a Department of Medicine, Division of Infectious Diseases, State University of New York Health Science Center, 450 Clarkson Avenue, Box 77, Brooklyn, NY 11203; b Department of Microbiology, Department of Veterans Affairs Medical Center at Brooklyn, Brooklyn, NY, USA
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Abstract |
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Introduction |
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Materials and methods |
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MICs were tested by the agar dilution method as recommended by the NCCLS.3 Antibiotic powders were obtained from their manufacturers as follows: ampicillin and gentamicin (Sigma Chemical Co., St Louis, MO, USA), ampicillinsulbactam and trovafloxacin (Pfizer, New York, USA), piperacillin and tazobactam (WyethAyerst, Philadelphia, PA, USA), cefotetan and meropenem (Zeneca, Wilmington, DE, USA), imipenem (Merck, Rahway, NJ, USA), ceftazidime (Glaxo Wellcome, Research Triangle Park, NC, USA), amikacin, cefepime, gatifloxacin (Bristol Myers Squibb, Plainsboro, NJ, USA), cefpodoxime (Pharmacia and Upjohn, Kalamazoo, MI, USA), ciprofloxacin (Bayer, West Haven, CT, USA), clavulanic acid (SmithKline Beecham, Collegeville, PA, USA). The MIC of ceftazidime was determined alone and in the presence of clavulanic acid or tazobactam, each at a fixed concentration of 4 mg/L. Isolates with cefpodoxime MICs 2 mg/L were presumed to possess an ESBL.3 ATCC isolates E. coli 25922, E. coli 35218 and Pseudomonas aeruginosa 27853 were used as controls. Pulsed field gel electrophoresis (PFGE) was performed on selected ceftazidime-resistant isolates of K. pneumoniae and E. coli using a modification of a previously described method.4
Antibiotic usage data, provided by 11 of 15 participating hospitals, were expressed as the average number of defined daily doses per 1000 patient days. When available, the actual number of units of each antibiotic dispensed during November 1997 was used. In some cases, only the average number of units purchased during the 6 months ending in November 1997 was available. The relationship between antibiotic usage and the rate of isolation of ESBL-producing K. pneumoniae at each hospital was evaluated by multiple linear regression analysis (True Epistat, Richardson, TX, USA). The average daily census and length of stay for each hospital were included as independent variables, along with the following antibiotic groups: anti-pseudomonal penicillins, ß-lactamase inhibitor combinations, cephalosporins plus aztreonam, carbapenems, quinolones and aminoglycosides.
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Results |
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A total of 409 isolates of K. pneumoniae were collected (17% of all Gram-negative bacteria). Only 62% were susceptible to ceftazidime (Table). The addition of clavulanate or tazobactam substantially increased the susceptibility to ceftazidime. Of note, six isolates from three hospitals had reduced susceptibility to both carbapenems (MIC 8>32 mg/L). Two isolates were not susceptible to any of the antibiotics tested. Overall, 44% of isolates were presumed to contain ESBLs. Although ESBL-containing isolates were obtained at all hospitals, the rate varied from 5 to 71%. Most ESBL-containing isolates remained susceptible to meropenem and cefepime; however, the MIC of cefepime for most isolates was in the 18 mg/L range (Table
). Approximately half of the ESBL-containing K. pneumoniae were susceptible to amikacin, ceftriaxone, piperacillintazobactam or quinolones. The addition of clavulanate or tazobactam decreased the MIC of ceftazidime by eight-fold or more for 56 and 50% of these isolates, respectively.
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E. coli
A total of 771 isolates of E. coli were collected (32% of all Gram-negative bacteria). The rates of resistance to ampicillin, co-trimoxazole and quinolones were 46, 23 and 5%, respectively. More than 95% were susceptible to the aminoglycosides, cephalosporins and meropenem. Fourteen of 15 hospitals submitted at least one ESBL-containing isolate (range 011.5%). Overall, the percentage of isolates presumed to contain ESBLs was 4.7%. PFGE performed on 18 of these isolates from six hospitals revealed nine unique isolates (Figure). Four of the hospitals had more than one unique isolate. One related isolate was shared by three hospitals, and related isolates were recovered more than once within two hospitals. No relationship was found between antibiotic usage and the isolation rate of ESBL-containing E. coli.
P. mirabilis
A total of 168 isolates of P. mirabilis were collected (7% of all Gram-negative bacteria). Surprisingly, 11% were resistant to the fluoroquinolones. Only 72% were susceptible to ampicillin, and 85% to gentamicin. At least 90% of isolates were susceptible to the remaining antibiotics. The MIC of ceftazidime for 16 of the 168 isolates (9.5%) was 2 mg/L. All but two of these isolates were susceptible to ampicillin sulbactam, suggesting the presence of an ESBL.
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Discussion |
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Jones et al.6 reported a ceftazidime susceptibility rate of 74% of isolates collected from hospitals throughout the USA. However, these isolates were selected by the hospitals because they were considered to be problems at their institutions.
Nearly one-third of the ESBL-containing K. pneumoniae isolates were not susceptible to cefotetan and this resistance was not abolished by the addition of clavulanate. These data suggest a high prevalence of isolates that may contain AmpC type ß-lactamases and/or outer membrane porin defects.7 The proliferation of isolates with these features is particularly worrying in view of the ability of such organisms to develop resistance to carbapenems.7 The potential for widespread proliferation of carbapenem-resistant K. pneumoniae should be a serious concern in this region.
There are few published reports of inter-hospital spread of ESBL-containing Enterobacteriaceae.8 This study provides evidence for considerable intra- and inter-hospital spread of ESBL-containing isolates in Brooklyn. Resistance plasmids can be transferred between unrelated isolates and species, and so these data may have underestimated the degree of sharing of ESBLs.
This study is the first to demonstrate an association between cephalosporin usage and ESBL-producing K. pneumoniae in multiple hospitals throughout a city. Unlike other reports, an inverse relationship between the use of the ß-lactamase inhibitor antibiotics and resistant K. pneumoniae was not demonstrated. The relatively high percentage of inhibitor-resistant isolates in this region may account for these findings. Alternatively, a reduction of cephalosporin use may be the lone factor in limiting the prevalence of ESBL-producing Enterobacteriaceae.
The city-wide ESBL-producing rate for E. coli remains fairly low at 4.7%. However, these isolates were present in all but one hospital and were shared among hospitals. These findings, along with the presence of ESBLs in up to 10% of isolates of P. mirabilis, highlight the fact that this problem is expanding and not confined to K. pneumoniae.
Multidrug-resistant ESBL-containing Enterobacteriaceae, particularly K. pneumoniae, have become endemic in Brooklyn, are spread between hospitals, and their presence is associated with cephalosporin and aztreonam usage. Control of this problem is likely to require a regional effort aimed at increasing surveillance and infection control, identification of colonized patients and coordinating antibiotic use strategies including the limitation of unnecessary antibiotic use.
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Acknowledgments |
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Notes |
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References |
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2
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Rahal, J. J., Urban, C., Horn, D., Freeman, K., Segal-Maurer, S., Maurer, J. et al. (1998). Class restriction of cephalosporin use to control total cephalosporin resistance in nosocomial Klebsiella. Journal of the American Medical Association 280, 12337.
3 . National Committee for Clinical Laboratory Standards. (1998). Performance Standards for Antimicrobial Susceptibility TestingEighth Informational Supplement. M100-S8. NCCLS, Villanova, PA.
4 . Barrett, T. J., Lior, H., Green, J. H., Khakhria, R., Wells, J. G., Bell, B. P. et al. (1994). Laboratory investigation of a multistate food-borne outbreak of Escherichia coli O157:H7 by using pulsed-field gel electrophoresis and phage typing. Journal of Clinical Microbiology 32, 30137.[Abstract]
5 . National Nosocomial Infections Surveillance. (1998). System Report, data summary from October 1986April 1998, issued June 1998. American Journal of Infection Control 26, 52233.[ISI][Medline]
6 . Jones, R. N., Pfaller, M. A., Doern, G. V., Erwin, M. E. & Hollis, R. J. (1998). Antimicrobial activity and spectrum investigation of eight broad-spectrum ß-lactam drugs: a 1997 surveillance trial in 102 medical centers in the United States. Diagnostic Microbiology and Infectious Disease 30, 21528.[ISI][Medline]
7 . Bradford, P. A., Urban, C., Mariano, N., Projan, S. J., Rahal, J. J. & Bush, K. (1997). Imipenem resistance in Klebsiella pneumoniae is associated with the combination of ACT-1, a plasmid-mediated AmpC ß-lactamase, and the loss of an outer membrane protein. Antimicrobial Agents and Chemotherapy 41, 5639.[Abstract]
8 . Monnet, D. L., Biddle, J. W., Edwards, J. R., Culver, D. H., Tolson, J. H., Martone, W. J. et al. (1997). Evidence of interhospital transmission of extended-spectrum ß-lactam-resistant Klebsiella pneumoniae in the United States, 1986 to 1993. Infection Control and Hospital Epidemiology 18, 4928.[ISI][Medline]
Received 4 August 1999; returned 22 November 1999; revised 11 January 2000; accepted 1 February 2000