Sung-Yeon Cho

Biomarkers of Sepsis

Sepsis remains a leading cause of death in critically ill patients, despite efforts to improve patient outcome. Thus far, no magic drugs exist for severe sepsis and septic shock. Instead, early diagnosis and prompt initial management such as early goal-directed therapy are key to improve sepsis outcome. For early detection of sepsis, biological markers (biomarkers) can help clinicians to distinguish infection from host response to inflammation. Ideally, biomarkers can be used for risk stratification, diagnosis, monitoring of treatment responses, and outcome prediction. More than 170 biomarkers have been identified as useful for evaluating sepsis, including C-reactive protein, procalcitonin, various cytokines, and cell surface markers. Recently, studies have reported on the usefulness of biomarker-guided antibiotic stewardships. However, the other side of these numerous biomarkers is that no novel single laboratory marker can diagnose, predict, and track the treatment of sepsis. The purpose of this review is to summarize several key biomarkers from recent sepsis studies.

The efficacy of non-carbapenem antibiotics for the treatment of community-onset acute pyelonephritis due to extended-spectrum β-lactamase-producing Escherichia coli

OBJECTIVE Extended-spectrum β-lactamase (ESBL)-producing Escherichia coli has become an important cause of community-onset urinary tract infections. We aimed to evaluate the efficacy of non-carbapenem antibiotics for acute pyelonephritis (APN) due to ESBL-producing E. coli. METHODS We conducted a retrospective cohort study of patients with community-onset APN due to ESBL-producing E. coli at a single centre in Korea from 2007 to 2013. Outcomes included both microbiological and clinical failure. To adjust for non-random assignment of antibiotics, the propensity score method of inverse probability of treatment weighting and a multivariable analysis using Cox proportional hazards modelling were employed to estimate the efficacy of non-carbapenem antibiotics as compared with carbapenems. RESULTS Of 152 eligible patients, 85 (55.9%) received carbapenems and 67 (44.1%) received non-carbapenems. Non-carbapenem antibiotics used in this cohort included aminoglycosides (n = 30), β-lactam/β-lactamase inhibitors (n = 13), fluoroquinolones (n = 12) and trimethoprim/sulfamethoxazole (n = 5). Microbiological failure was observed in 16 patients receiving carbapenems (16/83, 19.3%) versus 4 patients receiving non-carbapenem (4/67, 6.0%). After weighting, the risk of microbiological failure was similar between the two groups [weighted hazard ratio (HR) 0.99; 95% CI 0.31-3.19]. In a multivariable regression analysis combined with weights, the estimate did not change (weighted adjusted HR 0.96; 95% CI 0.41-2.27). The clinical failure rate was also similar in the two groups (weighted HR 1.05; 95% CI 0.24-4.62). CONCLUSIONS These results suggest that non-carbapenem antibiotics were as effective as carbapenems as definitive therapy for treating community-onset APN caused by ESBL-producing E. coli if they are active in vitro.

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

BackgroundVancomycin-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.MethodsWe 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.ResultsDuring 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).ConclusionsIn 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.

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.

Clinical Impact of Cytochrome P450 2C19 Genotype on the Treatment of Invasive Aspergillosis under Routine Therapeutic Drug Monitoring of Voriconazole in a Korean Population

Background Genetic polymorphisms of cytochrome P450 enzymes, especially CYP2C19 influence voriconazole pharmacokinetics. However, the impact of CYP2C19 genetic polymorphisms on the therapeutic efficacy and toxicity of voriconazole therapy are not well established. Materials and Methods In this prospective observational study, we analyzed all consecutive adult patients with hematologic diseases who were treated for invasive aspergillosis (IA) with voriconazole between January 2011 and June 2012. CYP2C19 genotype and routine therapeutic drug monitoring of voriconazole were performed. The target range for voriconazole trough levels was 1-5.5 mg/L. Results A total of 104 consecutive patients were enrolled, including 39 homozygous extensive metabolizers (EMs, 38%), 50 heterozygous extensive metabolizers (HEMs, 48%), and 15 poor metabolizers (PMs, 14%). The initial voriconazole trough levels were 1.8, 2.7, and 3.2 mg/L in EMs, HEMs, and PMs, respectively (P = 0.068). Out-of-range initial trough levels were most frequently observed in EMs (46%) followed by HEMs (26%) and PMs (0%) (P = 0.001). The frequency of initial trough levels < 1 mg/L but not > 5.5 mg/L differed significantly among the 3 groups (P = 0.005). However, treatment response, all-cause and IA-attributable mortality, and the occurrence of voriconazole-related adverse events did not differ significantly among the 3 groups (P = 0.399, P = 0.412, P = 0.317, and P = 0.518, respectively). Conclusions While none of the initial voriconazole trough levels in PMs was outside the target range, subtherapeutic initial trough levels were frequent in EMs. Although there was no significant relationship between CYP2C19 genotype and either the clinical outcomes of IA or toxicity of voriconazole, further large-scale multicenter studies using clinical data from homogeneous populations are required.

Amikacin therapy for urinary tract infections caused by extended-spectrum β-lactamase- producing Escherichia coli

Background/Aims: The number of urinary tract infections (UTIs) caused by extended-spectrum β-lactamase-producing Escherichia coli (ESBL-EC) is increasing. In an outpatient setting, there are limited therapeutic options to treat ESBL-producing pathogens. We evaluated the outcomes of amikacin outpatient parenteral antibiotic therapy (OPAT) for UTIs caused by ESBL-EC in patients not pre-treated with carbapenem. Methods: We retrospectively evaluated the outcomes of amikacin OPAT for UTIs caused by ESBL-EC. Results: From November 2011 to October 2012, eight females, who could not be hospitalized for carbapenem treatment, were treated with amikacin OPAT for nine episodes of non-bacteremic ESBL-EC UTIs. Seven of the eight patients had one or more comorbidities. Of the nine UTI cases, three had symptomatic lower UTIs and six had non-bacteremic upper UTIs. In all of the cases, symptomatic and laboratory improvements were observed following amikacin OPAT. One patient showed a delayed relapse with bilateral microabscesses 3 weeks after treatment cessation; however, a clinical and microbiological cure was eventually reached. All of the patients were able to tolerate amikacin OPAT without any significant nephrotoxicity or ototoxicity. Conclusions: Amikacin OPAT represents a feasible therapeutic option for non-bacteremic UTIs caused by ESBL-EC in settings with limited resources.

Carbapenem-resistant Enterobacteriaceae: Prevalence and Risk Factors in a Single Community-Based Hospital in Korea.

Background Carbapenemase-producing Enterobacteriaceae (CPE) are Gram-negative bacteria with increasing prevalence of infection worldwide. In Korea, 25 cases of CPE isolates were reported by the Korea Centers for Disease Control and Prevention in 2011. Most CPE cases were detected mainly at tertiary referral hospitals. We analyzed the prevalence and risk factors for carbapenem-resistant Enterobacteriaceae (CRE) in a mid-sized community-based hospital in Korea. Materials and Methods We retrospectively analyzed all consecutive episodes of Enterobacteriaceae in a mid-sized community-based hospital from January 2013 to February 2014. CRE was defined as organisms of Enterobacteriaceae showing decreased susceptibility to carbapenems. Risk factors for CRE were evaluated by a case–double control design. Carbapenemase was confirmed for CRE using a combined disc test. Results During 229,710 patient-days, 2,510 Enterobacteriaceae isolates were obtained. A total of 41 (1.6%) CRE isolates were enrolled in the study period. Thirteen species (31.7%) were Enterobacter aerogenes, 8 (19.5%) Klebsiella pneumoniae, 5 (12.2%) Enterobacter cloacae, and 15 other species of Enterobacteriaceae, respectively. Among the 41 isolates, only one (2.4%) E. aerogenes isolate belonged to CPE. For evaluation of risk factors, a total of 111 patients were enrolled and this included 37 patients in the CRE group, 37 in control group I (identical species), and 37 in control group II (different species). Based on multivariate analysis, regularly visiting the outpatient clinic was a risk factor for CRE acquisition in the control group I (P = 0.003), while vascular catheter and Charlson comorbidity index score ≥ 3 were risk factors in control group II (P = 0.010 and 0.011, each). Patients with CRE were more likely to experience a reduced level of consciousness, use a vasopressor, be under intensive care, and suffer from acute kidney injury. However, CRE was not an independent predictor of mortality compared with both control groups. Conclusion In conclusion, the prevalence of CRE was higher than expected in a mid-sized community-based hospital in Korea. CRE should be considered when patients have a vascular catheter, high comorbidity score, and regular visits to the outpatient clinic. This study suggests the need for appropriate prevention efforts and constant attention to CRE infection control in a mid-sized community-based hospital.

Breakthrough invasive fungal diseases during voriconazole treatment for aspergillosis: A 5-year retrospective cohort study

Abstract Breakthrough invasive fungal diseases (bIFDs) during voriconazole treatment are concerning, as they are associated with high rates of mortality and pathogen distribution. To evaluate the prevalence, incidence, patient characteristics, including IFD events, and overall mortality of bIFDs during voriconazole treatment for invasive aspergillosis (IA). We retrospectively analyzed the medical records of consecutive patients who had undergone voriconazole treatment for IA and who had bIFD events between January 2011 and December 2015. Eleven bIFD events occurred in 9 patients. The prevalence and incidence of bIFDs were 2.25% (9/368) and 0.22 cases per year, respectively. Overall mortality was 44.4% (4/9). The severity of the illness and persistence of immunodeficiency, mixed infection, and low concentration of the treatment drug at the site of infection were identified as possible causes of bIFDs. Seven of 11 events (63.6%) required continued voriconazole treatment with drug level monitoring. In 4 (36.3%) cases, the treatment was changed to liposomal amphotericin B. Two cases resulted in surgical resection (18.2%). Clinicians should be aware that bIFDs during voriconazole treatment for IA can occur, and active therapeutic approaches are required in these cases.

Determination of posaconazole concentration with LC-MS/MS in adult patients with hematologic malignancy.

BACKGROUND Posaconazole has an important role in the prophylaxis of invasive fungal infections (IFIs), however oral suspension formulation is associated with variable bioavailability. The relationship between posaconazole concentrations achieved with the oral suspension and the IFI occurrence were analyzed along with demographic and clinical covariates (mucositis, diarrhea, liver enzymes, co-medications, and food intake). METHODS One hundred twenty-two adult patients with AML/MDS undergoing remission induction chemotherapy were enrolled. They received posaconazole as prophylaxis and 557 posaconazole measurements were performed with a validated LC-MS/MS method. RESULTS The median (range) posaconazole concentration (ng/ml) on days 2, 3, 7, 14, and 21 was 271 (43-493), 564 (101-1461), 713 (85-2186), 663 (85-1994), and 497 (43-1872), respectively. Thirteen patients (11%) developed proven (1/13), probable (2/13), and possible IFIs (10/13). A significant relationship existed between lower steady-state posaconazole concentrations and a higher breakthrough IFI incidence by binary logistic regression (P=0.0108). Posaconazole value of ≥ 338 ng/ml on day 3 predicted the achievement of ≥ 500 ng/ml at day 7 (sensitivity: 78.5%, specificity: 66.7%, AUC: 0.747). Food intake (P=0.0014) and proton pump inhibitor (P=0.0063) were significantly associated with higher and lower posaconazole concentrations, respectively. CONCLUSIONS TDM of posaconazole oral suspension formulation is recommended based on the exposure-response relationship of the present study.

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 MSCs 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.