92 The Korean Journal of Internal Medicine Vol. 26, No. 1, March 2011 ducing P. mirabilis isolates are usually resistant to peni- cillins and cephalosporins. Thus, ciprofloxacin resistance severely limits already restricted treatment options. Additionally, the marked increase in the incidence of ESBL-producing P. mirabilis isolates in recent years is of great concern [1,3,13]. Although carbapenems remain the most effective option for treating serious infection caused by ESBL-producing P. mirabilis, the increasing use of car- bapenems has been paralleled by the rapid emergence of carbapenem resistance in nosocomial pathogens [14,15]. What is the explanation for the coexistence of these two resistance mechanisms in Gram-negative bacilli? The relationship between ciprofloxacin resistance and ESBL production may be due to the interplay between prior heavy antibiotic use and conditions favoring patient-to- patient transfer of multidrug-resistant organisms, as described elsewhere [6,9,12]. Additionally, there are other potential explanations for the association between ciprofloxacin resistance and broad-spectrum cephalosporins resistance; these include active efflux and outer membrane protein alterations [16]. For ciprofloxacin resistance in K. pneumoniae and E. coli, transfer of the same plasmid has been suggested as a fur- ther possible explanation for the coexistence of the two resistance mechanisms [17,18]. Plasmid-mediated ciprofloxacin resistance has recently been reported in such strains [19,20]. Furthermore, a new plasmid-mediated quinolone resistance gene, qnrC, was reported in a clinical isolate of P. mirabilis [21]. However, the basis for the ciprofloxacin resistance combined with ESBL production is not yet fully understood. Further investigation of the possible mechanisms is needed. Prior therapy with fluoroquinolones is an important risk factor for ciprofloxacin resistance in Gram-negative bacilli [22,23]. In this regard, we were unable to assess possible associations between ciprofloxacin resistance and prior use of antibiotics in this study because of the small num- ber of cases. Additionally, we sought to delineate the clini- cal features of Proteus bacteremia, rather than focusing on microbiological analyses, and so did not characterize ESBL types. Thus, misclassification with regard to ESBL production may have been possible in several patients. Finally, because our study was conducted in a large ter- tiary-care hospital, the results may not necessarily be applicable to other institutions. In conclusion, our investigation of risk factors for ciprofloxacin-resistant P. mirabilis bacteremia revealed a close association between ciprofloxacin resistance and ESBL production. This association is particularly trouble- some because the therapeutic options for serious infec- tions caused by ESBL-producing P. mirabilis are severely restricted. Conflict of interest No potential conflict of interest relevant to this article was reported. Acknowledgements This study was supported by a grant of the Korea Health 21 R&D Project, Ministry of Health, Welfare & Family Affairs, Republic of Korea (Grant No. A084063). REFERENCES 1. Endimiani A, Luzzaro F, Brigante G, et al. Proteus mirabilis bloodstream infections: risk factors and treatment outcome relat- ed to the expression of extended-spectrum beta-lactamases. Antimicrob Agents Chemother 2005;49:2598-2605. 2. O'Hara CM, Brenner FW, Miller JM. Classification, identifica- tion, and clinical significance of Proteus, Providencia, and Morganella. Clin Microbiol Rev 2000;13:534-546. 3. Wu JJ, Chen HM, Ko WC, Wu HM, Tsai SH, Yan JJ. Prevalence of extended-spectrum beta-lactamases in Proteus mirabilis in a Taiwanese university hospital, 1999 to 2005: identification of a novel CTX-M enzyme (CTX-M-66). Diagn Microbiol Infect Dis 2008;60:169-175. 4. Uh Y, Hwang GY, Kwon O, Yoon KJ, Kim HY. Isolation frequen- cy of extended spectrum beta-lactamase producing Escherichia coli, Klebsiella species, and Proteus mirabilis. Korean J Clin Microbiol 2007;10:119-122. 5. Hernandez JR, Martinez-Martinez L, Pascual A, Suarez AI, Perea EJ. Trends in the susceptibilities of Proteus mirabilis isolates to quinolones. J Antimicrob Chemother 2000;45:407-408. 6. Saito R, Okugawa S, Kumita W, et al. Clinical epidemiology of ciprofloxacin-resistant Proteus mirabilis isolated from urine sam- ples of hospitalised patients. Clin Microbiol Infect 2007;13:1204- 1206. 7. Clinical and Laboratory Standards Institute. Performance Standards for Antimicrobial Susceptibility Testing: Seventeenth Informational Supplement (Document M100-S17). Wayne (PA): Clinical and Laboratory Standards Institute, 2007. 8. Friedman ND, Kaye KS, Stout JE, et al. Health care--associated bloodstream infections in adults: a reason to change the accepted