Contradiction between in vitro and clinical outcome: Intravenous followed by oral azithromycin therapy demonstrated clinical efficacy in macrolide-resistant pneumococcal pneumonia

We conducted a multicenter, unblinded, non-comparative, phase 3 trial of azithromycin-intravenous therapy followed by oral administration in Japanese adults to evaluate clinical efficacy and safety against community-acquired pneumonia in order to obtain regulatory approval for the intravenous formulation in Japan. Azithromycin (500 mg, once daily) was intravenously administered for 2-5 days followed by oral 500 mg once daily administration to complete a total of 7-10 days treatment in 102 adults with moderate-to-severe community-acquired pneumonia. The efficacy rate in the Clinical Per Protocol Set overall was 84.5% (60/71 subjects) on Day 15 (primary analysis). The most common causative pathogen was Haemophilus influenzae (17 strains), followed by Streptococcus pneumoniae (14 strains), Moraxella catarrhalis (5 strains) and Mycoplasma pneumoniae (5 strains). Eleven of 14 S. pneumoniae isolates were resistant to azithromycin (MIC ≥2.0 μg/ml), of which 5 strains with a relatively low MIC of <32 μg/ml had only mef A gene and 6 strains with a high MIC of >64 μg/ml had only the erm B gene except for 2 isolates having both the mef A and erm B genes. Despite dominance of macrolide-resistant strains in Japan, clinical efficacy and bacterial eradication were achieved in 10 of 11 patients (90.9%). Intravenous-to-oral azithromycin therapy demonstrated excellent clinical and bacteriological effects on moderate-to-severe pneumococcal pneumonia despite a high MIC and resistance gene development. This discrepancy is referred to as the "in vivo-in vitro paradox". The current study results provide an insight into this paradox.