Wen Chien Ko

Outcome of Cephalosporin Treatment for Serious Infections Due to Apparently Susceptible Organisms Producing Extended-Spectrum β-Lactamases: Implications for the Clinical Microbiology Laboratory

ABSTRACT Although extended-spectrum beta-lactamases (ESBLs) hydrolyze cephalosporin antibiotics, some ESBL-producing organisms are not resistant to all cephalosporins when tested in vitro. Some authors have suggested that screening klebsiellae or Escherichia colifor ESBL production is not clinically necessary, and when most recently surveyed the majority of American clinical microbiology laboratories did not make efforts to detect ESBLs. We performed a prospective, multinational study of Klebsiella pneumoniae bacteremia and identified 10 patients who were treated for ESBL-producingK. pneumoniae bacteremia with cephalosporins and whose infecting organisms were not resistant in vitro to the utilized cephalosporin. In addition, we reviewed 26 similar cases of severe infections which had previously been reported. Of these 36 patients, 4 had to be excluded from analysis. Of the remaining 32 patients, 100% (4 of 4) patients experienced clinical failure when MICs of the cephalosporin used for treatment were in the intermediate range and 54% (15 of 28) experienced failure when MICs of the cephalosporin used for treatment were in the susceptible range. Thus, it is clinically important to detect ESBL production by klebsiellae or E. coli even when cephalosporin MICs are in the susceptible range (≤ 8 μg/ml) and to report ESBL-producing organisms as resistant to aztreonam and all cephalosporins (with the exception of cephamycins).

International Prospective Study of Klebsiella pneumoniae Bacteremia: Implications of Extended-Spectrum β-Lactamase Production in Nosocomial Infections

Context Worldwide prevalence of extended-spectrum -lactamase (ESBL)producing organisms is of great concern because of their broad antibiotic resistance. Contribution Analysis of consecutive cases of Klebsiella pneumoniae bacteremia at 12 hospitals on 6 continents shows that although incidence varies widely among institutions, almost one third of cases of nosocomial bacteremia and almost one half of intensive care unitbased infections were caused by ESBL-producing organisms. Patient-to-patient spread is common, and prevention requires careful attention to routine infection control measures. Cautions Specific antibiotic exposures before K. pneumoniae infection cannot be confirmed as risk factors for ESBL-related infections on the basis of this study. The Editors Since the discovery that resistance of Staphylococcus aureus to penicillin is mediated by a -lactamase, much effort has been made to create -lactam antibiotics that are stable to common -lactamases. Cephalosporin antibiotics containing an oxyimino side-chain represent a major advance in antibiotic development. The merger of the oxyimino chain and a 2-amino-5-thiazolyl nucleus (in such antibiotics as ceftriaxone, cefotaxime, and ceftazidime) resulted in stability to the effects of the common TEM-1 and SHV-1 -lactamases produced by gram-negative bacilli, such as Escherichia coli and Klebsiella pneumoniae. However, within a few years of the commercial release of these antibiotics, gram-negative bacilli (especially K. pneumoniae) that harbored mutated versions of the parent TEM and SHV enzymes were detected. These and other newly detected -lactamases (for example, the functionally similar CTX-M types) hydrolyze -lactam antibiotics containing the oxyimino side-chain. Genes encoding these extended-spectrum -lactamases (ESBLs) were carried on transferable plasmids. These plasmids frequently carried determinants of resistance to other classes of antibiotics, particularly the aminoglycosides (1, 2). Thus, ESBL-producing gram-negative bacilli were found to truly be multiresistant pathogens: The majority of these strains were resistant to all -lactam antibiotics (with the exception of cephamycins and carbapenems), most aminoglycosides, trimethoprimsulfamethoxazole, and sometimes the fluoroquinolones. Although the prevalence of ESBL production among gram-negative bacilli varies geographically (and may even vary from hospital to hospital within a city), widespread recognition of the advent of these -lactamases has been lacking (3). Previous studies of the epidemiology of ESBL-producing organisms have been largely limited to single institutions (4, 5). Because substantial information on the epidemiology of ESBL-producing K. pneumoniae or other gram-negative bacilli is lacking, we established a collaboration of researchers from 7 countries on 6 continents to prospectively enroll consecutive patients with K. pneumoniae bacteremia. Methods Study Design We performed a prospective observational study of 440 consecutive, sequentially encountered patients with K. pneumoniae bacteremia at 12 hospitals in South Africa, Taiwan, Australia, Argentina, the United States, Belgium, and Turkey. No patient was excluded from analysis. Patients were enrolled from 1 January 1996 to 31 December 1997. Patients were older than 16 years of age and had positive blood cultures for K. pneumoniae. The investigators completed a 188-item study form on each episode of K. pneumoniae bacteremia. Patients were followed for 1 month after the onset of bacteremia to assess clinical outcome, including death and infectious complications. The study was observational in that administration of antimicrobial agents and other therapeutic management was controlled by the patients physician rather than the investigators (6). The study was approved by institutional review boards as required by local hospital policy at the time of the study. Definitions All study definitions were established before data analysis. Nosocomial bacteremia was defined as K. pneumoniae bacteremia occurring more than 48 hours after admission to hospital. An episode of bacteremia was defined as the period of 14 days from the time of collection of the first blood culture positive for K. pneumoniae. Severity of acute illness was assessed at the time of the positive blood cultures by using the Pitt bacteremia score, a previously validated scoring system that is based on mental status, vital signs, requirement for mechanical ventilation, and recent cardiac arrest (Table 1) (7, 8). Severity of illness in patients in an intensive care unit at the time of onset of bacteremia was assessed by using the Acute Physiology and Chronic Health Evaluation-3 score (9). Site of infection was determined to be pneumonia, urinary tract infection, meningitis, incisional wound infection, other soft-tissue infection, intra-abdominal infection, or primary bloodstream infection according to Centers for Disease Control and Prevention definitions (10). Previous antibiotic therapy was defined as antibiotics given for at least 2 days within the 14 days before an episode of K. pneumoniae bacteremia (11). Antibiotic therapy for the episode of K. pneumoniae bacteremia was the receipt of antibiotics that are active in vitro against the blood culture isolate (that is, susceptible according to 1999 NCCLS breakpoints [12], given for at least 2 days within the first 5 days of collection of the first positive blood culture. Mortality was death from any cause within 14 days from the date of the first positive blood culture for K. pneumoniae. Table 1. The Pitt Bacteremia Score* Microbiological Analysis Production of ESBL was phenotypically determined by broth dilution using the NCCLS performance standards current as of January 1999 (12). A 3 twofold decrease in the minimal inhibitory concentration (MIC) for cefotaxime or ceftazidime tested in combination with clavulanic acid compared with its MIC when tested alone was considered phenotypic confirmation of ESBL production. For example, an isolate with a ceftazidime MIC of 8 g/mL and a ceftazidimeclavulanic acid MIC of 1 g/mL fulfills this definition of an ESBL-producing organism (12). The MICs of antibiotics commonly used in the treatment of gram-negative sepsis were determined for the ESBL-producing isolates by using the gradient diffusion method (Etest, AB Biodisk, Solna, Sweden). Pulsed-field gel electrophoresis was used to establish the genotypic relationships of ESBL-producing isolates from each hospital (11). Statistical Analysis All statistical comparisons were made by using PROPHET Statistics software, version 6.0 (ABTech-BBN Corp., Charlottesville, Virginia) or Stata software, version 7.0 (Stata Corp., College Station, Texas). For bivariate comparisons, the chi-square or Fisher exact test was used to compare categorical variables. Continuous variables were compared by using the t-test or the MannWhitney test. Length of stay before positive blood culture was missing for 10 (4%) patients, all of whom had been readmitted within 1 week of discharge. Length of stay for these 10 patients was therefore estimated by using a predictive model that assumed missing at random. Because previous receipt of antibiotics was not random, a propensity score model was used to further evaluate the effect of receipt of antibiotics containing an oxyimino group as a risk for ESBL production. The score was calculated by using a logistic model in which receipt of -lactam antibiotics containing an oxyimino group (cefuroxime, ceftriaxone, cefotaxime, ceftazidime, or aztreonam) was the dependent variable (scored as yes or no) and predictors were all available factors hypothesized to influence the receipt of antibiotic therapy (underlying patient conditions), with adjustment for center by using the indicator variables for site. Factors included in the calculation of this score were age, sex, admission from nursing home, underlying diseases (cancer, HIV infection, diabetes, or renal and liver disease), previous surgery, use of corticosteroids, presence of a central line, mechanical ventilatory support, presence of a nasogastric tube, and the indicator variables for site. A logistic model clustered on the patient that used receipt of antibiotics containing an oxyimino group and the quintile stratified score was then used to evaluate the risk for ESBL production. Role of the Funding Source Merck and Company provided support for laboratory studies but played no role in study design, conduct of the study, interpretation of the results, or approval of the study before publication. Results During the study period, 455 episodes of K. pneumoniae bacteremia occurred in 440 patients; of these, 202 (44.4%) episodes in 196 patients were community acquired and 253 (55.6%) episodes in 244 patients were nosocomially acquired. Table 2 shows the characteristics of the participants. Table 2. Characteristics of 244 Patients with Nosocomial Klebsiella pneumoniae Bacteremia Of the episodes of K. pneumoniae bacteremia, 18.7% (85 of 455) were due to ESBL-producing organisms and 81.1% (369 of 455) were due to nonESBL-producing organisms. One additional episode involved an isolate that showed a markedly elevated MIC for the oxyimino -lactam antibiotics but no decrease in MIC with the addition of clavulanic acid. This isolate had an MIC for cephamycin antibiotics in the resistant range and may have possessed an AmpC-like enzyme. This episode was excluded from further analysis. Seventy-eight of 253 (30.8%) episodes of nosocomial bacteremia were due to ESBL-producing organisms. Table 3 shows the sites of infection associated with nosocomial ESBL-producing K. pneumoniae bacteremia. Fewer episodes of community-acquired K. pneumoniae bacteremia (3.5% [7 of 202]) were due to ESBL-producing organisms (P <0.001) (risk ratio, 8.9 [95% CI, 4.2 to 18.8]). Of the 253 episodes of nosocomial bacteremia, 69 were acquired in the intensive care unit. Of these 69 episodes, 30 (43.5%) episodes o

Antibiotic Therapy for Klebsiella pneumoniae Bacteremia: Implications of Production of Extended-Spectrum β-Lactamases

The prevalence of extended-spectrum beta -lactamase (ESBL) production by Klebsiella pneumonia approaches 50% in some countries, with particularly high rates in eastern Europe and Latin America. No randomized trials have ever been performed on treatment of bacteremia due to ESBL-producing organisms; existing data comes only from retrospective, single-institution studies. In a prospective study of 455 consecutive episodes of Klebsiella pneumoniae bacteremia in 12 hospitals in 7 countries, 85 episodes were due to an ESBL-producing organism. Failure to use an antibiotic active against ESBL-producing K. pneumoniae was associated with extremely high mortality. Use of a carbapenem (primarily imipenem) was associated with a significantly lower 14-day mortality than was use of other antibiotics active in vitro. Multivariate analysis including other predictors of mortality showed that use of a carbapenem during the 5-day period after onset of bacteremia due to an ESBL-producing organism was independently associated with lower mortality. Antibiotic choice is particularly important in seriously ill patients with infections due to ESBL-producing K. pneumoniae.

Epidemiology of Ciprofloxacin Resistance and Its Relationship to Extended-Spectrum β-Lactamase Production in Klebsiella pneumoniae Isolates Causing Bacteremia

A prospective study of Klebsiella pneumoniae bacteremia was performed in 12 hospitals in 7 countries. Of 452 episodes of bacteremia, 25 (5.5%) were caused by K. pneumoniae that was resistant in vitro to ciprofloxacin. Extended-spectrum beta-lactamase (ESBL) production was detected in 15 (60%) of 25 ciprofloxacin-resistant isolates, compared with 68 (16%) of 427 ciprofloxacin-susceptible strains (P=.0001). Multivariate analysis revealed that risk factors for ciprofloxacin resistance in K. pneumoniae included prior receipt of a quinolone (P=.0065) and an ESBL-producing strain (P=.012). In all, 18% of ESBL-producing isolates were also ciprofloxacin-resistant. Pulsed-field gel electrophoresis showed that 11 of the 15 ciprofloxacin-resistant ESBL-producing strains belonged to just 4 genotypes, suggesting that patient-to-patient transmission of such strains occurred. The close relationship between ESBL production and ciprofloxacin resistance is particularly worrisome because the first reported instance of plasmid-mediated ciprofloxacin resistance has been in an isolate of K. pneumoniae also possessing an ESBL.

Community-Acquired Klebsiella pneumoniae Bacteremia: Global Differences in Clinical Patterns

We initiated a worldwide collaborative study, including 455 episodes of bacteremia, to elucidate the clinical patterns of Klebsiella pneumoniae. Historically, community-acquired pneumonia has been consistently associated with K. pneumoniae. Only four cases of community-acquired bacteremic K. pneumoniae pneumonia were seen in the 2-year study period in the United States, Argentina, Europe, or Australia; none were in alcoholics. In contrast, 53 cases of bacteremic K. pneumoniae pneumonia were observed in South Africa and Taiwan, where an association with alcoholism persisted (p=0.007). Twenty-five cases of a distinctive syndrome consisting of K. pneumoniae bacteremia in conjunction with community-acquired liver abscess, meningitis, or endophthalmitis were observed. A distinctive form of K. pneumoniae infection, often causing liver abscess, was identified, almost exclusively in Taiwan.

Virulence Characteristics of Klebsiella and Clinical Manifestations of K. pneumoniae Bloodstream Infections

Differences in clinical manifestations are due to virulence factors expressed by the organism.

Association between rmpA and magA Genes and Clinical Syndromes Caused by Klebsiella pneumoniae in Taiwan

BACKGROUND The association of the magA gene with the hypermucoviscosity phenotype relevant to the pathogenesis of Klebsiella pneumoniae liver abscess has been reported in Taiwan. Similarly, the rmpA gene, known as a positive regulator of extracapsular polysaccharide synthesis that confers a mucoid phenotype, may be another candidate gene causing hypermucoviscosity. However, the association of rmpA with K. pneumoniae clinical syndromes is unreported. We aimed to investigate the clinical correlation between rmpA and primary Klebsiella abscess, focusing on sites other than the liver. METHODS From July 2003 through December 2004, a total of 151 K. pneumoniae isolates recovered from 151 patients with bacteremia were collected from 2 large medical centers in southern Taiwan. Clinical data were collected from medical records. The genes rmpA and magA were amplified by polymerase chain reaction using specific primers. RESULTS The prevalences of hypermucoviscosity, rmpA, and magA were 38%, 48%, and 17%, respectively. As determined by statistical multivariate analysis, strains carrying rmpA were significantly associated with the hypermucoviscosity phenotype, and there was a significant correlation with purulent tissue infections, such as liver abscess and lung, neck, psoas muscle, or other focal abscess. CONCLUSION Our data support a statistical correlation between the rmpA gene and virulence in terms of abscess formation for these hypermucoviscous K. pneumoniae strains. Hypermucoviscosity associated with rmpA, together with a thorough physical examination, may be helpful as a guide to carry out appropriate diagnostic tests on patients with an initially unknown source of K. pneumoniae bacteremia, particularly when looking for the occurrence of an underlying abscess.

Clinical and Economic Impact of Multidrug Resistance in Nosocomial Acinetobacter baumannii Bacteremia

OBJECTIVE To investigate the impact of antimicrobial resistance on clinical and economic outcomes among hospitalized patients with multidrug-resistant (MDR) Acinetobacter baumannii bacteremia. DESIGN A retrospective, matched-cohort study. SETTING A tertiary care university teaching hospital. METHODS A matched case-control (1 : 1) study was conducted to compare the differences in clinical and economic outcomes of patients with MDR A. baumannii bacteremia and patients with non-MDR A. baumannii bacteremia. Case patients were matched to control patients on the basis of sex, age, severity of underlying and acute illness, and length of hospital stay before onset of bacteremia. RESULTS Forty-six (95.8%) of 48 cases with MDR A. baumannii bacteremia were eligible for the study and matched with appropriate controls. The sepsis-related mortality rate was 34.8% among cases and 13.0% among controls, for an attributable mortality rate of 21.8% (adjusted odds ratio, 4.1 [95% confidence interval, 1.1-15.7]; P=.036). After the onset of bacteremia, cases and controls had a significantly different length of hospital stay (54.2 vs 34.1 days; P=.006), hospitalization cost (US

Prevalence of Plasmid-Mediated Quinolone Resistance Determinants QnrA, QnrB, and QnrS among Clinical Isolates of Enterobacter cloacae in a Taiwanese Hospital

9,349 vs US

Comparison of prevalence of virulence factors for Klebsiella pneumoniae liver abscesses between isolates with capsular K1/K2 and non-K1/K2 serotypes

4,865; P=.001), and antibiotic therapy cost (US