Chung-Hao Huang

EMERGENCE OF REDUCED SUSCEPTIBILITY AND RESISTANCE TO FLUOROQUINOLONES IN ESCHERICHIA COLI IN TAIWAN AND CONTRIBUTIONS OF DISTINCT SELECTIVE PRESSURES

ABSTRACT A survey of 1,203 Escherichia coli isolates from 44 hospitals in Taiwan revealed that 136 (11.3%) isolates were resistant to fluoroquinolones and that another 261 (21.7%) isolates had reduced susceptibility. Resistance was more common in isolates responsible for hospital-acquired (mostly in intensive care units) infections (17.5%) than in other adult inpatient (11.4%; P = 0.08) and outpatient isolates (11.9%; P > 0.1). Similarly, reduced susceptibility was more common in isolates responsible for hospital-acquired infections (30.9%) than in other adult inpatient (21.0%; P = 0.04) and outpatient (21.4%; P = 0.06) isolates. Isolates from pediatric patients were less likely to be resistant (1.3 versus 12.0%; P < 0.01) but were nearly as likely to have reduced susceptibility (17.7 versus 21.9%;P > 0.1) as nonpediatric isolates. There was an inverse relationship in the proportion of isolates that were resistant versus the proportion that had reduced susceptibility among isolates from individual hospitals (R = 0.031; P < 0.05). In an analysis of isolates from two hospitals, all 9 resistant strains possessed double point mutations ingyrA and all 19 strains with reduced susceptibility strains had single point mutations; no mutations were found among fully susceptible strains. Risk factors for resistance included underlying cancer (odds ratio [OR], 83; 95% confidence interval [CI95], 7.3 to 2,241; P < 0.001), exposure to a quinolone (OR, undefined; P = 0.02), and exposure to a nonquinolone antibiotic (OR, 20; CI95, 2.2 to 482; P < 0.001); underlying cancer was the only independent risk factor (OR, 83; CI95, 8.6 to 807; P < 0.001). There were no significant associations between any of these factors and reduced susceptibility. Whereas acute and chronic quinolone use in cancer patients is a major selective pressure for resistance, other undetermined but distinct selective pressures appear to be more responsible for reduced susceptibility to fluoroquinolones in E. coli.

Laboratory diagnostics of dengue fever: An emphasis on the role of commercial dengue virus nonstructural protein 1 antigen rapid test

BACKGROUND/PURPOSE(S) In 2008, the Dengue NS1 Ag STRIP (Bio-Rad Laboratories, Marnes-la-Coquette, France) was introduced to routine dengue diagnostics in Taiwan, in addition to real-time reverse-transcription polymerase chain reaction (PCR), virus isolation, and capture immunoglobulin (Ig)M/IgG enzyme-linked immunosorbent assay (ELISA). This study aimed to evaluate the benefit of this assay and factors influencing the results of these diagnostic tests. METHODS Retrospectively, the authors enrolled laboratory-confirmed adult dengue patients from July 2008 to January 2012 in a tertiary hospital. The sensitivities of each test alone and in combination were analyzed by the duration of illness (early stage: day 0-day 3 and late stage: day 4-day 8). The factors influencing sensitivity of the Dengue NS1 Ag STRIP were examined. RESULTS There were 392 patients enrolled. The overall sensitivity of the Dengue NS1 Ag STRIP was 68.37% and PCR was 71.94%. With the assistance of the Dengue NS1 Ag STRIP, a diagnosis was made in 10.97% of patients without the need for second convalescent samples, and 4.34% more cases were detected. Independent factors for reduced Dengue NS1 Ag STRIP sensitivity were dengue virus (DENV) IgG seropositivity and a sample taken after the fifth day of illness. At the early stage, the PCR and the Dengue NS1 Ag STRIP combination had the highest sensitivity rate than other combinations. At the late stage, a combination of the Dengue NS1 Ag STRIP and capture IgM/IgG ELISA had better sensitivity rates. PCR and capture IgM/IgG ELISA in combination had sensitivity above 90% through the course of illness. CONCLUSION Dengue NS1 Ag STRIP is a useful tool for early dengue diagnosis. Its use can increase the diagnostic sensitivity and decrease the need of convalescent samples. Seeking treatment late (days postonset > 4) and DENV IgG seropositivity independently decrease the sensitivity of the Dengue NS1 Ag STRIP.

Acute psychosis related to use of trimethoprim/sulfamethoxazole in the treatment of HIV-infected patients with Pneumocystis jirovecii pneumonia: a multicentre, retrospective study

OBJECTIVES A recent study reported that trimethoprim/sulfamethoxazole caused acute psychosis in four renal transplant patients with Pneumocystis jirovecii pneumonia. We aimed to investigate the incidence of and factors associated with trimethoprim/sulfamethoxazole-related acute psychosis in HIV-infected patients with P. jirovecii pneumonia. METHODS We reviewed the medical records of HIV-infected patients who presented with P. jirovecii pneumonia and received trimethoprim/sulfamethoxazole at six major hospitals in Taiwan from July 2009 to May 2011. Acute psychosis was defined as the occurrence of hallucinations or delusions following the initiation of trimethoprim/sulfamethoxazole during hospitalization. RESULTS During the study period, 135 patients receiving trimethoprim/sulfamethoxazole for P. jirovecii pneumonia were enrolled and 16 (11.9%; 95% CI, 6.3%-17.4%) developed acute psychosis after a median duration of 5 days of trimethoprim/sulfamethoxazole treatment (range, 3-11 days). The incidence increased from 0% (0/16) in patients who received a daily trimethoprim dose of ≤12 mg/kg to 23.5% (4/17) in those who received a daily trimethoprim dose of >18 mg/kg. In multivariate logistic regression analysis, a higher daily dose of trimethoprim/sulfamethoxazole (OR, per 1 mg increase of trimethoprim, 1.40; 95% CI, 1.12-1.76; P = 0.0035) and use of adjunctive steroids (OR, 4.43; 95% CI, 1.14-17.15; P = 0.031) were associated with acute psychosis. CONCLUSIONS In this case series, 11.9% of HIV-infected patients developed acute psychosis while receiving trimethoprim/sulfamethoxazole for P. jirovecii pneumonia. While the study was limited by its retrospective design, the risk appeared to increase with increasing daily dose of trimethoprim/sulfamethoxazole in those vulnerable patients with multiple risks for acute psychosis.

Classification of dengue: The clinical use of World Health Organization 2009 guideline

Dengue is an acute febrile infectious illness that is endemic in many countries, including Taiwan. Worldwide surveillance revealed increasing trends of dengue cases and countries reporting dengue since 1980s. Dengue is commonly described as a dynamic illness that follows a course with three phasesdfebrile, critical, and recovery. The severity of symptoms differs among patients, and the conditions of those who have major complications or unfavorable outcomes usually begin to deteriorate at around the time their fever abates. The crucial question for clinical management is how to differentiate severe from nonsevere dengue cases in order to plan and implement appropriate care. The second-edition guideline published by World Health Organization (WHO) in 1997 categorized symptomatic dengue patients into three groups: dengue fever (DF), dengue hemorrhagic fever (DHF), and dengue shock syndrome (DSS). Dengue patients would be classified as DHF or DSS when they fulfill all the following four criteria: fever lasting for 2e7 days, hemorrhage tendency, thrombocytopenia (platelet count <10 per mL), and evidence of a plasma leakage. However, the criteria have certain shortcomings. One

Multicenter Study of Trimethoprim/Sulfamethoxazole-Related Hepatotoxicity: Incidence and Associated Factors among HIV-Infected Patients Treated for Pneumocystis jirovecii Pneumonia

The incidence of hepatotoxicity related to trimethoprim/sulfamethoxazole (TMP/SMX) administered at a therapeutic dose may vary among study populations of different ethnicities and hepatotoxic metabolites of TMP/SMX may be decreased by drug-drug interaction with fluconazole. We aimed to investigate the incidence of hepatotoxicity and the role of concomitant use of fluconazole in HIV-infected patients receiving TMP/SMX for Pneumocystis jirovecii pneumonia. We reviewed medical records to collect clinical characteristics and laboratory data of HIV-infected patients who received TMP/SMX for treatment of P. jirovecii pneumonia at 6 hospitals around Taiwan between September 2009 and February 2013. Hepatotoxicity was defined as 2-fold or greater increase of aminotransferase or total bilirubin level from baselines. Roussel UCLAF Causality Assessment Method (RUCAM) was used to analyze the causality of drug-induced liver injuries. NAT1 and NAT2 acetylator types were determined with the use of polymerase-chain-reaction (PCR) restriction fragment length polymorphism to differentiate common single-nucleotide polymorphisms (SNPs) predictive of the acetylator phenotypes in a subgroup of patients. During the study period, 286 courses of TMP/SMX treatment administered to 284 patients were analyzed. One hundred and fifty-two patients (53.1%) developed hepatotoxicity, and TMP/SMX was considered causative in 47 (16.4%) who had a RUCAM score of 6 or greater. In multivariate analysis, concomitant use of fluconazole for candidiasis was the only factor associated with reduced risk for hepatotoxicity (adjusted odds ratio, 0.372; 95% confidence interval, 0.145–0.957), while serostatus of hepatitis B or C virus, NAT1 and NAT2 acetylator types, or receipt of combination antiretroviral therapy was not. The incidence of hepatotoxicity decreased with an increasing daily dose of fluconazole up to 4.0 mg/kg. We conclude that the incidence of TMP/SMX-related hepatotoxicity was 16.4% in HIV-infected Taiwanese patients who received TMP/SMX for pneumocystosis. Concomitant use of fluconazole was associated with decreased risk for TMP/SMX-related hepatotoxicity.

Cyclooxygenase‐2 facilitates dengue virus replication and serves as a potential target for developing antiviral agents

Cyclooxygenase-2 (COX-2) is one of the important mediators of inflammation in response to viral infection, and it contributes to viral replication, for example, cytomegalovirus or hepatitis C virus replication. The role of COX-2 in dengue virus (DENV) replication remains unclear. In the present study, we observed an increased level of COX-2 in patients with dengue fever compared with healthy donors. Consistent with the clinical data, an elevated level of COX-2 expression was also observed in DENV-infected ICR suckling mice. Using cell-based experiments, we revealed that DENV-2 infection significantly induced COX-2 expression and prostaglandin E2 (PGE2) production in human hepatoma Huh-7 cells. The exogenous expression of COX-2 or PGE2 treatment dose-dependently enhanced DENV-2 replication. In contrast, COX-2 gene silencing and catalytic inhibition sufficiently suppressed DENV-2 replication. In an ICR suckling mouse model, we identified that the COX-2 inhibitor NS398 protected mice from succumbing to life-threatening DENV-2 infection. By using COX-2 promoter-based analysis and specific inhibitors against signaling molecules, we identified that NF-κB and MAPK/JNK are critical factors for DENV-2-induced COX-2 expression and viral replication. Altogether, our results reveal that COX-2 is an important factor for DENV replication and can serve as a potential target for developing therapeutic agents against DENV infection.

A Mucormycosis Case in a Cirrhotic Patient Successfully Treated with Posaconazole and Review of Published Literature

Mucormycosis is an invasive fungal infection associated with a high mortality rate, especially in immunocompromised hosts. Mucormycosis rarely occurs in cirrhotic patients. Here, we report a case of mucormycosis with underlying liver cirrhosis and diabetes mellitus. The patient suffered from maxillary sinusitis and osteomyelitis, and the infection was successfully treated with antifungal agents, surgical debridement, and hyperbaric oxygen therapy. The antifungal treatments used were liposomal amphotericin B, itraconazole, and posaconazole. Although our patient had liver cirrhosis (Child-Pugh classification B), no hepatic decompensation was developed during the treatment course of posaconazole. This is the first report of the safe and effective use of posaconazole for the treatment of mucormycosis in a cirrhotic patient.

Increased Production of Interleukin-4, Interleukin-10, and Granulocyte-Macrophage Colony-Stimulating Factor by Type 2 Diabetes’ Mononuclear Cells Infected with Dengue Virus, but Not Increased Intracellular Viral Multiplication

It has been reported that diabetes mellitus (DM) was an epidemiologically identified risk factor for development of dengue hemorrhagic fever (DHF)/severe dengue in dengue virus (DENV) affected patients, and T helper 2 (Th2) cytokines such as interleukin-4 (IL-4) and IL-10 each plays an important role in the immunopathogenesis of DHF in studies involving general population. To better understand the relationship between these epidemiological and immunological findings, we performed an in vitro study evaluating the sequential immunological reactions and viral load in the DENV infected mononuclear cells of adults with type 2 DM (T2DM group, n = 33) and normal adults (control group, n = 29). We found in the T2DM group significantly higher IL-4 level on the first (P = 0.049) and the third (P = 0.022) postinfection days, while higher IL-10 (P = 0.042) and granulocyte-macrophage colony-stimulating factor (GM-CSF) (P = 0.009) were detected on the third postinfection day. No significant difference in DENV viral load between the cultured mononuclear cells from both groups was found on the first and third post-infection days. These data immunologically suggest that patients with T2DM are at higher risk for development of DHF/severe dengue and strengthen the previously epidemiologically identified role of DM being a predictive risk factor for progressing into DHF/severe dengue in DENV-affected patients.

Development of a Simple Clinical Risk Score for Early Prediction of Severe Dengue in Adult Patients.

We aimed to develop and validate a risk score to aid in the early identification of laboratory-confirmed dengue patients at high risk of severe dengue (SD) (i.e. severe plasma leakage with shock or respiratory distress, or severe bleeding or organ impairment). We retrospectively analyzed data of 1184 non-SD patients at hospital presentation and 69 SD patients before SD onset. We fit a logistic regression model using 85% of the population and converted the model coefficients to a numeric risk score. Subsequently, we validated the score using the remaining 15% of patients. Using the derivation cohort, two scoring algorithms for predicting SD were developed: models 1 (dengue illness ≤4 days) and 2 (dengue illness >4 days). In model 1, we identified four variables: age ≥65 years, minor gastrointestinal bleeding, leukocytosis, and platelet count ≥100×109 cells/L. Model 1 (ranging from −2 to +6 points) showed good discrimination between SD and non-SD, with an area under the receiver operating characteristic curve (AUC) of 0.848 (95% confidence interval [CI], 0.771–0.924). The optimal cutoff value for model 1 was 1 point, with a sensitivity and specificity for predicting SD of 70.3% and 90.6%, respectively. In model 2 (ranging from 0 to +3 points), significant predictors were age ≥65 years and leukocytosis. Model 2 showed an AUC of 0.859 (95% CI, 0.756–0.963), with an optimal cutoff value of 1 point (sensitivity, 80.3%; specificity, 85.8%). The median interval from hospital presentation to SD was 1 day. This finding underscores the importance of close monitoring, timely resuscitation of shock including intravenous fluid adjustment and early correction of dengue-related complications to prevent the progressive dengue severity. In the validation data, AUCs of 0.904 (95% CI, 0.825–0.983) and 0.917 (95% CI, 0.833–1.0) in models 1 and 2, respectively, were achieved. The observed SD rates (in both cohorts) were <3% for patients with a score <1 point, but >50% for those with a score of ≥2 points, irrespective of the day of illness onset, suggesting that our simple risk score can be easily implemented in resource-limited countries for early prediction of dengue patients at risk of SD provided that they have rapid dengue confirmed tests. For patients with other acute febrile illnesses or bacterial infections usually have SD risk score of >1. Thus, these scoring algorithms cannot totally replace good clinical judgement of the physician, and most importantly, early differentiating dengue from other febrile illnesses is critical for appropriate monitoring and management.

Risk factors for microbiologic failure among Taiwanese adults with Mycobacterium abscessus complex pulmonary disease.

BACKGROUND The Mycobacterium abscessus complex is a common cause of pulmonary nontuberculous mycobacteria infections in Taiwan. We examined the risk factors associated with treatment outcome in Taiwanese adults with pulmonary disease caused by the M. abscessus complex. METHODS We retrospectively reviewed the records of all patients from a southern Taiwan medical center from 2006 to 2012 who had respiratory specimens identified as M. abscessus complex and met the American Thoracic Society criteria for pulmonary disease. RESULTS Of the 106 included patients, females (58.5%) and nonsmokers (79.2%) predominated. The mean age of patients was 64.8 years. Sixty-three patients (59.4%) had pre-existing lung disease. Previous mycobacterial pulmonary disease (34.9%) was the most common underlying disorder. Chest radiography indicated that bronchiectasis was common (47.2%) and that cavitations were less common (14.2%). Fifty-six patients received antibiotic treatment. Clinicians were more likely to prescribe antibiotics if the initial sputum acid-fast staining was positive (p < 0.001). Treatment outcome was analyzed in 26 patients who were treated for more than 3 months; three of these patients (11.5%) had clinical failure and 18 (69.2%) experienced sputum conversion. Patients with cavitary lesions were more likely to experience microbiologic failure (p = 0.02). Nine patients had positive cultures after antibiotic treatment for > 1 year. Previous mycobacterial pulmonary disease (p = 0.011) and cavitary lesion (p = 0.034) are risk factors for persistence of M. abscessus complex. CONCLUSION With antimicrobial therapy, previous mycobacterial disease, and cavitary lesion are associated with microbiologic failure in Taiwanese adults with M. abscessus complex pulmonary disease.