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.


BACKGROUND
NCT00809328.
Second Department of Internal Medicine, Nagasaki University School of Medicine, Nagasaki, Japan.
Shigeru
S
Kohno
Department of Microbiology and Infectious Diseases, Toho University Faculty of Medicine, Tokyo, Japan.
Kazuhiro
K
Tateda
Department of Internal Medicine 2, Oita University Faculty of Medicine, Oita, Japan.
Jun-ichi
J
Kadota
Department of Infectious, Respiratory, and Digestive Medicine, Faculty of Medicine, University of the Ryukyus, Okinawa, Japan.
Jiro
J
Fujita
Department of Clinical Infectious Diseases, School of Medicine, Showa University, Tokyo, Japan.
Yoshihito
Y
Niki
Research Division for Development of Anti-Infective Agents, Institute of Development, Aging and Cancer, Tohoku University, Miyagi, Japan.
Akira
A
Watanabe
Clinical Research, Development Japan, Pfizer Japan Inc., 3-22-7, Yoyogi, Shibuya-ku, Tokyo 151-8589, Japan. Electronic address: masahito.nagashima@pfizer.com.
Masahito
M
Nagashima
D061605:Administration, Intravenous; D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000900:Anti-Bacterial Agents / Q000008:administration & dosage* / Q000009:adverse effects; D017963:Azithromycin / Q000008:administration & dosage* / Q000009:adverse effects; D017714:Community-Acquired Infections / Q000175:diagnosis / Q000188:drug therapy* / Q000382:microbiology; D024881:Drug Resistance, Bacterial; D005260:Female; D006192:Haemophilus Infections / Q000175:diagnosis / Q000188:drug therapy / Q000382:microbiology; D006193:Haemophilus influenzae / Q000302:isolation & purification; D006801:Humans; D008297:Male; D008875:Middle Aged; D011018:Pneumonia, Pneumococcal / Q000175:diagnosis / Q000188:drug therapy* / Q000382:microbiology; D013296:Streptococcus pneumoniae / Q000302:isolation & purification*; D016896:Treatment Outcome; D055815:Young Adult
D000900:Anti-Bacterial Agents; D017963:Azithromycin
Community-acquired pneumonia; Intravenous azithromycin; Macrolide resistant; Pneumococcal pneumonia; Streptococcus pneumoniae