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Population-level macrolide consumption is associated with clarithromycin resistance in Helicobacter pylori: An ecological analysis

  • Chris Kenyon
    Correspondence
    Corresponding author at: HIV/STI Unit, Institute of Tropical Medicine, Antwerp, 2000, Belgium.
    Affiliations
    HIV/STI Unit, Institute of Tropical Medicine, Antwerp, Belgium

    Division of Infectious Diseases and HIV Medicine, University of Cape Town, Anzio Road, Observatory 7700, South Africa
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Open AccessPublished:May 28, 2019DOI:https://doi.org/10.1016/j.ijid.2019.05.028

      Highlights

      • Is the prevalence of clarithromycin resistance correlated with macrolide consumption?
      • At a country level, these two are significantly associated.
      • At a world region level these two are positively correlated (not statistically significant).

      Abstract

      Bystander selection has been shown to result in strong population-level correlations between the level of antimicrobial consumption in the general population and resistance to that antimicrobial or similar antimicrobials in a range of bacteria. The prevalence of clarithromycin resistance in Helicobacter pylori has been increasing rapidly resulting in increased difficulty to eradicate this infection. Using country- and WHO-world-region-level macrolide resistance data from a systematic review and macrolide consumption data from the MIDAS Quantum data base, we tested the hypothesis that the prevalence of clarithromycin resistance was correlated with macrolide consumption. At a country level, we found these variables to be positively correlated (Spearman’s rho = 0.49; P = 0.007). Whilst positive, the correlation between macrolide consumption and primary resistance was not statistically significant at world region level (Spearman’s rho = 0.95; P = 0.05).

      Keywords

      Introduction

      Increasing prevalence of resistance to macrolides in Helicobacter pylori (H. pylori) and the adverse effects this has on treatment success have led the World Health Organization to classify clarithromycin-resistant H. pylori as a high priority threat (
      • Savoldi A.
      • Carrara E.
      • Graham D.Y.
      • Conti M.
      • Tacconelli E.
      Prevalence of antibiotic resistance in Helicobacter pylori: a systematic review and meta-analysis in World Health Organization regions.
      ). In order to better understand the forces driving this antimicrobial resistance (AMR) we test the hypothesis that bystander selection plays a role. Bystander selection refers to the inadvertent selection of AMR in microbes not targeted by a specific antimicrobial therapy (
      • Tedijanto C.
      • Olesen S.W.
      • Grad Y.H.
      • Lipsitch M.
      Estimating the proportion of bystander selection for antibiotic resistance among potentially pathogenic bacterial flora.
      ). Macrolides for example, have been shown to result in a high prevalence of macrolide resistance in commensal nasopharyngeal streptococcal species (
      • Malhotra-Kumar S.
      • Lammens C.
      • Coenen S.
      • Van Herck K.
      • Goossens H.
      Effect of azithromycin and clarithromycin therapy on pharyngeal carriage of macrolide-resistant streptococci in healthy volunteers: a randomised, double-blind, placebo-controlled study.
      ). This is independent of the indication for their use (
      • Malhotra-Kumar S.
      • Lammens C.
      • Coenen S.
      • Van Herck K.
      • Goossens H.
      Effect of azithromycin and clarithromycin therapy on pharyngeal carriage of macrolide-resistant streptococci in healthy volunteers: a randomised, double-blind, placebo-controlled study.
      ). Bystander selection is particularly likely for bacteria like H. pylori that are highly prevalent and colonize humans for long periods during which time they may be exposed to antimicrobials taken for any indications (
      • Tedijanto C.
      • Olesen S.W.
      • Grad Y.H.
      • Lipsitch M.
      Estimating the proportion of bystander selection for antibiotic resistance among potentially pathogenic bacterial flora.
      ,
      • Malhotra-Kumar S.
      • Lammens C.
      • Coenen S.
      • Van Herck K.
      • Goossens H.
      Effect of azithromycin and clarithromycin therapy on pharyngeal carriage of macrolide-resistant streptococci in healthy volunteers: a randomised, double-blind, placebo-controlled study.
      ,
      • Kenyon C.
      Prevalence of macrolide resistance in Treponema pallidum is associated with macrolide consumption.
      ). Bystander selection has been shown to result in strong population-level correlations between the level of antimicrobial consumption in the general population and resistance to that antimicrobial or similar antimicrobials in a range of bacteria (
      • Kenyon C.
      Prevalence of macrolide resistance in Treponema pallidum is associated with macrolide consumption.
      ,
      • Bronzwaer S.L.
      • Cars O.
      • Buchholz U.
      • Molstad S.
      • Goettsch W.
      • Veldhuijzen I.K.
      • et al.
      A European study on the relationship between antimicrobial use and antimicrobial resistance.
      ,
      • Goossens H.
      • Ferech M.
      • Vander Stichele R.
      • Elseviers M.
      • Group E.P.
      Outpatient antibiotic use in Europe and association with resistance: a cross-national database study.
      ,
      • Riedel S.
      • Beekmann S.E.
      • Heilmann K.P.
      • Richter S.S.
      • Garcia-De-Lomas J.
      • Ferech M.
      • et al.
      Antimicrobial use in Europe and antimicrobial resistance in Streptococcus pneumoniae.
      ,
      • Kenyon C.
      • Buyze J.
      • Spiteri G.
      • Cole M.J.
      • Unemo M.
      Antimicrobial consumption is associated with decreased antimicrobial susceptibility of Neisseria gonorrhoeae in 24 European countries: an ecological analysis.
      ,
      • Seppala H.
      • Klaukka T.
      • Vuopio-Varkila J.
      • Muotiala A.
      • Helenius H.
      • Lager K.
      • et al.
      The effect of changes in the consumption of macrolide antibiotics on erythromycin resistance in group A streptococci in Finland. Finnish Study Group for Antimicrobial Resistance.
      ). A previous study limited to 18 European countries found that the prevalence of clarithromycin resistance in H. pylori was positively associated with national levels of macrolide consumption (
      • Megraud F.
      • Coenen S.
      • Versporten A.
      • Kist M.
      • Lopez-Brea M.
      • Hirschl A.M.
      • et al.
      Helicobacter pylori resistance to antibiotics in Europe and its relationship to antibiotic consumption.
      ). In the current study we assessed if the same association was present globally.

      Methods

      To test the bystander hypothesis globally, we used Spearman’s correlation to assess the correlation between macrolide consumption and the prevalence of macrolide resistance at two ecological levels - country and WHO world regions. Our AMR data came from a systematic review that provided pooled country- and world region-level prevalence of clarithromycin resistance based on studies published between 2007 and 2017 (
      • Savoldi A.
      • Carrara E.
      • Graham D.Y.
      • Conti M.
      • Tacconelli E.
      Prevalence of antibiotic resistance in Helicobacter pylori: a systematic review and meta-analysis in World Health Organization regions.
      ). In this review, AMR was assessed both geno- and phenotypically and was defined as the overall prevalence of AMR. This included both primary resistance and secondary resistance. These were defined according to if the resistance was prior to the first eradication treatment (primary resistance) or followed a previous eradication therapy (secondary resistance). At a country level, only combined primary and secondary resistance was reported whereas at a world region level this data was reported as combined and disaggregated (primary/secondary) resistance (except for Africa where the disaggregated data was not reported).
      National and WHO world region macrolide consumption were obtained from MIDAS Quantum data base of the marketing research company IQVIA (IQVIA, Danbury, CT, USA). IQVIA uses national sample surveys that are performed by pharmaceutical sales distribution channels to estimate antimicrobial consumption from the volume of antibiotics sold in retail and hospital pharmacies (
      • Klein E.Y.
      • Van Boeckel T.P.
      • Martinez E.M.
      • Pant S.
      • Gandra S.
      • Levin S.A.
      • et al.
      Global increase and geographic convergence in antibiotic consumption between 2000 and 2015.
      ). The sales estimates from this sample are projected with use of an algorithm developed by IQVIA to approximate total volumes for sales and consumption. Antimicrobial consumption estimates are reported as the number of standard doses (a dose is classified as a pill, capsule, or ampoule) per 1000 population per year (
      • Klein E.Y.
      • Van Boeckel T.P.
      • Martinez E.M.
      • Pant S.
      • Gandra S.
      • Levin S.A.
      • et al.
      Global increase and geographic convergence in antibiotic consumption between 2000 and 2015.
      ). We used data for the year 2012 (the midpoint of the 2007–2017 time period used to provide AMR data. The median value of all countries in a world region were used as summary measures of antimicrobial consumption and resistance prevalence at world regional level. All statistical analyses were performed in Stata 14.0.

      Results

      Country level

      Data was available for macrolide consumption and resistance was available in 31 and 52 countries, respectively. There were large differences in the prevalence of macrolide resistance (median 20.5%, interquartile range [IQR] 8–36%) and macrolide consumption (median 1664, IQR 998–2254). The prevalence of clarithromycin resistance was positively correlated with macrolide consumption in the 29 countries with data available for both variables (Rho = 0.49; P = 0.007; Figure 1a).
      Figure 1
      Figure 1Scatter plots of macrolide consumption (in number of standard doses per 1000 population per year) versus pooled clarithromycin resistance (expressed as a percentage) in countries (a) and WHO world regions for primary resistance (b) and combined primary and secondary resistance (c).

      World region

      The two world regions with the highest levels of macrolide consumption (Europe and Western Pacific) had the highest prevalence of clarithromycin resistance (Figure 1b and c). Whilst positive, the correlation between macrolide consumption and resistance was not statistically significant for primary resistance or combined primary and secondary resistance (Rho = 0.95; P = 0.05 and Rho = 0.60; P = 0.20, respectively).

      Discussion

      Our finding of a positive association between macrolide consumption and resistance in H. Pylori adds to the list of bug-drug combinations where bystander selection appears to play a role in the genesis of AMR. The analysis is ecological and thus susceptible to the ecological inference fallacy. It also uses AMR data from an 11-year period and compares this to a single time point of antimicrobial consumption. Our country-level analyses could only be performed on combined primary/secondary resistance figures which may have introduced a misclassification bias. Furthermore, there were only 29 countries with data on both consumption and AMR. Whilst these results should be re-analysed in larger datasets and further interrogated in modelling studies, the results are compatible with those showing the importance of bystander selection in other bacteria. The results are also biologically plausible as macrolide exposure has been shown in vivo and in vitro to lead to macrolide resistance inducing mutations in H. pylori and that these mutations persist long term (
      • Hulten K.
      • Gibreel A.
      • Skold O.
      • Engstrand L.
      Macrolide resistance in Helicobacter pylori: mechanism and stability in strains from clarithromycin-treated patients.
      ). Given the increasing difficulty to treat H. pylori, the study therefore serves as further evidence of the need for macrolide stewardship so as to limit the use of macrolides in the general population to clearly defined indications.

      Data availability

      The data we used is available from Salvoldi et al’s AMR review paper (
      • Savoldi A.
      • Carrara E.
      • Graham D.Y.
      • Conti M.
      • Tacconelli E.
      Prevalence of antibiotic resistance in Helicobacter pylori: a systematic review and meta-analysis in World Health Organization regions.
      ) and MIDAS Quantum data (https://www.iqvia.com).

      Funding

      No specific funding was received for this work.

      Transparency declarations

      None to declare. The authors declare that they have no conflicts of interest.

      Acknowledgements

      Nil.

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