de Azavedo and colleagues (3) reported that some newer fluoroquinolones possess activity against Canadian isolates of viridans group streptococci (VGS) that may have resistances to penicillins and macrolides. Since VGS organisms have been observed to be an important pathogen and cause of serious infections in neutropenic cancer patients (1, 2, 6), we tabulated the experience of the SENTRY Antimicrobial Surveillance Program for 1997 through 1999 in four geographic regions (74 medical centers in 33 countries) to potentially validate the experience in Canada (3). Each isolate was processed by reference broth microdilution methods (7, 8) at monitor sites in the United States (University of Iowa College of Medicine, Iowa City), The Netherlands (University of Utrecht, Utrecht), and Australia (Women's and Children's Hospital, Adelaide).
A total of 641 episodes of VGS bloodstream infections (BSI) were reported, and 637 organisms were available for antimicrobial susceptibility tests. The numbers of BSI isolates were 293 from North America (United States and Canada), 268 from Europe (14 countries), 50 from Latin America (11 countries), and 30 from the Asia-Pacific region. The isolates were identified by methods routinely used at the participant medical centers. The distribution of species was as follows: unidentified viridans group or alpha-hemolytic streptococci, 242 strains; Streptococcus mitis, 188 strains; S. oralis, 57 strains; S. sanguis, 33 strains; S. intermedius, 30 strains; S. salivarius, 28 strains; S. milleri, 25 strains; S. mutans, 19 strains; S. constellatus, 14 strains; S. uberis, 3 strains; and 1 strain each of S. canis and S. parasanguis.
Among the regions, various rates of penicillin and macrolide resistance were observed for these VGS. The lowest rate of penicillin susceptibility was detected in Europe (61.9%) followed by North America (64.5%), Asia-Pacific region (73.1%), and Latin America (76.0%). Europe also had an elevated occurrence of high-level resistance (penicillin MIC, ≥4 μg/ml): 10.4%. The highest rates of erythromycin-resistant strains were encountered in the Asia-Pacific region (42.3% resistance) followed by North America (38.9%), Europe (21.3%), and Latin America (14.0%). The overall rates of susceptibility to penicillin and erythromycin of the 637 VGS isolates were 64.7 and 63.1%, respectively. The rates in Canada (4) were 72% for penicillin and 71% for erythromycin.
The activities of six fluoroquinolones are presented in Table 1. The least potent agents were ciprofloxacin (MIC at which 90% of the isolates tested were inhibited [MIC90], >2 μg/ml) and levofloxacin (MIC90, 2 μg/ml); all other agents were at least twofold more potent against the VGS strains. Gatifloxacin, grepafloxacin, and trovafloxacin had the same MIC90 (0.5 μg/ml) and susceptibility rates of ≥96% (1 to 2% resistance). Although levofloxacin also had 97% susceptibility at the breakpoint of ≤2 μg/ml (7, 8), the three newer fluoroquinolones (gatifloxacin, grepafloxacin, and trovafloxacin) exhibited a potency advantage.
TABLE 1.
Susceptibilities of the 637 VGS isolatesa
| Fluoroquinolone (no. tested) | Cumulative % of strains inhibited at a MIC (μg/ml) of:
|
% Susceptible/resistantb | ||||||
|---|---|---|---|---|---|---|---|---|
| ≤0.06 | 0.12 | 0.25 | 0.5 | 1 | 2 | 4 | ||
| Ciprofloxacin (637) | <1 | 1 | 6 | 20 | 48 | 83 | 48/17 | |
| Levofloxacin (544) | 26 | 79 | 97 | 98 | 97/2 | |||
| Sparfloxacin (245)c | 11 | 43 | 87 | 97 | — | |||
| Gatifloxacin (637) | 3 | 18 | 63 | 95 | 97 | 98 | 99 | 97/2 |
| Grepafloxacin (300)c | 33 | 81 | 96 | 98 | — | |||
| Trovafloxacin (637) | 15 | 52 | 79 | 96 | 97 | 98 | 99 | 97/2 |
From the SENTRY Antimicrobial Surveillance Program, 1997 to 1999.
NCCLS criteria were used, where available (7, 8). The susceptibility and resistance criteria for ciprofloxacin were ≤1 and ≥4 μg/ml, respectively.
For sparfloxacin and grepafloxacin, 87 and 96%, respectively, were inhibited by ≤0.5 μg/ml), which are the breakpoints for S. pneumoniae (8).
The activities of three fluoroquinolones were analyzed in terms of the geographic sources of the VGS BSI strains. No significant difference was observed in the activity (MIC50 or MIC90) of gatifloxacin, levofloxacin, or trovafloxacin among the four regions, although the MICs for some strains from the Asia-Pacific region were lower (twofold for levofloxacin and trovafloxacin). Levofloxacin-resistant VGS strains were detected only in Europe (10 strains, for 7 of which [2.9%] the MIC was ≥8 μg) and in North America (3 strains, for 2 of which [0.9%] the MIC was ≥8 μg/ml).
VGS represent 1.3 to 1.8% of all BSI in reports from medical centers in the Americas (5). Although ranked 10th to 13th in overall occurrence among BSI isolates, these organisms produce very high morbidity and mortality in some immunocompromised patient populations (1, 2, 6). By using the Etest (AB Biodisk, Solna, Sweden) method at 10 cancer treatment centers, only 66.1% of VGS isolates were susceptible to penicillin, and newer fluoroquinolones or vancomycin appeared to have the widest spectrum of activity (6).
Several recent reports (3, 4, 6) described the potent activities of some fluoroquinolones such as clinafloxacin, gatifloxacin, grepafloxacin, levofloxacin, moxifloxacin, sparfloxacin, and trovafloxacin. Susceptibility rates for these newer agents in earlier reports were determined by using established or proposed interpretive criteria (8) and showed a spectrum against VGS ranging from 93.5% (levofloxacin) to 98.0% (clinafloxacin MIC, ≤1 μg/ml) (4, 6). The data presented here indicate that gyrase or topoisomerase mutations among VGS remain rare (1 to 3%) across a wide geographic area (SENTRY Program medical centers). Among the four newer fluoroquinolones in this report for which these streptococci showed susceptibilities of ≥96%, two compounds (levofloxacin and grepafloxacin) had MIC90 at the current susceptibility breakpoint concentration compared to lower and equal MIC90 (0.5 μg/ml) of gatifloxacin and trovafloxacin. Furthermore, the levofloxacin MIC50 (1 μg/ml) was only twofold below the applied susceptibility breakpoint (≤2 μg/ml) compared to the MIC50 of gatifloxacin and trovafloxacin (0.12 to 0.25 μg/ml), which were four- to eightfold below the concentration predictive of good clinical responses (≤1 μg/ml). The optimal therapeutic choice among these agents will also depend upon other factors such as safety, additional pharmacodynamic qualities, risk of resistant mutational events, and therapeutic cost.
Acknowledgments
We express appreciation to the SENTRY Program participants and the support provided by A. C. Fluit, J. Verhoef, J. Turnidge, J. Bell, M. Beach, K. Meyer, A. Rasmussen, and D. J. Biedenbach in the preparation of the manuscript.
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