagnose mucormycosis, direct microscopy preferably using optical brighteners, histopathology and culture are strongly recommended. Pathogen identification to species level by molecular methods and susceptibility testing are strongly recommended to establish epidemiological knowledge. The recommendation for guiding treatment based on MICs is supported only marginally. Imaging is strongly recommended to determine the extent of disease. To differentiate mucormycosis from aspergillosis in haematological malignancy and stem cell transplantation recipients, identification of the reverse halo sign on computed tomography is advised with moderate strength. For adults and children we strongly recommend surgical debridement in addition to immediate first-line antifungal treatment with liposomal or lipid-complex amphotericin B with a minimum dose of 5 mg/kg/day. Amphotericin B deoxycholate is better avoided because of severe adverse effects. For salvage treatment we strongly recommend posaconazole 4×200 mg/day. Reversal of predisposing conditions is strongly recommended, i.e. using granulocyte colony-stimulating factor in haematological patients with ongoing neutropenia, controlling hyperglycaemia and ketoacidosis in diabetic patients, and limiting glucocorticosteroids to the minimum dose required. We recommend against using deferasirox in haematological patients outside clinical trials, and marginally support a recommendation for deferasirox in diabetic patients. Hyperbaric oxygen is supported with marginal strength only. Finally, we strongly recommend continuing treatment until complete response demonstrated on imaging and permanent reversal of predisposing factors.

<h2>Abstract</h2> Mycoses summarized in the hyalohyphomycosis group are heterogeneous, defined by the presence of hyaline (non-dematiaceous) hyphae. The number of organisms implicated in hyalohyphomycosis is increasing and the most clinically important species belong to the genera <i>Fusarium, Scedosporium, Acremonium, Scopulariopsis, Purpureocillium</i> and <i>Paecilomyces.</i> Severely immunocompromised patients are particularly vulnerable to infection, and clinical manifestations range from colonization to chronic localized lesions to acute invasive and/or disseminated diseases. Diagnosis usually requires isolation and identification of the infecting pathogen. A poor prognosis is associated with fusariosis and early therapy of localized disease is important to prevent progression to a more aggressive or disseminated infection. Therapy should include voriconazole and surgical debridement where possible or posaconazole as salvage treatment. Voriconazole represents the first-line treatment of infections due to members of the genus <i>Scedosporium.</i> For <i>Acremonium</i> spp., <i>Scopulariopsis</i> spp., <i>Purpureocillium</i> spp. and <i>Paecilomyces</i> spp. the optimal antifungal treatment has not been established. Management usually consists of surgery and antifungal treatment, depending on the clinical presentation.

Unique characteristics, impact of therapy with antifungal agents, and outcome of infections with Scedosporium species were assessed in transplant recipients.The patients comprised a total of 80 transplant recipients with Scedosporium infections, including 13 patients from our institutions (University of Pittsburgh Medical Center [Pittsburgh, PA], University of Maryland [Baltimore], Duke University Medical Center [Durham, NC], Emory University [Atlanta, GA], and Hospital Gregorio Maranon [Madrid, Spain]) and 67 reported in the literature. The transplant recipients were compared with 190 non-transplant recipients with scedosporiosis who were described in the literature.Overall, 69% of the infections in hematopoietic stem cell transplant (HSCT) recipients and 53% of the infections in organ transplant recipients were disseminated. HSCT recipients, compared with organ transplant recipients, were more likely to have infections caused by Scedosporium prolificans (P=.045), to have an earlier onset of infection (P=.007), to be neutropenic (P<.0001), and to have fungemia (P=.04). Time elapsed from transplantation to Scedosporium infection in transplant recipients has increased in recent years (P=.002). The mortality rate among transplant recipients with scedosporiosis was 58%. In a logistic regression model using amphotericin B as comparison treatment, voriconazole was associated with a trend towards better survival (odds ratio [OR], 10.40; P=.08). Presence of disseminated infection (OR, 0.20; P=.03) predicted lower survival, and receipt of adjunctive surgery as treatment (OR, 5.52; P=.02) independently predicted a better survival in this model.Scedosporium infections in transplant recipients were associated with a high rate of dissemination and a poor outcome overall. The use of newer triazole agents warrants consideration as a therapeutic modality for these infections.

Following its emergence in late 2019, the spread of SARS-CoV-21,2 has been tracked by phylogenetic analysis of viral genome sequences in unprecedented detail3–5. Although the virus spread globally in early 2020 before borders closed, intercontinental travel has since been greatly reduced. However, travel within Europe resumed in the summer of 2020. Here we report on a SARS-CoV-2 variant, 20E (EU1), that was identified in Spain in early summer 2020 and subsequently spread across Europe. We find no evidence that this variant has increased transmissibility, but instead demonstrate how rising incidence in Spain, resumption of travel, and lack of effective screening and containment may explain the variant's success. Despite travel restrictions, we estimate that 20E (EU1) was introduced hundreds of times to European countries by summertime travellers, which is likely to have undermined local efforts to minimize infection with SARS-CoV-2. Our results illustrate how a variant can rapidly become dominant even in the absence of a substantial transmission advantage in favourable epidemiological settings. Genomic surveillance is critical for understanding how travel can affect transmission of SARS-CoV-2, and thus for informing future containment strategies as travel resumes. Analysis of the spread of the 20E (EU1) variant of SARS-CoV-2 through Europe suggests that international travel and insufficient containment, rather than increased transmissibility, led to a resurgence of infections.

Background. The efficacy of the combination of voriconazole and caspofungin when used as primary therapy for invasive aspergillosis in organ transplant recipients has not been defined. Methods. Transplant recipients who received voriconazole and caspofungin (n=40) as primary therapy for invasive aspergillosis (proven or probable) in a prospective multicenter study between 2003 and 2005 were compared to a control group comprising a cohort of consecutive transplant recipients between 1999 and 2002 who had received a lipid formulation of AmB as primary therapy (n=47). In vitro antifungal testing of Aspergillus isolates to combination therapy was correlated with clinical outcome. Results. Survival at 90 days was 67.5% (27/40) in the cases, and 51% (24/47) in the control group (HR 0.58, 95% CI, 0.30–1.14, P=0.117). However, in transplant recipients with renal failure (adjusted HR 0.32, 95% CI: 0.12–0.85, P=0.022), and in those with A. fumigatus infection (adjusted HR 0.37, 95% CI: 0.16–0.84, P=0.019), combination therapy was independently associated with an improved 90-day survival in multivariate analysis. No correlation was found between in vitro antifungal interactions of the Aspergillus isolates to the combination of voriconazole and caspofungin and clinical outcome. Conclusions. Combination of voriconazole and caspofungin might be considered preferable therapy for subsets of organ transplant recipients with invasive aspergillosis, such as those with renal failure or A. fumigatus infection.

We describe a large series of patients with chronic obstructive pulmonary disease (COPD) and probable invasive pulmonary aspergillosis (IPA), and the risk factors and incidence of the disease in patients with isolation of Aspergillus from lower respiratory tract samples. From 2000 to 2007, we retrospectively studied all patients admitted with COPD and isolation of Aspergillus (239; 16.3/1000 admissions). Multivariate logistic regression and survival curves were used. Fifty-three patients had probable IPA (3.6 cases of IPA per 1000 COPD admissions). IPA affects at least 22.1% of patients with COPD and isolation of Aspergillus in culture. In 33 of the 53 patients with probable IPA, serum galactomannan was determined; in 14 (42.4%) of these, the result was positive. Five variables were independent predictors of IPA with statistical significance: admission to the intensive-care unit, chronic heart failure, antibiotic treatment received in the 3 months prior to admission, the accumulated dosage of corticosteroids equivalent to >700 mg prednisone received in the 3 months prior to admission, and the similar accumulated dosage of corticosteroids received from admission to the first clinical isolation of Aspergillus. Multivariate analysis gave an area under the curve of 0.925 (95% CI 0.888-0.962; p <0.001). The overall mean survival of the cohort was 64.1% (28.3% for IPA patients and 75.2% for non-IPA patients). The median number of days of survival was 48 (95% CI 33.07-62.92). However, we found statistically significant differences between patients with IPA (29 days; 95% CI 20.59-37.40) and patients without IPA (86 days; 95% CI 61.13-110.86) (log rank, p <0.001).

Nocardia species is an uncommon pathogen that affects both immunosuppressed and immunocompetent patients. The clinical and microbiologic spectrum of nocardiosis has changed recently due to the widespread use of cotrimoxazole prophylaxis, the emergence of new types of immunosuppressed patients, and the improved identification of isolates using molecular techniques. Nocardia asteroides was traditionally considered the predominant organism, and prophylaxis with cotrimoxazole was considered almost universally protective. We conducted the current study to determine the incidence of nocardiosis and its microbiologic and clinical characteristics in a general hospital over the last 12 years. We reviewed the clinical records of all patients in whom Nocardia species was isolated from clinical specimens between 1995 and 2006. Nocardia isolates were identified by standard procedures and by 5′ end 16S rRNA gene polymerase chain reaction (PCR) and sequencing. Susceptibility to cotrimoxazole, minocycline, imipenem, linezolid, and amikacin was determined by the broth microdilution method following the guidelines of the Clinical and Laboratory Standards Institute. The incidence of Nocardia infections did not increase significantly during the study period (0.39/100,000 inhabitants in 1995-1998 and 0.55/100,000 inhabitants in 2003-2006). Nocardia was recovered from 43 patients. Six were considered to be colonized. The colonizing species were N. farcinica, N. nova, and N. asteroides. All colonized patients had severe underlying pulmonary conditions and were treated with antimicrobials (6 patients) or corticosteroids (4 patients). Invasive nocardiosis was diagnosed in 37 patients (86.5% were men, and their mean age was 55.8 ± 17.3 yr). The most common underlying condition in our institution was human immunodeficiency virus (HIV) infection (10 patients; 27%), followed by chronic obstructive pulmonary disease (8 patients; 21.6%), autoimmune diseases (8 patients; 21.6%), solid organ transplantation (7 patients; 18.9%), and cancer (4 patients; 10.8%). The most important risk factor for nocardiosis was corticosteroid administration (23 patients; 62.2%). Nocardiosis affected the lungs in 26 cases (70.3%), the skin in 3 cases (8.1%), and the central nervous system in 2 cases (5.4%). It was disseminated in 5 cases (13.5%) and caused otomastoiditis in 1 (2.7%). The species identified were N. cyriacigeorgica (32.4%), N. farcinica (24.3%), N. otitidiscaviarum (10.8%), N. veterana (8.1%), N. nova (5.4%), N. abscessus (5.4%), N. asiatica (2.7%), N. beijingensis (2.7%), N. brasiliensis (2.7%), N. carnea (2.7%), and Nocardia species (2.7%). Linezolid and amikacin were uniformly active against all the isolates, whereas 29.7% of isolates showed intermediate susceptibility to minocycline (minimum inhibitory concentration = 2 mg/L), 10.8% were resistant to cotrimoxazole, and 5.4% were resistant to imipenem. Nocardiosis occurred while the patients were on cotrimoxazole prophylaxis in 8 cases (21.6%). The strains isolated from these patients were susceptible to cotrimoxazole in 5 cases (62.5%) and resistant in 3 (37.5%). Overall, 13 patients died (35.1%); related mortality was 21.6% (8 patients). We conclude that HIV infection has become the most common underlying condition for invasive nocardiosis in our institution, followed by chronic lung disease. Previous use of corticosteroids was the main risk factor and was present in more than half the patients. New species of Nocardia have been identified, and administration of cotrimoxazole prophylaxis should no longer be considered highly reliable protection against nocardiosis. Larger studies of nocardiosis are required to better identify risk factors associated with mortality, and alternative and more effective methods of prevention must be developed. Abbreviations: AIDS = acquired immunodeficiency syndrome, CLSI = Clinical and Laboratory Standards Institute, CMV = cytomegalovirus, CNS = central nervous system, COPD = chronic obstructive pulmonary disease, CT = computed tomography, HAART = highly active antiretroviral therapy, HIV = human immunodeficiency virus, MIC = minimum inhibitory concentration, PCR = polymerase chain reaction.

The aetiological agents of many invasive fungal infections are saprobes and opportunistic pathogens. Some of these fungi are darkly pigmented due to melanin production and traditionally have been named ‘dematiaceous’. The melanized fungi cause a wide array of clinical syndromes ranging from superficial to deep-seated infections. Diagnosis relies on histopathological examination of clinical specimens and on examination of cultures. Sequencing is recommended for accurate species identification, especially for unusual or newly described pathogens. In cases of mycetoma and chromoblastomycosis, pathognomonic histological findings are useful and the Fontana–Masson stain, specific for melanin, usually confirms the diagnosis. There are no standardized therapies but voriconazole, posaconazole and itraconazole demonstrate the most consistent in vitro activity against this group of fungi. Oral itraconazole has been considered the drug of choice, given the extensive clinical experience with this drug. However, voriconazole may presumably be superior for central nervous system infections because of its ability to achieve good levels in the cerebrospinal fluid. Posaconazole is a well-tolerated alternative drug, backed by less clinical experience but with excellent salvage treatment results after failure of other antifungals. Amphotericin B has been useful as alternative therapy in some cases. Combination antifungal therapy is recommended for cerebral abscesses when surgery is not possible and for disseminated infections in immunocompromised patients.

A prospective, multicentre, population-based surveillance programme for Candida bloodstream infections was implemented in five metropolitan areas of Spain to determine its incidence and the prevalence of antifungal resistance, and to identify predictors of death. Between May 2010 and April 2011, Candida isolates were centralized to a reference laboratory for species identification by DNA sequencing and for susceptibility testing by EUCAST reference procedure. Prognostic factors associated with early (0–7 days) and late (8–30 days) death were analysed using logistic regression modelling. We detected 773 episodes: annual incidence of 8.1 cases/100 000 inhabitants, 0.89/1000 admissions and 1.36/10 000 patient-days. Highest incidence was found in infants younger than 1 year (96.4/100 000 inhabitants). Candida albicans was the predominant species (45.4%), followed by Candida parapsilosis (24.9%), Candida glabrata (13.4%) and Candida tropicalis (7.7%). Overall, 79% of Candida isolates were susceptible to fluconazole. Cumulative mortality at 7 and 30 days after the first episode of candidaemia was 12.8% and 30.6%, respectively. Multivariate analysis showed that therapeutic measures within the first 48 h may improve early mortality: antifungal treatment (OR 0.51, 95% CI 0.27–0.95) and central venous catheter removal (OR 0.43, 95% CI 0.21–0.87). Predictors of late death included host factors (e.g. patients' comorbid status and signs of organ dysfunction), primary source (OR 1.63, 95% CI 1.03–2.61), and severe sepsis or septic shock (OR 1.77, 95% CI 1.05–3.00). In Spain, the proportion of Candida isolates non-susceptible to fluconazole is higher than in previous reports. Early mortality may be improved with strict adherence to guidelines.

It is necessary to clarify the incidence of and risk factors for tuberculosis (TB) among solid-organ transplant (SOT) recipients as well as changes in the chronology, clinical presentation, and prognosis of the disease.A total of 4388 SOT recipients were monitored prospectively at 16 transplant centers included in the Spanish Network for Research in Infectious Diseases (REIPI). TB episodes were studied, and the incidence rate was calculated. Certain variables were analyzed, by Cox regression analysis, as potential risk factors for TB.Among the 4388 SOT recipients, 21 cases of TB were reported (0.48%). The median duration of follow-up was 360 days (range, 0-720 days). The global incidence of TB was 512 cases per 10(5) patients per year (95% confidence interval [CI], 317-783), which was higher than that in the general population in Spain (18.9 cases per 10(5) inhabitants per year; relative risk [RR], 26.6). The highest incidence (2072 cases per 10(5) patients per year; 95% CI, 565-5306) was observed among lung transplant recipients (RR, 73.3). Of the TB cases, 95% occurred within the first year after transplant, and 76% were pulmonary forms. Crude mortality was 19.0%, and attributable mortality was 9.5%. Multivariate analysis identified recipient age (RR, 1.05; 95% CI, 1.0-1.1) and receipt of a lung transplant (RR, 5.6; 95%, 1.9-16.9) as independent risk factors.TB incidence is increased among SOT recipients. The risk factors identified were age and receipt of a lung transplant. TB-attributable mortality (9.5%) is still high.

Tuberculosis is a particularly important condition in solid-organ transplant recipients because of the delay in treatment caused by the difficulties involved in its diagnosis and because of the pharmacological toxicity associated with this treatment. Both treatment delay and toxicity are responsible for the many clinical complications of and high mortality associated with tuberculosis in this population. The Consensus Statement from the Spanish Group for the Study of Infectious Diseases in Transplant Recipients defines the indications for treatment of latent tuberculosis infection in solid-organ transplant recipients, especially in patients with a high risk of pharmacological toxicity, as is the case with liver recipients. We established a series of recommendations regarding the types of drugs and the duration of treatment of tuberculosis in solid-organ recipients, giving special attention to pharmacological interactions between rifampin and immunosuppressive drugs (cyclosporine, tacrolimus, rapamycin, and corticosteroids).

Tuberculosis (TB) is a possible complication of solid organ and hematopoietic stem cell transplantation. The identification of candidates for preventive chemotherapy is an effective intervention to protect transplant recipients with latent infection with <i>Mycobacterium tuberculosis</i> from progressing to active disease. The best available proxy for diagnosing latent infection with <i>M. tuberculosis</i> is the identification of an adaptive immune response by the tuberculin skin test or an interferon-γ based <i>ex vivo</i> assay. Risk assessment in transplant recipients for the development of TB depends on, among other factors, the locally expected underlying prevalence of infection with <i>M. tuberculosis</i> in the target population. In areas of high prevalence, preventive chemotherapy for all transplant recipients may be justified without immunodiagnostic testing while in areas of medium and low prevalence, preventive chemotherapy should only be offered to candidates with positive <i>M. tuberculosis</i>-specific immune responses. The diagnosis of TB in transplant recipients can be challenging. Treatment of TB is often difficult due to substantial interactions between anti-TB drugs and immunosuppressive medications. This management guideline summarises current knowledge on the prevention, diagnosis and treatment of TB related to solid organ and hematopoietic stem cell transplantation and provides an expert consensus on questions where scientific evidence is still lacking.

There are limited prospective, controlled data evaluating survival in patients receiving early surgery vs medical therapy for prosthetic valve endocarditis (PVE).To determine the in-hospital and 1-year mortality in patients with PVE who undergo valve replacement during index hospitalization compared with patients who receive medical therapy alone, after controlling for survival and treatment selection bias.Participants were enrolled between June 2000 and December 2006 in the International Collaboration on Endocarditis-Prospective Cohort Study (ICE-PCS), a prospective, multinational, observational cohort of patients with infective endocarditis. Patients hospitalized with definite right- or left-sided PVE were included in the analysis. We evaluated the effect of treatment assignment on mortality, after adjusting for biases using a Cox proportional hazards model that included inverse probability of treatment weighting and surgery as a time-dependent covariate. The cohort was stratified by probability (propensity) for surgery, and outcomes were compared between the treatment groups within each stratum.Valve replacement during index hospitalization (early surgery) vs medical therapy.In-hospital and 1-year mortality.Of the 1025 patients with PVE, 490 patients (47.8%) underwent early surgery and 535 individuals (52.2%) received medical therapy alone. Compared with medical therapy, early surgery was associated with lower in-hospital mortality in the unadjusted analysis and after controlling for treatment selection bias (in-hospital mortality: hazard ratio [HR], 0.44 [95% CI, 0.38-0.52] and lower 1-year mortality: HR, 0.57 [95% CI, 0.49-0.67]). The lower mortality associated with surgery did not persist after adjustment for survivor bias (in-hospital mortality: HR, 0.90 [95% CI, 0.76-1.07] and 1-year mortality: HR, 1.04 [95% CI, 0.89-1.23]). Subgroup analysis indicated a lower in-hospital mortality with early surgery in the highest surgical propensity quintile (21.2% vs 37.5%; P = .03). At 1-year follow-up, the reduced mortality with surgery was observed in the fourth (24.8% vs 42.9%; P = .007) and fifth (27.9% vs 50.0%; P = .007) quintiles of surgical propensity.Prosthetic valve endocarditis remains associated with a high 1-year mortality rate. After adjustment for differences in clinical characteristics and survival bias, early valve replacement was not associated with lower mortality compared with medical therapy in the overall cohort. Further studies are needed to define the effect and timing of surgery in patients with PVE who have indications for surgery.

Solid organ transplant (SOT) recipients have a significant risk of invasive fungal diseases (IFD) caused mainly by Candida spp. and Aspergillus spp. Candida spp. is the most frequent agent of IFD in the transplant recipient. The absence of clinical trials and the epidemiological differences in IFD in different transplant programmes mean that there are no definitive recommendations for the diagnosis, treatment and prevention of IFD in SOT, so most of the evidence must be based on clinical experience.

Clinical data on patients with intra-abdominal candidiasis (IAC) is still scarce.We collected data from 13 hospitals in Italy, Spain, Brazil, and Greece over a 3-year period (2011-2013) including patients from ICU, medical, and surgical wards.A total of 481 patients were included in the study. Of these, 27% were hospitalized in ICU. Mean age was 63 years and 57% of patients were male. IAC mainly consisted of secondary peritonitis (41%) and abdominal abscesses (30%); 68 (14%) cases were also candidemic and 331 (69%) had concomitant bacterial infections. The most commonly isolated Candida species were C. albicans (n = 308 isolates, 64%) and C. glabrata (n = 76, 16%). Antifungal treatment included echinocandins (64%), azoles (32%), and amphotericin B (4%). Septic shock was documented in 40.5% of patients. Overall 30-day hospital mortality was 27% with 38.9% mortality in ICU. Multivariate logistic regression showed that age (OR 1.05, 95% CI 1.03-1.07, P < 0.001), increments in 1-point APACHE II scores (OR 1.05, 95% CI 1.01-1.08, P = 0.028), secondary peritonitis (OR 1.72, 95% CI 1.02-2.89, P = 0.019), septic shock (OR 3.29, 95% CI 1.88-5.86, P < 0.001), and absence of adequate abdominal source control (OR 3.35, 95% CI 2.01-5.63, P < 0.001) were associated with mortality. In patients with septic shock, absence of source control correlated with mortality rates above 60% irrespective of administration of an adequate antifungal therapy.Low percentages of concomitant candidemia and high mortality rates are documented in IAC. In patients presenting with septic shock, source control is fundamental.

The field of cardiothoracic transplantation (CT) has evolved significantly, but infections remain an important cause of morbidity and mortality, particularly fungal infections (FIs). The higher mortality associated with FIs has prompted the institution of center-specific anti-fungal prophylactic strategies.1Dummer J.S. Lazariashvilli N. Barnes J. Ninan M. Milstone A.P. A survey of anti-fungal management in lung transplantation.J Heart Lung Transplant. 2004; 23: 1376-1381Google Scholar, 2Husain S. Zaldonis D. Kusne S. Kwak E.J. Paterson D.L. McCurry K.R. Variation in antifungal prophylaxis strategies in lung transplantation.Transpl Infect Dis. 2006; 8: 213-218Google Scholar, 3Neoh C.F. Snell G.I. Kotsimbos T. et al.Antifungal prophylaxis in lung transplantation—a world-wide survey.Am J Transplant. 2011; 11: 361-366Google Scholar, 4Munoz P. Valerio M. Palomo J. et al.Targeted antifungal prophylaxis in heart transplant recipients.Transplantation. 2013; 96: 664-669Google Scholar, 5Delgado A. Nailor M.D. Initial posaconazole prophylactic dosing and serum levels in heart transplant patients.Conn Med. 2012; 76: 413-415Google Scholar In the absence of existing clinical trials, the International Society for Heart and Lung Transplantation (ISHLT) Infectious Diseases Council has committed to convening an international and multidisciplinary panel of experts in the field to address the issue. The panel members are recognized leaders in the field of heart and lung transplantation and mechanical circulatory support devices (MCSDs), and were selected from established transplant centers worldwide by the chairs. The panel members approved the most relevant questions to be addressed in the areas of epidemiology, diagnosis, prophylaxis, and treatment of FIs, including therapeutic drug monitoring (TDM) of anti-fungal agents in adult and pediatric heart, lung, and MCSD patients. The panel was subsequently divided into working groups, each headed by their respective chairs, for epidemiology, diagnosis, prophylaxis, treatment, TDM, and pediatrics. A comprehensive literature search was performed by the panel chairs and was disseminated to the working groups. The working groups reviewed the existing literature to answer the identified questions based on the published evidence or, in the absence of published evidence, to provide guidance based on prevailing expert knowledge and experience. Each group reviewed, evaluated, and summarized the relevant evidence and then presented its findings at a workshop held at the annual ISHLT meeting in Montreal on April 23, 2013. The recommendations were graded according to ISHLT Standards and Guidelines Committee documents. Disagreements were resolved by iterative discussion and consensus. Subsequently, each group chair prepared an article with input from the members of the group and submitted it to the cochairs. The articles were modified based on the feedback of the cochairs. The executive summaries for each topic were generated from the articles by the cochairs and were submitted to the ISHLT Standards and Guidelines Committee. Each panel member disclosed his or her potential conflicts of interest. The panel recommendations do not include management of Pneumocystis jiroveci, Cryptococcus, and endemic mycoses in CT recipients (Table 1 and Table 2).Table 1Important Definitions Used in the DocumentTermDefinitionColonizationPresence of fungus in the respiratory secretions (sputum or bronchoalveolar lavage [BAL]) detected by the culture, polymerase chain reaction (PCR) or biomarker (galactomannan [GM]/cryptococcal antigen) in the absence of symptoms, radiologic, and endobronchial changes.6Husain S. Mooney M.L. Danziger-Isakov L. et al.A 2010 working formulation for the standardization of definitions of infections in cardiothoracic transplant recipients.J Heart Lung Transplant. 2011; 30: 361-374Google ScholarInvasive fungal disease (IFD)Presence of fungus in the respiratory secretions (sputum or BAL) detected by the culture, PCR, or biomarker (GM/cryptococcal antigen) in the presence of symptoms, radiologic, and endobronchial changes, or presence of histologic changes consistent with fungal invasion of the tissue.6Husain S. Mooney M.L. Danziger-Isakov L. et al.A 2010 working formulation for the standardization of definitions of infections in cardiothoracic transplant recipients.J Heart Lung Transplant. 2011; 30: 361-374Google ScholarUniversal anti-fungal prophylaxisRefers to an anti-fungal medication started in the post-operative period in all patients, before any post-transplant isolation of a fungal pathogen.Targeted anti-fungal prophylaxisRefers to an anti-fungal medication started in the post-operative period, before any post-transplant isolation of a fungal pathogen or serologic marker of fungus, which is prescribed only to patients deemed at higher risk for IFD (e.g., cystic fibrosis patients and those with pre-transplant fungal colonization/infection or on augmented immunosuppression).Preemptive anti-fungal therapyRefers to an anti-fungal medication started after post-transplant isolation of a fungal pathogen or serologic marker of fungus in the absence of any evidence for IFD.Attack rateRefers to the cumulative incidence of IFD over time in a colonized transplant recipient. Open table in a new tab Table 2International Society for Heart and Lung Transplantation Standards and Guidelines Committee Grading CriteriaClass IEvidence and/or general agreement that a given treatment or procedure is beneficial, useful, and effectiveClass IIConflicting evidence and/or divergence of opinion about the usefulness/efficacy of the treatment or procedureClass IIaWeight of evidence/opinion is in favor of usefulness/efficacyClass IIbUsefulness/efficacy is less well established by evidence/opinionClass IIIEvidence or general agreement that the treatment or procedure is not useful or effective and in some cases may be harmfulLevel of evidence AData derived from multiple randomized clinical trials or meta-analysesLevel of evidence BData derived from a single randomized clinical trial or large non-randomized studiesLevel of evidence CConsensus of opinion of the experts and/or small studies, retrospective studies, registries Open table in a new tab All information on fungal colonization in lung transplant (LT) candidates has been obtained from observational studies, most of them from single centers. Therefore, confidence about the exact prevalence of fungal colonization in LT candidates is limited. The data are more robust in the cystic fibrosis (CF) population due to these patients’ ability to produce sputum. Studies have included colonization at any time pre-transplant, and there is a distinct lack of data regarding colonization rates at different times pre-transplant (e.g., little or no comparison of colonization rates in the months preceding transplant vs at the time of transplant). In addition, the frequency of sampling might influence the identification of fungal pathogens before LT. In a study examining explanted lungs, the overall prevalence was 5% (14 of 304),7Vadnerkar A. Clancy C.J. Celik U. et al.Impact of mold infections in explanted lungs on outcomes of lung transplantation.Transplantation. 2010; 89: 253-260Google Scholar whereas in studies with greater proportions of CF patients, 8% to 59% of patients were colonized with fungi, of which most of the isolates were Aspergillus species.8Helmi M. Love R.B. Welter D. Cornwell R.D. Meyer K.C. Aspergillus infection in lung transplant recipients with cystic fibrosis: risk factors and outcomes comparison to other types of transplant recipients.Chest. 2003; 123: 800-808Google Scholar, 9Nunley D.R. Ohori P. Grgurich W.F. et al.Pulmonary aspergillosis in cystic fibrosis lung transplant recipients.Chest. 1998; 114: 1321-1329Google Scholar, 10Iversen M. Burton C.M. Vand S. et al.Aspergillus infection in lung transplant patients: incidence and prognosis.Eur J Clin Microbiol Infect Dis. 2007; 26: 879-886Google Scholar, 11Kanj S.S. Tapson V. Davis R.D. Madden J. Browning I. Infections in patients with cystic fibrosis following lung transplantation.Chest. 1997; 112: 924-930Google Scholar The data on non-CF populations have been scarce, and studies have reported a prevalence of 0% to 52%.8Helmi M. Love R.B. Welter D. Cornwell R.D. Meyer K.C. Aspergillus infection in lung transplant recipients with cystic fibrosis: risk factors and outcomes comparison to other types of transplant recipients.Chest. 2003; 123: 800-808Google Scholar, 9Nunley D.R. Ohori P. Grgurich W.F. et al.Pulmonary aspergillosis in cystic fibrosis lung transplant recipients.Chest. 1998; 114: 1321-1329Google Scholar Multicenter studies with diverse geographic distributions, representative pre-transplant diagnoses, and standardized sampling techniques are needed to more accurately determine the prevalence of fungal colonization in LT candidates. Multiple studies have assessed the presence of fungal colonization in LT recipients (LTRs). Studies have focused primarily on colonization by molds, particularly Aspergillus species. Although these studies have differed, all have been case series of patients after LT.12Husain S. Paterson D.L. Studer S. et al.Voriconazole prophylaxis in lung transplant recipients.Am J Transplant. 2006; 6: 3008-3016Google Scholar, 13Luong M.L. Hosseini-Moghaddam S.M. Singer L.G. et al.Risk factors for voriconazole hepatotoxicity at 12 weeks in lung transplant recipients.Am J Transplant. 2012; 12: 1929-1935Google Scholar, 14Mitsani D. Nguyen M.H. Shields R.K. et al.Prospective, observational study of voriconazole therapeutic drug monitoring among lung transplant recipients receiving prophylaxis: factors impacting levels of and associations between serum troughs, efficacy, and toxicity.Antimicrob Agents Chemother. 2012; 56: 2371-2377Google Scholar, 15Weigt S.S. Elashoff R.M. Huang C. et al.Aspergillus colonization of the lung allograft is a risk factor for bronchiolitis obliterans syndrome.Am J Transplant. 2009; 9: 1903-1911Google Scholar, 16Cahill B.C. Hibbs J.R. Savik K. et al.Aspergillus airway colonization and invasive disease after lung transplantation.Chest. 1997; 112: 1160-1164Google Scholar, 17Cadena J. Levine D.J. Angel L.F. et al.Antifungal prophylaxis with voriconazole or itraconazole in lung transplant recipients: hepatotoxicity and effectiveness.Am J Transplant. 2009; 9: 2085-2091Google Scholar, 18Calvo V. Borro J.M. Morales P. et al.Antifungal prophylaxis during the early postoperative period of lung transplantation. Valencia Lung Transplant Group.Chest. 1999; 115: 1301-1304Google Scholar, 19Tofte N. Jensen C. Tvede M. Andersen C.B. Carlsen J. Iversen M. Use of prophylactic voriconazole for three months after lung transplantation does not reduce infection with Aspergillus: a retrospective study of 147 patients.Scand J Infect Dis. 2012; 44: 835-841Google Scholar, 20Shitrit D. Ollech J.E. Ollech A. et al.Itraconazole prophylaxis in lung transplant recipients receiving tacrolimus (FK 506): efficacy and drug interaction.J Heart Lung Transplant. 2005; 24: 2148-2152Google Scholar, 21Dhar D. Dickson J.L. Carby M.R. Lyster H.S. Hall A.V. Banner N.R. Fungal infection in cardiothoracic transplant recipients: outcome without systemic amphotericin therapy.Transpl Int. 2012; 25: 758-764Google Scholar The rates of fungal colonization ranged from 20% to 50%, and the numbers of patients in each of the series ranged from 32 to 455 patients.12Husain S. Paterson D.L. Studer S. et al.Voriconazole prophylaxis in lung transplant recipients.Am J Transplant. 2006; 6: 3008-3016Google Scholar, 13Luong M.L. Hosseini-Moghaddam S.M. Singer L.G. et al.Risk factors for voriconazole hepatotoxicity at 12 weeks in lung transplant recipients.Am J Transplant. 2012; 12: 1929-1935Google Scholar, 14Mitsani D. Nguyen M.H. Shields R.K. et al.Prospective, observational study of voriconazole therapeutic drug monitoring among lung transplant recipients receiving prophylaxis: factors impacting levels of and associations between serum troughs, efficacy, and toxicity.Antimicrob Agents Chemother. 2012; 56: 2371-2377Google Scholar, 15Weigt S.S. Elashoff R.M. Huang C. et al.Aspergillus colonization of the lung allograft is a risk factor for bronchiolitis obliterans syndrome.Am J Transplant. 2009; 9: 1903-1911Google Scholar, 16Cahill B.C. Hibbs J.R. Savik K. et al.Aspergillus airway colonization and invasive disease after lung transplantation.Chest. 1997; 112: 1160-1164Google Scholar, 17Cadena J. Levine D.J. Angel L.F. et al.Antifungal prophylaxis with voriconazole or itraconazole in lung transplant recipients: hepatotoxicity and effectiveness.Am J Transplant. 2009; 9: 2085-2091Google Scholar, 18Calvo V. Borro J.M. Morales P. et al.Antifungal prophylaxis during the early postoperative period of lung transplantation. Valencia Lung Transplant Group.Chest. 1999; 115: 1301-1304Google Scholar, 19Tofte N. Jensen C. Tvede M. Andersen C.B. Carlsen J. Iversen M. Use of prophylactic voriconazole for three months after lung transplantation does not reduce infection with Aspergillus: a retrospective study of 147 patients.Scand J Infect Dis. 2012; 44: 835-841Google Scholar, 20Shitrit D. Ollech J.E. Ollech A. et al.Itraconazole prophylaxis in lung transplant recipients receiving tacrolimus (FK 506): efficacy and drug interaction.J Heart Lung Transplant. 2005; 24: 2148-2152Google Scholar, 21Dhar D. Dickson J.L. Carby M.R. Lyster H.S. Hall A.V. Banner N.R. Fungal infection in cardiothoracic transplant recipients: outcome without systemic amphotericin therapy.Transpl Int. 2012; 25: 758-764Google Scholar Most of the larger series had rates of colonization greater than 30% and closer to 40%, suggesting that a rate of fungal colonization of 30% is likely the most accurate. In all series, the presence of CF greatly increased the rate of fungal colonization in LTRs. Patients with CF as their underlying diagnosis had rates from 42% to 76%. By contrast, the rates for non-CF patients ranged from 21% to 40%, and the rate was lowest among the non-CF patients in largest series (299 patients).7Vadnerkar A. Clancy C.J. Celik U. et al.Impact of mold infections in explanted lungs on outcomes of lung transplantation.Transplantation. 2010; 89: 253-260Google Scholar, 8Helmi M. Love R.B. Welter D. Cornwell R.D. Meyer K.C. Aspergillus infection in lung transplant recipients with cystic fibrosis: risk factors and outcomes comparison to other types of transplant recipients.Chest. 2003; 123: 800-808Google Scholar, 9Nunley D.R. Ohori P. Grgurich W.F. et al.Pulmonary aspergillosis in cystic fibrosis lung transplant recipients.Chest. 1998; 114: 1321-1329Google Scholar, 10Iversen M. Burton C.M. Vand S. et al.Aspergillus infection in lung transplant patients: incidence and prognosis.Eur J Clin Microbiol Infect Dis. 2007; 26: 879-886Google Scholar, 11Kanj S.S. Tapson V. Davis R.D. Madden J. Browning I. Infections in patients with cystic fibrosis following lung transplantation.Chest. 1997; 112: 924-930Google Scholar, 19Tofte N. Jensen C. Tvede M. Andersen C.B. Carlsen J. Iversen M. Use of prophylactic voriconazole for three months after lung transplantation does not reduce infection with Aspergillus: a retrospective study of 147 patients.Scand J Infect Dis. 2012; 44: 835-841Google Scholar, 22Husni R.N. Gordon S.M. Longworth D.L. et al.Cytomegalovirus infection is a risk factor for invasive aspergillosis in lung transplant recipients.Clin Infect Dis. 1998; 26: 753-755Google Scholar These studies demonstrate that the presence of CF results in higher rates of post-transplant fungal colonization. In another study, the Aspergillus species were most commonly responsible for colonization.23Sole A. Morant P. Salavert M. Peman J. Morales P. Aspergillus infections in lung transplant recipients: risk factors and outcome.Clin Microbiol Infect. 2005; 11: 359-365Abstract Full Text Full Text PDF Scopus (151) Google Scholar Of all the Aspergillus species, A fumigatus was the most common (59%), followed by A flavus (35%). The incidence of invasive fungal disease (IFD) is much lower than that of fungal colonization after LT,9Nunley D.R. Ohori P. Grgurich W.F. et al.Pulmonary aspergillosis in cystic fibrosis lung transplant recipients.Chest. 1998; 114: 1321-1329Google Scholar, 10Iversen M. Burton C.M. Vand S. et al.Aspergillus infection in lung transplant patients: incidence and prognosis.Eur J Clin Microbiol Infect Dis. 2007; 26: 879-886Google Scholar, 19Tofte N. Jensen C. Tvede M. Andersen C.B. Carlsen J. Iversen M. Use of prophylactic voriconazole for three months after lung transplantation does not reduce infection with Aspergillus: a retrospective study of 147 patients.Scand J Infect Dis. 2012; 44: 835-841Google Scholar with rates ranging from 3% to 14%. The rate in the largest series was closer to the lower percentage limit (e.g., 6.6% in 1 series with 335 patients and 8.6% in a large, multicenter trial).7Vadnerkar A. Clancy C.J. Celik U. et al.Impact of mold infections in explanted lungs on outcomes of lung transplantation.Transplantation. 2010; 89: 253-260Google Scholar, 8Helmi M. Love R.B. Welter D. Cornwell R.D. Meyer K.C. Aspergillus infection in lung transplant recipients with cystic fibrosis: risk factors and outcomes comparison to other types of transplant recipients.Chest. 2003; 123: 800-808Google Scholar, 9Nunley D.R. Ohori P. Grgurich W.F. et al.Pulmonary aspergillosis in cystic fibrosis lung transplant recipients.Chest. 1998; 114: 1321-1329Google Scholar, 10Iversen M. Burton C.M. Vand S. et al.Aspergillus infection in lung transplant patients: incidence and prognosis.Eur J Clin Microbiol Infect Dis. 2007; 26: 879-886Google Scholar, 11Kanj S.S. Tapson V. Davis R.D. Madden J. Browning I. Infections in patients with cystic fibrosis following lung transplantation.Chest. 1997; 112: 924-930Google Scholar, 12Husain S. Paterson D.L. Studer S. et al.Voriconazole prophylaxis in lung transplant recipients.Am J Transplant. 2006; 6: 3008-3016Google Scholar, 13Luong M.L. Hosseini-Moghaddam S.M. Singer L.G. et al.Risk factors for voriconazole hepatotoxicity at 12 weeks in lung transplant recipients.Am J Transplant. 2012; 12: 1929-1935Google Scholar, 14Mitsani D. Nguyen M.H. Shields R.K. et al.Prospective, observational study of voriconazole therapeutic drug monitoring among lung transplant recipients receiving prophylaxis: factors impacting levels of and associations between serum troughs, efficacy, and toxicity.Antimicrob Agents Chemother. 2012; 56: 2371-2377Google Scholar, 15Weigt S.S. Elashoff R.M. Huang C. et al.Aspergillus colonization of the lung allograft is a risk factor for bronchiolitis obliterans syndrome.Am J Transplant. 2009; 9: 1903-1911Google Scholar, 16Cahill B.C. Hibbs J.R. Savik K. et al.Aspergillus airway colonization and invasive disease after lung transplantation.Chest. 1997; 112: 1160-1164Google Scholar, 17Cadena J. Levine D.J. Angel L.F. et al.Antifungal prophylaxis with voriconazole or itraconazole in lung transplant recipients: hepatotoxicity and effectiveness.Am J Transplant. 2009; 9: 2085-2091Google Scholar, 18Calvo V. Borro J.M. Morales P. et al.Antifungal prophylaxis during the early postoperative period of lung transplantation. Valencia Lung Transplant Group.Chest. 1999; 115: 1301-1304Google Scholar, 24Borro J.M. Sole A. de la Torre M. et al.Efficiency and safety of inhaled amphotericin B lipid complex (Abelcet) in the prophylaxis of invasive fungal infections following lung transplantation.Transplant Proc. 2008; 40: 3090-3093Google Scholar, 25Singh N. Husain S. Aspergillus infections after lung transplantation: clinical differences in type of transplant and implications for management.J Heart Lung Transplant. 2003; 22: 258-266Google Scholar, 26Pappas P.G. Alexander B.D. Andes D.R. et al.Invasive fungal infections among organ transplant recipients: results of the Transplant-Associated Infection Surveillance Network (TRANSNET).Clin Infect Dis. 2010; 50: 1101-1111Google Scholar, 27Reichenspurner H. Gamberg P. Nitschke M. et al.Significant reduction in the number of fungal infections after lung-, heart-lung, and heart transplantation using aerosolized amphotericin B prophylaxis.Transplant Proc. 1997; 29: 627-628Google Scholar When the rarer but potentially severe invasive infection with Mucorales was examined, the rate was lower again, between 0.28% and 1.4%.26Pappas P.G. Alexander B.D. Andes D.R. et al.Invasive fungal infections among organ transplant recipients: results of the Transplant-Associated Infection Surveillance Network (TRANSNET).Clin Infect Dis. 2010; 50: 1101-1111Google Scholar, 28Silveira F.P. Husain S. Fungal infections in lung transplant recipients.Curr Opin Pulm Med. 2008; 14: 211-218Google Scholar In this setting, a pre-transplant diagnosis of CF was once again associated with an increased risk of post-transplant IFD.8Helmi M. Love R.B. Welter D. Cornwell R.D. Meyer K.C. Aspergillus infection in lung transplant recipients with cystic fibrosis: risk factors and outcomes comparison to other types of transplant recipients.Chest. 2003; 123: 800-808Google Scholar, 9Nunley D.R. Ohori P. Grgurich W.F. et al.Pulmonary aspergillosis in cystic fibrosis lung transplant recipients.Chest. 1998; 114: 1321-1329Google Scholar, 10Iversen M. Burton C.M. Vand S. et al.Aspergillus infection in lung transplant patients: incidence and prognosis.Eur J Clin Microbiol Infect Dis. 2007; 26: 879-886Google Scholar A paucity of studies have examined the incidence/prevalence of IFD after heart transplantation. The incidence in available studies has ranged from 0.12 per patient-year to 0.4 per 100 patient-years.21Dhar D. Dickson J.L. Carby M.R. Lyster H.S. Hall A.V. Banner N.R. Fungal infection in cardiothoracic transplant recipients: outcome without systemic amphotericin therapy.Transpl Int. 2012; 25: 758-764Google Scholar, 27Reichenspurner H. Gamberg P. Nitschke M. et al.Significant reduction in the number of fungal infections after lung-, heart-lung, and heart transplantation using aerosolized amphotericin B prophylaxis.Transplant Proc. 1997; 29: 627-628Google Scholar A multicenter study at 15 transplant centers in the United States suggested that the cumulative incidence of IFD after heart transplantation was 3.4% during the first year.26Pappas P.G. Alexander B.D. Andes D.R. et al.Invasive fungal infections among organ transplant recipients: results of the Transplant-Associated Infection Surveillance Network (TRANSNET).Clin Infect Dis. 2010; 50: 1101-1111Google Scholar Candida species accounted for 49% of the infections, and Aspergillus species accounted for 23%. More than 50% of the infections occurred in the first 90 days.26Pappas P.G. Alexander B.D. Andes D.R. et al.Invasive fungal infections among organ transplant recipients: results of the Transplant-Associated Infection Surveillance Network (TRANSNET).Clin Infect Dis. 2010; 50: 1101-1111Google Scholar Overall, IFD after heart transplantation is rare; when it occurs, it is usually during the first year after transplant, likely at a time when immunosuppression levels are higher. The presence of another case of invasive aspergillosis (IA) in the same institution in the preceding 3 months has been identified as a risk factor for early IA after heart transplantation; therefore, it is important that centers know their own epidemiology.19Tofte N. Jensen C. Tvede M. Andersen C.B. Carlsen J. Iversen M. Use of prophylactic voriconazole for three months after lung transplantation does not reduce infection with Aspergillus: a retrospective study of 147 patients.Scand J Infect Dis. 2012; 44: 835-841Google Scholar This area requires further study. Multiple case series have addressed this question, although no well-controlled trials have been performed to date.8Helmi M. Love R.B. Welter D. Cornwell R.D. Meyer K.C. Aspergillus infection in lung transplant recipients with cystic fibrosis: risk factors and outcomes comparison to other types of transplant recipients.Chest. 2003; 123: 800-808Google Scholar, 9Nunley D.R. Ohori P. Grgurich W.F. et al.Pulmonary aspergillosis in cystic fibrosis lung transplant recipients.Chest. 1998; 114: 1321-1329Google Scholar, 13Luong M.L. Hosseini-Moghaddam S.M. Singer L.G. et al.Risk factors for voriconazole hepatotoxicity at 12 weeks in lung transplant recipients.Am J Transplant. 2012; 12: 1929-1935Google Scholar, 14Mitsani D. Nguyen M.H. Shields R.K. et al.Prospective, observational study of voriconazole therapeutic drug monitoring among lung transplant recipients receiving prophylaxis: factors impacting levels of and associations between serum troughs, efficacy, and toxicity.Antimicrob Agents Chemother. 2012; 56: 2371-2377Google Scholar, 15Weigt S.S. Elashoff R.M. Huang C. et al.Aspergillus colonization of the lung allograft is a risk factor for bronchiolitis obliterans syndrome.Am J Transplant. 2009; 9: 1903-1911Google Scholar, 25Singh N. Husain S. Aspergillus infections after lung transplantation: clinical differences in type of transplant and implications for management.J Heart Lung Transplant. 2003; 22: 258-266Google Scholar, 29Egli A. Fuller J. Humar A. et al.Emergence of Aspergillus calidoustus infection in the era of posttransplantation azole prophylaxis.Transplantation. 2012; 94: 403-410Google Scholar, 30Silveira F.P. Kwak E.J. Paterson D.L. Pilewski J.M. McCurry K.R. Husain S. Post-transplant colonization with non-Aspergillus molds and risk of development of invasive fungal disease in lung transplant recipients.J Heart Lung Transplant. 2008; 27: 850-855Google Scholar These studies have included patients who have undergone heart-lung transplant, single LT, and bilateral LT, and all have demonstrated that invasive infections tend to occur during the first 6 months after transplant. Surveillance and interaction with the health care team is always more common during the first year after transplant, and thus, sampling bias might have played a role in the findings. However, immunosuppression is highest during the same time period, and patients are more frequently treated for rejection, potentially increasing their susceptibility to IFD. In a multicenter center study that assessed IFD during the first year post-transplant after solid organ transplantation (SOT), most infections occurred in the first 3 months after transplant for both lung and heart transplants. Approximately 66% occurred during that interval, with total incidences in the first year of 8.6% and 4.0% for lung and heart transplant recipients, respectively.26Pappas P.G. Alexander B.D. Andes D.R. et al.Invasive fungal infections among organ transplant recipients: results of the Transplant-Associated Infection Surveillance Network (TRANSNET).Clin Infect Dis. 2010; 50: 1101-1111Google Scholar This is in contrast to a previously reported literature review where a median time to onset of IA was 3.2 months.25Singh N. Husain S. Aspergillus infections after lung transplantation: clinical differences in type of transplant and implications for management.J Heart Lung Transplant. 2003; 22: 258-266Google Scholar The increase in the time to onset of IA in LTRs may be attributed to the widespread use of anti-fungal prophylaxis.3Neoh C.F. Snell G.I. Kotsimbos T. et al.Antifungal prophylaxis in lung transplantation—a world-wide survey.Am J Transplant. 2011; 11: 361-366Google Scholar Another study found that invasive candidiasis (IC) occurred at 52 days (range, 0–5,727 days) in LTR and at 66.5 days (range, 2–4,645 days) in heart transplant recipients, whereas IA was noted at 504 days (range, 3–4,417 days) in LTRs and at 382 days (range, 31–1,309) in heart transplant recipients.31Neofytos D. Fishman J.A. Horn D. et al.Epidemiology and outcome of invasive fungal infections in solid organ transplant recipients.Transpl Infect Dis. 2010; 12: 220-229Google Scholar A study of heart transplant recipients reported IA which occurred during the first 3 months after transplantation (early IA) accounted for 23 cases (median, 35 days [range 19–88 days] after transplantation); in the remaining 8 cases, IA occurred a median of 125.5 days (range, 91–301 days) after transplantation (late IA).32Munoz P. Ceron I. Valerio M. et al.Invasive aspergillosis among heart transplant recipients: a 24-year perspective.J Heart Lung Transplant. 2014; 33: 278-288Google Scholar Multiple studies, mostly single-center case series and cohort studies, have addressed the risk factors for IFD after LT. There has been a paucity of studies regarding the same question in heart transplantation. The main risk factor is a pre-transplant diagnosis of CF, which appears to result in increased rates of IFD after LT.8Helmi M. Love R.B. Welter D. Cornwell R.D. Meyer K.C. Aspergillus infection in lung transplant recipients with cystic fibrosis: risk factors and outcomes comparison to other types of transplant recipients.Chest. 2003; 123: 800-808Google Scholar, 9Nunley D.R. Ohori P. Grgurich W.F. et al.Pulmonary aspergillosis in cystic fibrosis lung transplant recipients.Chest. 1998; 114: 1321-1329Google Scholar, 10Iversen M. Burton C.M. Vand S. et al.Aspergillus infection in lung transplant patients: incidence and prognosis.Eur J Clin Microbiol Infect Dis. 2007; 26: 879-886Google Scholar, 19Tofte N. Jensen C. Tvede M. Andersen C.B. Carlsen J. Iversen M. Use of prophylactic voriconazole for three months after lung transplantation does not reduce infection with Aspergillus: a retrospective study of 147 patients.Scand J Infect Dis. 2012; 44: 835-841Google Scholar, 22Husni R.N. Gordon S.M. Longworth D.L. et al.Cytomegalovirus infection is a risk factor for invasive aspergillosis in lung transplant recipients.Clin Infect Dis. 1998; 26: 753-755Google Scholar Other important risk factors for IFD after LT include the presence of fungal colonization

Seasonal influenza infection may cause significant morbidity and mortality in transplant recipients. The purpose of this study was to assess the epidemiology of symptomatic influenza infection posttransplant and determine risk factors for severe disease.Twenty centers in the United States, Canada, and Spain prospectively enrolled solid organ transplant (SOT) or hematopoietic stem cell transplant (HSCT) recipients with microbiologically confirmed influenza over 5 consecutive years (2010-2015). Demographics, microbiology data, and outcomes were collected. Serial nasopharyngeal swabs were collected at diagnosis and upto 28 days, and quantitative polymerase chain reaction for influenza A was performed.We enrolled 616 patients with confirmed influenza (477 SOT; 139 HSCT). Pneumonia at presentation was in 134 of 606 (22.1%) patients. Antiviral therapy was given to 94.1% for a median of 5 days (range, 1-42 days); 66.5% patients were hospitalized and 11.0% required intensive care unit (ICU) care. The receipt of vaccine in the same influenza season was associated with a decrease in disease severity as determined by the presence of pneumonia (odds ratio [OR], 0.34 [95% confidence interval {CI}, .21-.55], P < .001) and ICU admission (OR, 0.49 [95% CI, .26-.90], P = .023). Similarly, early antiviral treatment (within 48 hours) was associated with improved outcomes. In patients with influenza A, pneumonia, ICU admission, and not being immunized were also associated with higher viral loads at presentation (P = .018, P = .008, and P = .024, respectively).Annual influenza vaccination and early antiviral therapy are associated with a significant reduction in influenza-associated morbidity, and should be emphasized as strategies to improve outcomes of transplant recipients.

Coronavirus disease 2019 (COVID-19) -associated pulmonary aspergillosis (CAPA) has emerged as a complication in critically ill COVID-19 patients. The objectives of this multinational study were to determine the prevalence of CAPA in patients with COVID-19 in intensive care units (ICU) and to investigate risk factors for CAPA as well as outcome.The European Confederation of Medical Mycology (ECMM) conducted a multinational study including 20 centres from nine countries to assess epidemiology, risk factors and outcome of CAPA. CAPA was defined according to the 2020 ECMM/ISHAM consensus definitions.A total of 592 patients were included in this study, including 11 (1.9%) patients with histologically proven CAPA, 80 (13.5%) with probable CAPA, 18 (3%) with possible CAPA and 483 (81.6%) without CAPA. CAPA was diagnosed a median of 8 days (range 0-31 days) after ICU admission predominantly in older patients (adjusted hazard ratio (aHR) 1.04 per year; 95% CI 1.02-1.06) with any form of invasive respiratory support (HR 3.4; 95% CI 1.84-6.25) and receiving tocilizumab (HR 2.45; 95% CI 1.41-4.25). Median prevalence of CAPA per centre was 10.7% (range 1.7%-26.8%). CAPA was associated with significantly lower 90-day ICU survival rate (29% in patients with CAPA versus 57% in patients without CAPA; Mantel-Byar p < 0.001) and remained an independent negative prognostic variable after adjusting for other predictors of survival (HR 2.14; 95% CI 1.59-2.87, p ≤ 0.001).Prevalence of CAPA varied between centres. CAPA was significantly more prevalent among older patients, patients receiving invasive ventilation and patients receiving tocilizumab, and was an independent strong predictor of ICU mortality.

Uncommon, or rare, yeast infections are on the rise given increasing numbers of patients who are immunocompromised or seriously ill. The major pathogens include those of the genera Geotrichum, Saprochaete, Magnusiomyces, and Trichosporon (ie, basidiomycetes) and Kodamaea, Malassezia, Pseudozyma (ie, now Moesziomyces or Dirkmeia), Rhodotorula, Saccharomyces, and Sporobolomyces (ie, ascomycetes). A considered approach to the complex, multidisciplinary management of infections that are caused by these pathogens is essential to optimising patient outcomes; however, management guidelines are either region-specific or require updating. In alignment with the One World-One Guideline initiative to incorporate regional differences, experts from diverse geographical regions analysed publications describing the epidemiology and management of the previously mentioned rare yeasts. This guideline summarises the consensus recommendations with regards to the diagnostic and therapeutic options for patients with these rare yeast infections, with the intent of providing practical assistance in clinical decision making. Because there is less clinical experience of patients with rare yeast infections and studies on these patients were not randomised, nor were groups compared, most recommendations are not robust in their validation but represent insights by use of expert opinions and in-vitro susceptibility results. In this Review, we report the key features of the epidemiology, diagnosis, antifungal susceptibility, and treatment outcomes of patients with Geotrichum, Saprochaete, Magnusiomyces, and Trichosporon spp infections.

<h2>Abstract</h2><h3>Objectives</h3> The standard RT-PCR assay for coronavirus disease 2019 (COVID-19) is laborious and time-consuming, limiting testing availability. Rapid antigen-detection tests are faster and less expensive; however, the reliability of these tests must be validated before they can be used widely. The objective of this study was to determine the performance of the Panbio™ COVID-19 Ag Rapid Test Device (PanbioRT) (Abbott) in detecting severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in nasopharyngeal swab specimens. <h3>Methods</h3> This prospective multicentre study was carried out in ten Spanish university hospitals and included individuals with clinical symptoms or epidemiological criteria of COVID-19. Only individuals with ≤7 days from the onset of symptoms or from exposure to a confirmed case of COVID-19 were included. Two nasopharyngeal samples were taken to perform the PanbioRT as a point-of-care test and a diagnostic RT-PCR test. <h3>Results</h3> Among the 958 patients studied, 325 (90.5%) had true-positive results. The overall sensitivity and specificity for the PanbioRT were 90.5% (95%CI 87.5–93.6) and 98.8% (95%CI 98–99.7), respectively. Sensitivity in participants who had a threshold cycle (<i>C</i>_T) < 25 for the RT-PCR test was 99.5% (95%CI 98.4–100), and in participants with ≤5 days of the clinical course it was 91.8% (95%CI 88.8–94.8). Agreement between techniques was 95.7% (κ score 0.90; 95%CI 0.88–0.93). <h3>Conclusions</h3> The PanbioRT performs well clinically, with even more reliable results for patients with a shorter clinical course of the disease or a higher viral load. The results must be interpreted based on the local epidemiological context.

Abstract Background There is a paucity of knowledge on the long-term outcome in patients diagnosed with COVID-19. We describe a cohort of patients with a constellation of symptoms occurring four weeks after diagnosis causing different degrees of reduced functional capacity. Although different hypothesis have been proposed to explain this condition like persistent immune activation or immunological dysfunction, to date, no physiopathological mechanism has been identified. Consequently, there are no therapeutic options besides symptomatic treatment and rehabilitation. Methods We evaluated patients with symptoms that persisted for at least 4 weeks after COVID-19. Epidemiological and clinical data were collected. Blood tests, including inflammatory markers, were conducted, and imaging studies made if deemed necessary. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) reverse transcription polymerase chain reaction (RT-PCR) in plasma, stool, and urine were performed. Patients were offered antiviral treatment (compassionate use). Results We evaluated 29 patients who reported fatigue, muscle pain, dyspnea, inappropriate tachycardia, and low-grade fever. Median number of days from COVID-19 to positive RT-PCR in extra-respiratory samples was 55 (39–67). Previous COVID-19 was mild in 55% of the cases. Thirteen patients (45%) had positive plasma RT-PCR results and 51% were positive in at least one RT-PCR sample (plasma, urine, or stool). Functional status was severely reduced in 48% of the subjects. Eighteen patients (62%) received antiviral treatment. Improvement was seen in most patients (p = 0.000) and patients in the treatment group achieved better outcomes with significant differences (p = 0.01). Conclusions In a cohort of COVID-19 patients with persistent symptoms, 45% of them have detectable plasma SARS-CoV-2 RNA. Our results indicate possible systemic viral persistence in these patients, who may benefit of antiviral treatment strategies.

To determine the spectrum and impact of mycelial fungal infections, particularly those due to non-Aspergillus molds, 53 liver and heart transplant recipients with invasive mycelial infections were prospectively identified in a multicenter study. Invasive mycelial infections were due to Aspergillus species in 69.8% of patients, to non-Aspergillus hyalohyphomycetes in 9.4%, to phaeohyphomycetes in 9.4%, to zygomycetes in 5.7%, and to other causes in 5.7%. Infections due to mycelial fungi other than Aspergillus species were significantly more likely to be associated with disseminated (P = .005) and central nervous system (P = .07) infection than were those due to Aspergillus species. Overall mortality at 90 days was 54.7%. The associated mortality rate was 100% for zygomycosis, 80% for non-Aspergillus hyalohyphomycosis, 54% for aspergillosis, and 20% for phaeohyphomycosis. Thus, non-Aspergillus molds have emerged as significant pathogens in organ transplant recipients. These molds are more likely to be associated with disseminated infections and to be associated with poorer outcomes than is aspergillosis.

To facilitate the design of strategies for prevention of invasive aspergillosis in solid-organ transplant recipients, this study investigates whether the development of early-onset and late-onset aspergillosis are related to different risk factors, thereby distinguishing 2 risk populations for this serious complication.A retrospective case-control study was performed, including 156 cases of proven or probable invasive aspergillosis in patients recruited from 11 Spanish centers since the start of the centers' transplantation programs.Among all patients, 57% had early-onset IA (i.e., occurred during the first 3 months after transplantation). Risk factor analysis in this group identified as significantly associated risk factors a more complicated postoperative period, repeated bacterial infections or cytomegalovirus disease, and renal failure or the need for dialysis. Among patients with late-onset infections (i.e., occurred > 3 months after transplantation), who comprised 43% of cases, the patients at risk were older, were in an overimmunosuppressed state because of chronic transplant rejection or allograft dysfunction, and had posttransplantation renal failure.Risk factors in patients with early-onset cases and patients with late-onset cases of posttransplantation invasive aspergillosis are not the same, a fact that could have implications for the preventive approaches used for this infection.

We describe an immune reconstitution syndrome (IRS)-like entity in the course of evolution of Cryptococcus neoformans infection in organ transplant recipients.The study population comprised a cohort of 83 consecutive organ transplant recipients with cryptococcosis who were observed for a median of 2 years in an international, multicenter study.In 4 (4.8%) of the 83 patients, an IRS-like entity was observed a median of 5.5 weeks after the initiation of appropriate antifungal therapy. Worsening of clinical manifestations was documented, despite cultures being negative for C. neoformans. These patients were significantly more likely to have received tacrolimus, mycophenolate mofetil, and prednisone as the regimen of immunosuppressive therapy than were all other patients (P = .007). The proposed basis of this phenomenon is reversal of a predominantly Th2 response at the onset of infection to a Th1 proinflammatory response as a result of receipt of effective antifungal therapy and a reduction in or cessation of immunosuppressive therapy.This study demonstrated that an IRS-like entity occurs in organ transplant recipients with C. neoformans infection. Furthermore, this entity may be misconstrued as a failure of therapy. Immunomodulatory agents may have a role as adjunctive therapy in such cases.

To discern whether the characteristics and outcome of invasive aspergillosis in liver transplant recipients have evolved during the past decade, 26 patients who underwent transplantation during 1990-1995 (known as "the earlier cohort") were compared with 20 patients who underwent transplantation during 1998-2001 (known as "the later cohort"). Twenty-three percent of the Aspergillus infections in the earlier cohort occurred > or =90 days after transplantation, compared with 55% of such infections in the later cohort (P=.026). The earlier cohort was significantly more likely to have disseminated infection (P=.034) and central nervous system (CNS) involvement (P=.0004) than was the later cohort. The mortality rate was significantly higher for the earlier cohort (92%) than for the later cohort (60%; P=.012). Only disseminated infection (not the year of transplantation) approached statistical significance as an independent predictor of outcome. In the current era, invasive aspergillosis occurs later in the posttransplantation period, is less likely to be associated with CNS infection, and is associated with a lower mortality rate, compared with invasive aspergillosis in the early 1990s.

Variables influencing the risk of dissemination and outcome of Cryptococcus neoformans infection were assessed in 111 organ transplant recipients with cryptococcosis in a prospective, multicenter, international study. Sixtyone percent (68/111) of the patients had disseminated infection. The risk of disseminated cryptococcosis was significantly higher for liver transplant recipients (adjusted hazard ratio [HR], 6.65; P=.048). The overall mortality rate at 90 days was 14% (16/111). The mortality rate was higher in patients with abnormal mental status (P=.023), renal failure at baseline (P=.028), fungemia (P=.006), and disseminated infection (P=.035) and was lower in those receiving a calcineurin-inhibitor agent (P=.003). In amultivariable analysis, the receipt of a calcineurin-inhibitor agent was independently associated with a lower mortality (adjusted HR, 0.21; P=.008), and renal failure at baseline with a higher mortality rate (adjusted HR, 3.14; P=.037). Thus, outcome in transplant recipients with cryptococcosis appears to be influenced by the type of immunosuppressive agent employed. Additionally, discerning the basis for transplant type-specific differences in disease severity has implications relevant for yielding further insights into the pathogenesis of C. neoformans infection in transplant recipients.

Aims To investigate the clinical features, echocardiographic characteristics, management, and prognostic factors of mortality of aorto-cavitary fistulization (ACF) in infective endocarditis (IE).Extension of infection in aortic valve IE beyond valvular structures may result in peri-annular complications with resulting necrosis and rupture, and subsequent development of ACF.Aorto-cavitary communications create intra-cardiac

Clinical characteristics, risks, and outcomes in solid organ transplant (SOT) recipients with zygomycosis in the era of modern immunosuppressive and newer antifungal agent use have not been defined.In a matched case-controlled study, SOT recipients with zygomycosis were prospectively studied. The primary outcome measure was success (complete or partial response) at 90 days.Renal failure (odds ratio [OR], 3.17; P = .010), diabetes mellitus (OR, 8.11; P < .001), and prior voriconazole and/or caspofungin use (OR, 4.41; P = .033) were associated with a higher risk of zygomycosis, whereas tacrolimus (OR, 0.23; P = .002) was associated with a lower risk of zygomycosis. Liver transplant recipients were more likely to have disseminated disease (OR, 5.48; P = .021) and developed zygomycosis earlier after transplantation than did other SOT recipients (median, 0.8 vs 5.7 months; P < .001). Overall the treatment success rate was 60%. Renal failure (OR, 11.3; P = .023) and disseminated disease (OR, 14.6; P = .027) were independently predictive of treatment failure, whereas surgical resection was associated with treatment success (OR, 33.3; P = .003). The success rate with liposomal amphotericin B was 4-fold higher even when controlling for the aforementioned variables.The risks identified for zygomycosis and for disseminated disease, including those that were previously unrecognized, have implications for further elucidating the biologic basis and for optimizing outcomes in SOT recipients with zygomycosis.

Objective Aspiration of endotracheal secretions is a major step in the prevention of ventilator-associated pneumonia (VAP). We compared conventional and continuous aspiration of subglottic secretions (CASS) procedures in ventilated patients after major heart surgery (MHS). Materials and methods Randomized comparison during a 2-year period. Results A total of 714 patients were randomized (24 patients were excluded from the study; 359 CASS patients; 331 control subjects). The results for CASS patients and control subjects (per protocol and intention-to-treat analysis) were as follows: VAP incidence, 3.6% vs 5.3% (p = 0.2) and 3.8% vs 5.1%, respectively; incidence density, 17.9 vs 27.6 episodes per 1,000 days of mechanical ventilation (MV) [p = 0.18] and 18.9 vs 28.7 episodes per 1,000 days of MV, respectively; hospital antibiotic use in daily defined doses (DDDs), 1,213 vs 1,932 (p < 0.001) and 1,392 vs 1,932, respectively (p < 0.001). In patients who had received mechanical ventilation for > 48 h, the comparisons of CASS patients and control subjects were as follows: VAP incidence, 26.7% vs 47.5% (p = 0.04), respectively; incidence density, 31.5 vs 51.6 episodes per 1,000 days of MV, respectively (p = 0.03); median length of ICU stay, 7 vs 16.5 days (p = 0.01), respectively; hospital antibiotic use, 1,206 vs 1,877 DDD (p < 0.001), respectively; Clostridium difficile-associated diarrhea, 6.7% vs 12.5% (p = 0.3), respectively; and overall mortality rate, 44.4% vs 52.5% (p = 0.3), respectively. Reintubation increased the risk of VAP (relative risk [RR], 6.07; 95% confidence interval [CI], 2.20 to 16.60; p < 0.001), while CASS was the only significant protective factor (RR, 0.40; 95% CI, 0.16 to 0.99; p = 0.04). No complications related to CASS were observed. The cost of the CASS tube was 9 vs 1.5 € for the conventional tube. Conclusions CASS is a safe procedure that reduces the use of antimicrobial agents in the overall population and the incidence of VAP in patients who are at risk. CASS use should be encouraged, at least in patients undergoing MHS. Aspiration of endotracheal secretions is a major step in the prevention of ventilator-associated pneumonia (VAP). We compared conventional and continuous aspiration of subglottic secretions (CASS) procedures in ventilated patients after major heart surgery (MHS). Randomized comparison during a 2-year period. A total of 714 patients were randomized (24 patients were excluded from the study; 359 CASS patients; 331 control subjects). The results for CASS patients and control subjects (per protocol and intention-to-treat analysis) were as follows: VAP incidence, 3.6% vs 5.3% (p = 0.2) and 3.8% vs 5.1%, respectively; incidence density, 17.9 vs 27.6 episodes per 1,000 days of mechanical ventilation (MV) [p = 0.18] and 18.9 vs 28.7 episodes per 1,000 days of MV, respectively; hospital antibiotic use in daily defined doses (DDDs), 1,213 vs 1,932 (p < 0.001) and 1,392 vs 1,932, respectively (p < 0.001). In patients who had received mechanical ventilation for > 48 h, the comparisons of CASS patients and control subjects were as follows: VAP incidence, 26.7% vs 47.5% (p = 0.04), respectively; incidence density, 31.5 vs 51.6 episodes per 1,000 days of MV, respectively (p = 0.03); median length of ICU stay, 7 vs 16.5 days (p = 0.01), respectively; hospital antibiotic use, 1,206 vs 1,877 DDD (p < 0.001), respectively; Clostridium difficile-associated diarrhea, 6.7% vs 12.5% (p = 0.3), respectively; and overall mortality rate, 44.4% vs 52.5% (p = 0.3), respectively. Reintubation increased the risk of VAP (relative risk [RR], 6.07; 95% confidence interval [CI], 2.20 to 16.60; p < 0.001), while CASS was the only significant protective factor (RR, 0.40; 95% CI, 0.16 to 0.99; p = 0.04). No complications related to CASS were observed. The cost of the CASS tube was 9 vs 1.5 € for the conventional tube. CASS is a safe procedure that reduces the use of antimicrobial agents in the overall population and the incidence of VAP in patients who are at risk. CASS use should be encouraged, at least in patients undergoing MHS.

Bloodstream infections (BSIs) are a major cause of morbidity and mortality in transplant recipients. The aim of this study is to describe the incidence, microbiology and outcomes of BSIs in transplant recipients in Spain. The Spanish Network for Research on Infection in Transplantation (RESITRA) is formed by 16 centers with transplant program in Spain. The incidence and characteristics of BSIs in transplant patients were obtained prospectively from the cohort. We included 3926 transplant recipients (2935 solid organ and 991 hematopoietic stem cell transplants). Overall, 730 episodes of BSIs were recorded with an incidence rate ranging from 3 episodes per 10 000 transplant days in kidney recipients to 44 episodes per 10 000 transplant days in allogeneic hematopoietic stem cell transplantation (HSCT). The most frequent sources were intravascular catheters and the most frequent microorganisms isolated were coagulase-negative staphylococci. Crude mortality of BSIs was 7.8%, being highest in liver recipients (16%). Multidrug resistant nonfermentative gram-negative BSIs had significantly worse prognosis than those caused by their susceptible counterparts (p = 0.015), but no differences were found between resistant and susceptible gram-negative enteric bacilli, S. aureus or Candida spp. BSIs are still a major concern in transplant recipients. The increasing isolations of multiresistant microorganisms represent a challenge for the next years.

The diagnosis of catheter-related infections relies on the presence of clinical manifestations of infection and the evidence of colonization of the catheter tip by bacteria, mycobacteria, or fungi. The reference method to confirm the latter requires the withdrawal of the catheter for culturing, which frequently turns out to be inconvenient, unnecessary and costly.New methods try to avoid these drawbacks and to assess the presence of tip colonization without withdrawal. Comparative quantitative blood cultures with a marked increase (≥5) in colony counts between blood obtained from the catheter lumen and from a peripheral vein simultaneously is one of those methods. It has a high sensitivity (>80%) and specificity (94–100%) but it is cumbersome and requires both an easy backflow of blood in the catheter and the existence of bacteremia. Cytocentrifugation and acridine orange staining of blood withdrawn from an infected catheter lumen has a sensitivity and a specificity of over 90% for the diagnosis of tip colonization.‘Superficial cultures’ comprise the semiquantitative culture of the hub, of the skin surrounding the catheter entrance and of the first subcutaneous portion (1 cm) of the catheter after swabbing. The sensitivity of this method is >90%, specificity is >80%, and positive and negative predictive values for catheters (considering together those with and without clinical data of infection) are 66 and 97%, respectively.Endoluminal brushing has proved to be an impractical and unreliable procedure, at least in our experience.New methods based on the speed of bacterial growth to detectable levels of microorganisms in conventional blood cultures are a new and interesting way of assessing catheter-related infections. Moreover, as the use of antimicrobial-coated catheters becomes more prevalent, the existing definitions of catheter colonization and catheter-related infection may need to be modified, because such coatings may lead to false-negative culture results.Many catheter infections, diagnosed without catheter withdrawal, can be handled nowadays with the so-called ‘antibiotic lock-in technique’, which consists in ‘locking’ the infected catheter lumen with a solution containing antibiotics. A high proportion of infected catheters, mainly those with coagulase-negative staphylococci, can be maintained in place and sterilized with this technique, including catheters in patients with therapeutic failure after receiving conventional intravenous antibiotic therapy.New diagnostic and therapeutic techniques may avoid the unnecessary withdrawal of thousands of efficient, difficult to replace and expensive intravascular lines.

Beta-agonists have been misused as growth promoting agents in meat producing animals over 20 years. Clenbuterol (CLB) was the main beta-agonist substance used illegally for this purpose. But other beta-agonist substances have been developed to be used for zootechnical purposes, such as ractopamine (RCT), licensed for this application in the United States and currently zilpaterol (ZIL), licensed in South Africa and Mexico. However, these compounds are banned in the European Union (EU) Council Directive 96/22/EC. An analytical method able to identify these three beta-agonists by liquid chromatography tandem mass spectrometry (LC–MS–MS), after clean-up with mixed-mode SPE Bond Elut Certify cartridges (6 mL, 300 mg) was developed and validated according to the Commission Decision 2002/657/EC. Decision limit (CCα) ranged from 40 to 110 pg mL−1 and from 80 to 150 pg g−1 (ppt) for urine and liver, respectively. Detection capability (CCβ) ranged from 180 to 270 pg mL−1 and 270 to 520 pg g−1 (ppt) for urine and liver respectively. This method appeared suitable for the control of these beta-agonists residues in liver and urine.

The incidence of candidemia in the overall population ranges from 1.7 to 10 episodes per 100,000 inhabitants and Candida is one of the ten leading causes of bloodstream infections in developed countries. An estimated 33-55% of all episodes of candidemia occur in intensive care units (ICU) and are associated with mortality rates ranging from 5% to 71%. Candida fungemia may have an endogenous or an exogenous origin, and in recent years a growing proportion of episodes of candidemia have been caused by Candida species other than albicans. The most important independent conditions predisposing to candidemia in ICU patients include prior abdominal surgery, intravascular catheters, acute renal failure, parenteral nutrition, broad-spectrum antibiotics, a prolonged ICU stay, the use of corticosteroids and mucosal colonization with Candida. In recent years, several studies have shown that ICU patients with mucosal Candida colonization, particularly if multifocal, are at a higher risk for invasive candidiasis, and that colonization selects a population amenable to antifungal prophylaxis or empirical therapy. Candidemia in ICUs is associated with a considerable increase in hospital costs and length of hospital stay.

This Task Force was supported and endorsed by the following Societies: European Respiratory Society, European Society of Intensive Care Medicine, European Society of Clinical Microbiology and Infectious Diseases and European Society of Anaesthesiology. ⇓In the last decade, considerable investigational efforts have been made in the field of the management of ventilator-associated pneumonia (VAP). Several studies have provided important insights into the relationship of histology and bacteriology of VAP, which remain fundamental for all future research. Moreover, epidemiological research has allowed establishment of concepts for empiric initial antimicrobial treatment that are expected to improve clinical outcomes. Important contributions have also been made regarding prevention of VAP. Fig. 1.— However, despite these advances, the majority of issues related to the management of VAP remain unresolved and are subject to controversy. This is particularly true for the diagnostic evaluation of the patient with suspected VAP. The lack of consensus regarding the best way to diagnose VAP explains in part why incidence rates vary widely from one study to another, from 5 to >50% of mechanically ventilated intensive care unit (ICU) patients. In this review, a panel of experts in the field of VAP from four European societies has tried to provide an overview of the most important aspects under debate. In order to stimulate further research and discussion, presentation of the main topics was focussed on the breaking current knowledge. The issue of attributable mortality, which is also a matter of controversy, will not be addressed in this review. Each section of the review has been written in an attempt to answer three main questions: 1) what is not controversial, 2) what is still controversial and 3) what should be investigated? The following topics were reviewed: clinical diagnosis, bacteriological and histological aspects, aetiology, diagnostic techniques, antimicrobial treatment and prevention. #### What is not controversial? Clinical criteria for the diagnosis …

In the absence of standardized diagnosis and the presence of unique clinical syndromes, it is not surprising that considerable differences exist in the number of reported incidences of disease and the outcomes of various infections in cardiothoracic transplant (CTTX) recipients. Publications to date have employed variable and heterogeneous definitions of CTTX-related infections, thereby limiting the comparison between the types and incidence of infections and the generalizability of these data across transplant centers. Currently, there are no standard international definitions for infections uniquely related to CTTX, with the exception of Chagas disease and toxoplasmosis.1Humar A. Michaels M. American Society of Transplantation recommendations for screening, monitoring and reporting of infectious complications in immunosuppression trials in recipients of organ transplantation.Am J Transplant. 2006; 6: 262-274Crossref PubMed Scopus (396) Google Scholar The purpose of the present working formulation is to provide consensus-derived expert opinion of definitions for infections in CTTX for epidemiologic, research and registry data use. Standard definitions of infections specifically related to CTTX will allow for meaningful comparison of the type and incidence of these infections between different types of CTTXs, different regimens of immunosuppression and between different transplant centers, thereby improving the reporting of infection-related morbidity and mortality after cardiothoracic transplantation. The definitions proposed herein are suitable for epidemiologic investigations and are intended to facilitate clinical decision-making. The definitions described in what follows have been reviewed and approved by a multidisciplinary working group of The International Society for Heart and Lung Transplantation (ISHLT). These definitions were adapted from surveillance definitions of healthcare-associated sinusitis, tracheobronchitis and pneumonia, used in reporting to the National Healthcare Safety Network (NHSN) and the Centers for Disease Control and Prevention's (CDC) surveillance system for patient and healthcare personnel safety.2Horan T.C. Andrus M. Dudeck M.A. CDC/NHSN surveillance definition of health care-associated infection and criteria for specific types of infections in the acute care setting.http://www.cdc.gov/nhsn/PDFs/pscManual/17pscNosInfDef_current.pdfGoogle Scholar Definitions of invasive fungal infection (IFI) were based on those proposed by the European Organization for Research and Treatment of Cancer and the Mycoses Study Group of the National Institutes of Health (EORTC/MSG),3De Pauw B. Walsh T.J. Donnelly J.P. et al.Revised definitions of invasive fungal disease from the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group.Clin Infect Dis. 2008; 46: 1813-1821Crossref PubMed Scopus (4238) Google Scholar whereas definitions from the American Society of Transplantation and other source documents represented the foundation for defining viral infections.1Humar A. Michaels M. American Society of Transplantation recommendations for screening, monitoring and reporting of infectious complications in immunosuppression trials in recipients of organ transplantation.Am J Transplant. 2006; 6: 262-274Crossref PubMed Scopus (396) Google Scholar, 4Ljungman P. Griffiths P. Paya C. Definitions of cytomegalovirus infection and disease in transplant recipients.Clin Infect Dis. 2002; 34: 1094-1097Crossref PubMed Scopus (1060) Google Scholar Bacterial infections are a major contributor of complications in the early post-transplant period in heart- and lung-transplanted patients.5Mattner F. Fischer S. Weissbrodt H. et al.Post-operative nosocomial infections after lung and heart transplantation.J Heart Lung Transplant. 2007; 26: 241-249Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar, 6Dauber J.H. Paradis I.L. Dummer J.S. Infectious complications in pulmonary allograft recipients.Clin Chest Med. 1990; 11: 291-308PubMed Google Scholar Some bacterial infections (e.g., pre-transplant colonization or donor-derived infections) have unique issues and implications in CTTX recipients5Mattner F. Fischer S. Weissbrodt H. et al.Post-operative nosocomial infections after lung and heart transplantation.J Heart Lung Transplant. 2007; 26: 241-249Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar, 7Horvath J. Dummer S. Loyd J. et al.Infection in the transplanted and native lung after single lung transplantation.Chest. 1993; 104: 681-685Crossref PubMed Scopus (105) Google Scholar, 8Kramer M.R. Denning D.W. Marshall S.E. et al.Ulcerative tracheobronchitis after lung transplantation A new form of invasive aspergillosis.Am Rev Respir Dis. 1991; 144: 552-556Crossref PubMed Google Scholar, 9Flume P.A. Egan T.M. Paradowski L.J. et al.Infectious complications of lung transplantation Impact of cystic fibrosis.Am J Respir Crit Care Med. 1994; 149: 1601-1607Crossref PubMed Scopus (169) Google Scholar, 10Frist W.H. Loyd J.E. Merrill W.H. et al.Single lung transplantation: a temporal look at rejection, infection, and survival.Am Surg. 1994; 60: 94-102PubMed Google Scholar, 11Gottlieb J. Mattner F. Weissbrodt H. et al.Impact of graft colonization with gram-negative bacteria after lung transplantation on the development of bronchiolitis obliterans syndrome in recipients with cystic fibrosis.Respir Med. 2009; 103: 743-749Abstract Full Text Full Text PDF PubMed Scopus (107) Google Scholar, 12Mattner F. Kola A. Fischer S. et al.Impact of bacterial and fungal donor organ contamination in lung, heart–lung, heart and liver transplantation.Infection. 2008; 36: 207-212Crossref PubMed Scopus (42) Google Scholar; therefore, the definitions for these infections for epidemiologic, research or ISHLT registry purposes are specifically addressed herein. Many other bacterial infections (e.g., methicillin-resistant Staphylococcus aureus or vancomysin-resistant enterococcus) are present similarly across hospitalized patients and solid-organ transplant (SOT) recipients and are therefore not directly addressed in what follows. The existing literature in CTTX has largely classified bacterial infections as "early" (e.g., post-operative) or "late" onset after transplantation, allowing transplant clinicians to determine the source of these infections and focus prevention strategy and early empirical antibiotic treatment regimens on the temporal onset of these infections. A further timeline is used to classify all infections diagnosed in the hospital setting as nosocomial, with onset 48 hours after the patient is admitted to the hospital, and community-acquired infection, with onset at the time of admission or within 48 hours of admission. The latter definitions of infection may be artificial in the setting of CTTX as some infections, although related to healthcare and immunosuppression, may not occur within the established time-line of nosocomial infections. To fully appreciate the impact of the potential source of infection, we propose using the categories of nosocomial (after 48 hours of hospitalization) and community-acquired (prior to 48 hours of hospitalization) with the added category of community-acquired "transplant-related" infections. This category would include infections by pathogens acquired by the CTTX patient prior to time of transplantation and that are clearly related to the immunocompromised state of the CTTX patient after transplantation that may increase the risk for specific bacterial pathogens that are not common in the community. These pathogens may be related to the donor or the recipient via pre-transplant colonization of the respiratory or gastrointestinal (GI) tract and can be therefore regarded as "transplant-related" in this setting.12Mattner F. Kola A. Fischer S. et al.Impact of bacterial and fungal donor organ contamination in lung, heart–lung, heart and liver transplantation.Infection. 2008; 36: 207-212Crossref PubMed Scopus (42) Google Scholar, 13Pittet D. Hugonnet S. Harbarth S. et al.Effectiveness of a hospital-wide programme to improve compliance with hand hygiene Infection Control Programme.Lancet. 2000; 356: 1307-1312Abstract Full Text Full Text PDF PubMed Scopus (1915) Google Scholar It is also to be noted that community-acquired pneumonia may be transplant-related if caused by organisms that are typically associated with transplants (e.g., fungal, multidrug-resistant or atypical bacteria). Respiratory bacterial infections occur frequently in lung transplant recipients. In one study, 72 episodes per 100 lung transplants per year were reported.14Aguilar-Guisado M. Givalda J. Ussetti P. et al.Pneumonia after lung transplantation in the RESITRA Cohort: a multicenter prospective study.Am J Transplant. 2007; 7: 1989-1996Crossref PubMed Scopus (165) Google Scholar The source of bacteria-causing pneumonia in lung transplant recipients may be the donor, the recipient or the hospital environment. Nosocomial transmission from other patients or healthcare workers can occur when hand hygiene or appropriate respiratory isolation measures for other hospitalized infected patients are not routinely practiced.11Gottlieb J. Mattner F. Weissbrodt H. et al.Impact of graft colonization with gram-negative bacteria after lung transplantation on the development of bronchiolitis obliterans syndrome in recipients with cystic fibrosis.Respir Med. 2009; 103: 743-749Abstract Full Text Full Text PDF PubMed Scopus (107) Google Scholar, 15Cantrell D. Shamriz O. Cohen M.J. et al.Hand hygiene compliance by physicians: marked heterogeneity due to local culture?.Am J Infect Control. 2009; 37: 301-305Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar, 16Quiros D. Lin S. Larson E.L. Attitudes toward practice guidelines among intensive care unit personnel: a cross-sectional anonymous survey.Heart Lung. 2007; 36: 287-297Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar, 17Whitby M. McLaws M.L. Ross M.W. Why healthcare workers don't wash their hands: a behavioral explanation.Infect Control Hosp Epidemiol. 2006; 27: 484-492Crossref PubMed Scopus (253) Google Scholar, 18Pittet D. Simon A. Hugonnet S. et al.Hand hygiene among physicians: performance, beliefs, and perceptions.Ann Intern Med. 2004; 141: 1-8Crossref PubMed Scopus (528) Google Scholar, 19Mattner F. Ruden A.S. Mattner L. et al.Thoracic organ transplantation may not increase the risk of bacterial transmission in intensive care units.Int J Hyg Environ Health. 2007; 210: 139-145Crossref PubMed Scopus (5) Google Scholar The definitions of bacterial pneumonia present significant challenges in CTTX. Frequent use of empirical anti-bacterial agents prior to specimen collection and the possibility of concurrent allograft rejection make the use of standard guidelines, as presented by the Centers for Disease Control and Prevention (CDC) for healthcare-associated infections (HCAIs), difficult to apply.2Horan T.C. Andrus M. Dudeck M.A. CDC/NHSN surveillance definition of health care-associated infection and criteria for specific types of infections in the acute care setting.http://www.cdc.gov/nhsn/PDFs/pscManual/17pscNosInfDef_current.pdfGoogle Scholar In addition, some microbiologic diagnostic procedures may not be routinely practiced at many transplant centers and this may limit the employment of diagnostic criteria for infections that require quantification of bacterial colony-forming units per milliliter in the bronchoalveolar lavage (BAL) samples. This methodology has not been validated in the immunocompromised host and is not standardized across institutions. Further, the thresholds proposed may underestimate the episodes of bacterial pneumonia in the CTTX population,20Ramirez P. Valencia M. Torres A. Bronchoalveolar lavage to diagnose respiratory infections.Semin Respir Crit Care Med. 2007; 28: 525-533Crossref PubMed Scopus (33) Google Scholar where early empirical intervention with anti-microbial agents prior to obtaining the samples with suspected pneumonia is common practice. Presence of endobronchial stents in lung transplant recipients further complicates the picture in defining various clinical syndromes. For these reasons, a specific classification of bacterial pneumoniae in CTTX recipients is proposed based on radiographic findings, clinical symptoms, microbiology and histopathology (including consideration of acute rejection in lung transplant patients). In lung transplant recipients, the use of differential cytology in BAL may be helpful.21Mamessier E. Milhe F. Badier M. et al.Comparison of induced sputum and bronchoalveolar lavage in lung transplant recipients.J Heart Lung Transplant. 2006; 25: 523-532Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar, 22Riise G.C. Kjellstrom C. Ryd W. et al.Inflammatory cells and activation markers in BAL during acute rejection and infection in lung transplant recipients: a prospective, longitudinal study.Eur Respir J. 1997; 10: 1742-1746Crossref PubMed Scopus (44) Google Scholar, 23Clelland C. Higenbottam T. Stewart S. et al.Bronchoalveolar lavage and transbronchial lung biopsy during acute rejection and infection in heart–lung transplant patients Studies of cell counts, lymphocyte phenotypes, and expression of HLA-DR and interleukin-2 receptor.Am Rev Respir Dis. 1993; 147: 1386-1392Crossref PubMed Google Scholar The predominance of neutrophils with intracellular bacteria (hematoxylin–eosin and gram stain) is more suggestive of the presence of a bacterial pneumonia than a high proportion of lymphocytes or eosinophils in BAL. On the other hand, a lymphocytic or eosinophilic BAL could indicate an acute graft reaction, although cytomegalovirus (CMV), other viruses and atypical pathogens would need to be ruled out. Acute rejection (AR) of the graft in lung transplant recipients presents a significant consideration in the diagnosis of all pneumonias, including those due to bacteria. There are frequent clinical scenarios where distinction between rejection and infection is critically dependent upon histopathologic findings. In many cases, evidence for infection and rejection coexist. Therefore, in the setting of lung transplantation, the diagnosis of bacterial (or any) pneumonia is more precisely defined by the confirmation or exclusion of AR when microbiologic criteria are not met.24Stewart S. Fishbein M.C. Snell G.I. et al.Revision of the 1996 working formulation for the standardization of nomenclature in the diagnosis of lung rejection.J Heart Lung Transplant. 2007; 26: 1229-1242Abstract Full Text Full Text PDF PubMed Scopus (896) Google Scholar The determination of AR requires histologic examination. If an AR is documented and clinical and laboratory criteria for bacterial pneumonia are also fulfilled, the diagnosis of AR and concomitant pneumonia is possible.24Stewart S. Fishbein M.C. Snell G.I. et al.Revision of the 1996 working formulation for the standardization of nomenclature in the diagnosis of lung rejection.J Heart Lung Transplant. 2007; 26: 1229-1242Abstract Full Text Full Text PDF PubMed Scopus (896) Google Scholar Accordingly, pneumonia should be indicated as pneumonia combined with an AR. •Direct examination by light microscopy [gram stain, modified acid-fast bacilli (AFB) stain for Nocardia spp, AFB stains for Mycobacteria].•Culture (including rapid culture methods for Legionella spp, Mycobacteria spp and prolonged culture periods for detection of bacteria-causing infective endocarditis).•BAL cell analysis: rule-out contamination with <1% epithelial cells,20Ramirez P. Valencia M. Torres A. Bronchoalveolar lavage to diagnose respiratory infections.Semin Respir Crit Care Med. 2007; 28: 525-533Crossref PubMed Scopus (33) Google Scholar then quantitative, semi-quantitative or qualitative culture of BAL material or lung biopsy, if available.•Quantitative, semi-quantitative or qualitative cytology of BAL.•Histopathology: special staining of lung tissue (if available) for bacteria (i.e., Brown and Brenn stain), Mycobacteria (AFB stain/auramine) and atypical bacteria (Fite stain for Nocardia, etc.).•Nucleic acid amplification [including polymerase chain reaction (PCR) methods and real-time PCR] methods for atypical respiratory bacteria (Legionella, Chlamydia and Mycoplasma spp).•Enzyme immunoassays (EIA) antigen tests for pneumococcal and legionella antigens from urine samples).•Serology (may be useful for research purposes only in select study designs). Definitions of bacterial pneumonia and colonization in CTTX are given in Table 1a, whereas the definitions of tracheobronchitis are given in Table 1b.Table 1aBacterial Pneumonia and Colonization in CTTXInfectionSigns/symptomsRadiologyMicrobiology/pathologyHistopathologic evidence of ARProven pneumonia, acute rejection (AR)- associated OR not AR associatedAt least one of the following: • Fever >38oC or hypothermia <36.5oC with no other recognized cause • Leukopenia (<4,000 WBC/mm3) or leukocytosis (≥15,000 WBC/mm3)And at least two of the following: • New-onset of purulent sputum OR change in character/quantity of sputum OR increased respiratory secretions suctioned • New-onset or worsening cough, dyspnea, tachypnea, OR pleural rub, rales OR bronchial breath sounds • Worsening gas exchange (O2 desaturations, PaO2/FIO2 ≤240, increased O2 requirements, increased ventilation demands) • Pleural effusionNew/worsening radiographic changes on chest X-ray or CT scanAt least one of the following: • Positive growth in blood culture unrelated to other source • Positive growth in culture of pleural fluid • Positive respiratory culture (sputum, bronchial secretions, BAL, bronchial protected sterile brushing) • ≥5% BAL-obtained cells containing intracellular bacteria on direct microscopic examAR may be present or absent or not investigatedProbable pneumoniaAs for provenAs for provenNegative microbiology PLUS absence of AR by histopathologyAR must be excludedPossible pneumoniaAs for provenAs for provenMicrobiology negative or not performed PLUS concomitant clinical diagnosis of AR (without histopathology)No histopathology performedNo pneumonia, proven ARAs for provenAs for provenNegative microbiology PLUS AR proven by histopathologyHistopathologic evidence of ARColonizationAsymptomatic OR no significant changes in symptoms; stable PFT; normal bronchoscopy without: • Endobronchial erythema AND • Purulent secretionsAbsent or unchangedRecovery of pathogen in absence of clinical or radiographic changesAR present or absent Open table in a new tab Table 1bBacterial Tracheobronchitis and Bronchial Anastomotic Infections in Lung Transplant RecipientsInfectionSigns/symptomsRadiologyMicrobiologyHistopathologic evidenceProven tracheobronchitisAt least one of the following: • New-onset purulent sputum OR change in character/quantity of sputum OR increased respiratory secretions suctioned • New-onset or worsening cough, dyspnea, tachypnea AND • One or more endobronchial lesions (erythema, ulceration, necrosis and pseudomembrane formation, including at the site endobronchial stent) without an alternative diagnosis and without evidence of invasive parenchymal disease (Figure 1b)Negative chest X-ray OR one CT scan without the following: • New/progressive and persistent infiltrate • Consolidation • CavitationMay be positive if concurrent pneumonia is presentAt least one of the following: • Positive respiratory culture (sputum, bronchial secretions or tissue, BAL, bronchial protected sterile brushing)Histology showing inflammation with organisms or positive culture from the sterile tissue ALONEProbable tracheobronchitisAs for provenAs for provenAs for provenNegative histologyProven bronchial anastomotic infectionAt least one of the following: • New-onset purulent sputum OR change in character/quantity of sputum OR increased respiratory secretions suctioned • New-onset or worsening cough, dyspnea, tachypneaAND endobronchial lesions (erythema, ulceration, necrosis and pseudomembrane formation) restricted to the site of anastomosis without involvement of other parts of bronchial tree or lung parenchymaAs for proven tracheobronchitis; may be positive if concurrent pneumonia is presentAs for proven tracheobronchitisAs for proven tracheobronchitisProbable bronchial anastomotic infectionAs for provenAs for provenAs for proven tracheobronchitisNegative histopathology Open table in a new tab 1Ventilator-associated pneumonia should be designated when reporting data. A distinction should be made between non-invasive and invasive ventilation.2Aspiration pneumonia should be considered if the criteria are fulfilled for pneumonia (Table 1a). The cause of this type of pneumonia should be noted.3Multiple or concurrent episodes of post-transplant pneumonia may occur. To determine a new episode in a single patient, resolution of the initial infection must be determined by clinical, laboratory or histologic evidence. The isolation of a new pathogen alone is not indicative of a new episode of pneumonia. In contrast, a second pneumonia may develop in a patient after single lung transplantation. Here, the contralateral lung may develop an "independent" pneumonia by another organism.4Sputum samples are frequently contaminated with airway colonizers (e.g., coagulase-negative Staphylococcus and Enterococcus spp), and therefore must be interpreted cautiously.5The interferon-gamma release assay (IGRA) serum test is not recommended for diagnosis of acute tracheobronchitis disease, although a positive result is an indication of latent disease or recent infection and a useful screening test if baseline IGRA testing is performed prior to transplantation.25Manuel O. Humar A. Preiksaitis J. et al.Comparison of quantiferon-TB gold with tuberculin skin test for detecting latent tuberculosis infection prior to liver transplantation.Am J Transplant. 2007; 7: 2797-2801Crossref PubMed Scopus (107) Google Scholar6Episodes of airway colonization are not recorded as infections.7Histologic representation of chronic graft rejection may not impact the diagnosis of bacterial pneumonia. Therefore, it is not included as criteria for pneumonia definition.26Yousem S.A. Berry G.J. Cagle P.T. et al.Revision of the 1990 working formulation for the classification of pulmonary allograft rejection: Lung Rejection Study Group.J Heart Lung Transplant. 1996; 15: 1-15PubMed Google Scholar8The definition of "possible pneumonia" category allows recording of pneumonia after lung transplantation even if required diagnostic procedures were missed, which may occur with prior anti-microbial treatment or delay in diagnostic testing, etc.9In lung transplant recipients, it is desirable to always give additional information if evidence of acute graft rejection exists either by clinical or by histopathologic diagnosis.10It is possible to have concurrent infections—pneumonia with sinusitis or anastomotic tracheobronchitis.11Quantification of organisms in BAL is not considered essential for the diagnosis of ventilator-associated pneumonia (VAP).27A randomized trial of diagnostic techniques for ventilator-associated pneumonia. N Engl J Med 2006;355:2619–30.Google Scholar However, invasive diagnostics may help withdraw anti-bacterial therapy, which may prevent further emergence of multi-resistant organisms in future.28Kwon Y. Milbrandt E.B. Yende S. Diagnostic techniques for ventilator-associated pneumonia: conflicting results from two trials.Crit Care. 2009; 13: 303Crossref PubMed Scopus (3) Google Scholar, 29Fagon J.Y. Chastre J. Wolff M. et al.Invasive and noninvasive strategies for management of suspected ventilator-associated pneumonia A randomized trial.Ann Intern Med. 2000; 132: 621-630Crossref PubMed Scopus (751) Google Scholar12The category of bacterial tracheobronchitis is classified into probable and proven categories. They can only be diagnosed in the presence of bronchoscopic findings. We have refrained from using the term microbiogically negative tracheobrochitis as it requires more evidence.13Endobronchial stent–associated tracheobronchitis or bronchial anastomotic infections, both fungal and bacterial, are categorized as probable (Table 2).Table 2Infections Associated With Ventilation or Endobronchial StentsInfectionSigns/symptomsRadiologyMicrobiologyHistopathologic evidenceVentilator-associated pneumonia (non-invasive or invasive ventilation); patient on ventilator for at least 48 hours continuouslyAt least one of the following: • Fever >38oC or hypothermia <36.5oC with no other recognized cause • Leukopenia (<4,000 WBC/mm3) or leukocytosis (≥11,000 WBC/mm3)And at least two of the following: • New-onset purulent sputum OR change in character/quantity of sputum OR increased respiratory secretions suctioned • New-onset or worsening pleural rub, rales OR bronchial breath sounds • Worsening gas exchange (O2 desaturations, PaO2/FIO2 ≤240, increased O2 requirements, increased ventilation demands)Two or more serial chest radiographs showing new/progressive infiltrate or consolidation OR one CT scan with at least one of the following: • New/progressive and persistent infiltrate • Consolidation • CavitationAt least one of the following: • Positive respiratory culture (sputum, bronchial secretions, BAL, bronchial protected sterile brushing). • ≥5% BAL-obtained cells containing intracellular bacteria on direct microscopic exam.Histology (biopsy showing histologic evidence of pneumonia OR positive culture from the sterile tissue ALONEEndobronchial stent associated:• Tracheobronchitis• Bronchial anastomotic infection• PneumoniaAt least one of the following: • New-onset purulent sputum OR change in character/quantity of sputum OR increased respiratory secretions suctioned • New-onset or worsening cough, dyspnea, tachypnea OR pleural rub, rales OR bronchial breath soundsAND endobronchial lesions restricted to the extent of endobrochial stent with or without involvement of anastomosis or other parts of bronchial tree or lung parenchymaChest radiograph without: • New or progressive and persistent infiltrate • Consolidation • Cavitation • NodulesOR CT scan without: • New or progressive and persistent infiltrate • Consolidation • Cavitation • Nodules • Positive respiratory culture (sputum, bronchial secretions, BAL, bronchial protected sterile brushing) • ≥5% BAL-obtained cells containing intracellular bacteria on direct microscopic exam • Positive culture for mold/yeast • OR positive PCR for mold /yeast • OR positive GM in the BALOR at least TWO positive sputum cultures/PCRs of fungal organisms (including Candida species)Not applicable Open table in a new tab 14No attempt is made to redefine atypical mycobacterial infections or pulmonary tracheobronchitis in lung transplant recipients and the use of existing definitions from European and North American societies are encouraged until further data emerge.30Chalermskulrat W. Sood N. Neuringer I.P. et al.Non-tuberculous mycobacteria in end stage cystic fibrosis: implications for lung transplantation.Thorax. 2006; 61: 507-513Crossref PubMed Scopus (132) Google Scholar, 31Griffith D.E. Aksamit T. Brown-Elliott B.A. et al.An official ATS/IDSA statement: diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases.Am J Respir Crit Care Med. 2007; 175: 367-416Crossref PubMed Scopus (4678) Google Scholar, 32Torre-Cisneros J. Doblas A. Aguado J.M. et al.Tuberculosis after solid-organ transplant: incidence, risk factors, and clinical characteristics in the RESITRA (Spanish Network of Infection in Transplantation) cohort.Clin Infect Dis. 2009; 48: 1657-1665Crossref PubMed Scopus (219) Google Scholar, 33Aguado J.M. Torre-Cisneros J. Fortun J. et al.Tuberculosis in solid-organ transplant recipients: consensus statement of the group for the study of infection in transplant recipients (GESITRA) of the Spanish Society of Infectious Diseases and Clinical Microbiology.Clin Infect Dis. 2009; 48: 1276-1284Crossref PubMed Scopus (215) Google Scholar15It is preferable to document the use of antibiotics in patients with pneumonia at the time of culture data collection. Cardiothoracic transplant recipients are at an increased risk for viral infections with severe clinical sequelae. Some viral infections have unique considerations and implications in CTTX recipients. The definitions for these viral infections are specifically addressed herein and may be used for epidemiologic, research or registry purposes in CTTX recipients. Many other non-respiratory viral infections present similarly across SOT recipients. Diagnosis and management of these viral infections have been addressed adequately in other guidelines1Humar A. Michaels M. American Society of Transplantation recommendations for screening, monitoring and reporting of infectious complications in immunosuppression trials in recipients of organ transplantation.Am J Transplant. 2006; 6: 262-274Crossref PubMed Scopus (396) Google Scholar and therefore will not be addressed herein. Respiratory viral infections, including newly emerging viruses, occur frequently in lung transplant recipients.34Hopkins P. McNeil K. Kermeen F. et al.Human metapneumovirus in lung transplant recipients and comparison to respiratory syncytial virus.Am J Respir Crit Care Med. 2008; 178: 876-881Crossref PubMed Scopus (109) Google Scholar Some epidemiologic studies have suggested an association between respiratory viral infection and the development of bronchiolitis obliterans syndrome (BOS).35Weinberg A. Zamora M.R. Li S. et al.The value of polymerase chain reaction for the diagnosis of viral respiratory tract infections in lung transplant recipients.J Cli

Suspicion of catheter-related bloodstream infection (CR-BSI) leads frequently to unnecessary catheter withdrawals, and many catheter-tip cultures yield negative results. The objective of this study was to compare the yield of 3 microbiological procedures to assess CR-BSI without catheter withdrawal.The study was prospectively performed in a group of patients without neutropenia or blood disorders who were admitted to the intensive care unit during a 37-month period with sepsis suspected on clinical grounds and who had central venous catheters inserted for >48 h. The microbiological procedures compared were semiquantitative cultures from hub and skin (superficial), differential quantitative blood cultures, and differential time to positivity between cultures of blood obtained from catheter hubs and peripheral blood.Of the 204 episodes of suspected CR-BSI included in the study, 28 were confirmed to be CR-BSI. We obtained the following results for sensitivity, specificity, positive and negative predictive values, and accuracy: superficial cultures, 78.6%, 92.0%, 61.1%, 96.4%, and 90.2%, respectively; differential quantitative blood cultures, 71.4%, 97.7%, 83.3%, 95.6%, and 94.1%, respectively; and differential time to positivity, 96.4%, 90.3%, 61.4%, 99.4%, and 91.2%, respectively.CR-BSI can be assessed without catheter withdrawal in patients without neutropenia or blood disorders who have catheters inserted for a short time and are hospitalized in the intensive care unit. Convenience, use of resources, and expertise should determine the technique of choice in different medical contexts. Because of ease of performance, low cost, and wide availability, we recommend combining semiquantitative superficial cultures and peripheral vein blood cultures to screen for CR-BSI, leaving differential quantitative blood cultures as a confirmatory and more specific technique.

Traditionally, infective endocarditis (IE) has been microbiologically diagnosed by blood cultures or serology. However, conventional microbiologic methods do not always provide an etiologic diagnosis. We conducted the current study to evaluate the usefulness of a universal real-time polymerase chain reaction (PCR) of the 16S rRNA gene followed by sequencing for the diagnosis of IE in explanted heart valve tissue (HV) as part of the routine of a clinical microbiology laboratory, and to compare it with conventional culture of blood or HV. We prospectively analyzed 177 HV samples by universal PCR and sequencing: 48 were from 35 patients with definite IE and 129 were from 120 patients without IE. Specific PCR tests were used when necessary to confirm broad-range PCR results. For the 35 patients with IE, all of the HV samples except for 2 from the same patient gave positive PCR results. The microorganisms identified matched those isolated by blood culture in 31 cases. The other 3 patients had negative blood culture IE, but PCR made possible the detection of Tropheryma whipplei, Bartonella quintana, and Streptococcus gallolyticus. For the negative control group, universal PCR was completely negative in 123 of the 129 samples. Sensitivity, specificity, and negative and positive predictive values of this real-time PCR method were 96%, 95.3%, 98.4%, and 88.5%, respectively, for the diagnosis of IE, using the Duke criteria to define IE and using blood culture results to identify etiologic microorganisms. Conventional HV culture correlated poorly with blood cultures and molecular techniques, and frequently represented tissue contamination resulting from valve handling. Our universal PCR method has proved to be more sensitive, specific, and rapid than conventional culture methods, and should therefore be included as a new major Duke criterion for the diagnosis of IE. According to the results of the current study, this technique should be used to supplement blood and HV culture. Conventional HV cultures are frequently responsible for false-positive and false-negative results, and are not always useful to establish the etiology of IE. Abbreviations: HV = heart valve tissue, IE = infective endocarditis, PCR = polymerase chain reaction.

Abstract Background Urinary tract infection (UTI) is the most common infection in renal transplant patients, but it is necessary to determine the risk factors for bacterial UTI in recipients of other solid organ transplants ( SOT s), as well as changes in etiology, clinical presentation, and prognosis. Methods In total, 4388 SOT recipients were monitored in 16 transplant centers belonging to the S panish N etwork for R esearch on I nfection in T ransplantation ( RESITRA ). The frequency and characteristics of bacterial UTI in transplant patients were obtained prospectively from the cohort ( S eptember 2003 to F ebruary 2005). Results A total of 192 patients (4.4%) presented 249 episodes of bacterial UTI (0.23 episodes per 1000 transplantation days); 156 patients were kidney or kidney–pancreas transplant recipients, and 36 patients were liver, heart, and lung transplant recipients. The highest frequency was observed in renal transplants (7.3%). High frequency of cystitis versus pyelonephritis without related mortality was observed in both groups. The most frequent etiology was E scherichia coli (57.8%), with 25.7% producing extended‐spectrum β‐lactamase ( ESBL ). In all transplants but renal, most cases occurred in the first month after transplantation. Cases were uniformly distributed during the first 6 months after transplantation in renal recipients. Age (odds ratio [ OR ] per decade 1.1, 95% confidence interval [ CI ] 1.02–1.17), female gender ( OR 1.74, 95% CI 1.42–2.13), and the need for immediate post‐transplant dialysis ( OR 1.63, 95% CI 1.29–2.05) were independent variables associated with bacterial UTI in renal and kidney–pancreas recipients. The independent risk factors identified in non‐renal transplants were age ( OR per decade 1.79, 95% CI 1.09–3.48), female gender ( OR 1.7, 95% CI 1.43–2.49), and diabetes ( OR 1.02, 95% CI 1.001–1.040). Conclusions UTI was frequent in renal transplants, but also not unusual in non‐renal transplants. Because E . coli continues to be the most frequent etiology, the emergence of ESBL ‐producing strains has been identified as a new problem. In both populations, most cases were cystitis without related mortality. Although the first month after transplantation was a risk period in all transplants, cases were uniformly distributed during the first 6 months in renal transplants. Age and female gender were identified as risk factors for UTI in both populations. Other particular risk factors were the need for immediate post‐transplant dialysis in renal transplants and diabetes in non‐renal transplants.

Staphylococcus aureus is the main cause of surgical site infection (SSI) after major heart surgery (MHS), with the patient's endogenous flora as the principal source. However, the influence of nasal carriage of S. aureus on the development of SSI after MHS has not been established and Centers for Disease Control and Prevention guidelines do not make a recommendation for or against decolonisation. We performed a one-year observational study in which patients undergoing MHS were screened for nasal carriage of S. aureus before surgery. Cases of SSI were recorded and the risk factors of patients with and without SSI were analysed. During the study period, 357 patients were included in the protocol. Ninety-six patients (27%) were found to be nasal carriers of S. aureus and nine (9.4%) of these had meticillin-resistant (MRSA) strains. The overall incidence of SSI was 6.4%, with 4.2% for mediastinitis and 2.2% for superficial SSI. Nasal carriers of S. aureus had a significantly higher incidence of SSI than non-carriers (12.5% vs 5%, P=0.01). Among MRSA carriers, the incidence of SSI reached 33% (P<0.001). S. aureus was responsible for 64% of SSIs. Multivariate analysis showed that the independent factors for SSI were S. aureus nasal carriage [relative risk (RR): 3.1; 95% confidence interval (CI): 1.4-7.3; P=0.009], reoperation (RR: 3.1; 95% CI: 1.8-19.2; P=0.04) and diabetes mellitus (RR: 5.9; 95% CI: 1.8-19.2; P=0.003). Nasal carriage of S. aureus significantly increases the rate of nosocomial SSI after MHS and decolonisation strategies should be implemented in this population.

The role of serum cryptococcal antigen in the diagnosis and determinants of antigen positivity in solid organ transplant (SOT) recipients with pulmonary cryptococcosis has not been fully defined.We conducted a prospective, multicenter study of SOT recipients with pulmonary cryptococcosis during 1999-2006.Forty (83%) of 48 patients with pulmonary cryptococcosis tested positive for cryptococcal antigen. Patients with concomitant extrapulmonary disease were more likely to have a positive antigen test result (P=.018), and antigen titers were higher in patients with extrapulmonary disease (P=.003) or fungemia (P=.045). Patients with single nodules were less likely to have a positive antigen test result than were those with all other radiographic presentations (P=.053). Among patients with isolated pulmonary cryptococcosis, lung transplant recipients were less likely to have positive cryptococcal antigen test results than were recipients of other types of SOT (P=.003). In all, 38% of the patients were asymptomatic or had pulmonary cryptococcosis detected as an incidental finding. Nodular densities or mass lesions were more likely to present as asymptomatic or incidentally detected pulmonary cryptococcosis than as pleural effusions and infiltrates (P=.008).A positive serum cryptococcal antigen test result in SOT recipients with pulmonary cryptococcosis appears to reflect extrapulmonary or more advanced radiographic disease.

The aim of the study was to describe the epidemiologic and clinical characteristics and identify the risk factors of short-term and 1-year mortality in a recent cohort of patients with infective endocarditis (IE).From January 2008, multidisciplinary teams have prospectively collected all consecutive cases of IE, diagnosed according to the Duke criteria, in 25 Spanish hospitals.Overall, 1804 patients were diagnosed. The median age was 69 years (interquartile range, 55-77), 68.0% were men, and 37.1% of the cases were nosocomial or health care-related IE. Gram-positive microorganisms accounted for 79.3% of the episodes, followed by Gram-negative (5.2%), fungi (2.4%), anaerobes (0.9%), polymicrobial infections (1.9%), and unknown etiology (9.1%). Heart surgery was performed in 44.2%, and in-hospital mortality was 28.8%. Risk factors for in-hospital mortality were age, previous heart surgery, cerebrovascular disease, atrial fibrillation, Staphylococcus or Candida etiology, intracardiac complications, heart failure, and septic shock. The 1-year independent risk factors for mortality were age (odds ratio [OR], 1.02), neoplasia (OR, 2.46), renal insufficiency (OR, 1.59), and heart failure (OR, 4.42). Surgery was an independent protective factor for 1-year mortality (OR, 0.44).IE remains a severe disease with a high rate of in-hospital (28.9%) and 1-year mortality (11.2%). Surgery was the only intervention that significantly reduced 1-year mortality.

Dalbavancin is a lipoglycopeptide with a very prolonged half-life enabling treatment with a single intravenous administration that has been approved to treat complicated skin and soft-tissue infections. Information on the efficacy and safety of dalbavancin in other situations is very scarce. This retrospective study included adult patients who received at least one dose of dalbavancin between 2016 and 2017 in 29 institutions in Spain. The primary objective was to report the use of dalbavancin in clinical practice, including its efficacy and tolerability. The potential impact of dalbavancin on reducing the length of hospital stay and hospital costs was also evaluated. A total of 69 patients received dalbavancin during the study period (58.0% male; median age 63.5 years). Dalbavancin was used to treat prosthetic joint infection (29.0%), acute bacterial skin and skin-structure infection (21.7%), osteomyelitis (17.4%) and catheter-related bacteraemia (11.6%). These infections were mainly caused by Staphylococcus aureus (27 isolates), coagulase-negative staphylococci (24 isolates) and Enterococcus spp. (11 isolates). All but two patients received previous antibiotics for a median of 18 days. Dalbavancin was administered for a median of 21 days (range 7–168 days), and concomitant antimicrobial therapy was prescribed to 25 patients (36.2%). The overall clinical success rate of dalbavancin was 84.1%. Adverse events, mainly mild in intensity, were reported in nine patients. Overall, dalbavancin was estimated to reduce hospitalisation by 1160 days, with an estimated overall cost reduction of €211 481 (€3064 per patient). Dalbavancin appears to be an effective therapy for many serious Gram-positive infections.

Major heart surgery (MHS) patients are a particularly high-risk population for nosocomial infections. Our objective was to identify risk factors for ventilator-associated pneumonia (VAP) in patients undergoing MHS. Prospective study including 1,844 patients operated from 2003 to 2006. Overall 106 patients (140 episodes) developed one or more episodes of VAP (5.7%, 22.2 episodes per 1,000 days of mechanical ventilation). VAP incidence was 45.9% in those patients requiring more than 48 h of MV. Enterobacteriaceae (32.8), Pseudomonas aeruginosa (28.6%) and Staphylococcus aureus (27.1%, of which 65.8% were methicillin resistant) were the principal microorganisms causing VAP. The independent risk factors for VAP were: age >70, perioperative transfusions, days of mechanical ventilation, reintubation, previous cardiac surgery, emergent surgery and intraoperative inotropic support. Median length of stay in the ICU for patients who developed VAP or not was, respectively, 25.5 versus 3 days (P < 0.001), and mortality was, respectively, 45.7 versus 2.8% in both populations (P < 0.001). We developed a predictive preoperative score with a sensitivity of 93% and a specificity of 40%. VAP is common in patients undergoing MHS that require more than 48 h of MV. In that “high-risk” population, innovative preventive measures should be developed and applied.

Current advances in transplantation practices may influence the development of cytomegalovirus (CMV) disease after renal transplantation.From September 2003 through February 2005, 1470 renal transplant recipients (55 of whom were kidney-pancreas transplant recipients) were prospectively studied in the 16 transplant centers affiliated with the Spanish Network of Infection in Transplantation, with use of an ad hoc-designed online database. Univariate and multivariate analyses with logistic regression were performed to detect risk factors for CMV disease.A total of 105 episodes of CMV disease (37 with visceral involvement) developed in 99 (6.7%) of 1470 patients. Attributable mortality appeared in 1 (1.0%) of 105 cases. Multivariate analysis showed that, apart from CMV serological mismatch, presence of rejection episodes, and the use of antilymphocitic drugs, a simultaneous pancreas transplantation (odds ratio [OR], 3.7; 95% confidence interval [CI], 1.5-9), use of cyclosporine (OR, 1.7; 95% CI, 1.18-2.9), a donor >60 years of age (OR, 2.3; 95% CI, 1.5-3.7), and chronic graft malfunction (OR, 1.8; 95% CI, 1.14-2.9) were independently associated with CMV disease, whereas use of sirolimus had a protective effect (OR, 0.27; 95% CI, 0.1-0.78).Additional risk factors related to current transplantation practices influence the epidemiology of CMV after renal transplantation and should be taken into account in the design of prophylactic strategies in this population of kidney or kidney-pancreas recipients.

We studied 19 cases of proven/probable mucormycosis diagnosed from 2007 to 2015 in our hospital and assessed the microbiological characteristics of the isolates. We recorded the incidence of mucormycosis and clinical and microbiological data of infected patients. Isolates were identified to molecular level and tested for their antifungal susceptibility to azoles, amphotericin B, and liposomal amphotericin B according to the CLSI M-38 A2 procedure. The incidence of mucormycosis in cases/100,000 hospital admissions during 2007-2015 increased significantly with respect to that reported in 1988-2006 (3.3 vs. 1.2; P<0.05). Patients mainly had hematological malignancies (52.6%) and/or trauma/surgical wounds (52.6%) and had received antifungal agents before the diagnosis of mucormycosis in 68% of cases. Diagnosis was by isolation (n = 17/19) and/or direct staining (n = 17/18) of Mucorales fungi in clinical samples. Identification was by panfungal PCR in patients with negative results in culture and in direct staining. The microorganisms identified were Lichtheimia spp. (42%), Rhizopus spp. (21%), Cunninghamella bertholletiae (16%), and others (21%). Liposomal amphotericin B was always more active than the other drugs against all the microorganisms except C. bertholletiae. All patients received antifungal treatment with 1 or more antifungal agents, mainly liposomal amphotericin B (17/19). Mortality was 47.4%, although this was significantly lower in the 11 patients in whom debridement was performed (18% vs. 87.5%) (P = 0.015). The incidence of mucormycosis has risen in recent years. The proportion of cases with soft tissue involvement was high, and Lichtheimia was the most frequently involved species. The highest antifungal activity was observed with liposomal amphotericin B.

Background. Solid-organ transplant (SOT) recipients are considered to be at increased risk for toxoplasmosis. However, risk factors for this infection have not been assessed. The aim of this study was to determine the risk factors, clinical features, and outcomes of toxoplasmosis in SOT recipients.

Human polyomaviruses (HPyVs) are a growing challenge in immunocompromised patients in view of the increasing number of now 12 HPyV species and their diverse disease potential. Currently, histological evidence of disease is available for BKPyV causing nephropathy and haemorrhagic cystitis, JCPyV causing progressive multifocal leukoencephalopathy and occasionally nephropathy, MCPyV causing Merkel cell carcinoma and TSPyV causing trichodysplasia spinulosa, the last two being proliferative skin diseases. Here, the current role of HPyV in solid organ transplantation (SOT) was reviewed and recommendations regarding screening, monitoring and intervention were made. Pre-transplant screening of SOT donor or recipient for serostatus or active replication is currently not recommended for any HPyV. Post-transplant, however, regular clinical search for skin lesions, including those associated with MCPyV or TSPyV, is recommended in all SOT recipients. Also, regular screening for BKPyV replication (e.g. by plasma viral load) is recommended in kidney transplant recipients. For SOT patients with probable or proven HPyV disease, reducing immunosuppression should be considered to permit regaining of immune control. Antivirals would be desirable for treating proven HPyV disease, but are solely considered as adjunct local treatment of trichodysplasia spinulosa, whereas surgical resection and chemotherapy are key in Merkel cell carcinoma. Overall, the quality of the clinical evidence and the strength of most recommendations are presently limited, but are expected to improve in the coming years.

Campylobacter is a very rare cause of bloodstream infection, although it has been found relatively frequently in patients infected with human immunodeficiency virus (HIV). The impact of highly active antiretroviral therapy (HAART) and new forms of immunosuppression on the incidence of Campylobacter bacteremia has not been sufficiently assessed. In this study we analyzed the incidence and microbiologic and clinical characteristics of Campylobacter bacteremia over 23 years. We reviewed the clinical records of all patients who had Campylobacter bacteremia from 1985 to 2007. Available strains were reidentified using universal polymerase chain reaction (PCR). During the study period, there were 71 episodes of Campylobacter bacteremia in 63 patients (0.24% of all bloodstream infections), and the incidence remained stable (mean, 0.06/1000 admissions per year and 0.47/100,000 inhabitants per year). Median age was 52 years (interquartile range, 31.25-72.5 yr), and 82% of patients were male. The underlying conditions included liver disease (21/64, 32.8%), HIV infection (15/64, 23.4%), malignancy (7/64, 10.9%), solid organ transplantation (2/64, 3%), hypogammaglobulinemia (10/64, 15.6%), and other (18/64, 31.2%). Twelve patients shared more than 1 underlying condition. Campylobacter bacteremia was community acquired in 81% of the episodes. The origin of the bloodstream infection was abdominal (43.5%), primary (26%), or extraintestinal (31%: respiratory 15%, cellulitis 4.8%, urinary 8%, other 3%). C jejuni was recovered in 66% of cases, C fetus in 19%, and C coli in 12%. Universal PCR was performed on 14 available strains. Molecular and conventional identification matched in 8 isolates. In contrast, molecular methods classified as C fetus (n = 2) and C jejuni (n = 1) 3 strains formerly identified only to genus level as Campylobacter species. In another 3 isolates, molecular identification was not consistent with the phenotypic identification (C fetus identified as C jejuni). Complications appeared in 23.9% of patients. Quinolone resistance was observed in 50% of the isolates. Only 37.8% of patients received appropriate empirical therapy. Mortality was 16.4%, although it was higher in HIV-infected patients than uninfected patients (33% vs. 10%; p = 0.04), in cases of hospital-acquired Campylobacter bacteremia compared with community-acquired cases (38.5% vs. 9.4%; p = 0.02), and in the presence of complications compared with patients without complications (100% vs. 0%; p < 0.001). The incidence of recurrence was 5% (3 patients with humoral immunodeficiency). There was a higher proportion of HIV-infected patients among patients with Campylobacter bacteremia in the pre-HAART era (1985-1996) than in the HAART era (1997-2007)-27.5% (11/40) vs. 14.3% (4/28)-although the difference was not statistically significant. Debilitating diseases such as chronic obstructive pulmonary disease emerged as predisposing conditions in the HAART era (0% before HAART era vs. 14.3% in HAART era; p = 0.032). Campylobacter bacteremia is no longer a significant disease of HIV-positive patients on HAART, but often affects other immunocompromised patients as well. Campylobacter bacteremia has an extraintestinal origin in as many as 31% of cases, and humoral immunodeficiency must be sought in patients with recurrent episodes. Quinolones should not be considered for empirical therapy. Abbreviations: AIDS = acquired immunodeficiency syndrome, ARIMA = autoregressive integrated moving average test, BSI = bloodstream infection, COPD = chronic obstructive pulmonary disease, HAART = highly active antiretroviral therapy, HIV = human immunodeficiency virus, IQR = interquartile range, PCR = polymerase chain reaction, rRNA = ribosomal ribonucleic acid.

Solid organ transplant (SOT) recipients are especially at risk of developing infections by multidrug resistant (MDR) Gram-negative bacilli (GNB), as they are frequently exposed to antibiotics and the healthcare setting, and are regulary subject to invasive procedures. Nevertheless, no recommendations concerning prevention and treatment are available. A panel of experts revised the available evidence; this document summarizes their recommendations: (1) it is important to characterize the isolate's phenotypic and genotypic resistance profile; (2) overall, donor colonization should not constitute a contraindication to transplantation, although active infected kidney and lung grafts should be avoided; (3) recipient colonization is associated with an increased risk of infection, but is not a contraindication to transplantation; (4) different surgical prophylaxis regimens are not recommended for patients colonized with carbapenem-resistant GNB; (5) timely detection of carriers, contact isolation precautions, hand hygiene compliance and antibiotic control policies are important preventive measures; (6) there is not sufficient data to recommend intestinal decolonization; (7) colonized lung transplant recipients could benefit from prophylactic inhaled antibiotics, specially for Pseudomonas aeruginosa; (8) colonized SOT recipients should receive an empirical treatment which includes active antibiotics, and directed therapy should be adjusted according to susceptibility study results and the severity of the infection.

Transplantation activity is increasing, leading to a growing number of patients at risk for toxoplasmosis. We reviewed toxoplasmosis prevention practices, prevalence, and outcomes for hematopoietic stem cell transplant (HSCT) and solid organ transplant (SOT; heart, kidney, or liver) patients in Europe. We collected electronic data on the transplant population and prevention guidelines/regulations and clinical data on toxoplasmosis cases diagnosed during 2010-2014. Serologic pretransplant screening of allo-hematopoietic stem cell donors was performed in 80% of countries, screening of organ donors in 100%. SOT recipients were systematically screened in 6 countries. Targeted anti-Toxoplasma chemoprophylaxis was heterogeneous. A total of 87 toxoplasmosis cases were recorded (58 allo-HSCTs, 29 SOTs). The 6-month survival rate was lower among Toxoplasma-seropositive recipients and among allo-hematopoietic stem cell and liver recipients. Chemoprophylaxis improved outcomes for SOT recipients. Toxoplasmosis remains associated with high mortality rates among transplant recipients. Guidelines are urgently needed to standardize prophylactic regimens and optimize patient management.

Aims Surgery for infective endocarditis (IE) is associated with high mortality. Our objectives were to describe the experience with surgical treatment for IE in Spain, and to identify predictors of in-hospital mortality. Methods Prospective cohort of 1000 consecutive patients with IE. Data were collected in 26 Spanish hospitals. Results Surgery was performed in 437 patients (43.7%). Patients treated with surgery were younger and predominantly male. They presented fewer comorbid conditions and more often had negative blood cultures and heart failure. In-hospital mortality after surgery was lower than in the medical therapy group (24.3 vs 30.7%, p = 0.02). In patients treated with surgery, endocarditis involved a native valve in 267 patients (61.1%), a prosthetic valve in 122 (27.9%), and a pacemaker lead with no clear further valve involvement in 48 (11.0%). The most common aetiologies were Staphylococcus (186, 42.6%), Streptococcus (97, 22.2%), and Enterococcus (49, 11.2%). The main indications for surgery were heart failure and severe valve regurgitation. A risk score for in-hospital mortality was developed using 7 prognostic variables with a similar predictive value (OR between 1.7 and 2.3): PALSUSE: prosthetic valve, age ≥ 70, large intracardiac destruction, Staphylococcus spp, urgent surgery, sex [female], EuroSCORE ≥ 10. In-hospital mortality ranged from 0% in patients with a PALSUSE score of 0 to 45.4% in patients with PALSUSE score >3. Conclusions The prognosis of IE surgery is highly variable. The PALSUSE score could help to identify patients with higher in-hospital mortality.

To assess the quality of antifungal use, to propose a point score for this evaluation and to estimate the potential economic savings of an antifungal stewardship programme.From December 2010 to January 2011, we identified 100 adult inpatients receiving systemic antifungals. Antifungal use was evaluated by means of a predefined score that considered indication, drug selection, dosage, adjustments after microbiology results, switching to an oral agent and length of treatment. Total antifungal prescriptions [in defined daily doses (DDDs) and days of therapy (DOTs)] and potential cost savings were calculated.Overall, 43% of prescriptions came from medical departments, 25% from haematology/oncology and 17% from intensive care units. The main reasons for starting antifungals were empirical (42%), pre-emptive (20%) and targeted treatment (20%). Antifungals were unnecessary in 16% of cases. Inadequacies in other aspects of antifungal prescription were: drug selection, 31%; dosing, 16%; no switch from intravenous to oral administration, 20%; no adjustment after microbiological results, 35%; and length of therapy, 27%. The number of antifungal DDDs per 1000 patient-days was 65.1. The total number of DOTs was 1556, which added a direct cost of €219 364. Only 51.3% of DOTs were considered optimal. The potential estimated savings would be €50 536.Major efforts should be made to improve the selection and duration of antifungal therapy. Our study demonstrated the potential cost savings that could be achieved by optimizing antifungal therapy. A stewardship programme should include an instrument to objectively evaluate the adequacy of antifungal use.

Cytomegalovirus (CMV) infection remains a major complication of solid organ transplantation. Because of management of CMV is variable among transplant centers, in 2011 the Spanish Transplantation Infection Study Group (GESITRA) of the Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC) developed consensus guidelines for the prevention and treatment of CMV infection in solid organ transplant recipients. Since then, new publications have clarified or questioned the aspects covered in the previous document. For that reason, a panel of experts revised the evidence on CMV management, including immunological monitoring, diagnostics, prevention, vaccines, indirect effects, treatment, drug resistance, immunotherapy, investigational drugs, and pediatric issues. This document summarizes the recommendations.

Influenza vaccine effectiveness is not optimal in solid organ transplant recipients (SOTR). We hypothesized that a booster dose might increase it. TRANSGRIPE 1–2 is a phase 3, randomized, controlled, multicenter, open-label clinical trial. Patients were randomly assigned (1:1 stratified by study site, type of organ, and time since transplantation) to receive 1 dose (control group) or 2 doses (booster group) of the influenza vaccine 5 weeks apart. A total of 499 SOTR were enrolled. Although seroconversion at 10 weeks did not meet significance in the modified intention-to-treat population, seroconversion rates were significantly higher in the booster arm for the per-protocol population (53.8% vs 37.6% for influenza A(H1N1)pdm; 48.1% vs 32.3% for influenza A(H3N2); and 90.7% vs 75% for influenza B; P < .05). Furthermore, seroprotection at 10 weeks was higher in the booster group: 54% vs 43.2% for A(H1N1)pdm; 56.9% vs 45.5% for A(H3N2); and 83.4% vs 71.8% for influenza B (P < .05). The number needed to treat to seroprotect 1 patient was <10. The clinical efficacy (99.2% vs 98.8%) and serious adverse events (6.4% vs 7.5%) were similar for both groups. In SOTR, a booster strategy 5 weeks after standard influenza vaccination is safe and effective and induces an increased antibody response compared with standard influenza vaccination consisting of a single dose. EudraCT (2011-003243-21).

It was our purpose to evaluate the clinical impact of systematic PET/CT for the diagnosis of infectious embolisms in patients with infectious endocarditis (IE) in comparison with a historic cohort of IE patients managed without this technique. Detection of extracardiac lesions is an essential component of the management and outcome of IE. Studies using PET/CT for the evaluation of patients with IE are scarce, lack a control group, evaluate a small number of patients, or consist of case reports.We performed a prospective cohort study (47 patients with definite IE undergoing PET/CT) with matched controls (94 patients with definite IE not undergoing PET/CT) from January 2012 to July 2013 in a tertiary hospital. The results were compared with those of conventional diagnostic techniques and clinical follow-up.PET/CT revealed at least 1 lesion in 35 patients (74.5%): 18 showed an embolic complication, 8 showed pathologic uptake on the valves or cardiac devices, 1 showed both, 5 had incidental noninfectious findings, and the findings for 3 were considered false-positive. The validity values for the efficacy of PET/CT in the diagnosis of septic lesions were as follows: sensitivity, 100%; specificity, 80%; positive predictive value, 90%; and negative predictive value, 100%. PET/CT was the only initially positive imaging technique in 15 true-positive cases (55.5%). The systematic use of PET/CT was associated with a 2-fold reduction in the number of relapses (9.6% vs. 4.2%, P = 0.25) and enabled significantly more infectious complications to be diagnosed (18% vs. 57.4%, P = 0.0001).PET/CT enables the extent of IE to be assessed using a single test. It is fast (<2 h) and comfortable for the patient, gathers whole-body data, and detects significantly more infectious complications.

The impact of early valve surgery (EVS) on the outcome of Staphylococcus aureus (SA) prosthetic valve infective endocarditis (PVIE) is unresolved. The objective of this study was to evaluate the association between EVS, performed within the first 60 days of hospitalization, and outcome of SA PVIE within the International Collaboration on Endocarditis-Prospective Cohort Study.Participants were enrolled between June 2000 and December 2006. Cox proportional hazards modeling that included surgery as a time-dependent covariate and propensity adjustment for likelihood to receive cardiac surgery was used to evaluate the impact of EVS and 1-year all-cause mortality on patients with definite left-sided S. aureus PVIE and no history of injection drug use.EVS was performed in 74 of the 168 (44.3%) patients. One-year mortality was significantly higher among patients with S. aureus PVIE than in patients with non-S. aureus PVIE (48.2% vs 32.9%; P = .003). Staphylococcus aureus PVIE patients who underwent EVS had a significantly lower 1-year mortality rate (33.8% vs 59.1%; P = .001). In multivariate, propensity-adjusted models, EVS was not associated with 1-year mortality (risk ratio, 0.67 [95% confidence interval, .39-1.15]; P = .15).In this prospective, multinational cohort of patients with S. aureus PVIE, EVS was not associated with reduced 1-year mortality. The decision to pursue EVS should be individualized for each patient, based upon infection-specific characteristics rather than solely upon the microbiology of the infection causing PVIE.

During recent years, inappropriate antifungal use has contributed to the global increase in antifungal resistance and has played a role in the shift in the aetiology of invasive fungal infections. Moreover, overuse of antifungals may also lead to higher toxicity associated with unnecessary medication exposure and to increased healthcare costs. Antifungal stewardship (AFS) programmes consist of multidisciplinary interventions, led by specialists in infectious disease, microbiology and pharmacy that cooperate and communicate with the major prescribing departments in order to optimise antifungal therapies evaluating the indication, dose, streamlining and duration. Herein, we review the available evidence for the use of AFS and their impact on health economics. We also describe our AFS program, the successive steps we followed and the main difficulties we found.

Antifungal stewardship (AFS) programmes are needed in tertiary-care hospitals. Our aim is to describe a bedside non-restrictive AFS programme, and to evaluate its economic impact. During the first year of the AFS a bundle of non-interventional measures were implemented. During the second year an infectious diseases specialist visited 453 patients receiving candins, liposomal amphotericin B, voriconazole or posaconazole. Monthly costs were studied with an interrupted time series (ITS) analysis. The main prescribing departments were haematology (35%), medical departments (23%), and intensive care units (20%). Reasons to start antifungal therapy were: targeted therapy (36%), prophylaxis (32%), empirical therapy (20%) and pre-emptive therapy (12%). At the initial visit, diagnostic advice was provided in 40% of cases. The most common therapeutic recommendations were to de-escalate the antifungal drug (17%) or to suspend it (7%). Annual total antifungal expenditure was reduced from US$3.8 million to US$2.9 million over the first 2 years, generating net savings of US$407,663 and US$824,458 per year after considering the cost of additional staff required. The ITS analyses showed a significant economic impact after the first 12 months of the intervention (p 0.042 at month 13), which was enhanced in the following 24 months (p 0.006 at month 35). The number of defined daily doses decreased from 66.4 to 54.8 per 1000 patient-days. Incidence of candidaemia was reduced from 1.49 to 1.14 (p 0.08) and related mortality was reduced from 28% to 16% (p 0.1). A collaborative and non-compulsory AFS program based on bedside intervention is an efficacious and cost-effective approach that optimizes the use of AF drugs.

To analyse the effectiveness of dalbavancin (DBV) in clinical practice as consolidation therapy in patients with bloodstream infection (BSI) and/or infective endocarditis (IE) produced by gram-positive cocci (GPC), as well as its safety and pharmacoeconomic impact.A multicentre, observational and retrospective study was conducted of hospitalised patients with IE and/or BSI produced by GPC who received at least one dose of DBV. Clinical response was assessed during hospitalization, at 3 months and at 1 year.Eighty-three patients with median age of 73 years were enrolled; 73.5% were male; 59.04% had BSI and 49.04% IE (44.04% prosthetic valve IE, 32.4% native IE, 23.5% pacemaker lead). The most frequently isolated microorganism was Staphylococcus aureus in BSI (49%) and coagulase-negative staphylococci in IE (44.1%). All patients with IE were clinically cured in hospital; at 12 months, there was 2.9% loss to follow-up, 8.8% mortality unrelated to IE, and 2.9% therapeutic failure rate. The percentage effectiveness of DBV to treat IE was 96.7%. The clinical cure rate for BSI was 100% during hospital stay and at 3 months; there were no recurrences or deaths during the follow-up. No patient discontinued treatment for adverse events. The saving in hospital stay was 636 days for BSI (315,424.20€) and 557 days for IE (283,187.45€).DBV is an effective consolidation antibiotic therapy in clinically stabilized patients with IE and/or BSI. It proved to be a cost-effective treatment, reducing the hospital stay, thanks to the pharmacokinetic/pharmacodynamic profile of this drug.

To describe the current epidemiology of bloodstream infection (BSI) in patients with cirrhosis; and to analyse predictors of 30-day mortality and risk factors for antibiotic resistance.Cirrhotic patients developing a BSI episode were prospectively included at 19 centres in five countries from September 2014 to December 2015. The discrimination of mortality risk scores for 30-day mortality were compared by area under the receiver operator risk and Cox regression models. Risk factors for multidrug-resistant organisms (MDRO) were assessed with a logistic regression model.We enrolled 312 patients. Gram-negative bacteria, Gram-positive bacteria and Candida spp. were the cause of BSI episodes in 53%, 47% and 7% of cases, respectively. The 30-day mortality rate was 25% and was best predicted by the Sequential Organ Failure Assessment (SOFA) and Chronic Liver Failure-SOFA (CLIF-SOFA) score. In a Cox regression model, delayed (>24 hours) antibiotic treatment (hazard ratio (HR) 7.58; 95% confidence interval (CI) 3.29-18.67; p < 0.001), inadequate empirical therapy (HR 3.14; 95% CI 1.93-5.12; p < 0.001) and CLIF-SOFA score (HR 1.35; 95% CI 1.28-1.43; p < 0.001) were independently associated with 30-day mortality. Independent risk factors for MDRO (31% of BSIs) were previous antimicrobial exposure (odds ratio (OR) 2.91; 95% CI 1.73-4.88; p < 0.001) and previous invasive procedures (OR 2.51; 95% CI 1.48-4.24; p 0.001), whereas spontaneous bacterial peritonitis as BSI source was associated with a lower odds of MDRO (OR 0.30; 95% CI 0.12-0.73; p 0.008).MDRO account for nearly one-third of BSI in cirrhotic patients, often resulting in delayed or inadequate empirical antimicrobial therapy and increased mortality rates. Our data suggest that improved prevention and treatment strategies for MDRO are urgently needed in the liver cirrhosis patients.

There is little information concerning infective endocarditis (IE) in patients with bicuspid aortic valve (BAV) or mitral valve prolapse (MVP). Currently, IE antibiotic prophylaxis (IEAP) is not recommended for these conditions. This study sought to describe the clinical and microbiological features of IE in patients with BAV and MVP and compare them with those of IE patients with and without IEAP indication, to determine the potential benefit of IEAP in these conditions. This analysis involved 3,208 consecutive IE patients prospectively included in the GAMES (Grupo de Apoyo al Manejo de la Endocarditis infecciosa en España) registry at 31 Spanish hospitals. Patients were classified as high-risk IE with IEAP indication (high-risk group; n = 1,226), low- and moderate-risk IE without IEAP indication (low/moderate-risk group; n = 1,839), and IE with BAV (n = 54) or MVP (n = 89). BAV and MVP patients had a higher incidence of viridans group streptococci IE than did high-risk group and low/moderate-risk group patients (35.2% and 39.3% vs. 12.1% and 15.0%, respectively; all p < 0.01). A similar pattern was seen for IE from suspected odontologic origin (14.8% and 18.0% vs. 5.8% and 6.0%; all p < 0.01). BAV and MVP patients had more intracardiac complications than did low/moderate-risk group (50% and 47.2% vs. 30.6%, both p < 0.01) patients and were similar to high-risk group patients. IE in patients with BAV and MVP have higher rates of viridans group streptococci IE and IE from suspected odontologic origin than in other IE patients, with a clinical profile similar to that of high-risk IE patients. Our findings suggest that BAV and MVP should be classified as high-risk IE conditions and the case for IEAP should be reconsidered.

<h2>Abstract</h2><h3>Objectives</h3> To summarize the available evidence on the diagnostic performance for invasive aspergillosis (IA) in non-hematological, non-solid organ transplantation critically ill patients of the following: (<i>i</i>) existing definitions of IA (developed either for classical immunocompromised populations or for non-immunocompromised critically ill patients); (<i>ii</i>) laboratory tests; (<i>iii</i>) radiology tests. <h3>Methods</h3> A systematic review was performed by evaluating studies assessing the diagnostic performance for IA of a definition/s and/or laboratory/radiology test/s vs. a reference standard (histology) or a reference definition. <h3>Results</h3> Sufficient data for evaluating the performance of existing definitions and laboratory tests for the diagnosis of IA in critically ill patients is available only for invasive pulmonary aspergillosis. Against histology/autopsy as reference, the AspICU definition showed a promising diagnostic performance but based on small samples and applicable only to patients with positive respiratory cultures. Studies on laboratory tests consistently indicated a better diagnostic performance of bronchoalveolar lavage fluid (BALF) galactomannan (GM) than serum GM, and a suboptimal specificity of BALF and serum (1,3)-β-D-glucan. <h3>Conclusions</h3> Evidence stemming from this systematic review will guide the discussion for defining invasive aspergillosis within the FUNDICU project. The project aims to develop a standard set of definitions for invasive fungal diseases in critically ill, adult patients.

The high transmissibility of SARS-CoV-2 before and shortly after the onset of symptoms suggests that only diagnosing and isolating symptomatic patients may not be sufficient to interrupt the spread of infection; therefore, public health measures such as personal distancing are also necessary. Additionally, it will be important to detect the newly infected individuals who remain asymptomatic, which may account for 50% or more of the cases. Molecular techniques are the "gold standard" for the diagnosis of SARS-CoV-2 infection. However, the massive use of these techniques has generated some problems. On the one hand, the scarcity of resources (analyzers, fungibles and reagents), and on the other the delay in the notification of results. These two facts translate into a lag in the application of isolation measures among cases and contacts, which favors the spread of the infection. Antigen detection tests are also direct diagnostic methods, with the advantage of obtaining the result in a few minutes and at the very "pointof-care". Furthermore, the simplicity and low cost of these tests allow them to be repeated on successive days in certain clinical settings. The sensitivity of antigen tests is generally lower than that of nucleic acid tests, although their specificity is comparable. Antigenic tests have been shown to be more valid in the days around the onset of symptoms, when the viral load in the nasopharynx is higher. Having a rapid and real-time viral detection assay such as the antigen test has been shown to be more useful to control the spread of the infection than more sensitive tests, but with greater cost and response time, such as in case of molecular tests. The main health institutions such as the WHO, the CDC and the Ministry of Health of the Government of Spain propose the use of antigenic tests in a wide variety of strategies to respond to the pandemic. This document aims to support physicians involved in the care of patients with suspected SC2 infection, in the context of a growing incidence in Spain since September 2020, which already represents the second pandemic wave of COVID-19.

We report here for the first time the presence of Candida parapsilosis isolates harbouring the Y132F ERG11 gene substitution in patients admitted to a Spanish hospital.We studied the available (n = 104) C parapsilosis isolates from patients admitted to the Son Espases reference hospital in the Balearic Islands from 1 April 2019 to 30 November 2020. Isolates were sourced from 70 patients: catheter (n = 41), blood cultures (n = 37), lower respiratory tract (n = 15), intra-abdominal (n = 8), and other samples (n = 3). Isolates were genotyped and tested for antifungal susceptibilities to amphotericin B, triazoles, anidulafungin, and micafungin using EUCAST E.Def 7.3.2. The ERG11 gene was sequenced in fluconazole-resistant isolates.Among the 104 isolates, fluconazole and voriconazole resistance was found in 87 (84%) and 30 (29%) isolates, respectively; all isolates were fully susceptible to echinocandins and amphotericin B. All fluconazole-resistant isolates harboured the Y132F substitution in the ERG11 gene and were grouped into 11 clonally related genotypes. A genotype accounted for 70% (61/87) of fluconazole-resistant isolates. Genotypes involving the fluconazole-resistant isolates were different from those found in the remaining fluconazole-susceptible genotypes. Fifty-six patients harboured fluconazole-resistant genotypes, and 35 of the 56 had candidaemia (48%), abdominal candidiasis (17%), or other forms of candidiasis (35%). Only 20% of the study patients infected by fluconazole-resistant genotypes had a history of azole use.Fluconazole resistance in C parapsilosis isolates from patients admitted to this reference hospital is not attributable to prior azole use, but rather to the presence of a group of fluconazole-resistant C parapsilosis genotypes that have become endemic.

A monkeypox virus (MPXV) outbreak has been ongoing worldwide since May 2022. The role of specimens other than skin lesions for MPXV diagnosis is unknown. We evaluated 140 different clinical specimens by real-time PCR. The highest positivity rates (97%) were from skin lesions of any part of the body, followed by plasma, pharyngeal and anal swabs. Testing specimens from multiple sites may improve the sensitivity and reduce false-negative test results.

Our work describes the frequency of superinfections in COVID-19 ICU patients and identifies risk factors for its appearance. Second, we evaluated ICU length of stay, in-hospital mortality and analyzed a subgroup of multidrug-resistant microorganisms (MDROs) infections.Retrospective study conducted between March and June 2020. Superinfections were defined as appeared ≥48 h. Bacterial and fungal infections were included, and sources were ventilator-associated lower respiratory tract infection (VA-LRTI), primary bloodstream infection (BSI), secondary BSI, and urinary tract infection (UTI). We performed a univariate analysis and a multivariate analysis of the risk factors.Two-hundred thirteen patients were included. We documented 174 episodes in 95 (44.6%) patients: 78 VA-LRTI, 66 primary BSI, 9 secondary BSI and 21 UTI. MDROs caused 29.3% of the episodes. The median time from admission to the first episode was 18 days and was longer in MDROs than in non-MDROs (28 vs. 16 days, p < 0.01). In multivariate analysis use of corticosteroids (OR 4.9, 95% CI 1.4-16.9, p 0.01), tocilizumab (OR 2.4, 95% CI 1.1-5.9, p 0.03) and broad-spectrum antibiotics within first 7 days of admission (OR 2.5, 95% CI 1.2-5.1, p < 0.01) were associated with superinfections. Patients with superinfections presented respect to controls prolonged ICU stay (35 vs. 12 days, p < 0.01) but not higher in-hospital mortality (45.3% vs. 39.7%, p 0.13).Superinfections in ICU patients are frequent in late course of admission. Corticosteroids, tocilizumab, and previous broad-spectrum antibiotics are identified as risk factors for its development.Nuestro trabajo describe la frecuencia de sobreinfecciones en pacientes con COVID-19 en UCI e identifica factores de riesgo asociados con su aparición. Secundariamente, evaluamos la estancia en UCI, mortalidad intrahospitalaria y analizamos un subgrupo de infecciones causadas por microorganismos multirresistentes (MDR).Estudio realizado entre marzo y junio de 2020. Definimos como sobreinfección a aquellas que aparecieron ≥48 h del ingreso. Incluimos las causadas por bacterias y hongos y evaluamos la infección respiratoria asociada a la ventilación mecánica (IRAVM), bacteriemia primaria, bacteriemia secundaria e infección del tracto urinario. Se realizó un análisis multivariante de los factores de riesgo.Incluimos 213 pacientes, documentándose 174 episodios de sobreinfección en 95 casos (44,6%): IRAVM 78 episodios, bacteriemia primaria 66, bacteriemia secundaria 9 e ITU 21. Los MDR causaron el 29,3% de los episodios. La mediana de tiempo hasta el primer episodio fue de 18 días, siendo mayor en las causadas por MDR vs. no MDR (28 vs. 16, p < 0,01). El análisis multivariante identificó la administración de corticoides (OR 4,9 IC 95% 1,4-16,9), tocilizumab (OR 2,4 IC 95% 1,1-5,9) y antibióticos de amplio espectro (OR 2,5 IC 95% 1,2-5,1) como factores de riesgo asociados. Los pacientes con sobreinfección presentaron una estancia en UCI más prolongada (35 vs. 12 días, p < 0,01) pero no mayor mortalidad intrahospitalaria (45,3% vs. 39,7%, p 0,13).Las sobreinfecciones en los pacientes con COVID-19 aparecen tardíamente. La administración de corticoides, tocilizumab y antibióticos de amplio espectro se asocia con su aparición.

To obtain information on the microbiology workload, etiology and antimicrobial susceptibility of urinary tract infection (UTI) pathogens isolated in European hospitals.We collected data available in the microbiology units of a large sample of European hospitals regarding the laboratory workload, diagnostic criteria, and etiology and antimicrobial resistance of the urinary isolates collected on one day (the study day).Data were received from a total of 228 hospitals from 29 European countries. The average rate of urine samples cultured per 1000 admissions in 1999 was 324. The criteria to consider a positive urine culture as significant were quite variable; > or =10(4) colony-forming units (CFU)/mL for bacteria or > or =10(3) CFU/mL in the case of yeasts were the most used cut-off points. On the study day, a total of 607 micro-organisms from 522 patients with nosocomial UTI were isolated. The six most commonly isolated micro-organisms were, in decreasing order: Escherichia coli (35.6%), Enterococci (15.8%), Candida (9.4%), Klebsiella (8.3%), Proteus (7.9%) and Pseudomonas aeruginosa (6.9%). Pseudomonas was isolated more frequently in non-EU countries. The study data reveal high rates of antimicrobial resistance in UTI pathogens, especially in non-EU countries, where Pseudomonas aeruginosa presented rates of aminoglycoside resistance as high as 72% to gentamicin, 69.2% to tobramycin and 40% to amikacin.Nosocomial UTI accounts for an important proportion of the workload in microbiology laboratories. A consensus on the practice and interpretation of urine cultures in Europe is needed. The levels and patterns of resistance of UTI pathogens must be a serious cause for concern and a clear reason for stricter guidelines and regulations in antimicrobial policy.

Abbreviations used in this article: AFG, angiofluoresceingraphy; AIDS, acquired immunodeficiency syndrome; HIV, human immunodeficiency virus; PPD, purified protein derivative.

ObjectivesTo estimate the incidence of nosocomially acquired urinary tract infections (NAUTI) in Europe and provide information on the clinical characteristics, underlying conditions, etiology, management and outcome of patients.Materials and methodsWe collected clinical information from NAUTI patients with a microbiology report on the named study day.ResultsA total of 141 hospitals from 25 European countries participated in the study. Written institutional bladder catheter guidelines were in place in 90.3% of EU hospitals and 55% of non-EU hospitals (P <0.05). The total number of new NAUTI episodes on the day of the study was 298, representing an incidence of 3.55 episodes/1000 patient-days and an estimated prevalence of 10.65/1000. The five most commonly isolated micro-organisms were Escherichia coli, Enterococcus sp., Candida sp., Klebsiella sp. and Pseudomonas aeruginosa. Patients from non-EU countries were younger, with more severe underlying diseases with a higher incidence of obstructive uropathy/lithiasis. Overall, 22.8% of patients had no ‘classic’ UTI-predisposing factors. Catheter-associated UTI (CAUTI) was present in 187 patients (62.8%). A closed drainage system was used in only 78.5% of catheterised patients. The indication for bladder catheterisation was not considered adequate in 7.6% of cases and continuation of bladder catheterisation was considered unnecessary in 31.3%. Opening of the closed drainage system was the most frequent major error in catheter management (16.8%). Antimicrobial treatment was not considered adequate in 19.8% of all cases.ConclusionsThe incidence of NAUTI in a large European population is 3.55/1000 patient-days. There is clearly room for improvement in the area of bladder catheterisation, catheter care and medical management of NAUTI. We recommend that European authorities draw up and implement practical and specific guidelines to reduce the incidence of this infection. To estimate the incidence of nosocomially acquired urinary tract infections (NAUTI) in Europe and provide information on the clinical characteristics, underlying conditions, etiology, management and outcome of patients. We collected clinical information from NAUTI patients with a microbiology report on the named study day. A total of 141 hospitals from 25 European countries participated in the study. Written institutional bladder catheter guidelines were in place in 90.3% of EU hospitals and 55% of non-EU hospitals (P <0.05). The total number of new NAUTI episodes on the day of the study was 298, representing an incidence of 3.55 episodes/1000 patient-days and an estimated prevalence of 10.65/1000. The five most commonly isolated micro-organisms were Escherichia coli, Enterococcus sp., Candida sp., Klebsiella sp. and Pseudomonas aeruginosa. Patients from non-EU countries were younger, with more severe underlying diseases with a higher incidence of obstructive uropathy/lithiasis. Overall, 22.8% of patients had no ‘classic’ UTI-predisposing factors. Catheter-associated UTI (CAUTI) was present in 187 patients (62.8%). A closed drainage system was used in only 78.5% of catheterised patients. The indication for bladder catheterisation was not considered adequate in 7.6% of cases and continuation of bladder catheterisation was considered unnecessary in 31.3%. Opening of the closed drainage system was the most frequent major error in catheter management (16.8%). Antimicrobial treatment was not considered adequate in 19.8% of all cases. The incidence of NAUTI in a large European population is 3.55/1000 patient-days. There is clearly room for improvement in the area of bladder catheterisation, catheter care and medical management of NAUTI. We recommend that European authorities draw up and implement practical and specific guidelines to reduce the incidence of this infection.

To determine the frequency, etiology, and risk factors of ventilator-associated pneumonia (VAP) and purulent tracheobronchitis (TBX) in patients who have undergone heart surgery. To study the predictive role of systematic surveillance cultures.Prospective study.Heart surgery intensive care unit.Intubated heart surgical patients.Systematic tracheal aspirate and protected brush catheter cultures of all intubated patients.Studied were the frequency of lower respiratory tract infection in ventilated patients and the role of surveillance cultures. The frequency of VAP was 7.87% (34.5 per 1,000 days of mechanical ventilation), and the criteria for purulent tracheobronchitis was fulfilled by 8.15% of patients (31.13 per 1,000 days of mechanical ventilation). After multivariate analysis, the variables independently associated with the development of respiratory tract infection were central nervous system disorder (relative risk [RR] = 4.7), ulcer disease (RR = 3.6), New York Heart Association score >/=3 (RR = 4), need for mechanical circulatory support (RR = 6.8), duration of mechanical ventilation >96 hrs (RR = 12.3), and reintubation (RR = 63.7). Mortality in our study was as follows: VAP patients, 57.1%; purulent tracheobronchitis patients, 20.7%; colonized patients, 11.5%; and noncolonized patients, 1.6%. Regular surveillance cultures were taken from all ventilated patients to assess the anticipative value of the cultures in predicting respiratory tract infection. A total of 1,626 respiratory surveillance samples were obtained. Surveillance cultures effectively predicted only one episode of VAP and one of tracheobronchitis.Patients undergoing heart surgery have a high frequency of VAP. VAP is associated with a poor prognosis. In this study, surveillance cultures failed as an anticipative diagnostic method.

<h3>Background:</h3> We report the largest series of group B streptococcal (GBS) bacteremia cases reported at a single institution. <h3>Methods:</h3> During a 10-year period (1985-1994), 90 GBS bacteremia cases (0.95% of significant bacteremic episodes) were detected. We describe the 51 episodes that occurred in nonpregnant adults for which enough clinical and microbiological information is available. <h3>Results:</h3> Incidence of GBS has significantly increased during the study period (from 0.08 per 1000 admissions in 1985 to 0.3 per 1000 in 1994). Mean age of patients was 63.3 years (range, 21-88 years) and 53% were men. The most common underlying conditions were liver diseases (35.3%), malignancies (33.3%), and diabetes mellitus (27.5%). Only 2 patients did not have any underlying condition and no patient with the human immunodeficiency virus had GBS bacteremia in our series. The origins of the episodes of bacteremia were as follows: primary bacteremia (39.2%), skin and soft tissue infections (15.7%), urinary tract infections (11.8%), pneumonia (9.8%), peritonitis (9.8%), catheter infection (5.9%), postendoscopic bacteremia (5.9%), and endocarditis (2%). All isolates were susceptible to penicillin G potassium, ampicillin sodium, cephalothin sodium, cefotaxime sodium, and vancomycin hydrochloride. One ciprofloxacin hydrochloride—resistant strain was discovered and resistance to erythromycin stearate increased from 8% in 1992 to 18% in 1994. The overall mortality rate was 33.3% and deaths were considered related to the GBS bacteremia in 25.5% of the cases. Factors for poor prognosis were central nervous system diseases, alcoholism, shock, renal failure, and consciousness impairment. <h3>Conclusions:</h3> Group B streptococcus is a rising cause of bacteremia in elderly patients with severe underlying conditions. It conveys high morbidity and mortality rates. Macrolides should not be used empirically for treatment of patients with penicillin allergies. Arch Intern Med. 1997;157:213-216

The impact of how positive blood culture results are reported on the evolution bloodstream infections (BSIs) has not been assessed.We randomly assigned patients with BSIs into 3 groups: group A (for which physicians received a conventional report), group B (for which physicians received a conventional report and a written alert on the chart with clinical advice), and group C (for which physicians received the above plus oral clinical advice). The adequacy of therapy before and after receipt of the different types of information was assessed.Overall, 297 episodes (109 in group A, 99 in group B, and 89 in group C) were studied. Patients who received inadequate treatment before receiving microbiological information had a longer mean (+/-SD) hospital stay (27.2+/-32.4 vs. 19.4+/-15.8 days; P=.017), a higher mean risk of Clostridium difficile-associated diarrhea (8.3% vs. 1.9%; P=.013), a higher mean overall mortality rate (30.8% vs. 19.4%; P=.025), and a higher mean risk of infection-related mortality (23.3% vs. 13.6%; P=.031). After receipt of microbiological reports, recommendations for changes in therapy were issued for patients in groups B (52.3%) and C (53.1%). For groups A, B, and C, the proportions of days on which adequate treatment was received were 66.3%, 92.1%, and 91.2% (P<.001); the mean numbers of defined daily doses of appropriate antibiotic therapy were 16.4, 22.2, and 20.7 (P=.003); the mean durations of hospital stay were 19.8, 23.6, and 24.1 days (P=.761); and the mortality rates during the late period were 12.9%, 15.6%, and 11% (P=.670), respectively. The mean costs of antimicrobials per episode in groups A, B, and C were 580.63, 537.98, and 434.53 (US707.85 dollars, US699.73 dollars, and US529.73 dollars, respectively).Written- or oral-alert reports with clinical advice should complement traditional microbiological reports for patients with BSIs.

The periannular extension of infection in prosthetic valve endocarditis (PVE) is a serious complication of infective endocarditis associated with high mortality. Periannular lesions in PVE occasionally rupture into adjacent cardiac chambers, leading to aortocavitary fistulae and intracardiac shunting. It is unknown whether the prognosis of patients with aortocavitary fistulae is worse than that of those with nonruptured abscesses. The aims of this study were to determine the distinctive clinical characteristics of patients with PVE and either aortocavitary fistulization or nonruptured abscesses. In a retrospective multicenter study of >872 PVE episodes, 150 patients (17%) with periannular complications in PVE in the aortic position were identified (29 with aortocavitary fistulization and 121 with nonruptured abscesses). Early-onset PVE was present in 73 patients (49%). Rates of heart failure (p = 0.09), ventricular septal defect (p <0.01), and third-degree atrioventricular block (p = 0.07) were higher in patients with fistulization. Surgical treatment was undertaken in 128 patients (83%). In-hospital mortality in the overall population was 39%. Multivariate analysis identified heart failure (odds ratio [OR] 3.3, 95% confidence interval [CI] 1.6 to 6.8), renal failure (OR 2.5, 95% CI 1.2 to 5.2), and co-morbidity (OR 2.4, 95% CI 1.1 to 5.1) as independent risk factors for death. Fistulous tract formation was not associated with increased in-hospital mortality (OR 1.6, 95% CI 0.7 to 3.7). The actuarial 5-year survival rate in surgical survivors was 100% in patients with fistulae and 78% in patients with nonruptured abscesses (log-rank p = 0.14). In conclusion, aortocavitary fistulous tract formation in PVE complicated with periannular complications is associated with higher rates of heart failure, ventricular septal defect, and atrioventricular block than nonruptured abscesses. Despite the frequent complications, fistulous tract formation in the current era of infective endocarditis is not an independent risk factor for mortality. The periannular extension of infection in prosthetic valve endocarditis (PVE) is a serious complication of infective endocarditis associated with high mortality. Periannular lesions in PVE occasionally rupture into adjacent cardiac chambers, leading to aortocavitary fistulae and intracardiac shunting. It is unknown whether the prognosis of patients with aortocavitary fistulae is worse than that of those with nonruptured abscesses. The aims of this study were to determine the distinctive clinical characteristics of patients with PVE and either aortocavitary fistulization or nonruptured abscesses. In a retrospective multicenter study of >872 PVE episodes, 150 patients (17%) with periannular complications in PVE in the aortic position were identified (29 with aortocavitary fistulization and 121 with nonruptured abscesses). Early-onset PVE was present in 73 patients (49%). Rates of heart failure (p = 0.09), ventricular septal defect (p <0.01), and third-degree atrioventricular block (p = 0.07) were higher in patients with fistulization. Surgical treatment was undertaken in 128 patients (83%). In-hospital mortality in the overall population was 39%. Multivariate analysis identified heart failure (odds ratio [OR] 3.3, 95% confidence interval [CI] 1.6 to 6.8), renal failure (OR 2.5, 95% CI 1.2 to 5.2), and co-morbidity (OR 2.4, 95% CI 1.1 to 5.1) as independent risk factors for death. Fistulous tract formation was not associated with increased in-hospital mortality (OR 1.6, 95% CI 0.7 to 3.7). The actuarial 5-year survival rate in surgical survivors was 100% in patients with fistulae and 78% in patients with nonruptured abscesses (log-rank p = 0.14). In conclusion, aortocavitary fistulous tract formation in PVE complicated with periannular complications is associated with higher rates of heart failure, ventricular septal defect, and atrioventricular block than nonruptured abscesses. Despite the frequent complications, fistulous tract formation in the current era of infective endocarditis is not an independent risk factor for mortality.

<h2>ABSTRACT</h2> Mucormycosis is the third invasive mycosis in order of importance after candidiasis and aspergillosis and is caused by fungi of the class Zygomycetes. The most important species in order of frequency is <i>Rhizopus arrhizus</i> (<i>oryzae</i>). Identification of the agents responsible for mucormycosis is based on macroscopic and microscopic morphological criteria, carbohydrate assimilation and the maximum temperature compatible with its growth. The incidence of mucormycosis is approximately 1.7 cases per 1000 000 inhabitants per year, and the main risk-factors for the development of mucormycosis are ketoacidosis (diabetic or other), iatrogenic immunosuppression, use of corticosteroids or deferoxamine, disruption of mucocutaneous barriers by catheters and other devices, and exposure to bandages contaminated by these fungi. Mucorales invade deep tissues via inhalation of airborne spores, percutaneous inoculation or ingestion. They colonise a high number of patients but do not cause invasion. Mucormycosis most commonly manifests in the sinuses (39%), lungs (24%), skin (19%), brain (9%), and gastrointestinal tract (7%), in the form of disseminated disease (6%), and in other sites (6%). Clinical diagnosis of mucormycosis is difficult, and is often made at a late stage of the disease or post-mortem. Confirmation of the clinical form requires the combination of symptoms compatible with histological invasion of tissues. The probable diagnosis of mucormycosis requires the combination of various clinical data and the isolation in culture of the fungus from clinical samples. Treatment of mucormycosis requires a rapid diagnosis, correction of predisposing factors, surgical resection, debridement and appropriate antifungal therapy. Liposomal amphotericin B is the therapy of choice for this condition. Itraconazole is considered to be inappropriate and there is evidence of its failure in patients suffering from mucormycosis. Voriconazole is not active <i>in vitro</i> against Mucorales, and failed when used <i>in vivo</i>. Posaconazole and ravuconazole have good activity <i>in vitro</i>. The overall rate of mortality of mucormycosis is approximately 40%.

The study was designed to identify a subset of heart transplant (HT) recipients who could benefit from the administration of targeted antifungal prophylaxis and to evaluate the efficacy of oral itraconazole as the preventive drug. We have analyzed the risk factors for invasive aspergillosis (IA) in our entire population of HT recipients (1988-2002) and also the role of oral itraconazole prophylaxis that was provided to all patients since 1995 [400 mg q.d. of itraconazole oral (PO) for 3-6 months]. There were 24 cases of IA. Our main results indicate that the independent risk factors for IA after heart transplantation are: re-operation (RR 5.8; 95% CI 1.8-18, p=0.002), cytomegalovirus (CMV) disease (RR 5.2; 95% CI 2-13.9, p=0.001), post-transplant hemodialysis (RR 4.9; 95% CI 1.2-18, p=0.02), and the existence of an episode of IA in the HT program 2 months before or after the transplantation date (RR 4.6; 95% CI 1.5-14.4, p=0.007). Itraconazole prophylaxis showed an independent protective value against developing IA (RR 0.2; 95% CI 0.07-0.9, p=0.03) and also determined a significantly prolonged 1-year survival (RR 0.5; 95% CI 0.3-0.8, p=0.01). We believe that antifungal prophylaxis in heart transplant patients should be offered at least to patients with one or more of these predisposing conditions.

Objective. The aim of this prospective, multicenter, noncomparative, open-label trial was to evaluate the prophylactic use of caspofungin in adult liver transplant recipients at high risk of developing invasive fungal infections (IFI). Methods. Patients received caspofungin for at least 21 days. A successful treatment outcome was defined as the absence of breakthrough IFI during the first 100 days after the onset of caspofungin. Results. According to study design, 71 patients were included. In the modified intention-to-treat analysis, successful treatment outcome was obtained in 88.7%. Two patients developed IFI: a Mucor and a Candida albicans surgical wound infections, respectively. Six more patients discontinued caspofungin because of drug-related altered liver function. No clinical side effects were related to caspofungin. Altered analytical data compatible with grade IV toxicity, irrespective of caspofungin attribution, were observed in 27.7% of patients at the end of caspofungin prophylaxis and in 15.4% of patients in safety visit (14 days after ending caspofungin administration) (P=0.13). Eight patients died, six during caspofungin administration and two during follow-up period, but none were attributed to IFI or caspofungin toxicity. Conclusion. These results show that caspofungin could be considered an efficacious and well-tolerated drug as antifungal prophylaxis in high-risk liver transplant recipients.

The extension of infection in native valve infective endocarditis (IE) from valvular structures to the periannular tissue is incompletely understood. It is unknown, for example, whether the prognosis of patients with aortocavitary fistulae is worse than that of those with nonruptured abscesses. The aims of this study were to determine the distinct clinical characteristics of patients with aortocavitary fistulae and nonruptured abscesses in native valve IE and to evaluate the impact of fistulization on the outcomes of patients with native aortic valve IE complicated with periannular lesions. In a retrospective multicenter study of 2,055 native valve IE episodes, 201 patients (9.8%) with periannular complications in aortic valve IE were identified (46 with aortocavitary fistulization and 155 with nonruptured abscesses). Rates of heart failure (p = 0.07), ventricular septal defect (p <0.001), and third-degree atrioventricular block (p = 0.07) were higher in patients with fistulization. Surgical treatment was undertaken in 172 patients (86%), and in-hospital mortality in the overall population was 29%. Multivariate analysis identified age >60 years (odds ratio [OR] 2.6, 95% confidence interval [CI] 1.3 to 5.2), renal failure (OR 3.0, 95% CI 1.5 to 6.0), and moderate or severe heart failure (OR 2.5, 95% CI 1.2 to 5.2) as independent risk factors for death. There was a trend toward increased in-hospital mortality in patients with aortocavitary fistulae (OR 1.5, 95% CI 0.7 to 3.0). The actuarial 5-year survival rate in surgical survivors was 80% in patients with fistulae and 92% in patients with nonruptured abscesses (log-rank p = 0.6). In conclusion, aortocavitary fistulous tract formation in the setting of native valve IE is associated with higher rates of heart failure, ventricular septal defect, and atrioventricular block than nonruptured abscess. Despite these higher rates of complications, fistulous tract formation in the current era of IE is not an independent risk factor for mortality.

Patients undergoing major heart surgery (MHS) represent a special subpopulation at risk for nosocomial infections. Postoperative infection is the main non-cardiac complication after MHS and has been clearly related to increased morbidity, use of hospital resources and mortality. Our aim was to determine the incidence, aetiology, risk factors and outcome of ventilator-associated pneumonia (VAP) in patients who have undergone MHS in Europe.Our study was a prospective study of patients undergoing MHS in Europe who developed suspicion of VAP. During a one-month period, participating units submitted a protocol of all patients admitted to their units who had undergone MHS.Overall, 25 hospitals in eight different European countries participated in the study. The number of patients intervened for MHS was 986. Fifteen patients were excluded because of protocol violations. One or more nosocomial infections were detected in 43 (4.4%) patients. VAP was the most frequent nosocomial infection (2.1%; 13.9 episodes per 1000 days of mechanical ventilation). The microorganisms responsible for VAP in this study were: Enterobacteriaceae (45%), Pseudomonas aeruginosa (20%), methicillin-resistant Staphylococcus aureus (10%) and a range of other microorganisms. We identified the following significant independent risk factors for VAP: ascending aorta surgery (odds ratio (OR) = 6.22; 95% confidence interval (CI) = 1.69 to 22.89), number of blood units transfused (OR = 1.08 per unit transfused; 95% CI = 1.04 to 1.13) and need for re-intervention (OR = 6.65; 95% CI = 2.10 to 21.01). The median length of stay in the intensive care unit was significantly longer (P < 0.001) in patients with VAP than in patients without VAP (23 days versus 2 days). Death was significantly more frequent (P < 0.001) in patients with VAP (35% versus 2.3%).Patients undergoing aortic surgery and those with complicated post-intervention courses, requiring multiple transfusions or re-intervention, constitute a high-risk group probably requiring more active preventive measures.

This multicenter, population-based study evaluated the laboratory workload produced by zygomycetes and the number of cases of zygomycosis in Spain during 2005. Less than 8% of the patients who harbored zygomycete isolates had zygomycosis. The incidence of zygomycosis (6 cases) was 0.43 cases/1,000,000 inhabitants and 0.62 cases/100,000 hospital admissions.

Information available on bloodstream infection (BSI) is usually restricted to short periods of time, certain clinical backgrounds, or specific pathogens, or is just outdated. We conducted the current prospective study of patients with BSI in a 1750-bed teaching hospital to evaluate workload trends and the incidence and etiology of BSI in a general hospital during the last 22 years, including the acquired immunodeficiency syndrome (AIDS) era. The main outcome measures were laboratory workload, trends in incidence per 1000 admissions and per 100,000 population of different microorganisms, and the impact of the human immunodeficiency virus (HIV) epidemic in the period 1985-2006. From 1985 to 2006 we had 27,419 episodes of significant BSI (22,626 patients). BSI incidence evolved from 16.0 episodes to 31.2/1000 admissions showing an annual increase of 0.83 episodes/1000 admissions (95% confidence interval, 0.61-1.05; p < 0.0001). The evolution of the incidence per 1000 admissions and per 100,000 population of different groups of microorganisms was as follows: Gram positives 8.2 to 15.7/1000 admissions and 66.8 to 138.3/100,000 population; Gram negatives 7.8 to 16.2/1000 admissions and 63.5 to 141.9/100,000 population; anaerobes 0.5 to 1.3/1000 admissions and 4.1 to 11.7/100,000 population; and fungi 0.2 to 1.5/1000 admissions and 1.7 to 12.5/100,000 population. All those differences were statistically significant. We observed the emergence of multiresistant Gram-positive and Gram-negative microorganisms. At least 2484 episodes of BSI (9.1%) occurred in 1822 patients infected with HIV. The incidence of BSI in HIV-infected patients increased from 1985 and reached a peak in 1995 (17.6% of BSI). Since 1995, the decrease was continuous, and in 2006 only 3.9% of all BSI episodes occurred in HIV-positive patients in our institution. We conclude that the BSI workload has increased in modern microbiology laboratories. Gram-positive pathogens have overtaken other etiologic agents of BSI. Our observation shows the remarkable escalation of some resistant pathogens, and the rise and relative fall of BSI in patients with HIV. Abbreviations: AIDS = acquired immunodeficiency syndrome, BSI = bloodstream infection, ESBL = extended-spectrum beta-lactamase, HAART = highly active antiretroviral therapy, HIV = human immunodeficiency virus, MRSA = methicillin-resistant Staphylococcus aureus.

Synergistic interactions were observed between CIs and antifungal agents against 53 (90%) of 59 Cryptococcus neoformans isolates from solid organ transplant recipients with cryptococcosis and may account for better outcomes in patients with cryptococcosis receiving these immunosuppressive agents.

<h3>Objective:</h3> To describe the contemporary features of coagulase-negative staphylococcal (CoNS) prosthetic valve endocarditis (PVE). <h3>Design:</h3> Observational study of prospectively collected data from a multinational cohort of patients with infective endocarditis. Patients with CoNS PVE were compared to patients with <i>Staphylococcus aureus</i> and <i>viridans</i> streptococcal (VGS) PVE. <h3>Setting:</h3> The International Collaboration on Endocarditis-Prospective Cohort Study (ICE-PCS) is a contemporary cohort of patients with infective endocarditis from 61 centres in 28 countries. <h3>Patients:</h3> Adult patients in the ICE-PCS with definite PVE and no history of injecting drug use from June 2000 to August 2005 were included. <h3>Interventions:</h3> None. <h3>Main outcome measures:</h3> Heart failure, intracardiac abscess, death. <h3>Results:</h3> CoNS caused 16% (n = 86) of 537 cases of definite non-injecting drug use-associated PVE. Nearly one-half (n = 33/69, 48%) of patients with CoNS PVE presented between 60 days and 365 days of valve implantation. The rate of intracardiac abscess was significantly higher in patients with CoNS PVE (38%) than in patients with either <i>S aureus</i> (23%, p = 0.03) or VGS (20%, p = 0.05) PVE. The rate of abscess was particularly high in early (50%) and intermediate (52%) CoNS PVE. In-hospital mortality was 24% for CoNS PVE, 36% for <i>S aureus</i> PVE (p = 0.09) and 9.1% for VGS PVE (p = 0.08). Meticillin resistance was present in 68% of CoNS strains. <h3>Conclusions:</h3> Nearly one-half of CoNS PVE cases occur between 60 days and 365 days of prosthetic valve implantation. CoNS PVE is associated with a high rate of meticillin resistance and significant valvular complications.

Solid-organ transplant (SOT) recipients are classically considered to be at increased risk for listeriosis. However, risk factors for this infection have not been assessed.We carried out a multicenter, matched case-control study (1:2 ratio) from January 1995 through December 2007. Control subjects were matched for center, transplant type, and timing. Conditional logistic regression was performed to identify independent risk factors. Clinical features and outcomes for all case patients were reviewed.Thirty patients (0.12%) with cases of listeriosis were identified among 25,997 SOT recipients at 15 Spanish transplant centers. In a comparison of case patients with 60 matched control subjects, the following independent risk factors for listeriosis were identified: diabetes mellitus (odds ratio [OR], 5.6; 95% confidence interval [CI], 1.6-19.6; ), P = .007 history of cytomegalovirus infection or disease within the preceding 6 months (OR, 35.9; 95% CI, 2.1-620; P = .014), receipt of high-dose prednisone within the preceding 6 months (OR, 6.2; 95% CI, 1.8-21.1; P = .003), and trimethoprim-sulfamethoxazole (TMP-SMZ) prophylaxis (OR, 0.07; 95% CI, 0.006-0.76; P = .029). Twenty-six patients (86.7%) had bacteremia, and 7 had shock at presentation. Other manifestations included meningoencephalitis (10 cases), spontaneous peritonitis (2), pleural empyema (1), brain abscesses (1), and liver abscesses (1). The 30-day mortality rate was 26.7% (8 of 30 patients died).Listeriosis in SOT recipients is uncommon but causes high mortality. Diabetes mellitus, cytomegalovirus infection or disease, and receipt of high-dose steroids are independent risk factors for this infection, whereas TMP-SMZ prophylaxis is a protective factor.

Cytomegalovirus infection remains a major complication of solid organ transplantation. In 2005 the Spanish Transplantation Infection Study Group (GESITRA) of the Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC) developed consensus guidelines for the prevention and treatment of CMV infection in solid organ transplant recipients. Since then, numerous publications have clarified or questioned the aspects covered in the previous document. These aspects include the situations and populations who must receive prophylaxis and its duration, the selection of the best diagnosis and monitoring technique and the best therapeutic strategy. For these reasons, we have developed new consensus guidelines to include the latest recommendations on post-transplant CMV management based on new evidence available. La infección por citomegalovirus (CMV) constituye una complicación importante en los pacientes sometidos a trasplante de órgano sólido (TOS). En el año 2005 el Grupo de Estudio de Infección en el Trasplante (GESITRA) de la Sociedad Española de Microbiología Clínica y Enfermedades Infecciosas (SEIMC) elaboró un documento de consenso para la profilaxis y el tratamiento de la infección por CMV en pacientes sometidos a TOS. Desde entonces han sido numerosas las publicaciones que o bien han aclarado, o bien han planteado nuevas dudas respecto a los aspectos tratados en el anterior documento. Entre estos aspectos se encuentran las situaciones y poblaciones que deben recibir profilaxis y su duración, la elección de la mejor técnica para el diagnóstico y monitorización y la elección de la mejor estrategia terapéutica. Todo ello justifica la necesidad de elaborar un nuevo documento de consenso que incluya las últimas recomendaciones en el manejo de la infección por CMV post-trasplante en base a las nuevas evidencias disponibles.

Infection prevention and control in health-care facilities in which hematopoietic cell transplant recipients are treated

The clinical significance of prolonged viral shedding (PVS) and viral load (VL) dynamics has not been sufficiently assessed in hospitalized patients with pandemic 2009 influenza A(H1N1). We performed a prospective study of adults with confirmed influenza A(H1N1) virus infection admitted to our hospital from 20 September 2009 to 31 December 2009. Consecutive nasopharyngeal swabs were collected every 2 days during the first week after diagnosis, and then every week or until viral detection was negative. Relative VL was measured on the basis of haemagglutinin and RNaseP gene analysis. PVS was defined as positive detection of influenza A(H1N1) virus by real-time RT-PCR at day 7 after diagnosis. We studied 64 patients: 16 (25%) presented PVS. The factors associated with PVS were admission to the intensive-care unit (69% vs. 33%, p 0.02), purulent expectoration (75% vs. 44%, p 0.04), higher dosage of oseltamivir (62.5% vs. 27%, p 0.016), corticosteroid treatment (50% vs. 21%, p 0.05), mechanical ventilation (MV) (50% vs. 12.5%, p 0.004), and longer stay (34 vs. 7 median days, p 0.003). Multivariate analysis revealed the factors independently associated with PVS to be immunosuppression (OR 5.15; 95% CI 1.2-22.2; p 0.03) and the need for MV (OR 11.7; 95% CI 2.5-54.4; p 0.002). VL at diagnosis correlated negatively with age and septic shock. VL dynamics of patients with acute respiratory distress syndrome and/or mortality were very different from those of other patients. PVS was detected in 25% of hospitalized patients with pandemic 2009 influenza A(H1N1) and was strongly associated with immunosuppression and the need for MV. Diagnostic VL and viral clearance varied with the clinical course.

ABSTRACT Aspergillus fumigatus complex comprises A. fumigatus and other morphologically indistinguishable cryptic species. We retrospectively studied 362 A. fumigatus complex isolates (353 samples) from 150 patients with proven or probable invasive aspergillosis or aspergilloma (2, 121, and 6 samples, respectively) admitted to the hospital from 1999 to 2011. Isolates were identified using the β-tubulin gene, and only 1 isolate per species found in each sample was selected. Antifungal susceptibility to azoles was determined using the CLSI M38-A2 procedure. Isolates were considered resistant if they showed an MIC above the breakpoints for itraconazole, voriconazole, or posaconazole (&gt;2, &gt;2, or &gt;0.5 μg/ml). Most of the samples yielded only 1 species ( A. fumigatus [ n = 335], A. novofumigatus [ n = 4], A. lentulus [ n = 3], A. viridinutans [ n = 1], and Neosartorya udagawae [ n = 1]). The remaining samples yielded a combination of 2 species. Most of the patients were infected by a single species ( A. fumigatus [ n = 143] or A. lentulus [ n = 2]). The remaining 5 patients were coinfected with multiple A. fumigatus complex species, although A. fumigatus was always involved; 4 of the 5 patients were diagnosed in 2009 or later. Cryptic species were less susceptible than A. fumigatus . The frequency of resistance among A. fumigatus complex and A. fumigatus to itraconazole, voriconazole, and posaconazole was 2.5 and 0.3%, 3.1 and 0.3%, and 4.2 and 1.8%, respectively, in the per-isolate analysis and 1.3 and 0.7%, 2.6 and 0.7%, and 6 and 4% in the per-patient analysis. Only 1 of the 6 A. fumigatus isolates in which the cyp51A gene was sequenced had a mutation at position G448. The proportion of patients infected by azole-resistant A. fumigatus isolates was low.

These guidelines are an update of the recommendations of the Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC) that were issued in 2004 (Enferm Infecc Microbiol Clin. 2004, 22:32-9) on the treatment of Invasive Candidiasis and infections produced by other yeasts. This 2010 update includes a comprehensive review of the new drugs that have appeared in recent years, as well as the levels of evidence for recommending them. These guidelines have been developed following the rules of the SEIMC by a working group composed of specialists in infectious diseases, clinical microbiology, critical care medicine, paediatrics and oncology-haematology. It provides a series of general recommendations regarding the management of invasive candidiasis and other yeast infections, as well as specific guidelines for prophylaxis and treatment, which have been divided into four sections: oncology-haematology, solid organ transplantation recipients, critical patients, and paediatric patients.

Frequency of enterococcal bloodstream infection (E-BSI) is increasing, and the number of episodes complicated by infective endocarditis (IE) varies. Performing transesophageal echocardiography (TEE) in all patients with E-BSI is costly and time-consuming. Our objectives were to identify patients with E-BSI who are at very low risk of enterococcal IE (and therefore do not require TEE) and to compare the outcome of E-BSI in patients with/without IE.Between September 2003 and October 2012, we performed a prospective cohort study (all patients with E-BSI) and a case-control study (patients with/without enterococcal IE) in our center.We detected 1515 patients with E-BSI and 65 with enterococcal IE (4.29% of all episodes of E-BSI, 16.7% of patients with E-BSI who underwent transthoracic echocardiography, and 35.5% of all patients with E-BSI who underwent TEE). We developed a bedside predictive score for enterococcal IE-Number of positive blood cultures, Origin of the bacteremia, previous Valve disease, Auscultation of heart murmur (NOVA) score-based on the following variables: Number of positive blood cultures (3/3 blood cultures or the majority if more than 3), 5 points; unknown Origin of bacteremia, 4 points; prior heart Valve disease, 2 points; Auscultation of a heart murmur, 1 point (receiver operating characteristic = 0.83). The best cutoff corresponded to a score ≥4 (sensitivity, 100%; specificity, 29%). A score <4 points suggested a very low risk for enterococcal IE and that TEE could be obviated.Enterococcal IE may be more frequent than generally thought. Depending on local prevalence of endocarditis, application of the NOVA score may safely obviate echocardiography in 14%-27% of patients with E-BSI.

Patients with pneumonia treated in the internal medicine department (IMD) are often at risk of healthcare-associated pneumonia (HCAP). The importance of HCAP is controversial. We invited physicians from 72 IMDs to report on all patients with pneumonia hospitalized in their department during 2 weeks (one each in January and June 2010) to compare HCAP with community-acquired pneumonia (CAP) and hospital-acquired pneumonia (HAP). We analysed 1002 episodes of pneumonia: 58.9% were CAP, 30.6% were HCAP and 10.4% were HAP. A comparison between CAP, HCAP and HAP showed that HCAP patients were older (77, 83 and 80.5 years; p < 0.001), had poorer functional status (Barthel 100, 30 and 65; p < 0.001) and had more risk factors for aspiration pneumonia (18, 50 and 34%; p < 0.001). The frequency of testing to establish an aetiological diagnosis was lower among HCAP patients (87, 72 and 79; p < 0.001), as was adherence to the therapeutic recommendations of guidelines (70, 23 and 56%; p < 0.001). In-hospital mortality increased progressively between CAP, HCAP and HAP (8, 19 and 27%; p < 0.001). Streptococcus pneumoniae was the main pathogen in CAP and HCAP. Pseudomonas aeruginosa and methicillin-resistant Staphylococcus aureus (MRSA) caused 17 and 12.3% of HCAP. In patients with a confirmed aetiological diagnosis, the independent risk factors for pneumonia due do difficult-to-treat microorganisms (Enterobacteriaceae, P. aeruginosa or MRSA) were HCAP, chronic obstructive pulmonary diseases and higher Port Severity Index. Our data confirm the importance of maintaining high awareness of HCAP among patients treated in IMDs, because of the different aetiologies, therapy requirements and prognosis of this population.

ABSTRACT Candida infective endocarditis is a rare disease with a high mortality rate. Our understanding of this infection is derived from case series, case reports, and small prospective cohorts. The purpose of this study was to evaluate the clinical features and use of different antifungal treatment regimens for Candida infective endocarditis. This prospective cohort study was based on 70 cases of Candida infective endocarditis from the International Collaboration on Endocarditis (ICE)-Prospective Cohort Study and ICE-Plus databases collected between 2000 and 2010. The majority of infections were acquired nosocomially (67%). Congestive heart failure (24%), prosthetic heart valve (46%), and previous infective endocarditis (26%) were common comorbidities. Overall mortality was high, with 36% mortality in the hospital and 59% at 1 year. On univariate analysis, older age, heart failure at baseline, persistent candidemia, nosocomial acquisition, heart failure as a complication, and intracardiac abscess were associated with higher mortality. Mortality was not affected by use of surgical therapy or choice of antifungal agent. A subgroup analysis was performed on 33 patients for whom specific antifungal therapy information was available. In this subgroup, 11 patients received amphotericin B-based therapy and 14 received echinocandin-based therapy. Despite a higher percentage of older patients and nosocomial infection in the echinocandin group, mortality rates were similar between the two groups. In conclusion, Candida infective endocarditis is associated with a high mortality rate that was not impacted by choice of antifungal therapy or by adjunctive surgical intervention. Additionally, echinocandin therapy was as effective as amphotericin B-based therapy in the small subgroup analysis.

ObjectivesPolymicrobial bloodstream infection (BSI) is an imprecisely defined entity purportedly associated with a worse outcome than monomicrobial BSI. This study examines trends in BSI episodes caused by bacteria and Candida spp. (mixed-BSI) in a large teaching hospital.

<h2>Abstract</h2><h3>Objectives</h3> To explore contemporary antibiotic management of infections caused by carbapenem-resistant Gram-negative bacteria in hospitals. <h3>Methods</h3> Cross-sectional, internet-based questionnaire survey. We contacted representatives of all hospitals with more than 800 acute-care hospital beds in France, Greece, Israel, Italy, Kosovo, Slovenia, Spain and selected hospitals in the USA. We asked respondents to describe the most common actual practice at their hospital regarding management of carbapenem-resistant <i>Enterobacteriaceae</i>, <i>Acinetobacter baumannii</i> and <i>Pseudomonas aeruginosa</i> through close-ended questions. <h3>Results</h3> Between January and June 2017, 115 of 141 eligible hospitals participated (overall response rate 81.6%, country-specific rates 66.7%–100%). Most were tertiary-care (99/114, 86.8%), university-affiliated (110/115, 89.1%) hospitals and most representatives were infectious disease specialists (99/115, 86.1%). Combination therapy was prescribed in 114/115 (99.1%) hospitals at least occasionally. Respondents were more likely to consider combination therapy when treating bacteraemia, pneumonia and central nervous system infections and for <i>Enterobacteriaceae</i>, <i>P. aeruginosa</i> and <i>A. baumannii</i> similarly. Combination of a polymyxin with a carbapenem was used in most cases, whereas combinations of a polymyxin with tigecycline, an aminoglycoside, fosfomycin or rifampicin were also common. Monotherapy was used for treatment of complicated urinary tract infections, usually with an aminoglycoside or a polymyxin. The intended goal of combination therapy was to improve the effectiveness of the treatment and to prevent development of resistance. In general, respondents shared the misconception that combination therapy is supported by strong scientific evidence. <h3>Conclusions</h3> Combination therapy was the preferred treatment strategy for infections caused by carbapenem-resistant Gram-negative bacteria among hospital representatives, even though high-quality evidence for carbapenem-based combination therapy is lacking.

The prognostic factors and optimal therapy for invasive pulmonary aspergillosis (IPA) after kidney transplantation (KT) remain poorly studied. We included in this multinational retrospective study 112 recipients diagnosed with probable (75.0% of cases) or proven (25.0%) IPA between 2000 and 2013. The median interval from transplantation to diagnosis was 230 days. Cough, fever, and expectoration were the most common symptoms at presentation. Bilateral pulmonary involvement was observed in 63.6% of cases. Positivity rates for the galactomannan assay in serum and bronchoalveolar lavage samples were 61.3% and 57.1%, respectively. Aspergillus fumigatus was the most commonly identified species. Six- and 12-week survival rates were 68.8% and 60.7%, respectively, and 22.1% of survivors experienced graft loss. Occurrence of IPA within the first 6 months (hazard ratio [HR]: 2.29; p-value = 0.027) and bilateral involvement at diagnosis (HR: 3.00; p-value = 0.017) were independent predictors for 6-week all-cause mortality, whereas the initial use of a voriconazole-based regimen showed a protective effect (HR: 0.34; p-value = 0.007). The administration of antifungal combination therapy had no apparent impact on outcome. In conclusion, IPA entails a dismal prognosis among KT recipients. Maintaining a low clinical suspicion threshold is key to achieve a prompt diagnosis and to initiate voriconazole therapy.

A prospective, population-based surveillance on candidaemia was implemented in five metropolitan areas of Spain from May 2010 to April 2011. We aimed to describe the distribution and susceptibility pattern of Candida species, and to evaluate risk factors for mortality in patients with oncological (solid tumours) and haematological malignancies. Adults (≥16 years) with cancer were included in the present report. Impact of therapeutic strategies on 7- and 30-day mortality were analysed by logistic regression, adjusting for propensity score by inverse weighting probability of receiving early antifungal treatment and catheter removal. We included 238 (32.6%) patients (195 oncological, 43 haematological). Compared with oncological patients, haematological patients were more likely to have received chemotherapy (53.5% versus 17.4%, p < 0.001) or corticosteroids (41.9% versus 21%, p < 0.001), and have neutropenia (44.2% versus 1.5%, p < 0.001). Overall, 14.8% of patients developed breakthrough candidaemia. Non-albicans Candida species (71.1% versus 55.6%, p 0.056) and Candida tropicalis (22.2% versus 7.6%, p 0.011) were more frequent in haematological patients. Based on EUCAST breakpoints, 27.6% of Candida isolates were non-susceptible to fluconazole. Resistance to echinocandins was negligible. Mortality at 7 and 30 days was 12.2% and 31.5%, respectively, and did not differ significantly between the patient groups. Prompt antifungal therapy together with catheter removal (≤48 hours) was associated with lower mortality at 7 days (adjusted OR 0.05; 95% CI 0.01–0.42) and 30 days (adjusted OR 0.27; 95% CI 0.16–0.46). In conclusion, non-albicans species are emerging as the predominant isolates, particularly in haematological patients. Prompt, adequate antifungal treatment plus catheter removal may lead to a reduction in mortality.

Streptococcus pneumoniae is an infrequent cause of severe infectious endocarditis (IE). The aim of our study was to describe the epidemiology, clinical and microbiological characteristics, and outcome of a series of cases of S. pneumoniae IE diagnosed in Spain and in a series of cases published since 2000 in the medical literature. We prospectively collected all cases of IE diagnosed in a multicenter cohort of patients from 27 Spanish hospitals (n = 2539). We also performed a systematic review of the literature since 2000 and retrieved all cases with complete clinical data using a pre-established protocol. Predictors of mortality were identified using a logistic regression model. We collected 111 cases of pneumococcal IE: 24 patients from the Spanish cohort and 87 cases from the literature review. Median age was 51 years, and 23 patients (20.7%) were under 15 years. Men accounted for 64% of patients, and infection was community-acquired in 96.4% of cases. The most important underlying conditions were liver disease (27.9%) and immunosuppression (10.8%). A predisposing heart condition was present in only 18 patients (16.2%). Pneumococcal IE affected a native valve in 93.7% of patients. Left-sided endocarditis predominated (aortic valve 53.2% and mitral valve 40.5%). The microbiological diagnosis was obtained from blood cultures in 84.7% of cases. In the Spanish cohort, nonsusceptibility to penicillin was detected in 4.2%. The most common clinical manifestations included fever (71.2%), a new heart murmur (55%), pneumonia (45.9%), meningitis (40.5%), and Austrian syndrome (26.1%). Cardiac surgery was performed in 47.7% of patients. The in-hospital mortality rate was 20.7%. The multivariate analysis revealed the independent risk factors for mortality to be meningitis (OR, 4.3; 95% CI, 1.4-12.9; P < 0.01). Valve surgery was protective (OR, 0.1; 95% CI, 0.04-0.4; P < 0.01). Streptococcus pneumoniae IE is a community-acquired disease that mainly affects native aortic valves. Half of the cases in the present study had concomitant pneumonia, and a considerable number developed meningitis. Mortality was high, mainly in patients with central nervous system (CNS) involvement. Surgery was protective.