Subinhibitory concentrations of telithromycin, clarithromycin and azithromycin reduce methicillin-resistant Staphylococcus aureus coagulase in vitro and in vivo.
BACKGROUND
Subinhibitory levels of clarithromycin and azithromycin have been shown to reduce the activity of bacterial virulence factors, but few studies have examined the effects of subinhibitory levels of telithromycin. Here, we examined the effects of telithromycin, clarithromycin and azithromycin on methicillin-resistant Staphylococcus aureus (MRSA) coagulase in vitro. We also examined the effects of these antibiotics on bacterial survival in a murine model of pulmonary infection, in which the number of bacteria in the lung correlates with the coagulase titre.


METHODS
The coagulase titre in MRSA strain NUMR101, a clinical isolate, was measured after a 16 h treatment with telithromycin, clarithromycin or azithromycin at the MIC (512 mg/L) and 1/2, 1/4, 1/8 and 1/16 of the MIC. In addition, we examined the effect of these drugs in a murine model of pulmonary infection induced by the intravenous injection of S. aureus enmeshed in agar beads. Treatment was started 1 day before infection and mice were treated once a day for 7 days by oral administration of 10 or 100 mg/kg telithromycin, clarithromycin or azithromycin, and the number of viable bacteria in the lungs was counted 24 h after the injection of the bacteria.


RESULTS
The coagulase titres in mice treated with 1/8 of the MIC of telithromycin, clarithromycin and azithromycin and in the control were 8, 4, 8 and 32, respectively. In the mouse model of infection, the log cfu/lung (mean +/- SEM; n = 5 or 6) were 6.62 +/- 0.81, 4.79 +/- 0.41, 6.15 +/- 0.38 and 8.41 +/- 0.30 for mice treated with 100 mg/kg/day of telithromycin, clarithromycin and azithromycin and for controls, respectively (P < 0.05 for all groups versus control).


CONCLUSIONS
Subinhibitory concentrations of telithromycin inhibit MRSA coagulase in vitro. In addition, the in vivo results indicate that pre-treatment with telithromycin, clarithromycin or azithromycin can reduce the bacterial load in a murine model of pulmonary infection.
Yanagihara
Katsunori
K
Department of Laboratory Medicine, Nagasaki University Graduate School of Medical Sciences, Nagasaki, Japan. kyana-ngs@umin.ac.jp
Morinaga
Yoshitomo
Y
Nakamura
Shigeki
S
Seki
Masafumi
M
Izumikawa
Koichi
K
Kakeya
Hiroshi
H
Yamamoto
Yoshihiro
Y
Yamada
Yasuaki
Y
Kamihira
Shimeru
S
Kohno
Shigeru
S
D000818:Animals; D017963:Azithromycin / Q000008:administration & dosage*; D017291:Clarithromycin / Q000008:administration & dosage*; D003030:Coagulase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D048628:Ketolides / Q000008:administration & dosage*; D008297:Male; D016106:Methicillin Resistance / Q000187:drug effects* / Q000502:physiology; D051379:Mice; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000201:enzymology
D003030:Coagulase; D004791:Enzyme Inhibitors; D048628:Ketolides; D017963:Azithromycin; D017291:Clarithromycin; C106791:telithromycin