Antibiotic resistance, stewardship, and consumption – Authors' reply (2019)

We agree with Koen B Pouwels and colleagues, that association does not mean cause and effect. In our paper, we acknowledged limitations in using national-level data on antibiotic usage and resistance patterns, and that antibiotic use is an important factor in antibiotic resistance. We note that our results, which show that the spread of resistant bacteria by anthropological factors is at least as important as antibiotic use, are supported by other studies.1Baker S Thomson N Weill FX Holt KE Genomic insights into the emergence and spread of antimicrobial-resistant bacterial pathogens.Science. 2018; 360: 733-738Crossref PubMed Scopus (156) Google Scholar Antibiotic sales data (IQVIA MIDAS database) have limitations, but these data provide the only source of harmonised global information on antibiotic consumption. Others have validated IQVIA MIDAS and demonstrated strong correlation with data from the European Surveillance of Antimicrobial Consumption Network.2Klein EY Van Boeckel TP Martinez EM et al.Global increase and geographic convergence in antibiotic consumption between 2000 and 2015.Proc Natl Acad Sci U S A. 2018; 115: E3463-E3470Crossref PubMed Scopus (1355) Google Scholar We used global resistance data on 114 member states from WHO. We also used data from ResistanceMap and interrogated literature searches on Escherichia coli resistance. The results we observed were similar across the datasets. Some associations could be surrogates for other markers that are underappreciated—even Pouwels' example of meticillin-resistant Staphylococcus aureus linked to unfair play of national football teams. This behaviour might reflect the culture of a country where rules are more often ignored, and thus, where support for hand hygiene campaigns, sensible antibiotic use and adequate public infrastructure are more likely scarce. Previous multivariate analysis3Collignon P Athukorala PC Senanayake S Khan F Antimicrobial resistance: the major contribution of poor governance and corruption to this growing problem.PLoS One. 2015; 10: e0116746Crossref PubMed Scopus (86) Google Scholar has also shown that higher levels of corruption are associated with higher antibiotic resistance rates. Others have shown that greater corruption is associated with higher regional antibiotic usage volumes within Europe.4Rönnerstrand B Lapuente V Corruption and use of antibiotics in regions of Europe.Health Policy. 2017; 121: 250-256Summary Full Text Full Text PDF PubMed Scopus (27) Google Scholar We used multiple regression analysis to disentangle many of the issues raised by Pouwels and colleagues. Since there is collinearity between some of the explanatory variables (eg, health system strength and antibiotics consumption), we observed a narrower list of statistically significant associations with multiregression than in our univariate analysis. Pouwels' supplementary figure, using purely simulated datapoints, serves to illustrate the well known problem that arises in interpreting simple bivariate correlations. Such graphs could equally well be drawn to imply a positive correlation of usage and resistance when in fact the underlying relationship is negative. The graphs in our appendix demonstrate that when important explanatory variables are not accounted for in the modelling (eg, poor infrastructure, poor health care expenditure), aggregated data can imply either a spurious positive or a spurious negative correlation between usage and resistance, even when there is no underlying relationship. We do not agree with Cédric Abat and colleagues, that “all simplifications including stating that antibiotic consumption in humans and animals favours the emergence of antibiotic resistance appear inherently wrong.” Rather, we agree there are examples where antibiotic usage does not correlate with observed resistance levels; however, there are also examples where positive linkages have been found.3Collignon P Athukorala PC Senanayake S Khan F Antimicrobial resistance: the major contribution of poor governance and corruption to this growing problem.PLoS One. 2015; 10: e0116746Crossref PubMed Scopus (86) Google Scholar, 5Nasrin D Collignon PJ Roberts L Wilson EJ Pilotto LS Douglas RM Effect of beta lactam antibiotic use in children on pneumococcal resistance to penicillin: prospective cohort study.BMJ. 2002; 324: 28-30Crossref PubMed Scopus (118) Google Scholar, 6Goossens H Ferech M Stichele RM Elseviers M Outpatient antibiotic use in Europe and association with resistance: a cross-national database study.Lancet. 2005; 365: 579-587Summary Full Text Full Text PDF PubMed Scopus (1542) Google Scholar We agree with what seems implicit in Abat's letter and associated references—namely, that a reduction of antibiotic consumption alone will not be sufficient to control antimicrobial resistance. We think that improving sanitation, increasing access to clean water, ensuring good governance, and increasing public health-care expenditure are all necessary to reduce global antimicrobial resistance. We believe that our conclusion remains appropriate, that contagion—the spread of resistant strains and resistance genes—seems to be a dominant contributing factor to global antibiotic resistance. This online publication has been corrected. The corrected version first appeared at thelancet.com/planetaryhealth on March 4, 2019 This online publication has been corrected. The corrected version first appeared at thelancet.com/planetaryhealth on March 4, 2019 TRW is HEFC funded by the UK Government. SG is supported by a grant from the Bill & Melinda Gates Foundation. RL is supported by IPA 16IPA1609427 from the US Centers for Disease Control and Prevention to Princeton University. Download .pdf (.6 MB) Help with pdf files Supplementary appendix Anthropological and socioeconomic factors contributing to global antimicrobial resistance: a univariate and multivariable analysisReduction of antibiotic consumption will not be sufficient to control antimicrobial resistance because contagion—the spread of resistant strains and resistance genes—seems to be the dominant contributing factor. Improving sanitation, increasing access to clean water, and ensuring good governance, as well as increasing public health-care expenditure and better regulating the private health sector are all necessary to reduce global antimicrobial resistance. Full-Text PDF Open AccessAntibiotic resistance, stewardship, and consumptionPeter Collignon and colleagues1 aim to improve understanding of global antibiotic resistance drivers by quantifying associations between antibiotic resistance and potential contributing factors. A recent systematic review including 565 studies primarily reporting patient-level data found that antibiotic exposure, underlying disease, and invasive procedures had the greatest evidence of being antibiotic resistance drivers.2 Given the small evidence base for the role of community factors,2 we fully concur with Collignon and colleagues about the importance of considering such factors in the spread of antibiotic resistance. Full-Text PDF Open AccessAntibiotic resistance, stewardship, and consumptionWe read with interest the work of Peter Collignon and colleagues,1 in which the authors studied the effect of cofactors on the prevalence of precise antibiotic resistance profiles. Amongst their discoveries, the authors identified inverse relationships between global antibiotic consumption and the antibiotic resistance profiles that they studied. Full-Text PDF Open AccessCorrection to Lancet Planet Health 2019; 3: e68Collignon P, Beggs JJ, Walsh TR, Gandra S, Laxminarayan R. Antibiotic resistance, stewardship, and consumption–Authors' reply. Lancet Planet Health 2019; 3: e68—The webappendix of this Correspondence was not included with the publication and has been added online as of March 4, 2019. Full-Text PDF Open Access