Effect of Azithromycin and Clarithromycin therapy on pharyngeal carriage of macrolide-resistant streptococci in healthy volunteers: a randomised, double-blind, placebo-controlled study

Department of Medical Microbiology, University of Antwerp, Belgium.
The Lancet (Impact Factor: 45.22). 03/2007; 369(9560):482-90. DOI: 10.1016/S0140-6736(07)60235-9
Source: PubMed


Resistance to antibiotics is a major public-health problem, and studies that link antibiotic use and resistance have shown an association but not a causal effect. We used the macrolides azithromycin and clarithromycin to investigate the direct effect of antibiotic exposure on resistance in the oral streptococcal flora of healthy volunteers.
Volunteers were treated with azithromycin (n=74), clarithromycin (74), or placebo (76) in a randomised, double-blind trial. Pharyngeal swabs were obtained before and after administration of study treatment through 180 days. The proportion of streptococci that were macrolide resistant was assessed and the molecular basis of any change in resistance investigated. Analyses were done on an intent-to-treat basis. This study is registered with, number NCT00354952.
The number of dropouts (n=20) was much the same in all groups until day 42; dropouts increased substantially at day 180 (105). Both macrolides significantly increased the proportion of macrolide-resistant streptococci compared with the placebo at all points studied, peaking at day 8 in the clarithromycin group (mean increase 50.0%, 95% CI 41.7-58.2; p<0.0001) and at day 4 in the azithromycin group (53.4%, 43.4-63.5; p<0.0001). The proportion of macrolide-resistant streptococci was higher after azithromycin treatment than after clarithromycin use, with the largest difference between the two groups at day 28 (17.4% difference, 9.2-25.6; p<0.0001). Use of clarithromycin, but not of azithromycin, selected for the erm(B) gene, which confers high-level macrolide resistance.
This study shows that, notwithstanding the different outcomes of resistance selection, macrolide use is the single most important driver of the emergence of macrolide resistance in vivo. Physicians prescribing antibiotics should take into account the striking ecological side-effects of such antibiotics.

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Available from: Surbhi malhotra-kumar, Oct 06, 2014
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    • "A significant association was found between antimicrobial consumption and the occurrence of resistance in the respiratory tract, through screening of Pasteurellaceae, among the most important bovine—and in a larger context veterinary—respiratory pathogens. Malhotra- Kumar et al. have shown in a randomised controlled clinical trial that a selection pressure exerted by oral antimicrobial therapy also is reflected in the resistance situation of commensal oral streptococci, and the authors refer to these bacteria as a source of resistance genes for respiratory pathogens[33]. Our observational study design comparing exposed versus non exposed animals was able to demonstrate that opportunistic respiratory pathogenic bacteria themselves can act as a reservoir of resistance. "
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    ABSTRACT: The aim of this study was to investigate the relationship between antimicrobial use and the occurrence of antimicrobial resistance in the digestive and respiratory tract in three different production systems of food producing animals. A longitudinal study was set up in 25 Belgian bovine herds (10 dairy, 10 beef, and 5 veal herds) for a 2 year monitoring of antimicrobial susceptibilities in E. coli and Pasteurellaceae retrieved from the rectum and the nasal cavity, respectively. During the first year of observation, the antimicrobial use was prospectively recorded on 15 of these farms (5 of each production type) and transformed into the treatment incidences according to the (animal) defined daily dose (TIADD) and (actually) used daily dose (TIUDD). Antimicrobial resistance rates of 4,174 E. coli (all herds) and 474 Pasteurellaceae (beef and veal herds only) isolates for 12 antimicrobial agents demonstrated large differences between intensively reared veal calves (abundant and inconstant) and more extensively reared dairy and beef cattle (sparse and relatively stable). Using linear mixed effect models, a strong relation was found between antimicrobial treatment incidences and resistance profiles of 1,639 E. coli strains (p<0.0001) and 309 Pasteurellaceae (p≤0.012). These results indicate that a high antimicrobial selection pressure, here found to be represented by low dosages of oral prophylactic and therapeutic group medication, converts not only the commensal microbiota from the digestive tract but also the opportunistic pathogenic bacteria in the respiratory tract into reservoirs of multi-resistance.
    Full-text · Article · Jan 2016 · PLoS ONE
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    • "However, correlation between macrolide use and resistance in Streptococcus pneumoniae has been well documented [10] [11]. For example, a randomized controlled trial by Malhotra-Kumar et al. showed a causal effect between AZM use in individuals and resistance in streptococci, which remained significant until 6 months after treatment [11]. "
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    ABSTRACT: Trachoma is caused by Chlamydia trachomatis and is a leading cause of blindness worldwide. Mass distribution of azithromycin (AZM) is part of the strategy for the global elimination of blinding trachoma by 2020. Although resistance to AZM in C. trachomatis has not been reported, there have been concerns about resistance in other organisms when AZM is administered in community settings. We identified studies that measured pneumococcal prevalence and resistance to AZM following mass AZM provision reported up to 2013 in Medline and Web of Science databases. Potential sources of bias were assessed using the Cochrane Risk of Bias Tool. A total of 45 records were screened, of which 8 met the inclusion criteria. We identified two distinct trends of resistance prevalence, which are dependent on frequency of AZM provision and baseline prevalence of resistance. We also demonstrated strong correlation between the prevalence of resistance at baseline and at 2-3 months ( r = 0.759 ). Although resistance to AZM in C. trachomatis has not been reported, resistance to this commonly used macrolide antibiotic in other diseases could compromise treatment. This should be considered when planning long-term trachoma control strategies.
    Full-text · Article · Nov 2015 · Journal of Tropical Medicine
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    • "More than 60 years ago, the introduction of penicillin played a decisive role in the treatment of infectious diseases [1]. Over the decades, antibiotic (ATB) overuse and misuse have unfortunately led to an increased rate of adverse side effects, a higher cost of treatment and a higher rate of antimicrobial resistance to community pathogens, a phenomenon which is now a worldwide public health problem [2]. In fact, the World Health Organization (WHO) selected combating antimicrobial resistance as the theme for World Health Day 2011[3]. "
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    ABSTRACT: Introduction: Indiscriminate use of antibiotics contributes to a global spread of antimicrobial resistance. Previous studies showed an excessive consumption of antibiotics purchased without medical prescription from community pharmacies, mainly in developing countries. There is a shortage of studies revealing the role of community pharmacists in the overuse of antibiotics. Our objective is to study the dispensing policy of non-medical prescription antibiotics in community pharmacies, assessing the possible influence of the socio-economic level of the area over this practice. Methods: A cross-sectional study was conducted between February and May 2011 among 100 pharmacists working in Beirut's pharmacies and its suburbs. Pharmacies were divided into 2 groups according to the socio-economic level of the population living in the pharmacy area. A self-administered questionnaire was filled by pharmacists. Results: Over-the-counter antibiotic availability existed in both higher and lower socio-economic areas: on the whole, 32% of antibiotics were dispensed without medical prescription, with higher frequency in lower socio-economic areas (p=0.003). Dispensing injectable antibiotics without medical prescription was significantly higher in lower socio-economic areas (p=0.021), as well as dispensing an association of 2 antibiotics without medical prescription (p=0.001). Pharmacists working in lower socio-economic areas recommended more frequent antibiotics to children and the elderly (p<0.001 and p=0.004, respectively). Conclusion: Dispensing antibiotics without medical prescription in Beirut community pharmacies is a common practice, particularly in lower socioeconomic areas. This public health problem should be addressed at the social, educational, and legislative levels.
    Full-text · Article · Aug 2014 · Journal of Infection and Public Health
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