1 Exponent, Inc., 1800 Diagonal Road, Suite 300, Alexandria, VA 22314; 2 Aventis US Pharma, Bridgewater, NJ, USA; 3 McMaster University School of Medicine, Hamilton, Ontario, Canada
Received 23 September 2004; returned 24 October 2004; revised 10 January 2005; accepted 14 January 2004
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Abstract |
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Methods: MEDLINE and EMBASE databases were searched and experts were consulted to identify published and unpublished literature reporting macrolide resistance rates. Identified studies were evaluated by two independent reviewers; those meeting a priori specified criteria (resistance by patient condition and strain, resistance thresholds, 19972003 isolates) were included. Data from included studies were abstracted by two independent reviewers using a standard review form. Discrepancies in abstracted data were resolved by the study investigator.
Results: Random-effects meta-analysis was performed for outcomes present in at least four studies overall and for specified subgroups. We identified 3849 studies and performed detailed review on 407; of these 29, published between 19982003, met the inclusion criteria. Mean resistance of S. pneumoniae isolates to azithromycin was 27.2% [95% confidence interval (CI) 24.629.7]; mean resistance to erythromycin was statistically equivalent (30.4%; 95% CI 28.132.7). Resistance of S. pyogenes to erythromycin (30.0%; CI 18.641.5) was similar to that of S. pneumoniae. Too few studies of clarithromycin were included to allow evaluation of resistance. In subgroup analyses, substantial variation in resistance to erythromycin was seen by geographic area.
Conclusions: Reported macrolide resistance of S. pneumoniae varies substantially and may be a significant issue in certain regions. Use of meta-analysis to aggregate individual studies enabled determination of robust values for macrolide resistance. This information is useful for clinical and policy decision makers in developing appropriate antibiotic strategies.
Keywords: antibiotic resistance , respiratory tract infections , streptococci
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Introduction |
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A growing recognition of the multifaceted problem of antimicrobial resistance led to the formation of the Federal Interagency Task Force on Antimicrobial Resistance in 1999. Its strategy report entitled A Public Health Action Plan to Combat Antimicrobial Resistance, provides the USA with a comprehensive approach to combat antimicrobial resistance.3 This report addressed four main areas: surveillance, prevention and control, research, and product development. Readily available public access to reliable drug susceptibility and resistance data is essential for monitoring antimicrobial patterns as they evolve and change over time. Similarly, the World Health Organization launched a campaign in late 2001 known as the Global Strategy for Containment of Antimicrobial Resistance to address the concern that, while national efforts are important, international travel and trade necessitates a global approach to resistance surveillance.
Many studies on macrolide resistance have been conducted. However, the small sample sizes result in limited power to detect statistically significant differences. Meta-analysis is an analytic technique for systematically combining outcomes across multiple studies. This technique allows a more robust determination of outcome values and has increased power to detect statistical significance. The objective of this study was to quantify the extent of macrolide resistance in S. pneumoniae.
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Methods |
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Literature search
Literature searches were performed to identify articles eligible for review. Searches were conducted in MEDLINE and EMBASE. All searches included the terms: (azithromycin OR zithromax OR clarithromycin OR biaxin OR erythromycin) AND (drug resistance, bacterial OR drug resistance, multiple OR clinical trial [publication type]). Searches were not limited by age group, i.e. paediatric or adult, or by condition. Literature searches for information on resistance to other macrolides were conducted and no published information was identified.
Inclusion criteria
Table 1 presents the inclusion criteria used to identify eligible articles. Use of data only from studies presenting resistance results for each macrolide individually rather than results for all macrolides combined allowed us to also assess medication-specific outcomes. This also resulted in exclusion of a number of broad surveillance studies that reported resistance only for all macrolides combined or did not report resistance associated with specific disease conditions. When data in an abstract or article were unclear, attempts were made to contact the authors for additional information (e.g. dates of data collection, MICs).
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The article review process required the completion of an eligibility check for each article. Each article was reviewed by two independent reviewers. Any differences for inclusion/exclusion or in data abstraction were discussed with the study director (M.T.H.) to reach consensus. Articles meeting the eligibility criteria were abstracted into data tables. All articles that were evaluated for inclusion were also subject to a review of references. In this manner, all publications and reports that were referenced in the retrieved articles were also appraised for potential inclusion in the meta-analysis. In addition, attempts were made to contact authors of included publications to determine whether they had participated in any more recent studies that they could share (i.e. papers in progress or in press). Data abstracted from each article included the study population characteristics, the sample size for each treatment group, and the percent resistant for the overall population and key subgroups. Outcomes from subgroups were also collected during the data abstraction process.
Analysis
Meta-analyses were performed using the random-effects model.4 This approach was used to assess the extent of bacterial resistance to macrolides of the entire relevant patient population, not only of patients participating in the included studies. Analyses were conducted on endpoints presented in four or more studies. Subgroup analyses were also performed if data were available from four or more studies. Heterogeneity of studies included in meta-analyses was assessed using the Q-statistic.4 Statistical equivalence between meta-analysis results was assessed using the method of Farrington and Manning,5 modified for the meta-analysis by using the average number of subjects per study as the n for each group.
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Results |
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We reviewed 3849 publications from MEDLINE and EMBASE published from 1998 to 2003 (see Figure 1). Candidate articles underwent a three-stage review; first, titles were reviewed in order to determine which abstracts to review; secondly, 1277 abstracts were reviewed to determine which full articles to review; and finally, 407 articles were reviewed for inclusion. Reasons for exclusion are listed in Table 2. Reports from a number of broad surveillance studies (e.g. PROTEKT) were excluded from this meta-analysis as they either did not provide resistance information separately for each macrolide (i.e. they presented pooled results across macrolides) and/or they did not provide resistance information for patients with only the selected disease conditions (e.g. lower respiratory tract infections). A total of 29 reports were included in the meta-analysis (Table 3).
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Subgroup (secondary) analyses for one or more endpoints above were conducted for several condition-, age-, setting- and geographic-defined subgroups. A full listing of subgroup analyses appears in Table 7.
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Primary analyses
The primary objective of the analysis was to evaluate the extent of bacterial resistance to specific macrolides. Results of the primary analyses are presented in Table 8. The mean resistance to azithromycin was 27.2% of S. pneumoniae isolates [95% confidence interval (CI) 24.629.7]; mean resistance to erythromycin (30.4%) was similar and not statistically different (95% CI 28.132.7). Equivalence testing using the approach of Farrington and Manning5 demonstrated equivalence in resistance rates between azithromycin and erythromycin based on the difference between the rates being < 10% (P < 0.05). There were insufficient data to perform meta-analysis on S. pneumoniae resistance to clarithromycin. Resistance of S. pyogenes to erythromycin was similar to S. pneumoniae resistance to erythromycin (30.0%; CI 18.641.5).
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Age
Resistance of S. pneumoniae to erythromycin (17 studies included in the analysis) and S. pyogenes to erythromycin (five studies) was examined in a paediatric population. Of these 17 studies, 13 included only healthy individuals while four were in patients with infectious disease. S. pneumoniae resistance to erythromycin (33.1%; CI 29.636.7) was greater than the resistance calculated for S. pyogenes (30.0%; CI 18.641.5). For S. pneumoniae, an additional analysis was conducted for a healthy paediatric population (13 studies). In this group, the resistance of S. pneumoniae to erythromycin was slightly lower than among the entire paediatric population (28.8%; CI 24.932.8).
Geography
Seven studies in the USA examined S. pneumoniae resistance to erythromycin (20.7%; CI 17.024.4) presented in 7. Overall, the percentage of erythromycin-resistant S. pneumoniae in the USA was less than that noted in Europe (32.0%; CI 23.840.3; six studies). This difference was not statistically significant. S. pneumoniae in Asia demonstrated significantly higher levels of resistance to erythromycin than that seen in the USA (57.3%; CI 36.677.9; four studies). In Europe, S. pyogenes showed greater resistance than did S. pneumoniae to erythromycin (36.8%; CI 22.551.2; four studies).
Condition
When all the conditions were combined (acute exacerbation of chronic bronchitis, acute sinusitis, community acquired pneumonia, otitis media, tonsillitis or pharyngitis), S. pneumoniae in patients with any infectious condition were more resistant to erythromycin (35.9%; CI 29.542.2; nine studies) than to azithromycin (23.8%; CI 21.526.1; four studies). S. pyogenes demonstrated similar resistance to erythromycin as did S. pneumoniae in patients with these diagnostic categories (37.0%; CI 23.650.5; four studies).
S. pneumoniae resistance to erythromycin was higher among patients with the aforementioned infectious diseases (35.9%; CI 29.542.2; nine studies) than among healthy controls (26.9%; CI 23.230.6; 14 studies), although the difference was not statistically significant.
Setting
Subgroup analyses were conducted for isolates taken from outpatient clinics versus community settings. In this context, outpatient settings refer to patients who presented at outpatient health-care facilities (e.g. hospital clinics), while community settings indicates general populations from whom samples were collected in non-health-care locations (i.e. in the community). S. pneumoniae from outpatient settings was more resistant to erythromycin (37.6%; CI 30.644.7; nine studies) than S. pneumoniae taken from the community (28.3%; CI 24.432.2; 12 studies). We did not identify any studies in which bacteria were isolated from inpatients. S. pyogenes from outpatient settings demonstrated erythromycin resistance similar to S. pneumoniae from outpatients (37.0%; CI 23.650.5; four studies).
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Discussion |
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There are several limitations of this meta-analysis. Of the 407 articles and abstracts fully evaluated for this meta-analysis, only 29 published reports met our strict inclusion criteria. Several studies that we reviewed were not included because either they did not report on the outcomes of interest or did not meet other a priori inclusion criteria. In addition, it is possible that there is a publication bias where studies reporting low levels of resistance would be less likely to be published. However, given the nature of this topic, it is likely that there would be equal interest in reports of low or high levels of resistance. It is therefore unlikely that any significant publication bias has affected our analysis.
Another limitation of any meta-analysis is in the combination of data from diverse sources, study populations and treatment protocols. While the inclusion criteria used for this study help to reduce heterogeneity, we cannot be certain that these studies are fully comparable. However, use of a statistical tool to assess potential heterogeneity among included studies (the Q-statistic) gives us further confidence in the meta-analysis results.
A greater proportion of articles included in the meta-analysis were from paediatric than from adult studies. This is not a surprising finding and may relate to the greater prevalence and frequency of medical visits by the paediatric population. Furthermore, these were the articles that met the a priori inclusion criteria, and thus represent an unbiased sample within these criteria.
Ideally, in addition to quantifying bacterial resistance, this analysis would also have explored the link between resistance and patient outcomes. However, a majority of the studies included in the meta-analysis did not provide information on patient outcomes. Thus, we were unable to evaluate this important link. Future studies of antibiotic resistance in community settings should include data on patient outcomes whenever possible to permit further exploration of the impact of resistance on outcome.
Finally, a number of large surveillance studies that are often used to discuss resistance did not meet our inclusion criteria. For example, several studies were excluded because they did not provide results separately by type of infectious disease (e.g. Farrell et al.7 and Felmingham et al.8 ). However, results from these surveillance studies provided similar results to those of the current meta-analysis. For example, Felmingham et al.8 reported that overall resistance of S. pneumoniae to erythromycin from the PROTEKT study was 31.1% (similar to our value of 30.4%, presented in Table 8). Resistance to azithromycin from this study was also 31.1%, similar to the meta-analysis value of 27.2%. Geographic variation in resistance rates also showed a similar pattern to the meta-analysis, although rates from PROTEKT tended to be higher. Thus, information on resistance collected in broad surveillance studies corroborates the results found in the meta-analysis.
Breakpoints used for determining bacterial resistance are also a crucial component in combining multiple studies of resistance. By limiting the studies by years of publication, we anticipated that breakpoints would be less likely to differ among the included studies. This was not entirely the case, as the most frequently cited breakpoints, those of the NCCLS, did vary from the 1993 to 2002 versions. However, the actual breakpoints used were very similar across the included studies and did not differ systematically (i.e. by region, country or date of publication).
Despite these limitations, this meta-analysis provides an important synthesis of the reported macrolide resistance rates for S. pneumoniae and S. pyogenes. Based on these results, macrolide resistance is consistently present in a sizeable proportion of multiple populations. As interest in resistance patterns and rates of common pathogens to antibiotics increases, these results can be used to influence treatment decisions and to formulate consensus recommendations for appropriate treatment paradigms. The meta-analysis technique used here can help to develop appropriate guidelines governing antibiotic use and to monitor drug resistance trends. Generally, rates of resistance in community-based studies are lower than in surveillance studies. For example, as recently presented by Bonvehi et al.,9 documented clarithromycin treatment failure rates were lower than the values that would have been predicted based on resistance rates from surveillance studies. These authors conclude that relevant resistance in the community may not be predicted by in vitro surveillance studies. Nuermberger and Bishai10 recently indicated similar conclusions in a review of macrolide-resistant S. pneumoniae. These authors reported that macrolide concentrations in alveolar epithelial lining fluid are higher than those in plasma, which may account for lower rates of macrolide treatment failure than predicted by in vitro resistance data. They further state that additional clinical data from large-scale observational studies will be needed to evaluate the link between in vitro macrolide resistance and treatment failure. Thus, analyses of community-based experiences can provide an important contribution to the understanding of real-world resistance issues from the perspective of day-to-day medical practice.
Rising rates of antibiotic resistance have a major impact on the ability of physicians to treat common infections. Patients may face more severe infections with increased duration as resistance increases; they may also experience heightened toxicity associated with the use of stronger antibiotics. Clinicians may eventually encounter infections caused by highly resistant pathogens for which no effective antibiotics are available. Preventative strategies coupled with the development of new generations of medications are necessary to ensure the continued availability of appropriate antibiotic therapy. In addition, antibiotic resistance undoubtedly has economic impacts, but these costs have not been well delineated.11 Economic studies of bacterial resistance have in general focused on inpatient facilities and Gram-positive infections. While these studies have reported substantial increases in length of stay and costs,1214 more work is need to evaluate the impact of resistance in outpatient and community settings.
In 2003, experts in a wide range of therapeutic specialties convened the Start Treatment with Appropriate Antibiotic Therapy (STAART) working group to discuss important issues surrounding the treatment of patients with community-acquired respiratory tract infections. The panel evaluated the hypothesis that the initial use of a tailored antimicrobial (i.e. with specific bactericidal activity and related characteristics) in relevant patients may be associated with improved clinical and microbiological outcomes and a decreased risk of resistance. This group defined the appropriate antimicrobial agent as one that has a focused spectrum of activity against common respiratory pathogens, resistant pathogens and atypical pathogens while having little activity on other endogenous microbial flora.
This meta-analysis demonstrates that resistance to macrolides is a significant issue in the USA as well as in Europe and Asia. Reported macrolide resistance in S. pneumoniae varies greatly from country to country and is likely to be an important problem in certain regions. Further work needs to be done in Australia, Canada, South America and Africa; an insufficient number of studies prevented these areas from being included in the subgroup meta-analyses. Given the range of modern travel and easy carriage of resistant organisms, further antibiotic resistance surveillance studies in these regions are important.
In summary, this meta-analysis has provided important information on resistance by S. pneumoniae and S. pyogenes to macrolide antibiotics. The use of the meta-analysis technique has allowed us to summarize data from individual studies and to determine robust values for both overall resistance and resistance among subgroups. These results will be useful in developing future guidelines and treatment paradigms for S. pneumoniae and S. pyogenes, as well as in helping to direct future research on the impact of bacterial resistance and appropriate antimicrobial use.
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Footnotes |
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Present address. Department of Pharmacotherapy, University of Utah, Salt Lake City, UT, USA.
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Acknowledgements |
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Transparency declarations
Four of the authors (C.A., B.L., R.N. and P.W.S.) were employees of Aventis Pharmaceuticals at the time of the study, and three (all except P.W.S.) have stock ownership or options in Aventis. M.T.H. and L.A.M. have consultancies with Aventis. M.T.H. also has consultancies with Abbott Laboratories, while L.A.M. has consultancies with Pfizer, in addition to receiving honoraria and grants from both Aventis and Pfizer.
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References |
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2 . Doern, G. V. (2001). Antimicrobial use and the emergence of antimicrobial resistance with Streptococcus pneumoniae in the United States. Clinical Infectious Diseases 33, Suppl. 3, S18792.[CrossRef][ISI][Medline]
3 . Interagency Task Force on Antimicrobial Resistance. (2003). A Public Health Action Plan to Combat Antimicrobial Resistance. Part 1: Domestic Issues. [Online]. http://www.cdc.gov/drugresistance/actionplan/aractionplan.pdf (20 September 2004, date last accessed) (2003).
4 . DerSimonian, R. & Laird, N. (1986). Meta-analysis in clinical trials. Controlled Clinical Trials 7, 17788.[CrossRef][ISI][Medline]
5 . Farrington, C. P. & Manning, G. (1990). Test statistics and sample size formulae for comparative binomial trials with null hypothesis of non-zero risk difference or non-unity relative risk. Statistics in Medicine 9, 144754.[ISI][Medline]
6 . Naaber, P., Tamm, E., Putsepp, A. et al. (2000). Nasopharyngeal carriage and antibacterial susceptibility of Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis in Estonian children. Clinical Microbiology and Infection 6, 6757.[CrossRef][ISI][Medline]
7
.
Farrell, D. J., Morrissey, I., Bakker, S. et al. (2002). Molecular characterization of macrolide resistance mechanisms among Streptococcus pneumoniae and Streptococcus pyogenes isolated from the PROTEKT 19992000 study. Journal of Antimicrobial Chemotherapy 50, Suppl. S1, 3947.
8
.
Felmingham, D., Reinert, R. R., Hirakata, Y. et al. (2002). Increasing prevalence of antimicrobial resistance among isolates of Streptococcus pneumoniae from the PROTEKT surveillance study, and comparative in vitro activity of the ketolide, telithromycin. Journal of Antimicrobial Chemotherapy 50, Suppl. S1, 2537.
9 . Bonvehi, P., Weber, K., Busman, T. et al. (2003). Comparison of clarithromycin and amoxicillin/clavulanic acid for community-acquired pneumonia in an era of drug-resistant Streptococcus pneumoniae. Clinical Drug Investigation 23, 491501.[ISI]
10 . Nuermberger, E. & Bishai, W. R. (2004). The clinical significance of macrolide-resistant Streptococcus pneumoniae: it's all relative. Clinical Infectious Diseases 38, 99103.[CrossRef][ISI][Medline]
11 . Cosgrove, S. E. & Carmeli, Y. (2003). The impact of antimicrobial resistance on health and economic outcomes. Clinical Infectious Diseases 36, 14337.[CrossRef][ISI][Medline]
12
.
Cosgrove, S. E., Kaye, K. S., Eliopoulous, G. M. et al. (2002). Health and economic outcomes of the emergence of third-generation cephalosporin resistance in Enterobacter species. Archives of Internal Medicine 162, 18590.
13 . Capitano, B., Leshem, O. A., Nightingale, C. H. et al. (2003). Cost effect of managing methicillin-resistant Staphylococcus aureus in a long-term care facility. Journal of the American Geriatrics Society 51, 1016.[ISI][Medline]
14 . Kim, T., Oh, P. I. & Simor, A. E. (2001). The economic impact of methicillin-resistant Staphylococcus aureus in Canadian hospitals. Infection Control and Hospital Epidemiology 22, 99104.[ISI][Medline]
15 . Abdel-Haq, N., Abuhammour, W., Asmar, B. et al. (1999). Nasopharyngeal colonization with Streptococcus pneumoniae in children receiving trimethoprimsulfamethoxazole prophylaxis. Pediatric Infectious Disease Journal 18, 6479.[CrossRef][ISI][Medline]
16 . Anzueto, A., Gotfried, M., Wikler, M. A. et al. (2002). Efficacy and tolerability of gatifloxacin in community treatment of acute exacerbations of chronic bronchitis. Clinical Therapeutics 24, 90617.[CrossRef][ISI][Medline]
17 . Avanzini, C., Bosio, K., Volpe, G. et al. (2000). Streptococcus pyogenes collected in Torino (northwest Italy) between 1983 and 1998: survey of macrolide resistance and trend of genotype by RAPD. Microbial Drug Resistance 6, 28995.[ISI][Medline]
18 . Bassetti, M., Manno, G., Collida, A. et al. (2000). Erythromycin resistance in Streptococcus pyogenes in Italy. Emerging Infectious Diseases 6, 1803.[ISI][Medline]
19 . Boost, M. V., O'Donoghue, M. M. & Dooley, J. S. (2001). Prevalence of carriage of antimicrobial resistant strains of Streptococcus pneumoniae in primary school children in Hong Kong. Epidemiology and Infection 127, 4955.[CrossRef][ISI][Medline]
20
.
Chiu, S. S., Ho, P. L., Chow, F. K. et al. (2001). Nasopharyngeal carriage of antimicrobial-resistant Streptococcus pneumoniae among young children attending 79 kindergartens and day care centers in Hong Kong. Antimicrobial Agents and Chemotherapy 45, 276570.
21 . Ciftci, E., Dogru, U., Guriz, H. et al. (2002). Investigation of risk factors for tonsillopharyngitis with macrolide resistant Streptococcus pyogenes in Turkish children. Pediatrics International 44, 64751.[CrossRef][ISI][Medline]
22 . Dellamonica, P., Pradier, C., Leroy, J. et al. (2002). Epidemiology and antibiotic susceptibility of nasopharyngeal S. pneumoniae and H. influenzae isolated from children attending day-care centers in 3 french departments. Médecine et Maladies Infectieuses 32, 65061.[CrossRef][ISI]
23 . Ford-Jones, E. L., Friedberg, J., McGeer, A. et al. (2002). Microbiologic findings and risk factors for antimicrobial resistance at myringotomy for tympanostomy tube placementa prospective study of 601 children in Toronto. International Journal of Pediatric Otorhinolaryngology 66, 22742.[CrossRef][ISI][Medline]
24 . Ghaffar, F., Muniz, L. S., Katz, K. et al. (2000). Effects of amoxicillin/clavulanate or azithromycin on nasopharyngeal carriage of Streptococcus pneumoniae and Haemophilus influenzae in children with acute otitis media. Clinical Infectious Diseases 31, 87580.[CrossRef][ISI][Medline]
25 . Gray, G. C., Witucki, P. J., Gould, M. T. et al. (2001). Randomized, placebo-controlled clinical trial of oral azithromycin prophylaxis against respiratory infections in a high-risk, young adult population. Clinical Infectious Diseases 33, 9839.[CrossRef][ISI][Medline]
26 . Herruzo, R., Chamorro, L., Garcia, M. E. et al. (2002). Prevalence and antimicrobial-resistance of S. pneumoniae and S. pyogenes in healthy children in the region of Madrid. International Journal of Pediatric Otorhinolaryngology 65, 11723.[CrossRef][ISI][Medline]
27 . Hjaltested, E. K. R., Bernatoniene, J., Erlendsdottir, H. et al. (2003). Resistance in respiratory tract pathogens and antimicrobial use in Icelandic and Lithuanian children. Scandinavian Journal of Infectious Diseases 35, 216.[Medline]
28 . Huebner, R. E., Wasas, A. D., Hockman, M. et al. (2003). Bacterial aetiology of non-resolving otitis media in South African children. Journal of Laryngology and Otology 117, 16972.[CrossRef][ISI][Medline]
29 . Jones, R. N., Andes, D. R., Mandell, L. A. et al. (2002). Gatifloxacin used for therapy of outpatient community-acquired pneumonia caused by Streptococcus pneumoniae. Diagnostic Microbiology and Infectious Disease 44, 93100.[CrossRef][ISI][Medline]
30 . Kacou-N'Douba, A., Bouzid, S. A., Guessennd, K. N. et al. (2001). Antimicrobial resistance of nasopharyngeal isolates of Streptococcus pneumoniae in healthy carriers: report of a study in 5-year-olds in Marcory, Abidjan, Cote d'Ivoire. Annals of Tropical Paediatrics: International Child Health 21, 14954.
31 . Li, W. C., Chiu, N. C., Hsu, C. H. et al. (2001). Pathogens in the middle ear effusion of children with persistent otitis media: implications of drug resistance and complications. Journal of Microbiology, Immunology, and Infection 34, 1904.
32 . Lopez, B., Cima, M. D., Vazquez, F. et al. (1999). Epidemiological study of Streptococcus pneumoniae carriers in healthy primary-school children. European Journal of Clinical Microbiology and Infectious Diseases 18, 7716.[CrossRef][ISI][Medline]
33 . Mainous, A. G., 3rd, Evans, M. E., Hueston, W. J. et al. (1998). Patterns of antibiotic-resistant Streptococcus pneumoniae in children in a day-care setting. Journal of Family Practice 46, 1426.[ISI][Medline]
34 . Nwabuisi, C. & Ologe, F. E. (2002). Pathogenic agents of chronic suppurative otitis media in Ilorin, Nigeria. East African Medical Journal 79, 2025.[Medline]
35 . Pfaller, M. A. & Jones, R. N. (2002). Gatifloxacin phase IV surveillance trial (TeqCES study) utilizing 5000 primary care physician practices: report of pathogens isolated and susceptibility patterns in community-acquired respiratory tract infections. Diagnostic Microbiology and Infectious Disease 44, 7784.[CrossRef][ISI][Medline]
36 . Raz, R., Soboh, S., Much, A. et al. (1999). Pneumococcal carriage in geriatric institute residents. Infectious Diseases in Clinical Practice 8, 2913.[ISI]
37 . Ronchetti, M. P., Guglielmi, F., Latini, L. et al. (1999). Resistance patterns of Streptococcus pneumoniae from children in central Italy. European Journal of Clinical Microbiology and Infectious Diseases 18, 3769.[CrossRef][ISI][Medline]
38 . Rosenblut, A., Santolaya, M. E., Gonzalez, P. et al. (2001). Bacterial and viral etiology of acute otitis media in Chilean children. Pediatric Infectious Disease Journal 20, 5017.[CrossRef][ISI][Medline]
39
.
Samore, M. H., Magill, M. K., Alder, S. C. et al. (2001). High rates of multiple antibiotic resistance in Streptococcus pneumoniae from healthy children living in isolated rural communities: association with cephalosporin use and intrafamilial transmission. Pediatrics 108, 85665.
40 . Skull, S., Shelby-James, T., Morris, P. et al. (1999). Streptococcus pneumoniae antibiotic resistance in Northern Territory children in day care. Journal of Paediatrics and Child Health 35, 46671.[CrossRef][ISI][Medline]
41 . Sokol, W. (2001). Epidemiology of sinusitis in the primary care setting: results from the 19992000 respiratory surveillance program. American Journal of Medicine 111, Suppl. 9A, 19S24S.[CrossRef][Medline]
42 . Syrogiannopoulos, G. A., Grivea, I. N., Fitoussi, F. et al. (2001). High prevalence of erythromycin resistance of Streptococcus pyogenes in Greek children. Pediatric Infectious Disease Journal 20, 8638.[CrossRef][ISI][Medline]