E D I T O R I A L C O M M E N TA R Y

Extended-Spectrum b-Lactamases in Multidrug-Resistant Escherichia coli: Changing the Therapy for HospitalAcquired and Community-Acquired Infections Marion S. Helfand and Robert A. Bonomo Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Case School of Medicine, Cleveland, Ohio

(See the article by Rodrı´guez-Ban˜o et al. on pages 1407–14)

Physicians rely on clinical experience and published guidelines to assist with choices in empirical therapy for communityacquired infections. For the treatment of bacteremic urinary tract infections, therapeutic guidelines often include advancedgeneration cephalosporins or fluoroquinolones [1]. In this issue of Clinical Infectious Diseases, Rodrı´guez-Ban˜o et al. [2] report 43 prospectively observed cases of extended-spectrum b-lactamase (ESBL)–producing Escherichia coli bloodstream infection. These represented 8.8% of all cases of E. coli bacteremia detected over a 4-year period at the Hospital Universitario Virgen Macarena, a 950-bed teaching hospital in Seville, Spain. The most common ESBL detected was of the CTX-M type, which was present in 70% of the cases. Predictably, patients who had bacteremia due to ESBL-producing E. coli possessed significant comorbidities. Overall, these patients were elderly (median age, 71 years) and male (70%) and had Received 23 August 2006; accepted 23 August 2006; electronically published 25 October 2006. Reprints or correspondence: Dr. Robert A. Bonomo, Infectious Diseases Section, Louis Stokes Veterans Affairs Medical Center, 10701 East Blvd., Cleveland, OH 44106 ([email protected]). Clinical Infectious Diseases 2006; 43:1415–6  2006 by the Infectious Diseases Society of America. All rights reserved. 1058-4838/2006/4311-0006$15.00

comorbidities of malignancies (44%), obstructive diseases of the urinary tract (40%), urinary catheters (33%), and venous catheters (47%). Previous use of antimicrobials was also prevalent: 72% of patients received antibiotics before presentation, and 59% of the patients received either a fluoroquinolone or an oxyiminocephalosporin. Twenty-two cases (51%) of infection were community acquired, with urinary and biliary tracts as the sources of bacteremia. Empirical therapy was inappropriate in 49% of cases. The crude mortality rate was 24% for nosocomial bloodstream infection and 29% for health care–related bloodstream infection. Fortunately, mortality was not associated with the strictlycommunity-acquired isolates. What is the molecular basis for the ESBL phenotype? In E. coli, resistance to b-lactam antibiotics (ampicillin) is usually mediated by the presence of a b-lactamase, TEM-1. A single amino acid mutation in TEM-1 (Gly238Ser, Arg164Ser, or Glu104Lys) creates a novel phenotype not usually observed in E. coli (resistance to ceftazidime and cefotaxime). Recent isolates of E. coli have demonstrated this resistance pattern with other b-lactamases (e.g., CTX-M type). The emergence of numerous CTX-M b-lactamase–producing strains, especially among community-acquired isolates, has changed the suscep-

tibility of these organisms. CTX-M b-lactamases confer resistance to penicillins and extended-spectrum cephalosporins (i.e., MICs increase more for cefotaxime than for ceftazidime). These single–amino acid substitutions in TEM b-lactamase increase the size of the active site cavity to better accommodate the bulky side chains of ceftazidime and cefotaxime. The CTXM b-lactamases rely on specific amino acid changes located along the edge of the active site to increase the mobility of this region, thereby allowing accommodation of the bulky cephalosporins [3]. The presence of CTX-M b-lactamases in isolates that are already resistant to sulfonamide, fluoroquinolone, and aminoglycoside leads to a multidrug-resistance phenotype of great significance in inpatient and outpatient settings [4, 5]. The presence of E. coli strains expressing CTX-M b-lactamases, especially in community isolates, has been described previously (reviewed in Pitout et al. [6]). In a contemporary study, Calbo et al. [7] examined the prevalence of E. coli producing CTX-M b-lactamases in urinary tract isolates in Barcelona, Spain, during the periods January 2000–January 2001 and October 2003–December 2003. In the first period of the study, only TEM and SHV ESBLs were detected. By 2003, 24% of urinary tract E. coli ESBL producers were of

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the CTX-M type. Overall, the prevalence of ESBL-producing E. coli increased from 0.47% to 1.7% (P ! .001). The use of cefuroxime was associated with communityacquired, ESBL-producing E. coli (CAESBLs; OR, 21.4; 95% CI, 5.38–85.22). One might question whether these community-acquired, ESBL-producing E. coli carry the same clinical significance as community-acquired or -associated methicillin-resistant Staphylococcus aureus (CAMRSA) skin and soft-tissue infection [8]. In the case of CA-MRSA, surgical debridement plays an integral part in the resolution of infection [9]. Urinary tract infections are extremely prevalent and not so simple to eradicate, although prophylactic therapies to decrease stone formation, adherence of E. coli, and colonization with multidrug-resistant strains might increase in importance in this new era of high-level drug resistance [1]. CA-MRSA infection also differs in that the infection is caused mainly by a single clone (USA300) and is transmitted through skin-skin contact with colonized or infected individuals. Thus, infection-control measures can reduce transmission. In the case of multidrug-resistant E. coli, antibiotic pressure may foster the emergence of resistance. It is not clear that antibiotic-control programs will have success in the community, but they are a way to begin to address this potential emerging infectious disease threat. What antibiotics can be recommended in the meantime for the empirical treatment of E. coli urinary tract infection and bacteremia? Patients with decreased glomerular filtration rates cannot be treated with urinary tract agents, such as nitrofurantoin. Mutator phenotypes have already been described in ESBL-producing E. coli that lead to fosfomycin resistance [10]. Tigecycline resistance is likely to

emerge, because this agent has received more widespread use for intra-abdominal infections; however, in an industry-sponsored study by Morosini et al. [4] that examined the activity of this agent against ESBL-producing organisms (61% of which were CTX-M–producing E. coli), all of the isolates were susceptible. Although 8.8% of cases of E. coli bacteremia were caused by ESBL-producing organisms, Rodrı´guez-Ban˜o and colleagues remained hesitant to endorse the empirical use of carbapenems when E. coli is suspected, because of the fear of selecting for carbapenem resistance in these organisms. To date, class A b-lactamases with carbapenemase activity have been uncommon (i.e., enteric bacilli–producing KPC, Sme1, and NMC-A b-lactamases are fortunately not widespread). Nevertheless, in the short term, the emergence of greater resistance among urinary tract isolates will mean that, in areas of high prevalence, empirical outpatient or inpatient therapy will no longer suffice; greater numbers of urine cultures (with ESBL phenotype testing) will be required, as well as possible administration of broad-spectrum agents, such as carbapenems, in selected high-risk patients. Once again, this calls for morerapid diagnostic testing and the development of new antimicrobial agents [6, 11]. The presence of ESBLs in E. coli—especially in urinary tract isolates from the community—threatens to alter long-established therapeutic paradigms. Acknowledgments Financial support. Advanced Career Development Award from the Department of Veterans Affairs (M.S.H.), Merit Review Program in the Department of Veterans Affairs (R.A.B.), and the National Institutes of Health (R01AI063517-01) Potential conflicts of interest. R.A.B. has served on the speakers’ bureaus of Wyeth Pharmaceuticals and Ortho-McNeil. M.S.H.: no conflicts.

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