Computational-Driven Epitope Verification and Affinity Maturation of TLR4-Targeting Antibodies.

Toll-like receptor (TLR) signaling plays a critical role in the induction and progression of autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematous, experimental autoimmune encephalitis, type 1 diabetes mellitus and neurodegenerative diseases. Deciphering antigen recognition by antibodies provides insights and defines the mechanism of action into the progression of immune responses. Multiple strategies, including phage display and hybridoma technologies, have been used to enhance the affinity of antibodies for their respective epitopes. Here, we investigate the TLR4 antibody-binding epitope by computational-driven approach. We demonstrate that three important residues, i.e., Y328, N329, and K349 of TLR4 antibody binding epitope identified upon in silico mutagenesis, affect not only the interaction and binding affinity of antibody but also influence the structural integrity of TLR4. Furthermore, we predict a novel epitope at the TLR4-MD2 interface which can be targeted and explored for therapeutic antibodies and small molecules. This technique provides an in-depth insight into antibody-antigen interactions at the resolution and will be beneficial for the development of new monoclonal antibodies. Computational techniques, if coupled with experimental methods, will shorten the duration of rational design and development of antibody therapeutics.

Redundant combinations of antianaerobic antimicrobials: impact of pharmacist-based prospective audit and feedback and prescription characteristics.

This study aimed to evaluate the impact of the intervention targeting the redundant combination of antianaerobic antimicrobials on its incidence and associated antimicrobial consumption. To reveal the characteristics of the combination and the change in the related workload over time was an additional aim of the study. The combinations of metronidazole or clindamycin with antianaerobic antimicrobials were classified into redundant or acceptable, according to the target indications. A pharmacist-based prospective audit and feedback targeting the redundant antianaerobic combination was conducted. Segmented regression analysis was performed to evaluate the impact of the intervention. As a quantitative index of the interventional activity, the change in the number of signed consultation notes was evaluated. After the initiation of the intervention, the median monthly cumulative incidence of the redundant combination decreased from 5.29 (Interquartile range [IQR] 4.94-5.70) to 3.33 (IQR 2.87-3.71) (p < 0.001) per 1000 admissions per month. The consumption of concurrently administered metronidazole and clindamycin decreased from 3.34 (IQR 2.97-4.10) to 1.74 (IQR 1.19-1.93) (p < 0.001) per 1000 patient-days per month. Segmented regression analysis revealed that the monthly cumulative incidence decreased by 28.5% after the initiation of the intervention (change in level - 1.640, p = 0.019) and the monthly consumption decreased by 33.9% (change in level - 1.409, p = 0.009). The number of consultation notes per 1000 admissions per month decreased over time (regression coefficient - 0.004, p < 0.001). The pharmacist-based intervention significantly reduced the incidence and associated antimicrobial consumption of the redundant antianaerobic combination. The overall related workload reduced steadily over time.

Toll-like receptor 2 downregulation and cytokine dysregulation predict mortality in patients with Staphylococcus aureus bacteremia.

BACKGROUND: Staphylococcus aureus bacteremia (SAB) presents heterogeneously, owing to the differences in underlying host conditions and immune responses. Although Toll-like receptor 2 (TLR2) is important in recognizing S. aureus, its function during S. aureus infection remains controversial. We aimed to examine the association of TLR2 expression and associated cytokine responses with clinical SAB outcomes. METHODS: Patients from a prospective SAB cohort at two tertiary-care medical centers were enrolled. Blood was sampled at several timepoints (≤5 d, 6-9 d, 10-13 d, 14-19 d, and ≥ 20 d) after SAB onset. TLR2 mRNA levels were determined via real-time PCR and serum tumor necrosis factor [TNF]-α, interleukin [IL]-6, and IL-10 levels were analyzed with multiplex-high-sensitivity electrochemiluminescent ELISA. RESULTS: TLR2 levels varied among 59 SAB patients. On days 2-5, TLR2 levels were significantly higher in SAB survivors than in healthy controls (p = 0.040) and slightly but not significantly higher than non-survivors (p = 0.120), and SAB patients dying within 7 d had lower TLR2 levels than survivors (P = 0.077) although statistically insignificant. IL-6 and IL-10 levels were significantly higher in non-survivors than in survivors on days 2-5 post-bacteremia (P = 0.010 and P = 0.021, respectively), and those dying within 7 d of SAB (n = 3) displayed significantly higher IL-10/TNF-α ratios than the survivors did (P = 0.007). CONCLUSION: TLR2 downregulation and IL-6 and IL-10 concentrations suggestive of immune dysregulation during early bacteremia may be associated with mortality from SAB. TLR2 expression levels and associated cytokine reactions during early-phase SAB may be potential prognostic factors in SAB, although larger studies are warranted.

Pharmacokinetic Characteristics and Limited Sampling Strategies for Therapeutic Drug Monitoring of Colistin in Patients With Multidrug-Resistant Gram-Negative Bacterial Infections.

BACKGROUND: Colistin is increasingly used as the last therapeutic option for the treatment of multidrug-resistant, Gram-negative bacterial infections. To ensure safe and efficacious use of colistin, therapeutic drug monitoring (TDM) is needed due to its narrow therapeutic window. This study aimed to evaluate the pharmacokinetic (PK) characteristics of colistin and to guide TDM in colistin-treated patients in Korea. METHODS: In a prospective study, we analyzed PK characteristics in 15 patients who intravenously received colistin methanesulfonate twice per day. Colistin methanesulfonate doses were adjusted based on renal function of the subjects. The appropriate blood sampling points for TDM were evaluated by analyzing the correlations between the PK parameters and the plasma concentrations at each time point. RESULTS: The mean values for the minimum, maximum, and average concentrations (Cmin, Cmax, and Caverage) of colistin at steady state were 2.29, 5.5, and 3.38 mg/L, respectively. The dose-normalized Cmin, Cmax, Caverage, and area under the plasma concentration-time curve from 0 to the last measurable concentration (AUClast) showed negative correlations with the creatinine clearance. The combination of the 0- and 2-hour post-dose plasma concentrations was evaluated as the appropriate sampling point for TDM. Two patients reported nephrotoxic adverse events during colistin administration. CONCLUSIONS: Our study clarifies the PK characteristics of successful colistin treatment using TDM. Further evaluations in a larger patient population are needed to confirm the clinical usefulness of colistin TDM.

Clinical Prediction Score for Community-Onset Bloodstream Infections Caused by Extended-Spectrum Beta-Lactamase-Producing Escherichia coli and Klebsiella Species.

BACKGROUND: This study aimed to identify the predictors and build a prediction score for community-onset bloodstream infections (CO-BSIs) caused by extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli and Klebsiella species. METHODS: All CO-BSIs caused by E. coli and Klebsiella species from 2012 to 2015 were grouped into derivation (BSIs from 2012 to 2014) and validation (BSIs in 2015) cohorts. A prediction score was built using the coefficients of the multivariate logistic regression model from the derivation cohort. RESULTS: The study included 886 CO-BSIs (594 and 292 in the derivation and validation cohorts, respectively). The independent predictors of CO-BSIs caused by ESBL-producing E. coli and Klebsiella species included: 1) identification of ESBL-producing microorganisms from any clinical culture within one year of admission, 2) beta-lactam or fluoroquinolone treatment within 30 days (with 2 or more courses within 90 days; with 1 course within 90 days), 3) hospitalization within one year, 4) the presence of an indwelling urinary catheter at the time of admission. The area under the curve (AUC) of the clinical prediction score was 0.72 (95% confidence interval [CI], 0.68-0.77). In the validation cohort, the AUC was 0.70 (95% CI, 0.63-0.77). CONCLUSIONS: The results of this study suggest a simple and easy-to-use scoring system to predict CO-BSIs caused by ESBL-producing E. coli and Klebsiella species.

Impact of Vancomycin MIC on Treatment Outcomes in Invasive Staphylococcus aureus Infections.

There are conflicting data on the association of vancomycin MIC (VAN-MIC) with treatment outcomes in Staphylococcus aureus infections. We investigated the relationship between high VAN-MIC and 30-day mortality and identified the risk factors for mortality in a large cohort of patients with invasive S. aureus (ISA) infections, defined as the isolation of S. aureus from a normally sterile site. Over a 2-year period, 1,027 adult patients with ISA infections were enrolled in 10 hospitals, including 673 (66%) patients with methicillin-resistant S. aureus (MRSA) infections. There were 200 (19.5%) isolates with high VAN-MIC (≥1.5 mg/liter) by Etest and 87 (8.5%) by broth microdilution (BMD). The all-cause 30-day mortality rate was 27.4%. High VAN-MIC by either method was not associated with all-cause 30-day mortality, and this finding was consistent across MIC methodologies and methicillin susceptibilities. We conclude that high VAN-MIC is not associated with increased risk of all-cause 30-day mortality in ISA infections. Our data support the view that VAN-MIC alone is not sufficient evidence to change current clinical practice.

Clinical and Molecular Characterization of Invasive Heteroresistant Vancomycin-Intermediate Staphylococcus aureus Infections in Korean Hospitals.

Invasive heteroresistant vancomycin-intermediate Staphylococcus aureus (h-VISA) isolates were identified and characterized in 10 Korean hospitals from July 2009 to June 2011. The prevalence of h-VISA infections was 3.3% (42/1,289). Most (41/42) were health care-associated infections caused by strains belonging to sequence type 5. Cases of persistent bacteremia were frequent (17/42), and 30-day mortality was high (16/40).

Clinical Progression and Cytokine Profiles of Middle East Respiratory Syndrome Coronavirus Infection.

Clinical progression over time and cytokine profiles have not been well defined in patients with Middle East respiratory syndrome coronavirus (MERS-CoV) infection. We included 17 patients with laboratory-confirmed MERS-CoV during the 2015 outbreak in Korea. Clinical and laboratory parameters were collected prospectively. Serum cytokine and chemokine levels in serial serum samples were measured using enzyme-linked immunosorbent assay. All patients presented with fever. The median time to defervescence was 18 days. Nine patients required oxygen supplementation and classified into severe group. In the severe group, chest infiltrates suddenly began to worsen around day 7 of illness, and dyspnea developed at the end of the first week and became apparent in the second week. Median time from symptom onset to oxygen supplementation was 8 days. The severe group had higher neutrophil counts during week 1 than the mild group (4,500 vs. 2,200/µL, P = 0.026). In the second week of illness, the severe group had higher serum levels of IL-6 (54 vs. 4 pg/mL, P = 0.006) and CXCL-10 (2,642 vs. 382 pg/mL, P < 0.001). IFN-α response was not observed in mild cases. Our data shows that clinical condition may suddenly deteriorate around 7 days of illness and the serum levels of IL-6 and CXCL-10 was significantly elevated in MERS-CoV patients who developed severe diseases.

Factors influencing culture positivity in pyogenic vertebral osteomyelitis patients with prior antibiotic exposure.

We conducted a retrospective cohort study to evaluate factors influencing tissue culture positivity in patients with pyogenic vertebral osteomyelitis exposed to antibiotics before diagnosis. Tissue culture was positive in 48.3% (28/58) of the patients, and the median antibiotic-free period was 1.5 days (range, 0.7 to 5.7 days). In a multivariate analysis, a higher C-reactive protein (CRP) level (adjusted odds ratio [aOR], 1.18; 95% confidence interval, 1.07 to 1.29) and open surgical biopsy (aOR, 6.33; 95% confidence interval, 1.12 to 35.86) were associated with tissue culture positivity.

Inappropriate continued empirical vancomycin use in a hospital with a high prevalence of methicillin-resistant Staphylococcus aureus.

Vancomycin is frequently inappropriately prescribed, especially as empirical treatment. The aim of this study was to evaluate (i) the amount of inappropriate continued empirical vancomycin use as a proportion of total vancomycin use and (ii) the risk factors associated with inappropriate continued empirical vancomycin use. We reviewed the medical records of adult patients who had been prescribed at least one dose of parenterally administered vancomycin between January and June 2012, in a single tertiary care hospital. When empirically prescribed vancomycin treatment was continued after 96 h without documentation of beta-lactam-resistant Gram-positive microorganisms in clinical specimens with significance, the continuation was considered inappropriate, and the amount used thereafter was considered inappropriately used. We identified risk factors associated with inappropriate continued empirical vancomycin use by multiple logistic regression. During the study period, the amount of parenterally administered vancomycin prescribed was 34.2 defined daily doses (DDDs)/1,000 patient-days (1,084 prescriptions for 971 patients). The amount of inappropriate continued empirical vancomycin use was 8.5 DDDs/1,000 patient-days, which represented 24.9% of the total parenterally administered vancomycin used (8.5/34.2 DDDs/1,000 patient-days). By multivariate analyses, inappropriate continued empirical vancomycin use was independently associated with the absence of any documented etiological organism (adjusted odds ratio [aOR], 1.60 [95% confidence interval {CI}, 1.06 to 2.41]) and suspected central nervous system (CNS) infections (aHR, 2.33 [95% CI, 1.20 to 4.50]). Higher Charlson's comorbidity index scores were inversely associated with inappropriate continued empirical vancomycin use (aHR, 0.90 [95% CI, 0.85 to 0.97]). Inappropriate continued empirical vancomycin use represented 24.9% of the total amount of vancomycin prescribed, which indicates room for improvement.

Why is asymptomatic bacteriuria overtreated?: A tertiary care institutional survey of resident physicians.

BACKGROUND: Asymptomatic bacteriuria (ABU) is common and often leads to unnecessary antimicrobial use. Reducing antibiotic overuse for ABU is therefore an important issue for antimicrobial stewardship. We performed this study to investigate the appropriateness of ABU management and to evaluate physicians' knowledge and practice regarding ABU. METHODS: We reviewed all urine cultures of ≥10(5) cfu/mL of bacteria among inpatients in a 900-bed hospital in 2011. Each episode of bacteriuria was classified into ABU or urinary tract infection (UTI). ABU was defined as a positive urine culture (≥10(5) cfu/mL) without symptoms or signs suggesting UTI. In October 2012 a cross-sectional survey of resident physicians was undertaken using an anonymous, self-administered questionnaire. RESULTS: We identified 219 ABU cases among 1167 positive urine cultures, of which 70 (32.0 %) were inappropriately treated. Female gender, old age, pyuria, hematuria, and positive nitrite on urinalysis were associated with inappropriate ABU treatment in a multivariate analysis (P < 0.05). The response rate to the survey was 74.2 % (95/128). The mean knowledge score was 37.3 %, and 33.7 % of respondents were able to distinguish ABU from UTI, but less than half knew the indications for treating ABU. Even after ABU was correctly diagnosed, concerns about postoperative infections (38.6 %), UTI (9.1 %), and abnormal urinalysis (29.5 %) prevented proper management. About half of the respondents reported to prescribing antibiotics for ABU despite knowing they were not indicated. CONCLUSIONS: About one third of ABUs were inappropriately managed. Lack of knowledge and discrepancies between knowledge and practice, contributed to antimicrobial overuse for ABU. Our findings highlight the importance of developing interventions, including education, audit and feedback, to tackle the problem of inappropriate treatment of ABU.

Effect of routine sterile gloving on contamination rates in blood culture: a cluster randomized trial.

BACKGROUND: Blood culture contamination leads to inappropriate or unnecessary antibiotic use. However, practical guidelines are inconsistent about the routine use of sterile gloving in collection of blood for culture. OBJECTIVE: To determine whether the routine use of sterile gloving before venipuncture reduces blood culture contamination rates. DESIGN: Cluster randomized, assessor-blinded, crossover trial (ClinicalTrials.gov registration number: NCT00973063). SETTING: Single-center trial involving medical wards and the intensive care unit. PARTICIPANTS: 64 interns in charge of collection of blood for culture were randomly assigned to routine-to-optional or optional-to-routine sterile gloving groups for 1854 adult patients who needed blood cultures. INTERVENTION: During routine sterile gloving, the interns wore sterile gloves every time before venipuncture, but during optional sterile gloving, sterile gloves were worn only if needed. MEASUREMENTS: Isolates from single positive blood cultures were classified as likely contaminant, possible contaminant, or true pathogen. Contamination rates were compared by using generalized mixed models. RESULTS: A total of 10 520 blood cultures were analyzed: 5265 from the routine sterile gloving period and 5255 from the optional sterile gloving period. When possible contaminants were included, the contamination rate was 0.6% in routine sterile gloving and 1.1% in optional sterile gloving (adjusted odds ratio, 0.57 [95% CI, 0.37 to 0.87]; P = 0.009). When only likely contaminants were included, the contamination rate was 0.5% in routine sterile gloving and 0.9% in optional sterile gloving (adjusted odds ratio, 0.51 [CI, 0.31 to 0.83]; P = 0.007). LIMITATION: Blood cultures from the emergency department, surgical wards, and pediatric wards were not assessed. CONCLUSION: Routine sterile gloving before venipuncture may reduce blood culture contamination.

Remdesivir and Ledipasvir among the FDA-Approved Antiviral Drugs Have Potential to Inhibit SARS-CoV-2 Replication.

The rapid spread of the virus, the surge in the number of deaths, and the unavailability of specific SARS-CoV-2 drugs thus far necessitate the identification of drugs with anti-COVID-19 activity. SARS-CoV-2 enters the host cell and assembles a multisubunit RNA-dependent RNA polymerase (RdRp) complex of viral nonstructural proteins that plays a substantial role in the transcription and replication of the viral genome. Therefore, RdRp is among the most suitable targets in RNA viruses. Our aim was to investigate the FDA approved antiviral drugs having potential to inhibit the viral replication. The methodology adopted was virtual screening and docking of FDA-approved antiviral drugs into the RdRp protein. Top hits were selected and subjected to molecular dynamics simulations to understand the dynamics of RdRp in complex with these drugs. The antiviral activity of the drugs against SARS-CoV-2 was assessed in Vero E6 cells. Notably, both remdesivir (half-maximal effective concentration (EC50) 6.6 µM, 50% cytotoxicity concentration (CC50) > 100 µM, selectivity index (SI) = 15) and ledipasvir (EC50 34.6 µM, CC50 > 100 µM, SI > 2.9) exerted antiviral action. This study highlights the use of direct-acting antiviral drugs, alone or in combination, for better treatments of COVID-19.

Emergence of Daptomycin-Nonsusceptible Methicillin-Resistant Staphylococcus aureus Clinical Isolates Among Daptomycin-Naive Patients in Korea.

This study was conducted to assess emergence of daptomycin-nonsusceptible (DAP-NS) phenotype in DAP-naive patients with invasive Staphylococcus aureus (ISA) infections in Korea. A total of 208 S. aureus clinical isolates were selected from a previous prospective study on ISA infections and evaluated for DAP-NS. Although DAP has never been introduced in Korea, five DAP-NS S. aureus strains (2.4%) were identified among 208 S. aureus strains collected from ISA infections. The DAP-NS phenotype was observed only in methicillin-resistant S. aureus (MRSA) strains, but not in methicillin-susceptible S. aureus strains. One DAP-NS MRSA strain belonged to sequence type 72 (ST72) and four were ST5 MRSA strains, three of which were heteroresistant vancomycin (VAN)-intermediate S. aureus. All these five DAP-NS MRSA strains were from healthcare-associated infections without prior exposure to VAN within 30 days. While the ST72 MRSA strain exhibited DAP-NS phenotype via charge repulsion mechanism, four ST5 DAP-NS S. aureus strains had charge-independent DAP-NS mechanism. None of the five DAP-NS strains displayed significant increase in cell wall thickness, indicating that altered cell wall thickness was not associated with the observed DAP-NS phenotype.

Hemophagocytic lymphohistiocytosis associated with SFTS virus infection: A case report with literature review.

BACKGROUND: Severe fever with thrombocytopenia syndrome (SFTS) is a new emerging zoonosis. Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening syndrome caused by hyperinflammation. Here, we report the case of SFTS-associated HLH. CASE SUMMARY: A 62-year-old man was admitted to local hospital with 8 days of fever and chill. He had leukopenia, thrombocytopenia, and developed seizure. An attending physician examined bone marrow to rule out hematologic malignancy. He was transferred to tertiary referral hospital for suspicious HLH. We decided to confirm its histologic feature for sure. Bone marrow and liver biopsy showed hemophagocyotic histiocytes. Serological tests for other infections were all negative except SFTS virus polymerase chain reactions (PCRs) as positive from serum, bone marrow, bronchoalveolar lavage fluid, and liver biopsy specimen. A definitive diagnosis was SFTS-associated HLH. During 2 weeks of conservative treatment, he succeeded in recovery from multiple organ failure. CONCLUSION: SFTS should be considered one of differential diagnosis of HLH. In certain endemic areas, SFTS infection deserves clinicians' attention because it can be presented hematologic diseases as HLH.

Cancer-specific incidence rates of tuberculosis: A 5-year nationwide population-based study in a country with an intermediate tuberculosis burden.

Population-based studies of the incidence of tuberculosis in cancer patients according to the type of cancer are limited. We investigated the cancer-specific incidence of tuberculosis in a nationwide population-based cohort in a country with an intermediate burden of tuberculosis.We used mandatory National Health Insurance claims data to construct a cancer cohort of adults (aged 20-99 years) with newly diagnosed malignancies other than lung cancer, from January 2008 to December 2012. Patients who developed tuberculosis in this period were identified in the cancer cohort and the general population. Standardized incidence ratios (SIRs) of tuberculosis in the cancer cohort according to type of cancer and time after cancer diagnosis were calculated by comparing the observed incidence rates with those inferred from the age- and gender-specific incidence rates in the general population.A total of 855,382 cancer patients and 1589,876 person-years (py) were observed. A total of 5745 patients developed tuberculosis; the mean incidence rate was 361.3 per 100,000 py, and the SIR was 2.22 (95% confidence interval [CI], 2.17-2.27). The incidence rate was highest for hematologic malignancy and lowest for thyroid cancer. It was also highest as 650.1 per 100,000 py, with SIR of 3.70 (CI, 3.57-3.83) for the first 6 months after diagnosis of malignancy and then declined. However, it still remained higher than that of the general population after 24 months (SIR = 1.43, CI, 1.36-1.51).The incidence of tuberculosis increases after diagnosis in patients with malignancies. The risk of tuberculosis differs according to the type of cancer and remains elevated even 24 months after cancer diagnosis. Tuberculosis should be considered an important comorbidity in patients with malignancies.

Impact of a hand hygiene campaign in a tertiary hospital in South Korea on the rate of hospital-onset methicillin-resistant Staphylococcus aureus bacteremia and economic evaluation of the campaign.

BACKGROUND: Hand hygiene (HH) is the most important factor affecting health care-associated infections. METHODS: We introduced a World Health Organization HH campaign in October 2010. The monthly procurement of hand sanitizers per 1,000 patient days was calculated, and the monthly incidence of methicillin-resistant Staphylococcus aureus bacteremia (MRSAB), classified into community- and hospital-onset (HO), was measured from a microbiologic laboratory database. Trends of MRSAB incidence were assessed using Bayesian structural time series models. A cost-benefit analysis was also performed based on the economic burden of HO MRSAB in Korea. RESULTS: Procurement of hand sanitizers increased 134% after the intervention (95% confidence interval [CI], 120%-149%), compared with the preintervention period (January 2008-September 2010). In the same manner, HH compliance improved from 33.2% in September 2010 to 92.2% after the intervention. The incidence of HO MRSAB per 100,000 patient days decreased 33% (95% CI, -57% to -7.8%) after the intervention. Because there was a calculated reduction of 65 HO MRSAB cases during the intervention period, the benefit outweighed the cost (total benefit [$851,565]/total cost [$167,495] = 5.08). CONCLUSIONS: Implementation of the HH campaign led to increased compliance and significantly reduced HO MRSAB incidence; it was also cost saving.

Electronic Alerts with Automated Consultations Promote Appropriate Antimicrobial Prescriptions.

BACKGROUND: To promote appropriate antimicrobial use in bloodstream infections (BSIs), we initiated an intervention program consisting of electronic alerts and automated infectious diseases consultations in which the identification and antimicrobial susceptibility test (ID/AST) results were reported. METHODS: We compared the appropriateness of antimicrobial prescriptions and clinical outcomes in BSIs before and after initiation of the program. Appropriateness was assessed in terms of effective therapy, optimal therapy, de-escalation therapy, and intravenous to oral switch therapy. RESULTS: There were 648 BSI episodes in the pre-program period and 678 in the program period. The proportion of effective, optimal, and de-escalation therapies assessed 24 hours after the reporting of the ID/AST results increased from 87.8% (95% confidence interval [CI] 85.5-90.5), 64.4% (95% CI 60.8-68.1), and 10.0% (95% CI 7.5-12.6) in the pre-program period, respectively, to 94.4% (95% CI 92.7-96.1), 81.4% (95% CI 78.4-84.3), and 18.6% (95% CI 15.3-21.9) in the program period, respectively. Kaplan-Meier analyses and log-rank tests revealed that the time to effective (p<0.001), optimal (p<0.001), and de-escalation (p = 0.017) therapies were significantly different in the two periods. Segmented linear regression analysis showed the increase in the proportion of effective (p = 0.015), optimal (p<0.001), and de-escalation (p = 0.010) therapies at 24 hours after reporting, immediately after program initiation. No significant baseline trends or changes in trends were identified. There were no significant differences in time to intravenous to oral switch therapy, length of stay, and 30-day mortality rate. CONCLUSION: This novel form of stewardship program based on intervention by infectious disease specialists and information technology improved antimicrobial prescriptions in BSIs.

Differences in characteristics between first and breakthrough neutropenic fever after chemotherapy in patients with hematologic disease.

OBJECTIVE: This study was conducted to compare the clinical and microbiological characteristics of first and breakthrough neutropenic fever in hematologic malignancy patients after chemotherapy. METHODS: Breakthrough neutropenic fever was any episode of fever, not present initially, that developed either during antibiotic therapy or within 1 week of discontinuation of therapy. A total of 687 neutropenic fever episodes in 241 patients were observed from April 2003 to March 2014. RESULTS: Blood cultures revealed 210 causative microorganisms: 199 (94.8%) were bacteria and 11 (5.2%) were fungi. Gram-negative bacteria predominated in both types of neutropenic episode (first 75% (120/160) vs. breakthrough 56% (18/32)) and the most common pathogen was Escherichia coli. Antibiotic resistance rates were higher in breakthrough episodes than first episodes (piperacillin/tazobactam 6% vs. 31%, p=0.006; ceftazidime 9% vs. 31%, p=0.025). Inappropriate empirical antibiotic treatment was also more frequent (0% vs. 19%, p=0.001), as was the 30-day mortality rate (4.3% (19/442) vs. 7.9% (19/245), p=0.058), although the latter effect was not statistically significant. CONCLUSION: It is concluded that the epidemiological profile of breakthrough neutropenic fever is different from that of first episode fever. These data reinforce the view that pooled reporting of neutropenic fever may be misleading, and that clinicians should approach breakthrough fever as a distinct entity.