Pharmacokinetic/pharmacodynamic evaluation of amoxicillin, amoxicillin/clavulanate and ceftriaxone in the treatment of paediatric acute otitis media in Spain

Abstract

Introduction

Acute otitis media is the most common respiratory tract infection in infancy and early childhood that is managed with antimicrobial agents. Ninety-three per cent of the cases diagnosed in Spain are treated with antibiotics, and Streptococcus pneumoniae and untypeable Haemophilus influenzae are the most frequently isolated pathogens. The aim of this work was to evaluate the usefulness of amoxicillin, amoxicillin/clavulanate and ceftriaxone for the empirical treatment of acute otitis media, looking at the pharmacokinetic variability and the antimicrobial susceptibility of paediatric strains of the two main pathogens responsible for AOM in Spain, Streptococcus pneumoniae and Haemophilus influenzae.

Methods

Free-drug plasma concentrations were simulated and the probability of target attainment at each minimum inhibitory concentration and the cumulative fraction of response (CFR) were determined. Microbiological susceptibility information was extracted from SAUCE 3 surveillance.

Results

CFR with amoxicillin varied from 83% to 96% against S. pneumoniae and from 78% to 86% against H. influenzae. CFR was always >85% with amoxicillin/clavulanate. With the 3-day ceftriaxone regimen, the probability of achieving free concentrations above MIC at 72 hours significantly increased compared to the single dose, with which CFR ranged from 70% to 84%.

Conclusions

High-dose amoxicillin (at least 80 mg/kg/day) should be the first-line therapy in uncomplicated infections, whereas amoxicillin/clavulanate (40 mg/kg/day) should be the choice when additional coverage for H. influenzae is desired. Administration of 3 daily doses of ceftriaxone increases bacteriological eradication probability when compared with one-day regimen, although additional clinical evaluations are necessary to establish the best target attainment with ceftriaxone.

Resumen

Introducción

La otitis media aguda (OMA) es la infección del tracto respiratorio más común en la infancia que es tratada con agentes antimicrobianos. El noventa y tres por ciento de los casos diagnosticados en España se tratan con antibióticos, siendo Streptococcus pneumoniae y Haemophilus influenzae no tipable los patógenos aislados más frecuentes. El objetivo de este trabajo ha sido evaluar la utilidad de amoxicilina, amoxicilina/clavulánico y ceftriaxona en el tratamiento empírico de OMA teniendo en cuenta la variabilidad farmacocinética y la sensibilidad antimicrobiana de las cepas pediátricas de los dos patógenos principales responsables de OMA en España, Streptococcus pneumoniae y Haemophilus influenzae.

Métodos

Se simularon las concentraciones de fármaco libre para cada antibiótico y se calculó la probabilidad de alcanzar el objetivo terapéutico para cada valor de concentración mínima inhibitoria (CMI) y la fracción de respuesta acumulada (CFR).

Resultados

La CFR de amoxicilina osció entre el 83% y el 96% frente a S. pneumoniae y entre el 78% y el 86% para H. influenzae. En el caso de amoxicilina/clavulánico, la CFR fue siempre >85%. Con ceftriaxona durante 3 días, la probabilidad de alcanzar concentraciones libres por encima de la CMI a las 72 horas fue significativamente superior a la probabilidad obtenida con una sola dosis, con valores de CFR que oscilaron entre el 70% y el 84%.

Conclusiones

Amoxicilina a altas dosis debería ser la primera opción para el tratamiento de infecciones no complicadas, mientras que amoxicilina/clavulánico deberá utilizarse cuando se sospecha que H. influenzae puede ser responsable de la infección. La administración de ceftriaxona durante 3 días incrementa la probabilidad de erradicar la infección repecto a la administración de una única dosis, aunque son necesarios estudios clínicos para establecer el mejor objetivo terapéutico con ceftriaxona.

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.