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Antimicrobial Agents and Chemotherapy, June 2005, p. 2561-2564, Vol. 49, No. 6
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.6.2561-2564.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Decreasing Prevalence of ß-Lactamase Production among Respiratory Tract Isolates of Haemophilus influenzae in the United States

Kris P. Heilmann, Cassie L. Rice, Ashley L. Miller, Norma J. Miller, Susan E. Beekmann, Michael A. Pfaller, Sandra S. Richter, and Gary V. Doern*

Division of Medical Microbiology, Department of Pathology, Roy J. and Lucille A. Carver University of Iowa College of Medicine, Iowa City, Iowa

Received 27 December 2004/ Returned for modification 20 January 2005/ Accepted 26 February 2005


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ABSTRACT
 
A total of 986 isolates of Haemophilus influenzae from patients with respiratory tract infections in 45 United States medical centers were characterized during the winter of 2002-2003. ß-Lactamase production was noted with 26.2% of isolates; 14.6% were resistant to trimethoprim-sulfamethoxazole. Resistance to other relevant antimicrobial agents was extremely uncommon. In comparison to the results of four previous national surveys conducted since 1994, the prevalence of ß-lactamase production with this pathogen appears to be decreasing.


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TEXT
 
Haemophilus influenzae is a common respiratory tract pathogen often implicated as a cause of acute otitis media, bacterial rhinosinusitis, acute exacerbation of chronic bronchitis, and community-acquired pneumonia. Resistance to ampicillin was first described in 1974 (18). The mechanism of ampicillin resistance in H. influenzae is production of either a TEM-1 or ROB-1 beta-lactamase (10). The prevalence of beta-lactamase-mediated ampicillin resistance steadily increased during the decade of the 1980s (15), reaching levels of 35 to 40% by the mid-1990s (3, 4, 6, 14). More recent studies have raised the question, are rates of beta-lactamase production decreasing (5, 7-9, 11-13, 16, 17, 22, 24, 25)? Beta-lactamase-negative ampicillin-resistant strains (BLNAR) were first described in 1980 (19); beta-lactamase-positive amoxicillin-clavulanate-resistant strains have also been reported (5-7, 22). Both phenotypes remain rare.

Resistance to chloramphenicol and tetracycline continues to occur infrequently, while resistance rates to trimethoprim-sulfamethoxazole (TMP-SMX) has steadily risen. One study conducted in 2000-2001 reported a rate of TMP-SMX resistance of 18% (16). Fluoroquinolone resistance remains uncommon with H. influenzae. The first reported isolate was in 1993, with a ciprofloxacin MIC of 8 µg/ml (1). Using a ciprofloxacin MIC of ≥0.12 µg/ml to define reduced susceptibility, a 5-year study conducted between 1997 and 2001 found an overall rate of 0.15% reduced ciprofloxacin susceptibility among 11,355 isolates (2). Only two isolates in this study had ciprofloxacin MICs of ≥1 µg/ml.

In this investigation, we examined the prevalence of beta-lactamase production and the rates of resistance for 16 antimicrobial agents versus a large collection of respiratory tract isolates of H. influenzae (n = 986) obtained from different patients in 45 United States medical centers between 1 November 2002 and 30 April 2003. The results of this survey are compared to results obtained during four previous studies conducted since 1994. The 45 medical centers that participated in this survey are listed in the Acknowledgments section. The number of isolates submitted by each center varied between 4 and 29 (mean = 22). Only isolates judged to be of clinical significance by the referring center were included. The following patient demographic information was supplied with each isolate: age, sex, in patient versus out patient, specimen source, and date of isolation. Organisms were sent to the University of Iowa, where their identity was confirmed as H. influenzae by standard methods and stock cultures prepared using the Microbank bead system (ProLab Diagnostics, Ontario, Canada) with subsequent storage at –80°C.

MICs were determined by broth microdilution as outlined by the NCCLS using Haemophilus Test Medium (20). MIC trays were prepared in house and frozen at –80°C. The following drugs were examined: ampicillin, amoxicillin-clavulanate, cefidinir, cefpodoxime, cefprozil, cefuroxime, ceftriaxone, clarithromycin, azithromycin, ciprofloxacin, levofloxacin, moxifloxacin, TMP-SMX, chloramphenicol, tetracycline, and telithromycin. Quality control was accomplished using Haemophilus influenzae ATCC 49247 and ATCC 49766. Beta-lactamase testing was performed using the Nitrocefin disk assay (Becton Dickinson Company, Sparks, Md.). Rates of resistance were determined using NCCLS MIC interpretive criteria (21). P values were calculated by the Chi-squared method.

Among 986 isolates from 2002-2003, the overall rate of ß-lactamase production was 26.2%. When sorted according to different patient demographic factors (Table 1), highest rates were noted among isolates of H. influenzae from females, patients between the ages of 6 to 20 years old, and organisms recovered from sinus aspirates and from outpatients. The prevalence of ß-lactamase production was found to vary only slightly when examined based on geographic region of the country, with the highest rate noted in the east north central region (i.e., 37.2%) and the lowest rate in the Pacific region (i.e., 19.4%).


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  		TABLE 1. Rates of beta-lactamase production sorted according to patient demographics (2002-2003)

The in vitro activity and resistance rates obtained with 16 antimicrobial agents versus this collection of H. influenzae are presented in Table 2. Only ampicillin and TMP-SMX were problematic in terms of resistance with overall resistance rates of 26% and 14.6%, respectively. Resistance rates with other agents varied between 0 and 1.7%. With the exception of ampicillin, resistance rates obtained with ß-lactamase-negative isolates were generally similar to those obtained with ß-lactamase-positive organisms, although in the cases of cefdinir, cefprozil, cefuroxime, chloramphenicol, and tetracycline, statistically significantly larger numbers of isolates in the latter category were found to be either intermediate or resistant. Among the 728 ß-lactamase negative isolates, 3.3% were ampicillin nonsusceptible (3.2% intermediate; 0.1% resistant) (BLNAR). All of these isolates were susceptible to amoxicillin-clavulanate. Among the 258 ß-lactamase-positive strains, 0.4% were amoxicillin-clavulanate resistant (BLPACR).


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  		TABLE 2. In vitro activity of 16 antimicrobial agents for 986 clinical isolates of Haemophilus influenzae (2002-2003)

It is evident from the results of this survey, in which the in vitro activity of various antimicrobial agents was assessed versus respiratory tract isolates of H. influenzae from across the United States, that resistance continues to be a problem with ampicillin/amoxicillin and TMP-SMX. In contrast, resistance was found to be uncommon with numerous other antimicrobial agents commonly used to treat respiratory tract infections. These included the advanced generation macrolides, azithromycin and clarithromycin, amoxicillin-clavulanate, expanded spectrum generation oral cephalosporins, tetracyclines, respiratory fluoroquinolones, and the recently introduced ketolide agent, telithromycin.

Resistance rates obtained in the current study were compared to the results of four previous survey conducted since 1994 (Table 3). The same isolate inclusion criteria and test methods were used in all studies as was the period of isolate collection (i.e., November 1 to April 30). Twenty-two centers participated in all five surveys; 32 participated in four of five surveys. The proportion of isolates from patients in different age groups and genders and from different specimens was roughly comparable in all five surveys. The results of our 1994-1995 survey have been described previously in the literature (5). The results of our 1997-1998, 1999-2000, and 2000-2001 surveys are data on file.


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  		TABLE 3. Comparison of resistant rates with Haemophilus influenzae during five study periods between 1994-1995 and 2002-2003

As depicted in Table 3, there appears to have been a steady decline in prevalence of ß-lactamase production during the past decade in the United States. This downward trend was statistically significant (P value <0.05). These findings are consistent with the observations of various point prevalence surveillance studies conducted sporadically during this period (5, 7-9, 11-13, 16, 17, 22, 24, 25). Importantly, strains with either the BLNAR and BLPACR phenotypes remain uncommon.

It is possible to speculate on the cause for the apparent decreasing prevalence of ß-lactamase production with H. influenzae. During the decade of the 1990s there has been a shift away from using amoxicillin and less potent oral cephalosporins such as cefaclor, loracarbef, and cefprozil in the treatment of community-acquired respiratory tract infections toward use of amoxicillin/clavulanate, macrolides, more potent advanced generation oral cephalosporins, and fluoroquinolones. It is possible that this changing paradigm has resulted in less pressure for selection of ß-lactamase-producing strains of H. influenzae.

It is reassuring to note that, not withstanding increased use of fluoroquinolones in the treatment of community-acquired respiratory tract infections in adults in the United States, a profile that began to change in 1997 with the introduction of levofloxacin, fluoroquinolone resistance has not yet developed as a problem with H. influenzae. In our survey, no isolates were found to be resistant to ciprofloxacin, levofloxacin, or moxifloxacin. This observation is consistent with the results of at least one previously published study (23). Further, we have observed no trend towards increasing fluoroquinolone MICs during the past decade.

In the broadest sense, these observations suggest that antibiotic cycling, even in the community setting, might represent one approach to dealing with the problem of resistance. It is also reassuring that antimicrobial resistance, at least with H. influenzae, appears to be a soluble problem.


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ACKNOWLEDGMENTS
 
This study was supported by a grant from Abbott Laboratories.

The authors are grateful to Linda Elliott for excellent clerical support. In addition, we sincerely appreciate the involvement of the following individuals in the 45 medical centers that comprised this study: Marilyn Bartel, St. Francis Hospital, Tulsa, OK; Paul Bourbeau, Geisinger, Danville, PA; David Bruckner, UCLA, Los Angeles, CA; Eileen Burd, Henry Ford Hospital, Detroit, MI; Joseph M. Campos, Children's Hospital, Washington, DC; Kim Chapin, Lahey Clinic, Burlington, MA; Franklin R. Cockerill III, Mayo Clinic, Rochester, MN; Ann Croft, ARUP, Salt Lake City, UT; Paola C. De Girolami, Beth Israel Deaconess, Boston, MA; Phyllis Della-Latta, Columbia Presbyterian, New York, NY; Gerald Denys, Methodist Hospital, Indianapolis, IN; Betty Forbes, SUNY, Syracuse, NY; Thomas Fritsche, University of Washington, Seattle, WA; Peter H. Gilligan, University of North Carolina, Chapel Hill, NC; Christine C. Ginocchio, North Shore-LIJ, Lake Success, NY; Beth Grover, University of S. Alabama, Mobile, AL; Ann Hall, VAMC, Tampa, FL; Gerri Hall, Cleveland Clinic Cleveland, OH; Diane C. Halstead, Baptist Medical Center, Jacksonville, FL; Dwight J. Hardy, University of Rochester, Rochester, NY; Mary Hayden, Rush-Presbyterian, Chicago, IL; Joan Hoppe-Bauer, Washington University, St. Louis, MO; Rebecca Horvath, University of Kansas, Kansas City, KS; Paul Iannini, Danbury Hospital, Danbury, CT; Stephen Jenkins, Carolinas Medical Center, Charlotte, NC; Robert Jerris, Dekalb General, Decatur, GA; James H. Jorgenson, UT Health Center, San Antonio, TX; Susan Kehl, Children's Hospital, Milwaukee, WI; Valerie Leslie, University Medical Center, Las Vegas, NV; Rohan Nadarajah, UCSF, San Francisco, CA; Gary Overturf, University of New Mexico, Albuquerque, NM; Ellena M. Peterson, UC-Irvine, Irvine, CA; Sharon Reed, UCSD, San Diego, CA; Michael Saubolle, Good Samaritan, Phoenix, AZ; Joseph D. Schwartzman, Dartmouth-Hitchcock, Lebanon, NH; David Sewell, VA Medical Center, Portland, OR; James Snyder, University of Louisville, Louisville, KY; Paul M. Southern, Jr., University of Texas, Dallas, TX; Clarisa Suarez, Mt. Sinai, Miami Beach, FL; Richard Thomson, Jr., Evanston Hospital, Evanston, IL; Allan L. Truant, Temple, Philadelphia, PA; James Versalovic, Texas's Children, Houston, TX; Ken B. Waites, University of Birmingham, Birmingham, AL; Michael L. Wilson, Denver Health Medical Center, Denver, CO.


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FOOTNOTES
 
* Corresponding author. Mailing address: Medical Microbiology Division Department of Pathology, University of Iowa College of Medicine, Iowa City, IA 52242. Phone: (319) 356-8616. Fax: (319) 356-4916. E-mail: gary-doern{at}uiowa.edu. Back


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Antimicrobial Agents and Chemotherapy, June 2005, p. 2561-2564, Vol. 49, No. 6
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.6.2561-2564.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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