Nosocomial Outbreak of Infections by Proteus mirabilis That Produces Extended-Spectrum CTX-M-2 Type β-Lactamase

Abstract

Nineteen multidrug-resistant Proteus mirabilis strains were isolated from 19 patients suffering from infections probably caused by P. mirabilis. These strains were recovered from urine or other urogenital specimens of 16 inpatients and three outpatients with a hospitalization history in a urology ward of Funabashi Medical Center, from July 2001 to August 2002. These strains demonstrated resistance to cefotaxime, ceftriaxone, cefpodoxime, and aztreonam, while they were highly susceptible to ceftazidime (MIC, <0.5 g/ml). The resistance level of these strains to cefotaxime was decreased by the presence of clavulanic acid. Therefore, the strains were speculated to produce extended-spectrum class A ␤-lactamases. These strains were later found to carry bla CTX-M-2 genes by both PCR and sequencing analyses. The profiles of SmaI-digested genomic DNA of 19 isolates were distinguished into five different clusters by biased sinusoidal field gel electrophoresis. Four of them, consisting of 18 isolates, were suggested to be a clonal expansion. These findings suggested that a nosocomial outbreak of infections by CTX-M-2-producing P. mirabilis had occurred in our medical center. Most patients suffered from urogenital malignancies with long-term catheterization. Cefazolin, cefoperazonesulbactam, and/or levofloxacin were mostly administered to the patients, but these agents seemed ineffective for eradication of CTX-M-2 producers. Early recognition and rapid identification of colonizing antimicrobialresistant bacteria, including CTX-M-2-producing P. mirabilis, would be the most effective measures to cope with further spread of this kind of hazardous microorganism in clinical environments.The increasing prevalence of plasmid-mediated extendedspectrum ␤-lactamases (ESBLs) in members of the family Enterobacteriaceae has become a serious clinical problem on a worldwide scale (8). ESBLs of Ambler's molecular class A (1) belonging to Bush's functional group 2be (10) are capable of hydrolyzing a wide range of ␤-lactams, including oxyimino-␤-lactams and monobactam, but usually remain ineffective against cephamycins such as cefoxitin, cefmetazole, and cefotetan as well as carbapenems. These class A ␤-lactamases tend to be blocked by ␤-lactamase inhibitors such as clavulanic acid (10). The majority of ESBLs are derivatives of TEM-1, TEM-2, or SHV-1 enzymes, resulting from a few amino acid substitutions (10). In contrast to these TEM-and SHV-derived ESBLs, CTX-M type ␤-lactamases, which constitute a new family of class A enzymes, are exclusively active against cefotaxime compared to other oxyimino-cephalosporins, including ceftazidime (39).More than 30 CTX-M-type ␤-lactamases have so far been described in various species of Enterobacteriaceae but mostly in Salmonella enterica serovar Typhimurium, Escherichia coli, and Klebsiella pneumoniae since the initial reports of Toho-1-producing E. coli in Japan (18) and CTX-M-1/MEN-1 in 1989 in Germany and France (2, 3). Strains producing other CTX-M enzymes have been isolated in separate geographic ...

Regional outbreak of CTX-M-2 β-lactamase-producing Proteus mirabilis in Japan

“…A diversity of ESBLs such as TEM-derived mutants was reported to be produced by P. mirabilis in Europe (Bonnet et al, 1999;Luzzaro et al, 2001;Biendo et al, 2005). CTX-M-2-, CTX-M-3-, CTX-M-13-and CTX-M-14-producing P. mirabilis has been reported in Hong Kong, Taiwan and Japan (Nagano et al, 2003;Ho et al, 2005;Wu et al, 2006). These data indicate a geographical feature of ESBL-producing P. mirabilis, with TEM types in Europe and CTX-M types in Eastern Asia.…”

“…Uniquely, the species isolated in Japan possessed the CTX-M-2 enzyme frequently and predominantly in the Enterobacteriaceae. Previous studies have reported that ESBL-producing P. mirabilis in hospitals always encoded additional b-lactamase genes (Ho et al, 2005;Wu et al, 2006), with the exception of nosocomial outbreaks by ESBL-producing clonal strains (Nagano et al, 2003;Kim et al, 2004). …”

“…Plasmid DNA was isolated from clinical isolates by the alkaline lysis method and used as a template for PCR (Birnboim & Doly, 1979). The ESBL types were determined by PCR using specific primers for bla TEM , bla SHV and bla CTX-M , using methods described elsewhere (Nagano et al, 2003). PCR experiments were also performed to detect the plasmid-encoded AmpC b-lactamases and metallo-b-lactamases according to a previously described method (Yano et al, 2001;Pérez-Pérez & Hanson, 2002).…”

“…The prevalence of ESBL-positive strains has been reported at 6.9 % in France , 7.0 % in Argentina (Quinteros et al, 2003), 8.8 % in Italy (Luzzaro et al, 2001) and 9.5 % in the US (Saurina et al, 2000). An outbreak of ESBL-producing P. mirabilis has been reported as a nosocomial infection caused by clonal spread (Nagano et al, 2003;Kim et al, 2004). However, less is known about the regional epidemiology and prevalence of intra-and interhospital spread of these organisms.…”

Extended‐Spectrum Beta‐Lactamases

“…These enzymes were likely originally derived from beta-lactamases in Kluyvera ascorbata and are interesting in that they hydrolyze cefotaxime more rapidly than ceftazidime and are more readily inhibited by tazobactam than clavulanic acid or sulbactam (4). Strains expressing CTX-M enzymes have been responsible for outbreaks in Canada, South America, Asia and Europe (5)(6)(7)(8).…”