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International audience; Background - Infective endocarditis (IE) is a common and serious complication in patients receiving chronic hemodialysis (HD). Objectives - This study sought to investigate whether there are significant differences in complications, cardiac surgery, relapses, and mortality between IE cases in HD and non-HD patients. Methods - Prospective cohort study (International Collaboration on Endocarditis databases, encompassing 7,715 IE episodes from 2000 to 2006 and from 2008 to 2012). Descriptive analysis of baseline characteristics, epidemiological and etiological features, complications and outcomes, and their comparison between HD and non-HD patients was performed. Risk factors for major embolic events, cardiac surgery, relapses, and in-hospital and 6-month mortality were investigated in HD-patients using multivariable logistic regression. Results - A total of 6,691 patients were included and 553 (8.3%) received HD. North America had a higher HD-IE proportion than the other regions. The predominant microorganism was Staphylococcus aureus (47.8%), followed by enterococci (15.4%). Both in-hospital and 6-month mortality were significantly higher in HD versus non-HD-IE patients (30.4% vs. 17% and 39.8% vs. 20.7%, respectively; p

Background Rezafungin (RZF) is a novel echinocandin exhibiting distinctive pharmacokinetics/pharmacodynamics. STRIVE was a phase 2, double-blind, randomized trial designed to compare the safety and efficacy of RZF once weekly (QWk) to caspofungin (CAS) once daily for treatment of candidemia and/or invasive candidiasis (IC). Methods Adults with systemic signs and mycological confirmation of candidemia and/or IC were randomized to RZF 400 mg QWk (400 mg), RZF 400 mg on week 1 then 200 mg QWk (400/200 mg), or CAS 70 mg as a loading dose followed by 50 mg daily for ≤4 weeks. Efficacy assessments included overall cure (resolution of signs of candidemia/IC + mycological eradication) at day 14 (primary endpoint), investigator-assessed clinical response at day 14, and 30-day all-cause mortality (ACM) (secondary endpoints), and time to negative blood culture. Safety was evaluated by adverse events and ACM through follow-up. Results Of 207 patients enrolled, 183 were in the microbiological intent-to-treat population (~21% IC). Overall cure rates were 60.5% (46/76) for RZF 400 mg, 76.1% (35/46) for RZF 400/200 mg, and 67.2% (41/61) for CAS; investigator-assessed clinical cure rates were 69.7% (53/76), 80.4% (37/46), and 70.5% (43/61), respectively. In total, 30-day ACM was 15.8% for RZF 400 mg, 4.4% for RZF 400/200 mg, and 13.1% for CAS. Candidemia was cleared in 19.5 and 22.8 hours in RZF and CAS patients, respectively. No concerning safety trends were observed; ACM through follow-up was 15.2% (21/138) for RZF and 18.8% (13/69) for CAS. Conclusions RZF was safe and efficacious in the treatment of candidemia and/or IC. Clinical Trials Registration NCT02734862, In a phase 2, randomized, double-blind, multicenter clinical trial conducted to evaluate rezafungin compared with caspofungin followed by fluconazole for primary treatment of patients with proven candidemia or invasive candidiasis, rezafungin demonstrated favorable safety and efficacy.

ObjectivesSubtypes A1 and B are the most prevalent HIV-1 clades in Greece. Subtype A1 epidemic is highly monophyletic and corresponds to transmissions that occurred locally. Our aim in this molecular epidemiology analysis was to investigate the role of early treatment in preventing new HIV-1 transmissions.MethodsOur analysis focused on 791 subtype A1 sequences from treatment-naïve individuals in Greece. Estimation of infection dates was performed by molecular clock calculations using Bayesian methods. We estimated the time interval between (1) the infection and sampling dates (linkage to care window), (2) the sampling dates and antiretroviral therapy (ART) initiation (treatment window), and (3) the infection dates and ART initiation (transmissibility window) for the study population. We also inferred the putative source of HIV infections between individuals of different groups divided according to the length of treatment, linkage to care or transmissibility window.ResultsA significant decline was detected for the treatment window during 2014–2015 versus the 2 previous years (p=0.0273), while the linkage to care interval remained unchanged during the study period. Inference of the putative source of HIV infections suggested that individuals with a recent diagnosis or narrow transmissibility window (time period between HIV infection and ART initiation) were not sources of HIV infections to other groups. Contrarily, a significant number of HIV infections originated from individuals with longer transmissibility window interval.ConclusionsOur findings showed that the treatment window is decreasing over time, presumably due to the updated treatment guidelines. Our study also demonstrates that people treated earlier after infection do not transmit at high rates, thus documenting the benefits of early ART initiation in preventing ongoing HIV-1 transmission.

Carbapenemase-producing Klebsiella pneumoniae (CP-Kp) are currently among the most important nosocomial pathogens in many geographic regions. A retrospective study was conducted between 2010 and 2014 in four hospitals located in a high-prevalence area (Athens, Greece) to describe the clinical features, treatment and outcomes of neutropenic patients with haematological diseases complicated with CP-Kp bloodstream infections. A total of 50 patients were identified, including 48 with haematological malignancies and 2 with aplastic anaemia. All patients had neutropenia (

Summary Background Healthcare-associated infections (HCAIs) are associated with increased morbidity and mortality and with excess costs. Central line-associated bloodstream infections (CLABSIs) are the most common HCAIs in neonates and children. Aim To establish national benchmark data for rates of CLABSI in neonatal and paediatric intensive care units (NICUs and PICUs) and paediatric oncology units (ONCs). Methods Active surveillance for CLABSI was conducted from June 2016 to February 2017. A collaborative of 14 NICUs, four PICUs, and six ONCs participated in the programme. Surveillance definitions of central line (CL), central line utilization (CLU) ratio, CLABSI event, and CLABSI rate were based on the Centers for Disease Control and Prevention's 2014 National Healthcare Safety Network criteria. Medical records were assessed daily for calculating CL-days, patient-days, and susceptibility of isolated organisms. Findings A total of 111 CLABSI episodes were recorded. The overall mean CLABSI rate was 4.41 infections per 1000 CL-days, and the CLU ratio was 0.31. CLABSI rates were 6.02 in NICUs, 6.09 in PICUs, and 2.78 per 1000 CL-days in ONCs. A total of 123 pathogens were isolated. The most common pathogens were Enterobacteriaceae (36%), followed by Gram-positive cocci (29%), non-fermenting Gram-negative bacteria (16%), and fungi (16%). Overall, 37% of Gram-negative pathogens were resistant to third-generation cephalosporins and 37% to carbapenems. Conclusion Nationally representative CLABSI rates were determined for paediatric patients. These data could be used to benchmark and serve as baseline data for the design and evaluation of infection control and antimicrobial stewardship interventions.

HIV-1 is transcriptionally active in activated T helper (Th)-cells and inactive in naive or resting memory Th-cells. Ets-2 is a preinduction transcriptional repressor of the IL-2 gene in naive Th-cells and a candidate transcriptional repressor of HIV-1 in the same cells, because the −279 to −250 upstream region of HIV-1-LTR [repressor–activator target sequence (RATS)], that participates in HIV-1-LTR transcriptional silencing, encompasses the AAGGAG Ets-2 binding site. In this proof of concept study, we investigated whether Ets-2 represses the expression of HIV-1. To assess whether Ets-2 can repress HIV-1 transcriptional activation acting through RATS, we transfected Jurkat cells with an Ets-2 overexpression plasmid (pCDNA3-ets-2) or Ets-2 silencing plasmids (ets-2-shRNA) and, as target genes, plasmids carrying the whole HIV-1-LTR sequence (HIV-1-LTR-CAT) or two copies of the RATS sequence (2× RATS-CAT) or a point mutation in the Ets-2 binding site (2× mutantRATS-CAT) or CMV-CAT (control). Ets-2 overexpression resulted in a significant reduction of HIV-1-LTR-CAT and 2× RATS-CAT activities in stimulated cells, but not of the 2× mutantRATS-CAT or CMV-CAT. Ets-2 silencing led to increased activities of HIV-1-LTR-CAT and 2× RATS-CAT in unstimulated cells, but had no effect on the activities of 2× mutantRATS-CAT and CMV-CAT. To assess Ets-2 binding to HIV-1-LTR–RATS in naive Th-cells, we isolated naive Th-cell nuclear proteins and passed them through an Ets-2 antibody column; electrophoretic mobility shift assays were performed using an RATS probe mixed with consecutive protein eluates. Ets-2 bound to the HIV-1-LTR–RATS in a dose-dependent manner. To assess Ets-2 binding to RATS in vivo, Jurkat cells were transfected with 2× RATS-CAT and stained for the Ets-2 protein and the RATS sequence by combining immunofluorescence and fluorescence in situ hybridization techniques. In unstimulated cells, Ets-2 bound to RATS, whereas no binding was observed in stimulated cells. To test for RATS specificity, the same experiments were performed with 2× mutantRATS-CAT, and no binding of Ets-2 was observed. The results were corroborated by chromatin immunoprecipitation assays performed with the same cells. Our results show that Ets-2 is a transcriptional repressor of HIV-1. Repression of HIV-LTR-RATS mediated by Ets-2 may account for the low-level transcription and replication of HIV-1 in naive Th-cells, and contribute to the viral latency and maintenance of viral reservoirs in patients, despite long-term therapy.

The presence of human immunodeficiency virus type 1 (HIV-1) drug resistance among drug-naïve patients remains stable, although the proportion of patients with virological failure to therapy is decreasing. The dynamics of transmitted resistance among drug-naïve patients remains largely unknown. The prevalence of non-nucleoside reverse transcriptase inhibitors (NNRTI) resistance was 16.9% among treatment-naïve individuals in Greece. We aimed to investigate the transmission dynamics and the effective reproductive number (Re) of the locally transmitted NNRTI resistance. We analyzed sequences with dominant NNRTI resistance mutations (E138A and K103N) found within monophyletic clusters (local transmission networks (LTNs)) from patients in Greece. For the K103N LTN, the Re was >1 between 2008 and the first half of 2013. For all E138A LTNs, the Re was >1 between 1998 and 2015, except the most recent one (E138A_4), where the Re was >1 between 2006 and 2011 and approximately equal to 1 thereafter. K103N and E138A_4 showed similar characteristics with a more recent origin, higher Re during the first years of the sub-epidemics, and a declining trend in the number of transmissions during the last two years. In the remaining LTNs the epidemic was still expanding. Our study highlights the added value of molecular epidemiology to public health.

Background High numbers of human immunodeficiency virus type 1 (HIV-1) infections among people who inject drugs (PWID) have been diagnosed in Athens, Greece, since 2011. We aimed to trace the geographic origin of HIV-1 infection for migrants who inject drugs and to investigate whether transmissions occur more frequently among migrants than among Greek nationals. Methods Multiple cross-sectional studies were pooled to assemble all persons diagnosed with HIV-1 in Greece between 1 January 2011 and 31 October 2014. Phylogenetic analyses used maximum likelihood estimation. The hypothesis of ethnic compartmentalization was tested by reconstructing ancestral states of characters at the tips using the criterion of parsimony over a set of bootstrap trees. Results Of 2274 persons, 38.4% were PWID. Phylogenetic analyses showed the existence of 4 major PWID-specific local transmission networks (LTNs): CRF14_BG (437 [58.6%]), CRF35_AD (139 [18.6%]), subtype B (116 [15.6%]), and subtype A (54 [7.2%]). Of 184 non-Greek PWID, 78.3% had been infected within the PWID-LTNs. For 173 (94.3%), the origin of their infection was assumed to be in Greece (postmigration). For PWID infected within LTNs, transmissions for subtype A and CRF14_BG occurred more frequently among migrants than would be expected by chance (phyloethnic study). Conclusions Our analysis showed that the majority of infections among migrants occurred postmigration. The existence of significant transmission networking among migrants highlights that this population is a priority for HIV prevention. As molecular analysis can estimate the probable country of HIV infection, it can help to inform the design of public health strategies.

Summary Background Immediate initiation of antiretroviral therapy (ART) in asymptomatic adults with CD4 counts higher than 500 cells per μL, as recommended, might not always be possible in resource-limited settings. We aimed to identify subgroups of individuals who would benefit most from immediate treatment. Methods The START trial was a randomised controlled trial in asymptomatic, HIV-positive adults previously untreated with ART. Participants with CD4 counts higher than 500 cells per μL were randomly assigned to receive immediate ART or to defer ART until CD4 counts were lower than 350 cells per μL. The primary endpoint of the study was serious AIDS-defining illnesses or death from AIDS and serious non-AIDS illnesses or non-AIDS-related death. In this post-hoc analysis, we estimated event rates and absolute risk reduction with immediate versus deferred ART, overall and by subgroup. Subgroups were prespecified in the study protocol or formed post hoc on the basis of baseline characteristics associated with morbidity and mortality in people with HIV. For continuous characteristics, approximate terciles were chosen as subgroup cutoff points, unless different cutoffs were clinically meaningful (eg, age ≥50 years). We estimated the number needed to treat immediately with ART for 1 year to prevent one primary event. Heterogeneity in the absolute risk reduction between subgroups was assessed with bootstrap tests. The START trial is registered with ClinicalTrials.gov, number NCT00867048. Findings Between April 15, 2009, and Dec 23, 2013, we enrolled 4684 participants from 35 countries across five continents, of whom 2325 were assigned to immediate ART and 2359 were assigned to deferred ART. The primary endpoint occurred in 42 participants in the immediate ART group (0·58 events per 100 person-years) and 100 participants in the deferred ART group (1·37 events per 100 person-years). The absolute risk reduction was 0·80 (95% CI 0·48–1·13) per 100 person-years with immediate treatment, and the number needed to treat immediately to prevent one event was 126 (95% CI 89–208). Significant heterogeneity in absolute risk reduction with immediate ART was found across subgroups according to age (p=0·0022), CD4 to CD8 ratio (p=0·0007), and plasma HIV RNA viral load (p=0·033) at baseline. The highest absolute risk reductions and the lowest numbers needed to treat were found in participants aged 50 years or older, those with CD4 to CD8 ratios of less than 0·5, and those with plasma HIV RNA viral loads of 50 000 copies per mL or higher. Interpretation Asymptomatic, ART-naive adults with CD4 counts higher than 500 cells per μL who are older, have a low CD4 to CD8 ratio, or a high plasma HIV RNA viral load benefit most from immediate initiation of ART and should be prioritised for treatment. Funding US National Institute of Allergy and Infectious Diseases.

Carbapenemase-producing Klebsiella pneumoniae strains (CP-Kps) are currently among the most important nosocomial pathogens. An observational study was conducted during 2009 to 2010 in two hospitals located in a high-prevalence area (Athens, Greece). The aims were (i) to evaluate the clinical outcome of patients with CP-Kp bloodstream infections (BSIs), (ii) to identify predictors of mortality, and (iii) to evaluate the various antibiotic schemes employed. A total of 205 patients with CP-Kp BSIs were identified: 163 (79.5%) were infected with KPC or KPC and VIM, and 42 were infected with VIM producers. For definitive treatment, 103 patients received combination therapy (two or more active drugs), 72 received monotherapy (one active drug), and 12 received therapy with no active drug. The remaining 18 patients died within 48 h after the onset of bacteremia. The all-cause 28-day mortality was 40%. A significantly higher mortality rate was observed in patients treated with monotherapy than in those treated with combination therapy (44.4% versus 27.2%; P = 0.018). The lowest mortality rate (19.3%) was observed in patients treated with carbapenem-containing combinations. In the Cox proportion hazards model, ultimately fatal disease (hazards ratio [HR], 3.25; 95% confidence interval [CI], 1.51 to 7.03; P = 0.003), the presence of rapidly fatal underlying diseases (HR, 4.20; 95% CI, 2.19 to 8.08; P < 0.001), and septic shock (HR, 2.15; 95% CI, 1.16 to 3.96; P = 0.015) were independent predictors of death. Combination therapy was strongly associated with survival (HR of death for monotherapy versus combination, 2.08; 95% CI, 1.23 to 3.51; P = 0.006), mostly due to the effectiveness of the carbapenem-containing regimens.

Objectives To report a case of intravascular lymphoma (IVL) in a Caucasian patient who presented with anasarca as his sole clinical sign. Material and Methods A man presented with anasarca-type oedema and fatigue. After excluding heart failure, hepatic cirrhosis, nephrotic syndrome, hypothyroidism, AL-amyloidosis and adverse drug reaction which can all cause oedema, we turned our attention to capillary permeability disorders. Results Closer review of the bone marrow aspirate demonstrated haemophagocytic histiocytosis, while core, renal and duodenal biopsies showed a B-cell IVL. Conclusion The differential diagnosis of anasarca, a relatively common clinical sign, should include IVL although the diagnosis may still be challenging. LEARNING POINTS Anasarca-type oedema is an unusual initial presentation of intravascular lymphoma (IVL) and is normally attributed to capillary permeability disorders. Two clinical forms of IVL have been recognized: a Western form and an Asian variant which is characterized by haemophagocytosis. Patients of Caucasian origin who have the clinical features of the Asian variant of IVL make the diagnosis of this condition even more challenging.

Objectives: Both total antimicrobial use and specific antimicrobials have been implicated as risk factors for healthcare-associated methicillin-resistant Staphylococcus aureus (HCA-MRSA) infection. The aims of this study were: (I) to explore predictors of a new HCA-MRSA infection in comparison with a new healthcare-associated methicillin-sensitive Staphylococcus aureus (HCA-MSSA); (II) to thoroughly assess the role of recent antibiotic use qualitatively and quantitatively. Methods: The time-period for our study was from October 1997 through September 2001. Through applying strict criteria, we identified two groups of inpatients, one with a new HCA-MRSA infection and one with a new HCA-MSSA infection. We recorded demographic, clinical and antibiotic use-related data up to 30 days before the positive culture date. Results: We identified 127 and 70 patients for each group, respectively. Two logistic regression models were carried out to assess the role of antimicrobial use (qualitatively and quantitatively). In model I, duration of hospital stay, presence of chronic wounds, aminoglycoside and fluoroquinolone use retained statistical significance. In model II, duration of hospital stay and history of intubation during the last month stood out as the only significant predictors of a subsequent HCA-MRSA infection. No significant differences in outcome were noted. Conclusions: The length of exposure to the hospital environment may be the best predictor of a new HCA-MRSA infection. Use of aminoglycosides and fluoroquinolones may also stand independently along with presence of chronic ulcers and surgical procedures. No independent association between quantitative antibiotic use and subsequent HCA-MRSA infection was documented. Keywords: methicillin-resistant Staphylococcus aureus, Staphylococcus aureus, antibacterial agents, fluoroquinolones

An isocratic HPLC method with detection at 248 nm was developed and fully validated for the determination of tigecycline in rabbit plasma. Minocycline was used as an internal standard. A Hypersil BDS RP-C18 column (250 × 4.6 mm, 5 μm particle size) was used with the mobile phase phosphate buffer (pH 7.10, 0.070 M)–acetonitrile (76 + 24, v/v) at a flow rate of 1.0 mL/min. The elution time of tigecycline and minocycline was approximately 8.1 and 9.9 min, respectively. Calibration curves of tigecycline were linear in the concentration range of 0.021–3.15 μg/mL in plasma. The LOD and LOQ in plasma were estimated as 7 and 21 ng/mL, respectively. The intraday and interday precision values of the method were in the range of 5.0–7.1 and 5.6–9.1%, while the corresponding accuracy values were in the ranges of 92.8–111.1 and 97.6–102.3%, respectively. At the LOQ, the intraday precision was 18.7%, while intraday and interday accuracy values were 97.3 and 98.0%, respectively. Robustness of the proposed method was studied using a Plackett-Burman experimental design. A pharmacokinetic profile is presented for confirmation of the applicability of the method to pharmacokinetic studies.

Background STRIVE was conducted to assess the safety and efficacy of rezafungin (RZF), a novel echinocandin with pharmacokinetics allowing once weekly dosing and high, front-loaded plasma drug exposure, and to help determine dosing for a Phase 3 study. Methods Adults (≥18 years) with mycologically confirmed candidemia and/or invasive candidiasis (IC) were randomized (1:1:1) to receive RZF IV for up to 4 weeks dosed at either 400 mg weekly (Group 1) or 400 mg on week 1 and 200 mg weekly thereafter (Group 2), or standard of care (SOC; daily caspofungin [CSP] with optional criteria-defined oral stepdown after ≥3 days of IV therapy; Group 3). Safety and efficacy were evaluated by treatment-emergent adverse events (TEAEs) and overall success at day 14 (1° endpoint; clinical cure + mycological success), investigator assessment of clinical cure, mycological success (in subjects with candidemia only), overall success in IC subjects only, and mortality. Outcomes at day 5 were also assessed. Results The rate of TEAEs was 88.6% in Group 1, 94.4% in Group 2, and 81.8% in Group 3. Severe AEs occurred in 37.1%, 27.8%, and 39.4% of the groups, respectively. There were no concerning trends in System Organ Class groups, specific AEs, or laboratory abnormalities. The most common Candida species isolated was C. albicans (n = 45), followed by C. glabrata (n = 17), C. tropicalis (n = 15), and C. parapsilosis (n = 13). A high number of indeterminate responses due to missing data points in Group 1 led to analyses including and excluding the indeterminate responses. Overall, clinical, and mycological response rates at day 14 are shown in Table 1. Overall response at day 5 (Table 2) was highest in the RZF 400 mg/200 mg group, followed by the RZF 400 mg/400 mg and SOC groups. The overall mortality rate was 15.2% in Group 1, 9.7% in Group 2, and 17.9% in Group 3. Conclusion RZF demonstrated safety and efficacy comparable to CSP in the treatment of candidemia/IC. There were no concerning trends in AEs. The efficacy rates were similar among all 3 treatment groups, trending higher with the RZF 400 mg/200 mg regimen on most efficacy outcomes, although the sample size is small and confirmation of these findings is required in a larger Phase 3 clinical trial. These findings support further clinical study of RZF in Phase 3. Disclosures G. R. Thompson, Cidara: Investigator, Research support. Mayne: Investigator, Research support. Astellas: Consultant and Investigator, Consulting fee and Research support. Scynexis: Investigator, Research support. Vical: Consultant, Consulting fee. A. Soriano, Cidara Therapeutics, Inc.: Investigator, Research grant. L. Ostrosky-Zeichner, Cidara Therapeutics: Grant Investigator, Research grant. K. Mena, Cidara Therapeutics: Employee, Salary. L. Navalta, Cidara Therapeutics, Inc.: Employee, Salary. T. Sandison, Cidara Therapeutics: Employee, Salary. P. Pappas, Cidara Therapeutics: Consultant and Grant Investigator, Research grant. IMMY: Consultant and Grant Investigator, Research grant. Scynexis: Consultant and Grant Investigator, Research grant. Gilead: Grant Investigator, Research grant.

Resume L’association synovite, acne, pustulose, hyperostose et osteite aseptique est connue sous le nom de syndrome Sapho. L’osteite atteint la paroi thoracique anterieure, en particulier les jonctions sternoclaviculaires et sternocostales superieures. Le diagnostic est difficile en l’absence d’atteinte cutanee et de lesions osseuses evocatrices. Les diagnostics differentiels incluent les osteomyelites bacteriennes, les neoplasies et la maladie de Paget. Nous rapportons ici une observation de syndrome Sapho associant une osteite aseptique du femur et une atteinte symetrique des jonctions sternocostales inferieures. La reconnaissance et le diagnostic de syndrome Sapho permettent d’eviter une antibiotherapie prolongee et des biopsies iteratives a visee diagnostique.

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.

From 1,246 specimens collected from 13 Greek hospitals, 266 vancomycin-resistant enterococci strains were isolated from 255 patients (20.5%). The VanA phenotype was present in 82 (30.8%) strains, the VanB phenotype in 17 (6.4%) strains, the VanC1 phenotype in 152 (57.1%) strains, and the VanC2/C3 phenotypes in 15 (5.6%) strains. When only VanA and VanB phenotypes were considered, the overall prevalence was 7.5%. Eighty-six isolates exhibiting the VanA or VanB phenotype were analyzed by pulsed-field gel electrophoresis (PFGE), and 46 PFGE groups were found.

To compare various strategies for antibacterial administration in terms of patient outcomes, overall costs and quality of care provided. Prospective, nonblind, randomized, clinical study. Tertiary care hospital in Greece from November 1995 to June 1996. 458 patients admitted to the internal medicine department who received antibacterial therapy for infectious diseases. Patients were randomized into 4 different antibacterial administration policies defined by various levels of restriction control. Efficacy and resource use data were obtained from clinical study case report forms, the hospital financial database and physician expert opinion. Outcomes included complete infection control, disease improvement, unchanged patient condition, infection needing surgical treatment, and death. Direct medical costs were estimated. The perspective adopted was that of the healthcare system (hospital budget; third-party payor). Cost-minimisation analysis was based on cost per patient treated. 382 eligible patient records examined showed no significant difference in clinical outcomes among patient groups. Baseline analysis showed the strict antibacterial control policy to produce statistically significant differences (p < 0.05) in various resource parameters. Accordingly, compared with all other patient groups, total cost per patient for that strategy was reduced by 26 to 30%. Also, patients in that group received fewer drug doses and underwent fewer treatment days, and antibacterial treatment was modified in fewer cases for these patients. Strict control of antibacterial administration in this hospital setting achieved lower direct medical costs with no harmful effect on patient outcomes or quality of care provided. Such a policy appears to be a useful option for both physicians and administrators.

Post-sternotomy infectious complications, including superficial and deep wound infections, sternal osteomyelitis and mediastinitis, are rarely caused by fungi. Trichosporon asahii is the main Trichosporon species that causes systemic infection in humans. Most cases involved neutropenic patients with hematologic malignancies. We report a unique case of a non-cancer, non-neutropenic but severely ill patient who developed an ultimately lethal T. asahii infection after sternotomy. We speculate that our patient had been colonized with the fungus and his surgical site infection may have been related to his emergency revascularization surgery. Therapy with liposomal amphotericin failed to sterilize the bloodstream despite in vitro susceptibility results. The addition of voriconazole helped sterilizing the bloodstream without changing the outcome. Physicians must be aware of the continuously expanding spectrum of infections with this emerging difficult-to-treat fungal pathogen.

A case of severe and irreversible pancytopenia secondary to acute primary cytomegalovirus infection in an immunocompetent woman is described. The patient presented with thrombocytopenia, lymphopenia, anemia, and abnormal liver function tests. Treatment with corticosteroids and intravenous immunoglobulin was ineffective in reconstituting hemopoiesis. The patient developed severe sepsis and eventually expired. Keywords: cytomegalovirus, pancytopenia, immunocompetent, fulminant, irreversible

Cytokines are potent polymorphonuclear leukocyte (PMN) activators and can decrease their deformability. We evaluated passive PMN deformability using the micropipette method after incubation with different concentrations of lipopolysaccharide (LPS), interleukins (IL-) 1, 6, 8 and 10, tumour necrosis factor (TNF), granulocyte (G) and granulocyte-macrophage (GM) colony-stimulating factors (CSF). TNF, IL-1, G-CSF, GM-CSF and, to a lesser degree, IL-6 significantly and in a dose-dependent fashion decrease PMN deformability. LPS had no direct effect on PMN deformability. When cytokines at concentrations with no effect on deformability were combined they increased PMN rigidity. The findings suggest that several cytokines and CSF impair directly, and not by activation alone, PMN deformability.

Background Intravenously administered antimicrobial agents have been the standard choice for the empirical management of fever in patients with cancer and granulocytopenia. If orally administered empirical therapy is as effective as intravenous therapy, it would offer advantages such as improved quality of life and lower cost. Methods In a prospective, open-label, multicenter trial, we randomly assigned febrile patients with cancer who had granulocytopenia that was expected to resolve within 10 days to receive empirical therapy with either oral ciprofloxacin (750 mg twice daily) plus amoxicillin–clavulanate (625 mg three times daily) or standard daily doses of intravenous ceftriaxone plus amikacin. All patients were hospitalized until their fever resolved. The primary objective of the study was to determine whether there was equivalence between the regimens, defined as an absolute difference in the rates of success of 10 percent or less. Results Equivalence was demonstrated at the second interim analysis,...

Adult onset Still's disease (AOSD) is a well-recognized clinical disorder characterized by involvement of various organs, including liver. However, acute hepatitis or hepatic failure is extremely rare, and most of the reported cases occurred during treatment with hepatotoxic drugs. Anakinra is an interleukin-1 receptor antagonist (IL-1Ra). Experimental and clinical data support a central role for IL-1Ra in fulminant hepatic failure. We report the case of a patient with AOSD complicated with acute hepatitis during treatment with corticosteroids, which was dramatically improved with anakinra.

We present a patient with chronic HIV-1 infection and primary multi-drug resistance, the magnitude of which was underestimated by the baseline genotypic resistance testing (GRT) due to reversion of some of the mutations of the transmitted strain. This resulted in complete failure of his first antiretroviral regimen with rapid appearance of presumably archived mutations to more than one antiretroviral classes. Interestingly, his viral load remained high even in the presence of the M184V mutation. Baseline GRT in chronic HIV infection may not give adequate information in the presence of acquired multi-drug-resistant HIV strains, which have one or more of their mutations reverted. The presence of 215 codon polymorphisms should alert physicians to the possible coexistence of archived nucleoside and non-nucleoside reverse transcriptase inhibitor mutations. In such a case, initiation of a regimen with a low genetic barrier to resistance may not be the best choice and, if done, should be done cautiously and with more frequent monitoring of treatment response than usual.

Pericarditis is an uncommon extraintestinal manifestation of inflammatory bowel disease (IBD), which may occur at any time during its natural course. Moreover, it may be associated with the medications used to treat IBD, especially mesalamine. We report on two patients with acute pericarditis who were subsequently diagnosed with Crohn's disease. It is likely that mild, longstanding, virtually asymptomatic intestinal disease preceded the onset of pericarditis in both cases.

We report the radiological findings of a thermometer having migrated to the posterior mediastinum after ingestion and perforation of the esophagus, in an asymptomatic patient. Asymptomatic migration of a foreign body in the mediastinum after ingestion is an extremely rare phenomenon. Management can be conservative or surgical.

The use of daptomycin in Gram-positive left-sided infective endocarditis (IE) has significantly increased. The purpose of this study was to assess the influence of high-dose daptomycin on the outcome of left-sided IE due to Gram-positive pathogens. This was a prospective cohort study based on 1,112 cases from the International Collaboration on Endocarditis (ICE)-Plus database and the ICE-Daptomycin Substudy database from 2008 to 2010. Among patients with left-sided IE due to Staphylococcus aureus , coagulase-negative staphylococci, and Enterococcus faecalis , we compared those treated with daptomycin (cohort A) to those treated with standard-of-care (SOC) antibiotics (cohort B). The primary outcome was in-hospital mortality. Time to clearance of bacteremia, 6-month mortality, and adverse events (AEs) ascribable to daptomycin were also assessed. There were 29 and 149 patients included in cohort A and cohort B, respectively. Baseline comorbidities did not differ between the two cohorts, except for a significantly higher prevalence of diabetes and previous episodes of IE among patients treated with daptomycin. The median daptomycin dose was 9.2 mg/kg of body weight/day. Two-thirds of the patients treated with daptomycin had failed a previous antibiotic regimen. In-hospital and 6-month mortalities were similar in the two cohorts. In cohort A, median time to clearance of methicillin-resistant S. aureus (MRSA) bacteremia was 1.0 day, irrespective of daptomycin dose, representing a significantly faster bacteremia clearance compared to SOC (1.0 versus 5.0 days; P < 0.01). Regimens with higher daptomycin doses were not associated with increased incidence of AEs. In conclusion, higher-dose daptomycin may be an effective and safe alternative to SOC in the treatment of left-sided IE due to common Gram-positive pathogens.

The resistance of gram-negative bacteria to most available antibiotics and the lack of new antimicrobial agents have prompted the re-emergence of colistin (CS) as potent treatment against most gram-negative microorganisms. Optimal dosing with CS suffers from poor pharmacokinetic characterization mainly due to the analytical challenge of assaying CS in biological fluids and the limited information on quantitative analysis of CS in plasma using high resolution mass spectrometry (MS). Hence, a rapid, simple and accurate analytical method based on ultra performance liquid chromatography (UPLC) combined with electrospray ionization (ESI) tandem mass spectrometry (MS/MS) on a hybrid quadrupole time of flight (QTOF) instrument has been developed and fully validated for the quantification of CS in human plasma. After the pretreatment of plasma samples by solid phase extraction (SPE) and the addition of the internal standard (reserpine, RSP) the analytes were chromatographed on an Acquity BEH C8 column (100 mm × 2.1 mm, 1.7 μm) using gradient elution with 0.5% aqueous acetic acid (AcOH) and acetonitrile with 0.5% AcOH (with CSA and CSB eluting at 1.39 and 1.31 min, respectively). Accurate mass measurement correction was performed on line using the leukine-enkephaline standard. The method presented good fit (regression coefficient≥0.998) over the quantitation range of 0.2-300 and 0.03-4.5 μg mL(-1) with the lower limit of quantitation (LLOQ) being 0.02 and 0.03 μg mL(-1) for CSA and CSB in human plasma, respectively. The intra- and inter-day precision, measured as %relative standard deviation, was better than 10%, whereas the accuracy expressed as %relative error was also better than 10%. The short term, freeze-thaw (three cycles) and in process stability showed non-significant degradation of CS under these conditions. The validation results showed that the developed method demonstrated adequate selectivity and sensitivity. The method has been successfully applied to plasma samples from patients suffering from cystic fibrosis and treated with CS, and the pharmacokinetic profile has been calculated.

The adherence of strains of Candida albicans to buccal epithelial cells as well as the phagocytosis of these organisms by human polymorphonuclear leucocytes (PMNL) was studied. The strains of C. albicans were obtained from patients' urine, from bird faeces and from soil. The strains of C. albicans obtained from patients and the environmental displayed greater adhering ability (23.8±6.4 and 27.5±5.2 respectively) than the avian strains (14.4±2.2) ( P P C. albicans may be more virulent for human beings.

Objectives To investigate intact blood-brain barrier (BBB) penetration by doripenem and characterize doripenem pharmacokinetics in CSF using a pharmacokinetic model. Patients and methods Thirty-eight neurological patients with no active neurological disease or CNS infection received a single 500 mg doripenem dose before pump implantation surgery, or lumbar puncture, for intrathecal baclofen administration. In most cases single CSF and blood samples were collected per patient and analysed for doripenem with HPLC. A two-stage pharmacokinetic analysis was performed to estimate: (i) empirical Bayesian estimates (EBEs) of individual doripenem plasma pharmacokinetic parameters, using plasma doripenem concentrations and literature population priors for a two-compartment model; and (ii) doripenem CSF pharmacokinetic parameters using simulated plasma concentrations from stage (i) as a forcing function. The mean values of the structural model parameters, k(CSF) (distribution rate constant) and PC (CSF/plasma partition coefficient), and the residual variability were estimated. Results The mean estimates of the parameters were k(CSF)= 0.105 h(-1) and PC= 0.053, corresponding to mean steady-state doripenem CSF concentrations of 0.20 mg/L and 0.40 mg/L for regimens of 3 × 500 mg daily and 3 × 1000 mg daily, respectively, and a mean equilibrium half-life of 6.6 h. The model was validated internally using a visual predictive check (VPC) and bootstrap. Simulating two dosing scenarios gave doripenem levels in the CSF above or close to the literature MIC values. Conclusions The present NONMEM software analysis shows that doripenem crosses intact BBB significantly and suggests that the drug should be further evaluated as a candidate to treat certain CNS infections, since drug penetration through BBB is enhanced by meningeal inflammation.

Hereditary hemorrhagic telangiectasia (HHT) is a disease characterized by arteriovenous malformations (AVMs). Brain abscess is a complication of HHT with AVMs. Literature provides evidence that Enterococcus faecalis can cause endodontic infections. We present the case of an HHT patient who developed brain abscess due to E. faecalis after a dental procedure.

A 51-year-old previously healthy man, an ex-smoker, was admitted to the authors' medical department with a 3-month history of dry cough; intermittent fever; painless, ulcerated cutaneous lesions over the trunk and limbs (Figure 1); and progressive weight loss. He was of Greek descent. His medical history was remarkable for nasal polyps, which were surgically removed 15 years earlier. Initially, he had been treated with antibiotics, without improvement. Several days before admission, chest radiography revealed pulmonary infiltrates in the left lower lobe. On admission, physical examination revealed a well-orientated man in mild distress, with inspiratory rhonchi at the lower part of the left lung and scattered erythematous nodules of variable size, some of which were ulcerated. Laboratory values were notable for leukopenia, 3.3 x 10(9)/L; total protein, 5.9 g/dL; globulin, 2.2 g/dL; serum glutamic oxaloacetic transaminase, 86 IU/L; serum glutamic pyruvic transaminase, 71 IU/L; and lactate dehydrogenase, 519 U/L. Computed tomograph (CT) of the chest showed multiple alveolar opacities bilaterally (Figure 2). Fiberoptic bronchoscopy did not reveal any important pathologic findings. Results of bronchial biopsy, cytology of bronchoalveolar lavage, washing, brushing, and sputum following bronchoscopy were negative. CT of the brai and sinonasal area revealed an abnormal low-density mass in the left nasal area. CT findings of the abdomen were negative, as were results of a bone marrow biopsy. There was no evidence of immunosuppression. The differential diagnosis, considering the evidence described, included granulomatous or infectious diseases, angiocentric lymphoproliferative lesions, and lymphomas. Biopsy of a skin lesion showed lymphoproliferative infiltration of the dermis with a follicular and angiocentric growth pattern and regional epidermal necrosis. Immunohistochemical stains showed that the tumor cell were positive for CD56 and CD3 (cytoplasmic positivity) and expressed the cytotoxic proteins T-cell intracellular antigen and granzyme B (Figure 3) They lacked TdT, CD34, CD7, CD8, TCL-1, and CD123. Findings from an in situ hybridization study for Epstein-Barr virus were negative. Give this result, molecular analysis ofT-cell receptor (TCR) gene rearrangements was performed using polymerase chain reaction-based TCR-gamma gene, wit negative results. The morphology and the immunophenotype were consistent with natural killer/T-cell lymphoma, nasal-type. Nasal involvement must be first excluded to proceed to the diagnosis of nasal-type natural killer-cell lymphoma. Indeed, histologic examination of the nasal mass revealed its polypoid nature. Thus, the authors were led to the diagnosis of extranodal extranasal natural killer/T-cell lymphoma, nasal-type, CD56-positive, Ep stein-Barr virus-negative, TCR-negative. The patient received combination chemotherapy and completed 4 cycles of cyclophosphamide, doxorubicin vincristine, and prednisone every 14 days for 2 months. Skin lesions improved, and there was no fever soon after the initiation of therapy. Reevaluatio after the fourth cycle, however, disclosed pulmonary infiltrations as well as leukemic infiltration of the central nervous system. The patient had receive systemic salvage chemotherapy and intrathecal infusions of methotrexate. Although the lung lesions had diminished at that time, the patient develope paraplegia, his clinical course rapidly deteriorated, and he eventually died.

Septic or suppurative deep venous thrombosis is an uncommon but occasionally lethal disease due to systemic complications. In most cases, it is caused by intravenous drug use or by percutaneous insertion of central venous catheter lines in critically ill patients. 1-3 Some patients have septic phlebitis after delivery or abortion or as a late complication of local infections such as pyonephrosis. 4 Most patients are admitted with clinical signs of severe sepsis and occasionally with complications as a result of septic embolization. 2 We report the case of an intravenous drug user with septic deep venous thrombosis of the left common femoral and external iliac veins diagnosed by sonography.

Introduction Although several studies did not demonstrate that daptomycin may cause significantly higher rates of pulmonary adverse effects when compared with vancomycin or penicillinase-resistant penicillins, there have been a few case reports of severe pulmonary complications associated with daptomycin administration. Case presentation A rare case of eosinophilic pneumonia occurring 10 days after daptomycin administration in a 78-year-old Caucasian man with possible infectious endocarditis is described. He developed new onset fever, up to 38.5°C, with bilateral pulmonary crackles on physical examination and with no signs of severe respiratory failure. A chest computed tomography-scan showed bilateral nodular consolidations with air bronchograms and pleural effusions. Immediate discontinuation of daptomycin was followed by vigorous improvement of clinical signs and symptoms with progressive resolution of pulmonary consolidations a month later. Conclusion Physicians should be aware of this rare but serious complication during daptomycin treatment, and prompt discontinuation of the offending agent, with or without additional supportive treatment, must occur immediately.

Objectives To identify risk factors for bloodstream infections (BSIs) caused by VIM-1-producing Klebsiella pneumoniae (VPKP). Methods Consecutive patients with K. pneumoniae BSIs were identified in three tertiary care hospitals between February 2004 and March 2006. Patients infected with VPKP were designated as cases and those infected with non-VPKP as controls. Potential risk factors for VPKP BSIs were examined by univariate and multivariate analysis. Results A total of 178 patients with K. pneumoniae BSIs were identified; 67 (37.6%) were infected with VPKP (cases) and 111 with non-VPKP (controls). In multivariate analysis, cases were more likely to have been in an intensive care unit (ICU) [odds ratio (OR), 6.78; 95% confidence interval (CI), 2.69-17.06; P 3 different classes of antibiotics (OR, 12.6; 95% CI, 2.17-73.27; P = 0.01) and have had prior use of carbapenems (OR, 2.83; 95% CI, 1.07-7.49; P = 0.03). Conclusions Stay in an ICU, prior use of carbapenems and prior exposure to >3 different classes of antibiotics were independent predictors for VPKP BSIs. These findings provide guidance for antibiotic policies and infection control strategies to contain the spread of VPKP.

We report an extreme case of high-grade needlestick exposure of a health-care worker to serum from multiple HIV-infected patients after trying to prematurely remove the respective tubes from an automated biochemical analyser. After review of the medical records of the eight source patients, we offered the health-care worker an expanded postexposure prophylaxis regimen including the entry inhibitor enfuvirtide. She refused to take subcutaneous injections, so we recommended the use of the integrase inhibitor raltegravir. She completed therapy without problems and periodic evaluation for HIV transmission up to nine months after the incident was negative.

Staphylococcus aureus (SA) bacteriuria may accompany SA bacteremia, but primary SA urinary tract infection (UTI) may also occur. Our clinical observation of SA UTIs following intravenous catheter-related phlebitis lead us to review hematogenous and ascending route-related risk factors in patients with primary SA UTIs. The charts from all patients with SA UTIs over a 1.5-year period were reviewed for concurrent or recent hospitalization, intravenous catheterization, and for known UTI risk factors. Patients with concurrent SA bacteremia were excluded. Patients with Escherichia coli UTIs during the same period were included as controls. Twenty cases of primary SA UTI were compared with 43 E. coli UTI cases and they did not differ in age, diabetes mellitus, prostatic hypertrophy, previous UTI, or other urinary tract (UT) abnormality. However, cases were more likely than controls to have had recent or concurrent hospitalization, UT catheterization, and history of recent phlebitis. In multivariate analysis, UT catheterization and recent hospitalization retained significant association with SA UTI. Similar results were shown for the methicillin-resistant SA UTI subgroup. Even though UT catheterization is the main predisposing factor for primary SA UTI, some cases may be mediated through unrecognized preceding bacteremia related to intravascular device exposure or other healthcare-related factors.