Individual-level effects of antibiotics on colonizing otitis pathogens in the nasopharynx

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Abstract

Background

Although there is evidence of an association between antibiotic consumption and resistant bacteria on a population level, the relationship on an individual level has been less well studied, particularly in terms of nasopharyngeal colonization. We have therefore analysed this association, using data from a closely followed cohort of children taking part in a vaccination trial.

Methods

109 children with early onset of acute otitis media (AOM) were randomised to heptavalent pneumococcal conjugate vaccine (PCV7) or no vaccination. They were followed for three years with scheduled appointments as well as sick visits. Nasopharyngeal cultures were obtained at all visits. Antibiotic treatments were recorded, as were risk factors for AOM, including siblings, short breast-feeding and parental smoking. Data were entered into a Cox regression model, and the findings of Streptococcus pneumoniae and Haemophilus influenzae with reduced susceptibility to the penicillin group were related to the number of previous courses of antibiotics.

Results

There was evidence of an association between the amount of previously consumed betalactams and colonization with beta-lactamasenegative ampicillin-resistant (BLNAR) H. influenzae (RR 1.21; 95% CI 1.03–1.43; p = 0.03), and also with the most commonly prescribed drug; amoxicillin (RR 1.39; 95% CI 1.09–1.76; p = 0.01). There was no evidence for an association between antibiotic consumption and betalactamase producing H. influenzae or S. pneumoniae with reduced susceptibility to penicillin. Furthermore, there was no evidence of an association between resistant bacteria and AOM risk factors or PCV7.

Conclusion

In this subgroup of children, most of whom were given several courses of antibiotics in early childhood, there was evidence of an association between betalactam/amoxicillin consumption and nasopharyngeal colonization with BLNAR strains, bacteria that have increased in prevalence during the last 10–15 years, and that are notoriously difficult to treat with oral antibiotics.

Introduction

Antibiotics constitute a force that promotes horizontal transfer and selection of resistant mutants. Consequently, bacterial resistance to antibiotic drugs has been an increasing problem worldwide, ever since the introduction of the first classes of antibiotics [1], [2]. On a population level, there is an association between antibiotic use and high resistance rates among upper airway pathogens [1], [3], but data on the individual level are more limited. It has been suggested that a suitable way of studying individual-level effects of antibiotics on colonizing bacteria would be to measure acquisition and loss rates in a cohort where subjects are serially cultured before, during, and after antibiotic therapy [4].

Since betalactams are the first-line drugs for airway infections in most countries, any type of resistance to this group of drugs will have a clinical impact. Most important in this context are Streptococcus pneumoniae with decreased susceptibility to penicillin (PNSP), beta-lactamase-positive ampicillin-resistant Haemophilus influenzae (BLPAR Hi) and beta-lactamase-negative ampicillin-resistant H. influenzae (BLNAR Hi). PNSP is a growing problem worldwide, particularly in Asia, where 70–80% of pneumococci are PNSP [5], [6]. In Europe, the corresponding figure is 1–36%, with lower prevalences in countries with lower antibiotic consumption [7], [8]. Beta-lactamase production was the first resistance mechanism to be described for H. influenzae, and it has long been the most common, although several countries have recently described a possible decline in prevalence [9]. BLNAR strains were discovered later, and had prevalence figures below 1% in most countries for many years. However, an increase has been observed during the last two decades, most notably in Japan, where 30–60% of H. influenzae isolates have been BLNAR [10], [11]. Europe has also been affected, but to a lesser extent (2–20%) [12]. Combinations of beta-lactamase production and changes in the penicillin-binding proteins have, in addition, been described [13]. In Sweden, a country with generally low isolation frequencies of resistant bacteria [7], [14], the prevalence of BLNAR Hi remained around 3% until 2009, when it started to increase [15].

In children, acute otitis media (AOM) is the most common reason for antibiotic prescriptions [16], and 10–15% of children have recurrent AOM (rAOM) [17], [18]. We performed a vaccination trial in children with early onset of AOM – a strong risk factor for rAOM - and noted a relatively high number of cultures with resistant bacteria, particularly BLNAR Hi, among the study subjects. The aim of this study was to investigate how the presence of resistant bacteria related to antibiotic consumption in this cohort.

Section snippets

Study design

The study was performed at the Department of Otorhinolaryngology, Head and Neck Surgery, Lund University Hospital, Sweden. The study was conducted according to Good Clinical Practice and the principles of the Declaration of Helsinki (as amended in Somerset West, South Africa 1996), and was approved by the ethics committee at Lund University. Before approval, the ethics committee demanded that no placebo or alternative vaccination was carried out in the control group. Children were included in

Study population, antibiotic treatment and culture findings

A total of 109 children were included in the study at an average age of five months, 52 of whom were randomised to receive PCV7 and 57 of which were randomised to the control group. The mean number of AOM episodes prior to inclusion was 1.6 and 1.8 in the vaccine and controls groups, respectively. Four children dropped out during the study, but the rest were followed for the stipulated three years. Eighty-nine children (82%) developed rAOM, and four were diagnosed with immune deficiencies that

Discussion

The present study provides insight into the association between antibiotic consumption and the acquisition of resistant otitis pathogens on an individual level in a small group of children with repeated infections and antibiotic treatments.

The antibiotic consumption among the children in this study was very high, reflecting that most of them developed rAOM, and that several children were also prescribed prophylactic antibiotics by paediatricians. Although penicillin V is the recommended drug in

Acknowledgements

The original study was given financial support by the Swedish Association of Local Authorities and Regions and the Prevenar® vaccine was kindly supplied by Wyeth Lederle Vaccines.

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