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JAC Advance Access originally published online on March 10, 2005
Journal of Antimicrobial Chemotherapy 2005 55(5):742-747; doi:10.1093/jac/dki071
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© The Author 2005. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions{at}oupjournals.org

Effect of opsonophagocytosis mediated by specific antibodies on the co-amoxiclav serum bactericidal activity against Streptococcus pneumoniae after administration of a single oral dose of pharmacokinetically enhanced 2000/125 mg co-amoxiclav to healthy volunteers

Luis Alou1, Lorenzo Aguilar1, David Sevillano1, María-José Giménez1, Beatriz Laguna1, Olatz Echeverría1, Antonio Carcas2, Rubin Lubomirov2, Julio Casal3 and José Prieto1,*

1 Microbiology Department, School of Medicine, Universidad Complutense, Avda. Complutense s/n, 28040 Madrid; 2 Clinical Pharmacology Unit, Universidad Autónoma, Arzobispo Morcillo s/n, 28029 Madrid; 3 Spanish National Reference Laboratory, Instituto de Salud Carlos III, Ctra. Majadahonda—Pozuelo, Km. 2, 28220 Majadahonda, Madrid, Spain

* Corresponding author. Tel: +34-91-3941508; Fax: +34-91-3941511; Email: jprieto{at}med.ucm.es

Objectives: To measure the effect of opsonophagocytosis mediated by complement activated by specific antibodies on the co-amoxiclav serum bactericidal activity against Streptococcus pneumoniae strains with reduced susceptibility to ß-lactams (amoxicillin MICs of 2, 4, 8 and 16 mg/L).

Methods: An open Phase I study measuring ex vivo bactericidal activity after anti-pneumococcal vaccination and an oral dose of 2000/125 mg sustained-release co-amoxiclav was carried out. The ex vivo bactericidal activity was investigated through killing curves over 3 h [assuring polymorphonuclear neutrophil (PMN) viability] with serum samples collected 1.5 h and 5 h after dosing. Global killing was measured as the area under the killing curve (AUKC; log cfu x h/mL). The AUKC of the control growth curve of S. pneumoniae in Hanks' balanced salt solution (AUKCK) was used as control. The effect of the presence of complement and/or PMN was evaluated by the difference in the AUKCK and the different AUKCs obtained in the presence of inactivated serum (AUKCIS), active serum (AUKCS), inactivated serum plus PMN (AUKCIS+PMN) and active serum plus PMN (AUKCS+PMN).

Results: Significant differences were found in all cases between the bactericidal activity of active serum+PMN (AUKCK – AUKCS+PMN) and that of inactivated serum (AUKCK – AUKCIS) with therapeutic indexes ranging from 0.56 to 3.04. At 1.5 h after dosing, a significantly higher bactericidal activity of co-amoxiclav was obtained when opsonophagocytosis occurred (samples with active serum and PMN) than when not occurring (killing curves with inactivated serum and without PMN), for all amoxicillin non-susceptible strains.

Conclusions: The results of this ex vivo study suggest that the collaboration of co-amoxiclav and complement-mediated opsonophagocytosis activated by specific antibodies may lay new approaches to overcome in vivo amoxicillin non-susceptibility.

Keywords: ß-lactams , Phase I study , polymorphonuclear neutrophils , ex vivo killing curves


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L. Alou, L. Aguilar, D. Sevillano, M.-J. Gimenez, F. Cafini, E. Valero, M.-T. Relano, and J. Prieto
Urine bactericidal activity against resistant Escherichia coli in an in vitro pharmacodynamic model simulating urine concentrations obtained after 2000/125 mg sustained-release co-amoxiclav and 400 mg norfloxacin administration
J. Antimicrob. Chemother., April 1, 2006; 57(4): 714 - 719.
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