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Susceptibility trends of haemophilus influenzae and Moraxella catarrhalis against orally administered antimicrobial agents: five-year report from the SENTRY Antimicrobial Surveillance Program

https://doi.org/10.1016/S0732-8893(03)00089-0Get rights and content

Abstract

The assessment of orally administered antimicrobial susceptibilities of common pathogens that cause community-acquired respiratory tract infections (CARTI) has become exceedingly important due to the number of office visits for this indication. Numerous local, regional and global studies have documented the susceptibilities of Haemophilus influenzae, Streptococcus pneumoniae, and Moraxella catarrhalis, the most common CARTI pathogens. SENTRY Antimicrobial Surveillance Program sites in North and Latin America, and Europe were requested to send a combined total of 100 isolates of these pathogens to the local monitor for reference broth microdilution testing (1997-2001). This study compared the susceptibility profiles of H. influenzae and M. catarrhalis isolates (13,370 strains) from the three geographic regions over a five year period. β-lactamase mediated ampicillin resistance among H. influenzae was highest among North American isolates (27.9%) compared to Latin America and Europe (16.2 to 16.3%), although it was noted that during the five year study period, ampicillin resistance was steadily increasing in the latter two regions. Cefprozil (84.3% susceptible) and clarithromycin (81.1% susceptible) were also less active against North American H. influenzae isolates. Latin American isolates were much less susceptible to trimethoprim/sulfamethoxazole (T/S; 59.3%) compared to the other regions (75.8 to 78.6%). M. catarrhalis isolates were also significantly less susceptible to T/S in Latin America (10.5% resistance). The production of β-lactamase enzymes among the M. catarrhalis isolates exceeded >95% in all three regions during the five year period. The fluoroquinolones (FQ) remained very active against these two respiratory pathogens with rare isolates with elevated FQ MIC results. It is apparent from this investigation that many commonly prescribed empiric treatments remain viable therapeutic options for CARTI caused by these two Gram-negative respiratory tract pathogens.

Introduction

The emergence of novel resistant mechanisms and the increase in resistant rates to commonly prescribed antimicrobials is a serious concern for physicians and pharmaceutical companies throughout the world. As a result of antimicrobial resistance, pharmaceutical companies must dedicate resources toward the active development of more potent and novel compounds to combat these pathogens.

The SENTRY Antimicrobial Surveillance Program was established in 1997 as a global, longitudinal investigation designed to monitor antimicrobial resistance among a variety of bacteria causing infection, and has allowed for the assessment of the in vitro activity of multiple antimicrobial agents tested against a wide range of clinically important pathogens. One objective of this surveillance program was to monitor community-acquired respiratory tract infections (CARTI) caused by the three most common bacterial pathogens (Haemophilus influenzae, Moraxella catarrhalis, Streptococcus pneumoniae) responsible for these diseases (The SENTRY Participants Group (Americas and Europe) et al 2001, Hoban et al 2001). CARTI, such as community-acquired pneumonia (CAP), acute exacerbations of chronic bronchitis (AECB), and acute bacterial sinusitis (ABS) are leading causes of primary care physician office visits. The majority of antimicrobial prescriptions are written for the treatment of these maladies (Jones, 2002b). In addition, CARTI are a major source of morbidity and mortality with pneumonia being the sixth leading cause of death overall and the primary cause of death due to infection in the United States (Bartlett et al., 2000).

Once a diagnosis of a CARTI is made, patients are routinely managed empirically with broad-spectrum oral antimicrobial agents such as macrolides, fluoroquinolones, and β-lactams (Jones, 2002b). Because H. influenzae, M. catarrhalis, and S. pneumoniae are part of the normal microbial flora of the upper respiratory tract and identification of a specific pathogen for CARTI is not routinely performed, it is imperative that any prescribed antimicrobial agent have proven activity against these bacteria, and not be adversely effected by resistant mechanisms they may possess (Hoban et al 2001, Lieberman et al 2002).

The emergence of clinical isolates expressing resistance to one or more typically used antimicrobial agents creates a significant challenge for the management of patients with CARTI (Hoban et al 2001, Jones 2002). β-lactamase production among H. influenzae and M. catarrhalis isolates has become the most commonly cited mechanism of resistance (Hoban et al., 2001). The percentage of ampicillin-resistant H. influenzae varies around the world with generally higher rates in the United States (28.5-31.5%) compared to Latin America (12.5%) and Europe (11.8-12.6%) (The SENTRY Participants Group (Americas and Europe) et al 2001, Hoban et al 2001). The vast majority of M. catarrhalis strains characteristically produce β-lactamase (>95.0%), although rare isolates resistant to tetracyclines, macrolides or trimethoprim/sulfamethoxazole have been documented, and these isolated occurrences of more rare phenotypes may go unreported during routine clinical testing (The SENTRY Participants Group (Americas and Europe) et al 2001, Dipersio et al 1998, Hoban et al 2001). Of more concern, albeit rare, are the isolated cases of H. influenzae and M. catarrhalis strains with reduced susceptibility (MICs ≥0.12 μg/ml) to fluoroquinolones, which are becoming more frequent (Biedenbach and Jones 2000, Dipersio et al 1998). Due to the widespread prevalence of some resistant phenotypes, the results of national surveillance programs can be useful for clinicians treating CARTI using empiric therapy (Pfaller and Jones, 2002).

In this study, we compared the in vitro activity of 40 antimicrobial agents (20 primarily oral agents reported here) including fluoroquinolones, β-lactams, macrolides, lincosamides, chloramphenicol, rifampin, tetracycline and trimethoprim/sulfamethoxazole. The organisms tested (13,370 clinical isolates) included H. influenzae (9,320 strains) and M. catarrhalis (4,050 strains) collected by more than 80 geographically diverse medical centers in North America, Latin America, and Europe from 1997 to 2001 as part of the SENTRY Program from patients diagnosed with CARTI. Identification of M. catarrhalis was confirmed at the monitoring site (Iowa City, IA) using colony morphology and tests for oxidase and butyrate esterase. The lack of growth on sheep blood agar and colony morphology were considered consistent with an identification for H. influenzae. Production of β-lactamase was assessed for all strains tested using the nitrocefin disk test (Remel, Lenexa, KS). All strains were tested using the National Committee for Clinical Laboratory Standards (NCCLS, 2000) recommended reference broth microdilution method (NCCLS, 2003) in validated dry-form panels (TREK Diagnostics, Cleveland, OH). Colonies from overnight cultures were suspended in 5 mL of cation-adjusted broth to a standard inoculum density (0.5 McFarland). Fifty microliters were inoculated in 10 mL of Haemophilus Test Medium (H. influenzae) or Mueller-Hinton broth (M. catarrhalis) and incubated for 16-24 h. Minimum inhibitory concentration (MIC) endpoints were determined visually and susceptibility breakpoints were those defined by the NCCLS (2003). For H. influenzae, susceptibility breakpoints as defined by the NCCLS (2003). M. catarrhalis was interpreted by H. influenzae criteria for all drugs except erythromycin where guidelines for staphylococci were applied (≤0.5 μg/ml). Quality control and colony counts were monitored using the following organisms: S. pneumoniae ATCC 49619, Staphylococcus aureus ATCC 29213, Pseudomonas aeruginosa ATCC 27853, Enterococcus faecalis ATCC 29212, H. influenzae ATCC 49247 and Escherichia coli ATCC 25922. All results were within published control limits (NCCLS, 2003).

Table 1 lists the in vitro activities of 18 selected orally administered compounds tested against 9,320 strains of H. influenzae. Ampicillin resistance rates in Europe (16.2%) and Latin America (16.3%) were similar and considerably lower than rates among North America strains (27.9%). Amoxicillin/clavulanate maintained excellent activity (≥99.7% susceptibility) including those strains that produced a β-lactamase. The activity of the second generation cephalosporins was generally similar across all regions with the exception of cefprozil (84.3% susceptible in North America compared to 94.2% in Europe and 94.9% in Latin America). Cefpodoxime (MIC90, 0.12 μg/ml) was the most potent cephalosporin tested. The activity of clarithromycin was also lower in North America (81.1% susceptible) compared to Europe and Latin America (89.6 and 91.0%, respectively). The greatest difference in antimicrobial activity between regions was observed with trimethoprim/sulfamethoxazole where only 59.3% of isolates in Latin America were susceptible compared to Europe and North America (75.8 and 78.6%, respectively). Rifampin-resistant strains were rarely isolated (0.5-1.2%) in any of the study regions. Thirteen strains of H. influenzae were isolated during the five year period which had elevated MIC values to fluoroquinolones (ciprofloxacin MIC ≥0.12 μg/ml). The majority of these strains were isolated in North America (eight) including one isolate with a MIC of >2 μg/ml (data not shown).

The antimicrobial activity of 17 orally administered agents tested against 4,050 M. catarrhalis strains is presented in Table 2. With the exception of penicillin and trimethoprim/sulfamethoxazole, all other tested agents had significant activity (≥95.0% susceptible) against the M. catarrhalis isolates. In fact, trimethoprim/sulfamethoxazole resistance (MIC ≥4/16 μg/ml) in Latin America (10.5%) was two-fold greater than those of the other regions (3.5-4.1%). Rifampin had slightly greater activity against M. catarrhalis than against H. influenzae with only Latin America reporting any resistant isolates (0.4%). Similar to H. influenzae, only 14 isolates of M. catarrhalis were noted to have elevated MICs to fluoroquinolones. Seven of these unusual strains (ciprofloxacin MIC ≥0.12 μg/ml) were isolated in North America including one strain with a MIC result of ≥2 μg/ml for ciprofloxacin, levofloxacin and gatifloxacin (data not shown).

The comprehensive results of this five year SENTRY Program study on the activity of commonly prescribed oral antimicrobial compounds against H. influenzae and M. catarrhalis isolated from patients diagnosed with CARTI shows continued activity with the notable exceptions of amino-penicillins (β-lactamase-mediated resistances), clarithromycin, cefprozil, and trimethoprim/sulfamethoxazole. Important or modest trends in resistant/susceptible rates for these antimicrobials were observed in all evaluated regions, usually more relevant among the H. influenzae.

For H. influenzae, ampicillin resistance rates over the five year study period demonstrated a modest increase in Europe (11.8 to 16.2%) and Latin America (12.5 to 16.3%). In contrast, the resistance rate in North America actually decreased (29.3 to 27.9%), although the rate in the United States was approximately 5% higher per year when compared to Canada. The activity of clarithromycin against H. influenzae decreased in all three regions during the study period, especially in North America (98.0 to 81.1% susceptible) compared to Europe (99.1 to 89.6% susceptible) and Latin America (99.0 to 89.1% susceptible). Although cefprozil activity was acceptable in Latin America (99.0-94.2% susceptible) and Europe (98.9-94.4% susceptible), lower susceptibility rates were documented in North American H. influenzae strains (90.0-84.3% susceptible). After ampicillin, trimethoprim/sulfamethoxazole was the least active of the antimicrobial agents tested against H. influenzae, where the following increases in resistance rates were observed: North America (16.6 to 21.4%), Europe (17.8 to 24.2%), and Latin America (30.8 to 40.7%; data not shown). No significant (p < 0.05) trends in M. catarrhalis susceptibility patterns were detected over the five monitored years although slight variations did occur.

The empiric management of CARTI presents one of the greatest challenges to health care providers throughout the world. CARTI has become: 1) the primary indication for physician office visits; 2) reason for the majority of antimicrobial prescriptions; 3) leading cause of death due to infection worldwide; and 4) guidelines for diagnosis and management still remain controversial (Bartlett et al 2000, Hoban et al 2001, Jones 2002, Lieberman et al 2002). Excessive use of a particular class of antimicrobial agents may lead to an increase in resistance prevalence and serious compromise of the clinical effectiveness of that agent against other species associated with CARTI (Jones, 2002a). Therefore, the need for ongoing longitudinal surveillance studies that monitor and report local, regional, national, and global trends in the antimicrobial activity for CARTI remains very important to assist physicians in therapeutic decision making (Pfaller and Jones 2002, National Committee for Clinical Laboratory Standards 2000).

Section snippets

Acknowledgements

The authors would like to thank K. Meyer, A. Mutnick, and M. Beach for their technical and editorial support in the preparation of this manuscript. This project was funded by an educational/research grant from Bristol-Myers Squibb.

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