There are two issues that have come to light in regard to using newer macrolides in these infections. First, there is clear resistance to erythromycin, azithromycin and clarithromycin among S. pneumoniae, H. influenzae and M. catarrhalis. Using pharmacokinetic/pharmacodynamic breakpoints it has been demonstrated that a third of S. pneumoniae are resistant to macrolides (3). Even more noteworthy is the fact that macrolides have no place in treating H. influenzae, particularly in patients with diseased mucosa, such as cigarette smokers. It is also worthwhile noting that only two classes of agents demonstrate consistent activity against all three pathogens; amoxicillin-clavulanic acid, particularly at high doses, and respiratory fluoroquinolones (levofloxacin, moxifloxacin and gatifloxacin).

Another important point to note is the high degree of cross-resistance between penicillin and macrolides (8). Thus, two thirds of fully penicillin-resistant S. pneumoniae (PRSP) are also resistant to macrolides (MRSP). While cross-resistance is common among the traditional classes of agents, this is not the case with fluoroquinolones, which maintain their efficacy against these multiply resistant pathogens.