Intra-host diversity of drug-resistant cytomegalovirus: A case report of cytomegalovirus infection after allogeneic hematopoietic cell transplantation.

Cytomegalovirus (CMV) is a major infectious agent causing severe complications in allogeneic hematopoietic cell transplantation (HCT) recipients, thereby warranting the need for aggressive preemptive or targeted antiviral therapy. However, prolonged or repeated use of antiviral agents, such as ganciclovir (GCV), foscarnet (FOS), and cidofovir (CDV), can result in drug-resistant CMV infection, posing challenges to successful outcomes. Here, we report a case of a patient with acute myeloid leukemia and drug-resistant CMV infection who presented with persistent CMV DNAemia, colitis, pneumonia, and encephalitis. An intra-host diversity of UL97 and UL54 mutations were detected through the genotypic resistance testing conducted on two blood samples (D+199 and D+224) and a cerebrospinal fluid (CSF) specimen (D+260) collected from the patient. UL97 L595W/L595F and L595W mutations were detected in the blood and CSF samples, respectively, that conferred GCV resistance. UL54 F412L mutation detected in all three samples conferred GCV/CDV resistance. However, the V787L mutation of UL54, conferring GCV/FOS resistance, was observed only in the D+224 blood sample. Despite combination therapy with FOS and high dose GCV and adjunctive therapy with leflunomide, the patient died from CMV infection and multiple organ failure on D+279. Further data on resistant mutations and intra-host diversity of CMV should be accumulated to elucidate the antiviral resistance and related outcomes.

Clinical Characteristics and Antimicrobial Susceptibility Trends in Citrobacter Bacteremia: An 11-Year Single-Center Experience.

BACKGROUND: Recently, Citrobacter freundii bacteremia outbreak in a neonatal intensive care unit has attracted public attention in Korea. However, Citrobacter bacteremia is uncommon and usually occurs in patients with underlying diseases such as malignancy and hepatobiliary diseases. Increase in resistance and emerging of multidrug resistance among Citrobacter species have gradually been reported. The aim of this study was to investigate the clinical characteristics and outcome of C. freundii and non-freundii bacteremia and antimicrobial susceptibility trends. MATERIALS AND METHODS: We reviewed the medical records of patients with Citrobacter bacteremia at St. Mary's Hospital, from 2007 to 2017. RESULTS: A total of 43 patients with a median age of 72 (24-93) years was identified and 90.7% of them had comorbidities. Twenty-nine (67.4%) patients had C. freundii bacteremia while 14 had non-freundii bacteremia (six of C. braakii, five of C. koseri, two of C. amalonaticus and one of C. youngae). A total of 26 (51.2%) patients had community-acquired infection and intra-abdominal infection including hepatobiliary tract was the most common portal of entry (24/43, 55.8%). Moreover, hepatobiliary tract was the leading primary site of nosocomial infection (9/17, 52.9%). Polymicrobial bacteremia was observed in 21 (48.8%) patients. The percentages of Citrobacter species susceptible to ampicillin, amikacin, aztreonam, cefazolin, cefoxitin, cefotaxime, cefepime, piperacillin-tazobactam, ciprofloxacin, and imipenem were 9.5%, 97.6%, 73.8%, 9.5%, 14.3%, 71.4%, 92.9%, 83.3%, 83.3% and 100%, respectively. The resistance rate did not increase during the study period. Of 39 patients treated with antibiotics, 36 (92.3%) received appropriate empirical antibiotics. Overall mortality was 18.6%. High Charlson comorbidity index and Pitt bacteremia score were significant risk factors for death in univariate analysis and showed trends in the multivariate analysis. No significant difference in clinical features and antimicrobial susceptibility rate was observed between C. freundii and non-freundii bacteremia. CONCLUSION: Citrobacter bacteremia was predominant in the elderly with comorbidities, while no pediatric case was observed. Hepatobiliary tract is the leading primary focus of bacteremia both in community-acquired and nosocomial infection. The rate of susceptibility to antibiotics has not changed in the last 11 years.

Epidemiology and Antifungal Susceptibility Profile of Aspergillus Species: Comparison between Environmental and Clinical Isolates from Patients with Hematologic Malignancies.

Global data on the epidemiology and susceptibility of Aspergillus are crucial in the management of invasive aspergillosis. Here, we aimed to determine the characteristics of clinical and environmental Aspergillus isolates, focusing mainly on hematologic malignancy patients. We prospectively collected all consecutive cases and clinical isolates of culture-positive proven/probable invasive aspergillosis patients from January 2016 to April 2018 and sampled the air inside and outside the hospital. Cryptic species-level identification of Aspergillus, antifungal susceptibilities, and cyp51 gene sequencing were performed, and clinical data were analyzed. This study was conducted as part of the Catholic Hematology Hospital Fungi Epidemiology (CAFÉ) study. A total of 207 proven/probable invasive aspergillosis and 102 clinical and 129 environmental Aspergillus isolates were included in this analysis. The incidence of proven/probable invasive aspergillosis was 1.3 cases/1,000 patient-days during the study period. Cryptic Aspergillus species accounted for 33.8%, with no differences in proportions between the clinical and environmental isolates. Section Nigri presented a high proportion (70.5%) of cryptic species, mainly from A. tubingensis and A. awamori: the former being dominant in environmental samples, and the latter being more common in clinical isolates (P < 0.001). Of 91 A. fumigatus isolates, azole-resistant A. fumigatus was found in 5.3% of all A. fumigatus isolates. Three isolates presented the TR34/L98H mutation of the cyp51A gene. Patients with invasive aspergillosis caused by azole-resistant A. fumigatus showed 100% all-cause mortality at 100 days. This study demonstrates the significant portion of cryptic Aspergillus species and clinical implications of azole resistance and underscores the comparison between clinical and environmental isolates.

PDCD4 Is an Androgen-Repressed Tumor Suppressor that Regulates Prostate Cancer Growth and Castration Resistance.

Androgen receptor (AR) transcriptional activity contributes to prostate cancer development and castration resistance. The growth and survival pathways driven by AR remain incompletely defined. Here, we found PDCD4 to be a new target of AR signaling and a potent regulator of prostate cancer cell growth, survival, and castration resistance. The 3' untranslated region of PDCD4 is directly targeted by the androgen-induced miRNA, miR-21. Androgen treatment suppressed PDCD4 expression in a dose responsive and miR-21-dependent manner. Correspondingly, AR inhibition dose-responsively induced PDCD4 expression. Using data from prostate cancer tissue samples in The Cancer Genome Atlas (TCGA), we found a significant and inverse correlation between miR-21 and PDCD4 mRNA and protein levels. Higher Gleason grade tumors exhibited significantly higher levels of miR-21 and significantly lower levels of PDCD4 mRNA and protein. PDCD4 knockdown enhanced androgen-dependent cell proliferation and cell-cycle progression, inhibited apoptosis, and was sufficient to drive androgen-independent growth. On the other hand, PDCD4 overexpression inhibited miR-21-mediated growth and androgen independence. The stable knockdown of PDCD4 in androgen-dependent prostate cancer cells enhanced subcutaneous tumor take rate in vivo, accelerated tumor growth, and was sufficient for castration-resistant tumor growth. IMPLICATIONS: This study provides the first evidence that PDCD4 is an androgen-suppressed protein capable of regulating prostate cancer cell proliferation, apoptosis, and castration resistance. These results uncover miR-21 and PDCD4-regulated pathways as potential new targets for castration-resistant prostate cancer.

Cytomegalovirus Colitis during Dasatinib Treatment for Patients with Hematologic Malignancy: Case Series and Literature Review.

Dasatinib, a tyrosine kinase inhibitor, is widely used for patients with chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia. Although the drug has a potent immunosuppressive effect, infectious complications during dasatinib treatment have been reported rarely. We describe five patients who developed cytomegalovirus (CMV) colitis during dasatinib treatment, in whom the colitis was initially confused with other causes. The patients, three with chronic myeloid leukemia, and two with acute lymphoblastic leukemia, were diagnosed with CMV colitis based on endoscopic and histologic findings. The patients who examined blood CMV polymerase chain reaction were all positive. The patients received antiviral therapy in the form of either ganciclovir or valganciclovir, and the overall treatment outcome was fair. These cases suggest that physicians should consider the possibility of CMV reactivation when treating diarrhea and/or hematochezia in patients on dasatinib.

Factors affecting the clinical relevance of Corynebacterium striatum isolated from blood cultures.

This study aimed to identify clinical or microbiological factors affecting the clinical relevance of Corynebacterium striatum isolated from blood cultures. A total of 64 isolates from 51 patients identified as C. striatum by matrix assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) and 16S rRNA gene sequencing were assessed. More than two blood cultures were positive in 25 (48.1%) patients. Diabetes, solid tumor, and a history of previous exposure to antibiotics were more common in patients with multiple positive blood cultures. Charlson comorbidity scores were also higher, and more isolates were recovered after 48 hours of hospital stay in patients with multiple positive blood cultures. Strains recovered from patients with multiple positive blood cultures produced significantly more biofilm. Based on multilocus sequence typing (MLST), sequence type (ST) 20 (31.3%) was the most dominant, followed by ST2 (20.3%) and ST23 (10.9%). There was no relationship between the number of positive blood culture sets and sequence typing. In multivariate analyses, Carlson comorbidity score (odds ratio [OR], 1.91; 95% confidence interval [CI], 1.09-3.36; P = 0.03) and biofilm formation were associated with multiple positive blood cultures (OR, 17.43; 95% CI, 3.71-81.91; P = 0.03). This study provides evidence that the biofilm phenotype could contribute to determining the clinical significance of C. striatum in patients with severe underlying conditions. The predominance of certain STs suggests the relatedness of C. striatum infection and the nosocomial environment.

Cell-type specific expression of oncogenic and tumor suppressive microRNAs in the human prostate and prostate cancer.

MiR-1 and miR-143 are frequently reduced in human prostate cancer (PCa), while miR-141 and miR-21 are frequently elevated. Consequently, these miRNAs have been studied as cell-autonomous tumor suppressors and oncogenes. However, the cell-type specificity of these miRNAs is not well defined in prostate tissue. Through two different microdissection techniques, and droplet digital RT-PCR, we quantified these miRNAs in the stroma and epithelium of radical prostatectomy specimens. In contrast to their purported roles as cell-autonomous tumor suppressors, we found miR-1 and miR-143 expression to be predominantly stromal. Conversely, miR-141 was predominantly epithelial. miR-21 was detected in both stroma and epithelium. Strikingly, the levels of miR-1 and miR-143 were significantly reduced in tumor-associated stroma, but not tumor epithelium. Gene expression analyses in human cell lines, tissues, and prostate-derived stromal cultures support the cell-type selective expression of miR-1, miR-141, and miR-143. Analyses of the PCa Genome Atlas (TCGA-PRAD) showed a strong positive correlation between stromal markers and miR-1 and miR-143, and a strong negative correlation between stromal markers and miR-141. In these tumors, loss of miR-1 and gain of miR-21 was highly associated with biochemical recurrence. These data shed new light on stromal and epithelial miRNA expression in the PCa tumor microenvironment.

Risk factors and clinical outcomes of breakthrough yeast bloodstream infections in patients with hematological malignancies in the era of newer antifungal agents.

Although yeast bloodstream infections (BSIs) are increasingly being reported in patients with hematological malignancies undergoing antifungal therapy, clinical information regarding breakthrough infections is scarce. The aim of this study was to determine the risk factors for and clinical outcomes of breakthrough yeast BSIs in patients with hematological malignancies in the era of newer antifungal agents. Between 2011 and 2014, all consecutive patients with hematological malignancies who developed yeast BSIs were included in a case-control study wherein breakthrough infections (cases) and de novo infections (controls) were compared. Of 49 patients with yeast BSIs, 21 (43%) met the criteria for breakthrough infections. The proportions of Candida krusei and Candida tropicalis in the cases and controls were significantly different (32% [7/22] vs. 3% [1/29], P = .015; 5% [1/22] vs. 38% [11/29], P = .007, respectively). Acute leukemia, presence of a central venous catheter and neutropenia in the 3 days prior to BSI were significant risk factors for breakthrough infections. Six-week mortality rates was 33% [7/21] in the cases and 43% [12/28] in the controls (P = .564). Refractory neutropenia and the Pitt bacteremia score were independent predictors of 6-week mortality. In conclusion, breakthrough infections accounted for a significant proportion of yeast BSIs in patients with hematological malignancies. However, these infections did not increase the risk of death by themselves. Our results suggest that current clinical management of breakthrough yeast BSIs, which includes switching to a different antifungal class and prompt catheter removal is reasonable.

Clinical Significance of Human Coronavirus in Bronchoalveolar Lavage Samples From Hematopoietic Cell Transplant Recipients and Patients With Hematologic Malignancies.

BACKGROUND.: The possible role of human coronavirus (HCoV) in lower respiratory tract disease (LRTD) in hematopoietic cell transplant (HCT) recipients and patients with hematologic malignancies (HM) has not been well studied. METHODS.: We conducted a retrospective review of HCT/HM patients with HCoV detected in bronchoalveolar lavage (BAL). HCoV strains were identified in BAL samples using strain-specific polymerase chain reaction. Mortality rates were compared among HCT recipients with LRTD caused by HCoV, respiratory syncytial virus (RSV), influenza virus, or parainfluenza virus (PIV) by multivariable Cox regression analysis. RESULTS.: We identified 35 patients (37 episodes) with HCoV LRTD. Among 23 available BAL samples, 48% were strain OC43, 22% were NL63, 17% were 229E, and 13% were HKU1. Overall, 21 patients (60%) required oxygen therapy at diagnosis and 19 (54%) died within 90 days of diagnosis. Respiratory copathogens were detected in 21 episodes (57%), including viruses (n = 12), fungi (n = 10), and bacteria (n = 8). Mortality rates were not different between patients with and without copathogens (P = .65). In multivariable models, mortality associated with HCoV LRTD was similar to that seen with RSV, influenza, and PIV LRTD in HCT recipients (adjusted hazard ratio, 1.34 [95% confidence interval, .66-2.71], P = .41 vs RSV, adjusted for cell source, cytopenia, copathogens, oxygen use, and steroid use). CONCLUSIONS.: HCoV LRTD in patients with HCT or HM is associated with high rates of oxygen use and mortality. Mortality associated with HCoV LRTD in HCT recipients appears to be similar to that seen with RSV, influenza virus, and PIV.

The demanding attention of tuberculosis in allogeneic hematopoietic stem cell transplantation recipients: High incidence compared with general population.

BACKGROUND: The risk of developing tuberculosis (TB) in allogeneic hematopoietic stem cell transplantation (HSCT) recipients is expected to be relatively high in an intermediate TB burden country. This single-center retrospective study was conducted to investigate risk factors and the incidence of TB after allogeneic HSCT. METHODS: From January 2004 to March 2011, 845 adult patients were enrolled. Starting April 2009, patients were given isoniazid (INH) prophylaxis based on interferon-γ release assay results. The incidence of TB was analyzed before and after April 2009, and compared it with that of the general population in Korea. RESULTS: TB was diagnosed in 21 (2.49%) of the 845 allogeneic HSCT patients. The median time to the development of TB was 386 days after transplantation (range, 49-886). Compared with the general population, the standardized incidence ratio of TB was 9.10 (95% CI; 5.59-14.79). Extensive chronic graft-versus-host disease (GVHD) was associated with the development of TB (P = 0.003). Acute GVHD, conditioning regimen with total body irradiation and conditioning intensity were not significantly related. INH prophylaxis did not reduce the incidence of TB (P = 0.548). Among 21 TB patients, one patient had INH prophylaxis. CONCLUSION: Allogeneic HSCT recipients especially those who suffer from extensive chronic GVHD are at a high risk of developing TB. INH prophylaxis did not statistically change the incidence of TB, however, further well-designed prospective studies are needed.

Human rhinovirus detection in the lower respiratory tract of hematopoietic cell transplant recipients: association with mortality.

Human rhinoviruses are the most common respiratory viruses detected in patients after hematopoietic cell transplantation. Although rhinovirus appears to occasionally cause severe lower respiratory tract infection in immunocompromised patients, the clinical significance of rhinovirus detection in the lower respiratory tract remains unknown. We evaluated 697 recipients transplanted between 1993 and 2015 with rhinovirus in respiratory samples. As comparative cohorts, 273 recipients with lower respiratory tract infection caused by respiratory syncytial virus (N=117), parainfluenza virus (N=120), or influenza (N=36) were analyzed. Factors associated with mortality were analyzed using Cox proportional hazard models. Among 569 subjects with rhinovirus upper respiratory tract infection and 128 subjects with rhinovirus lower respiratory tract infection, probabilities of overall mortality at 90 days were 6% and 41%, respectively (P<0.001). The survival rate after lower respiratory tract infection was not affected by the presence of co-pathogens (55% in patients with co-pathogens, 64% in patients without, P=0.34). Low monocyte count (P=0.027), oxygen use (P=0.015), and steroid dose greater than 1 mg/kg/day (P=0.003) before diagnosis were significantly associated with mortality among patients with lower respiratory tract infection in multivariable analysis. Mortality after rhinovirus lower respiratory tract infection was similar to that after lower respiratory tract infection by respiratory syncytial virus, parainfluenza virus or influenza in an adjusted model. In summary, transplant recipients with rhinovirus detection in the lower respiratory tract had high mortality rates comparable to viral pneumonia associated with other well-established respiratory viruses. Our data suggest rhinovirus can contribute to severe pulmonary disease in immunocompromised hosts.

Lower Respiratory Tract Diseases Caused by Common Respiratory Viruses among Stem Cell Transplantation Recipients: A Single Center Experience in Korea.

PURPOSE: To describe the incidence, clinical courses, and risk factors for mortality of lower respiratory tract diseases (LRDs) caused by common respiratory viruses (CRVs) in stem cell transplantation (SCT) recipients. MATERIALS AND METHODS: We retrospectively reviewed the medical records of 1038 patients who received SCT between January 2007 and August 2011 at a single center in Korea. RESULTS: Seventy-one CRV-LRDs were identified in 67 (6.5%) patients. The human parainfluenza virus (HPIV) was the most common causative pathogen of CRV-LRDs at 100 days [cumulative incidence estimate, 23.5%; 95% confidence interval (CI), 3.3-43.7] and 1 year (cumulative incidence estimate, 69.2%; 95% CI, 45.9-92.5) following SCT. The 30-day overall mortality rates due to influenza-LRDs, respiratory syncytial virus-LRDs, HPIV-LRDs, and human rhinovirus-LRDs were 35.7, 25.8, 31.6, and 42.8%, respectively. Co-pathogens in respiratory specimens were detected in 23 (33.8%) patients. The overall mortality at day 30 after CRV-LRD diagnosis was 32.8% (22/67). High-dose steroid usage (p=0.025), a severe state of immunodeficiency (p=0.033), and lymphopenia (p=0.006) were significantly associated with death within 30 days following CRV-LRD diagnosis in a univariate analysis. Multivariate logistic regression analysis revealed that high-dose steroid usage [odds ratio (OR), 4.05; 95% CI, 1.12-14.61; p=0.033] and lymphopenia (OR, 6.57; 95% CI, 1.80-24.03; p=0.004) were independent risk factors for mortality within 30 days of CRV-LRDs. CONCLUSION: CRV-LRDs among SCT recipients showed substantially high morbidity and mortality rates. Therefore, the implement of an active diagnostic approaches for CRV infections is required for SCT recipients with respiratory symptoms, especially those receiving high-dose steroids or with lymphopenia.

Therapeutic drug monitoring and safety of intravenous voriconazole formulated with sulfobutylether ß-cyclodextrin in haematological patients with renal impairment.

Because of concerns about accumulation of cyclodextrin, oral voriconazole is recommended for patients with renal impairment. However, intravenous voriconazole may occasionally be imperative in critically ill patients with life-threatening invasive aspergillosis. We investigated the clinical effects of intravenous voriconazole formulated with sulfobutylether ß-cyclodextrin (SBECD) in patients with renal impairment. A prospective observational study was conducted on 25 adult patients with haematological malignancies who were treated with intravenous voriconazole for invasive aspergillosis. Among them, seven patients had a baseline creatinine clearance (CrCl) <50 ml min(-1) (case). Although voriconazole trough concentrations were significantly higher in cases (5.84 mg l(-1) ) than controls (2.28 mg l(-1) ), the proportion of concentrations within the target range did not differ between two groups (4/7 and 12/18, respectively; P = 0.658). The frequency of severe adverse events in cases (3/7) was comparable to that of controls (4/18; P = 0.355). No patients showed significant deterioration in renal function after the voriconazole therapy even in patients with renal impairment. Although CrCl <50 ml min(-1) was associated with higher voriconazole concentrations, its clinical impact remains unclear. SBECD-formulated intravenous voriconazole did not lead to a higher incidence of severe adverse events including nephrotoxicity in haematological patients with CrCl <50 ml min(-1) .

Immunomodulatory effect of mesenchymal stem cells on the immune response of macrophages stimulated by Aspergillus fumigatus conidia.

Mesenchymal stem cells (MSCs) are known to exert potent immunosuppression and anti-inflammatory effects. There is growing interest in their use for immunotherapy for controlling inflammation as well as acute organ injury. However, there are few reports regarding MSC's immunomodulatory effects in the settings of fungal infection. In this study, we attempted to examine the immunomodulatory effects of MSCs in response to Aspergillus fumigatus We measured the cytokine response of murine MSCs on the immune response of murine macrophages (J774A.1 cells) evoked by A. fumigatus conidia. In addition, we evaluated the effect of granulocyte-macrophage colony-stimulating factor (GM-CSF) on the MSC-related cytokine response and fungal growth. As a results, after conidia stimulation, tumor necrosis factor (TNF)-α was down-regulated and interleukin (IL)-10 was up-regulated in MSC-treated J774A.1 cells when compared to J774A.1 cells alone. In addition, fungal growth was reduced in MSC-treated J774A.1 cells when compared to J774A.1 cells, which recovered by GM-CSF. However, the effect of MSCs on the cytokine response was not reversed by GM-CSF. NF-κB translocation decreased in MSC-treated J774A.1 cells compared to J774A.1 cells alone. In conclusion, MSCs demonstrate immunomodulatory properties in both aspects of cytokines and fungal growth. The anti-inflammatory effect of MSCs with regard to cytokine response might be associated with decreased NF-κB translocation, and is not reversed by GM-CSF.

Cost-benefit Analysis of Posaconazole Versus Fluconazole or Itraconazole as a Primary Antifungal Prophylaxis in High-risk Hematologic Patients: A Propensity Score-matched Analysis.

PURPOSE: Posaconazole is effective for the prophylaxis of invasive fungal infections (IFIs) in patients with acute myeloid leukemia or myelodysplastic syndrome during remission induction chemotherapy. However, a cost-benefit analysis of posaconazole versus fluconazole or itraconazole has not been conducted in Korea. METHODS: We retrospectively reviewed data for all consecutive patients who received primary antifungal prophylaxis during remission induction chemotherapy in our acute myeloid leukemia/myelodysplastic syndrome cohort from December 2010 to November 2013. Patient characteristics and factors known as a risk of IFI were matched with propensity score analysis. We evaluated the medical cost according to the prophylactic antifungal agents (posaconazole vs fluconazole/itraconazole), the development of breakthrough IFIs, and survival status after propensity score matching in a 1:1 ratio. FINDINGS: Of the 419 baseline patients, 100 patients in each group were analyzed after matching. A significant decrease was found in the development of breakthrough proven or probable IFIs (3.0% vs 14.0%; P = 0.009) and the rate of empirical antifungal therapy (EAFT) (12.0% vs 46.0%; P < 0.001) in the posaconazole group. Total in-hospital medical costs per patient were not statistically different between posaconazole and fluconazole/itraconazole prophylaxis. However, the daily medical cost was lower for posaconazole prophylaxis, resulting in a total daily cost savings of $72 (₩79,458) per patient (P = 0.002). In the cases of breakthrough proven/probable IFIs, EAFT, and in-hospital deaths, the total medical costs per patient were significantly higher than in nonproven/probable IFIs, non-EAFT, and in-hospital survivors, as much as $7,916 (₩8,700,758), $4605 (₩5,062,529), and $11,134 (₩12,238,422), respectively. Costs for the antifungal agent used in targeted or empirical therapy were lower in the posaconazole group, resulting in a savings of $697 (₩766,347) per patient (P < 0.001). IMPLICATIONS: Posaconazole appears to be cost beneficial for primary antifungal prophylaxis in high-risk patients with hematologic malignancy, at a single center, in Korea. Cost-benefit is closely related with clinical outcomes, including breakthrough IFI development, EAFT, and survival status.

Posaconazole for primary antifungal prophylaxis in patients with acute myeloid leukaemia or myelodysplastic syndrome during remission induction chemotherapy: a single-centre retrospective study in Korea and clinical considerations.

Posaconazole was introduced as the primary antifungal prophylaxis (PAP) in acute myeloid leukaemia (AML) or myelodysplastic syndrome (MDS) patients during remission induction chemotherapy. Data on breakthrough invasive fungal infections (IFIs) from various centres are essential, as there are several considerations in treating IFIs in the posaconazole era. The aim of this study was to evaluate the effectiveness of posaconazole PAP and identify characteristics of IFIs at a single centre in Korea. We retrospectively reviewed consecutive patients with AML/MDS undergoing remission induction chemotherapy between December 2010 and November 2013. Of the 424 patients, 140 received posaconazole and 284 received fluconazole prophylaxis. The incidence of breakthrough proven/probable IFIs (15.5% vs. 2.9%, P < 0.001) and empirical antifungal treatment (EAFT) (45.8% vs. 12.9%, P < 0.001) decreased in the posaconazole group compared to the fluconazole group. In the posaconazole PAP group, two cases of breakthrough mucormycosis were noted among 13 proven/probable/possible IFI cases (15.4%). Overall and IFI-related mortality was 12.1% and 1.9% respectively. Fungus-free survival was significantly higher in the posaconazole group (74.7% vs. 87.1%, P = 0.028). Breakthrough IFIs and EAFT decreased significantly after posaconazole PAP. The benefit in fungus-free survival was noted with posaconazole PAP. Clinicians should be vigilant to identify non-Aspergillus IFIs with active diagnostic effort.

Chenodeoxycholic Acid Reduces Hypoxia Inducible Factor-1α Protein and Its Target Genes.

This study evaluated HIF-1α inhibitors under different hypoxic conditions, physiological hypoxia (5% O2) and severe hypoxia (0.1% O2). We found that chenodeoxy cholic acid (CDCA) reduced the amount of HIF-1α protein only under physiological hypoxia but not under severe hypoxia without decreasing its mRNA level. By using a proteasome inhibitor MG132 and a translation inhibitor cyclohexamide, we showed that CDCA reduced HIF-1α protein by decreasing its translation but not by enhancing its degradation. The following findings indicated that farnesoid X receptor (FXR), a CDCA receptor and its target gene, Small heterodimer partner (SHP) are not involved in this effect of CDCA. Distinctly from CDCA, MG132 prevented SHP and an exogenous FXR agonist, GW4064 from reducing HIF-1α protein. Furthermore a FXR antagonist, guggulsterone failed to prevent CDCA from decreasing HIF-1α protein. Furthermore, guggulsterone by itself reduced HIF-1α protein even in the presence of MG132. These findings suggested that CDCA and guggulsterone reduced the translation of HIF-1α in a mechanism which FXR and SHP are not involved. This study reveals novel therapeutic functions of traditional nontoxic drugs, CDCA and guggulsterone, as inhibitors of HIF-1α protein.

Stenotrophomonas maltophilia bloodstream infection in patients with hematologic malignancies: a retrospective study and in vitro activities of antimicrobial combinations.

BACKGROUND: Stenotrophomonas maltophilia causes serious infections in immunocompromised hosts. Here, we analyzed the clinical characteristics of S. maltophilia bloodstream infection (BSI) in patients with hematologic malignancies and evaluated in vitro synergistic effects of antimicrobial combinations. METHODS: We retrospectively reviewed all consecutive episodes of S. maltophilia BSIs in adult hematologic patients from June 2009 to May 2014, with in vitro susceptibility and synergy tests using high-throughput bioluminescence assay performed for available clinical isolates. RESULTS: Among 11,004 admissions during 5-year period, 31 cases were identified as S. maltophilia BSIs. The incidence rate of S. maltophilia BSI was 0.134 cases/1,000 patient-days. Overall and attributable mortality of S. maltophilia BSI was 64.5% and 38.7%, respectively. Severe neutropenia (adjusted hazard ratio [HR] 5.24, p =0.013), shock at the onset of BSI (adjusted HR 6.05, p <0.001), and pneumonia (adjusted HR 3.15, p =0.017) were independent risk factors for mortality. In vitro susceptibilities to ceftazidime, levofloxacin, ticarcillin-clavulanic acid (TIM) and trimethoprim-sulfamethoxazole (SXT) were 11.1%, 44.0%, 40.7%, and 88.9%, respectively. MIC50/MIC90 for moxifloxacin and tigecycline were 1/4 mg/L and 4/8 mg/L. The 50% and 90% fractional inhibitory concentrations (FIC(50)/FIC(90)) of clinical isolates against a combination of SXT and TIM were 0.500/0.750. For SXT plus levofloxacin or moxifloxacin, FIC(50)/FIC(90) were 0.625/1.000 and 0.625/0.625, respectively. CONCLUSION: S. maltophilia BSIs show high mortality, which is related to severe neutropenia, shock, and S. maltophilia pneumonia. Based upon drug susceptibility testing, the primary treatment of choice for S. maltophilia BSIs should be SXT in hematologic patients, rather than quinolones, with combination therapies including SXT serving as a feasible treatment option.

Epidemiology and clinical features of bloodstream infections in hematology wards: one year experience at the catholic blood and marrow transplantation center.

BACKGROUND: The aim of this study was to investigate the clinical features and epidemiology of bloodstream infections (BSIs) in 2 distinctive hematological wards of the Catholic Blood and Marrow Transplantation (BMT) center. MATERIALS AND METHODS: We retrospectively reviewed the medical data of patients who developed BSIs from June 2009 to May 2010 in 2 hematologic wards at the Catholic BMT center. Ward A is a 44-bed unit mainly conducting conventional high dose chemotherapy and ward B is a 23-bed unit exclusively conducting BMT. RESULTS: Overall, 222 BSI episodes were developed from 159 patients. Acute myeloid leukemia in ward A and multiple myeloma in ward B were more frequent than in ward B and A, respectively. Sex, age, presence of neutropenia, shock, Pitt bacteremia score, type of central catheter, level of C-reactive protein, duration of admission days, type of BSI, overall mortality and distribution of organisms were not different between the 2 wards. There were 202 monomicrobial and 20 polymicrobial BSI episodes, including 2 fungemia episodes. The incidence rate of overall BSIs per 1,000 patient-days was higher in ward A than in ward B (incidence rate ratio 2.88, 95% confidence interval 1.97-4.22, P<0.001). Among 243 organisms isolated, the number of gram positives, gram negatives and fungi were 122, 119 and 2, respectively. Escherichia coli was the most common organism in both ward A and B (27.6% and 42.4%), followed by viridians streptococci (18.6% and 15.2%) and Klebsiella pneumoniae (13.3% and 9.0%). Extended spectrum beta-lactamase (ESBL) producers accounted for 31.9% (23/72) of E. coli and 71.0% (22/31) of K. pneumoniae. Out of 19 Enterococcus faecium, 7 isolates (36.8%) were resistant to vancomycin. The crude mortality rates at 7 and 30 days after each BSI episode were 4.5% (10/222) and 13.1% (29/222), and were significantly higher in the patients with shock compared with those without shock (20.5% vs. 1.1%, P<0.001 and 38.5% vs. 7.7%, P<0.001, respectively). CONCLUSIONS: The incidence rate of BSIs was higher in patients receiving chemotherapy than those receiving BMT, but the distribution of organisms was not different between the 2 wards. E. coli was the most common causative BSI organism in hematologic wards followed by viridians streptococci and K. pneumoniae.

Impact of vancomycin resistance on mortality in neutropenic patients with enterococcal bloodstream infection: a retrospective study.

BACKGROUND: Vancomycin-resistant Enterococcus (VRE) bloodstream infection (BSI) is generally associated with the delayed administration of adequate antibiotics. The identification of risk factors and outcomes of VRE BSI is necessary for establishing strategies for managing neutropenic fever in patients with hematological malignancies. METHODS: We retrospectively analysed consecutive cases of enterococcal BSI in patients with neutropenia after chemotherapy or stem cell transplantation between July 2009 and December 2011 at a single center. RESULTS: During the 30-month period, among 1,587 neutropenic patients, the incidence rate of enterococcal BSI was 1.76 cases per 1,000 person-days. Of the 91 enterococcal BSIs, there were 24 cases of VRE. VRE BSI was associated with E. faecium infection (P < .001), prolonged hospitalization (P = .025) and delayed administration (≥ 48 hours after the febrile episode) of adequate antibiotics (P = .002). The attributable mortality was 17% and 9% for VRE and vancomycin-susceptible Enterococcus (VSE), respectively (P = .447). The 30-day crude mortality was 27% and 23% for VRE and VSE, respectively (OR 1.38, 95% CI 0.53-3.59; P = .059). Only SAPS-II was an independent predictive factor for death (adjusted OR 1.12, 95% CI 1.08-1.17; P < .001). CONCLUSIONS: In conclusion, vancomycin resistance showed some trend towards increasing 30-day mortality, but is not statistically significant despite the delayed use of adequate antibiotics (≥48 hours). Only underlying severity of medical condition predicts poor outcome in a relatively homogeneous group of neutropenic patients.