Introduction

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The worldwide increase in pneumococcal resistance to antibiotics is worrying. ^{1 2} An important contributor to antibiotic resistance is the excessive use of antibiotics in young children with respiratory symptoms.³ It is widely accepted that antibiotic resistance is related to both the extent and amount of antibiotics used. However, there are few prospective data to support these presumptions. Carriage of resistant pneumococci in childhood has been associated with younger age, attendance at daycare centres, and previous use of antibiotics.^4-6 In our two year prospective study in a community setting we studied the nasal carriage of pneumococci, their sensitivity profile, and the intake of antibiotics by preschool children in Canberra, Australia.

	Methods

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A cohort of 484 children from Canberra participated in the study from September 1997 to September 1999. General practitioners were first recruited into the study, then these doctors were asked to recruit the first 15 children who visited their practice for any reason. The parents of all participants kept a daily diary of the children's respiratory symptoms, visits to the doctor, and use of drugs, with detailed information on antibiotic use, including the name of the drug, duration of use, and the reason for taking it. Informed consent was obtained from the parents during recruitment. Nasal swabs were collected from the children up to four times over the 25 months of the study. Pneumococci were identified by colony characteristics and were tested for susceptibility to penicillin.⁷ The study period was divided into 12 periods of 60 days each. To limit misclassification of antibiotic use we considered only those children whose diary observations were complete for at least 75% of observation days. We also excluded from the main analysis swabs that were collected from children who were receiving continuous antibiotic therapy.

We defined penicillin as including penicillin V, amoxicillin, and amoxicillin clavulate. Cephalosporin refers also to cefalexin and ceclor. The term  lactam refers to either penicillin or cephalosporin.

We used two sided Fisher's exact tests for our univariate analyses and multiple logistic regression models to model the odds of carriage of a resistant organism. We accounted for correlation between repeated observations on the same child. ^{8 9} We assessed a range of covariates as possible confounders of the association between antibiotic use and carriage of a resistant organism. A potential confounder was entered into the logistic model if adjustment for the variable resulted in a distortion of the odds ratio of 10%.¹⁰

	Results

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From the four nasal swab collections 631 pneumococcal isolates from 461 children were found37%, 46%, 39%, and 46% of the swabs collected on each occasion (the higher percentages were from the swabs collected in winter). Of the 631 pneumococcal isolates, 86 (13.6%) were resistant to penicillin, and six isolates were highly resistant.

Elsewhere we have described in detail the pattern of antibiotic resistance in the isolates collected from these children.¹¹ Over half (334 (52.9%)) the isolates were resistant to at least one of the six antibiotics for which sensitivity was tested (penicillin, erythromycin, co-trimoxazole, tetracycline, chloramphenicol, and cefotaxime); 119 (18.9%) were resistant to two or more antibiotics; and 5 (0.8%) were resistant to all six.

Of the 631 pneumococcal isolates, 456 were collected from the children whose diary records of drug treatment and medical visits were at least 75% complete in the six months before collection of the swab. Of these isolates 68 (14.9%) were resistant to penicillin. These children took  lactam antibiotics for 0 to 85 days. Of the 456 isolates, 199 (43.6%) were from children with at least one day of  lactam use in the previous six months. Over three quarters of the children (355 (76.9%)) received an antibiotic at some point in the two year study period, and the overall mean period of antibiotic use per child per year was 17.6 days.

To consider the relation between antibiotic use and resistance, we used a logistic model to assess the odds of carrying a penicillin resistant pneumococcal isolate against  lactam use in each two month period before swab collection over the 24 months of the study. Age, sex, number of siblings, type of day care, duration of day care, and any hospital admission were assessed for their possible confounding effects. The use of  lactam antibiotics in the two months before swab collection was significantly associated with isolation of a penicillin resistant pneumococcus, and the relation was not confounded by the variables tested (adjusted odds ratio 2.03 (95% confidence interval 1.15 to 3.56; P=0.01)). The odds ratio adjusted for the clustering effect of multiple swabs in any one child was slightly >1 for  lactam prescriptions in the penultimate and last two month periods before swabbing (odds ratios of 1.27 and 1.25, respectively), but the 95% confidence intervals of these estimates included 1. If children had received both a penicillin and a cephalosporin preparation in the two month period before swabbing, the odds ratio of carrying a resistant organism was 4.67 (1.27 to 17.09; P=0.02).

The percentages of penicillin resistant isolates were similar in the group that had no  lactam use (12% (32/257)) and the group that had only a relatively short course of  lactam (11% (7/64)), but this percentage increased as the number of days of use increased beyond seven days, to 26% (16/61) in children who had >14 days' use (figure).

View larger version (15K): [in this window] [in a new window]   Penicillin resistance in pneumococcus isolates taken from children, and  lactam use in the six months before swab collection

Although the children who received  lactam antibiotics for >7 days in the six months before swab collection were more likely to carry a penicillin resistant pneumococcus than the children who had not received  lactam preparations in that period, this association was significant only in children who had received >14 days of  lactam (table).

We further explored the association between duration of  lactam use and penicillin resistance by using duration of use as a continuous rather than a categorical variable. Using a logistic regression model adjusted for the effect of clustering within children, we found that for each additional day of use in the six months before the swab collection, the odds of a child carrying a penicillin resistant pneumococcus increased by 4% (adjusted odds ratio 1.04 (1.01 to 1.06; P=0.001)).

	Discussion

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Our results show that the likelihood of children carrying a resistant organism is in the short term related to the amount of  lactam recently taken. Therefore if the amount of  lactam prescribed could be reduced, it follows that selection and transmission of resistant strains would occur less often.

Antibiotics are being overused in children of this age group in Australia. We found that 47% of all episodes of respiratory symptoms resulted in a visit to the general practitioner and that up to 48% of children who visited their general practitioner received an antibiotic on their first visit. Elsewhere we have examined the severity of symptoms in children who received antibiotics and those who did not receive them, and we did not find any difference between the two groups.¹¹ This accords with the growing evidence from randomised controlled trials that the benefits of antibiotics in most early childhood respiratory illnesses are trivial or non-existent. ^{12 13} The likelihood that antibiotic use will, in the short term, result in carriage of a resistant organism needs to be built into clinical decision making.

A substantial reduction of  lactam use in preschool children could quickly result in reduced carriage of penicillin resistant pneumococci. A recent randomised trial compared dosages of 90 mg/day of amoxicillin for five days and 40 mg/day for 10 days in children and found that the higher dose of shorter duration was associated with lesser subsequent carriage of resistant pneumococci.¹⁴ This supports our findings on the duration of  lactam use. If these drugs are to retain their clinical usefulness, new prescribing policies are needed in community practice.

	Acknowledgments

We acknowledge the enthusiastic support of 50 general practitioners in Canberra and the parents of the children who participated in the study, and we thank Dr Rennie D'Souza for comments on an early manuscript and Anna Wilkinson for contacting parents.

Contributors: See bmj.com

	Footnotes

Funding: The study was funded by research grants to RMD from the general practice evaluation programme of the Australian Department of Health and Aged Care and from SmithKline Beecham Pharmaceuticals to RMD.

Competing interests: None declared.

The full version of this article appears on bmj.com

	References

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(Accepted 1 October 2001)