Diagnostic role of inflammatory and anti-inflammatory cytokines and effector molecules of cytotoxic T lymphocytes in tuberculous pleural effusion.

BACKGROUND AND OBJECTIVE: Early diagnosis of tuberculous pleural effusion (TPE) remains difficult. While some inflammatory markers in pleural effusion (PE) are helpful in diagnosis, the roles of anti-inflammatory cytokines and effector molecules of cytotoxic T lymphocytes have not been investigated. METHODS: Lymphocyte-predominant exudative PE samples were assayed for inflammatory and anti-inflammatory cytokines and effector molecules of cytotoxic T lymphocytes. Logistic regression analysis was used to predict the probability of TPE and identify independently associated factors. Receiver operating characteristic (ROC) curve analysis was applied to determine the optimal cut-off value for the predicted probability. RESULTS: Of 95 patients enrolled, 35 had TPE, 46 had malignant PE and 14 had PE due to other aetiologies. Interferon-γ (IFN-γ), adenosine deaminase (ADA), decoy receptor (DcR) 3, monocyte chemo-attractant protein (MCP)-1, IFN-induced protein (IP)-10, granzyme A and perforin were higher in TPE than in PE of other aetiologies. By logistic regression analysis, IFN-γ ≥ 75 pg/mL, ADA ≥ 40 IU/mL, DcR3 ≥ 9.3 ng/mL and soluble tumour necrosis factor receptor 1 (TNF-sR1) ≥ 3.2 ng/mL were independent factors associated with TPE. The predicted probability based on the four predictors had an area under the ROC curve of 0.920, with 82.9% sensitivity and 86.7% specificity under the cut-off value of 0.303. In the TPE group, patients with positive PE/pleural culture for Mycobacterium tuberculosis had higher pleural IFN-γ, MCP-1, IP-10 and perforin than those with positive sputum but negative PE culture. CONCLUSIONS: While pleural interferon-γ and ADA are conventional markers for diagnosing TPE, simultaneous measurements of DcR3 and TNF-sR1 can improve the diagnostic efficacy.

Increasing incidence of nontuberculous mycobacteria, Taiwan, 2000-2008.

To assess the species distribution and epidemiologic trends of nontuberculous mycobacteria, we examined isolates from patients in Taiwan. During 2000-2008, the proportion increased significantly from 32.3% to 49.8%. Associated disease incidence increased from 2.7 to 10.2 cases per 100,000 patients. Mycobacterium avium complex and M. abscessus were most frequently isolated.

Safety of fluoroquinolone use in patients with hepatotoxicity induced by anti-tuberculosis regimens.

BACKGROUND: Fluoroquinolones are frequently used to replace agents in first-line anti-tuberculosis (anti-TB) regimens in patients with TB who have drug-induced hepatic dysfunction. We investigated the safety of using fluoroquinolone in an area where TB is endemic and where there is a high incidence of drug-induced liver injury. METHODS: From September 2003 through August 2006, patients who had aspartate aminotransferase and/or alanine aminotransferase levels >3 times the upper limit of normal in the presence of hepatitis symptoms or who had aspartate aminotransferase and/or alanine aminotransferase levels >5 times the upper limit of normal after receipt of anti-TB treatment were enrolled. The control group received ethambutol, with or without streptomycin; study groups received either (1) ethambutol plus levofloxacin, with or without streptomycin; or (2) ethambutol plus moxifloxacin, with or without streptomycin. The outcome measurement was the time from onset of hepatitis to normalization of liver functions. RESULTS: One hundred thirty-four (11.3%) of 1191 patients received a diagnosis of hepatotoxicity and needed to stop anti-TB treatment. The risk factor was abnormal baseline transaminase levels. Twenty-two of the 134 patients received the control medication, 40 received levofloxacin, and 45 received moxifloxacin; the remaining patients were excluded from the study. There were no significant prestudy differences between groups. Time to liver function normalization was almost the same for all groups (mean +/- standard deviation, 29.1+/-21.4, 25.5+/-17.6, and 29.7+/-14.3 days, respectively). CONCLUSIONS: Abnormal baseline transaminase levels are the independent risk factors for anti-TB therapy-induced hepatitis. Levofloxacin and moxifloxacin caused no additional hepatotoxicity when they were used by patients with hepatitis induced by first-line anti-TB drugs.

A prospective study of hepatitis during antituberculous treatment in Taiwanese patients and a review of the literature.

BACKGROUND/PURPOSE: The present study prospectively investigated the incidence of and factors associated with hepatitis during antituberculous treatment in patients with tuberculosis and various underlying diseases. The results were compared with those of previously published studies. METHODS: Patients treated with antituberculous agents were enrolled from July 1, 2000 to July 31, 2001, in the divisions of chest and infectious diseases at National Taiwan University Hospital and followed until November 30, 2001. Hepatitis was defined as an aminotransferase level>5 times the upper limit of normal (ULN), or >3 times ULN in the presence of symptoms of hepatitis, or total bilirubin level>3 mg/dL. Studies reporting the incidence of hepatitis during antituberculous treatment were reviewed for comparison. RESULTS: Among 261 patients, median age was 58 years (range, 17-90 years), 17.7% had abnormal baseline liver function tests and 18.4% had concurrent hepatotoxic drug use. Fifteen patients (5.7%) had hepatitis B virus infection, 17 (6.5%) had hepatitis C virus infection, 14 (5.4%) had liver cirrhosis, and 15 (5.7%) had human immunodeficiency virus infection. Hepatitis occurred in 42 patients (16.1%), with 60% of the events in the first 2 months of treatment. Such an incidence was comparable to that in other Asian countries (5.3-18.2%) and slightly higher than that in Western countries (2.4-19%). In multivariate analysis, abnormal liver function tests at baseline and liver cirrhosis were independent factors for development of hepatitis. CONCLUSION: Elevation of liver function tests was not uncommon during antituberculous treatment, especially in the first 2 months. Patients with abnormal liver function tests at baseline or liver cirrhosis should be closely monitored.

Extensively drug-resistant Mycobacterium tuberculosis during a trend of decreasing drug resistance from 2000 through 2006 at a Medical Center in Taiwan.

BACKGROUND: Drug resistance rates are one of the most important aspects in the national tuberculosis (TB) control program, and drug-resistant TB, especially extensively drug-resistant (XDR) TB, is not well understood in Taiwan. The objectives of this study were to investigate the prevalence of drug resistance from 2000 through 2006 and to identify XDR TB isolates to elucidate the clinical characteristics of patients with XDR TB at National Taiwan University Hospital. METHODS: The prevalence of drug resistance among clinical, nonduplicate Mycobacterium tuberculosis isolates was analyzed. Testing of susceptibility to antituberculosis agents, including isoniazid, rifampicin, ethambutol, streptomycin, rifabutin, ofloxacin, ethinamide, and para-aminosalicylic acid, was performed using the proportional method. Minimum inhibitory concentrations of amikacin, capreomycin, isepamycin, linezolid, cycloserine, ciprofloxacin, levofloxacin, moxifloxacin, and gemifloxacin were determined for 40 available multidrug-resistant M. tuberculosis isolates. RESULTS: Significant decreasing trends in rates of resistance to isoniazid, ethambutol, and at least 1 of the 3 first-line agents were observed among 2625 M. tuberculosis isolates from 2000 through 2006. Among these 2625 isolates, 150 (5.7%) were multidrug resistant, and 10 M. tuberculosis isolates (0.4%) fulfilled the definition of XDR M. tuberculosis. Nine (90%) of 10 patients with XDR TB had a previous history of TB and received anti-TB treatment before acquisition of XDR TB. CONCLUSIONS: The remaining high prevalence of multidrug-resistant TB and the presence of XDR TB during a trend of decreasing drug resistance are alarming. Continuous surveillance of clinical isolates of M. tuberculosis is needed to identify XDR TB, especially in patients who have a history of TB and have received prior anti-TB treatment.

Recurrent bilateral pneumothoraces: a rare complication of miliary tuberculosis.

Pneumothorax as a complication of adult cavitary pulmonary tuberculosis is well known and not at all rare, but its occurrence as a complication of miliary tuberculosis is extremely rare. We report a 22-year-old woman who had nonproductive cough and fever for 3 days. Chest radiography showed diffuse, symmetrical miliary nodulation throughout both lung fields. The patient was treated for a presumed diagnosis of miliary tuberculosis with standard antituberculous regimen. Bilateral pneumothorax occurred simultaneously during hospitalization and chest tube thoracostomy was performed. Three days later, recurrent right pneumothorax developed. Video-assisted thoracoscopic surgery (VATS) lung biopsy of the right lung was performed and pathology showed granulomatous interstitial pneumonia with acid-fast positive bacilli. Lung tissue culture was positive for Mycobacterium tuberculosis. In the following 2 months, bilateral pneumothorax recurred twice and chemical pleurodesis with minocycline was performed on both sides, but air leakage persisted. VATS pleurodesis was performed on both sides successfully without recurrence of pneumothorax on either side. Our experience highlights the fact that pneumothorax should be suspected in an adult with miliary tuberculosis who suddenly develops acute respiratory distress. Recurrent pneumothorax can be managed, apart from medical therapy of miliary tuberculosis, with surgical intervention.

Disseminated tuberculosis: a 10-year experience in a medical center.

Disseminated tuberculosis remains a diagnostic challenge because the presentations are nonspecific. In the current retrospective study we describe the clinical characteristics and outcome of disseminated tuberculosis. From January 1995 to December 2004, patients with culture-confirmed tuberculosis who fulfilled the criteria for disseminated tuberculosis were selected and their medical records reviewed. Their clinical isolates were genotyped. Of the 3058 patients with culture-confirmed tuberculosis, 164 (5.4%) had disseminated disease; 14.0% of patients had acquired immunodeficiency syndrome. The most common radiographic finding was miliary lung lesions (47.0%); 31.1% of patients died at the end of the study. Poor prognostic factors included hypoalbuminemia, hyperbilirubinemia, renal insufficiency, and delayed antituberculosis treatment. Clinical findings suggestive of disseminated tuberculosis were miliary lung lesions, serum ferritin >1000 microg/L, infiltrative liver disease, and adjusted calcium >2.6 mmol/L. Simultaneously performing mycobacterial culture and histopathologic examination of bone marrow biopsy was more sensitive and faster than just performing mycobacterial blood culture in diagnosing disseminated tuberculosis. Of the 64 preserved Mycobacterium tuberculosis isolates, 47 (73.4%) were clustered and 27 (42.2%) were Beijing family. Since prognosis was worse in patients with delayed treatment, a high index of suspicion is required, especially in those with clinical findings suggestive of disseminated tuberculosis.

In vitro activities of various piperacillin and sulbactam combinations against bacterial pathogens isolated from Intensive Care Units in Taiwan: SMART 2004 programme data.

We investigated the in vitro activity of various piperacillin and sulbactam combinations against Gram-negative bacterial isolates from Intensive Care Units (ICUs) in Taiwan. Antimicrobial susceptibility testing of 1030 bacterial isolates recovered from ICUs of nine major teaching hospitals was performed using the agar dilution method. Sulbactam was added to piperacillin either at a fixed sulbactam concentration of 4 mg/L and 8 mg/L or at a piperacillin:sulbactam ratio of 2:1 and 4:1. Piperacillin/sulbactam at a ratio of 2:1 or a fixed 8 mg/L concentration of sulbactam had better activities against Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis and Serratia marcescens than other piperacillin/sulbactam formulations. For Pseudomonas aeruginosa, piperacillin/sulbactam (2:1 or 4:1 ratios) had MIC(90) values (minimum inhibitory concentration for 90% of the organisms) of 64 mg/L (>90% susceptibility) compared with 64 mg/L for cefoperazone/sulbactam (68% susceptibility) and 128 mg/L for piperacillin/tazobactam (82% susceptibility). For Acinetobacter baumannii, both piperacillin/sulbactam (either 2:1 ratio or a fixed 8 mg/L sulbactam) and cefoperazone/sulbactam were the most potent agents. Adding sulbactam to piperacillin resulted in increased susceptibility rates among piperacillin-resistant P. aeruginosa (53-57% in either 2:1 or 4:1 ratios) and A. baumannii (38-46% in either 2:1 ratio or a fixed 8 mg/L concentration of sulbactam) isolates. Results of susceptibility tests with piperacillin/sulbactam are dependent on the method used. Piperacillin/sulbactam combinations possessed better in vitro activities than piperacillin alone or piperacillin/tazobactam against P. aeruginosa and A. baumannii.

Identification of alpha-enolase as an autoantigen in lung cancer: its overexpression is associated with clinical outcomes.

PURPOSE: Although existence of humoral immunity has been previously shown in malignant pleural effusions, only a limited number of immunogenic tumor-associated antigens (TAA) have been identified and associated with lung cancer. In this study, we intended to identify more TAAs in pleural effusion-derived tumor cells. EXPERIMENTAL DESIGN: Using morphologically normal lung tissues as a control lysate in Western blotting analyses, 54 tumor samples were screened with autologous effusion antibodies. Biochemical purification and mass spectrometric identification of TAAs were done using established effusion tumor cell lines as antigen sources. We identified a p48 antigen as alpha-enolase (ENO1). Semiquantitative immunohistochemistry was used to evaluate expression status of ENO1 in the tissue samples of 80 patients with non-small cell lung cancer (NSCLC) and then correlated with clinical variables. RESULTS: Using ENO1-specifc antiserum, up-regulation of ENO1 expression in effusion tumor cells from 11 of 17 patients was clearly observed compared with human normal lung primary epithelial and non-cancer-associated effusion cells. Immunohistochemical studies consistently showed high level of ENO1 expression in all the tumors we have examined thus far. Log-rank and Cox's analyses of ENO1 expression status revealed that its expression level in primary tumors was a key factor contributing to overall- and progression-free survivals of patients (P < 0.05). The same result was also obtained in the early stage of NSCLC patients, showing that tumors expressing relatively higher ENO1 level were tightly correlated with poorer survival outcomes. CONCLUSIONS: Our data strongly support a prognostic role of ENO1 in determining tumor malignancy of patients with NSCLC.

Antibody responses to pneumococcal polysaccharide vaccine in Taiwanese patients with chronic obstructive pulmonary disease.

BACKGROUND/PURPOSE: A study was undertaken to assess the antibody responses to a 23-valent pneumococcal polysaccharide vaccine and clinical outcome in Taiwanese patients with chronic obstructive pulmonary disease (COPD). METHODS: From January to December 1999, 80 Taiwanese patients with COPD were enrolled. Each patient received a 23-valent pneumococcal polysaccharide vaccine (Pneumovax 23). Specific IgG antibodies to pneumococcal capsular antigens of serotypes 4, 6B, 7F, 9V, 14, 18C, 19F, and 23F were measured before vaccination, and 6 weeks and 52 weeks after vaccination. RESULTS: Detectable prevaccination IgG antibody (> 1 microg/mL) was found in the range of 27.5% of patients for serotype 7F to 96.2% for serotype 14. Antibody concentrations in prevaccination sera were not different between middle-aged (< 65 years old) and elderly patients (> or = 65 years old). The percentage of elderly patients with postvaccination antibody concentration > 2 -fold higher than that prior to vaccination ranged from 84% for serotype 18C to 90% for serotypes 7F, 9V, and 19F. The change in antibody level (fold and absolute increases) postvaccination was not significantly different among the different age groups. CONCLUSION: Taiwanese elderly adults with COPD, even in advanced age, can mount a significant antibody response to pneumococcal polysaccharide vaccine. This study may support the existing recommendation that pneumococcal vaccine be offered to persons > or = 65 years old with COPD.

Comparison of in vitro activities of tigecycline with other antimicrobial agents against Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis in Taiwan.

We compared the in vitro activities of tigecycline to those of other agents against 300 nonduplicate isolates of Streptococcus pneumoniae (194 isolates), Haemophilus influenzae (60 isolates), and Moraxella catarrhalis (46 isolates) recovered from patients treated in three major hospitals in Taiwan from August through December, 2003. All of these isolates were inhibited at 0.5 mg/L of tigecycline. For S. pneumoniae isolates, 72% were not susceptible to penicillin (69% intermediate and 3% resistant) and 96% were not susceptible to azithromycin. Among the 178 isolates resistant to azithromycin, 53 isolates (30%) had the M phenotype and 70% had the cMLSB phenotype. The rate of nonsusceptibility to ertapenem, telithromycin, moxifloxacin, and quinupristindalfopristin in S. pneumoniae was 3%, 2%, 1%, and 57%, respectively. For H. influenzae, 36 (60%) were not susceptible to ampicillin, among which 31 possessed beta-lactamase. A high rate (8.3%) of H. influenzae isolates with beta-lactamase-negative and ampicillin-resistant phenotype was found. All H. influenzae isolates were susceptible to azithromycin, but 40% of them were not susceptible to clarithromycin. Ninety-eight percent (44 isolates) of M. catarrhalis possessed beta-lactamase. All three fluoroquinolones tested were highly active (MIC90 < or =0.12 mg/L) against H. influenzae and M. catarrhalis.

Double-blind randomized parallel group study comparing the efficacy and safety of tiotropium and ipratropium in the treatment of COPD patients in Taiwan.

BACKGROUND/PURPOSE: To compare the efficacy and safety of tiotropium and ipratropium in patients with chronic obstructive pulmonary disease (COPD) in Taiwan. METHODS: This double-blind, randomized, placebo-controlled, parallel group study was conducted at six hospitals in Taiwan. COPD patients aged > or = 40 years, with a forced expiratory volume in 1 second (FEV1) < or = 65% of predicted and FEV1/forced vital capacity (FVC) < or = 70% were enrolled. After a 2-week screening/baseline period, 132 patients were randomized to receive 4 weeks of treatment with either tiotropium 18 microg once daily from a dry powder inhaler (HandiHaler) or two puffs of ipratropium 20 microg four times daily from a metered dose inhaler. The primary outcome was the change in trough FEV1 from baseline to week 4. The secondary outcome measures were trough FVC response, FEV1 and FVC responses at 2 hours postinhalation. RESULTS: After 4 weeks, trough FEV1 had increased by 61.7 +/- 25.3 mL for tiotropium but decreased by 16.4 +/- 27.9 mL for ipratropium. The difference between groups was significant (p < 0.05; 95% CI, 10-146.1). The trough FVC also increased by 137.2 +/- 49.3 mL for tiotropium but was decreased by 84.5 +/- 54.5 mL for ipratropium (p < 0.001; 95% CI, 89.0-354.3). No major drug-related adverse events associated with tiotropium and ipratropium were observed. CONCLUSION: Tiotropium 18 microg once daily using HandiHaler was significantly more effective than ipratropium 40 microg four times daily in improving trough FEV1 and FVC over a 4-week period. The safety profiles of both drugs are comparable.

Aberrant p53 expression correlates with expression of vascular endothelial growth factor mRNA and interleukin-8 mRNA and neoangiogenesis in non-small-cell lung cancer.

PURPOSE: To evaluate interactions between expressions of tumor suppressor gene p53 and angiogenic factors vascular endothelial cell growth factor (VEGF) and interleukin-8 (IL-8) and their effect on tumor angiogenesis and patient prognosis in non--small-cell lung cancer (NSCLC). PATIENTS AND METHODS: p53, VEGF, IL-8, and the microvessel endothelium were immunostained, and VEGF and IL-8 mRNA expression were quantified using the real-time quantitative reverse-transcription polymerase chain reaction in 65 NSCLC surgical specimens. Aberrant p53 expression was correlated with VEGF and IL-8 mRNA expression, microvessel count (MVC), other clinical-pathologic variables, and patients' survival. RESULTS: Tumors with high aberrant p53 expression showed significantly higher VEGF and IL-8 mRNA expression and MVC than those with low aberrant p53 expression (P <.001). When tested as a continuous variable, aberrant p53 expression correlated strongly and positively with VEGF and IL-8 mRNA expression and MVC (P <.0001). Tumors with high aberrant p53 expression were associated with mediastinal or distant lymph node metastasis (P =.006). Survival and postoperative relapse time were significantly shorter in patients with high aberrant p53 expression tumors than in those with low aberrant expression tumors (P <.0001). A significant difference in survival was also seen between patients with high and low tumoral VEGF mRNA expression and between those with high and low tumoral IL-8 mRNA expression (P <.0001). CONCLUSION: We report here for the first time that aberrant p53 expression is strongly positively correlated with VEGF mRNA and IL-8 mRNA expression in NSCLC. This result indicates that aberrant p53 expression may play a significant role in regulation of VEGF and IL-8 expression and be involved in controlling angiogenesis and explains the adverse prognosis of cancers with high aberrant p53 expression.

Mycobacterium tuberculosis inducing disseminated intravascular coagulation.

Disseminated intravascular coagulation (DIC) can develop infrequently in patients with tuberculosis and has a very high mortality rate. We conducted a retrospective study to evaluate the incidence of tuberculosis-induced DIC and to investigate the clinical manifestation, outcome, and prognostic factors of such patients. From January 2002 to December 2003, all culture-proven tuberculosis patients who developed DIC before starting anti-tuberculosis treatments were selected for this study. Patients who had other clinical conditions or were infected by other pathogens that may have been responsible for their DIC were excluded. Survival analysis was performed for each variable with possible prognostic significance. Our results showed that 27 (3.2%) out of the 833 patients with culture-proven tuberculosis had tuberculosis-induced DIC with a mortality rate of 63.0%. The most common clinical manifestations were fever (63.0%) and multiple patches of pulmonary consolidation (59.3%). Seven (25.9%) patients had disseminated tuberculosis. Twelve (44.4%) developed acute respiratory distress syndrome and three (11.1%) were associated with hemophagocytosis. Twenty-four (88.9%) patients had findings that were unusual for an acute bacterial infection, such as positive acid-fast smear, miliary pulmonary lesions, lymphocytotic exudative pleural effusion, and mediastinal lymphadenopathy. Early anti-tuberculosis treatment significantly improved survival. In conclusion, tuberculosis can cause DIC. Patients with non-miliary, non-disseminated tuberculosis could also develop the rare clinical manifestation. Since the prognosis was very poor in patients not treated at an early stage, a high index of suspicion is required, especially in those with clinical findings suggestive of tuberculosis.

Analysis of host versus tumor interaction in cancer patients: opposing role of transforming growth factor-beta1 and interleukin-6 in the development of in situ tumor immunity.

A different degree of immunodeficiency is often found at tumor sites in cancer patients. At the late stage many patients develop malignant effusion that contains large numbers of tumor cells and host immune cells that constantly interact with each other. These sites may provide an ideal model to examine in situ anti-tumor immunity. The T cells in effusion were found to be immunodeficient, which suggested a defective anti-tumor cytotoxic T lymphocytes response. To pursue the mechanism for the T cell deficiency, we determined the production of immunomodulating cytokines in the effusion and detected the presence of transforming growth factor-beta1 (TGFbeta), prostaglandin E2, IL-6, IL-10, and IFNgamma. There was no detectable IL-2, IL-4, IL-12, or TNFalpha. The most prominent feature was the presence of TGFbeta and IL-6 at a very high level. Thus, the possible role of these two cytokines on T cell competence was further determined. TGFbeta was found to induce T cell anergy and reduced the production of perforin in T killer cells and their lytic activity. These events lead to the induction of peripheral T cell tolerance with profound T cell deficiency. IL-6 did not affect perforin production or cytolytic activity of the T killer cells. But the CD4+ CD25+ regulatory T cells (TR) that were often employed by TGFbeta to suppress T cell response were reduced in the malignant effusion, consistent with the fact that IL-6 down-regulates TR and this may represent the host's vigorous response to the tumor's subversion. These results show that TGFbeta and IL-6 might play pivotal but opposing roles in the host tumor interaction that, together with other immunomodulating components, determines the outcome for the development of local tumor immunity.

Relationships between antimicrobial use and antimicrobial resistance in Gram-negative bacteria causing nosocomial infections from 1991-2003 at a university hospital in Taiwan.

This study was conducted to evaluate the relationship between antimicrobial resistance and antimicrobial use in a university hospital in Taiwan. Disk susceptibility data of Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, Serratia marcescens, Proteus spp., Pseudomonas aeruginosa, Acinetobacter spp., Stenotrophomonas maltophilia and other non-fermentative Gram-negative bacilli causing nosocomial infections were evaluated. Data on annual patient-days and annual consumption (defined daily dose (DDD) per 1000 patient-days) of extended-spectrum cephalosporins (cefotaxime, ceftriaxone, ceftazidime, flumoxef, cefepime and cefpirome), beta-lactam-beta-lactamase inhibitor combinations (ticarcillin/clavulanic acid and piperacillin/tazobactam), carbapenems (imipenem and meropenem), aminoglycosides (amikacin, gentamicin and tobramycin), fluoroquinolones (ciprofloxacin (oral and injectable) and oral levofloxacin and moxifloxacin) from 1991 to 2003 were analysed. Increasing trends of incidences of several of these bacteria causing all nosocomial infections or nosocomial bloodstream infections were noted from 1991 to 2003. The annual patient-days of the hospital significantly increased, from 360210 in 1991 to 672676 in 2002 (linear regression analysis, P < 0.05), but slightly decreased in 2003 (629168) owing to the severe acute respiratory syndrome epidemic in Taiwan. The rise in cefotaxime-resistant or ciprofloxacin-resistant E. coli and meropenem-resistant P. aeruginosa was significantly correlated with increased consumption of extended-spectrum cephalosporins, beta-lactam-beta-lactamase inhibitor combinations, carbapenems, fluoroquinolones and aminoglycosides (for ciprofloxacin-resistant E. coli and meropenem-resistant P. aeruginosa only) in the hospital (Pearson's correlation coefficient, r > 0.72 (or < -0.72) and P-value < 0.05). Increased ciprofloxacin-resistant K. pneumoniae and meropenem-resistant Acinetobacter spp. was significantly associated with the increased usage of extended-spectrum cephalosporins but not with the other four classes of antibiotics. This 13-year study in a hospital demonstrated significant changes in antimicrobial use, which may have affected antimicrobial resistance in certain Gram-negative bacteria at the hospital.

Nosocomial infections due to methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci at a university hospital in Taiwan from 1991 to 2003: resistance trends, antibiotic usage and in vitro activities of newer antimicrobial agents.

A rapid increase of nosocomial methicillin-resistant Staphylococcus aureus (MRSA) infection (from 39% in 1991 to 75% in 2003) and vancomycin-resistant enterococci (VRE) (from 1.2% in 1996 to 6.1% in 2003) at a university hospital in Taiwan was found. The noticeable rise of MRSA and VRE was significantly correlated with the increased consumption of glycopeptides, beta-lactam-beta-lactamase inhibitor combinations, extended-spectrum cephalosporins, carbapenems and fluoroquinolones (Pearson's correlation coefficient, P < 0.05). Minimum inhibitory concentrations (MICs) of 100 non-duplicate blood isolates of MRSA (in 2003) and of 25 non-duplicate isolates of vancomycin-resistant Enterococcus faecalis and 172 vancomycin-resistant Enterococcus faecium (in 1996-2003) causing nosocomial infection recovered from various clinical specimens of patients treated at the hospital to nine antimicrobial agents were determined by the agar dilution method. All of these isolates were susceptible to linezolid and were inhibited by 0.5mg/L of tigecycline, and all MRSA isolates were inhibited by daptomycin 1mg/L, including two isolates of MRSA with heteroresistance to vancomycin. Daptomycin had two-fold better activity against vancomycin-resistant E. faecalis (MIC90, 2 mg/L) than against vancomycin-resistant E. faecium (MIC90, 4 mg/L). Decreased susceptibilities of vancomycin-resistant E. faecium and MRSA to quinupristin/dalfopristin (non-susceptibility 25% and 8%, respectively) were found. Telithromycin had poor activity against the isolates tested (MIC90, 8 mg/L). Linezolid, daptomycin and tigecycline may represent therapeutic options for infections caused by these resistant Gram-positive organisms.

Characterization of a 411-bp fragment of the rpoB gene in clinical isolates of Mycobacterium tuberculosis in a university hospital in northern Taiwan.

BACKGROUND AND PURPOSE: This study analyzed rpoB gene mutation and its correlation with demographic and clinical data, and the drug resistance profile in 41 consecutive patients with rifampin (RIF)-resistant Mycobacterium tuberculosis isolated at National Taiwan University Hospital from 2000 to 2002. METHODS: The 411-bp fragment of the rpoB gene from 94 M. tuberculosis isolates (including 41 RIF-resistant and 53 RIF-susceptible isolates) was amplified and sequenced. RESULTS: Of the 41 RIF-resistant isolates, 87.8% (36/41) showed mutations in rpoB. The following mutations were identified: Ser531 (68.3%), His526 (9.8%), Ser522 (4.9%) and Gln513 (4.9%). No silent substitutions were observed. No mutation within the entire 411-bp fragment was found in 12.2% (5/41) of the RIF-resistant isolates and 100% (53/53) of the RIF-susceptible isolates. Patients whose RIF-resistant isolates did not have rpoB mutation had higher frequencies of the following characteristics: elderly, no previous history of tuberculosis, human immunodeficiency virus-negative, no extrapulmonary tuberculosis involvement and favorable prognosis. Drug resistance patterns in RIF-resistant M. tuberculosis strains were significantly correlated with isoniazid resistance, i.e., multidrug-resistant strains (90.2%). CONCLUSIONS: RIF-resistant M. tuberculosis isolates with rpoB mutation were clustered in the 69-bp core region in this study. Rapid detection of RIF resistance could be achieved by testing for rpoB mutation in Taiwan.

Quality of sputum smear microscopy in Taiwan.

BACKGROUND AND PURPOSE: Four mycobacteriology laboratories in northern Taiwan collected slides from their routine work for an international training course on quality assurance of sputum smear microscopy held from 19-27 August 2004 in Taipei. Rechecking of a random sample of these slides provided an opportunity to evaluate the quality of sputum smear microscopy in the collaborating laboratories. METHODS: Participants used a systematic sampling method to choose 100 to 120 slides from a set of 600 to 800 slides for evaluating the quality of smear and rechecking. Recheckers were blinded to the microscopy results reported by the testing laboratories. Discordant slides were re-examined by a second rechecker in order to make the final decision. RESULTS: A total of 433 slides were evaluated for smear quality. Of these 433 slides, 177 (41%) had proper smear size, 194 (45%) proper thickness and 212 (49%) proper staining. Rechecking of slides revealed that 2 of 4 laboratories had at least 1 high false-negative and 3 of 4 laboratories had at least 1 low false-negative result. CONCLUSIONS: We conclude that: 1) the 2 laboratories with high false-negative results need a supervisory visit in order to determine the causes; and 2) the national tuberculosis program should direct more attention to the quality of sputum smear microscopy and develop a formal plan for external quality assessment of sputum smear microscopy in Taiwan.

The role of bronchoscopic assessment in esophageal cancer - clinical and survival analysis in 153 patients.

BACKGROUND AND PURPOSE: The diagnostic value and indications for fiberoptic bronchoscopy in the preoperative assessment of patients with esophageal cancer have not been fully studied. We evaluated the role of fiberoptic bronchoscopic examination in the stage work-up of patients with esophageal cancer and correlated the results with survival time analysis. METHODS: The medical records of 153 patients with an initial diagnosis of esophageal cancer were reviewed. Clinical data, bronchoscopic findings, treatment courses, and survival time of these patients were analyzed. RESULTS: On initial bronchoscopic examinations, distortion/compression of the normal structure and protrusion at the posterior wall of the trachea or bronchus were the most common bronchoscopic findings (35.9%). We stratified patients into 3 subgroups according to bronchoscopic findings of direct invasion, external compression, and negative findings. The symptoms of dyspnea, hoarseness, aspiration and fever were more frequent in patients with direct airway invasion compared with patients with external compression and negative bronchoscopic findings (p < 0.02). Washing and brushing cytology examinations were all negative in patients with external compression of the airway. There was a significant difference of survival time among these 3 groups of patients (direct invasion: 5.6 +/- 0.6 months; external compression: 12.3 +/- 0.9 months; negative findings: 13.3 +/- 1.1 months, p < 0.01). Direct airway invasion and original cancer stage were the most important variables for survival in the multivariate analysis, and the hazard ratio for prognosis was 2.5 (95% confidence interval [CI], 1.1-4.6) and 4.2 (95% CI, 1.5-9.3), respectively. Twelve patients (80%) with tracheoesophageal (TE) fistulae died within 3 months after diagnosis due to aspiration pneumonia and septic shock. CONCLUSIONS: The role of bronchoscopic examination in patients with esophageal cancer for preoperative evaluation resides in its ability to predict airway invasion and its impact on survival. Advanced cancer stage (stage IV) and direct airway invasion (especially TE fistula) were significantly associated with poor prognosis. These results suggest that patients suffering from dyspnea, hoarseness, aspiration and fever, implicating a high probability of airway invasion, are more likely to benefit from bronchoscopic examination and proper management in order to prevent aspiration or complications.