Efficacy of clarithromycin against experimentally induced pneumonia caused by clarithromycin-resistant Haemophilus influenzae in mice.
Clarithromycin is a 14-member lactone ring macrolide with potent activity against Haemophilus influenzae, including ampicillin-resistant strains. We evaluated the in vivo efficacy of clarithromycin at 40 mg/day and 100 mg/day for 3 days in the treatment of a murine model of pneumonia using a macrolide-resistant H. influenzae strain, which was also ampicillin resistant. The MIC of clarithromycin was 64 microg/ml. The viable bacterial counts in infected tissues after treatment with 100 mg clarithromycin/kg of body weight were lower than the counts obtained in control and 40-mg/kg clarithromycin-treated mice. The concentrations of macrophage inflammatory protein 2 (MIP-2) and interleukin 1beta (IL-1beta) in bronchoalveolar lavage fluid (BALF) samples from mice treated at both concentrations were lower than in the control group. Pathologically, following infection, clarithromycin-treated mice, particularly at a dose of 100 mg/kg, showed lower numbers of neutrophils in alveolar walls, and inflammatory changes had apparently improved, whereas large aggregates of inflammatory cells were observed within the alveoli of control mice. In addition, we demonstrated that clarithromycin has bacteriological effects against intracellular bacteria at levels below the MIC. Our results indicate that clarithromycin may be useful in vivo for macrolide-resistant H. influenzae, and this phenomenon may be related to the good penetration of clarithromycin into bronchoepithelial cells. We also believe that conventional drug susceptibility tests may not reflect the in vivo effects of clarithromycin.
Nakamura
Shigeki
S
Second Department of Internal Medicine, Nagasaki University Hospital, and Department of Molecular Microbiology and Immunology, Nagasaki University Graduate School of Biomedical Science, Nagasaki, Japan.
Yanagihara
Katsunori
K
Araki
Nobuko
N
Yamada
Koichi
K
Morinaga
Yoshitomo
Y
Izumikawa
Koichi
K
Seki
Masafumi
M
Kakeya
Hiroshi
H
Yamamoto
Yoshihiro
Y
Kamihira
Shimeru
S
Kohno
Shigeru
S
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D055745:Bronchioles / Q000187:drug effects / Q000276:immunology; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D045744:Cell Line, Tumor; D054426:Chemokine CXCL2 / Q000378:metabolism; D017291:Clarithromycin / Q000494:pharmacology* / Q000627:therapeutic use*; D004195:Disease Models, Animal; D024881:Drug Resistance, Bacterial / Q000235:genetics / Q000502:physiology; D004797:Enzyme-Linked Immunosorbent Assay; D006192:Haemophilus Infections / Q000188:drug therapy* / Q000276:immunology / Q000382:microbiology; D006193:Haemophilus influenzae / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D053583:Interleukin-1beta / Q000378:metabolism; D008297:Male; D051379:Mice; D008826:Microbial Sensitivity Tests; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology; D011014:Pneumonia / Q000188:drug therapy* / Q000276:immunology / Q000382:microbiology; D011650:Pulmonary Alveoli / Q000187:drug effects / Q000276:immunology
D000900:Anti-Bacterial Agents; D054426:Chemokine CXCL2; D053583:Interleukin-1beta; D017291:Clarithromycin