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Contradiction between in vitro and clinical outcome: intravenous followed by oral azithromycin therapy demonstrated clinical efficacy in macrolide-resistant pneumococcal pneumonia.
J Infect Chemother. 2014 Mar; 20(3):199-207.JI

Abstract

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.

REGISTRATION NUMBER

NCT00809328.

Authors+Show Affiliations

Second Department of Internal Medicine, Nagasaki University School of Medicine, Nagasaki, Japan.Department of Microbiology and Infectious Diseases, Toho University Faculty of Medicine, Tokyo, Japan.Department of Internal Medicine 2, Oita University Faculty of Medicine, Oita, Japan.Department of Infectious, Respiratory, and Digestive Medicine, Faculty of Medicine, University of the Ryukyus, Okinawa, Japan.Department of Clinical Infectious Diseases, School of Medicine, Showa University, Tokyo, Japan.Research Division for Development of Anti-Infective Agents, Institute of Development, Aging and Cancer, Tohoku University, Miyagi, Japan.Clinical Research, Development Japan, Pfizer Japan Inc., 3-22-7, Yoyogi, Shibuya-ku, Tokyo 151-8589, Japan. Electronic address: masahito.nagashima@pfizer.com.

Pub Type(s)

Clinical Trial, Phase III
Journal Article
Multicenter Study
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

24477328

Citation

Kohno, Shigeru, et al. "Contradiction Between in Vitro and Clinical Outcome: Intravenous Followed By Oral Azithromycin Therapy Demonstrated Clinical Efficacy in Macrolide-resistant Pneumococcal Pneumonia." Journal of Infection and Chemotherapy : Official Journal of the Japan Society of Chemotherapy, vol. 20, no. 3, 2014, pp. 199-207.
Kohno S, Tateda K, Kadota J, et al. Contradiction between in vitro and clinical outcome: intravenous followed by oral azithromycin therapy demonstrated clinical efficacy in macrolide-resistant pneumococcal pneumonia. J Infect Chemother. 2014;20(3):199-207.
Kohno, S., Tateda, K., Kadota, J., Fujita, J., Niki, Y., Watanabe, A., & Nagashima, M. (2014). Contradiction between in vitro and clinical outcome: intravenous followed by oral azithromycin therapy demonstrated clinical efficacy in macrolide-resistant pneumococcal pneumonia. Journal of Infection and Chemotherapy : Official Journal of the Japan Society of Chemotherapy, 20(3), 199-207. https://doi.org/10.1016/j.jiac.2013.10.010
Kohno S, et al. Contradiction Between in Vitro and Clinical Outcome: Intravenous Followed By Oral Azithromycin Therapy Demonstrated Clinical Efficacy in Macrolide-resistant Pneumococcal Pneumonia. J Infect Chemother. 2014;20(3):199-207. PubMed PMID: 24477328.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Contradiction between in vitro and clinical outcome: intravenous followed by oral azithromycin therapy demonstrated clinical efficacy in macrolide-resistant pneumococcal pneumonia. AU - Kohno,Shigeru, AU - Tateda,Kazuhiro, AU - Kadota,Jun-ichi, AU - Fujita,Jiro, AU - Niki,Yoshihito, AU - Watanabe,Akira, AU - Nagashima,Masahito, Y1 - 2013/12/11/ PY - 2013/04/05/received PY - 2013/10/17/revised PY - 2013/10/22/accepted PY - 2014/1/31/entrez PY - 2014/1/31/pubmed PY - 2015/1/1/medline KW - Community-acquired pneumonia KW - Intravenous azithromycin KW - Macrolide resistant KW - Pneumococcal pneumonia KW - Streptococcus pneumoniae SP - 199 EP - 207 JF - Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy JO - J Infect Chemother VL - 20 IS - 3 N2 - UNLABELLED: 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. REGISTRATION NUMBER: NCT00809328. SN - 1437-7780 UR - https://www.unboundmedicine.com/medline/citation/24477328/Contradiction_between_in_vitro_and_clinical_outcome:_intravenous_followed_by_oral_azithromycin_therapy_demonstrated_clinical_efficacy_in_macrolide_resistant_pneumococcal_pneumonia_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S1341-321X(13)00049-4 DB - PRIME DP - Unbound Medicine ER -