The history of cytomegalovirus and its diseases.

Intranuclear inclusions typical of cytomegalovirus infections were first noticed in 1881 by German scientists who thought they represented protozoa. After viruses were grown in cell cultures, Weller, Smith and Rowe independently isolated and grew CMV from man and mice in 1956-1957. Antibodies in 30-100% of normal adults indicate not only a past infection, but the presence of a present latent infection. The presence of CMV DNA in tissues and most organs surveyed indicates the ubiquity of latent infection. CMV disease requires the virus and some deficiency of immunity such as occurs in the immature fetus, in AIDS, and in transplant patients on immunosuppressive drugs. Antiviral agents can inhibit CMV replication but they cannot prevent or cure latent infections. A pharmacological approach using the many leads in understanding latency is needed.

Effect of banning vancomycin analogue avoparcin on vancomycin-resistant enterococci in chicken farms in Taiwan.

Avoparcin, a vancomycin analogue, was banned as a feed additive in Taiwan in 2000. A nationwide surveillance was conducted to study the prevalence of vancomycin-resistant enterococci (VRE) on chicken farms between 2000 and 2003. Among the 1021 E. faecalis and 967 E. faecium isolates studied, resistance to tetracycline, erythromycin, high-level aminoglycosides, ciprofloxacin and chloramphenicol either increased or remained high except vancomycin. The proportion of VRE decreased, between 2000 and 2003, from 13.7% (22/161) to 3.7% (11/299) for E. faecalis, and 3.4% (4/119) to 0% (0/300) for E. faecium. Only 8.8% (7/80) of the chicken farms surveyed harboured VRE in 2003 compared with 25% (15/60) in 2000. All VRE were resistant to tetracycline and erythromycin. All VRE possess the vanA gene but nearly all (79 of 83 isolates) were susceptible to teicoplanin, indicating VanB phenotype. Some clones were detected from different farms in various regions over the years. We conclude that the frequency of VRE in chicken farms decreased in association with a ban on avoparcin; and the continued presence of VRE may be due to the ability of some strains to persist in the farms, transfer of vancomycin resistance determinants or co-selection by the continued use of other antibiotics.

Etiology of community acquired pneumonia among adult patients requiring hospitalization in Taiwan.

BACKGROUND: There has not been a comprehensive multi-center study investigating the microbial profile of community acquired pneumonia (CAP) in Taiwan. METHODS: A prospective study of adult CAP patients requiring hospitalization between December 2001 and April 2002 was carried out in 13 hospitals in Taiwan. Etiology was determined based on laboratory data from blood and sputum cultures plus serology from paired serum and urine antigen detection tests. RESULTS: Etiology was assigned to 99 (58.9%) of the 168 patients having the most complete data for etiology determination, with mixed infection in 21 (12.5%) patients. More than half (51.8%) of the patients were>60 years and 63.7% of the patients were males. The most common etiologic agent was Streptococcus pneumoniae (40, 23.8%), the majority (60%, 24 cases) of which was detected by positive urine antigen test. Other common agents included Mycoplasma pneumoniae (24, 14.3%), Chlamydia pneumoniae (12, 7.1%), Influenza A virus (11, 6.5%), Klebsiella pneumoniae (8, 4.8%) and Haemophilus influenzae (8, 4.8%). The prevalence of S. pneumoniae and M. pneumoniae was highest in patients>60 years (25/87, 28.7%), and<44 years (12/59, 19%), respectively; while K. pneumoniae comprised a larger proportion (4/22, 18%) in the 45-59 years group. CONCLUSIONS: S. pneumoniae was the most common etiology agent in adult patients hospitalized due to CAP in Taiwan and the spectrum of other major pathogens was similar to studies conducted elsewhere in the world. Empiric treatment recommendations developed in other parts of the world may be appropriately adapted for local use after taking into account local resistance profiles. Our data also support the recommendation that urine antigen test be added as an adjunct to adult CAP etiology diagnosis protocol.

Risk factors for fatal candidemia caused by Candida albicans and non-albicans Candida species.

BACKGROUND: Invasive fungal infections, such as candidemia, caused by Candida species have been increasing. Candidemia is not only associated with a high mortality (30% to 40%) but also extends the length of hospital stay and increases the costs of medical care. Sepsis caused by Candida species is clinically indistinguishable from bacterial infections. Although, the clinical presentations of the patients with candidemia caused by Candida albicans and non-albicans Candida species (NAC) are indistinguishable, the susceptibilities to antifungal agents of these species are different. In this study, we attempted to identify the risk factors for candidemia caused by C. albicans and NAC in the hope that this may guide initial empiric therapy. METHODS: A retrospective chart review was conducted during 1996 to 1999 at the Veterans General Hospital-Taipei. RESULTS: There were 130 fatal cases of candidemia, including 68 patients with C. albicans and 62 with NAC. Candidemia was the most likely cause of death in 55 of the 130 patients (42.3 %). There was no significant difference in the distribution of Candida species between those died of candidemia and those died of underlying conditions. Patients who had one of the following conditions were more likely to have C. albicans, age > or = 65 years, immunosuppression accounted to prior use of steroids, leukocytosis, in the intensive care unit (ICU), and intravascular and urinary catheters. Patients who had undergone cancer chemotherapy often appeared less critically ill and were more likely to have NAC. CONCLUSION: Clinical and epidemiological differences in the risk factors between candidemia caused by C. albicans and NAC may provide helpful clues to initiate empiric therapy for patients infected with C. albicans versus NAC.

Antibiotic prescribing by ambulatory care physicians for adults with nasopharyngitis, URIs, and acute bronchitis in Taiwan: a multi-level modeling approach.

BACKGROUND: Imprudent prescribing of antibiotics in ambulatory care in Asia is of great concern. However, an adequate understanding of factors associated with antibiotic prescribing patterns in Asia has not been achieved. OBJECTIVE: Our aim was to identify patient and physician characteristics that influence antibiotic prescribing for adults with nasopharyngitis (common colds), upper respiratory tract infections (URIs) or bronchitis in Taiwan. METHODS: Generalized Estimating Equations (GEE) were used to analyze all 128,260 episodes of common colds, URIs and bronchitis generated by a random sample of 137,935 adult National Health Insurance (NHI) beneficiaries (> or = 18 years old) in Taiwan in 2000. RESULTS: Multivariate analysis results revealed substantial variations across different physician groups. Physician age and accreditation level of the physician's practice setting were the characteristics most associated with prescribing of antibiotics at the initial encounters for these episodes of care. Urban practising physicians (adjusted OR 1.69, 95% CI 1.29-2.21) and those who were self-dispensing or with on-site pharmacists (adjusted OR 1.32, 95% CI 1.19-1.46) were also higher prescribers of antibiotics for adults. Other significant physician predictors included physician specialty, patient volume, and ownership of practice setting. CONCLUSIONS: Results suggest that both accessibility to updated medical information and economic incentives of the attending physician may shape prescribing of antibiotics in ambulatory care in Taiwan. Interventions should be developed to influence these modifiable factors to reduce antibiotic prescriptions of questionable value.

Changes before and after a policy to restrict antimicrobial usage in upper respiratory infections in Taiwan.

The Bureau of National Health Insurance (BNHI) of Taiwan issued a new reimbursement regulation effective from 1 February 2001 forbidding the use of antimicrobials in ambulatory patients with upper respiratory infections (URI) without evidence of bacterial infection. We evaluated the effect of this regulation by analysing changes in the types of infections diagnosed and the amount of antibiotics prescribed in 1999, 2000 and 2001. Between 1999 and 2001, antimicrobials for respiratory infections decreased from 18.0 to 9.97 DDD/1000 per day or by 44.6% (P=0.0000+). Antimicrobials for URI decreased from 8.32 in 1999 to 3.28 DDD/1000 per day in 2001 or by 60.6% (P=0.0000+); from 2000 to 2001 the decrease was 55.8%. Reduction of antimicrobials for URI from 1999 to 2001 accounted for 62.8% of the reduction of antimicrobials in respiratory infections or 51.3% of the total reduction of antimicrobials. Reduction in aminopenicillins was responsible for most of the decrease.

Antimicrobial usage in ambulatory patients with respiratory infections in Taiwan, 2001.

BACKGROUND AND PURPOSE: Excess use of antimicrobials by ambulatory patients is a determinant of antimicrobial resistance. This study investigated the types of illnesses for which antimicrobials were prescribed and the amounts prescribed with special emphasis on respiratory infections for the year in which the Bureau of National Health Insurance (BNHI) enforced a policy to restrict antimicrobials for upper respiratory infections. The number of ambulatory patients seen and the types of ambulatory facilities in Taiwan were also described. METHODS: Raw data were obtained from the BNHI database on every 500 th visit in 2001. Medical diagnoses were categorized according to the ICD-9-CM system. Antimicrobial consumption was expressed in defined daily doses per 1000 population per day (DDD/1000/day). RESULTS: Among the population of 22.3 million in Taiwan, there were 285.8 million ambulatory patient visits (12.8 per person), including 108.9 million visits (4.9 per person) for respiratory infections, of which 62.7 million (2.8 per person) were for upper respiratory infections (URI). Antimicrobial consumption was 19.83 DDD/1000/day [standard error (SE), 0.00055], of which 9.97 DDD/1000/day (SE, 0.00047) were for respiratory infections and 4.03 DDD/1000/day (0.00055) were for URI. 23.6% of visits for URI entailed a prescription for antimicrobials. About two-thirds (66.5%) of ambulatory patients were seen in clinics, mostly private ones, and 67.6% of all antimicrobials were received there. Aminopenicillins and cephalosporins constituted 35.2% and 19.5%, respectively, of antimicrobials prescribed. CONCLUSIONS: Despite the new BNHI rule restricting antimicrobial usage for URI, Taiwan still has an excessive number of ambulatory patient visits, especially for respiratory infections and URI. The majority of antimicrobials used were for URI. They were mostly prescribed in private clinics rather than hospital outpatient departments.

The status of antimicrobial resistance in Taiwan among Gram-positive pathogens: the Taiwan Surveillance of Antimicrobial Resistance (TSAR) programme, 2000.

In the Taiwan Surveillance of Antimicrobial Resistance programme, isolates were collected from 21 hospitals over a 3-month period in 2000 (TSAR II) and rates of resistance in Gram-positive pathogens were determined. Resistance rates were high including oxacillin resistance in Staphylococcus aureus (60%) and coagulase-negative staphylococci (80%), high-level gentamicin resistance (HLGR) in Enterococcus faecalis (60%) and penicillin non-susceptibility in Streptococcus pneumoniae (69%). Oxacillin resistance had increased from 1998 (TSAR I) and may be spreading into outpatient settings. In contrast, less than 2% enterococci were vancomycin-resistant. No linezolid resistance was found in either staphylococci or enterococci.

The status of antimicrobial resistance in Taiwan among gram-negative pathogens: the Taiwan surveillance of antimicrobial resistance (TSAR) program, 2000.

In a nationwide surveillance of antimicrobial resistance (Taiwan Surveillance of Antimicrobial Resistance, TSAR), isolates were collected from 21 medical centers and regional hospitals throughout Taiwan over a three-month period in 2000 (TSAR II). This report summarizes susceptibility data of 7 common Gram-negative bacilli (Escherichia coli, Klebsiella pneumoniae, Serratia marcescens, Proteus mirabilis, Enterobacter cloacae, Pseudomonas aeruginosa, and Acinetobacter baumannii) in the TSAR II collection and compared selected key forms of resistance by epidemiologic factors and with isolates collected in 1998 (TSAR I) as well as with data from international surveillance studies. Resistance of the 5 Enterobacteriaceae species to most of the commonly prescribed "first-line" antimicrobials in Taiwan, such as ampicillin (78% in E. coli, 68% in P. mirabilis), gentamicin (19% in K. pneumonia to 66% in S. marcescens), and trimethoprim/sulfamethoxazole (29% in K. pneumoniae to 70% in P. mirabilis), was high, several of which are higher than other countries. Resistance to certain broad-spectrum antimicrobials is also more acute in Taiwan than most Western countries, such as ceftazidime resistant A. baumannii (73%) and ciprofloxacin resistant E. coli (12%). Differences in geographic regions and specimen types were associated with certain forms of resistance in TSAR II; however, the resistance problem is prevalent among both inpatients and outpatients of not only medical centers but also regional hospitals throughout Taiwan.

Susceptibilities of Candida species to amphotericin B and fluconazole: the emergence of fluconazole resistance in Candida tropicalis.

OBJECTIVE: To determine the susceptibilities of Candida species isolated from Taiwan to amphotericin B and fluconazole. DESIGN: Prospective surveillance study. METHODS: Each hospital was asked to submit up to 10 C. albicans and 40 non-albicans Candida species during the collection period, from April 15 to June 15, 1999. One isolate was accepted from each episode of infection. The broth microdilution method was used to determine susceptibilities to amphotericin B and fluconazole. RESULTS: Only 3 of 632 isolates, one each of C. famata, C. krusei, and C. tropicalis, were resistant to amphotericin B. A total of 53 (8.4%) of 632 clinical yeast isolates, consisting of 4% C. albicans, 8% C. glabrata, 15% C. tropicalis, and 70% C. krusei, were resistant to fluconazole. In contrast, no C. parapsilosis isolate was resistant to fluconazole. Isolates from tertiary-care medical centers had higher rates of resistance to fluconazole than did those from regional and local hospitals (11.4% vs 6.6%). Isolates from different sources showed different levels of susceptibility to fluconazole. All of the isolates with the exception of C. tropicalis and C. krusei isolated from blood were susceptible to fluconazole. A pattern of co-resistance to both amphotericin B and fluconazole was observed. CONCLUSIONS: Non-albicans Candida species had higher rates of resistance to fluconazole than did C. albicans (44 of 395 [11.2%] vs 9 of 237 [3.8%]; P = .002). The increasing rate of fluconazole resistance in C. tropicalis (15%) is important because C. tropicalis is one of the most commonly isolated non-albicans Candida species.

Distribution and antifungal susceptibility of Candida species causing candidemia from 1996 to 1999.

Susceptibilities to amphotericin B and fluconazole of 383 Candida species isolated from blood were determined. Candida albicans was the most common species (55.6%), followed by Candida parapsilosis (17.5%), Candida tropicalis (16.5%), Candida glabrata (5.2%), Candida guilliermondii (2.3%), and others (2.9%). All but three isolates, Candida ciferrii, C. tropicalis, and C. glabrata, one each, were susceptible to amphotericin B. A total of 367 (95.8%) and 15 (4.2%) isolates were susceptible and susceptible-dose dependent to fluconazole, respectively. Only one isolate, a C. glabrata, was resistant to fluconazole. Few patients (13%) having prior fluconazole treatments may explain the low rate of resistance to fluconazole in this study.

The roles of mutations in gyrA, parC, and ompK35 in fluoroquinolone resistance in Klebsiella pneumoniae.

In a survey of 541 Klebsiella pneumoniae isolates from 44 hospitals in Taiwan, three distinct populations were identified by the disk diffusion method according to the disribution of zone diameters of ciprofloxacin. Isolates with resistant, reduced-susceptible, and susceptible to fluoroquinolone were defined as CIP zone diameters of < or = 15 mm, 16-26 mm, and > or = 27 mm, respectively. Thus, in addition to 38 (7%) resistant isolates, there were 30 (5.5%) reduced-susceptible isolates and 473 (87.5%) susceptible isolates. A total of 34 isolates consisting of nine resistant, 13 reduced-susceptible, and 12 susceptible isolates were assessed for point mutations in gyrA and parC and the outer membrane profiles. The susceptibility to fluoroquinolone of 13 reduced-susceptible isolates was not altered in the presence of carbonyl cyanide m-chlorophenylhydrazone, an efflux inhibitor, showing that efflux is not a major contributor to reduced susceptibility. In addition to single mutation in gyrA, OmpK35 porin loss can also be the first step for developing fluoroquinolone resistance. No strain possesses a parC mutation without the simultaneous presence of a gyrA mutation, suggesting that mutations in parC play a complementary role for higher-level of fluoroquinolone resistance and fluoroquinolone resistance is a multistep process.

Epidemiology of invasive pneumococcal infection in Taiwan: antibiotic resistance, serogroup distribution, and ribotypes analyses.

From July, 1998, to June, 1999, pneumococcal isolates from 288 patients with invasive disease in Taiwan were serogrouped and tested for their susceptibility to various antibiotics. Automated ribotyping was used to study their molecular epidemiology. The mortality rate among those > or = 65 years was higher than those 18 or 19-64 years (p < 0.001). The total incidence of infection was significantly higher during the cooler season than the warmer season (p = 0.017). Among strains isolated from children aged < or = 18 years, 76% were not susceptible to penicillin, a rate that was significantly higher (p < 0.001) than that for adults (45%), as was the susceptibility to azithromycin, erythromycin, and trimethoprim-sulfamethoxazole (p < 0.005). The most prevalent serogroup encountered in the invasive isolates was 23, followed by 6, 14, 19, and 3. Isolation of Streptococcus pneumoniae in cerebrospinal fluid was at high rate in children under 5 years (p = 0.00012). Molecular typing revealed a high degree of polymorphism among the isolates. Among serogroup 23 and 19 isolates, a high proportion had the same ribotypes, the Taiwan23F-15 and Taiwan19F-14 isolates, suggesting the circulation of a Taiwanese epidemic strain. In Taiwan, S. pneumoniae isolates should be tested for their resistance profile for children < or = 18 years old, as these are more likely to harbor high-level resistance. Control of pneumococcal infection with the 7-valent-conjugated vaccine should also be considered because it is estimated that it would cover nearly 90% of the serotypes among pediatric invasive disease.

CTX-M-14, a plasmid-mediated CTX-M type extended-spectrum beta-lactamase isolated from Escherichia coli.

Four Escherichia coli isolates harboring CTX-M-14, with a single Ala231-->Val substitution compared to CTX-M-9, had three different ribotypes. Cefotaxime resistance was plasmid encoded and conjugatively transferable. Three isolates had the same plasmid restriction enzyme digestion profile, suggesting clonal spread of a resistant plasmid. A high k(cat)/K(m) value for cefotaxime (20.3 microM(-1) s(-1)) but low values for ceftazidime and aztreonam (< 0.02 microM(-1) s(-1)) were observed in hydrolysis assays, indicating resistance to cefotaxime (MIC > or = 64 microg/ml) but susceptibility to ceftazidime (MIC < or = 2 microg/ml).

Antibiotic usage in community-acquired infections in hospitals in Taiwan.

BACKGROUND AND PURPOSE: Using an epidemiologically meaningful in-hospital population with community-acquired infections, we evaluated antibiotic therapy in terms of indication and choice of antibiotic and microbiologic work-up. METHODS: Infectious disease specialists evaluated charts of 436 patients from 9 hospitals and selected those who received antibiotics within 3 days of admission. Each antibiotic prescribed was marked for appropriateness of indication and choice. Microbiologic isolates were evaluated for their clinical significance. RESULTS: The most common infections were in the lower respiratory tract (46.1%). Each patient received a mean of 2.25 antibiotics for 8.1 +/- 6.4 days. Of the 975 courses of antibiotics given in the study period, indication and choice were correct in 37.4% and unsatisfactory in 14.5%. The vast majority of antibiotics used (79.2%) were first-line antibiotics--usually first-generation cephalosporins, aminoglycosides, and aminopenicillins. Most patients (66%) had a microbiology laboratory work-up, but only 37.4% were judged by evaluators to have a meaningful microbiologic diagnosis. Among the 201 patients with lower respiratory tract infections, 105 (52.2%) had a diagnosis of pneumonia. A positive isolate was recovered in 30 (28.6%) patients, and most of these isolates (20, 68.7%) were aerobic gram-negative rods. There were three positive blood cultures but none grew Streptococcus pneumoniae. CONCLUSIONS: Antibiotics were used excessively in number and duration. The microbiologic work-up had little effect on the indication and choice of antibiotics. Community-acquired pneumonia differed markedly from that in Western countries in that only 3.3% were caused by S. pneumoniae.

Community-acquired Acinetobacter baumannii bacteremia in adult patients in Taiwan.

We determined the clinical and microbiologic characteristics of community-acquired Acinetobacter baumannii bacteremia in 19 adult patients. We found that malignancy was the most frequent underlying disease. The overall mortality rate was 58%. All 14 available isolates were identified as genomic species 2 (A. baumannii) by 16S ribosomal DNA sequencing and were found to be genetically distinct by pulsed-field gel electrophoresis.

Vancomycin-resistant enterococci from humans and retail chickens in Taiwan with unique VanB phenotype-vanA genotype incongruence.

Vancomycin resistant enterococci (VRE) with VanB phenotype-vanA genotype incongruence were found in all 39 VRE isolated from chicken carcasses and four human VRE isolates in Taiwan. Three identical mutations in the vanS gene were found in the VanB phenotype-vanA genotype VRE sequenced. This finding indicates possible transmission of glycopeptide resistance among different hosts.

Use of automated riboprinter and pulsed-field gel electrophoresis for epidemiological studies of invasive Haemophilus influenzae in Taiwan.

A total of 87 invasive isolates of Haemophilus influenzae isolated throughout Taiwan from 1994 to 1998 was collected; 57 were from children <14 years old. In all, 60.9% of isolates were resistant to ampicillin and produced beta-lactamase. Ribotyping revealed six different profiles in 55 isolates of type b, nine profiles in 10 isolates of non-type b and 12 profiles in 22 isolates of non-typable H. influenzae. Among isolates from 35 cases of meningitis, 30 (86%) were in ribogroups 1, 2 and 3 with >90% genetic similarity. Compared with all the other ribogroups, ribogroups 1, 2 and 3, which encompassed all H. influenzae type b, were significantly more prevalent as a cause of meningitis in children <14 years old. Further subtyping of the predominant ribogroup by pulsed-field gel electrophoresis (PFGE) identified differences of 0-6 bands among these isolates of ribogroup 1, which indicated distant relatedness. Automated ribotyping was found to be a useful method and was less time-consuming for molecular epidemiology studies of H. influenzae. PFGE is suggested as an addition to ribotyping to improve discrimination if H. influenzae type b is involved. Differentiating ribogroups between type b and non-type b H. influenzae by genotyping may help to understand the molecular characteristics of outbreaks, endemicity and value of vaccination. According to the results of ribotyping and PFGE, it seems possible that spread of invasive H. influenzae type b had occurred and ribotyping confirmed that there was no clonal spread of non-type b H. influenzae in Taiwan.