目的: 腸桿菌群(Enterobacter cloacae complex)是造成院內感染的常見致病菌之一。文獻中卻少有文章提及腸桿菌群內各亞型對各種抗生素之體外抗藥性試驗，與被感染病人臨床差異性；且具廣效性β-內醯氨酶 (extended-spectrum β-lactamase, ESBL)腸桿菌群菌血症病人的治療，目前尚無研究顯示何種藥物較為合適。所以本研究目的: 探討此類細菌所造成菌血症臨床特性及危險因子，用迴朔式分析碳青黴烯類抗生素(carbapenems)治療的角色；藉由熱休克蛋白60基因基因分析(heat shock protein 60 genotyping)方法，鑑定出腸桿菌群內各菌種；比較各菌種在體外抗藥性試驗之不同，及所造成菌血症病人在臨床表現與癒後的差異性。
實驗設計: 2001到2008年腸桿菌群菌血症菌株中，挑選cefotaxime-nonsusceptible菌株進入本研究，先進行熱休克蛋白60基因基因分析鑑定亞型 (subspecies)；再由聚合酶連鎖反應 (polymerase chain reactions)分析ESBL基因型，及由cefepime-clavunate ESBL Etest檢測ESBL表現型。若帶有ESBL基因菌株造成之菌血症病人，視為病例組；相反地，若菌血症菌株不帶有ESBL基因且不具有ESBL表現型，歸於對照組。
結果: 八年內610株菌血症菌株中，共有258 (42.3%) cefotaxime-nonsusceptible菌株納入本研究，其中帶有ESBL基因菌株有138株，120株不帶有ESBL基因且不具有ESBL表現型。 在138有ESBL基因菌株中，133 (96.3%)株有blaSHV-12，3 (2.1%)株有blaCTX-M3，2 (1.4%)株同時有blaSHV-12與 blaCTX-M3。在258株菌株中，Enterobacter hormaechei 是腸桿菌群中最主要亞型 (147株, 59.5%)，且相較於其他亞型，有較高的比例有ESBL (57.8% vs. 42.0%, P<0.001)。排除兒童案例後，共有206為病人納入分析，其中病例組有121人，對照組有85人；E. hormaechei菌血症病人比其他亞型菌血症病人，較常有ESBL基因 (65.0% vs. 49.4%, P=0.02)；但兩群病人臨床特性、菌血症嚴重度、死亡率皆相近。進一步分析病例組與對照組病患，發現病例組有較常見多重細菌菌血症、疾病嚴重度較高、較常見於在醫院或加護病房內、較長的加護病房與總住院天數等。使用碳青黴烯類抗生素作為確定性療法 (definitive therapy)，病例組敗血症相關死亡率低於使用非碳青黴烯類的ß-內醯胺 (non-carbapenem β-lactams) (5/53, 9.4% vs. 13/44, 29.5%; P=0.01)。多變數分析時，此一差異性未達統計上意義。分析病例組中62位病患菌血症發生後14天內曾做血液培養追蹤，碳青黴烯類抗生素治療比非碳青黴烯類的ß-內醯胺，較少發生breakthrough bacteremia (18/31, 58.0% vs. 3/31, 9.6%; P<0.001)。
結論: 具ESBL基因腸桿菌群菌血症病人治療，使用碳青黴烯類抗生素比非碳青黴烯類ß-內醯胺佔有優勢。依熱休克蛋白60基因鑑定腸桿菌群亞型，E. hormaechei 是腸桿菌群最主要亞型，且較常有ESBL基因。但不同腸桿菌群亞型病人之臨床特性與癒後，無明顯差異。

Objectives: Enterobacter cloacae complex is one of important nosocomial pathogens. However, clinical characteristics and differences of antibiotics in vitro susceptibility between subspecies within E. cloacae complex were not discussed in the literature and few clinical studies specifically dealing with extended-spectrum β-lactamase (ESBL)-producing E. cloacae complex infections have been published. The aims of this study were to establish clinical characteristics and risk factors of ESBL-producing Enterobacter bacteremia, to analyze the role of carbapenem therapy, as well as to study the clinical and microbiological differences between subspecies within E. cloacae complex.
Methods: During an eight-year period, cefotaxime-nonsusceptible bacteremic isolates were studied by hsp60 genotyping. The ESBL-production phenotype was examined by cefepime-clavunate ESBL Etest and encoding genes were detected by polymerase chain reactions. The designation of a case was based on the presence of ESBL genes in the bacteremic isolate. The causative isolate without the ESBL phenotype and genes was regarded as a control.
Results: Of 610 E. cloacae bacteremic isolates, 138 (22.6 %) harboring ESBL genes and 120 (19.6 %) with cefotaxime-nonsusceptible without ESBL phenotype and genes were collected. Of the former group, 133 (96.3%) had blaSHV-12, three (2.1%) blaCTX-M3, and two (1.4%) both blaSHV-12 and blaCTX-M3. After exclusion of 11 untypable isolates, 247 E. cloacae complex isolates were divided into 13 clusters by hsp60 genotyping, and E. hormaechei was the predominant subspecies (147 isolate, 59.5%). After exclusion of age <18 year, there were 206 adults with E. cloacae bacteremia, 121 patients in the ESBL group and 85 in the control group. All clinical characteristics, severity, and outcome were similar between adults with bacteremia caused by E. cloacae complex and those by other genospecies, but higher proportion of the isolates harboring ESBL genes in adults with bacteremia caused by E. hormaechei than those by other genospecies was observed (80/123, 65.0% vs. 41/83, 49.4%; P=0.02). In further analyses of differences between the case and control group, more episodes of hospital-onset or polymicrobial bacteremia, increased severity of illness, more bacteremic onset in intensive care units (ICUs), and longer stay in the hospital or ICU after bacteremic onset, were noted in the ESBL group. However, the crude and sepsis-related mortality rates in two groups were similar. Of the ESBL group, the sepsis-related mortality rate of patients definitively treated by a carbapenem was lower than that of those by non-carbapenem ß-lactams (5/53, 9.4% vs. 13/44, 29.5%; P=0.01), though the difference was not significant in the hierarchical multivariate analysis (P=0.46). Among 62 patients with follow-up blood cultures within 14 days after bacteremic onset, breakthrough bacteremia was more common in those treated by a non-carbapenem β-lactam agent than those treated by a carbapenem (18/31, 58.0% vs. 3/31, 9.6%; P<0.001).
Conclusions: As compared with non-carbapenem β-lactam agents, carbapenem therapy may have therapeutic benefits for patients with ESBL-producing E. cloacae complex bacteremia. In addition, E. hormaechei was the major subspecies of E. cloacae complex bacteremia with cefotaxime nonsusceptibility and its high proportion of harboring ESBL genes were demonstrated. But, the subspecies identification within E. cloacae complex was of a limited clinical value in terms of clinical characteristics and outcome.

Bell, J. M., J. D. Turnidge, and R. N. Jones. 2003. Prevalence of extended-spectrum beta-lactamase-producing Enterobacter cloacae in the Asia-Pacific region: results from the SENTRY Antimicrobial Surveillance Program, 1998 to 2001. Antimicrob Agents Chemother 47 (12):3989-93.
Brenner, D. J., A. C. McWhorter, A. Kai, A. G. Steigerwalt, and J. J. Farmer, 3rd. 1986. Enterobacter asburiae sp. nov., a new species found in clinical specimens, and reassignment of Erwinia dissolvens and Erwinia nimipressuralis to the genus Enterobacter as Enterobacter dissolvens comb. nov. and Enterobacter nimipressuralis comb. nov. J Clin Microbiol 23 (6):1114-20.
Canton, R., A. Oliver, T. M. Coque, C. Varela Mdel, J. C. Perez-Diaz, and F. Baquero. 2002. Epidemiology of extended-spectrum beta-lactamase-producing Enterobacter isolates in a Spanish hospital during a 12-year period. J Clin Microbiol 40 (4):1237-43.
Chia, J. H., C. Chu, L. H. Su, C. H. Chiu, A. J. Kuo, C. F. Sun, and T. L. Wu. 2005. Development of a multiplex PCR and SHV melting-curve mutation detection system for detection of some SHV and CTX-M beta-lactamases of Escherichia coli, Klebsiella pneumoniae, and Enterobacter cloacae in Taiwan. J Clin Microbiol 43 (9):4486-91.
Choi, S. H., J. E. Lee, S. J. Park, M. N. Kim, E. J. Choo, Y. G. Kwak, J. Y. Jeong, J. H. Woo, N. J. Kim, and Y. S. Kim. 2007. Prevalence, microbiology, and clinical characteristics of extended-spectrum beta-lactamase-producing Enterobacter spp., Serratia marcescens, Citrobacter freundii, and Morganella morganii in Korea. Eur J Clin Microbiol Infect Dis 26 (8):557-61.
Chow, J. W., M. J. Fine, D. M. Shlaes, J. P. Quinn, D. C. Hooper, M. P. Johnson, R. Ramphal, M. M. Wagener, D. K. Miyashiro, and V. L. Yu. 1991. Enterobacter bacteremia: clinical features and emergence of antibiotic resistance during therapy. Ann Intern Med 115 (8):585-90.
Clinical and Laboratory Standards Institute. 2008. Performance standards for antimicrobial susceptibility tests; 16th informational supplement. Document. M100–S16. Wayne, PA:CLSI.
David N. Gilbert, Robert C. Moellering, Jr., George M. Eliopoulos, Henry F. Chambers, and Michael S. Saag. 2009. Selected pharmacologic faetures of antimicrobial agents. The Sanford Guide to Antimicrobial Therapy:78-82.

De Gheldre, Y., M. J. Struelens, Y. Glupczynski, P. De Mol, N. Maes, C. Nonhoff, H. Chetoui, C. Sion, O. Ronveaux, and M. Vaneechoutte. 2001. National epidemiologic surveys of Enterobacter aerogenes in Belgian hospitals from 1996 to 1998. J Clin Microbiol 39 (3):889-96.
Garner, J. S., W. R. Jarvis, T. G. Emori, T. C. Horan, and J. M. Hughes. 1988. CDC definitions for nosocomial infections, 1988. Am J Infect Control 16 (3):128-40.
Garrec, H., L. Drieux-Rouzet, J. L. Golmard, V. Jarlier, and J. Robert. 2011. Comparison of nine phenotypic methods for detection of extended-spectrum beta-lactamase production by Enterobacteriaceae. J Clin Microbiol 49 (3):1048-57.
Goh, S. H., S. Potter, J. O. Wood, S. M. Hemmingsen, R. P. Reynolds, and A. W. Chow. 1996. HSP60 gene sequences as universal targets for microbial species identification: studies with coagulase-negative staphylococci. J Clin Microbiol 34 (4):818-23.
Ho, P. L., R. H. Shek, K. H. Chow, R. S. Duan, G. C. Mak, E. L. Lai, W. C. Yam, K. W. Tsang, and W. M. Lai. 2005. Detection and characterization of extended-spectrum beta-lactamases among bloodstream isolates of Enterobacter spp. in Hong Kong, 2000-2002. J Antimicrob Chemother 55 (3):326-32.
Hoffmann, H., and A. Roggenkamp. 2003. Population genetics of the nomenspecies Enterobacter cloacae. Appl Environ Microbiol 69 (9):5306-18.
Hoffmann, H., S. Stindl, W. Ludwig, A. Stumpf, A. Mehlen, J. Heesemann, D. Monget, K. H. Schleifer, and A. Roggenkamp. 2005. Reassignment of enterobacter dissolvens to Enterobacter cloacae as E. cloacae subspecies dissolvens comb. nov. and emended description of Enterobacter asburiae and Enterobacter kobei. Syst Appl Microbiol 28 (3):196-205.
Hoffmann, H., S. Stindl, W. Ludwig, A. Stumpf, A. Mehlen, D. Monget, D. Pierard, S. Ziesing, J. Heesemann, A. Roggenkamp, and K. H. Schleifer. 2005. Enterobacter hormaechei subsp. oharae subsp. nov., E. hormaechei subsp. hormaechei comb. nov., and E. hormaechei subsp. steigerwaltii subsp. nov., three new subspecies of clinical importance. J Clin Microbiol 43 (7):3297-303.
Jacoby, G. A., and L. S. Munoz-Price. 2005. The new beta-lactamases. N Engl J Med 352 (4):380-91.
Lautenbach, E., J. B. Patel, W. B. Bilker, P. H. Edelstein, and N. O. Fishman. 2001. Extended-spectrum beta-lactamase-producing Escherichia coli and Klebsiella pneumoniae: risk factors for infection and impact of resistance on outcomes. Clin Infect Dis 32 (8):1162-71.
Lee, C. C., W. J. Lin, H. I. Shih, C. J. Wu, P. L. Chen, H. C. Lee, N. Y. Lee, C. M. Chang, L. R. Wang, and W. C. Ko. 2007. Clinical significance of potential contaminants in blood cultures among patients in a medical center. J Microbiol Immunol Infect 40 (5):438-44.
Liappis, A. P., V. L. Kan, C. G. Rochester, and G. L. Simon. 2001. The effect of statins on mortality in patients with bacteremia. Clin Infect Dis 33 (8):1352-7.
Ma, L., F. Y. Chang, C. P. Fung, T. L. Chen, J. C. Lin, P. L. Lu, L. Y. Huang, J. C. Chang, and L. K. Siu. 2005. Variety of TEM-, SHV-, and CTX-M-type beta-lactamases present in recent clinical isolates of Escherichia coli, Klebsiella pneumoniae, and Enterobacter cloacae from Taiwan. Microb Drug Resist 11 (1):31-9.
Marcos, M., A. Inurrieta, A. Soriano, J. A. Martinez, M. Almela, F. Marco, and J. Mensa. 2008. Effect of antimicrobial therapy on mortality in 377 episodes of Enterobacter spp. bacteraemia. J Antimicrob Chemother.
Mehlen, A., M. Goeldner, S. Ried, S. Stindl, W. Ludwig, and K. H. Schleifer. 2004. Development of a fast DNA-DNA hybridization method based on melting profiles in microplates. Syst Appl Microbiol 27 (6):689-95.
National Nosocomial Infections Surveillance (NNIS) report, data summary from October 1986-April 1996, issued May 1996. A report from the National Nosocomial Infections Surveillance (NNIS) System. 1996. Am J Infect Control 24 (5):380-8.
Paauw, A., M. P. Caspers, F. H. Schuren, M. A. Leverstein-van Hall, A. Deletoile, R. C. Montijn, J. Verhoef, and A. C. Fluit. 2008. Genomic diversity within the Enterobacter cloacae complex. PLoS One 3 (8):e3018.
Pai, H., J. Y. Hong, J. H. Byeon, Y. K. Kim, and H. J. Lee. 2004. High prevalence of extended-spectrum beta-lactamase-producing strains among blood isolates of Enterobacter spp. collected in a tertiary hospital during an 8-year period and their antimicrobial susceptibility patterns. Antimicrob Agents Chemother 48 (8):3159-61.
Paterson, D. L., and R. A. Bonomo. 2005. Extended-spectrum beta-lactamases: a clinical update. Clin Microbiol Rev 18 (4):657-86.
Paterson, D. L., W. C. Ko, A. Von Gottberg, S. Mohapatra, J. M. Casellas, H. Goossens, L. Mulazimoglu, G. Trenholme, K. P. Klugman, R. A. Bonomo, L. B. Rice, M. M. Wagener, J. G. McCormack, and V. L. Yu. 2004. International prospective study of Klebsiella pneumoniae bacteremia: implications of extended-spectrum beta-lactamase production in nosocomial Infections. Ann Intern Med 140 (1):26-32.
Philippon, A., G. Arlet, and P. H. Lagrange. 1994. Origin and impact of plasmid-mediated extended-spectrum beta-lactamases. Eur J Clin Microbiol Infect Dis 13 Suppl 1:S17-29.
Pitout, J. D., M. D. Reisbig, E. C. Venter, D. L. Church, and N. D. Hanson. 2003. Modification of the double-disk test for detection of enterobacteriaceae producing extended-spectrum and AmpC beta-lactamases. J Clin Microbiol 41 (8):3933-5.
Preisig-Muller, R., G. Muster, and H. Kindl. 1994. Heat shock enhances the amount of prenylated Dnaj protein at membranes of glyoxysomes. Eur J Biochem 219 (1-2):57-63.
Rupp, M. E., and P. D. Fey. 2003. Extended spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae: considerations for diagnosis, prevention and drug treatment. Drugs 63 (4):353-65.
Sanders, W. E., Jr., and C. C. Sanders. 1997. Enterobacter spp.: pathogens poised to flourish at the turn of the century. Clin Microbiol Rev 10 (2):220-41.
Schellevis, F. G., J. van der Velden, E. van de Lisdonk, J. T. van Eijk, and C. van Weel. 1993. Comorbidity of chronic diseases in general practice. J Clin Epidemiol 46 (5):469-73.
Schlesinger, J., S. Navon-Venezia, I. Chmelnitsky, O. Hammer-Munz, A. Leavitt, H. S. Gold, M. J. Schwaber, and Y. Carmeli. 2005. Extended-spectrum beta-lactamases among Enterobacter isolates obtained in Tel Aviv, Israel. Antimicrob Agents Chemother 49 (3):1150-6.
Sturenburg, E., I. Sobottka, D. Noor, R. Laufs, and D. Mack. 2004. Evaluation of a new cefepime-clavulanate ESBL Etest to detect extended-spectrum beta-lactamases in an Enterobacteriaceae strain collection. J Antimicrob Chemother 54 (1):134-8.
Tang, Y. W., N. M. Ellis, M. K. Hopkins, D. H. Smith, D. E. Dodge, and D. H. Persing. 1998. Comparison of phenotypic and genotypic techniques for identification of unusual aerobic pathogenic gram-negative bacilli. J Clin Microbiol 36 (12):3674-9.
Wu, T. L., J. H. Chia, L. H. Su, C. Chu, A. J. Kuo, and C. H. Chiu. 2006. Dissemination of extended-spectrum beta-lactamase-producing Enterobacteriaceae in intensive care units of a medical center in Taiwan. Microb Drug Resist 12 (3):203-9.
Ye, Y., J. B. Li, D. Q. Ye, and Z. J. Jiang. 2006. Enterobacter bacteremia: Clinical features, risk factors for multiresistance and mortality in a Chinese University Hospital. Infection 34 (5):252-7.
Yu, W. L., K. C. Cheng, C. J. Chi, H. E. Chen, Y. C. Chuang, and L. T. Wu. 2006. Characterisation and molecular epidemiology of extended-spectrum beta-lactamase-producing Enterobacter cloacae isolated from a district teaching hospital in Taiwan. Clin Microbiol Infect 12 (6):579-82.
Yu, W. L., Y. C. Chuang, and J. Walther-Rasmussen. 2006. Extended-spectrum beta-lactamases in Taiwan: epidemiology, detection, treatment and infection control. J Microbiol Immunol Infect 39 (4):264-77.