Objectives: To define standardized endpoints to aid the design of trials that compare antibiotic therapies for bloodstream infections (BSI).Methods: Prospective studies, randomized trials or registered protocols comparing antibiotic therapies for BSI, published from 2005 to 2016, were reviewed. Consensus endpoints for BSI studies were defined using a modified Delphi process.Results: Different primary and secondary endpoints were defined for pilot (small-scale studies designed to evaluate protocol design, feasibility and implementation) and definitive trials (larger-scale studies designed to test hypotheses and influence clinical practice), as well as for Staphylococcus aureus and Gram-negative BSI. For pilot studies of S. aureus BSI, a primary outcome of success at day 7 was defined by: survival, resolution of fever, stable/improved Sequential Organ Failure Assessment (SOFA) score and clearance of blood cultures, with no microbiologically confirmed failure up to 90 days. For definitive S. aureus BSI studies, a primary outcome of success at 90 days was defined by survival and no microbiologically confirmed failure. For pilot studies of Gram-negative BSI, a primary outcome of success at day 7 was defined by: survival, resolution of fever and symptoms related to BSI source, stable or improved SOFA score and negative blood cultures. For definitive Gram-negative BSI studies, a primary outcome of survival at 90 days supported by a secondary outcome of success at day 7 (as previously defined) was agreed.Conclusions: These endpoints provide a framework to aid future trial design. Further work will be required to validate these endpoints with respect to patient-centred clinical outcomes. (C) 2016 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

OBJECTIVE:The management of infective endocarditis (IE) may differ from international guidelines, even in reference centres. This is probably because most recommendations are not based on hard evidence, so the consensus obtained for the guidelines does not represent actual practices. For this reason, we aimed to evaluate this question in the particular field of antibiotic therapy. METHODS:Thirteen international centres specialized in the management of IE were selected, according to their reputation, clinical results, original research publications and quotations. They were asked to detail their actual practice in terms of IE antibiotic treatment in various bacteriological and clinical situations. They were also asked to declare their IE-related in-hospital mortality for the year 2015. RESULTS:The global compliance with guidelines concerning antibiotic therapy was 58%, revealing the differences between theoretical 'consensus', local recommendations and actual practice. Some conflicts of interest were also probably expressed. The adherence to guidelines was 100% when the protocol was simple, and decreased with the seriousness of the situation (Staphylococus spp. 54%-62%) or in blood-culture-negative endocarditis (0%-15%) that requires adaptation to clinical and epidemiological data. CONCLUSION:Worldwide experts in IE management, although the majority of them were involved and co-signed the guidelines, do not follow international consensus guidelines on the particular point of the use of antibiotics.

BACKGROUND:Treatment of chronic hepatitis B (CHB) with polymerase inhibitors is key to prevent disease flares and progression toward advanced liver disease. Efficacy and tolerability of newer agents has been reported anecdotally in transplant recipients.METHODS:In this prospective, observational study, we assessed outcomes of therapy with tenofovir (TDF), entecavir (ETV), and telbivudine (LdT) in 13 heart transplant recipients (HTR) with CHB.RESULTS:Most patients were hepatitis B e antigen negative, had low baseline hepatitis B virus (HBV) DNA, and normal aminotransferases. Liver biopsy showed a median fibrosis score of 1.5 (range 0-4). Glomerular filtration rate (GFR) was <50 mL/min in 7 patients (54%). Two patients were started on de novo ETV before transplant. Eleven previously treated patients were switched to TDF (n = 9) or LdT (n = 2). Median treatment duration was 33 months (range 1-71). HBV DNA remained suppressed in 6 patients and became undetectable in 5. Aminotransferases went down to the normal range in all patients, with a single flare in 1 patient. One patient lost hepatitis B surface antigen. No cases occurred of hepatic decompensation, hepatocellular carcinoma, or liver-related death. The GFR remained largely stable, and no cases of TDF-related hyper-phosphaturia were observed.CONCLUSIONS:This study indicates that newer antivirals are effective and safe in HTR with CHB.

Yellow nail syndrome is a rare cause of edema due to a disordered lymphatic drainage. We recently observed two cases of long-standing, chronic edema, whose nature could not be understood despite innumerable diagnostic procedures. The diagnosis was suspected based on an attentive clinical exam and confirmed by radionuclide lymph scan. Yellow nail syndrome has to be considered in the differential diagnosis in cases of systemic edema, as well as long standing pleural effusions, particularly in patients with bronchiectasis or sinusitis. Clues to diagnosis are the presence of dystrophic, yellowish nails, peripheral lymphedema and relapsing pleural effusions and/or ascites. Long-term control of symptoms is difficult to achieve and may benefit from the judicious use of diuretics and intravenous albumin and by topical alpha-tocopherol. Pleurodesis may be needed. Other pathologic conditions are often associated to yellow nail syndrome and should be ruled out.

Few data have been published regarding the epidemiology and outcome of infective endocarditis (IE) in patients with chronic hepatic disease (CHD). A retrospective analysis of the Studio Endocarditi Italiano (SEI) database was performed to evaluate the epidemiology and outcome of CHD+ patients compared with CHD− patients. The diagnosis of IE was defined in accordance with the modified Duke criteria. Echocardiography, diagnosis, and treatment procedures were in accordance with current clinical practice. Among the 1722 observed episodes of IE, 300 (17.4 %) occurred in CHD+ patients. The cause of CHD mainly consisted of chronic viral infection. Staphylococcus aureus was the most common bacterial species in CHD+ patients; the frequency of other bacterial species (S. epidermidis, streptococci, and enterococci) were comparable among the two groups. The percentage of patients undergoing surgery for IE was 38.9 in CHD+ patients versus 43.7 in CHD− patients (p = 0.06). Complications were more common among CHD+ patients (77 % versus 65.3 %, p < 0.001); embolization (43.3 % versus 26.1 %, p < 0.001) and congestive heart failure (42 % versus 34.1 %, p = 0.01) were more frequent among CHD+ patients. Mortality was comparable (12.5 % in CHD− and 15 % in CHD+ patients). At multivariable analysis, factors associated with hospital-associated mortality were having an infection sustained by S. aureus, a prosthetic valve, diabetes and a neoplasia, and CHD. Being an intravenous drug user (IVDU) was a protective factor and was associated with a reduced death risk. CHD is a factor worsening the prognosis in patients with IE, in particular in patients for whom cardiac surgery was required.

The study aimed to prospectively assess incidence and risk factors for colistin-associated nephrotoxicity. This is a secondary analysis of a multicentre, randomized clinical trial, comparing efficacy and safety of colistin versus the combination of colistin plus rifampicin in severe infections due to extensively drug-resistant (XDR) Acinetobacter baumannii. The primary end point was acute kidney injury (AKI) during colistin treatment, assessed using the AKI Network Criteria, and considering death as a competing risk. A total of 166 adult patients without baseline kidney disease on renal replacement therapy were studied. All had life-threatening infections due to colistin-susceptible XDR A. baumannii. Patients received colistin intravenously at the same initial dose (2 million international units (MIU) every 8 h) with predefined dose adjustments according to the actual renal function. Serum creatinine was measured at baseline and at days 4, 7, 11, 14 and 21 (or last day of therapy when discontinued earlier). Outcomes assessed were 'time to any kidney injury' (AKI stages 1-3) and 'time to severe kidney injury' (considering only AKI stages 2e3 as events). When evaluating overall mortality, AKI occurrence was modelled as a time-dependent variable. AKI was observed in 84 patients (50.6%, stage 1 in 40.4%), with an incidence rate of 5/100 person-days (95% CI 4-6.2). Risk estimates of AKI at 7 and 14 days were 30.6% and 58.8%. Age and previous chronic kidney disease were significantly associated with any AKI in multivariable analysis. Neither 'any' nor 'severe AKI' were associated with on-treatment mortality (p 0.32 and p 0.54, respectively). AKI occurs in one-third to one-half of colistin-treated patients and is more likely in elderly patients and in patients with kidney disease. As no impact of colistin-associated AKI on mortality was found, this adverse event should not represent a reason for withholding colistin therapy, whenever indicated. (C) 2016 Published by Elsevier Ltd on behalf of European Society of Clinical Microbiology and Infectious Diseases.

Infection with HIV may lead to the development of cardiomyopathy as improved antiretroviral regimens continue to prolong patient life. However, advanced therapeutic options, such as heart transplant, have until recently been precluded to HIV-positive persons. A favorable long-term outcome has been obtained after kidney or liver transplant in HIV-positive recipients fulfilling strict virological and clinical criteria. We recently reported the first heart transplant in a HIV-infected patient carried out in our center. In this article, we detail the major challenges we faced with the management of antiretroviral and immunosuppressive treatments over the first 3 years post-transplant. The patient had developed dilated cardiomyopathy while on antiretroviral treatment with zidovudine, lamivudine and efavirenz. He was in WHO Stage 1 of HIV infection and had normal CD4+ count and persistently undetectable HIV-RNA. In spite of cardiac resynchronization therapy and maximal drug therapy, the patient progressed to end stage heart failure, requiring heart transplant. He was placed on a standard immune suppressive protocol including cyclosporine A and everolimus. Despite its potential pharmacokinetic interaction with efavirenz, everolimus was chosen to reduce the long-term risk of opportunistic neoplasia. Plasma levels of both drugs were monitored and remained within the target range, although high doses of everolimus were needed. There were no infectious, neoplastic or metabolic complications during a 3-year follow-up. In summary, our experience supports previous data showing that cardiac transplantation should not be denied to carefully selected HIV patients. Careful management of drug interactions and adverse events is mandatory.

DHCR7 rs12785878, CYP2R1 rs10741657, and GC rs7041 single nucleotide polymorphisms.Results: DHCR7 GG genotype (p=0.003) and the severity of fibrosis (p=0.03) were independent factors associated with lower 25(OH)D serum levels in multiple linear regression analysis.Interestingly, 53.8% (7/13) of patients with DHCR7 GG genotype had severe liver fibrosis, compared to 27.1% (67/247) of those with DHCR7 TT/TG genotype (p=0.03),By multivariate logistic regression analysis, severe fibrosis was independently associated with older age (OR, 1.056; 95% CI, 1.023-1.089,p=0.001), low cholesterol (OR, 0.984; 95% CI, 0.974-0.994,p=0.002), high triglycerides (OR, 1.008; 95% CI, 1.002-1.015,p=0.01), low 25(OH)D (OR, 0.958; 95% CI, 0.919-0.999,p=0.04),DHCR7 GG genotype (OR, 4.222; 95% CI, p=0.03), moderate-severe steatosis (OR, 2.588; 95% CI, 1.355-4.943;p=0.004), and moderate-severe necroinflammatory activity (grading) (OR, 2.437; 95% CI, p=0.001).No associations were found between liver fibrosis and both CYP2R1 and GC genotypes. Conclusion:In G1CHC patients, GG homozygosis for DHCR7 gene and lower 25(OH)D levels are independently associated with the severity of liver fibrosis.

Background: Pegylated interferons (Peg-IFN) alpha 2a and alpha 2b show different pharmacokinetic properties, that affect absorption, serum half-life and excretion.Notwithstanding, both subtypes are still used indifferently for the treatment of hepatitis C in traditional dual combination as well as with newer agents.In this study, we assessed whether standard doses of Peg-IFN alpha 2a and 2b affect in a differential manner the early HCV viral kinetics.Methods: Patients with liver biopsy-proven, HCV-RNA+, chronic active hepatitis C undergone antiviral treatment with PR between 2007 and 2011 were studied.Histology grading and staging, IL28B status and viral genotype were analysed.HCV-RNA quantitation was performed by Cobas Taqman 5 minutes before treatment start and subsequently after 48/72 hours, 7, 14 and 28 days.Results: 187 patients were studied (median age 55 yrs, males 57%, cirrhosis 29%).85 patients (45%) received Peg-IFN alpha 2a, 102 (55%) Peg-IFN alpha 2b.The two groups were homogeneous for HCV genotype and well balanced for IL28B genotype distribution (Table 1).

Our results suggest that successful translation of this approach to humans could hold promise as one strategy to protect the liver graft from becoming infected with HCV.

BACKGROUND:The characteristics of patients with infective endocarditis (IE) vary significantly by region of the world. The aim of this study was to evaluate the contemporary epidemiology, characteristics, and outcome of IE in a large, nationwide cohort of Italian patients.METHODS:We conducted a prospective, observational study at 24 medical centers in Italy, including all the consecutive patients with a definite or possible diagnosis of IE (modified Duke criteria) admitted from January 2004 through December 2009. A number of clinical variables were collected through an electronic case report form and analyzed to comprehensively delineate the features of IE. We report the data on patients with definite IE.RESULTS:A total of 1,082 patients with definite IE were included. Of these, 753 (69.6%) patients had infection on a native valve, 277 (25.6%) on a prosthetic valve, and 52 (4.8%) on an implantable electronic device. Overall, community-acquired (69.2%) was more common than nosocomial (6.2%) or non-nosocomial (24.6%) health care-associated IE. Staphylococcus aureus was the most common pathogen (22.0%). In-hospital mortality was 15.1%. From the multivariate analysis, congestive heart failure (CHF), stroke, prosthetic valve infection, S. aureus, and health care-associated acquisition were independently associated with increased in-hospital mortality, while surgery was associated with decreased mortality.CONCLUSIONS:The current mortality of IE remains high, and is mainly due to its complications, such as CHF and stroke.

Background/aim. The combination of pegylated interferon (PEG-IFN) and ribavirin (RBV) is the current treatment for chronic hepatitis C (CHC). The treatment is thought to suppress viral replication and induce viral clearance via immunomodulatory effects. For this reason, concern exists for the use of this treatment in recipients of a solid organ transplantation. We sought to evaluate the safety and efficacy of PEG-IFN/RBV in heart transplant recipients with CHC.Methods. From June 2005 to September 2009, we treated three CHC patients with heart transplantation. PEG-IFN alpha2b and RBV doses and treatment duration were set according to the hepatitis C virus (HCV) genotype and body weight as per current recommendations. Dose reductions were dictated by individual patient tolerability. Cardiac safety was monitored by clinical examinations, echocardiography, and measurement of troponin I and B-type natriuretic peptide, as well as endomyocardial biopsies.Results. All three patients, displayed HCV genotype 1b infection, viral loads of >5 logs, and a Scheuer fibrosis score >= 2. Two of them completed the prescribed treatment course becoming sustained virological responders. The other patient had an initial complete virological response, but subsequently experienced a viral breakthrough after reduction of PEG-IFN and withdrawal of RBV due to severe anemia. We observed no cardiovascular adverse events nor rejection episodes. Posttreatment clinical history and examination, electrocardiography, and echocardiography did not show any sign of graft dysfunction.Conclusions. Treatment with PEG-IFN/RBV may be safely offered to stable heart transplant recipients with CHC and signs of liver disease progression. Close monitoring of treatment safety is mandatory.

Cardiac Implantable Electronic Device (CIED) infections are an emerging clinical issue. There are no national recommendations on the management of these infections, also due to the limited number of dedicated and high quality clinical studies. Therefore, researchers from southern Italian centres have decided to share the clinical experience gathered so far in this field and report practical recommendations for the diagnosis and treatment of adult patients with CIED infection or endocarditis. Here we review the risk factors, diagnostic issues (microbiological and echocardiographic) and aetiology, and describe extensively the best therapeutic approach. We also address the management of complications, follow-up after discharge and the prevention of CIED infections. In this regard, a multidisciplinary approach is fundamental to appropriately manage the initial diagnostic process and the comorbidities, to plan proper antimicrobial treatment and complete percutaneous hardware removal, with the key support of microbiology and echocardiography.

Bacterial infections are a contraindication to organ transplantation, but infective endocarditis may require heart transplantation when otherwise untreatable. We describe a heart transplant patient with cardiomyopathy and ongoing defibrillator endocarditis due to Staphylococcus epidermidis. An initial attempt at percutaneous extraction of the 5 implanted leads was unable to eradicate the infection and was complicated by severe decompensation, requiring a new implant for biventricular pacing. Despite continuing bactericidal treatment, the patient showed persistent infection on the implanted leads with further hemodynamic deterioration. The decision was therefore made to list the patient for heart transplantation. The procedure was successful in removing all of the hardware. No recurrence of infection was observed despite persistence of large vegetations on the removed defibrillator leads. The patient had an uneventful postoperative course, remaining free of symptoms with negative blood cultures at 3 months' follow-up. Our experience showed that active infection of defibrillator leads may not represent an absolute contraindication to heart transplantation when all other medical and surgical treatments have been proven to be ineffective.

BACKGROUND/OBJECTIVES:Pulmonary nocardiosis (PN) chiefly affects immunocompromised patients, particularly transplant recipients. Cotrimoxazole is still the mainstay of treatment, but it is associated with nephro- and myelo-toxicity, and can show unpredictable activity against Nocardia isolates.METHODS:Over a 20-year period, Nocardia isolates were identified from 12 heart transplant (HTx) recipients with PN. The in vitro activity of various antibacterials, alone or in combination, was assessed using disk-diffusion, minimal inhibitory concentration (MIC), and time-kill methodology. The in vitro results were compared with the clinical outcome of the patients.RESULTS:Seven different Nocardia strains were identified. Disk diffusion and MIC determinations showed that all isolates were susceptible to amikacin, netilmicin, and linezolid, and that moxifloxacin was the most active of the fluoroquinolones. All but 1 of the isolates were susceptible to imipenem. Time-kill studies showed that imipenem/amikacin and imipenem/moxifloxacin combinations were bactericidal for most isolates. Of 12 patients who received 3-4 weeks' intravenous (IV) treatment with amikacin or ciprofloxacin in combination with a beta-lactam, followed by 1-3 months' oral cotrimoxazole, moxifloxacin, or linezolid, 11 were cured; 1 patient died, but not related to Nocardia.CONCLUSION:Initial PN treatment in HTx recipients can be successfully carried out with bactericidal combinations such as imipenem plus amikacin or moxifloxacin, administered IV for 3-4 weeks. Within 1 month, a significant clinical and radiological improvement may be observed. In our experience, a <3 month oral regimen with cotrimoxazole, moxifloxacin, or doxycycline may then be used. This may allow a reduction of side effects and treatment-related burden, without any recurrence.