Original articlePharmacokinetic/pharmacodynamic evaluation of amoxicillin, amoxicillin/clavulanate and ceftriaxone in the treatment of paediatric acute otitis media in SpainEvaluacion farmacocinetica/farmacodinamica de agentes antimicrobianos para el tratamiento de la otitis media aguda en España
Introduction
Acute otitis media (AOM) is the most common respiratory tract infection in infancy and early childhood that is managed with antimicrobial agents1. Ninety-three per cent of the cases diagnosed as AOM in Spain are treated with antibiotics2, and Streptococcus pneumoniae and untypeable Haemophilus influenzae are the most frequently isolated pathogens.
It is well known that antibiotics shorten the course of AOM, but many cases remit spontaneously with no complications. Thus clinicians should avoid prescribing antibiotics routinely. Initial observation seems to be suitable for many children, if follow-up can be assured, whereas antibiotic treatment may be necessary in the very young (spontaneous resolution is lower in children younger than 2 years) or in severe or prolonged cases. When antibiotic therapy is indicated, selection of the most appropriate antibiotic should be based on the patient's risk factors, physical examination, symptoms, local resistance patterns and treatment guidelines. By using pharmacokinetic (PK) and pharmacodynamic (PD) principles, an evaluation of the usefulness of treatments with antibiotics can be made in order to predict the likelihood of a successful clinical outcome3.
In patients treated with ß-lactams, bacteriological eradication can be predicted if free drug concentrations at the site of infection are above the minimum inhibitory concentrations (ƒT>MIC) of the pathogen for a time interval that exceeds 40%-50% of the dosing interval4.
In a recent study5, we evaluated the antimicrobial treatments in children with AOM in Spain taking into account the PK/PD approach. Only ceftriaxone and high-dose amoxicillin/clavulanate provided adequate efficacy indexes against S. pneumoniae and H. influenzae. Macrolides and azithromycin were not included in the study as they should not be empirically used in Spain due to the resistance of S. pneumoniae.
In that study, neither PK nor PD variability were considered. But, in fact, all organisms display a range of susceptibilities to any given antibiotic. Besides, a distribution of serum antibiotic concentration is observed in any population receiving the same antibiotic. Thus, the main objective of this work was to evaluate the usefulness of amoxicillin, amoxicillin/clavulanate and ceftriaxone for the treatment of AOM in Spain, assessing the probability of achieving the requisite PD exposure against S. pneumoniae and H. influenzae and taking into account the PK and PD variability in a simulated paediatric population.
Section snippets
Acquisition of microbiological data
Information on the minimum inhibitory concentration (MIC) values of amoxicillin, amoxicillin/clavulanate and ceftriaxone from 373 paediatric strains of S. pneumoniae and 438 of H. influenzae was extracted from the SAUCE 3 surveillance and provided by the Medical Department of GlaxoSmithKline6, 7. The clinical isolates of S. pneumoniae and H. influenzae were obtained from community-acquired respiratory tract infections and collected between November 2001 and October 2002. Around 49% of the S.
Results
Figure 1, Figure 2 show the antimicrobial susceptibility of S. pneumoniae and H. influenzae paediatric strains to amoxicillin and amoxicillin/clavulanate, respectively. According to breakpoints recommended by CLSI for non-meningeal infections11, both were very active against S. pneumoniae with susceptibilities >90%. Amoxicillin/clavulanate was also very active against H. influenzae, with a susceptibility of 100%, but amoxicillin was less active. Among H. influenzae isolates, 15.5% were
Discussion
Considering that AOM is typically treated empirically, the treatment of choice should target the most frequently isolated pathogens. In this study PK/PD simulations were performed to evaluate different dose regimens of amoxicillin, amoxicillin/clavulanate and ceftriaxone, taking into account the antimicrobial susceptibility of paediatric strains of the two main pathogens responsible for the disorder in Spain, S. pneumoniae and H. influenzae, together with the pharmacokinetic variability in
Conflict of interest
The authors have no conflicts of interest to declare.
Acknowledgements
The authors would like to thank the Medical Department of GlaxoSmithKline for providing specific MIC distributions obtained from the SAUCE 3 surveillance.
Martín Herrero is an employee of GSK, without any other financial interests in the company.
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