Departments of 1 Pharmacy, 2 Neurology, 3 Medicine, 4 Clinical Pathology and 5 Pediatric Neurology, Chang Gung Memorial Hospital-Kaohsiung, 123 Ta Pei Road, Niao Sung Hsiang, Kaohsiung; 6 Department of Biological Science, National Sun Yat-Sen University, Taiwan
Received 19 August 2002; returned 17 October 2002; revised 28 December 2002; accepted 18 January 2003
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Abstract |
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Keywords: clinical features, in vitro antimicrobial susceptibilities, community-acquired Klebsiella pneumoniae meningitis
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Introduction |
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Materials and methods |
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Clinical isolates of CSF samples were obtained from the 27 patients with K. pneumoniae meningitis hospitalized at our institution. No duplicate isolates from the same patient and no strains from a single outbreak were included. All isolates of K. pneumoniae specimens were inoculated into tryptic soy agar with 5% sheep serum at 35°C and allowed to grow for 2 days before testing.
Antimicrobial agents were supplied by individual pharmaceutical companies as standard reference powders of known potency for laboratory use. Cefepime and aztreonam were supplied by Bristol-Myers Squibb (Syracuse, NY, USA), ceftazidime by GlaxoSmithKline (Greenford, UK), cefotaxime by Hoechst Marion Roussel (Frankfurt, Germany), meropenem by Sumitomo Pharmaceuticals (Osaka, Japan), ceftriaxone by Hoffman-La Roche (Basel, Switzerland), ceftizoxime by Fujisawa (Japan), moxalactam and flumoxef by Shionogi Pharmaceutical (Osaka, Japan), imipenem/cilastatin by Merck (Elkton, VA, USA) and ciprofloxacin by Bayer (Leverkusen, Germany).
Appropriate antimicrobial therapy was defined as the administration of one or more antimicrobial agents demonstrated to be effective against K. pneumoniae by susceptibility tests and capable of passing through the bloodbrain barrier in adequate amounts.5 Antibiotic susceptibility was tested using the KirbyBauer disc diffusion method (BBL MuellerHinton II agars; Becton Dickinson). The antimicrobial susceptibilities of all strains were determined concomitantly by means of the broth dilution method as described in NCCLS guidelines for MICs. All drugs were diluted in serial two- fold concentrations. The MIC was the lowest concentration of antimicrobial agent that completely inhibited visible growth. Quality control strains were obtained from the American Type Culture Collection (Rockville, MD, USA), and Escherichia coli ATCC 25922 was used as the internal control for each run of the test.
The definition of an ESBL is that the enzyme can increase the affinity and hydrolytic ability for oxyimino compounds but is not inhibited by clavulanic acid or tazobactam. In this study, the Etest (AB Biodisk, Solna, Sweden) ESBL screen test was also performed in order to detect ESBL-producing strains. The Etest is a quantitative test for determining antimicrobial susceptibility. It comprises a predefined antimicrobical gradient on a plastic strip. The Etest ESBL screen strip, which contains ceftazidime and clavulanic acid, is a convenient and reliable alternative for the detection of ESBL-producing strains.9
The initial level of consciousness was defined as the consciousness at the start of appropriate antimicrobial therapy, and was classified into two groups: group I with normal consciousness, or inattention, confusion and clouded consciousness [Glasgow coma scale score (GCS) >7 points]; and group II with stupor or coma (GCS 7 points). Variables including gender, underlying conditions, clinical manifestations, the presence or absence of bacteraemia, and antimicrobial agents between the groups of patients who died and those who survived were analysed by means of
2 test or Fishers exact test. Age [mean (years) ± S.D.] between the two patient groups was compared using Students t-test. Stepwise logistic regression was used to evaluate the relationships between clinical factors and therapeutic outcomes, with adjustments made for other potentially confounding factors. The stepwise procedure starts with forward selection followed by backward elimination of variables. Variables with a zero cell count in a 2 x 2 table were eliminated from the logistic analysis, while only variables with a strong association with treatment failure (P < 0.05) were included in the final model. All analyses were conducted using SAS software (1990).10
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Results |
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Discussion |
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Community-acquired K. pneumoniae meningitis in adults is commonly associated with many underlying medical problems, such as diabetes mellitus and liver cirrhosis, with a higher prevalence of bacteraemia and shock.6 These conditions were also found in this study. Since the clinical course of these patients was fulminant, it may have been difficult for physicians to detect the primary pyogenic focus before the patients died. Metastatic infections are a well-known complication of bacteraemia.13,15 In Taiwan, devastating metastatic septic abscesses in diabetic patients with K. pneumoniae meningitis are common and should always be considered as possible.13,15
Despite the use of potent antibiotics with excellent in vitro activity, such as third- or fourth-generation cephalosporins, the case fatality rate for K. pneumoniae meningitis remains high.5,6 In studies from Singapore17 and northern parts of Taiwan,6 mortality rates of patients with K. pneumoniae meningitis were 100% and 48.5%, respectively. In recent years, there has been an increased proportion of K. pneumoniae meningitis cases resistant to third-generation cephalosporins; most of them were nosocomial meningitis in post-neurosurgical state.18 In this study, the overall mortality was 33% (9/27). Although the choice of different antimicrobial agents was not shown to be statistically significant in this study, the case fatality rate of K. pneumoniae meningitis in those patients treated with cefepime (1/6; 16.7%) was lower than that of those treated with ceftazidime (8/21; 38%). Cefepime had superior activity, with MIC90s about two-fold lower than those of ceftazidime. However, the case numbers were too small to draw a statistical conclusion.
Septic shock is a well-known prognostic factor5,6 that may significantly influence the outcome of patients. The prognosis among patients who remained free of HHNK was better, but its influence on the prognosis was not statistically significant in this study. In this study, patients with a GCS score of 7 points seemed to have poor outcomes; therefore, the first dose of an appropriate antibiotic should be administrated before a patients consciousness deteriorates to a GCS score of
7. Because this is a retrospective study, the commencement of antibiotic therapy is different for each patient according to the preference of his/her doctor, which may cause potential bias in statistical analysis. Although the sample size is not large, the numbers of variables considered for the multiple logistic regression analysis is small. Furthermore, based on the stepwise procedures, only one variable was selected as the important variable predicting the outcomes. Therefore the maximum likelihood estimates of the coefficients are valid in the analysis.
In conclusion, although parenteral third- and fourth-generation cephalosporins are the mainstay of treatment for community-acquired K. pneumoniae meningitis, the fatality rates remain high. If prognostic factors are considered, the presence of septic shock and the initial level of consciousness were major determinants of survival and neurological outcomes for patients with community-acquired K. pneumoniae meningitis. Early diagnosis and choice of appropriate antibiotics according to antimicrobial susceptibilities are essential to improve outcomes.
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Footnotes |
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References |
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