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Recently, several cases of symptomatic, sometimes fatal bradycardia during the first days of direct-acting antiviral (DAA) (eg, sofosbuvir [SOF]) administration have been reported. We analyzed in detail electrocardiographic (ECG) changes during SOF- or non-SOF-based chronic hepatitis C (CHC) treatment, specifically focusing on bradyarrhythmias. All 39 consecutive patients treated at our center with any interferon-free regimen between June and December 2015 were included in this study (26 SOF-based therapy vs 13 no-SOF interferon-free regimens). ECG tracings were obtained from all patients the first day of treatment and after 7, 14, and 28 days. ECG parameters (P-wave, QRS, QT interval, JT interval, Tapex -Tend interval duration) were compared between the 2 groups at baseline and at the 3 different time points during antiviral therapy. There were no cases of symptomatic bradycardia/syncope. In the SOF group, QTc duration rose after 1 week (from 424.3 to 431.2 milliseconds; P = .013) and returned to baseline during therapy. QT dispersion dropped since week 1 (from 85.6 to 67.2 milliseconds) and remained significantly reduced until the end of the observation period (72.9 msec) (P = .003). JT dispersion reduced up to week 2 (P = .010) and returned to baseline at week 4; in the no-SOF group, QRS dispersion transiently reduced (from 41 to 34.5 milliseconds, day 7). No other significant changes were observed in the remaining parameters. In CHC patients treated with SOF and other DAAs, ECG parameter changes were mild and/or transient and did not translate into clinically significant electrophysiological effects in the absence of amiodarone coadministration.

Daptomycin is commonly used at doses >6 mg/kg/day for various indications, including infective endocarditis (IE). A systematic assessment of skeletal muscle, renal, haematological, hepatic and pulmonary toxicity of high-dose daptomycin (HDD) in IE is lacking. A total of 102 IE patients treated with HDD were included in this non-comparative, observational, single-centre cohort study conducted from 2007 to 2014. The incidence, timing, severity and evolution of adverse events (AEs) were assessed. Patients had a median age of 61.5 years and a high prevalence of co-morbidities. Staphylococci were cultured in 87.2% of cases (62.2% meticillin-resistant). The median daptomycin dose was 8.2 mg/kg/day for a median of 20 days (range, 1–60 days). HDD was withdrawn due to AEs in 12 patients (11.8%). On-treatment death occurred in 4 cases (3.9%, none HDD-related). Muscle toxicity occurred in 15 patients in a median of 15 days after HDD starts, which was largely mild and reversible with ongoing HDD use. Mild renal toxicity was observed in 9 patients (8.8%) after a median of 12 days of HDD (RIFLE—Risk in 8, Injury in 1). A rise of peripheral blood eosinophils occurred in 16 patients (15.7%). There were three cases of eosinophilic interstitial pneumonia. Four patients (3.9%) had mild allergic or idiosyncratic reactions. No other hepatic or haematological AEs were observed. Our current experience with 102 patients suggests that HDD is safe in significantly ill IE patients with multiple co-morbidities. Muscle toxicity was clinically negligible. Most importantly, there was no significant renal toxicity. Eosinophils should be carefully monitored.

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

Gram-positive bacteria, especially methicillin-resistant Staphylococcus aureus (MRSA), are known to be common pathogens in children and adolescents in both healthcare and community-associated infections.1–3 Treatment of resistant pathogens including MRSA and vancomycin-resistant enterococci remains challenging even with standard antimicrobial protocols.4–6 Higher mortality has been reported because of MRSA infections than infections caused by methicillin-susceptible S. aureus.7,8 Several treatment options are available for the management of MRSA infections in adults; however, these options are limited for pediatric patients owing to a lack of sufficient safety and efficacy data.1 Clindamycin, vancomycin and linezolid are currently the only antibiotics approved by the US Food and Drug Administration for the management of MRSA infections in pediatric patients.1 Daptomycin is a cyclic lipopeptide that is active against a wide range of Gram-positive bacteria. Its mechanism of action involves calcium-dependent binding to the bacterial cell membrane, resulting in rapid depolarization of the membrane potential and bacterial cell death, without cell lysis and release of inflammatory mediators.9,10 Daptomycin is a concentration-dependent bactericidal agent indicated for the treatment of adult patients with complicated skin and soft-tissue infection (cSSTI), right-sided endocarditis caused by S. aureus, and bacteremia associated with cSSTI or right-sided endocarditis.11 Daptomycin is not approved for the treatment of pediatric patients,12 and limited data are currently available regarding its use in the treatment of Gram-positive infections in this population.1 A few case reports and retrospective studies have described that use of daptomycin is beneficial in treating Gram-positive infections in children.2,12 The European Cubicin Outcomes Registry and Experience (EU-CORESM) study was a retrospective, noninterventional registry developed to collect real-world data on the use of daptomycin in the treatment of patients with Gram-positive infections. This subgroup analysis evaluated the safety and effectiveness of daptomycin in children and adolescent patients from the EU-CORE study.

The classical pegylated interferon α (peg-IFNα) and ribavirin (RBV) treatment of chronic hepatitis C (CHC) is progressively being replaced by new direct acting antivirals, whose costs remain a major barrier to widespread use. Using baseline data and viral kinetics, we developed a predictive algorithm to allocate to DAA patients who are not going to respond to peg-IFNα/RBV. This prospective study evaluated 205 CHC patients treated with peg-IFNα/RBV. HCVRNA kinetics during the initial 3 days of therapy and baseline variables including age, genotype, fibrosis and ALTs were used to construct a prediction rule in terms of sustained virological response (SVR). One hundred and twenty-one patients achieved an SVR (59%). Variables independently associated with SVR were HCVRNA, ALT, glycaemia, viral genotype, and fibrosis. The decline of viremia from baseline to 48/72 h was significantly different in SVR compared to non-SVR patients (2.2 vs. 0.65 log10 IU/mL; p 1.2 logs had a positive predictive value of 92%. A combination of HCVRNA kinetics and a score based on pre-treatment parameters was highly accurate in predicting SVR in most patients. Outcome of peg-IFNα/RBV treatment may be predicted combining evaluation of baseline variables and HCVRNA kinetics. This allows to individualize treatment, reserving newer and more expensive DAAs to CHC patients who are in most need of them.

Background: Recent scientific reports have shown that older persons treated with antipsychotics for dementia-related behavioural symptoms have increased mortality. However, the impact of these drugs prescribed during hospitalization has rarely been assessed. We aimed to investigate whether antipsychotics are associated with an increased risk of mortality during hospitalization and at 3-month follow-up in elderly inpatients. Methods: We analyzed data gathered during two waves (2010 and 2012) by the REPOSI (Registro Politerapie Società Italiana Medicina Interna). All new prescriptions of antipsychotic drugs during hospitalization, whether maintained or discontinued at discharge, were collected, and logistic regression models were used to analyze their association with in-hospital and 3-month mortality. Covariates were age, sex, the Short Blessed Test (SBT) score, and the Cumulative Illness Rating Scale. Results: Among 2703 patients included in the study, 135 (5%) received new prescriptions for antipsychotic drugs. The most frequently prescribed antipsychotic during hospitalization and eventually maintained at discharge was haloperidol (38% and 36% of cases, respectively). Patients newly prescribed with antipsychotics were older and had a higher Cumulative Illness Rating Scale comorbidity index both at admission and at discharge compared to those who did not receive a prescription. Of those prescribed antipsychotics, 71% had an SBT score ≥10 (indicative of dementia), 12% had an SBT score of 5-9 (indicative of questionable dementia); and 17% had an SBT score

Background Infective endocarditis (IE) due to gram-negative (GN) bacilli is uncommon. Although multi- and extensively-drug resistant (MDR/XDR) GN infections are emerging, very few data are available on IE due to these microrganisms. Methods In this study, we describe the clinical characteristics, course and outcome of five contemporary, definite, MDR/XDR GNIE cases seen at our centre. Results All patients had been admitted to a hospital during the 6 months before IE onset, 2 were on hemodialysis and 3 on intravenous medications. Three of the 5 cases were hospital-acquired. Intracardiac prosthetic devices were present in all cases (3 central venous lines, 2 prosthetic heart valves, 2 pacemakers). Mean Charlson comorbidity index was 5.8. Causative pathogens were XDR Pseudomonas aeruginosa (2 cases), XDR Acinetobacter baumannii, MDR Burkolderia cepacia and MDR Escherichia coli (1 case each). Concomitant pathogens with a MDR/XDR phenotype were isolated in 4 patients. Both valves and intracardiac devices and left and right sides of the heart were involved. The rate of complications was high. Antibiotic treatment hinged on the use of colistin, a carbapenem or both. Cardiovascular surgical procedures were performed in 3 patients. Despite aggressive therapeutic regimens, outcomes were poor. Clearance of bacteremia was obtained in 3 patients, in-hospital death occurred in 3 patients, only 1 patient survived during follow up. Conclusions MDR/XDR GN are emerging as a cause of IE in carriers of intracardiac prostheses with extensive healthcare contacts and multiple comorbidities. Resistant GNIE has a complicated course and shows a dismal prognosis.

ABSTRACT: Acinetobacter baumannii is a drug-resistant Gram-negative pathogen increasingly causing hospital-acquired infections in critically ill patients. In this review, we summarize the current mechanisms of antimicrobial resistance in A. baumannii and describe in detail recent in vitro and in vivo experimental data on the activity of antimicrobial combinations against this microorganism. We then introduce the rationale for the use of combination antibiotic therapy in resistant A. baumannii infections. Finally, we present and critically discuss both uncontrolled clinical studies and the few randomized clinical trials of combination antimicrobial therapy for these infections, with a special focus on ongoing multinational trials and optimal approach to future research in this field.

Background Extensively drug-resistant (XDR) Acinetobacter baumannii may cause serious infections in critically ill patients. Colistin often remains the only therapeutic option. Addition of rifampicin to colistin may be synergistic in vitro. In this study, we assessed whether the combination of colistin and rifampicin reduced the mortality of XDR A. baumannii infections compared to colistin alone. Methods This multicenter, parallel, randomized, open-label clinical trial enrolled 210 patients with life-threatening infections due to XDR A. baumannii from intensive care units of 5 tertiary care hospitals. Patients were randomly allocated (1:1) to either colistin alone, 2 MU every 8 hours intravenously, or colistin (as above), plus rifampicin 600 mg every 12 hours intravenously. The primary end point was overall 30-day mortality. Secondary end points were infection-related death, microbiologic eradication, and hospitalization length. Results Death within 30 days from randomization occurred in 90 (43%) subjects, without difference between treatment arms (P = .95). This was confirmed by multivariable analysis (odds ratio, 0.88 [95% confidence interval, .46-1.69], P = .71). A significant increase of microbiologic eradication rate was observed in the colistin plus rifampicin arm (P = .034). No difference was observed for infection-related death and length of hospitalization. Conclusions In serious XDR A. baumannii infections, 30-day mortality is not reduced by addition of rifampicin to colistin. These results indicate that, at present, rifampicin should not be routinely combined with colistin in clinical practice. The increased rate of A. baumannii eradication with combination treatment could still imply a clinical benefit. Clinical trials registration NCT01577862.

Chronic hepatitis B is prevalent in the transplant setting and may cause significant complications. Effective control of viral replication is needed. Besides lamivudine, very little data are available on safety and efficacy of other drugs. We describe our experience with adefovir dipivoxil (ADV) in eight heart transplant recipients. Studies included a baseline liver biopsy, thrice-monthly clinical, biochemical, and virological evaluations, including genotyping and viral load, polymerase gene sequencing for resistance mutations, liver and kidney function tests, and liver ultrasound. Of eight patients, six had fibrosis score ≤2 and negative HBeAg and seven had hepatitis B virus (HBV) genotype D. Upon ADV start, median HBV-DNA was 5.8 logs IU/mL and alanine aminotransferase (ALT) levels were mostly normal. All patients had prior mild-to-moderate renal functional impairment. Seven of eight patients started ADV after a previous course of lamivudine. Five of these seven patients became HBV-DNA undetectable within eight months. One patient with low baseline viremia started ADV de novo and suppressed HBV-DNA. Median treatment duration was 66 months. ADV daily dose was halved in one patient due to renal function worsening. No ALT flares, hypophosphatemia, liver decompensation, liver cancer, or emergence of resistance was observed. Our data suggest that ADV may be a safe and effective rescue treatment for heart transplant recipients with lamivudine-resistant chronic hepatitis B.

[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., PH is supported by an Australian Postgraduate Award from the University of Queensland. VGF was supported by R01AI068804 from National Institutes of Health. KSK is supported by the National Institute of Allergy and Infectious Diseases (NIAID), DMID Protocol no. 10-0065 and R01AI119446. ACC and AYP were supported by an Australian National Health and Medical Research Council Career Development Fellowship. HS receives funding from the German Centre for Infection Research (DZIF), Germany. JRB receives funding for research from Ministerio de Economía y Competitividad, Instituto de Salud Carlos III—co-financed by European Development Regional Fund ‘A way to achieve Europe' ERDF, Spanish Network for the Research in Infectious Diseases (REIPI RD12/0015). JRB and MP receive funding from Innovatives Medicine Initiative (IMI), European Union's Seventh Framework Programme (FP7/2007-2013) and EFPIA companies (COMBACTE, COMBACTE-CARE and COMBACTE-MAGNET projects, grant agreements 1155223, 115620 and 115737). RU and MP are supported by the European Union 7th Framework Programme (Project ‘AIDA’). SYCT is supported by an NHMRC Career Development Fellowship 1065736. JT received funding from NHMRC (Project Grant ID 1044941).

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 2–3 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.

Background Host factors and complications have been associated with higher mortality in infective endocarditis ( IE ). We sought to develop and validate a model of clinical characteristics to predict 6‐month mortality in IE . Methods and Results Using a large multinational prospective registry of definite IE (International Collaboration on Endocarditis [ ICE ]–Prospective Cohort Study [ PCS ], 2000–2006, n=4049), a model to predict 6‐month survival was developed by Cox proportional hazards modeling with inverse probability weighting for surgery treatment and was internally validated by the bootstrapping method. This model was externally validated in an independent prospective registry ( ICE ‐ PLUS , 2008–2012, n=1197). The 6‐month mortality was 971 of 4049 (24.0%) in the ICE ‐ PCS cohort and 342 of 1197 (28.6%) in the ICE ‐ PLUS cohort. Surgery during the index hospitalization was performed in 48.1% and 54.0% of the cohorts, respectively. In the derivation model, variables related to host factors (age, dialysis), IE characteristics (prosthetic or nosocomial IE , causative organism, left‐sided valve vegetation), and IE complications (severe heart failure, stroke, paravalvular complication, and persistent bacteremia) were independently associated with 6‐month mortality, and surgery was associated with a lower risk of mortality (Harrell's C statistic 0.715). In the validation model, these variables had similar hazard ratios (Harrell's C statistic 0.682), with a similar, independent benefit of surgery (hazard ratio 0.74, 95% CI 0.62–0.89). A simplified risk model was developed by weight adjustment of these variables. Conclusions Six‐month mortality after IE is ≈25% and is predicted by host factors, IE characteristics, and IE complications. Surgery during the index hospitalization is associated with lower mortality but is performed less frequently in the highest risk patients. A simplified risk model may be used to identify specific risk subgroups in IE .

Persons on hemodialysis (HD) are at high risk of infective endocarditis (IE). In non-comparative retrospective studies, a higher rate of mortality was reported in IE on HD. We assessed risk factors, clinical characteristics, and outcomes of IE in HD. This was a prevalence study with a case control methodology on a set of data from the prospectively followed cohort of the Studio Endocarditi Italiano (SEI), conducted between 2004 and 2011. Included were 42 consecutive cases of IE HD subjects and 126 controls not on HD, matched for age, sex, type of IE, and heart side involved. Clinical, echocardiographic, microbiological features, and disease complications and therapeutic modalities were assessed. HD patients were more often diabetics (42.9 vs 18.2 % in no-HD; p = 0.007) and immune-suppressed (16.7 vs 3.2 %; p = 0.02), and had a higher rate of predisposing cardiac conditions (45 vs 25 %; p = 0.031). A higher prevalence of health care-related acquisition and a shorter diagnostic delay was observed in IE on HD, that was more likely to be caused by staphylococci and less by streptococci (p

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.

Infective endocarditis (IE) is a complex infection associated with high mortality. Daptomycin, a cyclic lipopeptide antibiotic highly active against Gram-positive bacteria, has recently been incorporated into IE treatment guidelines. This retrospective analysis provides insights into the use of daptomycin in IE in the European Cubicin(®) Outcomes Registry Experience (EU-CORE(SM)) between 2006 and 2010.Three hundred and seventy-eight (10%) of 3621 enrolled patients received daptomycin for treatment of IE. Two hundred and fifty-nine (69%) had left-sided IE (LIE) and 182 patients (48%) underwent concomitant surgery.Staphylococcus aureus was the most frequently identified pathogen (n=92; methicillin susceptible, n=50) and daptomycin was used empirically in 134 patients. Among cases of second-line therapy (n=312), the most common reason for switching to daptomycin was failure of the previous regimen (including glycopeptides and penicillins). Daptomycin was administered at 6 mg/kg in 224 patients and at ≥ 8 mg/kg in 72 patients. Clinical success rates were 80% overall, 91% for right-sided IE (RIE) and 76% for LIE, with similar rates seen for infections caused by methicillin-susceptible S. aureus (84%) and methicillin-resistant S. aureus (81%). The clinical success rate in patients treated with ≥ 8 mg/kg daptomycin was 90% [n=72 (RIE, 91%; LIE, 89%)]. No new safety signals were observed.In patients with IE registered in EU-CORE, daptomycin was most frequently used as second-line treatment after treatment failure. The majority of patients had LIE and most commonly received daptomycin for the treatment of staphylococcal infections. Clinical success was high in this difficult-to-treat population. The role of doses ≥ 8 mg/kg per day in the empirical treatment of IE deserves further investigation.

The purpose of this study was to evaluate post-marketing efficacy and safety data for therapy with daptomycin (DAP) in Italy. Data from patients treated with DAP at 30 centres between January 2006 and July 2009 were analysed according to the protocol of the EU-CORE(SM). In 359 patients, DAP was most commonly prescribed for skin and skin-structure infections (55%), infective endocarditis (13%), and bacteraemia (12.5%). DAP was associated with rapid improvement, and clinical success rates ranging from 77 to 91%, despite almost half of the patient population being ≥65 years of age, 86% having significant underlying disease, and many being affected by drug-resistant pathogens. Staphylococcus aureus represented 35% of all pathogens isolated. Success rates for all staphylococcal and enterococcal infections were >80%, including methicillin-resistant S. aureus (MRSA) and methicillin-susceptible S. aureus (MSSA). Clinical outcomes were similar for DAP whether used as first- or second-line therapy. DAP was well tolerated even with prolonged treatment.

Use of rifampicin (RIF) in combination with colistin (COL) has been proposed for the treatment of multidrug-resistant Acinetobacter baumannii infections owing to in vitro synergism. The aim of the present study was to evaluate the molecular epidemiology and mechanisms of RIF resistance in 57 clinical isolates of A. baumannii in two tertiary care hospitals in Naples (Italy) from 2006 to 2010. Amongst the collection, 36 isolates showed high RIF minimum inhibitory concentrations (MICs) (256 mg/L to ≥512 mg/L), 16 showed intermediate MICs (8–16 mg/L) and 5 had low MICs (4 mg/L). Of the 36 isolates with elevated RIF MICs, 35 were assigned to sequence type ST2 and 1 to ST78. Amongst the 57 isolates, 35 carried at least one mutation in rpoB , including H535L in 9 isolates and double mutations D525N and P544L in 7 isolates, whilst 22 showed no rpoB mutations. Treatment with the efflux pump inhibitor phenyl-arginine-β-naphthylamide (PAβN) of resistant isolates with no mutations in rpoB and different RIF MICs reduced the MIC by >10-fold and restored the synergism between RIF and COL in time–kill studies, whilst it had no effect on strains carrying rpoB mutations. In conclusion, the emergence of elevated RIF MICs in A. baumannii isolates from our geographical area was mostly caused by mutations in rpoB ; low to intermediate RIF MICs were also caused by altered membrane permeability to the drug. The phenomenon was contributed by the selection of two prevalent clones both assigned to ST2 genotype. These data may have implications for the correct identification of cases with A. baumannii infection that would not benefit from addition of RIF to COL.

M.-F. Tripodi, E. Durante-Mangoni, R. Fortunato, S. Cuccurullo, Y. Mikami, C. Farina, R. Utili. In vitro activity of multiple antibiotic combinations against Nocardia: relationship with a shortterm treatment strategy in heart transplant recipients with pulmonary nocardiosis. Transpl Infect Dis 2010. All rights reserved 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

Co-infection with HBV and HCV seems to be associated with more severe liver disease in retrospective and cross-sectional studies in adults, but no data are available when co-infection is acquired in youth. The long-term outcome of infection acquired in youth was assessed in patients co-infected with HBV and HCV and in patients with HBV infection only. Twenty-seven patients with HBV and HCV co-infection and 27 patients infected with HBV only were enrolled. Seventy-six per cent of the patients were treated with alpha-interferon for 1 year. After a median follow-up of 23 years, the annual progression rate of fibrosis was 0.07 in patients co-infected with HBV and HCV, and in those infected with HBV it was 0.07 and 0.11 (P < 0.004) for HBe and anti-HBe-positive patients, respectively. In co-infected patients, the development of cirrhosis was observed in 2 (7.4%) and of hepatocellular carcinoma (HCC) in 1 (3.7%), while in those with HBV, cirrhosis appeared in one patient (3.7%). Alcohol intake (OR = 9.5 +/- 1.2; 95% CI = 6.6-13.9; P < 0.0001) was independently associated with cirrhosis and HCC. alpha-interferon showed no efficacy during treatment, but the treated group showed higher HCV RNA clearance during post-treatment follow-up. Co-infection with HBV and HCV and single HBV infection acquired in youth showed a low rate of progression to liver fibrosis, no liver failure, and low development of HCC during a median follow-up of 23 years (range 17-40).

Background Pneumocystis jiroveci pneumonia may be a life-threatening opportunistic infection in immunosuppressed solid organ transplant recipients. Despite effective treatment with high-dose trimethoprim-sulfamethoxazole and steroids, morbidity is often severe and lethality remains high. New therapeutic approaches are therefore warranted. Caspofungin, a beta-1,3-glucan synthesis inhibitor, has shown activity against the cyst forms of P. jiroveci in experimental animal models. We here report our preliminary clinical experience with caspofungin as an additional drug to the standard trimethoprim-sulfamethoxazole regimen. Methods Four solid organ transplant patients with severe hypoxemic P. jiroveci pneumonia were treated with the combination of trimethoprim-sulfametoxazole and caspofungin. In two cases, caspofungin was added as salvage treatment due to failure of trimethoprim-sulfametoxazole monotherapy. Results In these four patients, the use of caspofungin as an additional drug to the standard trimethoprim-sulfamethoxazole regimen led to a rapid improvement and a complete cure of pneumonia. No side effects or drug interactions were observed. Discussion This preliminary clinical experience suggests that the addition of caspofungin to trimethoprim-sulfamethoxazole, which is active against trophic forms, may provide a synergistic activity against P. jiroveci by fully inhibiting the organism life cycle.

Background Cytomegalovirus (CMV) infection is a major complication of immunosuppression after heart transplant. Recent studies suggest the actual immunosuppressive regimen may affect the risk of CMV infection. Objectives To evaluate incidence, risk factors and clinical consequences of CMV infection and assess the possible differential effect of distinct immunosuppressive protocols. Study design Single centre, prospective cohort study of 378 consecutive heart transplant recipients undergoing CMV monitoring. Preemptive treatment was the standard of care. Patients were grouped as follows: group A, without any CMV infection; group B, with CMV infection not requiring pre-emptive treatment; group C, treated for CMV infection or disease. Results Most recipients never required antiviral therapy because of no CMV infection/disease (group A, 31%) or CMV levels below the cut-off for pre-emptive treatment (group B, 28%). Group C recipients (41%) were significantly older than group A patients (49.1 ± 13.2 vs. 44.8 ± 15.1 years; p = 0.028). Most cases occurred within the second month post-transplant. CMV viremia was detected in 77% and 62% of patients primed with thymoglobulin or ATG Fresenius, respectively, (OR 2.06, 95% C.I. 1.27–3.34; p = 0.0034). Use of everolimus was associated with a significantly lower rate of CMV infection compared to azathioprine or mycophenolate (OR 0.19, 95% C.I. 0.09–0.39; p Conclusion In a large and homogeneous cohort of heart transplant recipients, we observed a strong relationship between the immune suppressive regimen and CMV infection, as well as an increased incidence of other opportunistic infections in recipients with CMV infection/disease.

International audience; Background - 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. Methods - 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. Results - 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). Conclusions - 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.

Background Pegylated-interferon-α (peg-IFN-α) is the mainstay of treatment for chronic hepatitis C (CHC). Treatment is often complicated by neutropaenia due to inhibition of haematopoiesis. However, there are no data on the kinetics of granulocyte-colony stimulating factor (G-CSF), a major neutrophil growth factor, in this setting. We therefore evaluated G-CSF synthesis in CHC patients on peg-IFN-α treatment. Methods A total of 40 CHC patients were studied. None had pre-existing haematological disorders, or hepatitis B virus or HIV coinfection. For controls, 30 healthy subjects were used. Laboratory examinations, including liver function tests, were performed at baseline and monthly over treatment and follow-up. Serum G-CSF was measured in all patients and controls at baseline and in a subgroup of 20 CHC patients also at weeks 2, 4, 24, 48 and 72 after treatment start. Results CHC patients had a significantly lower pre-treatment neutrophil count (3,256 ±1,197 versus 3,804 ±859; P=0.03). Notwithstanding, they showed lower baseline G-CSF serum levels than healthy controls (16.1 ±6.2 versus 19.4 ±7.5; P=0.048). Consistently, baseline G-CSF levels were poorly correlated with the neutrophil count in CHC patients (r=-0.2; P=0.2). Moreover, serum G-CSF levels did not increase in any of the 20 CHC patients during peg-IFN-α treatment, despite declining neutrophil counts. Conclusions The lower neutrophil counts observed in CHC might be related to an absolute deficiency in G-CSF production. In the human model of neutropaenia induced by peg-IFN-α, we show that endogenous G-CSF levels are not physiologically up-regulated to overcome the decline in neutrophil counts. Our study provides a rationale for the evaluation of recombinant human G-CSF treatment in peg-IFN-α-induced neutropaenia.

Clinical and epidemiological characteristics of Streptococcus bovis endocarditis were prospectively studied among 199 patients with definite endocarditis. Thirty patients (15.1%) had S. bovis endocarditis. Compared with patients with non–S. bovis endocarditis, these 30 patients were older (mean age, 58.6*12.4 years vs. 46.0*17.0 years; P < .001) and had higher rates of bivalvular involvement (43.3% vs. 7.7%; P

Antibodies against envelope glycoprotein 1 and 2 (anti-E1/E2) have been suggested to influence HCV replication levels. Hepatitis B virus (HBV) may interfere with hepatitis C virus (HCV) replication. At present there are no data on anti-E1/E2 antibody responses or on the effect of interferon (IFN) treatment in HBV–HCV co-infection. Accordingly, we evaluated serum anti-E1/E2 antibodies in 50 patients (median age, 26.5; males, 30) with chronic hepatitis, 38 with HCV and 12 with HBV–HCV co-infection, who had undergone α-IFN treatment. Before starting IFN, the HCV group showed higher HCV-RNA levels (bDNA assay) than the HBV–HCV group (median 3.75 vs. 0.64 × 106 Eq/ml, respectively; P

Background Although surgical management with early debridement and closed mediastinal irrigation has proved successful in reducing early mortality following poststernotomy deep sternal wound infection, recurrence rates are still up to 20%. This study compared the effectiveness and safety of wound dressing with granulated sugar versus early muscle flap surgery in the management of recurrent postoperative Staphylococcal mediastinitis. Methods Between January 1995 and January 2002, 25 patients with severe recurrent staphylococcal mediastinitis were treated with granulated sugar wound dressing (group A) or with wound debridement, v-shape sternectomy and associated muscle flap surgery (group B). Clinical outcomes and perioperative data were analyzed. Outcomes were compared between the groups evaluating the length of time for normalization of white blood cell (WBC) count and of body temperature and length of hospital stay. Patient characteristics determining best treatment option were identified. Survival and incidence of recurrence at follow-up were also analyzed. Results Study groups proved homogenous as to preoperative characteristics. Complete cure was achieved earlier in group A than in group B (defervescence: p = 0.0005; WBC normalization: p = 0.0001, respectively). Hospital stay was shorter in group A. A statistically significant difference was found in hospital mortality (16% overall) between the two groups with better outcomes in group A ( p = 0.039). In the patient subset with the most severe preoperative profile (hemodialysis, tracheostomy, inotropic support) surgical treatment produced worse results than the sugar dressing method ( p = 0.048). No case of recurrence was observed. Conclusions Both treatments proved effective in recurrent type IV A Staphylococcal mediastinitis. Granulated sugar proved a safer option in severely compromised patients.

The pathogenesis of infective endocarditis (IE) involves activation of the haemostasis system at the site of endocardial defects. Whether prothrombotic conditions are associated with IE by enhancing early vegetation formation is unknown. In this study, we assess the prevalence and clinical significance of two major conditions associated with thrombophilia in patients with IE. Mutations G20210A of the prothrombin (PTH) gene and G1691A of factor V (FV Leiden) gene were studied by means of allele-specific polymerase chain reaction in 203 IE patients, 175 valvular heart disease (VHD) patients and 200 blood donors (BD). IE patients show higher cumulative frequencies of mutated alleles of PTH and FV Leiden [6.4 vs 3.25 %; OR 2.03 (95 % CI 0.97–3.66); p = 0.047] compared to BD, but not VHD. Device-related IE is enriched with FV Leiden, and prosthetic valve IE with PTH mutations (allele frequency 8.3 vs 2.2 % in native valve IE; p = 0.021). Vegetation size and embolic complications are not influenced by the examined thrombophilias. A trend for a higher mortality was observed in IE patients with any of the two thrombophilias studied. Our data do not support a role for factor V Leiden and G20210A prothrombin gene mutations in the susceptibility to IE. Whether any of these genetic polymorphisms play a role in a specific subtype of IE needs to be re-examined in larger studies.

Infections due to drug-resistant Gram-negative rods are an emerging risk factor for increased mortality after solid organ transplant. Extensively drug-resistant (XDR) Acinetobacter baumannii (Acb) is a major threat in several critical care settings. The limited available data on the outcome of XDR Acb infections in organ transplant recipients mostly comes from cases of donor-derived infections. However, recipients of life-saving organs are often critically ill patients, staying long term in intensive care units, and therefore at high risk for nosocomial infections. In this report, we describe our experience with the exceedingly complex management of a recipient-born XDR Acb bloodstream infection clinically ensued shortly after heart transplant. We also review the current literature on this mounting issue relevant for intensive care, transplant medicine and infectious diseases.

Pegylated interferon (peg-IFN)-α2a and -α2b show different pharmacokinetic properties but are used interchangeably for hepatitis C treatment in traditional dual combinations and with newer agents. We assessed whether peg-IFN antiviral effects vary with peg-IFN subtype, affecting viral response in a differential manner.Chronic hepatitis C patients treated with ribavirin combined with peg-IFN-α2a (N = 109) or -α2b (N = 114) were studied. Hepatitis C virus RNA quantitation was performed by Cobas TaqMan 5 min before treatment start and subsequently after 48/72 h and 7, 14, 28 and 90 days. Antiviral effect was assessed in terms of viraemia changes over treatment. Histology grading and staging, interleukin-28B (IL28B) status and baseline viral genotype, alanine aminotransferase, gamma glutamyltransferase and glucose were analysed.Viraemia decline after 48/72 h and 7 days was significantly greater with peg-IFN-α2b (1.96 and 2.12 vs 1.49 and 1.20 log10 IU/mL with peg-IFN-α2a; p0.001). Differences were of larger extent in patients with advanced fibrosis (p = 0.002), genotype 1 infection (p = 0.002) and CT/TT genotypes of IL28B (p = 0.001). A rebound in viral load was observed significantly more often after the first dose in patients treated with peg-IFN-α2b (78 vs 28 % in those with peg-IFN-α2a; p = 0.0001). Differences between peg-IFNs disappeared by day 28 of treatment.There are significant pharmacodynamic differences between peg-IFN-α2a and -α2b in the early phase of chronic hepatitis C treatment. The greater early viral decline observed with peg-IFN-α2b was essentially confined to 'difficult to treat' patients. Whether this could affect response-guided treatment decision making, as well as triple drug regimens, needs to be assessed.

Background: The aim of the present study was to evaluate the association between heart failure (HF) and chronic kidney disease (CKD) in tertiary care centers using the clinical records of patients enrolled in internal medicine departments.Patients and methods: We used the clinical records of 1380 elderly patients to identify patients with a history of HF and CKD using admission ICD codes and glomerular filtration rate (GFR) formulas. Magnitude and strength of such associations were investigated by univariable and multivariable analysis.Results: Of the 1380 patients enrolled, 27.9% had HF (age 80 ± 7, BMI 27 ± 6 kg/m2) and 17.4% CKD (age 81 ± 7, BMI 26.8 ± 6 kg/m2). Both groups were significantly older (P

Infective endocarditis (IE) is a systemic illness whose hallmarks are cardiac disease and bloodstream infection. Although both of these conditions are exceedingly common among medical inpatients, and even more so in critically ill patients, IE is rarely found as the underlying cause of bacteremia with heart failure. Population-based studies [1] estimate that the current rate of community acquired, ‘spontaneous’ IE ranges from 3 to 10 cases every 100,000 person-years. Fewer data are available regarding hospital-acquired IE, even though risk factors for this condition are commonly encountered [2]. The diagnosis of IE has always been a clinical challenge. Historically, IE was first recognized in the sixteenth century at post-mortem examinations, but only in the mid1800s were signs and symptoms of live affected patients described. In 1885, in the Gulstonian lectures on ‘malignant endocarditis’, Sir William Osler presented a comprehensive review of the disease, delineating the evidence that was, and still remains, key to the diagnosis, including persistent bacteremia, heart valve involvement, embolic events and immunologic phenomena. Over subsequent years, it has become clear that there is a need to adopt strict case definitions, in order to improve diagnostic accuracy and to allow comparison of research data. In 1981, Von Reyn et al. introduced the Beth Israel criteria, to differentiate between IE and bacteremia from other foci in patients with heart disease. The concept of ‘definite’ IE was based on microbiologic (Gram’s stain and culture) or pathologic (vegetations or active valvulitis) evidence of the disease at either autopsy or surgically-explanted valves. In the absence of these ‘definite’ IE criteria, cases were categorized as ‘probable’, ‘possible’ or ‘rejected’. The subsequent definitions of IE diagnostic criteria resulted from the evolving epidemiology of the disease as well as the advances of bacteriology and imaging techniques. The advent of echocardiography, and in particular transesophageal echocardiography, paved the way for a revolution in the clinical diagnosis of IE, generating the still viable Duke University criteria, developed in 1994 by Durack et al. Indeed, when performed with adequate equipment and by experienced personnel, TEE is thought to possess a nearly absolute negative predictive value, showing either typical or atypical findings in essentially all IE patients. These criteria were further revised in 2001 to include serologic and molecular diagnosis of difficult-to-grow causative agents. Thus, the Duke criteria were a significant step forward toward a ‘clinically definite’ diagnosis of IE, incorporating the major criteria relating to microbiologic and echocardiographic finding. Still, their application depends on clinical probability, and several issues remain unanswered regarding their validity in special patient subgroups, such as the elderly, implantable electronic device carriers and prosthetic valve recipients, in whom clinical and echocardiographic findings may be more problematic and elusive. For these reasons, the adjunctive diagnostic significance of newer techniques, such as 3D echocardiography, multislice cardiac CT scan and 18FDGpositron emission tomography scan, is currently being evaluated. Thus, the greater the use of increasingly accurate diagnostic modalities, the lesser the role for pathologic criteria. At least theoretically, this would seem to be true. E. Durante-Mangoni (&) R. Utili Cattedra di Medicina Interna, U.O.C. Medicina Infettivologica e dei Trapianti, Ospedale Monaldi, II Universita di Napoli, Via Bianchi, 80131 Naples, Italy e-mail: emanuele.durante@unina2.it

Pulmonary nocardiosis is an infrequent but insidious disease in transplant patients. It has occurred in our centre in 3 out of 233 heart-transplant recipients since 1988. Common clinical features were mild symptoms and a severe nodular lung involvement. Early diagnosis was based upon cultures of bronchoalveolar lavage or fine-needle aspirate specimens of the lung lesions. Susceptibility studies and tests of antibiotic synergism guided the therapy. Two patients were treated with a combination of piperacillin-tazobactam and ciprofloxacin, and one with imipenem and amikacin, for 3-4 wk followed by a 3-month course of trimethoprim-sulphamethoxazole. The nocardial disease was successfully treated in the 3 patients; however, one died of subsequent invasive pulmonary aspergillosis. In the absence of consensus on the length of therapy, this experience suggests that a synergistic combination of a beta-lactam/beta-lactamase inhibitor with ciprofloxacin or amikacin followed by a short course of trimethoprim-sulphamethoxazole may be effective in eradicating nocardial disease and may reduce the need for long-term treatment.

The role of HCV RNA levels and host factors in the severity of liver injury was studied. Enrolled were 298 consecutive liver biopsy-proven chronic hepatitis (CH) C patients (179 men; median age: 52 years, range 19–68; CH, 198; cirrhosis, 100) and 18 chronic hepatitis C with normal ALT. HCV genotypes were: 1a, 4.3%; 1b, 53%; 2a/c, 28%; 3a, 7%; 4, 1.3%, and mixed 6.4%. Serum HCV RNA levels were similar for all genotypes (median: 2.8 × 106 eq/ml; range

Background . Mortality after deep sternal wound infection (DSWI) ranges between 5% and 47%. Variables predicting hospital mortality and prolonged hospital stay are still to be assessed. Methods . Among 13,420 patients who underwent cardiac surgery in our institution between 1979 and 1999, DSWI developed in 112 cases (0.8%). Multiple variables were recorded prospectively and analyzed retrospectively as predictors of hospital death and prolonged (>30 days) hospital stay. The analyzed variables were divided into three groups: (1) related to the patient, including demographic variables and preoperative conditions; (2) related to cardiac operation; and (3) related to infection. Predictive variables were assessed by univariate and multivariate logistic regression analysis. Results . Hospital mortality was 16.9%. The hospital stay of the 93 discharged patients ranged between 16 and 180 days (mean 31.3 ± 15.2). Length of cardiac operation, length of stay in intensive care unit, interval between symptoms of DSWI and wound debridement were found to be the most significant predictors of bad outcome following DSWI. Conclusions . In our study demographic variables and preoperative conditions did not affect the prognosis of DSWI. Lower mortality rate and shorter hospital stay could be achieved with earlier and aggressive treatment of DSWI.

Pulmonary aspergillosis is a severe complication in heart transplant recipients. The drug of choice for this infection is amphotericin B, but its use is limited because of its side effects. We observed six cases of pulmonary aspergillosis in a group of 200 patients who had received heart transplants from January 1988 to January 1999. Predisposing factors such as previous rejection, neutropenia and/or cytomegalovirus reactivation were present in all patients. The clinical presentation was characterized by fever and a non-productive cough. X-rays showed monolateral or diffuse infiltrate with or without nodular lesions. The median interval between symptoms and diagnosis was 5 d (range 4-7). Diagnosis was made by culturing trans-tracheal aspirate samples. Aspergillus fumigatus was isolated in 3 patients and A. niger in the other 3. All patients were treated with itraconazole at 200-400 mg/day for 20--60 d and all recovered. One patient treated with the lowest dosage for the shortest term had a recurrence after 1 month and needed a second 30-day course of itraconazole at a higher dosage. No significant side effects were registered. Itraconazole is effective in the therapy of pulmonary aspergillosis, particularly when an early diagnosis is made.

We conducted a long-term prospective study of 89 cancer survivor children who had acquired hepatitis B virus (HBV) and/or hepatitis C virus (HCV) during treatment for neoplasia, the aim being to evaluate the natural history of the diseases and the effect of interferon (IFN) treatment. Patients were followed up for a median period of 13 years (range, 8 to 20); 46 were infected by HBV, 11 by HCV, and 32 coinfected by HBV and HCV. A spontaneous clearance of hepatitis B surface antigen (HBsAg) occurred more frequently in coinfected patients (19%) than in the HBV-infected (2%; P = .004), with an annual seroconversion rate of 2.1% and 0.2%, respectively (P= .008). Loss of hepatitis Be antigen (HBeAg) occurred in 44% of coinfected and in 28% of HBV-infected patients. Clearance of serum HCV-RNA was observed in 34% and 9%, respectively, of coinfected and HCV-infected patients. Seventeen HBV-infected, 4 HCV-infected, and 16 coinfected patients received -IFN treatment. In the HBV group, 6 patients (35%) cleared serum HBV DNA and seroconverted to anti-HBe; in the HCV-group, none cleared HCV-RNA. In the coinfected group, 1 patient cleared both HBV DNA and HCV-RNA, 6 patients cleared serum HCV-RNA alone, and 1 only HBV DNA and HBeAg. Overall, the diseases showed a mild histological course with no evidence of liver cirrhosis. A reciprocal interference on viral replication between HBV and HCV may occur in coinfected patients. Treatment seems to be effective for selected cases and is justified in view of the uncertain prognosis of the disease in these patients.

OBJECTIVE To evaluate the efficacy of a long-term course of alpha-interferon (alpha-IFN) in the treatment of HCV-related mixed cryoglobulinaemia and to determine the impact of cryoglobulinaemia on therapeutic response to IFN in chronic hepatitis C (CHC) patients. DESIGN Prospective controlled study. SETTING University Medical Centre. PARTICIPANTS Ninety consecutive CHC patients, 50 with cryoglobulinaemia (25 symptomatic and 25 asymptomatic; median cryocrit, 8%; chronic persistent hepatitis (CPH) 7, chronic active hepatitis (CAH) 27, cirrhosis 16) and 40 without cryoglobulinaemia (CPH 6, CAH 20, cirrhosis 14). HCV genotypes in the cryoglobulinaemic and non-cryoglobulinaemic groups were: 1b 40% and 45%; 2a 40% and 30%; others 20% and 25%, respectively. INTERVENTIONS Twelve-month course of alpha-IFN 2a, 3 MU, three times weekly. MAIN OUTCOME MEASURES Disappearance of cryoglobulinaemia and related syndrome, clearance of serum HCV RNA and normalization serum transaminase levels at the end of treatment (response) and after 12 months follow-up (sustained response). RESULTS Overall, cryoglobulinaemic patients showed a similar response to IFN to those without cryoglobulinaemia (44% vs. 42.5%, respectively). In the cryoglobulinaemic group, symptomatic patients showed a lower response rate than asymptomatic patients (28% vs. 60%, respectively; P

Hepatitis C virus core antigen (HCVcoreAg) may be measured in serum with a sensitive, recently validated assay. Beyond its value as a marker of viral infection, there are little data on its relation with clinical, histological, and virological parameters. In this study, the significance of HCVcoreAg levels was studied in a prospective cohort of 114 patients with chronic hepatitis C. HCVcoreAg was measured by a commercial chemiluminescent microparticle immunoassay. Clinical and virological data included quantitative HCV-RNA, HCV genotype, ALT, GGT, IL28B rs12979860 polymorphism as well as liver histology parameters. HCVcoreAg levels were correlated significantly with HCV-RNA (r=0.56; P0.0001) but also with ALT levels (r=0.258; P0.01) and liver necroinflammatory activity (r=0.205; P0.04). Patients harbouring HCV genotype 3 showed lower levels of HCVcoreAg than both genotype 1 and two patients. In genotype 3, a direct correlation between steatosis and HCVcoreAg was found. Levels of HCVcoreAg also varied according to the IL28B genotype. These data suggest that the evaluation of HCVcoreAg serum levels may provide relevant data for the baseline clinical evaluation of chronic hepatitis C patients. HCVcoreAg serum levels may be a useful tool to further the understanding of chronic hepatitis C pathobiology.

Cardiac implantable electronic device (CIED) infections are an emerging clinical problem. A growing number of dedicated and high quality clinical studies are currently being generated. We here review the most recent advances in the diagnosis and treatment of patients with CIED infection including intracardiac lead endocarditis. We discuss the current etiology and risk factors, and appraise the major diagnostic issues, describing our center's therapeutic approach. We also address the management of CIED infection complications.

Blood coagulation plays a key role in the pathogenesis of infective endocarditis (IE). Conditions associated with thrombophilia could enhance IE vegetation formation and promote embolic complications.In this study, we assessed prevalence, correlates, and clinical consequences of hyper-homocysteinemia (h-Hcy) in IE.Homocysteine (Hcy) plasma levels were studied in 246 IE patients and 258 valvular heart disease (VHD) patients, as well as in 106 healthy controls.IE patients showed Hcy levels comparable to VHD patients (14.9 [3-81] vs 16 [5-50] μmol/L, respectively; P = 0.08). H-Hcy was observed in 48.8% of IE patients and 55.8% of VHD (P = 0.13). Vegetation size and major embolic complications were not related to Hcy levels. IE patients with h-Hcy had a higher prevalence of chronic kidney disease and a higher 1-year mortality (19.6% vs 9.9% in those without h-Hcy; OR 2.21 [1.00-4.89], P = 0.05). However, at logistic regression analysis, h-Hcy was not an independent predictor of 1-year mortality (OR 1.87 [95% CI 0.8-4.2]; P = 0.13).Our data suggest h-Hcy in IE is common, is related to a worse renal function, and may be a marker of cardiac dysfunction rather than infection. H-Hcy does not appear to favor IE vegetation formation or its symptomatic embolic complications.

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.

Heart failure (HF) is the most common complication of infective endocarditis. However, clinical characteristics of HF in patients with infective endocarditis, use of surgical therapy, and their associations with patient outcome are not well described.To determine the clinical, echocardiographic, and microbiological variables associated with HF in patients with definite infective endocarditis and to examine variables independently associated with in-hospital and 1-year mortality for patients with infective endocarditis and HF, including the use and association of surgery with outcome.The International Collaboration on Endocarditis-Prospective Cohort Study, a prospective, multicenter study enrolling 4166 patients with definite native- or prosthetic-valve infective endocarditis from 61 centers in 28 countries between June 2000 and December 2006.In-hospital and 1-year mortality.Of 4075 patients with infective endocarditis and known HF status enrolled, 1359 (33.4% [95% CI, 31.9%-34.8%]) had HF, and 906 (66.7% [95% CI, 64.2%-69.2%]) were classified as having New York Heart Association class III or IV symptom status. Within the subset with HF, 839 (61.7% [95% CI, 59.2%-64.3%]) underwent valvular surgery during the index hospitalization. In-hospital mortality was 29.7% (95% CI, 27.2%-32.1%) for the entire HF cohort, with lower mortality observed in patients undergoing valvular surgery compared with medical therapy alone (20.6% [95% CI, 17.9%-23.4%] vs 44.8% [95% CI, 40.4%-49.0%], respectively; P.001). One-year mortality was 29.1% (95% CI, 26.0%-32.2%) in patients undergoing valvular surgery vs 58.4% (95% CI, 54.1%-62.6%) in those not undergoing surgery (P.001). Cox proportional hazards modeling with propensity score adjustment for surgery showed that advanced age, diabetes mellitus, health care-associated infection, causative microorganism (Staphylococcus aureus or fungi), severe HF (New York Heart Association class III or IV), stroke, and paravalvular complications were independently associated with 1-year mortality, whereas valvular surgery during the initial hospitalization was associated with lower mortality.In this cohort of patients with infective endocarditis complicated by HF, severity of HF was strongly associated with surgical therapy and subsequent mortality, whereas valvular surgery was associated with lower in-hospital and 1-year mortality.

Background Cardiac implantable electronic device (CIED)-related endocarditis is a growing challenge because of increasing incidence and significant mortality. Current treatment is based on complete hardware removal coupled with long-term administration of effective and safe antimicrobials. Daptomycin at the dose of 6 mg/kg/day has been found to be effective in staphylococcal endocarditis, but limited data exist on CIED endocarditis. Moreover, whether higher doses could be more effective but equally safe in this setting is currently unknown. Methods We report here our experience with high-dose daptomycin in the treatment of 25 cases of CIED endocarditis due to staphylococci. Results Patients were mostly elderly and male, with large lead vegetations and severe comorbidities. Pathogens were Staphylococcus epidermidis (56%), Staphylococcus aureus (28%), and other coagulase-negative staphylococci (16%). Only 4 patients (16%) had a normal pretreatment renal function. The median daptomycin daily dose was 8.3 mg/kg (range, 6.4-10.7). Daptomycin was administered for a median of 20 days (range, 8-52). Percutaneous lead extraction was performed in 88% of patients. Two patients (8%) failed to clear bacteremia. The overall clinical success of treatment was 80%, whereas a complete microbiological success was observed in 92% of patients. Creatine phosphokinase values were monitored and increased above normal in 5 cases (20%). No serious adverse event related to high-dose daptomycin was observed and no patient required discontinuation because of muscle toxicity. Conclusions Our experience suggests that high-dose daptomycin may be a safe therapeutic option in staphylococcal CIED endocarditis and may be associated with high microbiological responses and clinical success.

Despite high rates of valve disease, non-bacterial thrombotic endocarditis remains an uncommon condition, the individual susceptibility to which might be influenced by an inherited thrombophilic state.A comprehensive hemostasis study was conducted in a 17-year-old patient with definite nonbacterial thrombotic endocarditis, including a genetic screening for all major inherited thrombophilias.Non-bacterial thrombotic endocarditis was detected on a bicuspid aortic valve. A hemostasis work-up showed that the patient had severe hyperhomocysteinemia, and was homozygous for the C677T mutation of the methylenetetrahydrofolate reductase gene.Based on the present clinical case, a novel hypothesis was proposed that the pathophysiology of non-bacterial thrombotic endocarditis might be affected by a genetic predisposition, such as an inherited thrombophilic state.

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.

The risk of infection is higher in intensive care units than in the other hospital department because of multiple factors contributing. In particular, it is estimated that the frequency of nosocomial infections is much higher in the patients hospitalized in the ICU than in patients hospitalized in other wards, with an incidence equal to 34%. In this study,we have assessed the grade of dangerous antibiotic resistance in intensive care units in our local reality.We have retrospectively analyzed the results for the microbiological test performed in 2003 and 2008 in the intensive care unit of A.O.R.N.V. Monaldi (Naples). The bacterial strains, once isolated from cultures, were identified microscopic analytical methods, biochemical methods and other manual and automated way. With regard to the Gram positive bacteria belonging to the Staphylococcus genus, it was evaluated carefully methicillin resistance and the MIC to vancomycin, confirmed by E-test in case of VISA strains. Besides it has been assessed and confirmed by test the vancomycin resistance of the Enterococcus, in case of VRE strains, and its resistance to high levels of gentamicin.With regard to the Gram negative bacteria, instead, it was evaluated the production of ESBL in the Enterobacteriaceae and the resistance to carbapenems of the Pseudomonas aeruginosa.

Background Chronic hepatitis C patients with coexisting heart disease are often denied antiviral treatment due to safety concerns. However, this is not evidence-based. Aims To evaluate safety and efficacy of pegylated interferon and ribavirin in chronic hepatitis C patients with heart disease. Methods Patients with overt heart disease (ischaemic heart disease, prior mechanical heart valve replacement, chronic arrhythmias and cardiomyopathy) and chronic hepatitis C were treated with standard pegylated interferon/ribavirin doses for standard duration. Cardiovascular safety was monitored by electrocardiography, echocardiography and measurement of troponin and B-type natriuretic peptide. Results Twenty-three patients (65.2% male, median age 57 years, 47.8% genotype 1) were treated. Three patients (13%) suspended treatment prematurely; 52% obtained sustained virological response, 39% relapsed, 9% were non-responders. No serious adverse event was observed. Post-treatment clinical examination, electrocardiography and echocardiography did not show any sign of progression of the pre-existing heart disease. Conclusions Treatment with pegylated interferon/ribavirin may be safely offered to carefully selected chronic hepatitis C patients with coexisting, clinically significant heart disease. In these patients, the outcome of antiviral treatment overlaps that observed in other patient subgroups.