PURPOSE: We have recently demonstrated that clarithromycin, at sub-MIC concentrations, attenuates the production of pneumolysin, the most important virulence factor of the pneumococcus, even in isolates with high-level macrolide resistance. We wished to determine whether clarithromycin also interfered with the growth of these microorganisms.
METHODS: We studied ermB-expressing strains of S. pneumoniae (macrolide MIC > 256 ug/ml), which were exposed to sub-MIC concentrations of clarithromycin, from the outset, or 6 hours after initiation of culture. In one representative strain, growth was also studied in the presence of catalase or CSP-1, and measurements were also made of ATP concentrations, evidence of protein synthesis, and gene expression.
RESULTS: Exposure of the test strains to sub-MIC concentrations of clarithromycin from the outset of culture resulted in transient suppression of bacterial growth for 10-12 hours. Exposure at 6 hours resulted in an abrupt halt in growth followed by recovery. Inhibition of growth was associated with a marked decrease in ATP production (72.3%) and of protein synthesis (92.3%), but was not prevented by prior inclusion of catalase or CSP-1. Inhibition of growth was overcome by prior culture of the strains in clarithromycin. A four-fold increase in ermB expression was detected within 15 minutes of exposure to the antibiotic.
CONCLUSION: Exposure of pneumococci expressing high-level macrolide resistance to clarithromycin, at sub-MIC concentrations, resulted in transient suppression of growth.
CLINICAL IMPLICATIONS: If operative in vivo, the transient inhibition of pneumococcal growth and the accompanying attenuation of pneumolysin production may explain why the addition of a macrolide to standard beta-lactam therapy is associated with improved outcome in patients with severe pneumococcal infections, even with strains expressing macrolide resistance.
DISCLOSURE: Charles Feldman, Grant monies (from industry related sources) KPK is in receipt of research funding from Bayer, Forrest and Johnson & Johnson; RA has received a research grant from Abbott Laboratories in partial support of the current study.; Consultant fee, speaker bureau, advisory committee, etc. CF has acted on an advisory board for MSD, Abbott, Janssen Cilag, Pfizer/Wyeth, and Sanofi Aventis, and acts as a speaker for Abbott, Sanofi Aventis and Winthrop, Glaxo Smith Kline, MSD, Bayer, Cipla and Sandoz, and has received assistance for congress travel from Abbott, Glaxo Smith Kline and Sanofi Aventis; RC, HS, NW, LdG, none to declare; AvG serves on advisory boards for Pfizer/Wyeth, Glaxo Smith Kline and Novartis; KPK has received in the past year consultant fees from Bayer and Pfixer/Wyeth, and acts on the advisory boards of Bayer, Pfizer/Wyeth, Merck, and Glaxo Smith Kline; ATL, DJI, TJM, none to declare.; No Product/Research Disclosure Information