Clinical and bacteriological implications of macrolide resistance in group A streptococcal pharyngitis

Jose E. Martin-Herrero*, Cesar Garcia-Rey, Rafael Dal-Ré and Lorenzo Aguilar

Medical Department, GlaxoSmithKline, Severo Ochoa 2, Parque Tecnológico de Madrid, 28760 Tres Cantos, Madrid, Spain

Keywords: macrolides, resistance, clarithromycin, penicillin, Streptococcus pyogenes

Sir,

Portier et al.1 reported a multicentre, open-label, comparative study of 5 day clarithromycin modified release (MR) versus 10 day penicillin V in the treatment of pharyngitis due to group A ß-haemolytic streptococci (GABHS), showing equivalence between both treatments.

In this study, Portier et al. provide the clinical and bacteriological results for the patients infected with clarithromycin-resistant strains, but there is no comparison with results of patients infected with susceptible strains. In fact, patients infected with a clarithromycin-resistant strain were excluded from the per protocol (PP) analysis. We have performed further analysis, using a Fisher two-sided test, to evaluate whether patients infected with a clarithromycin-resistant strain had different bacteriological and clinical results from patients infected with a clarithromycin-susceptible strain when treated with clarithromycin or penicillin V.

In the intention-to-treat analysis (ITT), in the group of patients treated with clarithromycin, clinical cure at visit three was obtained in 89.6% (146 of 163) of patients with susceptible strains, and in 71.4% (10 of 14) of patients with resistant strains [P = 0.066; odds ratio (OR) 3.4; 95% confidence interval (CI) 0.7–13.5], thus showing a better response in the former group. With respect to the bacteriological eradication at visit three (the principal criterion for efficacy analysis), the success rate was much higher in the group with susceptible strains than in the group with resistant ones [88.3% (121 of 137) versus 28.6% (4 of 14); P < 0.001; OR 18.9; 95% CI 4.6–89.4]. When the comparison between patients infected with a clarithromycin-susceptible and those infected with a clarithromycin-resistant strain was performed in the group of patients treated with penicillin V, a statistically significant difference was found for bacteriological efficacy (86.1% versus 60%; P = 0.019; OR 4.14; 95% CI 1.07–14.66) but not for clinical efficacy (P = 0.31). Nevertheless, it should be taken into account that, in the bacteriological evaluation of the patients infected with a clarithromycin-resistant strain, five of 15 patients (five of six of those considered ‘not cured’) were classified as indeterminate (a much higher proportion than in the group of patients infected with a clarithromycin-susceptible strain). If the patients with indeterminate results are excluded from the analysis, then in the group treated with clarithromycin, differences between patients with a clarithromycin-susceptible and those with a clarithromycin-resistant strain would be even larger for both bacteriological (96.8% versus 33.3%; P < 0.0001; OR 60.5; 95% CI 10.19–382.72) and clinical (95.4% versus 76.9%; P = 0.032; OR 6.26; 95% CI 1.08–32.6) efficacy; whereas in the patients treated with penicillin V, no differences would be found with respect to bacteriological (P = 1.0) and clinical efficacy (P = 1.0) between patients with a clarithromycin-susceptible strain and those with a clarithromycin-resistant strain.

In the PP analysis of the group treated with clarithromycin, clinical cure at visit three was obtained in 95.2% (120 of 126) of patients with susceptible strains, and in 71.4% (10 of 14) of patients with resistant strains (P < 0.01), with an OR of 8 (95% CI 1.38–39.76). As in the ITT analysis, the principal criterion for efficacy analysis (bacteriological eradication rate) was achieved at a much higher rate in the group with susceptible strains than in the group with resistant strains [89.6% (146 of 163) versus 28.6% (four of 14); P < 0.001] with an OR of 42.5 (95% CI 8.90–221.3). In the penicillin V group, significant differences were also found for bacteriological efficacy (92% versus 60%; P = 0.002; OR 7.70; 95% CI 1.78–30.79) but not for clinical efficacy (P = 0.1) between patients with clarithromycin-susceptible and those with clarithromycin-resistant strains. As with the ITT analysis, when patients classified as indeterminate are excluded, in the clarithromycin group for bacteriological (94.4% versus 33.3%; P < 0.0001; OR 34; 95% CI 6.72–183.75) and clinical (95.2% versus 76.9%; P < 0.038; OR 6; 95% CI 1–33.03) efficacy the differences between patients with clarithromycin-susceptible and -resistant strains persist. Nevertheless, in the penicillin V group, no differences are observed in either bacteriological (P = 0.5) or clinical efficacy (P = 1.0).

These data support the effect of macrolide resistance on bacteriological and clinical failure in GABHS pharyngitis, and indicate that failure in bacteriological eradication during clarithromycin therapy is more likely to occur in patients infected with clarithromycin-resistant GABHS. This finding may be of utmost importance in areas with a high prevalence of macrolide resistance, such as Spain.2 The difference observed in bacteriological efficacy in the penicillin V group between patients with clarithromycin-susceptible and patients with clarithromycin-resistant strains may have two explanations: (i) biologically, there is an association between macrolide resistance and cell invasiveness in GABHS (strains combining macrolide resistance and ability to enter human respiratory tract cells may be able to escape both ß-lactams, by virtue of intracellular location, and macrolides, by virtue of resistance);3 and (ii) methodologically, the proportion of patients classified as indeterminate was more unbalanced in patients with clarithromycin-resistant strains (33.3%) than in those with clarithromycin-susceptible strains (3.6% and 0.8% in the ITT and PP analysis, respectively; P < 0.001 in both cases), which could have biased negatively the bacteriological results of penicillin V.

The major contribution of this study is the demonstration that macrolide resistance is clinically relevant in GABHS pharyngitis. Further studies with a larger number of resistant cases are needed to confirm these findings.

Footnotes

* Corresponding author. Tel: +34-91-807-0803; Fax: +34-91-807-0596; E-mail: jmh29217{at}gsk.com Back

References

1 . Portier, H., Filipecki, J., Weber, P. et al. (2002). Five day clarithromycin modified release versus 10 day penicillin V for group A streptococcal pharyngitis: a multi-centre, open-label, randomized study. Journal of Antimicrobial Chemotherapy 49, 337–44.[Abstract/Free Full Text]

2 . Pérez-Trallero, E., Fernández-Mazarrasa, C., García-Rey, C. et al. (2001). Antimicrobial susceptibilities of 1,684 Streptococcus pneumoniae and 2,039 Streptococcus pyogenes isolates and their ecological relationships: Results of a 1-year (1998–1999) multicenter surveillance study in Spain. Antimicrobial Agents and Chemotherapy 45, 3334–40.[Abstract/Free Full Text]

3 . Facinelli, B., Spinaci, C., Magi, G. et al. (2001). Association between erythromycin resistance and ability to enter human respiratory cells in group A streptococci. Lancet 358, 30–3.[CrossRef][ISI][Medline]





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