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Treatment assessment and patient outcome for sepsis depend predominantly on the timely administration of appropriate antibiotics1–3. However, the clinical protocols used to stratify and select patient-specific optimal therapy are extremely slow4. In particular, the major hurdle in performing rapid antimicrobial susceptibility testing (AST) remains in the lengthy blood culture procedure, which has long been considered unavoidable due to the limited number of pathogens present in the patient’s blood. Here we describe an ultra-rapid AST method that bypasses the need for traditional blood culture, thereby demonstrating potential to reduce the turnaround time of reporting drug susceptibility profiles by more than 40–60 h compared with hospital AST workflows. Introducing a synthetic beta-2-glycoprotein I peptide, a broad range of microbial pathogens are selectively recovered from whole blood, subjected to species identification or instantly proliferated and phenotypically evaluated for various drug conditions using a low-inoculum AST chip. The platform was clinically evaluated by the enrolment of 190 hospitalized patients suspected of having infection, achieving 100% match in species identification. Among the eight positive cases, six clinical isolates were retrospectively tested for AST showing an overall categorical agreement of 94.90% with an average theoretical turnaround time of 13 ± 2.53 h starting from initial blood processing.

ABSTRACTSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern have been emerging. However, knowledge of temporal and spatial dynamics of SARS-CoV-2 is limited. This study characterized SARS-CoV-2 evolution in immunosuppressed patients with long-term SARS-CoV-2 shedding for 73–250 days, without specific treatment. We conducted whole-genome sequencing of 27 serial samples, including 26 serial samples collected from various anatomic sites of two patients and the first positive sample from patient 2‘s mother. We analysed the intrahost temporal dynamics and genomic diversity of the viral population within different sample types. Intrahost variants emerging during infection showed diversity between individual hosts. Remarkably, N501Y, P681R, and E484K, key substitutions within spike protein, emerged in vivoduring infection and became the dominant population. P681R, which had not yet been detected in the publicly available genome in Korea, appeared within patient 1 during infection. Mutually exclusive substitutions at residues R346 (R346S and R346I) and E484 (E484K and E484A) of spike protein and continuous turnover of these substitutions occurred. Unique genetic changes were observed in urine samples. A household transmission from patient 2 to his mother, at least 38 days after the diagnosis, was characterized. Viruses may differently mutate and adjust to the host selective pressure, which could enable the virus to replicate efficiently for fitness in each host. Intrahost variants could be candidate variants likely to spread to the population eventually. Our findings may provide new insights into the dynamics of SARS-CoV-2 in response to interactions between the virus and host.

Baricitinib and dexamethasone have randomised trials supporting their use for the treatment of patients with COVID-19. We assessed the combination of baricitinib plus remdesivir versus dexamethasone plus remdesivir in preventing progression to mechanical ventilation or death in hospitalised patients with COVID-19.

ABSTRACTThe microbiological characteristics of Staphylococcus aureuscausing infective endocarditis (IE) have not been investigated thoroughly. We compared the characteristics of S. aureusisolates from patients with and without IE. Cases of S. aureusbacteremia (SAB) were collected from 10 hospitals over 7 years. Cases of native valve IE were matched with non-IE controls according to the following criteria: central-line-associated infection, community-acquired infection, methicillin susceptibility, and if possible, the primary site of infection. Genes coding virulence factors were analyzed using multiplex polymerase chain reactions. Fibrinogen and fibronectin-binding properties were assessed using in vitrobinding assays. The fibronectin-binding protein A gene (fnbpA) was sequenced. Of 2,365 cases of SAB, 92 had IE. After matching, 37 pairs of S. aureusisolates from the IE cases and non-IE controls were compared; fnbpAwas detected in 91.9% of the IE isolates and 100% of the non-IE isolates (p= 0.24). While the fibrinogen binding ratio was similar (1.07 ± 0.33 vs. 1.08 ± 0.26, p= 0.89), the fibronectin-binding ratio was significantly higher in the IE-group (1.31 ± 0.42 vs. 1.06 ± 0.31, p= 0.01). The proportions of major single-nucleotide polymorphisms in fnbpAwere as follows: E652D (2.9% vs. 2.7%), H782Q (65.6% vs. 60.6%), and K786N (65.6% vs. 72.7%). The fibronectin-binding ratio was positively correlated with the number of SNPs present in IE cases (p< 0.001) but not in the non-IE controls (p= 0.124). Fibronectin-binding might play a key role in SAB IE. However, the degree of binding may be mediated by genetic variability between isolates.

We report on a patient with severe fever with thrombocytopenia syndrome who fully recovered. Imaging with 2-deoxy-2-fluoro-glucose positron emission tomography showed hypermetabolism in regional lymph nodes and the spleen. Histopathological findings of affected lymph nodes showed subacute necrotizing lymphadenitis and the presence of virus-infected cells.

ABSTRACTSome proportion of type A blaZgene-positive methicillin-susceptible Staphylococcus aureusstrains exhibit the cefazolin inoculum effect (CIE). The type A blaZgene was divided into two groups by single nucleotide polymorphisms (SNPs) at Ser226Pro and Cys229Tyr. The median cefazolin MICs at a high inoculum concentration were 5.69 μg/ml for the Ser-Cys group and 40.32 μg/ml for the Pro-Tyr group (P= 0.01). The SNPs at codons 226 and 229 in the amino acid sequence encoded by the blaZgene were closely associated with the CIE.

ABSTRACTStaphylococcal cassette chromosome mecelement (SCCmec) type-dependent clinical outcomes may vary due to geographical variation in the presence of virulence determinants. We compared the microbiological factors and mortality attributed to methicillin-resistant Staphylococcus aureus(MRSA) bacteremia between SCCmectypes II/III and type IV. All episodes of MRSA bacteremia in a tertiary-care hospital (South Korea) over a 4.5-year period were reviewed. We studied the microbiological factors associated with all blood MRSA isolates, including spatype, agrtype, agrdysfunction, and the genes for Panton-Valentine leukocidin (PVL) and phenol-soluble modulin (PSM)-mec, in addition to SCCmectype. Of 195 cases, 137 involved SCCmectypes II/III, and 58 involved type IV. The mortality attributed to MRSA bacteremia was less frequent among the SCCmectype IV (5/58) than that among types II/III (39/137, P= 0.002). This difference remained significant when adjusted for clinical factors (adjusted odds ratio [aOR], 0.14; 95% confidence interval [CI], 0.04 to 0.49; P= 0.002). Of the microbiological factors tested, agrdysfunction was the only significant factor that showed different positivity between the SCCmectypes, and it was independently associated with MRSA bacteremia-attributed mortality (aOR, 4.71; 95% CI, 1.72 to 12.92; P= 0.003). SCCmectype IV is associated with lower MRSA bacteremia-attributed mortality than are types II/III, which might be explained by the high rate of agrdysfunction in SCCmectypes II/III in South Korea.

ABSTRACTWe 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.

ABSTRACTVancomycin 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.

ABSTRACTThere is little information about the effectiveness of ciprofloxacin in regions where ciprofloxacin-resistant Escherichia coliis prevalent. This study was conducted to evaluate whether ciprofloxacin is effective as the initial empirical antibiotic for treatment of uncomplicated acute pyelonephritis (APN) due to ciprofloxacin-resistant E. coli. A total of 255 women with clinical diagnoses of uncomplicated APN due to E. coliwere enrolled in the emergency department between March 2005 and December 2008. All enrolled patients were initially treated with ciprofloxacin. Patients were followed up 4 to 7 days after the start of therapy and 14 to 21 days after its completion. At the first follow-up visit, ciprofloxacin was changed to the appropriate antibiotic when necessary, depending on the antibiotic susceptibility results. Not only improvement of symptoms and signs but also microbiologic eradication was assessed at each visit. Fifteen percent (39/255) of the E. coliisolates were resistant to ciprofloxacin. There was no statistically significant difference between the clinical cure rates of the ciprofloxacin-susceptible group and the ciprofloxacin-resistant group at the first follow-up (87.0% versus 76.9%, P= 0.135) or the second follow-up (98.6% versus 94.9%, P= 0.177). However, there was a lower microbiologic cure rate in the ciprofloxacin-resistant group than in the ciprofloxacin-susceptible group (92.4% versus 41.7%, P= 0.000) at the first follow-up visit. No complications occurred in the ciprofloxacin-resistant group during the follow-up period. Our findings indicate that ciprofloxacin is an appropriate choice for empirical therapy of uncomplicated APN and has no serious adverse outcomes, if it is tailored appropriately, even for women infected with ciprofloxacin-resistant E. coli.

ABSTRACTAbout 20% of methicillin-susceptible Staphylococcus aureus(MSSA) isolates have a substantial inoculum effect with cefazolin, suggesting that cefazolin treatment may be associated with clinical failure for serious MSSA infections. There are no well-matched controlled studies comparing cefazolin with nafcillin for the treatment of MSSA bacteremia. A retrospective propensity-score-matched case-control study was performed from 2004 to 2009 in a tertiary care hospital where nafcillin was unavailable from August 2004 to August 2006. The cefazolin group (n= 49) included MSSA-bacteremic patients treated with cefazolin during the period of nafcillin unavailability, while the nafcillin group (n= 84) comprised those treated with nafcillin. Treatment failure was defined as a composite outcome of a change of antibiotics due to clinical failure, relapse, and mortality. Of 133 patients, 41 patients from each group were matched by propensity scores. There were no significant differences in baseline characteristics between the matched groups. The treatment failure rates were not significantly different at 4 or 12 weeks (10% [4/41] versus 10% [4/41] at 4 weeks [P> 0.99] and 15% [6/41] versus 15% [6/41] at 12 weeks [P> 0.99]). Cefazolin treatment was interrupted less frequently than nafcillin treatment due to drug adverse events (0% versus 17%; P= 0.02). Cefazolin had clinical efficacy similar to that of nafcillin and was more tolerable than nafcillin for the treatment of MSSA bacteremia.

ABSTRACTInformation about the genotype of varicella-zoster virus (VZV) is useful to monitor outbreaks of vaccine strains. However, in South Korea, where varicella vaccine was introduced in 1988, there are limited data about the genotype of VZV. VZV was isolated from vesicular lesions of patients with herpes zoster or varicella in South Korea between January 2007 and June 2009. DNAs were purified from single-passage isolates. The genotype was determined by sequence analysis of open reading frame (ORF) 22. The PstI restriction enzyme site in ORF 38 and the BglI restriction enzyme site in ORF 54 were evaluated by restriction enzyme analysis. Forty-four patients with herpes zoster and nine patients with varicella were enrolled. The median age of patients with herpes zoster was 59.5 (range, 10 to 77) years, and the median age of patients with varicella was 8 (range, 6 to 9) years. In sequence analysis of ORF 22, all isolates were genotype J, irrespective of the age group. In restriction enzyme analysis, 51 of 54 (94.3%) isolates contained a PstI site in ORF 38, and all isolates contained a BglI site in ORF 54. Our data suggest that genotype J has been circulating since the 1940s in South Korea.

ABSTRACTWe used several molecular typing methods to analyze 196 methicillin-resistant Staphylococcus aureus(MRSA) and 139 methicillin-susceptible S. aureus(MSSA) isolates collected between 1996 and 2005. The sequence type 72 MRSA has increased in frequency in the community in the Republic of Korea and in hospitals in recent years.

A high-throughput, accurate screening is crucial for the prevention and control of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Current methods, which involve sampling from the nasopharyngeal (NP) area by medical staffs, constitute a fundamental bottleneck in expanding the testing capacity. To meet the scales required for population-level surveillance, self-collectable specimens can be used; however, its low viral load has hindered its clinical adoption. Here, we describe a magnetic nanoparticle functionalized with synthetic apolipoprotein H (ApoH) peptides to capture, concentrate, and purify viruses. The ApoH assay demonstrates a viral enrichment efficiency of >90% for both SARS-CoV-2 and its variants, leading to an order of magnitude improvement in analytical sensitivity. For validation, we apply the assay to a total of 84 clinical specimens including nasal, oral, and mouth gargles obtained from COVID-19 patients. As a result, a 100% positivity rate is achieved from the patient-collected nasal and gargle samples, which exceeds that of the traditional NP swab method. The simple 12 min pre-enrichment assay enabling the use of self-collectable samples will be a practical solution to overcome the overwhelming diagnostic capacity. Furthermore, the methodology can easily be built on various clinical protocols, allowing its broad applicability to various disease diagnoses.

ABSTRACTIn active tuberculosis (TB), Mycobacterium tuberculosis-specific T cells are compartmentalized more to the site of infection than to the circulating blood. Therefore, an M. tuberculosis-specific enzyme-linked immunospot (ELISPOT) assay with samples from the site of infection may permit a more sensitive or specific diagnosis of active central nervous system (CNS) TB than that achieved by the assay with blood alone. Therefore, we prospectively evaluated the usefulness of circulating and compartmentalized mononuclear cell (MC; i.e., peripheral blood mononuclear cell [PBMC] and cerebrospinal fluid [CSF] MC)-based ELISPOT assays (i.e., the T-SPOT.TB test) for the diagnosis of active TB in patients with suspected CNS TB. The clinical categories of CNS TB were classified as described previously (G. E. Thwaites, T. T. Chau, K. Stepniewska, N. H. Phu, L. V. Chuong, D. X. Sinh, N. J. White, C. M. Parry, and J. J. Farrar, Lancet 360:1287-1292, 2002). Thirty-seven patients with suspected CNS TB were enrolled over a 12-month period. Of these, 31 (84%) showed clinical manifestations of suspected TB meningitis and 6 (16%) gave indications of intracranial tuberculoma with disseminated TB. The final clinical categories of the 37 patients with suspected CNS TB were as follows: 12 (32%) were classified as having CNS TB (7 with confirmed TB, 3 with probable TB, and 2 with possible TB) and 25 (68%) were classified as not having active TB. The sensitivity and specificity of the PBMC ELISPOT assay were 91% (95% confidence interval [CI], 59% to 100%) and 63% (95% CI, 41% to 81%), respectively. By comparison, the sensitivity and specificity of the CSF MC ELISPOT assay were 75% (95% CI, 19% to 99%) and 75% (95% CI, 43% to 95%), respectively. When the ratio of the CSF MC ELISPOT assay results to the PBMC ELISPOT results was 2 or more, the sensitivity and specificity were 50% (95% CI, 7% to 93%) and 100% (95% CI, 74% to 100%), respectively. The ELISPOT assay with PBMCs and CSF MCs is a useful adjunct to the current tests for the diagnosis of CNS TB.

Objective.To control an outbreak of Shewanella algaeand S. putrefaciensinfections by identifying the risk factors for infection and transmission.Design.Matched case-control study.Setting.A university-affiliated tertiary acute care hospital in Seoul, Republic of Korea, with approximately 1,600 beds.Patients.From June 20, 2003, to January 16, 2004, a total of 31 case patients with Shewanellacolonization or infection and 62 control patients were enrolled in the study.Interventions.Requirement to use single-use measuring cups and standard precautions (including hand washing before and after patient care and use of gloves).Results.S. algaeor S. putrefacienswas isolated from blood, for 9 (29.0%) of 31 patients who acquired one of the organisms; from bile, for 8 (25.8%), and from ascitic fluid, for 8 (25.8%). The attack rate of this outbreak was 5.8% (31 patients infected or colonized, of 534 potentially exposed on ward A) and the pathogenicity of the two species together was 77.4% (24 patients infected, of 31 who acquired the pathogens). The estimated incubation period for Shewanellaacquisition was 3–49 days. Using logistic analysis, we identified the following risk factors: presence of external drainage catheters in the hepatobiliary system (odds ratio [OR], 20; P< .001), presence of hepatobiliary disease (OR, 6.4; P< .001), admission to the emergency department of the hospital (OR, 2.9; P= .039), wound classification of “contaminated” or “dirty or infected” (OR, 16.5; P= .012), an American Society of Anesthesiologists score of 3 or higher (OR, 8.0; P= .006), duration of stay in ward A (OR, 1.1; P< .001), and, for women, an age of 60–69 years (OR, 13.3; P= .028). A Shewanellaisolate was recovered from the surface of a shared measuring cup, and 12 isolates of S. algaeshowed the same pulsed-field gel electrophoresis pattern.Conclusions.This Shewanellaoutbreak had a single-source origin and spread by contact transmission via a contaminated measuring cup. Shewanellaspecies are emerging as potentially serious human pathogens in hospitals and could be included in hospital infection surveillance systems.

ABSTRACTLimited data on the clinical outcome of vancomycin treatment compared with that of beta-lactam treatment in patients with methicillin-susceptible Staphylococcus aureusbacteremia (MSSA-B) are available. We used different and complementary approaches: (i) a retrospective cohort study using a propensity score to adjust for confounding by treatment assignment and (ii) a matched case-control study. Of all patients with S. aureusbacteremia (SAB) in two university-affiliated hospitals over a 7-year period, 294 patients with MSSA-B were enrolled in the cohort study. The cases for the case-control study were defined as patients who received vancomycin treatment for MSSA-B; the controls, who were patients that received beta-lactam treatment for MSSA-B, were selected at a 1:2 (case:control) ratio according to the objective matching scoring system and the propensity score system. In the cohort study, SAB-related mortality in patients with vancomycin treatment (37%, 10/27) was significantly higher than that in those with beta-lactam treatment (18%, 47/267) (P= 0.02). In addition, multivariate analysis revealed that vancomycin treatment was associated with SAB-related mortality when independent predictors for SAB-related mortality and propensity score were considered (adjusted odds ratio of 3.3, 95% confidence interval of 1.2 to 9.5). In the case-control study using the objective matching scoring system and the propensity score system, SAB-related mortality in case patients was 37% (10/27) and in control patients 11% (6/54) (P< 0.01). Our data suggest that vancomycin is inferior to beta-lactam in the treatment of MSSA-B.

In addition to vancomycin-intermediate Staphylococcus aureus (VISA), S. aureus with a vancomycin MIC of 4 µg/ml has been reported to be the cause of therapeutic failure. This study was designed to determine the prevalence of methicillin-resistant S. aureus (MRSA) with a vancomycin MIC of 4 µg/ml and to clarify the clinical characteristics of infections caused by these isolates. During the 8-week period from April to May, 2001, 27 hospitals participated in a nationwide surveillance program for VISA and vancomycin-resistant S. aureus (VRSA) in Korea. After screening on brain–heart infusion agar containing 4 µg/ml of vancomycin as previously described, 100 isolates with confluent growth were tested. The medical records of the patients involved were reviewed. Even though VISA or VRSA was not detected among 3,756 MRSA isolates, 18 (0.5%) had a vancomycin MIC of 4 µg/ml. The infections in 12 of these patients, excluding 5 that were colonized, were 8 chronic osteomyelitis, 1 surgical site infection, 1 pneumonia, 1 intra-abdominal infection, and 1 catheterrelated infection. Although 11 cases were exposed to glycopeptides for a long time (median 56 days), the site of infection became culture-negative in only 1 case. Two patients died of their S. aureus infections. MRSA with a vancomycin MIC of 4 µg/ml was rare. Chronic osteomyelitis was the most common type of infection, and prolonged exposure to glycopeptides was associated with reduced susceptibility to vancomycin.

This study was conducted to evaluate risk factors for antimicrobial resistance and influence of resistance on mortality in Pseudomonas aeruginosa bacteremia. Data on 190 patients with P. aeruginosa bacteremia were analyzed retrospectively. Antimicrobial resistance to antipseudomonal antibiotics was evaluated. The main outcome measure was 30-day mortality. In P. aeruginosa bacteremia, resistance rates to piperacillin (PIP), ceftazidime (CAZ), ciprofloxacin (CIP), and imipenem (IPM) were 29 (56/190), 19 (36/190), 17 (32/190) and 15% (28/190), respectively. Prior uses of fluoroquinolones or carbapenems were independent risk factors for resistance to CIP and IPM, and prior use of extended-spectrum cephalosporins was a risk factor for PIP-R. An indwelling urinary catheter was a risk factor for PIP-R, CAZ-R, and CIP-R. An invasive procedure was a risk factor for CIP-R and IPM-R. The 30-day mortality rate was 44% (33/75) in patients infected by strains resistant to any of the antipseudomonal antibiotics, but 33.9% (39/115) in those by strains susceptible to all antipseudomonal antibiotics (p = 0.161). Among patients with bloodstream infection due to antimicrobial-resistant P. aeruginosa, those infected by IPM-R strains had the highest mortality (IPM-R, 53.6% vs. CAZ-R, 47.2% vs. CIP-R 46.9%, PIP-R, 39.3%). In this study regarding P. aeruginosa bacteremia, prior uses of fluoroquinolones, carbapenems, or extended-spectrum cephalosporins, a prior invasive procedure, and an indwelling urinary catheter were found to be associated with antimicrobial resistance. The patients with bloodstream infection caused by antimicrobial-resistant P. aeruginosa, especially to imipenem, had a tendency toward higher mortality than those infected by susceptible strains.

ABSTRACTThe marked increase in the incidence of infections due to antibiotic-resistant gram-negative bacilli in recent years is of great concern, as patients infected by those isolates might initially receive antibiotics that are inactive against the responsible pathogens. To evaluate the effect of inappropriate initial antimicrobial therapy on survival, a total of 286 patients with antibiotic-resistant gram-negative bacteremia, 61 patients with Escherichia colibacteremia, 65 with Klebsiella pneumoniaebacteremia, 74 with Pseudomonas aeruginosabacteremia, and 86 with Enterobacterbacteremia, were analyzed retrospectively. If a patient received at least one antimicrobial agent to which the causative microorganisms were susceptible within 24 h of blood culture collection, the initial antimicrobial therapy was considered to have been appropriate. High-risk sources of bacteremia were defined as the lung, peritoneum, or an unknown source. The main outcome measure was 30-day mortality. Of the 286 patients, 135 (47.2%) received appropriate initial empirical antimicrobial therapy, and the remaining 151 (52.8%) patients received inappropriate therapy. The adequately treated group had a 27.4% mortality rate, whereas the inadequately treated group had a 38.4% mortality rate (P= 0.049). Multivariate analysis showed that the significant independent risk factors of mortality were presentation with septic shock, a high-risk source of bacteremia, P. aeruginosainfection, and an increasing APACHE II score. In the subgroup of patients (n= 132) with a high-risk source of bacteremia, inappropriate initial antimicrobial therapy was independently associated with increased mortality (odds ratio, 3.64; 95% confidence interval, 1.13 to 11.72; P= 0.030). Our data suggest that inappropriate initial antimicrobial therapy is associated with adverse outcome in antibiotic-resistant gram-negative bacteremia, particularly in patients with a high-risk source of bacteremia.

AbstractObjectives:To evaluate the clinical features of ciprofloxacin-resistant Enterobacterbacteremia and to examine the risk factors for ciprofloxacin resistance in Enterobacterspecies isolates causing bacteremia.Design:A case-control study.Setting:A 1,500-bed, tertiary-care university hospital and referral center.Patients:All patients older than 16 years with Enterobacterspecies isolated from blood were enrolled. The medical records of 183 patients with clinically significant Enterobacterbacteremia from January 1998 to December 2002 were identified. We compared patients with bacteremia caused by ciprofloxacin-susceptible isolates with patients with bacteremia caused by ciprofloxacin-resistant isolates.Results:Twenty-three (12.6%) of the patients had bacteremia caused by isolates resistant to ciprofloxacin. There were no significant differences in age, gender, underlying diseases, primary site of infection, or Acute Physiology and Chronic Health Evaluation II score between the ciprofloxacin-resistant and the ciprofloxacin-susceptible groups. Broad-spectrum cephalosporin resistance, defined as resistance to cefotaxime or ceftazidime in vitro, was detected in 21 (91.3%) of 23 ciprofloxacin-resistant isolates compared with 65 (40.6%) of 160 ciprofloxacin-susceptible isolates (P< .001). Multivariate analysis revealed that independent risk factors for ciprofloxacin resistance were the prior receipt of fluoroquinolones (P< .001) and broad-spectrum cephalosporin resistance (P< .001).Conclusions:In Enterobacterspecies isolates causing bacteremia, ciprofloxacin resistance was closely associated with the prior receipt of fluoroquinolones and broad-spectrum cephalosporin resistance. The close relationship between ciprofloxacin resistance and broad-spectrum cephalosporin resistance is particularly troublesome because it severely restricts the therapeutic options for Enterobacterspecies infection.

ABSTRACTThis study was conducted to evaluate risk factors for mortality and treatment outcome of bloodstream infections due to extended-spectrum beta-lactamase (ESBL)-producing Escherichia coliand Klebsiella pneumoniae(ESBL-EK). ESBL production in stored K. pneumoniaeand E. coliblood isolates from Jan 1998 to Dec 2002 was phenotypically determined according to NCCLS guidelines and/or the double-disk synergy test. A total of 133 patients with ESBL-EK bacteremia, including 66 patients with ESBL-producing K. pneumoniaeand 67 with ESBL-producing E. coli, were enrolled. The overall 30-day mortality rate was 25.6% (34 of 133). Independent risk factors for mortality were severe sepsis, peritonitis, neutropenia, increasing Acute Physiology and Chronic Health Evaluation II score, and administration of broad-spectrum cephalosporin as definitive antimicrobial therapy (P< 0.05 for each of these risk factors). In 117 of the 133 patients, excluding 16 patients who died within 3 days after blood culture sample acquisition, the 30-day mortality rates according to definitive antibiotics were as follows: carbapenem, 12.9% (8 of 62); ciprofloxacin, 10.3% (3 of 29); and others, such as cephalosporin or an aminoglycoside, 26.9% (7 of 26). When patients who received appropriate definitive antibiotics, such as carbapenem or ciprofloxacin, were evaluated, mortality in patients receiving inappropriate empirical antimicrobial therapy was found not to be significantly higher than mortality in those receiving appropriate empirical antimicrobial therapy (18.9 versus 15.5%; P= 0.666). Carbapenem and ciprofloxacin were the most effective antibiotics in antimicrobial therapy for ESBL-EK bacteremia. A delay in appropriate definitive antimicrobial therapy was not associated with higher mortality if antimicrobial therapy was adjusted appropriately according to the susceptibility results. Our data suggest that more prudent use of carbapenem as empirical antibiotic may be reasonable.

AbstractObjective:To evaluate risk factors and treatment outcomes of bloodstream infections caused by extended-spectrum beta-lactamase-producing Klebsiella pneumoniae(ESBL-KP).Design:Retrospective case-control study. Stored blood isolates of K. pneumoniaewere tested for ESBL production by NCCLS guidelines, double-disk synergy test, or both.Setting:A 1,500-bed, tertiary-care university hospital and referral center.Patients:Sixty case-patients with bacteremia due to ESBL-KP were compared with 60 matched control-patients with non-ESBL-KP.Results:There were no significant differences in age, gender, APACHE II score, or underlying diseases between the groups. Independent risk factors for infections caused by ESBL-KP were urinary catheterization, invasive procedure within the previous 72 hours, and an increasing number of antibiotics administered within the previous 30 days. Complete response rate, evaluated 72 hours after initial antimicrobial therapy, was higher among control-patients (13.3% vs 36.7%; P= .003). Treatment failure rate was higher among case-patients (35.0% vs 15%; P= .011). Overall 30-day mortality rate was 30% for case-patients and 28.3% for control-patients (P= .841). Case-patients who received imipenem or ciprofloxacin as a definitive antibiotic had 10.5% mortality. The mortality rate for initially ineffective therapy was no higher than that for initially effective therapy (9.1% vs 11.1%; P= 1.000), but statistical power was low for evaluating mortality in the absence of septic shock.Conclusion:For K. pneumoniaebacteremia, patients with ESBL-KP had a higher initial treatment failure rate but did not have higher mortality if antimicrobial therapy was appropriately adjusted in this study with limited statistical power.

ABSTRACTCases of bacteremia caused by AmpC-type-β-lactamase-producing Klebsiella pneumoniaeisolates were retrospectively studied to determine the epidemiologic features and clinical outcomes of bloodstream infections. Among 389 blood isolates recovered from 1998 to 2002, 65 isolates (16.7%) were found to be extended-spectrum β-lactamase (ESBL) or AmpC β-lactamase producers. The β-lactamases from 61 of the 65 isolates were characterized; 28 of 61 isolates produced AmpC-type enzymes (14 isolates each produced DHA-1 and CMY-1-like enzymes), 32 isolates produced TEM or SHV-related ESBLs, and 1 isolate produced a CTX-M-14-like enzyme. To compare the clinical features and outcomes of bloodstream infections caused by AmpC producers with those caused by TEM- or SHV-related ESBL producers, 27 patients infected with isolates producing AmpC-type enzymes (AmpC group) and 25 patients infected with isolates producing TEM- or SHV-related enzymes (ESBL group) were analyzed. There was no significant difference between the AmpC and the ESBL groups in terms of risk factors. When the initial response was assessed at 72 h after antimicrobial therapy, the treatment failure rate for the AmpC group was 51.9% (14 of 27 patients) and the 7- and 30-day mortality rates were 14.8 and 29.6%, respectively, which were similar to those for the ESBL group. When the mortality rate for the patients who received extended-spectrum cephalosporins as definitive treatment was assessed, all four patients in the DHA-1 group and one of three patients in the CMY-1-like group died. In summary, the prevalence of AmpC enzyme-producing K. pneumoniaewas high at the Seoul National University Hospital, and the clinical features and outcomes for the patients infected with AmpC-producing organisms were similar to those for the patients infected with TEM- or SHV-related ESBL producers.

ABSTRACTStaphylococcus aureus, one of the most frequently isolated pathogens in both hospitals and the community, has been particularly efficient at developing resistance to antimicrobial agents. As methicillin-resistant S. aureus(MRSA) has prevailed and, furthermore, as S. aureuswith reduced susceptibility to vancomycin has emerged, the therapeutic options for the treatment of S. aureusinfections have become limited. To update the current status of antibiotic resistance, clinical S. aureusisolates were collected from eight university-affiliated hospitals from June 1999 to January 2001. Susceptibility tests with 28 antibiotics were performed by the disk diffusion method. Among a total of 682 isolates, the methicillin resistance rate was 64% (439 of 682), and most of the MRSA isolates were resistant to multiple classes of antibiotics. Although a constitutive macrolide-lincosamide-streptogramin B resistance phenotype was common, no isolates were resistant to quinupristin-dalfopristin or linezolid. Rifampin, fusidic acid, trimethoprim-sulfamethoxazole, and arbekacin showed superior in vitro activity compared with the other antibiotics against the MRSA isolates. No isolates showed reduced susceptibility to vancomycin.

The present study was conducted to identify risk factors for ciprofloxacin resistance in bloodstream infections due to extended-spectrum β -lactamase-producing Escherichia coli and Klebsiella pneumoniae (ESBL-EK). ESBL production was determined in stored E. coli and K. pneumoniae blood isolates from January, 1998, to December, 2002, by National Committee for Clinical Laboratory Standards (NCCLS) guidelines and/or double-disk synergy test. Antimicrobial susceptibility was determined by the disk diffusion test method. A total of 133 patients with ESBL-EK bacteremia were analyzed retrospectively. A total of 80 (60.2%) patients experienced bacteremia due to strains resistant to ciprofloxacin. There were no significant differences in age, sex, and APACHE II score between the ciprofloxacin-resistant group (CIP-R) and-susceptible group (CIPS). The most common primary site of infection in CIP-R was pancreaticobiliary tract infection (46/80, 57.5%) and that in CIP-S was unknown primary site (23/53, 43.4%). Independent risk factors for ciprofloxacin resistance were: prior use of fluoroquinolones (OR, 5.53; 95% CI, 1.56-25.42, p = 0.032), indwelling urinary catheter (OR, 3.68; 95% CI, 1.27-10.67, p = 0.017), and invasive procedure within 72 hr prior to bacteremia (OR, 4.03; 95% CI, 1.44-11.25, p = 0.008). Our data suggest that strategies designed to reduce the ciprofloxacin resistance rate in ESBL-EK strains should focus on limiting the use of fluoroquinolones and minimizing invasive procedures, including insertion of a urinary catheter.

AbstractObjective:To evaluate the outcome of attempted Hickman catheter salvage in neutropenic cancer patients with Staphylococcus aureusbacteremia who were not using antibiotic lock therapy.Design:Retrospective cohort study.Setting:A university-affiliated, tertiary-care hospital with 1,500 beds for adult patients.Patients:All neutropenic cancer patients who had a Hickman catheter and S. aureusbacteremia (32 episodes in 29 patients) between January 1998 and March 2002.Methods:Salvage attempts were defined as cases where the Hickman catheter was not removed until we obtained the results of follow-up blood cultures performed 48 to 72 hours after starting treatment with antistaphylococcal antibiotics. Salvage was considered to be successful if the Hickman catheter was still in place 3 months later without recurrent bacteremia or death.Results:Catheter salvage was attempted in 24 (75%) of the 32 episodes. Of the salvage attempts, the success rate was 50% (12 of 24). Salvage attempts were successful in 14% (1 of 7) of the episodes with positive follow-up blood cultures, and in 65% (11 of 17) of those with negative follow-up blood cultures (P= .07). If the analysis is confined to cases with no external signs of catheter infection, salvage attempts were successful in 14% (1 of 7) of the episodes with positive follow-up blood cultures and in 80% (8 of 10) of those with negative follow-up blood cultures (P= .02).Conclusion:In neutropenic cancer patients with S. aureusbacteremia, attempted catheter salvage without antibiotic lock therapy was successful in 50% of the cases.

The prevalence of transmitted resistance to antiretroviral drugs varies geographically, with little known about this effect in Asia. In Korea, zidovudine has been widely administered, without charge, through the National AIDS program since the early 1990s; with other potent antiretroviral agents also being introduced in the late 1990s. An analysis of the drug susceptibility to antiretroviral drugs was performed by genotyping of the drug-resistant mutations in HIV on plasma samples from 50 HIV-infected patients who had received no treatment, between February 1998 and November 2002, which was interpreted according to the consensus guidelines of the International AIDS Society-USA panel. The median CD4 cell count was 100 cells/mm3; the mean plasma RNA level was (5.19 ± 0.56) log copies per milliliter. Of the 50 subjects tested 4 (8.0%) had one or more major drug-resistance mutation. The prevalence of resistance to multiple classes of drugs was 2.0%. No mutations, associated with resistance to nonnucleoside reverse transcriptase inhibitors, were identified. Resistant mutations of the reverse-transcriptase gene were found at codons 67, 70, 118, 215, and 219, and a resistant mutation of the protease gene was found only at codon 46 (2.6%, 1 of 39). There was an 8.0% prevalence of primary drug resistance to antiretroviral drugs in Korean patients infected with HIV-1.

To determine HIV-1 subtypes in Korean patients, we analyzed the nucleotide sequences of the HIV-1 env gene isolated from 19 Korean patients. DNA was extracted from cultured lymphocytes and the proviral V3 env gene was amplified by nested polymerase chain reaction. DNA sequences were determined using a cycle sequencer with fluorescence-labeled dye terminators, and aligned using a set of reference sequences. The phylogenetic tree was constructed by the neighbor-joining method. Most of the enrolled patients were in the advanced stage of AIDS with CD4+ lymphocyte counts ranging from 10 to 560 (median 50) per mm3. Eighteen of the nineteen patients' sequences fall into subtype B (95%) and one was subtype A (5%). The tetrameric motifs at the tip of the V3 loop were comprised of GPGR (10 cases, 53%), GPGS (5 cases, 26%), and GPGQ, GPGG, GQGR, and APGS (one case each, 5%). Subtype B was found to be the most predominant clade of HIV-1 in our AIDS patients.

The human polyomavirus JC virus (JCV) is the etiologic agent of the fatal demyelinating central nervous system disease progressive multifocal leukoencephalopathy (PML), which occurs in 4–7% of AIDS patients. Two Korean AIDS patients with PML were assayed for JCV, and the virus was genotyped by polymerase chain reaction, DNA sequencing and phylogenetic analysis. Using immunohistochemical analysis, we also examined the distribution of JCV antigen in the brains of the patients. The JCV genome was detected in peripheral lymphocytes, brain and cerebrospinal fluid from these Korean PML patients. Although type 2 is the most common genotype in Asia, the genotype of the JCV in these two AIDS patients was characterized as type 1, which is of European origin. We found that JCV antigen was selectively detected in oligodendrocytes and astrocytes of the brains from these patients. Compared to the prototype type 1 (Mad-1), two different nucleotides (G→C) in the KOR-1 strain identified here were found at positions 2488 and 2490 of the major capsid protein VP1 gene. In summary, this is the first report of PML in Korean AIDS patients; it is also the first isolation of JCV type 1 in PML in East Asians.

Members of HIV-1 group M are responsible for the vast majority of AIDS cases worldwide and have been classified on the basis of their phylogenetic relationships into nine roughly equidistant clades, termed subtypes. Although there are no known phenotypic correlates for these genotypes, the disproportionate spread of certain of these lineages has been taken to indicate that subtype-specific biological differences may exist. The subtype nomenclature thus remains an important molecular epidemiological tool with which to track the course of the group M pandemic. In this study, we have characterized HIV-1 strains described previously as unusual subtype A variants on the basis of partial sequence analysis. Six such strains from Cyprus (CY), South Korea (KR), and the Democratic Republic of Congo (CD) were PCR amplified from infected cell culture or patient PBMC DNA, cloned, and sequences in their entirety (94CY017, 97KR004, 97CDKTB48, and 97CDKP58) or as half genomes (97CDKS10 and 97CDKFE4). Distance and phylogenetic analyses showed that four of these viruses (94CY017, 97CDKTB48, 97CDKFE4, and 97CDKS10) were closely related to each other, but quite divergent from all other HIV-1 strains, except for subtype A viruses, which represented their closest relatives. In phylogenetic trees from gag, pol, env, and nef regions, the four newly characterized HIV-1 strains formed a distinct sister clade to subtype A, which was as closely related to subtype A as subsubtypes F1 and F2 are to each other. According to current nomenclature rules, this defines a subsubtype, which we have tentatively termed A2. The two other viruses, 97KR004 and 97CDKP58, as well as a full-length HIV-1 sequence from the sequence database (ZAM184), were found to represent complex A2/D, A2/G, and A2/C recombinants, respectively. These results indicate that HIV-1 subtype A is composed of two subsubtypes (A1 and A2), both of which appear to have a widespread geographic distribution. The A2 viruses described here represent the first reference reagents for this new group M lineage.

Can aggressive anti-human immunodeficiency virus (HIV) induction regimens be simplified after sufficient virus suppression is achieved? In vitrostudies were conducted to evaluate the hypothesis that aggressive induction regimens could be followed by less aggressive maintenance regimens. A clinical HIV-1 isolate and lymphoblastoid cell line (H9) were employed. Virus multiplicities were varied, as were drug inhibitory concentrations (IC90, IC99) and induction periods (1, 2 and 3 weeks) of a three-drug regimen (zidovudine plus lamivudine and indinavir), following which maintenance regimens (no drug, zidovudine alone, indinavir alone, zidovudine plus lamivudine) were employed. After 1 week inductions at IC99concentrations, viral rebound occurred on none or one-drug maintenance regimens but not on a two-drug regimen. After 2 week inductions, viral rebound occurred with no-drug maintenance, but not with one- and two-drug regimens. After 3 week inductions, viral rebound did not occur in zero-, one-, or two-drug maintenance regimens, although HIV-1 DNA persisted in cultured cells. These studies suggest that although some induction–maintenance regimens will fail, after a sufficient period of HIV-1 suppression with a three-drug antiretroviral regimen, maintenance on fewer drugs may be feasible.

Stereotypic neutralizing antibody clonotypes specific for SARS-CoV-2 receptor binding domain in patients with COVID-19 and healthy individuals.

Functional impairment of interferon, a natural antiviral component of the immune system, is associated with the pathogenesis and severity of COVID-19. We aimed to compare the efficacy of interferon beta-1a in combination with remdesivir compared with remdesivir alone in hospitalised patients with COVID-19.

ABSTRACTWe retrospectively reviewed medical records to identify the factors that affect the results of culture in patients with pyogenic vertebral osteomyelitis. In multivariate analysis, the presence of paravertebral abscess was associated with positive results of microbiologic culture. Prior antibiotic exposure, especially of longer duration, was strongly associated with negative results.

ABSTRACTSeventy-three liver abscess isolates of serotype K1 Klebsiella pneumoniaefrom a nationwide collection in Korea were genotypically characterized using pulsed-field gel electrophoresis and multilocus sequence typing. We found that serotype K1 K. pneumoniaestrains that caused liver abscesses in Korea were genotypically related and that most were sequence type 23.

Background:After the Middle East respiratory syndrome coronavirus outbreak in Korea in 2015, the government newly established the additional reimbursement for infection prevention to encourage infection control activities in the hospitals. The new policy was announced in December 2015 and was implemented in September 2016. We evaluated how infection control activities improved in hospitals after the change of government policy in Korea. Methods:Three cross-sectional surveys using the WHO Hand Hygiene Self-Assessment Framework (HHSAF) were conducted in 2013, 2015, and 2017. Using multivariable linear regression model including hospital characteristics, we analyzed the changes in total HHSAF scores according to the survey time. Results:In total, 32 hospitals participated in the survey in 2013, 52 in 2015, and 101 in 2017. The number of inpatient beds per infection control professionals decreased from 324 in 2013 to 303 in 2015 and 179 in 2017. Most hospitals were at intermediate or advanced levels of progress (90.6% in 2013, 86.6% in 2015, and 94.1% in 2017). In a multivariable linear regression model, the total HHSAF scores were significantly associated with hospital teaching status (β coefficient of major teaching hospital, 52.6; 95% CI, 8.9–96.4; P= .018), bed size (β coefficient of 100-bed increase, 5.1; 95% CI, 0.3–9.8; P= .038), and survey time (β coefficient of 2017 survey, 45.1; 95% CI, 19.3–70.9; P= .001). Conclusions:After the national policy implementation, the number of infection control professionals increased, and the promotion of hand hygiene activities was strengthened in Korean hospitals.Funding:NoneDisclosures:None

ABSTRACTWe report that vaccine dilution (1:1 or 1:10) and previous vaccinia virus vaccination status had no significant effect on cell-mediated immune responses (i.e., the immediate vaccinia virus-specific gamma interferon-producing T-cell response measured by enzyme-linked immunospot assay) 1 month after smallpox vaccination (Lancy-Vaxina; Berna Biotech, Switzerland).

ABSTRACTWe describe a case of bacteremia due to imipenem-susceptible Shewanella algae. Despite treatment with imipenem, the patient developed a spinal epidural abscess, from which imipenem-resistant S. algaewas isolated. The development of resistance should be monitored when S. algaeinfection is treated with imipenem, even though the strain is initially susceptible to imipenem.