Should HLA-B*5701 Screening Be Performed in Every Ethnic Group before Starting Abacavir?

Human leukocyte antigen allele (HLA)-B*5701 is associated with abacavir hypersensitivity. However, the carriage rate of HLA-B*5701 has rarely been studied in Asians. In 534 Korean patients with human immunodeficiency virus infection, HLA-B*5701 status was determined by polymerase chain reaction with HLA-B*5701-specific primers. No patients had the HLA-B*5701 allele (95% confidence interval, 0%-0.7%). This explains the paucity of immunologically confirmed cases of abacavir hypersensitivity in Koreans.Saag M, 2008, CLIN INFECT DIS, V46, P1111, DOI 10.1086/529382Mallal S, 2008, NEW ENGL J MED, V358, P568*PAN ANT GUID AD A, 2008, GUID US ANT AG HIV 1Waters LJ, 2007, AIDS, V21, P2533Sun HY, 2007, J ANTIMICROB CHEMOTH, V60, P599, DOI 10.1093/jac/dkm243Rauch A, 2006, CLIN INFECT DIS, V43, P99Phillips EJ, 2006, CLIN INFECT DIS, V43, P103Martin AM, 2005, TISSUE ANTIGENS, V65, P571, DOI 10.1111/j.1399-0039.2005.00401.xLee KW, 2005, TISSUE ANTIGENS, V65, P437, DOI 10.1111/j.1399-0039.2005.00386.xMiddleton D, 2004, TISSUE ANTIGENS, V63, P555Phillips EJ, 2002, AIDS, V16, P2223Saito S, 2000, TISSUE ANTIGENS, V56, P522Park MH, 1999, TISSUE ANTIGENS, V53, P3861

Lack of Effect of Dexamethasone on Growth of Orientia Tsutsugamushi Gilliam in Mouse L929 Cells

PURPOSE: Previous studies and our own clinical experience suggest that concurrent corticosteroid treatment for severe rickettsial disease with multiorgan failure may improve the clinical course or reduce mortality. However, the use of corticosteroids as adjunctive treatment for rickettsial diseases is controversial. We attempted to determine the influences of corticosteroid on the growth of Orientia tsutsugamushi in vitro to justify and evaluate the clinical applicability of corticosteroid in rickettsial disease. MATERIALS AND METHODS: L929 cells were infected with Orientia tsutsugamushi Gilliam. Dexamethasone was added to the cells at final concentrations of 10¹ and 10⁷ pg/mL. Cultures were incubated at 35°C and processed for flow cytometry on the 6th day after addition of dexamethasone. RESULTS: Observation on the 6th day after treatment with dexamethasone in infected cultures revealed that there was no difference in fluorescence intensity among the treatment wells. Treatment of the cells with dexamethasone at concentrations of 10¹ and 10⁷ pg/mL showed no influence on the growth of Orientia tsutsugamushi. CONCLUSION: Our results to show that isolated corticosteroid does not enhance the replication of Orientia tsutsugamushi in vitro. Concurrent use of anti-inflammatory or immunosuppressive doses of corticosteroids in conjunction with antibiotics may not have detrimental effects on the course of scrub typhus.ope

Phase Variation of Biofilm Formation in Staphylococcus aureus by IS256 Insertion and Its Impact on the Capacity Adhering to Polyurethane Surface

While ica gene of Staphylococcus epidermidis is known to undergo phase variation by insertion of IS256, the phenomenon in Staphylococcus aureus has not been evaluated. Six biofilm-positive strains were tested for the presence of biofilm-negative phase-variant strains by Congo red agar test. For potential phase-variant strains, pulsed-field gel electrophoresis was done to exclude the possibility of contamination. To investigate the mechanism of the biofilm-negative phase variation, PCR for each ica genes were done. Changes of ica genes detected by PCR were confirmed by southern hybridization, and their nucleotides were analyzed by DNA sequencing. Influence of ica genes and biofilm formation on capacity for adherence to biomedical material was evaluated by comparing the ability of adhering to polyurethane surface among a biofilm-negative phase-variant strain and its parent strain. A biofilm-negative phase-variant S. aureus strain was detected from 6 strains tested. icaC gene of the phase-variant strain was found to be inactivated by insertion of additional gene segment, IS256. The biofilm-negative phase-variant strain showed lower adhering capacity to polyurethane than its parent strain. This study shows that phase variation of ica gene occurs in S. aureus by insertion of IS256 also, and this biofilm-negative phase variation reduces adhering capacity of the bacteria

Clinical Features, Risk Factors and Outcomes of Bacteremia due to Enterococci with High-Level Gentamicin Resistance: Comparison with Bacteremia due to Enterococci without High-Level Gentamicin Resistance

High-level gentamicin resistance (HLGR) in enterococci has increased since the 1980s, but the clinical significance of the resistance and its impact on outcome have not been established. One hundred and thirty-six patients with bacteremia caused by enterococci with HLGR (HLGR group) were compared with 79 patients with bacteremia caused by enterococci without HLGR (non-HLGR group). Hematologic malignancy, neutropenia, Enterococcus faecium infection, nosocomial infection and monomicrobial bacteremia were more common in the HLGR group than the non-HLGR group, and APACHE II scores were also higher (P<0.05, in each case). Neutropenia, monomicrobial infection, stay in intensive care at culture, and use of 3rd generation cephalosporin, were independent risk factors for acquisition of HLGR enterococcal bacteremia. Fourteen-day and 30-day mortalities were higher in the HLGR group than the non-HLGR group in univariate analysis (37% vs. 15%, P=0.001; 50% vs. 22%, P<0.001). However, HLGR was not an independent risk factor for mortality due to enterococcal bacteremia in multivariate analysis. Therefore, HLGR enterococcal bacteremia is associated with more severe comorbid conditions and higher mortality than non-HLGR enterococcal bacteremia but the HLGR itself does not contribute significantly to mortality

Predictive scoring models for persistent gram-negative bacteremia that reduce the need for follow-up blood cultures: a retrospective observational cohort study

Background Although the risk factors for positive follow-up blood cultures (FUBCs) in gram-negative bacteremia (GNB) have not been investigated extensively, FUBC has been routinely carried out in many acute care hospitals. We attempted to identify the risk factors and develop a predictive scoring model for positive FUBC in GNB cases. Methods All adults with GNB in a tertiary care hospital were retrospectively identified during a 2-year period, and GNB cases were assigned to eradicable and non-eradicable groups based on whether removal of the source of infection was possible. We performed multivariate logistic analyses to identify risk factors for positive FUBC and built predictive scoring models accordingly. Results Out of 1473 GNB cases, FUBCs were carried out in 1268 cases, and the results were positive in 122 cases. In case of eradicable source of infection, we assigned points according to the coefficients from the multivariate logistic regression analysis: Extended spectrum beta-lactamase-producing microorganism (+ 1 point), catheter-related bloodstream infection (+ 1), unfavorable treatment response (+ 1), quick sequential organ failure assessment score of 2 points or more (+ 1), administration of effective antibiotics (− 1), and adequate source control (− 2). In case of non-eradicable source of infection, the assigned points were end-stage renal disease on hemodialysis (+ 1), unfavorable treatment response (+ 1), and the administration of effective antibiotics (− 2). The areas under the curves were 0.861 (95% confidence interval [95CI] 0.806–0.916) and 0.792 (95CI, 0.724–0.861), respectively. When we applied a cut-off of 0, the specificities and negative predictive values (NPVs) in the eradicable and non-eradicable sources of infection groups were 95.6/92.6% and 95.5/95.0%, respectively. Conclusions FUBC is commonly carried out in GNB cases, but the rate of positive results is less than 10%. In our simple predictive scoring model, zero scores—which were easily achieved following the administration of effective antibiotics and/or adequate source control in both groups—had high NPVs. We expect that the model reported herein will reduce the necessity for FUBCs in GNB cases

Salvage Treatment for Persistent Methicillin-Resistant Staphylococcus aureus Bacteremia: Efficacy of Linezolid With or Without Carbapenem

Background. Persistent methicillin-resistant Staphylococcus aureus (MRSA) bacteremia is associated with high mortality rates, but no treatment strategy has yet been established. We performed this study to evaluate the efficacy of linezolid with or without carbapenem in salvage treatment for persistent MRSA bacteremia. Methods. All adult patients with persistent MRSA bacteremia for >= 7 days from January 2006 through March 2008 who were treated at Seoul National University Hospital were studied. The results of linezolid salvage therapy with or without carbapenem were compared with those of salvage therapy with vancomycin plus aminoglycosides or rifampicin. Results. Thirty-five patients with persistent MRSA bacteremia were studied. The early microbiological response (ie, negative results for follow-up blood culture within 72 hours) was significantly higher in the linezolid-based salvage therapy group than the comparison group (75% vs 17%; P = .006). Adding aminoglycosides or rifampicin to vancomycin was not successful in treating any of the patients, whereas linezolid-based therapy gave an 88% salvage success rate (P < .001). The S. aureus-related mortality rate was lower for patients treated with a linezolid salvage regimen than for patients continually treated with a vancomycin-based regimen (13% vs 53%; P = .030). Conclusions. Linezolid-based salvage therapy effectively eradicated S. aureus from the blood for patients with persistent MRSA bacteremia. The salvage success rate was higher for linezolid therapy than for vancomycin-based combination therapy.Jenkins TC, 2008, CLIN INFECT DIS, V46, P1000, DOI 10.1086/529190Falagas ME, 2008, LANCET INFECT DIS, V8, P53, DOI 10.1016/S1473-3099(07)70312-2Hawkins C, 2007, ARCH INTERN MED, V167, P1861Kollef MH, 2007, CLIN INFECT DIS, V45, pS191, DOI 10.1086/519470Micek ST, 2007, CLIN INFECT DIS, V45, pS184, DOI 10.1086/519471*CLIN LAB STAND I, 2007, M100S17 CLIN LAB STAHidayat LK, 2006, ARCH INTERN MED, V166, P2138Howden BP, 2006, ANTIMICROB AGENTS CH, V50, P3039, DOI 10.1128/AAC.00422-06Hageman JC, 2006, CLIN INFECT DIS, V43, pE42Jacqueline C, 2006, ANTIMICROB AGENTS CH, V50, P2547, DOI 10.1128/AAC.01501-05Sakoulas G, 2006, CLIN INFECT DIS, V42, pS40Jones RN, 2006, CLIN INFECT DIS, V42, pS13Khatib R, 2006, SCAND J INFECT DIS, V38, P7, DOI 10.1080/00365540500372846Wu VC, 2006, CLIN INFECT DIS, V42, P66Jacqueline C, 2005, ANTIMICROB AGENTS CH, V49, P45, DOI 10.1128/AAC.49.1.45-51.2005*CDCP, 2005, CA MRSA CLIN FAQS CDFowler VG, 2004, J INFECT DIS, V190, P1140Wisplinghoff H, 2004, CLIN INFECT DIS, V39, P309, DOI 10.1086/421946Khosrovaneh A, 2004, CLIN INFECT DIS, V38, P1328Howden BP, 2004, CLIN INFECT DIS, V38, P521KIM SH, 2004, 42 ANN M INF DIS SOC, P142Fowler VG, 2003, ARCH INTERN MED, V163, P2066Kim SH, 2003, CLIN INFECT DIS, V37, P794Moise PA, 2002, J ANTIMICROB CHEMOTH, V50, P1017, DOI 10.1093/jac/dkf215Li JS, 2000, CLIN INFECT DIS, V30, P633You I, 2000, DIAGN MICR INFEC DIS, V36, P37Lowy FD, 1998, NEW ENGL J MED, V339, P520Hiramatsu K, 1997, LANCET, V350, P1670LIBMAN H, 1984, ARCH INTERN MED, V144, P5411

Can a routine follow-up blood culture be justified in Klebsiella pneumoniae bacteremia? a retrospective case–control study

Background : The need for mandatory confirmation of negative conversion in Klebsiella pneumoniae bacteremia (KpB) has not been adequately addressed. We conducted a retrospective case–control study of adult patients with KpB over a 5-year period in two tertiary-care hospitals to determine the risk factors for persistent bacteremia and to reevaluate the necessity of follow-up blood culture in KpB. Methods : Persistent KpB is defined as the finding of K. pneumoniae in more than two separate blood-culture samples for longer than a two-day period in a single episode. The case- and control-groups were patients with persistent and non-persistent KpB, respectively, and they were matched 1-to-3 according to age and gender. Results : Among 1068 KpB episodes analyzed after excluding polymicrobial infection and repeated KpB, follow-up blood cultures were performed in 862 cases (80.7%), 62 of which (7.2%) were persistent. Independent risk factors for persistence were intra-abdominal infection, higher Charlsons comorbidity weighted index score, prior solid organ transplantation, and unfavorable treatment response, which was defined as positivity for at least two parameters among fever, leukocytosis, and no decrease of C-reactive protein on the second day after initial culture. A proposed scoring system using four variables, namely, intra-abdominal infection, nosocomial KpB, fever and lack of C-reactive protein decrease, the last two being assessed on the second day after the initial blood culture, showed that only 4.9% of the patients with no risk factors or with only intra-abdominal infection had persistent KpB. Conclusions : Though persistent KpB is uncommon, follow-up blood culture was performed in as many as 80% of the cases in this study. A more careful clinical assessment is warranted to reduce the cost and patient inconvenience involved in follow-up blood culture.Peer Reviewe

The E3 ligase HUWE1 inhibition as a therapeutic strategy to target MYC in multiple myeloma

Proteasome inhibitors have provided a significant advance in the treatment of multiple myeloma (MM). Consequently, there is increasing interest in developing strategies to target E3 ligases, de-ubiquitinases, and/or ubiquitin receptors within the ubiquitin proteasome pathway, with an aim to achieve more specificity and reduced side-effects. Previous studies have shown a role for the E3 ligase HUWE1 in modulating c-MYC, an oncogene frequently dysregulated in MM. Here we investigated HUWE1 in MM. We identified elevated expression of HUWE1 in MM compared with normal cells. Small molecule-mediated inhibition of HUWE1 resulted in growth arrest of MM cell lines without significantly effecting the growth of normal bone marrow cells, suggesting a favorable therapeutic index. Studies using a HUWE1 knockdown model showed similar growth inhibition. HUWE1 expression positively correlated with MYC expression in MM bone marrow cells and correspondingly, genetic knockdown and biochemical inhibition of HUWE1 reduced MYC expression in MM cell lines. Proteomic identification of HUWE1 substrates revealed a strong association of HUWE1 with metabolic processes in MM cells. Intracellular glutamine levels are decreased in the absence of HUWE1 and may contribute to MYC degradation. Finally, HUWE1 depletion in combination with lenalidomide resulted in synergistic anti-MM activity in both in vitro and in vivo models. Taken together, our data demonstrate an important role of HUWE1 in MM cell growth and provides preclinical rationale for therapeutic strategies targeting HUWE1 in MM