The ultimate goal of antimicrobial chemotherapy for community-acquired RTIs is to optimize the pharmacokinetic and pharmacodynamic parameters that most closely relate to clinical efficacy. For azithromycin, the ketolides, the strep-togramins, and the fluoroquinolones, the pharmacodynamic parameter that correlates best with efficacy is concentration above the MIC rather than time above the MIC. For these agents, the aim is to maximize drug concentrations to which the target pathogen is exposed and higher doses and longer dosing intervals can be used. In this case, parameters such as the AUC/MIC ratio or the maximal drug concentration (Cmax)/MIC ratio correlate most closely with clinical efficacy.
SPECTRUM OF ACTIVITY
A group of key pathogens accounts for the majority of cases of community-acquired RTIs. These include Streptococcus pneumo-niae, Haemophilus influenzae, Moraxella catarrhalis, and Streptococcus pyogenes. The atypical pathogens Chlamydia spp., Legionella spp., and Mycoplasma supp. have also gained recognition in recent years as important causes of community-acquired RTIs, particularly community-acquired pneumonia (CAP).
Telithromycin has shown a broad spectrum of activity in vitro against most usual bacterial strains isolated from upper or lower RTIs. Moreover, telithromycin has a more consistent activity than the macro-lides against the most frequent respiratory isolates such as penicillin-resistant S. pneu-moniae, M. catarrhalis, H. influenzae, and S. pyogenes (Table 1).
Comparative In Vitro Activity of Telithromycin, Macrolides, and Quinolones Against Respiratory Tract Pathogens
|Range MIC (mg/L)|
Results from in vitro studies demonstrated that telithromycin was active against 221 pneumococcal strains, including isolates with intermediate levels of resistance to penicillin and erythromycin-resistant isolates. It was also more active than other macrolides, particularly against erythromycin-resistant strains. All strains were inhibited by <0.5 mcg of telithro-
mycin. In a related study, telithromycin was active at <0.5 mcg against 99% of 584 pneumococcal strains isolated from central and eastern Europe and at <0.2 mcg against 100% of these strains, irrespective of the macrolide resistance mechanism.
Comparable results have been reported for S. pyogenes. In 599 S. pyogenes strains, telithromycin MICs were lower and percent susceptibility rates were higher than those for erythromycin canadian, azithromycin, and clarithromycin. All strains except those with ermB were telithromycin-susceptible. This is different than for S. pneumoniae, where strains with this resistance are usually susceptible to telithromycin.
Gram-Negative and Atypical Organisms
In a comparison, in vitro activity study of telithromycin and macrolides, telithromycin was more active than canadian clarithromycin and showed activity comparable to that of azi-thromycin against H. influenzae (MIC90 4 mcg/ml), whether the strains were beta-lactamase positive or negative. Also, an MIC90 of 0.06 mcg/ml was recorded with telithromycin against M. catarrhalis. Like the macrolides, telithromycin is not as active against H. influenzae as it is against S. pneu-moniae. In a related study, telithromycin showed a much better range of activity than macrolides against Neisseria meningitidis, Neisseria gonorrhoeae, saprophytic Neisseria spp. isolates, and M. catarrhalis, with macrolide MIC90s between eight- and 10-fold higher.
With respect to telithromycin’s activity against atypical organisms, in vitro studies carried out in Japan and France demonstrated the superior activity of telithromycin compared to four of five macrolides, and several quinolones against clinical isolates of human strains of Mycoplasma spp. In the Japanese study, against M. pneumoniae, telithromycin was less potent than azithromycin canadian, but was more active than the four other macrolides, and minocycline and levofloxacin. In the French study, telithromycin MICs of <0.25 mcg/ml were found for all isolates, except for M. hominis, whereas levofloxacin generic was active at concentrations of <1 mcg/ml.