Bum Sik Chin

Geographic and Temporal Trends in the Molecular Epidemiology and Genetic Mechanisms of Transmitted HIV-1 Drug Resistance: An Individual-Patient- and Sequence-Level Meta-Analysis

Background Regional and subtype-specific mutational patterns of HIV-1 transmitted drug resistance (TDR) are essential for informing first-line antiretroviral (ARV) therapy guidelines and designing diagnostic assays for use in regions where standard genotypic resistance testing is not affordable. We sought to understand the molecular epidemiology of TDR and to identify the HIV-1 drug-resistance mutations responsible for TDR in different regions and virus subtypes. Methods and Findings We reviewed all GenBank submissions of HIV-1 reverse transcriptase sequences with or without protease and identified 287 studies published between March 1, 2000, and December 31, 2013, with more than 25 recently or chronically infected ARV-naïve individuals. These studies comprised 50,870 individuals from 111 countries. Each set of study sequences was analyzed for phylogenetic clustering and the presence of 93 surveillance drug-resistance mutations (SDRMs). The median overall TDR prevalence in sub-Saharan Africa (SSA), south/southeast Asia (SSEA), upper-income Asian countries, Latin America/Caribbean, Europe, and North America was 2.8%, 2.9%, 5.6%, 7.6%, 9.4%, and 11.5%, respectively. In SSA, there was a yearly 1.09-fold (95% CI: 1.05–1.14) increase in odds of TDR since national ARV scale-up attributable to an increase in non-nucleoside reverse transcriptase inhibitor (NNRTI) resistance. The odds of NNRTI-associated TDR also increased in Latin America/Caribbean (odds ratio [OR] = 1.16; 95% CI: 1.06–1.25), North America (OR = 1.19; 95% CI: 1.12–1.26), Europe (OR = 1.07; 95% CI: 1.01–1.13), and upper-income Asian countries (OR = 1.33; 95% CI: 1.12–1.55). In SSEA, there was no significant change in the odds of TDR since national ARV scale-up (OR = 0.97; 95% CI: 0.92–1.02). An analysis limited to sequences with mixtures at less than 0.5% of their nucleotide positions—a proxy for recent infection—yielded trends comparable to those obtained using the complete dataset. Four NNRTI SDRMs—K101E, K103N, Y181C, and G190A—accounted for >80% of NNRTI-associated TDR in all regions and subtypes. Sixteen nucleoside reverse transcriptase inhibitor (NRTI) SDRMs accounted for >69% of NRTI-associated TDR in all regions and subtypes. In SSA and SSEA, 89% of NNRTI SDRMs were associated with high-level resistance to nevirapine or efavirenz, whereas only 27% of NRTI SDRMs were associated with high-level resistance to zidovudine, lamivudine, tenofovir, or abacavir. Of 763 viruses with TDR in SSA and SSEA, 725 (95%) were genetically dissimilar; 38 (5%) formed 19 sequence pairs. Inherent limitations of this study are that some cohorts may not represent the broader regional population and that studies were heterogeneous with respect to duration of infection prior to sampling. Conclusions Most TDR strains in SSA and SSEA arose independently, suggesting that ARV regimens with a high genetic barrier to resistance combined with improved patient adherence may mitigate TDR increases by reducing the generation of new ARV-resistant strains. A small number of NNRTI-resistance mutations were responsible for most cases of high-level resistance, suggesting that inexpensive point-mutation assays to detect these mutations may be useful for pre-therapy screening in regions with high levels of TDR. In the context of a public health approach to ARV therapy, a reliable point-of-care genotypic resistance test could identify which patients should receive standard first-line therapy and which should receive a protease-inhibitor-containing regimen.

Incidence and risk factors of infection in a single cohort of 110 adults with systemic lupus erythematosus

Infection is a major cause of mortality in patients with systemic lupus erythematosus (SLE). This study describes infectious complications in SLE patients and analyzes the risk factors for infection at the time of SLE diagnosis and during the course of SLE in a case-control study. Of 110 patients enrolled, 42 (38%) had at least 1 episode of infectious disease. The incidence of infectious disease was 4.4/100 patient-years (py) with a total follow-up duration of 954 y. In multivariate analysis, independent predictors of infection at the time of SLE diagnosis were an SLE disease activity index (SLEDAI) > 12 (p = 0.01), C3 levels < 90 mg/dl (p = 0.01) and positive anti-ds DNA antibodies (p < 0.01). Frequent flare-ups (p = 0.04) and follow-up duration ≥8 y (p = 0.023) were also significant risk factors for infectious diseases. It is mandatory to closely observe SLE patients with risk factors for developing infectious diseases.

Extensively drug-resistant Acinetobacter baumannii: risk factors for acquisition and prevalent OXA-type carbapenemases—a multicentre study

In this study, we investigated the risk factors for and carbapenem resistance mechanisms of extensively drug-resistant Acinetobacter baumannii (XDR-AB). Isolates of XDR-AB were collected from seven tertiary care hospitals in South Korea. A case-control study for risk factor analysis was performed and the presence of the metallo-β-lactamase (MBL) and OXA genes was examined. The control group consisted of adult inpatients receiving care from the same hospital. XDR-AB were isolated from 26 patients who were studied for risk factor analysis. Third-generation cephalosporin use [odds ratio (OR)=9.6, 95% confidence interval (CI) 1.3-171.3; P=0.02] and Acute Physiology and Chronic Health Evaluation (APACHE) II score (OR=1.2, 95% CI 1.1-1.5; P=0.004) were identified as risk factors for acquisition of XDR-AB. Pulsed-field gel electrophoresis (PFGE) showed clonal epidemic isolates in hospitals. MBLs were not detected, and all 30 XDR-AB isolates had upregulated OXA-type carbapenemase genes. These results suggest that third-generation cephalosporin use and disease severity are associated with XDR-AB acquisition amongst typical adult inpatients. This study also points to intrahospital spread of XDR-AB. Upregulated OXA-type carbapenemases are prevalent in XDR-AB founded in South Korean hospitals.

Vancomycin-resistant enterococci bacteremia: Risk factors for mortality and influence of antimicrobial therapy on clinical outcome

OBJECTIVES This study evaluated the effects of antimicrobial treatment against vancomycin-resistant enterococci (VRE) and delayed administration of anti-VRE therapy on mortality, and determined independent risk factors for delayed all-cause mortality of VRE bacteremia patients. METHODS Over 10 years, 153 patients with clinically significant monomicrobial VRE bacteremia were identified among a total of 2834 patients in a VRE cohort. The main outcomes were immediate (7-day) and delayed (28-day, 60-day) all-cause mortality. RESULTS The 7-day (P<0.001) and 28-day (P=0.041) mortalities were lower in the group receiving anti-VRE therapy, but the 60-day mortality (P=0.113) was unaffected. The mortalities of patients receiving anti-VRE therapy later than 72h after the onset of bacteremia were no different from that of patients receiving treatment within 72h. Both a higher APACHE II score (hazard ratio [HR], 1.10; P<0.001 and HR, 1.12; P<0.001, respectively) and the presence of septic shock at the onset of bacteremia (HR, 1.91; P=0.047 and HR, 1.78; P=0.034, respectively) were independent risk factors for 28-day and 60-day mortality. CONCLUSION These findings suggest that in spite of antibiotic therapy against VRE, patients with VRE bacteremia eventually have a higher risk of death because of severe illness at the onset of bacteremia.

Risk factors and outcomes of bloodstream infections with metallo-β-lactamase-producing Acinetobacter

The spread of Gram-negative bacilli with acquired metallo-β-lactamase (MBL) threatens the successful treatment of major nosocomial infections. The objective of this study was to evaluate the differences in the clinical characteristics of bacteremia caused by MBL-producing Acinetobacter species and MBL non-producing isolates. Two retrospective case-control studies were conducted using data on patients with Acinetobacter bacteremia, who were admitted between January 2001 and December 2005 at a 1500-bed, tertiary-care teaching hospital. Case group 1 (n=27) included patients from whom imipenem-resistant Acinetobacter was isolated in blood culture, and case group 2 (n=7) consisted of those patients from group 1 who yielded MBL-producing isolates. The control group (n=41) included patients from whom carbapenem-susceptible Acinetobacter isolates were isolated in blood culture. Multivariate analysis revealed that the independent risk factors for imipenem-resistant Acinetobacter bacteremia were neutropenia and prolonged use of carbapenem. The independent risk factors for MBL-producing Acinetobacter bacteremia were neutropenia and prolonged use of cephalosporins. The results of this study suggest that a prolonged use of cephalosporins may be associated with MBL-producing Acinetobacter bacteremia.

Risk factors of all-cause in-hospital mortality among Korean elderly bacteremic urinary tract infection (UTI) patients

Urinary tract infection (UTI) is the most frequent cause of bacteremia/sepsis in elderly people and increasing antimicrobial resistance in uropathogens has been observed. To describe the characteristics of bacteremic UTI in elderly patients and to identify the independent risk factors of all-cause in-hospital mortality, a retrospective cohort study of bacteremic UTI patients of age over 65 was performed at a single 2000-bed tertiary hospital. Bacteremic UTI was defined as the isolation of the same organism from both urine and blood within 48 h. Eighty-six elderly bacteremic UTI patients were enrolled. Community-acquired infection was the case for most patients (79.1%), and Escherichia coli accounted for 88.6% (70/79) among Gram-negative organisms. Non-E. coli Gram-negative organisms were more frequent in hospital-acquired cases and male patients while chronic urinary catheter insertion was related with Gram-positive urosepsis. The antibiotic susceptibility among Gram-negative organisms was not different depending on the source of bacteremic UTI, while non-E. coli Gram-negative organisms were less frequently susceptible for cefotaxime, cefoperazone/sulbactam, and aztreonam. All-cause in-hospital mortality was 11.6%, and functional dependency (adjusted hazard ratio=HR=10.9, 95% confidence interval=95%CI=2.2-54.6) and low serum albumin (adjusted HR=27.0, 95%CI=2.0-361.2) were independently related with increased all-cause in-hospital mortality.

Clinical Review of Endogenous Endophthalmitis in Korea: A 14-Year Review of Culture Positive Cases of Two Large Hospitals.

Purpose To identify the clinical features and outcomes of endogenous endophthalmitis in Korea. Materials and Methods We reviewed 18 patients with endogenous endophthalmitis at 2 Korean hospitals, treated over a 14 year period between January 1993 and December 2006. Results The comorbidities observed in these cases were diabetes mellitus and liver cirrhosis. The most common pathogens, which were found in 7 patients each (38.9%), were Klebsiella pneumonia and Pseudomonas aeruginosa. All patients were treated with systemic antibiotics and fortified topical antibiotics. A surgical approach including vitrectomy was performed in 9 cases (50.0%). The prognosis was generally poor, and visual acuity improved slightly in 6 patients (33.3%). Conclusion In this study, diabetes mellitus and Klebsiella pneumonia showed a close relationship with endogenous endophthalmitis, respectively. Endogenous endophthalmitis is a serious risk to sight and careful attention to establishing the diagnosis and management may decrease the ocular morbidity.

Acquisition of extensive drug-resistant Pseudomonas aeruginosa among hospitalized patients: risk factors and resistance mechanisms to carbapenems.

Extensive drug-resistant Pseudomonas aeruginosa (XDRPA) strains, defined as resistant to all available antipseudomonal antibiotics, have been reported recently. This study aimed to investigate the risk factors for XDRPA acquisition by patients and the resistance mechanisms to carbapenems. From June to November 2007, XDRPA isolates were collected from patients in eight tertiary care hospitals. A case-control study was performed to determine factors associated with XDRPA acquisition. EDTA-imipenem disc synergy tests, and polymerase chain reaction amplification and sequencing were performed to detect the presence of metallo-β-lactamases (MBLs). Risk factor analysis was performed for 33 patients. Mechanical ventilation [odds ratio (OR) 8.2, 95% confidence interval (CI) 1.3-52.2; P = 0.026] and APACHE II score (OR 1.2, 95% CI 1.0-1.3; P = 0.007) were identified as independent risk factors for XDRPA acquisition. Pulsed-field gel electrophoresis of XDRPA identified clonal epidemic isolates co-existing with sporadic isolates. Eight of 43 (19%) XDRPA isolates were shown to produce MBLs; four produced VIM-2 and four produced IMP-6. This study suggests a major role for mechanical ventilation in XDRPA acquisition. Moreover, pulsed-field gel electrophoresis identified a clonal epidemic within hospitals. Taken together, these results suggest that patient-to-patient transmission contributes to XDRPA acquisition in Korea.

Disseminated Mycobacterium kansasii infection associated with skin lesions: a case report and comprehensive review of the literature.

Mycobacteruim kansasii occasionally causes disseminated infection with poor outcome in immunocompromised patients. We report the first case of disseminated M. kansasii infection associated with multiple skin lesions in a 48-yr-old male with myelodysplastic syndrome. The patient continuously had taken glucocorticoid during 21 months and had multiple skin lesions developed before 9 months without complete resolution until admission. Skin and mediastinoscopic paratracheal lymph node (LN) biopsies showed necrotizing granuloma with many acid-fast bacilli. M. kansasii was cultured from skin, sputum, and paratracheal LNs. The patient had been treated successfully with isoniazid, rifampin, ethmabutol, and clarithromycin, but died due to small bowel obstruction. Our case emphasizes that chronic skin lesions can lead to severe, disseminated M. kansasii infection in an immunocompromised patient. All available cases of disseminated M. kansasii infection in non HIV-infected patients reported since 1953 are comprehensively reviewed.

Blood Stream Infections by Candida glabrata and Candida krusei: A Single-Center Experience

Background/Aims The increasing incidence of Candida glabrata and Candida krusei infections is a significant problem because they are generally more resistant to fluconazole. We compared the risk factors associated with C. glabrata and C. krusei fungemia with Candida albicans fungemia and examined the clinical manifestations and prognostic factors associated with candidemia. Methods We retrospectively reviewed demographic data, risk factors, clinical manifestations, and outcomes associated with C. glabrata and C. krusei fungemia at a tertiary-care teaching hospital during a 10-years period from 1997 to 2006. Results During the study period, there were 497 fungemia episodes. C. glabrata fungemia accounted for 23 episodes and C. krusei fungemia accounted for 8. Complete medical records were available for 27 of these episodes and form the basis of this study. Compared to 54 episodes of C. albicans fungemia, renal insufficiency and prior fluconazole prophylaxis were associated with development of C. glabrata or C. krusei fungemia. The overall mortality was 67%. The fungemia-related mortality of C. glabrata and C. krusei was higher than that of C. albicans (52 vs. 26%, p=0.021). Empirical antifungal therapy did not decrease the crude mortality. Multiple logistic regression analysis showed that high APACHE II scores, catheter maintenance, and shock were independently associated with an increased risk of death. Conclusions Renal insufficiency and prior fluconazole prophylaxis were associated with the development of C. glabrata or C. krusei fungemia. Fungemia-related mortality of C. glabrata or C. krusei was higher than that of C. albicans. Outcomes appeared to be related to catheter removal, APACHE II scores, and shock.