Summary: In contemporary ambulatory practice, clarithromycin and azithromycin, which have a similar antibacterial spectrum in vitro, are used interchangeably in cases of immediate allergy to beta-lactams . Given previous clinical investigations on pathogen eradication, there are evident differences between the two antibiotics; clarithromycin (provided macrolide sensitivity) is efficient in the eradication of Streptococcus pyogenes in cases of streptococcal tonsillitis. Streptococcus pneumoniae is efficiently eradicated with clarithromycin in cases of acute otitis media. Unfortunately, available clinical research has revealed that azithromycin is not an efficient eradicator of these pathogens of bacterial upper respiratory tract infections. Azithromycin is a useful and convenient component in combined (with beta-lactam) empiric treatment of community-acquired pneumonia in both children and adults. Such a combination covers both typical (e.g. streptococcus pneumoniae) and atypical pathogens of community-acquired pneumonia. The anti-inflammatory properties of azithromycin are additional benefits of such a combination. Proper use of each of these antibiotics should protect against the development of antibiotic resistance.