Clinical features and in vitro antimicrobial susceptibilities of community-acquired Klebsiella pneumoniae meningitis in Taiwan

Ping-Yu Lee1, Wen-Neng Chang2, Cheng-Hsien Lu2,*, Mei-Wen Lin1, Ben-Chung Cheng3, Chun-Chih Chien4, Chin-Jung Chang5 and Hsueh-Wen Chang6

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


    Abstract
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Twenty-seven adult patients were identified as having community-acquired Klebsiella pneumoniae meningitis. The K. pneumoniae isolates, collected from cerebrospinal fluid samples, were tested for in vitro antimicrobial susceptibilities. The prognostic factors of these 27 patients were also analysed. All of the third- and fourth-generation cephalosporins tested, as well as monobactam, carbapenem and ciprofloxacin, had good activities against the isolated K. pneumoniae strains. None of the clinical isolates was detected as being an extended-spectrum ß-lactamase-producing pathogen. Among the third- and fourth-generation cephalosporins, ceftizoxime, cefepime, ceftriaxone and cefotaxime had superior activities, with MIC90s about four- to eight-fold lower than those of ceftazidime and moxalactam. Mortality rates of patients classified by different antimicrobial agents were as follows: ceftazidime 38% (8/21) and cefepime 16.7% (1/6). The presence of septic shock and the initial level of consciousness at the start of appropriate antimicrobial therapy were the major determinants of survival and neurological outcomes in these 27 patients. Early diagnosis and choice of appropriate antibiotics according to antimicrobial susceptibilities may improve therapeutic outcomes.

Keywords: clinical features, in vitro antimicrobial susceptibilities, community-acquired Klebsiella pneumoniae meningitis


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
The relative prevalence rates for causative pathogens associated with bacterial meningitis can vary with time period, geographical distribution, age, underlying medical and/or surgical condition, and mode of infection.13 In Taiwan,4,5 Klebsiella pneumoniae has become an increasingly common pathogen of adult community-acquired bacterial meningitis. Although parenteral third-generation cephalosporins appear to be a major therapeutic advance in the treatment of K. pneumoniae meningitis,6 highly resistant strains that produce plasmid-mediated, extended-spectrum ß-lactamases (ESBLs) have been reported, which may influence therapeutic outcomes.7 The detection of ESBL-producing strains and evaluation of in vitro antimicrobial susceptibilities have become an important part of the work of clinical laboratories. This study was undertaken to determine the in vitro susceptibilities of several antimicrobial agents against these organisms using the agar dilution method; the clinical features were analysed statistically in order to improve strategies for managing this potentially fatal central nervous system (CNS) infection.


    Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Over a period of 4 years (1998–2001), 65 cases were identified as having culture-proven adult community-acquired bacterial meningitis at Kaohsiung Chang Gung Memorial Hospital (Table 1). As the largest medical centre in southern Taiwan, this facility is a 2482 bed acute-care teaching hospital, which serves as a tertiary care centre for the entire country. Among them, 28 adult patients were identified as having community-acquired K. pneumoniae meningitis, in 27 of whom there was isolation of a bacterial pathogen in one or more cerebrospinal fluid (CSF) samples, whereas in the other patient CSF findings were typical of bacterial meningitis, with classic clinical manifestations and positive cultures from blood. The criteria for a definite diagnosis of K. pneumoniae meningitis and enrolment in this study were as follows: (i) a positive culture of CSF in patients with clinical presentations of acute bacterial meningitis; and (ii) at least one of the following parameters of bacterial inflammation of CSF: (a) a leucocyte count of >0.25 x 103 cells/mm3 with predominant polymorphonuclear cells; (b) a CSF lactate concentration of >3.5 mmol/L; (c) a glucose ratio (CSF glucose/serum glucose) of <0.4; or (d) CSF glucose of <2.5 mmol/L if no simultaneous blood glucose was determined.15 Patients were excluded from this study if K. pneumoniae was isolated from blood cultures with clinical presentations of acute bacterial meningitis or if they were considered to have mixed bacterial meningitis with at least two bacterial organisms isolated from the initial CSF cultures.


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Table 1.  Causative organisms of culture-proven adult community-acquired meningitis, 1998–2001
 
Definitions used in this study for the modes of contraction of K. pneumoniae meningitis were modified from previous reports.15,8 ‘Community-acquired’ K. pneumoniae meningitis was defined as meningitis contracted outside a hospital environment. Patients were excluded from this study if they had a history of head trauma with skull fracture or neurosurgical procedures including CSF shunting, and if they had evidence of concomitant chronic meningitis or meningoencephalitis. The criteria for hyperglycaemic hyperosmolar non-ketotic state (HHNK) in this study were defined as follows: (i) a calculated serum osmolarity at admission >=350 mOsmol/L; (ii) serum glucose >=33.3 mmol/L; (iii) arterial pH >=7.25; and (iv) serum ketone body negative.

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 blood–brain barrier in adequate amounts.5 Antibiotic susceptibility was tested using the Kirby–Bauer disc diffusion method (BBL Mueller–Hinton 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 {chi}2 test or Fisher’s exact test. Age [mean (years) ± S.D.] between the two patient groups was compared using Student’s 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


    Results
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
The 27 patients included 19 males (mean age ± S.D., 52.2 ± 13.1; range 23–71 years) and eight females (mean age ± S.D., 59.5 ± 18.2; range 20–74 years). The underlying conditions are shown in Table 2. Except for three patients, all cases (24/27) with Klebsiella meningitis were associated with one or more underlying conditions, including diabetes mellitus, alcoholism/or liver cirrhosis, chronic otitis media, chronic obstructive pulmonary diseases and intrahepatic stone. Seventeen patients were admitted in a conscious disturbed state. Fever was found in all but two cases. Metastatic septic abscess in diabetic patients with K. pneumoniae meningitis occurred in five patients, accounting for 19% (5/27) of the episodes. Among them, one had brain abscess alone, two had liver abscess alone and two had multiple metastatic abscesses. Five patients with diabetes mellitus progressed to HHNK and three of these died. Seizure or status epilepticus was found in eight patients, three of whom died. Septic shock occurred in seven patients, five of whom died. Other clinical manifestations for this disease in our subjects are listed in Table 3.


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Table 2.  Underlying conditions
 

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Table 3.  Clinical manifestations
 
Mortality rates of patients classified by different antimicrobial agents used were as follows: 38% (8/21) for ceftazidime and 16.7% (1/6) for cefepime. The MICs corresponding to these 11 comparative drugs against all tested K. pneumoniae strains are shown in Table 4. For K. pneumoniae strains, all of the third- and fourth-generation cephalosporins, as well as monobactams, carbapenems and ciprofloxacin, had good activity against the tested isolates. Among the carbapenems, meropenem had superior activity with MIC50s and MIC90s ~32-fold lower than those of imipenem. Among third- and fourth-generation cephalosporins, ceftizoxime, cefepime, ceftriaxone and cefotaxime had superior activities, with MIC90s about four- to eight-fold lower than those of ceftazidime and moxalactam. None of the clinical isolates was detected as being an ESBL-producing strain.


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Table 4.  Antimicrobial susceptibilities of K. pneumoniae isolates
 
Potential prognostic factors are listed in Table 5. According to the statistical analysis, the presence of septic shock and the initial level of consciousness at the start of appropriate antimicrobial therapy were significant prognostic factors. Variables used for the stepwise logistic regression included the presence of septic shock, different antimicrobial agents and level of consciousness at the start of appropriate antimicrobial therapy. The results revealed that after analysis for all the above variables, only the presence of septic shock (P = 0.013; odds ratio 0.10; 95% confidence interval 0.01–0.72) was independently associated with treatment failure.


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Table 5.  Prognostic factors of patients
 

    Discussion
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
In Taiwan, K. pneumoniae meningitis is one of the most common causative pathogens of community-acquired bacterial meningitis.5,6 It has been known to commonly cause invasive infections, including pyogenic liver abscess, bacteraemia, pneumonia and endophthalmitis.6,1114 The reason for the geographical preponderance of these severe manifestations of K. pneumoniae infections in Taiwan is unknown. The geographical diversity of Klebsiella infections possibly results from interactions between bacterial variables, host variables, socioeconomic factors and possible genetic susceptibilities of different racial groups.15 In this study, diabetes mellitus and other debilitating diseases such as liver cirrhosis seemed to be predisposing factors. The increased frequency of K. pneumoniae infections in diabetics is well known, but the precise cause has not been elucidated; however, it has been postulated that hyperglycaemia may enhance capsule formation and thereby increase the virulence of Klebsiella bacilli.16

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 patient’s 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.


    Footnotes
 
* Corresponding author. Tel: +886-7-7317123 ext. 2283; Fax: +886-7-7902684; E-mail: chlu99{at}ms44.url.com.tw Back


    References
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
1 . Durand, M. L., Calderwood, S. B., Weber, D. J., Miller, S. I., Southwick, F. S., Caviness, V. S. et al. (1993). Acute bacterial meningitis in adults: a review of 493 episodes. New England Journal of Medicine 328, 21–8.[Abstract/Free Full Text]

2 . Schuchat, A., Robinson, K., Wenger, J. D., Harrison, L. H., Farley, M., Reingold, A. L. et al. (1997). Bacterial meningitis in the United States in 1995. New England Journal of Medicine 337, 970–6.[Abstract/Free Full Text]

3 . Sigurardottir, B., Bjornsson, O. M., Jonsdottir, K. E., Erlendsdottir, H. & Gudmundsson, S. (1997). Acute bacterial meningitis in adults. A 20-year overview. Archives of Internal Medicine 157, 425–30.[Abstract]

4 . Tang, L. M., Chen, S. T., Hsu, W. C. & Lyu, R. K. (1999). Acute bacterial meningitis in adults: a hospital-based epidemiological study. Quarterly Journal of Medicine 92, 719–25.[Abstract/Free Full Text]

5 . Lu, C. H., Chang, W. N. & Chang, H. W. (2000). Adult bacterial meningitis in southern Taiwan: epidemiologic trend and prognostic factors. Journal of the Neurological Sciences 182, 36–44.[CrossRef][ISI][Medline]

6 . Tang, L. M., Chen, S. T., Hsu, W. C. & Chen, C. M. (1997). Klebsiella meningitis in Taiwan: an overview. Epidemiology and Infection 119, 135–42.[CrossRef][ISI][Medline]

7 . Smith, C. E., Tillman, B. S., Howell, A. W., Longfield, R. D. & Jorgensen, J. H. (1990). Failure of ceftazidime–amikacin therapy for bacteremia and meningitis due to Klebsiella pneumoniae producing an extended-spectrum ß-lactamase. Antimicrobial Agents and Chemotherapy 34, 1290–3.[ISI][Medline]

8 . Garner, J. S., Jarvis, W. R., Emori, T. G., Horan, T. C. & Hughes, J. M. (1988). CDC definitions for nosocomial infections, 1988. American Journal of Infection Control 16, 128–40.[ISI][Medline]

9 . Cormican, M. G., Marshall, S. A. & Jones, R. N. (1996). Detection of extended-spectrum ß-lactamase (ESBL)-producing strains by the E-test ESBL screen. Journal of Clinical Microbiology 34, 1880–4.[Abstract]

10 . SAS Statistical Institute. (1990). SAS User’s Guide. SAS Statistical Institute, Cary, NC, USA.

11 . Wang, J. H., Liu, Y. C., Lee, S. S., Yen, M. Y., Chen, Y. S., Wang, J. H. et al. (1998). Primary liver abscess due to Klebsiella pneumoniae in Taiwan. Clinical Infectious Diseases 6, 1434–8.

12 . Chen, C. W., Jong, G. M. & Shiau, J. J. (1992). Adult bacteremic pneumonia: bacteriology and prognostic factors. Journal of the Formosan Medical Association 91, 754–9.[Medline]

13 . Wang, L. S., Lee, F. Y., Cheng, D. L., Liu, C. Y., Hinthorn, D. R. & Lost, P. M. (1990). Klebsiella pneumoniae bacteremia: analysis of 100 episodes. Journal of the Formosan Medical Association 89, 756–63.[Medline]

14 . Liliang, P. C., Lin, Y. C., Su, T. M., Rau, C. S., Lu, C. H., Chang, W. N. et al. (2001). Klebsiella brain abscess in adults. Infection 29, 81–6.[CrossRef][ISI][Medline]

15 . Ko, W. C., Paterson, D. L., Sagnimeni, A. J., Hansen, D. S., Von Gottberg, A., Mohapatra, S. et al. (2002). Community-acquired Klebsiella pneumoniae bacteremia: global differences in clinical patterns. Emerging Infectious Diseases 8, 160–6.[ISI][Medline]

16 . Soscia, J. L., DiBenedetto, R. & Crocco, J. (1964). Klebsiella pneumoniae meningitis: report of a case and review of the literature. Archives of Internal Medicine 113, 569–72.[ISI][Medline]

17 . Nadarajah, M. (1981). Bacterial meningitis—a five year review, 1975–1979. Annals of the Academy of Medicine (Singapore) 10, 11–3.

18 . Lu, C. H., Chang, W. N. & Chuang, Y. C. (1999). Resistance to third generation cephalosporins in adult Gram-negative bacillary meningitis. Infection 27, 208–11.[ISI][Medline]





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