Individual use of antibiotics and prevalence of ß-lactamase production among bacterial pathogens from middle ear fluid

Nana Thranea,b,*, Charlotte Olesena, Henrik T. Sørensenc,d and Henrik C. Schønheyderc,e

a The Danish Epidemiology Science Centre, Department of Epidemiology and Social Medicine, University of Aarhus, Aarhus C; b The Medical Research Unit, Ringkjøbing County; c The Clinical Epidemiological Research Unit, Aalborg Hospital, Aalborg; d The Department of Medicine V, Aarhus University Hospital, Aarhus C; e The Department of Clinical Microbiology, Aalborg Hospital, Aalborg, Denmark


    Abstract
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Prescription data and clinical laboratory data were analysed to assess the influence of previous antibiotic therapy on the prevalence of ß-lactamase in isolates of Haemophilus influenzae and Moraxella catarrhalis from primary specimens of middle ear fluid from 2129 children aged 0–5 years. The prevalence of ß-lactamase-positive H. influenzae was 6.6% [95% confidence interval (CI): 3.5–9.8%] in children who received antibiotics 5–90 days before isolation of the organism compared with 7.0% (95% CI: 3.9–10.2%) in those who did not. The prevalence of ß-lactamase-positive M. catarrhalis was 90.9% (95% CI: 84.0–97.8%) in children who received antibiotics compared with 86.7% (95% CI: 79.0–94.4%) in those who did not.


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Otitis media is the major reason for prescribing antibiotics for pre-school children.1 It is important to know to what extent previous antibiotic therapy is associated with antibiotic resistance in children. Antibiotic susceptibility is a predictor of clinical outcome in patients with otitis media because of the correlation between resistance in vitro and clinical failure.2

We analysed clinical microbiology laboratory data and prescription data to assess the association between the prevalence of resistance in Haemophilus influenzae and Moraxella (Branhamella) catarrhalis isolates from primary specimens of middle ear fluid and previous (0–90 days) antibiotic therapy, and more specifically the resistance prevalence according to the type of antibiotic prescribed.


    Materials and methods
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
We identified all middle ear specimens obtained by tympanocentesis or spontaneous perforation in 0- to 5-year-old children in the County of Northern Jutland, Denmark, from 1 April 1997 to 31 March 1999. Only the first specimen from each child was included to augment similarity of the clinical courses of the patients. We also excluded all children who had had samples taken in the previous 2 years.

The Department of Clinical Microbiology at Aalborg Hospital provides diagnostic bacteriological data to all physicians in the county. Susceptibility testing was carried out by tablet diffusion (Neo-Sensitabs, Rosco, Taastrup, Denmark), on chocolate agar for H. influenzae and on Danish horse blood agar (Statens Serum Institut, Copenhagen, Denmark) for M. catarrhalis. Resistant isolates were tested for ß-lactamase production (Cefinase, BBL, Becton-Dickinson, USA). Few (n = 4) ß-lactamase-negative isolates of H. influenzae showed a reduced susceptibility to ampicillin (MIC >= 2 mg/L) and to cefuroxime (MIC between 4 and 12 mg/L), and we included these among the ß-lactamase-positive isolates. A 1 µg oxacillin disc was employed to screen for the presence of penicillin resistance in Streptococcus pneumoniae, and this was confirmed by penicillin Etest (Biodisk, Solna, Sweden). Microbiological data were retrieved from the laboratory information system (ADBakt, Autonik, Sweden), which recorded the date of plate inoculation but not the date of sampling.

The National Health Service records identified all prescriptions of systemic antibiotics [anatomical therapeutic chemical (ATC) code J01] that were purchased on prescription only from 1 January 1997 to 31 March 1999. Record linkage was accomplished using the personal identification number, which is allocated to all citizens at birth.

We examined the prevalence of ß-lactamase in isolates of H. influenzae and M. catarrhalis stratified into gender and age groups (0–1, 2–3, 4–5 years). Prevalence was analysed in relation to antibiotic treatment 0–4, 5–14, 5–30 and 5–90 days before sampling. The time window 0–4 days reflects a period where we could not be sure that the prescription was redeemed before sampling. We compared ß-lactamase prevalence in children who received only broad-spectrum penicillins (amoxycillin/pivampicillin/ampicillin/amoxycillin with clavulanic acid/pivmecillinam) with children who received only penicillin V.

We calculated the prevalence odds ratios (ORs) to estimate the association between prescription of antibiotics and antimicrobial resistance. ORs were adjusted for age and gender by logistic regression analyses using SPSS 9.0.


    Results
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
We analysed specimens from 2129 children, of whom 58.0% were boys. The age groups were represented as follows: 0–1 years, 69.1%; 2–3 years, 19.8%; and 4–5 years, 11.1%. H. influenzae was found in 725 (34.1%), S. pneumoniae in 446 (20.9%), M. catarrhalis in 201 (9.4%) and Streptococcus pyogenes in 188 (8.8%) of cultures. Mixed cultures were obtained from 82/2129 (3.8%) of children who had both H. influenzae and M. catarrhalis in their samples. We found no difference in the distribution of pathogens in children who did or did not receive antibiotics before isolation of the organism.

The overall prevalence of ß-lactamase was 6.8% for H. influenzae and 91.0% for M. catarrhalis isolates (Table IGo). Resistance to penicillin was found in 1.1% (n = 5) of the S. pneumoniae isolates.


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Table I. Age and gender distribution of patients yielding isolates of H. influenzae andM. catarrhalis
 
A total of 2334 prescriptions for systemic antibiotics were dispensed for 64.4% of the 2129 children during the period before samples were taken. We found no difference in ß-lactamase prevalence in isolates from children who received antibiotics 0–4 or 5–90 days before isolation of the organism and those from children who had not received previous antibiotic therapy (Table IIGo). However, restricted analyses showed that ß-lactamase prevalence in H. influenzae isolated from children who redeemed a prescription 5–14 days before isolation of the infecting organism was 10.2% (95% CI: 4.2–16.2%) (n = 98) and 9.3% (95% CI: 5.3–13.3%) in children who received prescriptions 5–30 days before isolation of the organism (n = 204) (data not shown).


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Table II. Resistance of H. influenzae and M. catarrhalis isolates in relation to antibiotic treatment in the 0–90 days preceding isolation from middle ear fluid in children aged 0–5 years
 
Overall, 89.1% of all prescribed antibiotics were penicillins (broad-spectrum 59.4% and penicillin V 29.7%). Table IIGo illustrates the resistance prevalence in relation to the type of antibiotic prescribed.


    Discussion
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
No strong association was found between overall use of antibiotics and antimicrobial resistance in middle ear pathogens, irrespective of whether their ß-lactamase prevalence was high or low.

Registries based on information collected at a centralized administration point are inexpensive and valid data sources. The strengths of our study are: (i) the linkage between routine clinical data and administrative prescription data; (ii) the use of individual patient data; and (iii) the absence of recall bias with regard to exposure to antibiotics. The weaknesses include the following. (i) Lack of clinical details. Restriction to first samples did not ensure that the patients did not differ with respect to clinical course. Bias may have been introduced by differences in clinical practice between physicians (confounding by indication). A high resistance prevalence in the period just before isolation of the organism could reflect pre-treatment resistance if a sample was taken because there was no clinical response to antibiotic treatment. (ii) The patient's compliance with the prescribed drug regimen was unknown. (iii) Antibiotic therapy received during hospital admission and prescription drugs purchased in another county are not included in the analyses.

The prevalence of ß-lactamase-positive H. influenzae and penicillin-resistant S. pneumoniae isolates from middle ear fluid found in this study was among the lowest reported in the past 5–10 years, while the prevalence of ß-lactamase-positive M. catarrhalis was similar to that reported in other countries.3

Our findings are in contrast to those of a Swedish study, which found a higher prevalence of resistant H. influenzae in throat/nasopharyngeal swabs in patients who were treated with antibiotics 0–4 months before sampling.4 However, this study included all age groups and all upper respiratory tract infections. Our findings were in accordance with studies of resistance prevalence in middle ear fluid showing that recent (<1 month before sampling) antibiotic treatment seemed to slightly increase antimicrobial resistance.57

Most studies demonstrate a trend towards the finding that the broader the antimicrobial spectrum the higher the prevalence of resistance, although statistical significance may not be reached.6 Eliasson et al.,8 however, did not find any association in a study of children treated for respiratory tract infections.

Currently we cannot establish whether the higher ß-lactamase prevalence observed in the short period (<1 month) was due to the effect of antibiotics on the microbial flora of the upper respiratory tract. Confounding by indication should be taken into account because the studies of prevalence do not include microbiological examination before treatment. Hence, according to Pichichero et al.,9 children with persistent otitis media harboured resistant pathogens more often than other children, but sampling of middle ear fluid was also more likely to be undertaken in this group. However, prospective studies showed that the proportion of resistant pathogens among groups of children increased during the 0–30 days after start of treatment.8,10 Unfortunately, the effect beyond 1 month has not been studied.

Throughout the world, therapy of otitis media is complicated by the growing resistance of common ear pathogens. Even if the ecological effects of antibiotics on the individual pathogen may be transitory, the carriers are prone to spread the resistant microorganism to others, i.e. in day care centres or in families.10 In several countries, penicillin V is no longer on the list of recommended drugs for otitis media. Penicillin V is still prescribed in Denmark, and the low prevalence of penicillin-resistant pneumococci and ß-lactamase-positive H. influenzae observed in this study support the validity of this policy.


    Acknowledgments
 
We wish to thank the staff at the Department of Health Insurance and Preventive Medicine and Hospital Registries in the County of Northern Jutland for their invaluable assistance in preparing the data for analysis. The study was supported by The Medical Research Unit, Ringkjøbing County, and by the Danish Medical Research Council (grant no. 9700677). The activities of the Danish Epidemiology Science Centre were financed by a grant from the Danish National Research Foundation.


    Notes
 
* Correspondence address. The Danish Epidemiology Science Centre, University of Aarhus, Vennelyst Boulevard 6, 8000 Aarhus C, Denmark. Tel: +45-8942-6111; Fax: +45-8613-1580; E-mail: nthrane{at}dadlnet.dk Back


    References
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
1 . Nyquist, A. C., Gonzales, R., Steiner, J. F. & Sande, M. A. (1998). Antibiotic prescribing for children with colds, upper respiratory tract infections, and bronchitis. Journal of the American Medical Association 279, 875–7.[Abstract/Free Full Text]

2 . Dagan, R., Leibovitch, E., Fliss, D. M. & Leiberman, A. (1998) Treatment failures in otitis media—what can we learn? Ear, Nose and Throat Journal 77,Suppl., 16–21.[Medline]

3 . Jacobs, M. R., Dagan, R., Appelbaum, P. C. & Burch, D. J. (1998). Prevalence of antimicrobial-resistant pathogens in middle ear fluid: multinational study of 917 children with acute otitis media. Antimicrobial Agents and Chemotherapy 42, 589–95.[Abstract/Free Full Text]

4 . Henning, C., Bengtsson, L., Jorup, C. & Engquist, S. (1997). Antibiotic resistance in Streptococcus pneumoniae, Haemophilus influenzae and Streptococcus pyogenes in respiratory tract infections in outpatients. Scandinavian Journal of Infectious Diseases 29, 559–63.[ISI][Medline]

5 . Leibovitz, E., Raiz, S., Piglansky, L., Greenberg, D., Yagupsky, P., Fliss, D. M. et al. (1998). Resistance pattern of middle ear fluid isolates in acute otitis media recently treated with antibiotics. Pediatric Infectious Disease Journal 17, 463–9.[ISI][Medline]

6 . Syriopoulou, V., Scheifele, D., Smith, A. L., Perry, P. M. & Howie, V. (1978). Increasing incidence of ampicillin resistance in Haemophilus influenzae. Journal of Pediatrics 92, 889–92.[ISI][Medline]

7 . Harrison, C. J., Marks, M. I. & Welch, D. F. (1985). Microbiology of recently treated acute otitis media compared with previously untreated acute otitis media. Pediatric Infectious Disease Journal 4, 641–6.[ISI]

8 . Eliasson, I., Holst, E., Mölstad, S. & Kamme, C. (1990). Emergence and persistence of beta-lactamase-producing bacteria in the upper respiratory tract in children treated with beta-lactam antibiotics. American Journal of Medicine 88,Suppl. A, 51–5.

9 . Pichichero, M. E. & Pichichero, C. L. (1995). Persistent acute otitis media: I. Causative pathogens. Pediatric Infectious Disease Journal 14, 178–83.[ISI][Medline]

10 . Dagan, R., Leibovitz, E., Greenberg, D., Yagupsky, P., Fliss, D. M. & Leiberman, A. (1998). Dynamics of pneumococcal nasopharyngeal colonization during the first days of antibiotic treatment in pediatric patients. Pediatric Infectious Disease Journal 17, 880–5.[ISI][Medline]

Received 17 March 2000; returned 12 July 2000; revised 5 September 2000; accepted 9 October 2000





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