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Journal of Clinical Microbiology, October 2006, p. 3775-3777, Vol. 44, No. 10
0095-1137/06/$08.00+0     doi:10.1128/JCM.00456-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Contemporary Prevalence of BRO ß-Lactamases in Moraxella catarrhalis: Report from the SENTRY Antimicrobial Surveillance Program (North America, 1997 to 2004)

Lalitagauri M. Deshpande,1* Helio S. Sader,1 Thomas R. Fritsche,1 and Ronald N. Jones1,2

JMI Laboratories, North Liberty, Iowa,1 Tufts University School of Medicine, Boston, Massachusetts2

Received 2 March 2006/ Returned for modification 19 April 2006/ Accepted 22 July 2006


   ABSTRACT
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A total of 7,860 community-acquired Moraxella catarrhalis isolates (SENTRY Antimicrobial Surveillance Program, 1997 to 2004) were tested by broth microdilution methods, and 399 randomly selected strains from North American sites were tested for BRO-1 and BRO-2 by PCR methods. Several antimicrobials remained very active, including amoxicillin-clavulanate (MIC90s, ≤0.25 µg/ml), azithromycin (MIC90s, ≤0.12 µg/ml), ceftriaxone (MIC90s, 0.5 µg/ml), and levofloxacin (MIC90s, ≤0.03 to 0.06 µg/ml). The BRO-2 incidence rates by year were 3 to 4% overall (96 to 97% for BRO-1) and were the highest in Canada (7.9%), with the incidence in the United States being only 2.0%.


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Moraxella catarrhalis, a common inhabitant of the upper respiratory tract, has historically been considered a relatively harmless commensal. Over time, however, this gram-negative coccobacillus has become recognized as the third most common upper respiratory tract pathogen in children and in adults with chronic obstructive pulmonary disease (3, 7, 14, 16). Nasopharyngeal carriage of M. catarrhalis is therefore a risk factor for serious respiratory tract infections and otitis media among children (10).

Although M. catarrhalis is susceptible to a number of antimicrobial agents (7, 9), greater than 90% of M. catarrhalis isolates are resistant to penicillin by means of BRO-1 or BRO-2 ß-lactamase production. The sequence and the genetic context of BRO genes suggest that BRO-2 was acquired by interspecies gene transfer, possibly from a gram-positive organism (1, 2), and that BRO-1 evolved from BRO-2 and spread by horizontal transfer via subsequent transformational events. Isolates carrying BRO-1 are usually more resistant to ampicillin than those carrying BRO-2 and have become more widespread and predominant (1). BRO-2 has been reported among M. catarrhalis isolates at rates less than 15% in the 1980s (8, 11), 4.8% from 1984 to 1994 (11, 15, 16), 2.1% from 1994 to 1995, and 3.1% in 1997 and 1998 (13). Although the rate of ß-lactamase-mediated penicillin resistance in M. catarrhalis has been generally stable at >95% (9), the differential prevalence of the BRO-1 and the BRO-2 enzymes has not been determined in North America since 1998.

Community-acquired M. catarrhalis isolates (SENTRY Antimicrobial Surveillance Program, 1997 to 2004) were tested in Mueller-Hinton broth by the microdilution methods of the Clinical and Laboratory Standards Institute (CLSI; formerly the National Committee for Clinical Laboratory Standards) (4), including 7,860 strains collected worldwide and 3,671 strains collected from North America. Species identification was confirmed by standard biochemical tests, including the oxidase and butyrate disk tests (Remel, Lenexa, Kans.). ß-Lactamase production was confirmed by the nitrocefin disk test (Remel). The isolates and appropriate quality control strains were tested for their susceptibilities to numerous antimicrobial agents by using validated panels manufactured by TREK Diagnostics (Cleveland, Ohio). Interpretations of the results of tests for susceptibility to all antimicrobials were made according to the CLSI (2006) criteria for Haemophilus influenzae (6) for comparison purposes only, since no categorical interpretive guidelines have been published for M. catarrhalis.

Approximately 100 ß-lactamase-positive M. catarrhalis-infected samples from the United States (39 sites) and Canada (7 sites) were randomly selected for each of the years 1997, 1999, 2001, and 2003. Equal representation was achieved across all participant sites, with random sampling also used within each institutional collection. Simultaneously, disk diffusion tests were performed with penicillin, ceftriaxone, and methicillin disks (Remel) by the CSLI methods (5). BRO-1 and BRO-2 were detected by PCR methods by using the primers and the interpretations described by Levy and Walker (11). All BRO-2-positive strains and seven other isolates from different medical centers producing BRO-1 (controls) were typed by automated riboprinting (EcoRI) and by pulsed-field gel electrophoresis (PFGE) protocols to assess clonal relationships.

The MIC90s and percent susceptibilities for M. catarrhalis isolates from the worldwide collection, the North American subset, and the randomly selected yearly isolate sample (100 strains from each of 4 years) used for the PCR studies are shown in Table 1. The North American subset chosen for PCR testing was representative of the worldwide collection in terms of the rates of susceptibility to key antimicrobials. Several agents remained very potent against M. catarrhalis: amoxicillin-clavulanate (MIC90s, ≤0.25 µg/ml), azithromycin (MIC90s, ≤0.12 µg/ml), ceftriaxone (MIC90s, 0.25 to 0.5 µg/ml), cefuroxime (MIC90s, 2 µg/ml), levofloxacin (MIC90s, ≤0.03 to 0.06 µg/ml), tetracycline (MIC90s, ≤2 µg/ml), and trimethoprim-sulfamethoxazole (MIC90s, ≤0.5/9.5 µg/ml).


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  		TABLE 1. Results of testing for susceptibility to selected antimicrobial agents for nearly 8,000 M. catarrhalis isolates

 
The BRO-2 occurrence rates were only 4, 4, 3, and 3% for 1997, 1999, 2001, and 2003, respectively. Overall, the rate among Canadian isolates (8/101 isolates; 7.9%) was markedly higher than that observed among U.S. isolates (6/298; 2.0%). Two BRO-2-producing isolates were recovered from sites in Manitoba, Nova Scotia, Ontario, Ohio, and Massachusetts (Table 2). The identical PFGE pattern (pattern E; Table 2) was observed in all strains from the Nova Scotia and Ontario sites.


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  		TABLE 2. Geographic distribution of BRO-2-producing M. catarrhalis isolates

 
BRO-2-producing isolates are considered more susceptible to ß-lactam antimicrobial agents than BRO-1 producers (13). Differences among the penicillin and ampicillin MIC distributions were observed for the two enzyme types (Table 3). Disk diffusion testing was also used to complement the MIC data in an attempt to discriminate between enzyme types. The penicillin MIC distribution was trimodal (≤0.03, 1 to 2, and >4 µg/ml) and the ceftriaxone MIC distribution was bimodal (0.016 and 0.5 µg/ml), but the MICs and the zone diameter distributions of the BRO-1 and the BRO-2 strains overlapped significantly. They were best discriminated by the methicillin disk (mean zone diameters for BRO-1 and BRO-2, 10.6 and 19.4 mm, respectively) and penicillin disk (mean zone diameters for BRO-1 and BRO-2, 13.9 and 24.1 mm, respectively), but no breakpoint zone diameter could accurately discriminate between the two enzyme types (data not shown; MICs are provided in Table 3).


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  		TABLE 3. Distribution of penicillin and ampicillin MICs among BRO-1- and BRO-2-producing M. catarrhalis isolates

 
Ribotyping, a common epidemiologic tool, gave an acceptable banding pattern (seven to eight bands) for M. catarrhalis isolates but did not discriminate between the isolates. All the M. catarrhalis isolates tested (14 BRO-2 producers and 7 BRO-1 producers) belonged to the same ribogroup (ribogroup 105.572.8). In contrast, PFGE revealed seven different types and eight subtypes among the 21 isolates tested. The BRO-2-producing strains could be divided into five types and two subtypes, with two potential BRO-2 epidemiologic clusters easily identified from Canada (Nova Scotia and Ontario; Table 2). Four PFGE patterns showed subtypes that were distributed among BRO-1- and BRO-2-producing isolates in the same medical centers.

This prevalence update for BRO-1 and BRO-2 enzymes in M. catarrhalis isolates (1997 to 2004) indicated stability at rates of 96 to 97% and 3 to 4%, respectively, in North America. The prevalence of BRO-2 among Canadian isolates showed a clear difference compared to that among the U.S. isolate pool. In our hands, phenotypic tests (which provided zone diameters or MICs) could not distinguish between these ß-lactamase types, necessitating the use of molecular applications (11). Also, automated ribotyping failed to demonstrate its usefulness as an epidemiologic test for M. catarrhalis. PFGE was very effective in discriminating between isolates, as has been observed in an earlier study (12). Clonal spread among community-acquired isolates producing BRO-1 and BRO-2 was evident, even from this small sample of North American M. catarrhalis strains.


   FOOTNOTES
 
* Corresponding author. Mailing address: JMI Laboratories, 345 Beaver Kreek Centre, Suite A, North Liberty, IA 52317. Phone: (319) 665-3370. Fax: (319) 665-3371. E-mail: gauri-deshpande{at}jmilabs.com. Back


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Journal of Clinical Microbiology, October 2006, p. 3775-3777, Vol. 44, No. 10
0095-1137/06/$08.00+0     doi:10.1128/JCM.00456-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.




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